Term
| What are the 5 classes of abused drugs? |
|
Definition
1) depressants (EtOH, benzos, barbituates, etc)
2) stimulants (cocaine, amphetamines, etc)
3) opioids (morphine, heroin, oxycodone, etc)
4) psychedelics (LSD, mescaline, etc)
5) other (cannabis, steroids, nicotine, etc) |
|
|
Term
| What brain system is the primary drug sensitive element of reward & reinforcement? |
|
Definition
| mesotelecephalic DA system |
|
|
Term
| What subsystem is critical to reward & reinforcement? |
|
Definition
| mesolimbic DA (VTA to NAC) |
|
|
Term
| Are addictive drugs direct or indirect agonists of reward & reinforcement? |
|
Definition
|
|
Term
| What happens when there is blockage of the DA system in regards to drug addiction? |
|
Definition
| decreased self administration |
|
|
Term
| What increases in the acute drug state (minutes to hours)? |
|
Definition
| increased mesolimbic DA & other NTs (s.a. 5-HT) in reward & reinforcement |
|
|
Term
| What increases in the chronic drug state (days to years)? |
|
Definition
| cAMP, CREB, Δ Fos B in tolerance, sensitization, dependence |
|
|
Term
| What increases in short term abstinance of drugs (hours to days)? |
|
Definition
| Glu, NE, DA, 5-HT, CRF in withdrawl |
|
|
Term
| What increases in long term drug abstinance (days to years)? |
|
Definition
| synaptic plasticity, CRF & glucocorticoids in craving & relapse |
|
|
Term
| What is the sourse of EtOH? |
|
Definition
1) fermentation & distillation
2) beverages
3) other (s.a. tinctures, solvents, denatured) |
|
|
Term
| What are the characteristics of EtOH? |
|
Definition
1) sm. stable molecule
2) clear, colorless liquid with a weak odor
3) fully miscible (can mix with) water
4) hygroscopic (attracts water from atmosphere)
5) low potency |
|
|
Term
|
Definition
1) GI
2) pulmonary
2) integument (infants) |
|
|
Term
| Where does EtOH distribute to after absorption? |
|
Definition
| rapid & wide - cross BBB & placenta |
|
|
Term
|
Definition
| no, therefore no fat deposit uptake or need for protein binding/sequestration |
|
|
Term
|
Definition
sm. percent urine, feces, sweat
very sm. percent via lungs
mostly metabolized via ADH, but secondarily via CYP240 |
|
|
Term
| Which form of metabolism of EtOH is inducible? |
|
Definition
|
|
Term
| Which EtOH metabolism pathway is NAD dependent & for which NAD is the rate-limiting step? |
|
Definition
|
|
Term
| What is EtOH metabolized to via ADH? |
|
Definition
|
|
Term
What is acetaldehyde metabolized to?
Via what? |
|
Definition
| acetate via aldehyde dehydrogenase |
|
|
Term
| What happens to acetate after being converted from EtOH? |
|
Definition
|
|
Term
|
Definition
| blocks oxidation of acetaldehyde to acetate |
|
|
Term
| How many calories is generated from metabolism of EtOH? |
|
Definition
|
|
Term
| How long does it take to metabolize 1 drink of EtOH? |
|
Definition
|
|
Term
| What NTs does EtOH affect? |
|
Definition
| 1) biphasic effect on NE & DA turnover
2) GABAA & NMDA-Glu receptor actions
3) Ca2+ channel & PI-specific phosphokinase |
|
|
Term
Psychological Sx
EtOH Acute Intoxication |
|
Definition
1) dose-related excitation followed by depression
2) cognitive, emotional & behavioral functions
3) differentiated congitive state
4) labile affect
5) decreased attention
6) disorganized actions |
|
|
Term
Neurological Sx
EtOH Acute Intoxication |
|
Definition
1) anterograde amnesia
2) positional nystagmus
3) EEG change |
|
|
Term
CV Sx
EtOH Acute Intoxication |
|
Definition
| 1) myocardial depression (moderate dose)
2) labile BP & arrhythmias (high dose)
3) CVA potential (high dose)
4) cutaneous VD
5) elevation of HDL3 |
|
|
Term
Renal Sx
EtOH Acute Intoxication |
|
Definition
|
|
Term
Endocrine Sx
EtOH Acute Intoxication |
|
Definition
1) increased ACTH release
2) increased oxytocin
3) decreased FSH/LH |
|
|
Term
| What changes occur in EtOH tolerance? |
|
Definition
| 1) membrance change
2) GABA receptor & Glu(NMDA) receptor & Ca2+ channcel changes
3) induction of CYP450 |
|
|
Term
|
Definition
hyperirritability
anxiety
tremor
insomnia
nausea
sweating
hallucinations
seizure
Dilerium Tremens |
|
|
Term
|
Definition
confusion
disorientation
agitation
hyperpyresis |
|
|
Term
|
Definition
supportive therapy (ventilation, fluids, electrolytes)
flumazenil (not really used) |
|
|
Term
|
Definition
substitution therapy (benzos, barbituates)
Sx therapy (phenytoin, gabapentin)
supportive therapy (thiamine, NSAIDs) |
|
|
Term
|
Definition
discontinue all sedative-hypnotics
disulfram (prophylactic)
naltrexone (anti-craving)
acamprosate (anti-craving) |
|
|
Term
| What is the source of cocaine? |
|
Definition
erythroxyline coca
benzoyl methyl ecgonine
(alkaloid) |
|
|
Term
| What are the different preparations of cocaine? |
|
Definition
1) cocaine HCl (diluents)
2) cocaine Sulphate ('pasta')
3) cocaine free base (crack) |
|
|
Term
| How is cocaine administered? |
|
Definition
1) oral (chew/drink)
2) insufflation (snorting)
3) injection (IV)
4) inhalation (smoking) |
|
|
Term
| How is cocaine absorbed/distributed? |
|
Definition
lipophilic => fat deposition
vasoconstriction
rate of uptake is route dependent
uptake can continue for hours
cross BBB |
|
|
Term
Metabolism/Excretion
cocaine |
|
Definition
1) primarily esteric hydrolysis
2) plasma cholinesterases & hepatic esterase => benzolecgonine methyl ester
3) N-methylation => Norcocaine
4) cocaethylene = active metabolite with EtOH
metabolites renally excreted |
|
|
Term
| What is the plasma half life of cocaine? |
|
Definition
|
|
Term
|
Definition
local athesthetic
vasocontrictor
psychomotor stimulation
indirect - sympathomimetic |
|
|
Term
|
Definition
| 1) voltage gated Na2+, blocks GNa, no Δ in RP
2) blocks presynaptic NE uptake from cleft (sympathomimetic)
3) binds DA transported => alteration of DA affinity |
|
|
Term
The Controlled Substances Act of 1970 classifies:
A) All drugs in the U.S. Pharmacopoeia for abuse potential
B) mood altering drugs according to MOA
C) diazepam as a Schedule I b/c of its potential for abuse
D) mood altering drugs on the basis of their abuse potential
E) codeine in Schedule II due to its low therapeutic value |
|
Definition
|
|
Term
The potential for psychomotor stimulants is:
A) greatest when used daily by insufflation
B) proven to be genetically determined in man
C) a function of dose, frequency and route of use
D) the same as that for tolerance
E) greater than that for depressants |
|
Definition
|
|
Term
The effects of mood/mind altering drugs are all related to the following EXCEPT:
A) drug dose
B) mental set
C) environmental setting
D) drug experience
E) urine drug level |
|
Definition
|
|
Term
"Risk factors" for chemical dependence are:
A) genetic vulnerability
B) mood disorders
C) physical availability
D) cultural influence
E) all of the above |
|
Definition
|
|
Term
Epidemiological studies on the prevalence of ED Mentions for drug-related medical problems show the highest rates for:
A) heroin
B) hallucinogens
C) EtOH
D) cocaine
E) maijuana |
|
Definition
|
|
Term
BAC (clood EtOH content) after consuming the same 3 drinks of Scotch Whiskey will be highest in which of the following:
A) 5'10", 70kg male
B) 5'10", 55kg female
C) 6'1", 80kg male
D) 4'9", 65kg female
E) 6'9", 90kg male |
|
Definition
|
|
Term
A can of "ice" beer contains about the same amount of pure EtOH as a "highball" with a jigger blend of whiskey.
A) True
B) False |
|
Definition
|
|
Term
EtOH is metabolized at a fixed rate (zero-order kinetics) b/c:
A) only one enzyme is capable of metabolizing EtOH to acetaldehyde
B) both ADH & Aldehyde DH are zero order enzymes
C) acetaldehyde build-up inhibits ADH in situ
D) ADH is saturated by intoxicating levels of EtOH
E) acetaldehyde oxidation is rate-limiting for the whole pathway |
|
Definition
|
|
Term
Excessive EtOH intake may cause a patient to:
A) manifest horizontal nystagmus
B) limit his/her focus of attention
C) experience anterograde amnesia
D) none of the above
E) all of the above |
|
Definition
|
|
Term
Sleep that is induced by EtOH is not restful b/b\c:
A) limbic system activity is enhanced
B) REM is suppressed
C) reticular formation is depressed
D) delta wave sleep is experienced
E) gonadotropin release is suppressed |
|
Definition
|
|
Term
Acute pharmacological actions of EtOH include all of the following EXCEPT:
A) release of epi
B) elevated plasma FFAs
C) decrease in BP
D) cutaneous VD
E) decrease in HR |
|
Definition
|
|
Term
Pathology associated with chronic abuse of EtOH includes all of the following EXCEPT:
A) cirrhosis
B) gastritis
C) polyneuropathy
D) tinnitus
E) pancreatitis |
|
Definition
|
|
Term
FAS is characterized by:
A) craniofacial dysmorphism
B) psychomotor retardation
C) absence of catch-up growth
D) none of the above
E) all of the above |
|
Definition
|
|
Term
The 'common' abstinence syndrome for EtOH dependence is characterized by:
A) onset within 2 hrs
B) delirium tremons
C) REM sleep deprivation
D) tremulousness
E) none of the above |
|
Definition
|
|
Term
Uncomplicated EtOH withdrawl is managed by which of the following:
A) phenobarbital
B) lithium carbonate
C) chlorpromazine
D) disulfiram
E) phenytooin |
|
Definition
|
|
Term
Disulfiram is used in long term therapy for alcoholism b/c it:
A) blocks the compulsion to drink
B) normalizes the alcoholic's mood
C) delays the onset of withdrawl
D) produces a calming, sedative effect
E) makes one who drinks feel sick |
|
Definition
|
|
Term
Cocaine characteristically produces tha same psychomotor stimulation as:
A) amphetamines
B) angel dust
C) mescaline
D) scopolamine
E) heroin |
|
Definition
|
|
Term
Withdrawl from crack/cocaine present with all the signs/Sx EXCEPT:
A) lethargy
B) anorexia
C) craving
D) agitation
E) depression |
|
Definition
|
|
Term
| What 7 drug types are used to manage CVDs? |
|
Definition
1) Diuretics
2) Agents that interfere with Angiotensin II
3) Sympatholytic agents
4) Calcium Channel Blockers
5) Vasodilators
6) Agents that increase cardiac contractility
7) Drugs for arrythmias |
|
|
Term
| What are the 5 diuretics? |
|
Definition
1) Chlorthalidone
2) Hydrochlorothiazide
3) Amiloride
4) Furosemide
5) Spironolactone
(Chlorinate Hydros [i.e. water] due to Animal Fur Sprinkles) |
|
|
Term
|
Definition
| increase loss of sodium into the forming urine => increased urine flow & water loss |
|
|
Term
| Where are all filtered organic metabolites reabsorbed? |
|
Definition
|
|
Term
| What happens to water when an organic metabolite is reabsorbed in the proximal tubule? |
|
Definition
| water is passively reabsorbed to maintain constant osmolarity |
|
|
Term
| What catalyzes Na+ reabsorption? |
|
Definition
| 3 pivotal proteins in luminal cells (=> water reapsorption) |
|
|
Term
| How is Na+ in the luminal fluid exchanged for intracellular protons? |
|
Definition
| Na+/proton exchanger on cell's luminal membrane |
|
|
Term
Where is sodium pumped after being exchanged for protons in kidney?
How? |
|
Definition
| from cell to interstitium/blood via Na/K ATPase |
|
|
Term
| What buffers the luminal proton in the early proximal tubule? |
|
Definition
| bicarb (to form carbonic acid) |
|
|
Term
| What happens to carbonic acid once formed from luminal proton & bicarb? |
|
Definition
| dehydrated to CO2 to passively diffuses into cell to be rehydrated to carbonic acid again by carbonic anhydrase |
|
|
Term
| Once carbonic acid is reformed in the cell, what happens? |
|
Definition
| dissociated & bicard is transported to the blood => leaves proton to be re-used again for sodium exchange |
|
|
Term
| Is reabsorption of bicarb more or less extensive than reabsorption of Na+? |
|
Definition
|
|
Term
| What happens in the late proximal tubule since bicarb reabsorption is more extensive than Na+ reabsorption? |
|
Definition
| luminal fluid contains mainly NaCl, whose reabsorption continuses for proton exchange, but can no longer be buffered by bicarb => acidification of luminal pH |
|
|
Term
| What exchanger in the kidney brush border is activated due to the decrease in pH? |
|
Definition
| Cl-/base exchanger => Cl- reabsorption |
|
|
Term
| What specialized water channel is used for water passage? |
|
Definition
|
|
Term
| Why is AQP 1 needed in the kidney? |
|
Definition
| throughout the proximal tubule, the volume of water that is retrieved exceed the permeability of the bilayer of the cell membrane |
|
|
Term
| What effect does inhibition of carbonic anhydrase have? |
|
Definition
| indirectly reduces the activity of the Na+/proton exchanger => loss of NaHCO3 & water |
|
|
Term
| Are carbonic anhydrase inhibitors used for CVDs? |
|
Definition
| no, but there is a topical form used in the eye |
|
|
Term
| Where do osmotic diuretics that do not permeate the luminal membrane (s.a. mannitol) exert their primary effect? |
|
Definition
| in the proximal tubule by increasing the osmolality of the forming urine => decreased water reabsorption |
|
|
Term
| Why must mannitol be given IV? |
|
Definition
| causes diarrhea when given PO |
|
|
Term
| What happens to water in the loop of henle? |
|
Definition
| passively absorbed into hypertonic interstitium |
|
|
Term
| What happens to water in the thick ascending loop? |
|
Definition
|
|
Term
What electrolytes are transported out of the lumen in the thick ascending loop?
Via what? |
|
Definition
| Na+ & K+ via Na+/K+/2Cl- symporter |
|
|
Term
| Once Na+ is pumped from the luminal fluid in the thick ascending loop, what happens to it? |
|
Definition
| pumped into blood via Na/K ATPase (in exchange for K) |
|
|
Term
| What happens as a result of the increased intracellular K+ when Na+ is exchanged into the blood? |
|
Definition
| cell loses potassium into lumen via K+ channel => more positive luminal potential |
|
|
Term
| What is the positive lumunal postential due to K+ the driving force for in the thick ascending loop? |
|
Definition
| Na/K/2Cl symporter
reabsorption of Ca2+ & Mg2+ |
|
|
Term
How much of Na reabsorbed is reabsorbed in the proximal tubule?
thick ascending limb? |
|
Definition
|
|
Term
MOA
loop (high ceiling) diuretics |
|
Definition
| direct inhibitor of NaK2Cl symporter => Sodium loss (can have severe diuretic effect) |
|
|
Term
| What are the 2 loop diuretics? |
|
Definition
| Furosemide & eracrynic acid |
|
|
Term
def
juxtaglomerular apparatus |
|
Definition
| microscopic structure in kidney next to the glomerulus b/w the vascular pole of the renal sorpuscle & the distal convoluted tubule of same nephron. |
|
|
Term
| What are the 3 microscopic components of the juxtaglomerular apparatus (JGA)? |
|
Definition
1) juxtaglomerular cells
2) macula densa
3) extraglomerular mesangial cells |
|
|
Term
|
Definition
| located in the affarent arteriole of glomerulus that act as an intra-renal pressor sensor & secrete renin |
|
|
Term
|
Definition
| cells that line the distal tubule & sense changes in concentration of NaCl |
|
|
Term
def
extraglomerular mesangial cells |
|
Definition
| communicate by means of gap junctions with structural mesangial cells surrounding the glomerular capillaries |
|
|
Term
| What causes increased renin secretion by juxtaglomerular cells? |
|
Definition
| decreased NaCl load delivered to macula densa |
|
|
Term
| What does the NaCl load of the kidney depend on? |
|
Definition
| NaCl accumulation by NaK2Cl |
|
|
Term
Do loop diruetics increase or decrease NaCl load?
What does that do to renin secretion? |
|
Definition
| decrease NaCl load => increased renin secretion |
|
|
Term
|
Definition
| break down angiotensinogen to form angiotensin I (=> angiotensin II by ACE => vasoconstriction => increased BP) |
|
|
Term
| To minimize the unwanted renin release with loops diuretics, what is commonly co-administered with them? |
|
Definition
|
|
Term
| What happens to water in the distal convoluted tubule? |
|
Definition
|
|
Term
What electrolytes are absorbed in the distal convoluted tubule?
via what? |
|
Definition
| NaCl via electrically neutral NaCC (sodium & chloride symporter) |
|
|
Term
Is the lumen of the distal convoluted tubule positively charged like in the thick ascending loop of henle?
Why or why not? |
|
Definition
| no b/c back diffusion of K from cells to lumen doesn't occur (therefore no driving force for reabsorption of cations Ca2+ & Mg2+) |
|
|
Term
| Since there is no driving force for Ca2+ reabsorption, how is Ca2+ reabsorption made possible in the distal convoluted tuble? |
|
Definition
| Ca2+ channel & Ca2+/Na+ exchanger, both under the influence of PTH |
|
|
Term
| Where in the distal convoluted tubule are PTH receptors? |
|
Definition
| membrane of tubular cells |
|
|
Term
|
Definition
| inhibit NaCl symporter of the distal convoluted tubule |
|
|
Term
| Are thiazide or loop diuretics more potent? |
|
Definition
|
|
Term
| Can thiazide & loop diuretics be used in combination? |
|
Definition
|
|
Term
| What are the 3 thiazide diuretics? |
|
Definition
1) Chlorthalidone
2) Hydrochlorothiazide
3) Metolazone |
|
|
Term
| What in the last distal tubule/early collecting duct is there for more possible Na reabsorption? |
|
Definition
| ENaC (epi. Na Channel) in the principal cells |
|
|
Term
| What is the driving force for ENaC? |
|
Definition
| electrochemical grandient maintained by Na/K ATPase on the basolateral side of cell |
|
|
Term
What happens to the lumen potential due to ENaC?
What is the consequence of that? |
|
Definition
| becomes more negative => Cl- reabsorption (from lumen) & K+ secretion (to lumen) |
|
|
Term
| What happens in the late distal tubule/early collecting duct as a consequence to the increased delivery of Na to the principal cells due to a loop or thiazide diuretic? |
|
Definition
| increased loss of K+ => hypokalemia |
|
|
Term
| What ion's presence increases the hypokalemic effect caused by loop or thiazide diuretics? |
|
Definition
|
|
Term
| Why does bicarb enhance the hypokalemic effect of loop or thiazide diuretics? |
|
Definition
| bicarb cannot be reabsorbed in the late distal tubule/early collecting duct, but contributes to the negative lumen potential |
|
|
Term
| What effect does the negative lumenal potential of the late distal tubule/early collecting duct have on intercalated cells? |
|
Definition
| increased proton expulsion via ATP-dependent proton pump |
|
|
Term
| What hormone controls the reabsorption of Na+ via ENaC & secretion of K+? |
|
Definition
|
|
Term
| How does aldosterone control the activity of ENaC? |
|
Definition
| enhances transcription & therefore the functional activity of ENaC |
|
|
Term
| How much of Na reabsorption occurs in the collecting duct? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
mild diuretic action
blunts hypokalemic SE produced by diuretics |
|
|
Term
| How is potassium "wasting" caused by diuretics managed? |
|
Definition
|
|
Term
|
Definition
| competitive antagonist of aldosterone |
|
|
Term
|
Definition
|
|
Term
| What effect do amiloride & apironolactone have on K+? |
|
Definition
| can cause hyperkalemia due to "postassium sparing" |
|
|
Term
| What happens to water in the collecting duct? |
|
Definition
|
|
Term
| What AQP is constitiutively present in the basolateral membrane of the collecting duct (despite being impermable to water)? |
|
Definition
|
|
Term
| What hormone can promote water reabsorption in the collecting duct? |
|
Definition
| ADH (antidiuretic hormone) |
|
|
Term
| How does ADH promote water reabsorption in the collecting duct? |
|
Definition
| increases AQP 2 in the apical membrane. |
|
|
Term
| What drug reduces the expression of AQP in the kidney? |
|
Definition
|
|
Term
| What effect does Li have due to the dramatic reduction of AQP expression? |
|
Definition
| nephrogenic diabetes insipidus |
|
|
Term
| Which diuretics work on the proximal convoluted tubule? |
|
Definition
| carbonic anhydrase inhibitors |
|
|
Term
| Which diuretics act on the thick ascending limb of the loop of henle? |
|
Definition
| loop diuretics (inhibits NK2Cl co-transporter) |
|
|
Term
| Which diuretics act on the distal convoluted tubule? |
|
Definition
| thiazide diuretics (inhibit NCC) |
|
|
Term
| Which diuretics act on the collecting tubule? |
|
Definition
| potassium sparing (amiloride blocks ENaC, spironolactone competes with aldosterone for the aldosterone receptor) |
|
|
Term
SOA
loop diuretics
s.a. furosemide & wthacrynic acid |
|
Definition
1) combat edema associated with heart failure, liver, and renal syndromes.
2) relieve pulmonary congestion in heart failure
3) with saline administration against acute hypercalcemia
4)Other: mild hyperkalemia, elimination of bromide, fluoride, and iodide ions in toxic OD & acute renal failure |
|
|
Term
| How does furosemide relieve pulmonary congestion in heart failure? |
|
Definition
| decrease congestion & left ventricular pressure prior to onset of diuresis |
|
|
Term
| Why are loop diuretics used to eliminate bromide, fluoride, & iodide ions in acute renal failure? |
|
Definition
| increase urine flow & K excretion => help of flushing of intratubular casts |
|
|
Term
|
Definition
|
|
Term
Elinination
loop diuretics |
|
Definition
| tubular secretion & filtration |
|
|
Term
| What does the half life of furosemide depend on? |
|
Definition
| renal function (usually ~1.5 hrs) |
|
|
Term
|
Definition
hypokalemia
alkalosis
hypomagnesemia
dehydration (± hypercalcemia)
hyperuricemia
gouty attacks
hearing loss/allergic rxn (dose related - rare) |
|
|
Term
Tx
hypokalemia & alkalosis caused by loop diuretics |
|
Definition
| concurrent administration of potassium sparing agents or KCl supplements |
|
|
Term
Tx
hypomagnesemia caused by loop diuretics |
|
Definition
|
|
Term
|
Definition
| NSAIDs (inhibit COX) decrease duretic effect |
|
|
Term
SOA
thiazide (& thiazide-like) diuretics
s.a. hydrochlorothiazide, chlorthalidone, metolazone |
|
Definition
1) edema associated with cardiac, hepatic, & renal conditions
2) anti-hypertensive (first line - low dose)
3) with ACEI or loop diuretic for CHF
4) idiopathic hypercalciuria with kidney stones
5) nephrogenic diabetes insipidus (paradoxical effect) - even NDI caused by Li, tho Li levels will need to be monitored due to decreased clearance due to diuretic
6) unmask hypercalcemic conditions s.a. hyperparathyroidism, sarcoidosis, & paraneoplastic syndromes (tho cannot induce frank hypercalcemia) |
|
|
Term
| What limits the use of thiazide diuretics (except metolazone)? |
|
Definition
|
|
Term
| How do thiazide diuretics emit their anti-hypertensive actions? |
|
Definition
1) diuretic effect => reduced arterial pressure by volume depletion
2) decreased peripheral resistance due to indirect effects on smooth muscle cells mediated by depletion of intracellular Na => decreased intracellular Ca => more refractory sm. muscles |
|
|
Term
| How do diuretics lower BP? |
|
Definition
1) lower peripheral resistance with no significant effect on HR or CO
2) decreased plasma volume & renal blood flow
3) increase plasma renin |
|
|
Term
|
Definition
hypokalemia
metabolic alkalosis
hyperuricemia
hyperglycemia
alteration of lipid profile
hyponatremia (severe tho rare) |
|
|
Term
Tx
hypokalemic metabolic acidosis caused by thiazide diuretics |
|
Definition
| potassium sparing agents or KCl supplements |
|
|
Term
| Why can thiazide diuretics cause hyperuricemia? |
|
Definition
| complete with uric acid for secretion by organic acid secretory system in the promixal tubule |
|
|
Term
| When should thiazide diuretics be used with caution? |
|
Definition
| patients with diabetes or dyslipidemia |
|
|
Term
Aborption
thiazide diuretics |
|
Definition
|
|
Term
Excretion
Thiazide diuretics |
|
Definition
| organic acid secretory system in proximal tubule |
|
|
Term
| How long is the half life of thiazide diuretics? |
|
Definition
| variable, but long enough for once daily dosing |
|
|
Term
|
Definition
|
|
Term
|
Definition
1) severe CHF (± ACEI to recude morbitity & mortality)
2) antagonize myocardial fibrosis induced by aldosterone
3) with thiazide & loop diuretics to reduce K loss
4) primary & secondary aldosteronism
5) edema caused by hepatic cirrhosis |
|
|
Term
|
Definition
hyperkalemia
endocrine-like effects
increased risk to breast cancer |
|
|
Term
| What are the 3 agents that interfere with Angiotensin II? |
|
Definition
1) Losartan
2) Lisinopril
3) Enalapril
(Losar angiotensin II vasoconstricts, need List for Enlargement) |
|
|
Term
MOA
agents that interfere with angiotensin II |
|
Definition
| interfer with it's synthesis or by antagonizing its binding to its receptor |
|
|
Term
| How is angiotensin II formed? |
|
Definition
| serial proteolytic cleavage of angiotensinogen to angiotensin I (via renin) to angiotensin II (via ACE) |
|
|
Term
|
Definition
| granular juxtaglomerular cells |
|
|
Term
| What controls renin secretion? |
|
Definition
1) inversely proportional to NaCl load to macula densa
2) changes in renal BP are sensed by juxtaglomerular cells in the affarent arterioles of the glomerulus, and increased intra-renal pressure inhibits renin secretion
3) β1 agonists increase renin secretion
4) angiotensin II feeds back on an AT I receptor => inhibition |
|
|
Term
| What mediates NaCl transport into the macula densa? |
|
Definition
1) NK2Cl symporter in thick ascending limb of loop of henle
2) NaCC symporter in the distal convoluted tubules
(therefore increase in renin accompanies administration of loop & thiazide diuretics) |
|
|
Term
| Why do NSAIDs decrease renin secretion? |
|
Definition
| inhibit prostaglandin synthesis & prostaglandins stimulate renin secretion |
|
|
Term
|
Definition
| cleaves amino terminal decapeptide from angiotensinogen => angitensin I |
|
|
Term
| What does the renin-mediated cleavage of angtitensinogen to angitensin I depend on? |
|
Definition
| concentration of angiotensinogen |
|
|
Term
| Where is angiotensinogen produced & secreted? |
|
Definition
|
|
Term
| What regulates the liver production/secretion of angiotensinogen? |
|
Definition
| corticosteroids, estrogens, & thyroid hormones |
|
|
Term
Function
ACE (angiotensin converting enzyme) |
|
Definition
1) cleave the 2 C-terminal residues og angiotensin I to angiotensin II
2) catlyze degradation of bradykinin |
|
|
Term
|
Definition
| surface of vascular endothelium of most organs, but mainly lung & kidney |
|
|
Term
|
Definition
1) increased arterial pressure
2) Na & fluid retention (direct & indirect), including the release of aldosterone
3) vascular & cardiac remodeling |
|
|
Term
| What mediates the effects of angiotensin II? |
|
Definition
AT1 receptor
many mechanisms of signal transduction |
|
|
Term
Vascular effect
angiotensin II |
|
Definition
(thru AT1)
induce direct contriction of arteriolar smooth muscle => increased vascular resistance |
|
|
Term
Where is angiotensin vascular effect more pronounced?
least? |
|
Definition
most: kidney
least: sk. muscle beds |
|
|
Term
| How does angiotensin II induce vasocontriction? |
|
Definition
1) enhnaces the release of NE (from sympathetic nerves) & Epi (from adrenal glands) => neuronal NE uptake reduced & increased vascular sensitivity
2) increase sympathetic tone in areas of CNA not protected by BBB |
|
|
Term
| Is angiotensin II a more or less potent vasoconstrictor than NE? |
|
Definition
| much more in the affected beds |
|
|
Term
Renal Effects
angiotensin II |
|
Definition
1) marked increase in Na retention
2) GFR effects |
|
|
Term
| How does angiotensin cause increased Na retention? |
|
Definition
1) directly stimulates Na/H exchange in the proximal tubule & enhances aldosertone secretion
2) decreased renal blood flow due to AT1-mediated contraction of renal s. muscle & enhanced sympathetic tone |
|
|
Term
| What effects do angiotensin II have on GFR? |
|
Definition
1) decreased GFR due to mesangial cell constriction & constriction of affarent arterioles
2) increased GFR due to constriction of efferent arterioles |
|
|
Term
Effects on CV Structure
angiotensin II |
|
Definition
1) increased wall:lumen ratio in vessels
2) concentric cardiac hypertrophy (seen in HTN) |
|
|
Term
| How does angiotensin II cause increased lumen:wall ratio in vessels & concentric cardiac hypertrophy? |
|
Definition
1) increases mirgration, proliferation & hypertrophy of vascular s. muscle cells
2) hypertrophy of cardia myocytes
3) increases ECM synthesis by cardiac & vascular fibroblasts |
|
|
Term
| How does angiotensin II also indirectly cause cardiac hypertrophy & remodeling? |
|
Definition
1) increased cardiac preload (volume expansion)
2) increased afterload (greater peripheral resistance)
3) increased aldosterone => myocardial fibrosis |
|
|
Term
|
Definition
| inhibit ACE => decreased peripheral resustance w/o increasing HR, reducing cardiac & vascular remodeling, & promote natriuresis |
|
|
Term
|
Definition
"-pril's"
enalapril
lisinopril |
|
|
Term
|
Definition
anti-HTN (both renin high & renin low - can be combined with diuretic)
heart failure
venntricular dysfunction after infarction
diabetic nephropathy |
|
|
Term
| Why are ACEIs helpful in managing all stages of CHF? |
|
Definition
1) reduce preload (venodilation & improved renal hemodynamics)
2) recude afterload (decreased peripheral resistance & increased arterial competence)
=> slowing of progress of ventricular dilation, increased CO & SV, reduce vascular remodeling, blunt effects of high renin level caused by diuretics |
|
|
Term
| How do ACEIs decrease intra-glomerular pressure? |
|
Definition
| decrease resistance in the glomerular efferent arteriole => decreased GFR |
|
|
Term
| What effect is seen due to decreased GGFR & improved renal blood flow due to ACEIs? |
|
Definition
| reduced proteinuria & imporoved renal function (natriuresis) in chronic renal disease |
|
|
Term
Metabolism
enalapril & lisinopril |
|
Definition
prodrugs, cleave ester bond to form active metabolite
subject to first pass metabolism |
|
|
Term
|
Definition
|
|
Term
|
Definition
1) hypotension (severe enough to cause loss of consciousness with high renin activity)
2) persistant dry cough (most common)
3) hyperkalemia (patients with renal insufficiency or K sparing Tx, KCl Tx, or β blockers, in combination with NSAIDs)
4) acute renal failure (in patients with bilateral renal a. stenosis) |
|
|
Term
| What causes the persistant dry cough seen in ACEIs? |
|
Definition
| increased bradykinin & lung prostaglandins |
|
|
Term
| Why is hyperkalemia seen with ACEIs? |
|
Definition
| ACEIs are potassium sparing since they reduce aldosterone secretion (why ACEIs are often given in conjunction with diuretics) |
|
|
Term
|
Definition
| NSAIDS => hyperkalemia & antagonism of anti-HTN effects |
|
|
Term
|
Definition
pregnancy (teratogenic)
(less effective in african americans & elderly) |
|
|
Term
|
Definition
| inhibits renin competitively => decreased angiotensin II synthesis |
|
|
Term
|
Definition
| antagonist of angiotensin II at the AT1 receptor (=> similar effects as ACEIs) |
|
|
Term
| When might a AT1 antagonist s.a. losartan or valsartan be used over an ACEI? |
|
Definition
patients that develop ACEI-mediated cough
(similar efficacy & SOAs otherwise) |
|
|
Term
|
Definition
|
|
Term
|
Definition
| same as ACEIs - teratogenic & less effective in african americans |
|
|
Term
| What sympatholytic agents could be used in heart conditions? |
|
Definition
1) β antagonists
2) others |
|
|
Term
| What 7 β blockers are used for CVDs? |
|
Definition
1) propranol
2) metoprolol
3) atenolol
4) pindolol
5) labetalol
6) esmolol
7) sotalol |
|
|
Term
|
Definition
HTN
cardiac arrythmias
angina
acute MI
heart failure |
|
|
Term
|
Definition
1) reduced HR at AV node, decreased conduction velocity, & increased refractory period
2) reduction of cardiac contractility => decreased cardiac work & reduced oxygen consumptuon
3) suppression of renin release (sympathetic stimulation og JGA) |
|
|
Term
| What helps minimize myocardiac oxygen consumption in patients with angina & heart failure? |
|
Definition
|
|
Term
| How do β blockers help arrythmias? |
|
Definition
| decrease in conduction velosity & increase in refractory period in the AV node => reduction of reentry & precention of propagation of atrial arrythmias to ventricles |
|
|
Term
| Why are β blockers useful in Tx of MI? |
|
Definition
| suppress ventricular ectopic beats |
|
|
Term
| Why do β blockers prevent recurrance of MIs & prolong survival? |
|
Definition
1) reduction of maladaptive myocardial proliferation & overt myocardial toxicity that occurs after prolonged sympathetic stimulation
2) produce slower, regular, & more efficient heart beat & reduced peripheral resistance |
|
|
Term
| What does the recdution of cardiac work by β blockers during exertion useful for? |
|
Definition
| prevents occurance of anginal episodes & improves exercise tolerance |
|
|
Term
| What improved SV in obstructive cardiomyopathy? |
|
Definition
| slowing of ventricular ejection & decreased peripheral resistance |
|
|
Term
| What is beneficial in dissecting aortic aneurism? |
|
Definition
| decreased rate of development of systolic pressure |
|
|
Term
| Why are β blockers useful in HTN? |
|
Definition
1) decreased NE-mediated cardiac hypertrophy
2) inhibit renin release via β1 antagonism in JGA
(no effects on CO & HR) |
|
|
Term
| Why are β blockers used to control the cardiac effects of thyrotoxicosis? |
|
Definition
| ability to reduce chronotropism & iontropism |
|
|
Term
| Are β blockers usually the initial therapy for HTN? |
|
Definition
no, tho effective
usually given with diuretic |
|
|
Term
| Why are β blockers postassium sparing? |
|
Definition
| reduction of aldosterone secretion |
|
|
Term
|
Definition
(due to excessive β blockade)
bradycardia, heart failure, hypotension, bronchospasm
CNS: depression, fatigue, insomnia, hallucinations, impotence
hypoglycemia (in diabetics - caution)
negative lipid profile effects |
|
|
Term
|
Definition
|
|
Term
| Which β blockers have less serum lipid effects? |
|
Definition
| those with intrinsic sympathomimetic effects s.a. pindolol & labetalol |
|
|
Term
| Why should β blockers be tapered prior to discontinuing? |
|
Definition
| withdrawl effects s.a. hypertensive crisis & acute coronary events (inc. MI) due to up-regulation of prostsynaptic adrenergic receptors induced by long-term Tx |
|
|
Term
|
Definition
| NSAIDS reduce anti-HTN effects |
|
|
Term
|
Definition
non-selective β blocker
undergoes extensive 1st pass metabolism (like many β blokcers)
shows marked blood level variation |
|
|
Term
|
Definition
| selective β1 blocker (at low doses) |
|
|
Term
Can β1 selective blockers be used in asthmatics?
Why or why not? |
|
Definition
| no b/c specificity is NOT absolute => risk of bronchospasm |
|
|
Term
|
Definition
β1 selective antagonist
does NOT undergo 1st pass metabolism |
|
|
Term
|
Definition
non-selective β blocker
less cadriodepressant effects & ledd effect on serum lipids due to "agonistic" effects |
|
|
Term
|
Definition
α1 & non selective β blocker
some β sympathomimetic activity
reduces peripheral resistance with less effect on HR & CO & no effect on lipids |
|
|
Term
| When can labetalol be used when most other β blockers can't? |
|
Definition
pregnant women
as effective in african americans |
|
|
Term
|
Definition
|
|
Term
|
Definition
ultra-short acting β1 selective blocker (half like ~10 min)
used for supraventricular arrythmias, HTN, & myocardial ischemia in acutely ill individuals |
|
|
Term
|
Definition
| non-selective β blocker & potassium channel blocker |
|
|
Term
| What are the 3 other sympatholytic agents? |
|
Definition
1) Methyldopa
2) clonidine
3) prazosin |
|
|
Term
|
Definition
1) actively transported into the brain & metabolized to methylNE => methylNE is released to central synpases where it acts as a selective α2 receptor agonist => inhibition of NE release
2) in the periphery: methylNE is stroed in the secretory vesicles instead of NE & induces the same posten VC effects as NE
=> dampening of vasomotor tone (not suppression of peripheral adrenergic activity) |
|
|
Term
| Where are α2 receptors found? |
|
Definition
|
|
Term
|
Definition
| lower peripheral resistance w/o exerting significant effects of HR, CO, renal flow, plasma volume, or renin secretion |
|
|
Term
|
Definition
CNS: sedation, dry mouth, reduced libido, Parkinsonian Sx, hyperprolactinemia (=> galactorrhea)
hepatotoxicity (rare)
hemolytic anemia (common) |
|
|
Term
| When can methyldopa be used for HTN that is contraindicated for β blockers? |
|
Definition
pregnancy
(tho due to SE, limits use. can be combined with a diuretic) |
|
|
Term
|
Definition
sensitive α2 receptor agonist => inhibition of central release of NE => reduction of adrenergic outflow from solitary tract in the medulla oblongata
(at higher doses, also activates α2 receptors of vascular s. muscle of skin & mucosa =? VC)
some of clonidine's hypotensive effects seem to be mediated thru activation of imidazoline receptors in the rostral ventrolateral medulla |
|
|
Term
|
Definition
~methyldopa
lowers peripheral resistance with little effect on HR, CO, renal flow, plasma volume, & renin secretion |
|
|
Term
| What can be co-administered with clonidine to potentiate it's anti-HTN effects? |
|
Definition
|
|
Term
| In what way can clonidine be administered to blunt sympathetic activity caused by some vasodilators? |
|
Definition
|
|
Term
|
Definition
(related to reduction of sympathetic tone)
sedation, dry mouth, postural hypotension, impotence, symptomatic bradycardia (or even sinus arrest), AV block
contact dermatitis (patch) |
|
|
Term
|
Definition
| depressed patients (withdraw use if develops) |
|
|
Term
| What happens if clonidine (or other α2 agonists) are withdrawn abruptly? |
|
Definition
| increased sympathetic tone => withdrawl syndrome: headaches, tremors, tachycardia, rebound HTN |
|
|
Term
|
Definition
| TCAs decrease anti-HTN effects |
|
|
Term
| Why doesn't guanethidine have any central effects? |
|
Definition
| too polar to pass the BBB |
|
|
Term
|
Definition
taken up by postganglionic sympathetic fibers & accumulated in the synaptic vesicles where is replaces NE => decrease of NE stores
also, stabilizes neuronal cell membrane =? inhibition of NE release |
|
|
Term
|
Definition
orthostatic hypotension, diarrhea, impaired ejaculation
(therefore decreased clinical use as anti-HTN) |
|
|
Term
|
Definition
| blocks ability of neuronal vesicles to take up & store sympathetic amines (NE, DA, & 5-HT) centrally & peripherally |
|
|
Term
|
Definition
due to depletion of central amines stores: sedation, depression, & Parkinson Sx
(reduced anti-HTN use due to SE, but used in low doses with diuretic for mild/moderate HTN, elderly, developing countries) |
|
|
Term
MOA
phentolamine & phenoxybenzamine |
|
Definition
| nonselective α receptor blockers |
|
|
Term
SOA
phentolamine & phenoxybenzamine |
|
Definition
| clinical Tx & Dx of pheochromocytoma & impotence |
|
|
Term
|
Definition
| selective α1 receptor blocker => decreaed arteriolar resistance & increased venous capacitance |
|
|
Term
| What happens to 50% of parients 90 min after initial dose of an α1 blocker? |
|
Definition
| excessive hypotensive effects (patients become less susceptible to this over time) |
|
|
Term
SE
prazosin & other α1 receptor blockers |
|
Definition
orthostatic hypotension (most common & dependent on palsma volume), tho minimal when Na & water retention occur with subsequent hypervolemia
increased risk of heart failure with doxazocin |
|
|
Term
CI
prazosin (& other α1 antagonists) |
|
Definition
| monotherapy for HTN (use with diuretic or β blocker) |
|
|
Term
SOA
prazosin & other α1 receptor blockers |
|
Definition
HTN
urinary Sx with benign prostatic hyperplasia |
|
|
Term
| What are the 4 calcium channel blockers? |
|
Definition
1) Nifedipine
2) amlodipine
3) verapamil
4) diltiazem
("-pine" for Vit D [to compensate for Ca Channel block]) |
|
|
Term
Function
voltage-gated calcium channels |
|
Definition
| excitation, excitation-contraction coupling, & contraction |
|
|
Term
| What are the types of Ca channels? |
|
Definition
L, N, T (& others)
based on electrophysiological properties & sensitivities to omega conotoxins |
|
|
Term
| What Ca Channel types is the main VGCC in cardiac & vascular tissues? |
|
Definition
|
|
Term
Function
L type Ca Channel |
|
Definition
1) mediates the entry of extracellular calcium into s. muscle cells & into the cardiomyocytes that form the atria & ventricles
2) carried Ca currents in the electrophysiology specialized cardiac cells => formation of sinus & atrioventricular nodes |
|
|
Term
| What happens when drugs bind VGCCs? |
|
Definition
| recudes the frequency of VGCC opening => marked reduction in transmembrane Ca current |
|
|
Term
| What are the 2 main categories of Ca channel blockers? |
|
Definition
1) dihydropyridines
2) non0dihydropyridines |
|
|
Term
What are the dihydropyridines?
non-dihydropyridines? |
|
Definition
dihydropyridines: nefedipine & amlodipine (-pines)
non-dihydropyridines: verapamil & diltazem (Vit D) |
|
|
Term
| How do dihydropyridines differ from non-dihydropyridines? |
|
Definition
chemical structures
DDIs
toxicities |
|
|
Term
| Where does half of the Ca required for maximal contraction come from in the vascular s. muscle? |
|
Definition
half from sER
half from outside of cell |
|
|
Term
Effect
blockage of extracellular VGCCs |
|
Definition
| 1) decreased arteriolar s. muscle tone & therefore peripheral resistance (more prominent in Ni>Am>Ve>Di )
2) reduced cardiac inotropism (more prominent Ni |
|
|
Term
Do Ca Channel blockers have an effect on cardiac preload?
Why or why not? |
|
Definition
| no b/c no effects on venous beds |
|
|
Term
Do dihydropyridines or non-hydropyridines cause marked sudden peripheral vasodilation?
What does this cause? |
|
Definition
dihydropyridines
causes baroreflex mediated increase in sympathetic tone, overcoming the negative inotropic effect |
|
|
Term
Effects
dihydropryridine & non-hydropyridine Ca Channel blockers on automatism of sinus node & conduction thru AV node |
|
Definition
Dihydropyridines: minimal effect on sinus node & no effect on AV conduction (due slow Ca inward current w/o affecting rate of recovery of slow Ca channels)
non-dihydropyridines: marked effects on both => reduction of HR & AV conduction velocity (due to reduction of Ca influx & rate of channel recovery) |
|
|
Term
| Due to the effects on sinus node & AV node conduction, which type of Ca channel blocker should be used for Tx of supraventricular tachyarrythmias? |
|
Definition
|
|
Term
|
Definition
1) β blockers due to additive decreased cardiac conractility, HR, & AV conduction => severe side effects s.a. bradycardia, heart block, & heart failure
2) patients with cardiac block
3) systolic dysfunction |
|
|
Term
SE
non-dihydropyridines s.a. verapamil & ditltiazem |
|
Definition
bradycardia
heart failure (due to depression of cardiac contractility)
cardaic block (due to depression of AV conduction)
hypotension |
|
|
Term
|
Definition
short-acting agents: sudden vasodilation => powerful baroreflex-mediated increase in HR & cardiac inotropism => subsequwnt enhancement of myocardial oxygen consumption => acute CV events
(NOT observed with long-acting dihydropyridines)
long-acting agents: induce gradual peripheral VD |
|
|
Term
SE
all Ca Channel blockers |
|
Definition
flushing
peripheral edema
dizziness
orthostatic hypotension (not common) |
|
|
Term
|
Definition
no DDI with NSAIDs
DDIs related to metabolism - either increased or decreased |
|
|
Term
Metabolism
Ca Channel blockers |
|
Definition
first pass metabolism susceptible
extensively bound to plasma proteins
extensively metabolized by liver |
|
|
Term
| Why are dihydropyridines good anti-HTN? |
|
Definition
| block vascular VGCCs with little effect on cardiac channels |
|
|
Term
|
Definition
|
|
Term
| Why is amlopidine a commonly used antihypertensive? |
|
Definition
1) long half-life => once daily dosing
2) minimal cardiac effects
3) safely administered to patients with heart failure since it's the only dihydropyridine to reduce mortality w/ L ventricular dysfunction |
|
|
Term
| Why are non-dihydropyridines more cardioselective than vasoselective? |
|
Definition
| interact at different sites in VGCCs than dihydropyridines |
|
|
Term
SOA
non-dihydropyridines s.a. diltiazem & verapamil |
|
Definition
more often cardiac, rather than anti-HTN
superventricular tachycardias
prevention of ventricular arrythmias in patients with atrial fibrillation |
|
|
Term
|
Definition
due to α1 blocking properties => anti-HTN effect => severe hypotension when used with wuinidine (another α blocker)
decreases digoxin's renal clearance => required dose of cardiac glycoside to be lowered |
|
|
Term
|
Definition
1) nitroglycerin
2) isosorbide dinitrate |
|
|
Term
|
Definition
| increase NO in smooth muscle => activation of guanylyl cylase to catalyze the synthesis of cGMP => dephosphorylation of myosin light chains => s. muscle relaxation |
|
|
Term
| Are veins or arteries more sensitive to nitrates? |
|
Definition
| veins (then arterioles & precapillary sphincters) |
|
|
Term
| What does increased cascular capacitance lead to? |
|
Definition
| decreased ventricular filling pressure |
|
|
Term
| What can improve cardiac output & decrease pulmonary congestion in failing hearts? |
|
Definition
|
|
Term
| What effect do nitrates have on arterial compartment? |
|
Definition
| reduce peripheral resistance => subsequent reduction beneficial redistribution of the coronary flow from the epicardium to the endocardium |
|
|
Term
| Why aren't nitrates used for their intestinal, hepatic, and renal sm. muscle cell relaxation? |
|
Definition
|
|
Term
SOA
nitrates s.a. nitroglycerin & isosorbate dinitrate |
|
Definition
classic, variant, & unstable angina
heart failure |
|
|
Term
| What is the principal benefit of nitrates in classical angina? |
|
Definition
reduction of myocardial oxygen consumption due to:
1) decreased venous return to the hear => subsequent reduction of intraventricular pressure & ventricular radius (positive determinants of cardiac wall stress)=> decreased coronary flow resistance
2) reduction in peripheral vascular resistance => reduction in afterload (positive determinant of myocardial oxygen consumption) |
|
|
Term
| What is the benefit of nitrates in variant angina? |
|
Definition
| dilation of epidural arteries with redistribution of the epicardium to the endocardium & prevention of arterial spasm |
|
|
Term
| What are the benefits of nitrates in unstable angina? |
|
Definition
1) reduced myocardial oxygen demand
2) coronary artery dilation
3) NO decreases platelet aggregation |
|
|
Term
SE
nitrates s.a. nitroglycerin & isosorbide dinitrate |
|
Definition
orthostatic hypotension
reflex tachycardia
throbbing headache (due to meningeal artery pulsations) |
|
|
Term
Tx
reflex tachycardia due to nitrates |
|
Definition
|
|
Term
How are nitrates administered in Tx for actue angina?
Why? |
|
Definition
| sublingually due to rapid absorption & reach heart without extensive first pass metabolism |
|
|
Term
| How are nitrates administered in prevention of angina attacks? |
|
Definition
| PO, tho need increased doses |
|
|
Term
Does nirtoglycerin or isosorbide dinitrite have a longer half life?
Why? |
|
Definition
| isosorbide dinitrate due to longer half life & it has 2 active catabolites |
|
|
Term
| What are the convienent administrations of nitroglycerin? |
|
Definition
|
|
Term
| Why can some patients develop a tolerance to nitrates? |
|
Definition
|
|
Term
|
Definition
| PDE-5 inhibitors (s.a. seldenafil [viagra]) => potentiation & therefore profound hypotension & possible MI |
|
|
Term
| What are the 2 drugs that act directly on arteriolar s. muscle to cause vasodilation => decreased peripheral resistance? |
|
Definition
1) Hyralazine
2) Sodium Nitroprusside |
|
|
Term
SE
monotherapy with vasodilators s.a. hydralazine & sodium nitroprusside |
|
Definition
1) baroreceptor-mediated increase on HR & CO
2) increase in renin secretion & plasma volume |
|
|
Term
| What are vasodilators usually co-administered with? |
|
Definition
| β blockers to decrease tachycardia & renin secretion |
|
|
Term
| Why are arterial dilators less effective in classic angina than nitrates? |
|
Definition
| induce arteriolar dilation w/o exerting any effect on the epicardial coronary arteries |
|
|
Term
|
Definition
SE in arterial dilators in patients with CAD.
arterioles below atherosclerotic plaque of the obstructed coronary vessel are already maximally dilated & therefore only little responsive to arterial vasodilators => diversion of blood from ischemic myocardial areas => propagation of angina attacks or MI |
|
|
Term
|
Definition
|
|
Term
|
Definition
1) with β blockers & diuretics for complicated HTN
2) with nitrates for heart failure (due to reduction of afterload) |
|
|
Term
|
Definition
lupus-like syndrome or other immune related diseases (generally reversible upon drug withdrawl)
limits clinical use |
|
|
Term
|
Definition
| generation of NO via enzymatic & nonenzymatic pathways => activation of guanylyl cyclease => increase cGMP => dilation of arterioles & venules => reduction of peripheral resistance & afterload, and decreased preload |
|
|
Term
| What does decreased pre- & after- load do to hypertensive patients with preserved cardiac function? |
|
Definition
|
|
Term
| What does decreased pre- & after- load do to hypertensive patients with severe left ventricular dysfunction? |
|
Definition
|
|
Term
| Why is sodium nitroprusside different from other arteriolar vasodilators? |
|
Definition
| cardiac effect associated with a modest incrase in HR & overall reduction in myocardial oxygen consumption |
|
|
Term
|
Definition
1) hypertensive emergencies
2) other emergencies with a combined pre- & after- load is needed s.a. acute aortic dissection, cardiogenic shock (secondary to massive acute MI or rupture of papillary muscle)
3) induction of controlled hypotension in normotensive patients under surgical anesthesia |
|
|
Term
| How long are the effects of sodium nitroprusside when administered IV? |
|
Definition
| 30 sec onset, 2 min peak, 3 minute dissapation |
|
|
Term
SE
high dose/long duration sodium nitroprusside |
|
Definition
| CN &/or thiocyanide poisoning (due to nitroprusside metabolism => CN & NO release => CN reduction to thiocyanide) |
|
|
Term
| When is CN accumulation more common in sodium nitroprusside? |
|
Definition
| patients with impaired renal function |
|
|
Term
| How can CN accumulation be prevented in sodium nitroprusside administration? |
|
Definition
| concurrent administration of sodium thiosulfate |
|
|
Term
| What 3 agents increase cardiac contractility? |
|
Definition
1) Digoxin
2) Bipyridines
3) adrenergic agonists |
|
|
Term
| What is the only cardiac glycoside available in the U.S.? |
|
Definition
|
|
Term
|
Definition
| inhibit Na/K ATPase => sodium accumulation in cytoplasm => increases Na/Ca exchanger to remove intracellular Na => increased cytosolic Ca => Ca sccumulation in sarcoplasmic reticulum => larger amount of Ca released from sarcoplasmic reticulum => increased efficiency of contractions w/o increasing cardiac work |
|
|
Term
| Why does CO in the failing heart increase in digoxin use? |
|
Definition
| due to positive inotropic effect => reduced stimulus for increased sympathetic tone => decreased HR & vascular tone |
|
|
Term
| What causes heart size & oxygen demand to decrease with digoxin use? |
|
Definition
| decreased filling pressure & increased systolic ejactulation |
|
|
Term
| How can digoxin reduce edema? |
|
Definition
| improved renal blood flow & increased GFR |
|
|
Term
|
Definition
1) sudden death
2) delayed after potentials => initiation of second, extra contraction => afterpotentials & ventricular fibrillation
3) increased sympathetic tone |
|
|
Term
| What effect does digoxin have on the ventricular AP? |
|
Definition
| shortens due to increased potassium conductance in response to the higher levels of cytoplasmic Ca |
|
|
Term
|
Definition
| anti-digoxin Fab fragment |
|
|
Term
| What mediates the cardiac effects of digoxin? |
|
Definition
|
|
Term
| What cardiac effects of digoxin are mediated by the vagus? |
|
Definition
1) decrease in conduction velocity
2) increase in the refractory period of AV node
3) opposite effects in atrial muscle |
|
|
Term
| What blocks the cardiac effects of digoxin? |
|
Definition
|
|
Term
| Why doesn't digoxin affect Na/K ATPase throught the body? |
|
Definition
| there are at least 4 isoforms of the α subunit of the ATPase that determine the degree of drug sensitivity |
|
|
Term
|
Definition
N/V/D, anorexia (due to inhibition of Na/K ATPase in the GI & chemoreceptor trigger zone)
CNS effects (inc. aberrations in color vision) |
|
|
Term
| What are an important determinant of digoxin's effects? |
|
Definition
| serum electrolytes (esp. potassium) |
|
|
Term
| What effect does serum potassium have on digoxin? |
|
Definition
| inhibits digoxin's binding to α subunit of Na/K ATPase, therefore hyperkalemia reduces digoxin's effects & hypokalemia increased the cardiac pacemaker rate, AP duration & arrythmogenesis (digoxin induced arrythmias) |
|
|
Term
| What can cause hypokalemia? |
|
Definition
|
|
Term
| What effect does hypercalcemia & hypomagnesemia have on digoxin? |
|
Definition
| increased risk of digoxin induced arrythmias |
|
|
Term
|
Definition
| well absorbed PO & widely distributed |
|
|
Term
|
Definition
| well absorbed PO & widely distributed |
|
|
Term
| What can digoxin overdose in patients with low bioavailability due to GI microflora? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| quinidine => reduction of renal elimination => toxicity |
|
|
Term
MOA
bipyradines s.a. inamrinone & milrinone |
|
Definition
| inhibitors of isoform of cAMP phosphodiesterase that is found in cardiac & s. muscle => enhanced intracellular AMP => amplification of cardiac & vascular effects of catecholamines => activation of AC => increased cAMP => increased myocardial contraction & VD |
|
|
Term
|
Definition
| serious toxicities inc. arrythmias, marrow & hepatic toxicities |
|
|
Term
|
Definition
| only avaiable IV for acute heart failure & temporary management of severe CHF |
|
|
Term
| What 3 adrenergic agonists are used to increase cardiac contractility? |
|
Definition
1) Dobutamine
2) DA
3) isoproterenol |
|
|
Term
|
Definition
| sympathomimetic amine whose preparation is a racemic mixture that exert opposite effects on the α1 receptors, but are both full agonists of β1 & β2 receptors |
|
|
Term
|
Definition
moderate increase in HR
increase in cardiac contractility => increased CO
systolic pressure increased, but diastolic pressure unchanged (peripheral resistance unaffected)
myocardial oxygen consumption is only moderately increased |
|
|
Term
|
Definition
1) short-term medical Tx of acute cardiac decompensation after cardiac surgery
2) patients with acute heart failure or MI
3) Dx presence of coronary obstructions |
|
|
Term
|
Definition
1) caution advised in MI since infusion of dobutamine may increase the size of the MI due to increased myocardial oxygen consumption
2) caution in patients with atrial fibrillation since infusion can increase ventricular response rate since it faciliates AV conduction |
|
|
Term
| What effect does DA have when secreted by epithelium of proximal tubule? |
|
Definition
| lacal diuretic & natriuretic |
|
|
Term
| Why is oral DA ineffective? |
|
Definition
| catabolized by MAO & COMT |
|
|
Term
What mediates the cardivascular effects of DA?
What are the effects |
|
Definition
affinity of DA for several receptor types:
low dose - D1: s. muscle VD of renal, mesenteric & coronary beds
β1 receptor agonist: increase HR, cardiac contractility => increased systolic BP, no change to diastolic BP
high dose - α1 receptor: induce peripheral resistance |
|
|
Term
|
Definition
short-term Tx of severe congestive heart failure associated with conpromised renal function
cardiogenic & septic shock |
|
|
Term
|
Definition
| potent nonselective β agonist with low affinity for α receptors |
|
|
Term
|
Definition
1) promptly enhance HR or AV conduction in patients with bradycardia or AV blocks which prepared to be implanted an artificial pacemaker
2) patients with torsades de pointes to facilitate the restoration of sinus rhythm
(NOT used in asthma or shock) |
|
|
Term
| Where do the electrical impulses that drive the heart originate? |
|
Definition
|
|
Term
| What causes the depolarization (phase 0) of the SA node? |
|
Definition
|
|
Term
| What causes repolarization (phase 3) of SA node? |
|
Definition
| outward K current (delayed rectifier) |
|
|
Term
| What happens to the diastolic potential (phase 4) of SA & AV nodes? |
|
Definition
|
|
Term
| What causes diastolic depolarization of SA node? |
|
Definition
| inward Na current that is partially mitigated by outward rectifying K current |
|
|
Term
| What accounts for the automaticity of the SA node? |
|
Definition
| gradual depolarization during phase 4 => threshold reached |
|
|
Term
| Is the AP of ventricular muscle, atrial muscle, or Purkinje fibers automatic? |
|
Definition
| no, tho all cardiac tissue has the potential to become automatic |
|
|
Term
| What causes depolarization (phase 0) in ventricular muscle? |
|
Definition
| inward Na current => active inactivation |
|
|
Term
| What limits the positive excursion of the Na influx in ventricular muscle? |
|
Definition
|
|
Term
| What maintains the plateau (phase 2) of ventricular muscle? |
|
Definition
| blanace of inward calcium thru L type & T type channcel & outward conductance of K channels |
|
|
Term
| What causes phase 3 repolarization of ventricular muscle? |
|
Definition
|
|
Term
| Is diastole (phase 4) more or less stable in ventricular muscle than AV & SA nodes? |
|
Definition
|
|
Term
| Wuses phase 4 (diastole) in ventricular muscle? |
|
Definition
| inward Na & Ca vs. outward K + effects of Na/K ATPase & Na/Ca exchanger |
|
|
Term
|
Definition
|
|
Term
|
Definition
| ventricular depolarization |
|
|
Term
|
Definition
| ventricular reploarization |
|
|
Term
| Why is artial repolarization not recorded in an EKG? |
|
Definition
|
|
Term
| Why is artial repolarization not recorded in an EKG? |
|
Definition
|
|
Term
|
Definition
| period b/w atrial & ventricular depolarizations |
|
|
Term
|
Definition
| plateau of the ventricular AP |
|
|
Term
|
Definition
| period from ventricular depolarization until repolarization |
|
|
Term
| What are the 5 possible mechanisms of caridac arrythmias? |
|
Definition
1) altered automaticity
2) triggered activity
3) conduction block
4) defects
5) accessory pathways |
|
|
Term
| How can altered automaticity occur and cause arrythmias? |
|
Definition
1) abnormal electrical activity can occur is the SA nodal rate is pathologically low (after MI?) and a latent pacemaker generates and "esacpe" rhythm.
2) :ectopic: rhytms can develop when latent pacemakers arise that have faster intrinsic rate than SA node (due to ischemia, electrolyte imbalance or high sympathetic activity) |
|
|
Term
| How do altered trigger activities cause arrythmias? |
|
Definition
| normal APs trigger afterdepolarization |
|
|
Term
| How do early afterdepolarizations (EAD) occur? |
|
Definition
| when QT interval is prolonged and exceeds the refractory period so that an AAP can occur before ventricular repolarization |
|
|
Term
| What can sustained EAD lead to? |
|
Definition
| torsades (dangerous arrythmias) |
|
|
Term
| What causes delayed afterdepolarizations (DAD)? |
|
Definition
| after ventricular repolarization, with an unknown mechanism, but cardiac glycoside toxicity appears to be related to increased intracellular calcium |
|
|
Term
| What does a barrier to conduction of the heart cause? |
|
Definition
|
|
Term
|
Definition
| pathological self-sustaining electrical circuit that stimulates a region of the myocardium repeatedly & rapidly |
|
|
Term
| What can cause a barrier in conduction of the heart? |
|
Definition
| a region of damaged tissue that will not support normal conduction, but will allow retrograde conduction at a slower than normal velocity |
|
|
Term
| What happens when normal conduction is prevented through the damaged myocardium? |
|
Definition
the impulse flows around the barrier and enters the damaged area
[image] |
|
|
Term
| What can cause a "circus rhythm" in the heart? |
|
Definition
| if the retrograde slow is slow enough, that the refractory period of the normal tissue is past, the returning current will depolarize the tissue |
|
|
Term
| What causes a conduction block? |
|
Definition
| when the AP fails to propagate b/c of unexcitable myocardium (drugs, trauma, scarring, ischemia can cause this) |
|
|
Term
| How does a conduction block cause arrythmias? |
|
Definition
| tissue beyond the block can generate escape rhythms |
|
|
Term
|
Definition
| pathways that bypass the AV node (exist only in some individuals) |
|
|
Term
def
Wolf-White-Parkinson syndrome |
|
Definition
| the Bundle of Kent predisposes the individual to re-entry and tachyarryhtmias |
|
|
Term
|
Definition
| short circuit b/w atria & ventricles that competes with the normal pathway |
|
|
Term
| How many classes are there of anti-arrythmic drugs? |
|
Definition
|
|
Term
MOA
Class I antiarrythmics |
|
Definition
sodium channcel blocker =>
1) decreased phase 4 slope in the SA node => decreased automaticity
2) decreasing phase 0 upstroke => increases threshold |
|
|
Term
| What are the 3 subclasses of class I antiarrythmics? |
|
Definition
|
|
Term
| What subdivides the class I antiarrythmics? |
|
Definition
| time for recovery of the sodium channel from blockade (A more rapidly than C) |
|
|
Term
| What is the most important property of sodium channel blockers as an antiarrythmic? |
|
Definition
state dependent.
This is b/c sodium channel exists in 3 states: an open state (ion flux) followed by an inactive state (closed, but not repolarized) and then finally a resting state (ready to open - after repolarization) |
|
|
Term
| When do most sodium channel blockers bind? |
|
Definition
open &/or inactivated
(they dissociate from resting channels) |
|
|
Term
| Since sodium channel blockers bind the open/inactive state, do they bind better when the firing rate is high or low? |
|
Definition
|
|
Term
| When do sodium channel blocker dissociate more slowly? |
|
Definition
| ischemic tissue where depolarization lasts longer |
|
|
Term
| Can sodium channel blockers bind anyother channels? |
|
Definition
| yes, they're not specific |
|
|
Term
What is the class I agent?
Is it class IA, IB, or IC? |
|
Definition
|
|
Term
|
Definition
Sodium channel effects: increases threshold & decreased conduction velocity in mycoardium
Potassium channel effects: prolongs AP => prolongs QRS |
|
|
Term
|
Definition
| second choice: atrial & ventricular arrythmias, sustained ventricular arrythmias after MI |
|
|
Term
| Where should all class I antiarrythmics be started? |
|
Definition
|
|
Term
|
Definition
induction of torsades de pointes
hypotension due to ganglionic blockade
long-term Tx: lupus-like disease with ANAs |
|
|
Term
MOA
class II antiarrythmics |
|
Definition
β blocker =>
1)reduced HR
2)increased AV conduction time
3)increased PR interval
4)inhibit afterdepolarization-mediated automaticity |
|
|
Term
SOA
class II antiarrythmics |
|
Definition
1) prevent ventricular tachycardia in the face of further atrial flutter or fibrillation
2) prevent the recurrences of paroxysmal supraventricular tachycardias |
|
|
Term
| What are the 2 class II anticarrythmics? |
|
Definition
|
|
Term
|
Definition
| IV for immediate control of atrial tachycardia |
|
|
Term
|
Definition
| atrial & ventricular tachyarrythmias |
|
|
Term
SE
class II antiarrythmics |
|
Definition
|
|
Term
CI
class II antiarrhythmics |
|
Definition
| wolf-white-parkinson syndrome |
|
|
Term
MOA
class III antiarrythmics |
|
Definition
| block outward potassium channels => inhibit repolarization of myocardium |
|
|
Term
| What does prolongation of the AP cause? |
|
Definition
| increases refractoriness & decreases re-entry |
|
|
Term
SE
class III antiarrythmics |
|
Definition
| prolongation of QT => increased EADs & torsades de pointes |
|
|
Term
| Where should Tx of class III antiarrythmics begin? |
|
Definition
|
|
Term
| What is the class III antiarrythmic? |
|
Definition
|
|
Term
|
Definition
1) inhibits sodium, potassium, & calcium channels
2) α & β receptor blocker |
|
|
Term
| What other class of antiarrythmics does amiodarone share properties with? |
|
Definition
|
|
Term
|
Definition
1) prolongs refractoriness
2) increases AV conduction time
3) bradycardia |
|
|
Term
|
Definition
PO:
restoring sinus rhythm in atrial tachycardia
recurrent ventricular tachycardias & fibrillation |
|
|
Term
|
Definition
PR, QRS, QT prolonged
low incidence of torsades de pointes (paradox)
bradycardia
decreased contraction
heart block
pneumonitis => pulmonary fibrosis & hyper- or hypo- thyroidism
CNS Sx |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
MOA
class IV antiarrythmics |
|
Definition
| Ca channel blockers => reduction of phase 0 SA & AV nodal APs => bradycardia & prolonged AV nodal conduction velocity & refractoriness |
|
|
Term
| What are the 2 antiarrythmics? |
|
Definition
1) diltizem
2) verapamil
(Vit D) |
|
|
Term
SOA
class IV antiarrythmics |
|
Definition
supress EADs & DADs
re-entrant supraventricular tachycardia
reduce the risk of ventricular tachycardia driven by atrial flutter or fibrillation |
|
|
Term
CI
class IV antiarrythmics |
|
Definition
| wolf-white-parkinson syndrome |
|
|
Term
SE
class IV antiarrythmics |
|
Definition
bradycardia
hypotension
decreased contraction |
|
|
Term
DDI
class IV antiarrythmics |
|
Definition
| interactions with β blockers & raise digoxin levels & others |
|
|
Term
| What are the 4 Misc. antiarrythmic agents? |
|
Definition
1) digoxin
2) potassium
3) adenosine
4) magnesium sulfate |
|
|
Term
|
Definition
| binds to P1 purinergic receptors that open G-protein regulated potassium channels => inhibition of SA nodal, atrial, & AV nodal conduction |
|
|
Term
|
Definition
| terminate supraventricular arrythmias |
|
|
Term
|
Definition
|
|
Term
|
Definition
digoxin related arrythmias
drug induced torsades de pointes
arrythmias due to hypomagnesemia |
|
|
Term
| How many medications are allowed per Rx? |
|
Definition
|
|
Term
| Which Rx types are not allowed refills? |
|
Definition
C-IIs
(tho you can give them 3 separate Rx for up to a 90 day supply - don't post-date the Rx, and electronic not allowed) |
|
|
Term
| What is needed for all Rx? |
|
Definition
1) tamper proof Rx pads
2) DEA #
3) date/time
4) physician name/pager #
5) patient: hight/weight/allergies |
|
|
Term
| How can Rx be transmitted? |
|
Definition
written (legibly)
verbal
electronic |
|
|
Term
| When writing Rx are abbreviations ok to use? |
|
Definition
| Avoid when possible, but generally accepted ones ok (never use ones commonly misinterpreted) |
|
|
Term
| How should dosing be written on Rx to ensure the safety of the patient? |
|
Definition
1) ALWAYS use leading zeros (0.5mg)
2) NEVER use training zeros(5mg NOT 5.0mg)
3) NEVER use u for units
4) NEVER abbreviate drug name |
|
|
Term
| What do we know about medication errors? |
|
Definition
| common, costly, deadly, often preventable |
|
|
Term
|
Definition
| list of approved or recommended drugs for a given hospital, health-system or health plan |
|
|
Term
| Where is the source of most medication errors? |
|
Definition
|
|
Term
| What failures can cause medication errors? |
|
Definition
1) incomplete info about patient
2) unclear communication
3) lack of independent check
4) lack of/too many computer warnings
5) ambiguous drug reference
6) drug storage |
|
|
Term
| 45 y/o white male. Generally good conition but overweight (BMI 29).
Lab data: Cholesteroltotal = 244, LDL = 206, HDL = 38, CRP = 2.6
Family Hx of heart attacks and smokes 1 pack/day.
Is he a candidate for cholesterol-lowering Tx? If so, what agent should be tried first? |
|
Definition
|
|
Term
| What is the #1 cause of dealth in the US? |
|
Definition
| heart disease (stroke #3) |
|
|
Term
| What is a major root cause of both heart disease & stroke? |
|
Definition
|
|
Term
|
Definition
| build-up of plaque within arteries |
|
|
Term
|
Definition
| asymptomatic for decades until heart attack/stroke |
|
|
Term
|
Definition
| high serum cholesterol levels lead to plaque build up |
|
|
Term
| What 2 Tx strategies arose from the lipid hypothesis of atherosclerosis? |
|
Definition
1) limit dietary fat intake
2) development of cholesterol lowering drugs (statins) |
|
|
Term
| What are the 3 outcomes of atherosclerosis? |
|
Definition
1) stenosis (usually not the issue)
2) reupture of vulnerable plaque => MI
3) emboli => MI or stroke |
|
|
Term
| How do lipid circulate the blood? |
|
Definition
| ithin larger lipoprotein particles (LDL, HDL, etc) |
|
|
Term
| What drives the self-assembly of higher-order lipid structures like bilayer membranes & lipoprotein particles of lipids? |
|
Definition
| hydrophobic effect (thermodynamic urge to sequester hydrophobic moietis from water) |
|
|
Term
Function
lipoprotein particles |
|
Definition
| provide mechanism to circulate water-insoluble fats |
|
|
Term
| Is the surface of lipoproteins a mono- or bi- layer? |
|
Definition
|
|
Term
|
Definition
| control & mediate specific receptor interactions |
|
|
Term
| What are lipoproteins composed of? |
|
Definition
| various amounts of phospholipids. triglycerides, cholesterol, cholesterol esters, apolipoproteins |
|
|
Term
|
Definition
| carries mainly cholesterol & cholesterol esters |
|
|
Term
| What apolipoprotein directs interaction with LDL receptor? |
|
Definition
|
|
Term
|
Definition
| cholesterol transport b/w liver & peripheral tissues |
|
|
Term
|
Definition
| organizes LDL and mediates LDL removal from blood by mediating binding to LDLR & then endocytosis |
|
|
Term
|
Definition
| mediates reverse cholesterol transport where cholesterol is removed from foam cells within atherosclerotic plaque into HDL particle |
|
|
Term
|
Definition
| contains triglycerides & cholesterol absorbed from the diet - distributes free fatty acids to peripheral tissues |
|
|
Term
|
Definition
| distribute triglycerides & cholesterol synthesized or store within the liver to peripheral tissue. Also feeds peripheral tissues with fatty acids thru triglyceride hydrolysis |
|
|
Term
| What are VLDLs coverted to as triglycerides are removed? |
|
Definition
|
|
Term
| Why is stenosis generally not a problem with atherosclerotic plaque build up? |
|
Definition
| compensatory VD maintain proper BP & flow |
|
|
Term
| What lipids accumulate in the aterial wall in plaques? |
|
Definition
|
|
Term
| What are recruited from circulation to sites of plaques since the artery is "damaged"? |
|
Definition
| immune cells s.a. monocytes/macs |
|
|
Term
How are macs coverted to foam cells?
What happens once they become foam cells? |
|
Definition
| digest oxidized LDL, but are unable to catabolize it => accumulation of injested froduct until foam cell ruptures => re-release of oxidized LDL => more monocyte recruitment |
|
|
Term
| What is the smallest & most dense lipoprotein particle? |
|
Definition
|
|
Term
| What apolipoprotein is seen in HDL? |
|
Definition
|
|
Term
|
Definition
| membrane component essential for all animal life |
|
|
Term
| What are the 3 ways cholesterol levels within the body are modulated (and therefore the 3 places cholesterol levels can me modified)? |
|
Definition
1) dietary intake
2) new synthesis (~10x more than is taken in thru diet - made in liver)
3) excretion (via bile acids) |
|
|
Term
|
Definition
| detergent-like molecules derived from cholesterol secreted by gall bladder to solubilize dietary fat & protein (most secreted bile acids are recycled) |
|
|
Term
| What drug blocks intestinal absorption of cholesterol (& therefore dietary intake)? |
|
Definition
|
|
Term
| What drugs block cholesterol biosynthesis? |
|
Definition
|
|
Term
| What drugs increase bile acid secretion by blocking recycling to gall bladder? |
|
Definition
|
|
Term
|
Definition
| regulates serum LDL-C levels by removing circulating LDL particles |
|
|
Term
| How does LOL bind to LDLR? |
|
Definition
| thru B-100 apoplipoprotein |
|
|
Term
|
Definition
| clathrin-mediated endocytosis |
|
|
Term
| What happens once LDL is endocytosed? |
|
Definition
| receptor & ligand dissociate => receptor is receycled back to cell surface & LDL hydrolyzed |
|
|
Term
| What regulates LDLR expression for endocytosis? |
|
Definition
cellular cholesterol levels
i.e. in times of starvation LDLR is upregulated with decreaed serum LDL-C |
|
|
Term
def
familial hypercholesterolemia |
|
Definition
| pathologically high serum LDL-C levels |
|
|
Term
| What causes familial hypercholesterolemia? |
|
Definition
| mutations at the LDL receptors - either no functioning LDLRs produced or truncated forms are produced |
|
|
Term
| What are the products of the cholesterol biosynthetic pathway? |
|
Definition
| farnesyl PP & geranylgeranyl PP -> cholesterol -> steroid hormones, Vit D, & bile acids |
|
|
Term
|
Definition
| inhibitors of HMG-CoA => inhibition of cholesterol biosynthesis |
|
|
Term
| What does the decreased cholesterol levels manufactured by statins do to LDL levels? |
|
Definition
| increased LDLR => decreased LDL-C in circulation |
|
|
Term
| Does increasing bile acid secretion => decreased cirulating LDL-C? |
|
Definition
|
|
Term
| What drugs have the greatest efficiency at reducing the risk of both coronary heart disease & stroke? |
|
Definition
|
|
Term
| What are the 7 major risk factors for CHD (coronary heart disease)? |
|
Definition
1) prior/ongoing CHD
2) diabetes
3) age (increasing)
4) dyslipidemia (high LDL, low HDL)
5) family Hx of premature CHD
6) current smoker
7) obesity |
|
|
Term
| What is the target total cholesterol level? |
|
Definition
|
|
Term
| What is the target HDL level? |
|
Definition
|
|
Term
| What is the target LDL level? |
|
Definition
| <100 (>160 high, >190 very high) |
|
|
Term
| What is the target triglyceride level? |
|
Definition
| <150 (>200 high, >500 very high) |
|
|
Term
| When is LDL target level lowered? |
|
Definition
| higher the risk, lower the target level |
|
|
Term
What is target LDL for very high risk?
high risk?
moderate high risk?
moderate risk? |
|
Definition
very high: <70
high: <100
moderate high: <130
moderate (0-1 risk factor): <160 |
|
|
Term
| Why are statins considered a major medical breakthrough? |
|
Definition
| overall reduction of morbidity & mortality provided |
|
|
Term
| What are the 7 statin drugs? |
|
Definition
1) Lovastatin
2) Simvastatin
3) Pravastatin
4) Fluvastatin
5) Atorvastatin
6) Rosuvastatin
7) Pitavastatin
(-vastatin) |
|
|
Term
| What is the most perscribed drug? |
|
Definition
|
|
Term
Function
HMG-CoA reductase |
|
Definition
| converting HMG-CoA to mevalonate |
|
|
Term
|
Definition
| competitive inhibition of HMG-CoA reductase |
|
|
Term
| How are LDL levels improved with diet/exercise regulation? |
|
Definition
| cells starving for cholesterol => up regulation of LDLRs => decreased serum LDL-C |
|
|
Term
| How do statins act as an HMG-CoA competitive inhibitor? |
|
Definition
have a side group that mimics the HMG-CoA substrate
(lovastatin & simvastatin must be activated in the liver first) |
|
|
Term
| What is the major site of statin action? |
|
Definition
| liver b/c that's the major site of cholesterol storage & biosynthesis |
|
|
Term
|
Definition
Major: lower LDL (by 25-55%)
Minor:
1) modest HDL elevation (by 10-20%)
2) lower triglycerides (by 30-50%)
3) improved endothelial function (improved vascular tone)
4) increased plaque stability
5) reduced inflammation
6) reduced LDL oxidation
7) reduced coagulation
8) cancer Tx? |
|
|
Term
| Why do statins seem to be relatively safe (i.e. profound toxicities since cholesterol is vital to life)? |
|
Definition
| statin do not eliminate cholesterol from the body |
|
|
Term
|
Definition
1) myopathy (most frequent - myalgia)
2) rhabdomyolysis (rare, but serious -rapid muscle breakdown => kidney failure) |
|
|
Term
Tx
statin induced myopathy |
|
Definition
| dose reduction or change statin |
|
|
Term
| What must be done to prevent rhabdomyolysis? |
|
Definition
| test blood creatinine levels |
|
|
Term
| What is the desired value for total cholesterol:HDL? |
|
Definition
|
|
Term
| What 4 other drug types can statins be combined with to be more efficacious? |
|
Definition
1) bild acid-binding resins
2) fibrates (for high triglycerides)
3) niacin (for high triglycerides & LDL)
4) ezetimide (combination = vytorin) |
|
|
Term
| What do studies suggest with increasing statin dose? |
|
Definition
| increasing dose = increasing benefit |
|
|
Term
| What are the 6 other lipid-lowering drugs? |
|
Definition
1) bile acid-binding resins
2) niacin
3) fibric acid derivatives
4) fish oil
5) ezetimide
6) CEPT inhibitors |
|
|
Term
MOA
bile acid sequesterants |
|
Definition
| increase bile acid excretion |
|
|
Term
|
Definition
| unknown - reduces liver secretion of VLDL |
|
|
Term
|
Definition
| activates PPARα => lowers liver release of VLDL & triglyceride synthesis |
|
|
Term
|
Definition
| reduce fasting triglyceride levels |
|
|
Term
|
Definition
| reduce dietary intake of cholesterol by intestine |
|
|
Term
|
Definition
|
|
Term
| What are the 3 bile acid-binding resins? |
|
Definition
1) cholestyramine
2) colestipol
3) colesevelam |
|
|
Term
MOA
bile acid sequestrants |
|
Definition
| reside in intestine & tightly bind to bile acids => elimination => more cholesterol to be diverted to bile acid synthesis => decreased liver cholesterol => increased LDLR & less serum LDL-C |
|
|
Term
| Why are bile acid-binding resins often not used as a monotherapy? |
|
Definition
| depletion is compensated by up-regulation of biosynthetic pathway |
|
|
Term
SE
bile acid-binding resins |
|
Definition
nausea
constipation
indigestion
unpleasant to eat
decreased absorption of fat soluble vitamins & drugs |
|
|
Term
|
Definition
|
|
Term
|
Definition
lower LDL
raise HDL
lower triglyerides |
|
|
Term
|
Definition
| hypertriglyceridemia (often used with statins) |
|
|
Term
|
Definition
increased risk of myopathy & rhabdomyolysis
extreme flushing & itching (low compliance) |
|
|
Term
|
Definition
1) gemfibrozil
2) ciprofibrate
3) fenofibrate
(-fibr-) |
|
|
Term
|
Definition
lower triglycerides (VLDL)
raise HDL |
|
|
Term
|
Definition
| hypertriglyceridemia (often in comination with statins) |
|
|
Term
|
Definition
| increased risk of myopathy & rhabdomyolysis |
|
|
Term
|
Definition
| modest effect on LDL as a monotherapy, but drastic effect when combined with statins |
|
|
Term
|
Definition
| increased cardiovascular events & death |
|
|
Term
| Why are there so many long term complications for diabetics, even those on insulin? |
|
Definition
| once or twice daily insulin doesn't replicate the body's natural minute by minute regulation of glucose |
|
|
Term
| Is T1 or T2 DM more common? |
|
Definition
| T2 (~95% of all DM cases) |
|
|
Term
| What does an increase in blood glucose do to pancreatic secretion? |
|
Definition
| decreased glucagon, increased insulin |
|
|
Term
| What causes long-term DM complications? |
|
Definition
| prolonged glucose toxicity |
|
|
Term
|
Definition
chronic metabolic disorder characterized by high blood glucose concentration (hyperglycemia) due to:
1) insulin deficiency (T1DM)
2) impaired insulin response due to underlying insulin resistance + inpaired β cell response (T2DM) |
|
|
Term
| What happens to the the glucose in hyperglycemia when it reaches the kidney? |
|
Definition
| overwhelms kidney & uselessly excreted |
|
|
Term
| What is the aim of DM Tx? |
|
Definition
restore euglemia (normal glucose regulation) to delay onset of long-term complications
therefore mixture of long & short term insulins needed |
|
|
Term
|
Definition
1) covalent addition of glucose to proteins
2) increased glucose metabolism => increased accumulation of oxidants
3) osmotic effects of high glucose |
|
|
Term
| What are the long-term complications of DM? |
|
Definition
1) CV: dysregulated lipid metabolism - atherosclerosis, 3-5x increased risk MI, stroke
2) Retinopathy (most common adult onset blindness)
3) Nephropathy (~30% of patients on dialysis)
4) Neuropathy (deterioration of peripheral motor & sensory nerves => ulceration & gangrene => amputation) |
|
|
Term
|
Definition
|
|
Term
| When does T1DM onset occur? |
|
Definition
|
|
Term
|
Definition
| total deficiency in insulin production due to destruction of pancreatic β cells (auto-immune) |
|
|
Term
|
Definition
|
|
Term
|
Definition
Sx of starvation since glucose can't be uptaken into peripheral tissues
ketone bodies = main source of energy => ketoacidosis
wasting
can be fatal |
|
|
Term
|
Definition
|
|
Term
| When does the onset of T2DM occur? |
|
Definition
|
|
Term
Are T2 diabetics able to produce insulin?
T1? |
|
Definition
|
|
Term
| What is the hallmark of early T2DM? |
|
Definition
| elevated circulating insulin accompanying hyperglycemia |
|
|
Term
| What is the body's compensatory mechanism to overcome decreased insulin sensitivity? |
|
Definition
| increased insulin production |
|
|
Term
| What happens in disease progression of T2DM? |
|
Definition
| decreased compensatory insulin secretion (i.e. increasing β cell insufficency) |
|
|
Term
|
Definition
| unknown, but there is a genetic compnent & an association with obesity (~70% of T2 diabetics are obese) |
|
|
Term
|
Definition
1) insulin replacement
2) diet & exercise
3) anti-diabetic agents s.a. sulfonylureas, metformin, thiazolinediones, glinides, exenatide |
|
|
Term
| What 2 hormones produced by adipose tissue have effects on metabolism, appetite, & T2DM? |
|
Definition
|
|
Term
|
Definition
increases metabolism
decreases appetite |
|
|
Term
|
Definition
| instigates much of the insulin-resistant phenotype of T2DM |
|
|
Term
| What is the normal blood glucose level? |
|
Definition
fasting: 90
post-prandial: 130-150
(diabetics baseline may be 300-350) |
|
|
Term
| What is the consequence of insulin overdose? |
|
Definition
| hypoglycemia => coma & death |
|
|
Term
| How do diabetic patients self-monitor their blood glucose levels? |
|
Definition
|
|
Term
| What allows for a long-term measure of average blood glucose levels (1-2 mo. measure of Tx efficiency)? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| When is glucagon secreted? |
|
Definition
| in response to low glucose levels |
|
|
Term
| What is insulin composed of? |
|
Definition
|
|
Term
| What is insulin derived from? |
|
Definition
| proteolytic processing of proinsulin |
|
|
Term
|
Definition
uptake, utilixation, & storage of glucose, aa & fat after a meal (mostly in liver, muscle, & fat cells)
depress hydrolysis of glycogen to glucose and catabolism of fatty acids & aa coupled with gluconeogenesis |
|
|
Term
Effect
Insulin
Carbohydrate metabolism |
|
Definition
1) increase cellular uptake of glucose via increasing activity of cell surface glucose transporters
2) decrease glycogenolysis (esp. in liver)
3) decrease gluconeogenesis from non-carbohydrate sources |
|
|
Term
| What is the key step in insulin-regulated glucose uptake in asipose & muscle cells? |
|
Definition
| tranfer of GLUT4 glucose transporter from an intracellular pool to cell surface membrane |
|
|
Term
Effect
insulin
on fat metabolism |
|
Definition
1)increases fatty acid & triglyceride synthesis in liver & asipose tissue
2) decreases utilization of fatty acids by lipolysis |
|
|
Term
Effect
insulin
on protein metabolism |
|
Definition
1) increases protein synthesis (esp. in muscle)
2) decreases the wasting catabolism of protein & aa |
|
|
Term
|
Definition
| binds to receptor which activates intracellular domain TK => intracellular cascade |
|
|
Term
| Where does the removal of the C peptide of proinsulin occur? |
|
Definition
| as proinsulin passes thru the Golgi apparatus |
|
|
Term
| What happens to the mature insulin & C peptide after cleavage? |
|
Definition
| stored together for release |
|
|
Term
| What mediates insulin secretion? |
|
Definition
| metabolic action of the glucose in the pancreatic β cells |
|
|
Term
| What happens when the β cells detect elevated glucose? |
|
Definition
| increased uptake => increased catabolism => increased levels of cytoplasmic ATP => depolarization by K+ channel regulated by ATP => opening of plasma membrane Ca2+ channel => Ca2+ influx => exocytotic release of insulin |
|
|
Term
|
Definition
|
|
Term
| Where is insulin degradated? |
|
Definition
| mainly in the liver(first pass metabolism), kidneys, & muscle |
|
|
Term
| How much of insulin in degraded by 1st pass metabolism? |
|
Definition
| ~50% (not: the effect that the liver sees more insulin is NOT replicated in injectible insulin) |
|
|
Term
| What is the primary target of glucagon? |
|
Definition
| liver - to stimulate glycogenolysis & gluconeogenesis => increased blood glucose levels |
|
|
Term
| What is the only clinical use of glucagon? |
|
Definition
| reversal of diabetic coma due to insulin OD when administration of oral glucose is not possible |
|
|
Term
| Though normal regulation of insulin can be achieved by insulin Tx, how do diabetics control diabetes? |
|
Definition
| multiple daily injections of different insulin preparations |
|
|
Term
| What is the treatment principle of insulin? |
|
Definition
| provide different insulin amounts throughout the day as needed by a panel of insulin preparations having different solubilities |
|
|
Term
| What is the difference b/w soluble & less soluble insulin? |
|
Definition
soluble: rapidly absorbed into the blood
insoluble: leach away from the subq injection site more slowly => baseline insulin levels |
|
|
Term
What insulin is used for rapid absorption?
intermediate?
slow? |
|
Definition
rapid: soluble/regular
intermediate: NPH/Lenate
slow: ultralente |
|
|
Term
| Which 3 insulins are the most rapid acting (most soluble)? |
|
Definition
1) Lisopro (humalog)
2) aspart (novolog)
3) glulysine |
|
|
Term
| What is the "peakless" insulin (ults=long acting)? |
|
Definition
|
|
Term
| Do the different insulin preparations have different binding/efficacy as well as solubility? |
|
Definition
|
|
Term
| Which insulin preparations are mixed with proatmine to slow absorption? |
|
Definition
|
|
Term
| Which insulin preparations are mixed in a zinc suspension? |
|
Definition
| Lente insulin & ultralente insulin |
|
|
Term
Typical Tx Regimen
Insulin |
|
Definition
| self-administration of subq injections just before each meal utilizing a mizture of different preparations (rapid & long acting) |
|
|
Term
|
Definition
hypoglycemia Sx:
sweating, tremor, blurred vision, mental confusion => coma => death |
|
|
Term
| What other factors can promote a hypoglycemic state in a diabetic (even with normal insulin dosing)? |
|
Definition
| insufficient food intake, exercise, stress |
|
|
Term
|
Definition
| injesting sugar via glucose tablets or orange juice |
|
|
Term
|
Definition
new insulin replacement therapy with continuous insulin infusion
(SE: inf. at pump penetration site) |
|
|
Term
def
glucose tolerance test |
|
Definition
| changes in blood glucose monitored folloing injestion of a glucose tablet |
|
|
Term
|
Definition
| convenient self-injection system pre-loaded with multiple insulin doses |
|
|
Term
|
Definition
| metforman (previously sulfonylureas) |
|
|
Term
| Does insulin resistance mean a person have T2DM? |
|
Definition
| no, there are individuals with insulin resistance, but are able to compensate for the resistance by over production of insulin |
|
|
Term
|
Definition
| insulin secretogue - stimulate insulin release - requires functional β cells
molecularly: blocks ATP sensitive K+ channels => open Ca2+ channels => insulin release |
|
|
Term
| When glucose enters the β cell, what happens to ATP sensitive K+ channcels? |
|
Definition
| close (=> open Ca2+ channels => insulin release) |
|
|
Term
|
Definition
PO (absorbed thru GI)
T2DM |
|
|
Term
| How many generations are there of sulfonylureas? |
|
Definition
|
|
Term
| What drugs are in the first generation sulfonylureas? |
|
Definition
1) tolbutamide
2) chlopropamide |
|
|
Term
| What is the difference b/w 1st & 2nd generation sulfonylureas? |
|
Definition
| 100x more potent, but more expensive |
|
|
Term
| What drugs are 2nd generation sulfonylureas? |
|
Definition
|
|
Term
| What happens to sulfonylureas in circulation? |
|
Definition
| protein-bound (esp. albumin) |
|
|
Term
Metabolism/Excretion
sulfonylureas |
|
Definition
| liver metabolism, urine metabolite excretion |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| t1/2
glyburide & glipizide |
|
Definition
| 2-4 hrs (tho hypoglycemic effects last 12-24 hrs) |
|
|
Term
|
Definition
| 1) hypoglycemia (esp. those with long t1/2)
2) stimulates appetite (may contribute to underlying obesity)
3) fairly high failure rate due to pancreatic insufficency (need to be supplemented or replaced at this point) |
|
|
Term
| What are the 2 glintinides? |
|
Definition
1) repaglinide
2) nateglinide |
|
|
Term
|
Definition
| ~ sulfonylureas (induced insulin secretion via K+ channel closure) |
|
|
Term
| What is the advantage of glintides over sulfonylureas? |
|
Definition
| flexible dosing and avoids much of the potential for hypoglycemia associated with longer duration sulfonylureas |
|
|
Term
| What is the most perscribed anti-diabetic? |
|
Definition
|
|
Term
| What types of drug is metformin? |
|
Definition
|
|
Term
|
Definition
DOES NOT stimulate insulin release (therefore no risk for hypoglycemia)
1) reduce glucose output from liver (reduced gluconeogenesis)
2) enhanced insulin action of peripheral tissue (reduced insulin resistance)
molecularly: activates AMP kinase |
|
|
Term
|
Definition
PO for T2DM
can be co-administered with sulfonylureas for synergy |
|
|
Term
| What are the 3 advantages of metformin over sulfonylureas? |
|
Definition
1) no risk of hypoglycemia
2) reduces insulin resistance (Tx underlying cause of disease)
3) does not increase appetite - associated anorexic effect (potential benefit for Tx) |
|
|
Term
|
Definition
lactic acidosis (sm. risk, but potentially fatal)
GI Sx (N/V/D, anorexia, abdominal discomfort) |
|
|
Term
|
Definition
| kidney diseases (increased risk for lactic acidosis) |
|
|
Term
| What are the 2 thiazolidinediones (glitazones)? |
|
Definition
1) rosiglitazone
2) pioglitazone |
|
|
Term
|
Definition
reduction of insulin resistance & blood glucose => potentiation of insulin action of peripheral tissue
molecularly: antagonist ligand for PPARγ expressed in white adipocytes - nuclear receptor of steroid receptor family |
|
|
Term
|
Definition
PO for T2DM
may be comined with insulin, metformin, or sulfonylureas |
|
|
Term
|
Definition
1) CV - MI risk
2) hepatotoxicity |
|
|
Term
| Does oral or IV glucose produce the greater or the same insulin response? |
|
Definition
|
|
Term
| Why does oral glucose induce a 3-4x greater insulin response than IV glucose? |
|
Definition
| induces release of gut hormones GLP-1(glucagon like peptide) & GIP (glucose dependent insulinotropic peptide) that acts on β cells to amplify the insulin release |
|
|
Term
|
Definition
| drugs that exploit the endocrinology of GLP1 & GIP for Tx of T2DM |
|
|
Term
| What are the 2 incretins? |
|
Definition
1) Exenatide
2) DPP-4 inhibitors |
|
|
Term
| Why do incretins not have the risk of hypoglycemia like the sulfonylureas? |
|
Definition
| they induce insulin secretion, but only in the presence of high glucose (i.e. just enhance the body's natural response to glucose) |
|
|
Term
| Why is GLP1's use as an anti-diabetic drug limitied? |
|
Definition
| short half life in circulation due to DDP4 mediated degradation |
|
|
Term
|
Definition
| GLP1 homolog (derived from Gila monster sailvary glands - longer t1/2 since resistant to DPP4 protease) |
|
|
Term
|
Definition
1) induces insulin release
2) depresses glucagon release
(1+2 => blunted post-prandial glucose surge)
3) delays gastric emptying (=> blunts appetite => significant weight loss) |
|
|
Term
|
Definition
| combination with sulfonylureas or metformin for T2DM (2x daily injections) |
|
|
Term
|
Definition
Nausea (tolerance develops)
increased risk of hypoglycemia with sulfonylureas |
|
|
Term
|
Definition
|
|
Term
|
Definition
| increased t1/2 & action of endogenous GLP1 |
|
|
Term
| What is the benefit of sitagliptin of exenatide? |
|
Definition
PO vs. injection
no GI Sx
(tho no wt. loss benefit) |
|
|
Term
| What do all PO anti-diabetic drugs depend on? |
|
Definition
| endogenous insulin production ∴ as β pancreatic cells fail, parenteral insulin may be needed toward the end of disease progression |
|
|
Term
| What are the 2 α-Glucosidase inhibitors? |
|
Definition
|
|
Term
MOA
α-glucosidase inhibitors |
|
Definition
| reduce intestinal absorption of glucose by slowing intestinal degradation of starches & sucrose => blunting of post-prandial spiking of blood glucose levels |
|
|
Term
|
Definition
| not effective as a monotherapy, but can be used in combination with other PO anti-diabetic drugs when there is a failure to adequately control post-mealtime glucose spikes in T2DM |
|
|
Term
SE
α-glucosidase inhibitors |
|
Definition
flatulence
diarrhea
(due to undigested carbohydrates that reach the lower intestine where gases are produced by bacterial flora) |
|
|
Term
|
Definition
1) set the body's basal metabolic rate
2) functions in development
3) FBI of own biosynthesis |
|
|
Term
| Thru what 2 hormones does the thyroid set the body's basal metabolic rate? |
|
Definition
1) thyroxine (T4)
2) triiodothryronine (T3) |
|
|
Term
| What are the 2 main thyroid disorders that can result from deficient or excessive hormone secretion? |
|
Definition
| hypo- or hyper- theyroidism |
|
|
Term
| What 2 types of pharacological agents are there for thyroid disorders? |
|
Definition
1) Thyroid hormones (T3 & T4) - hormone replacement for hypothyroidism
2) Anti-thyroid agents (thiureylenes) - Tx for hyperthyroidism |
|
|
Term
|
Definition
| increase basal metabolic rate by increasing:
1) respiration (increased O2 utilization & CO2 production)
2) carbohydrate metabolism
3) fat metabolism
4) body temp
5) HR
6) neuromuscular activity |
|
|
Term
| What occurs in development in the absence of thyroid hormones? |
|
Definition
| Cretinism (MR & dwarfism) |
|
|
Term
| How do thyroid hormones act as self-FBI? |
|
Definition
| act on anterior pituitary to depress release of peptide hormone TSH (thyroid stimulating hormone) or thyrotropin |
|
|
Term
What is the ultimate sensor & controller of the body's basal metabolic rate?
Why? |
|
Definition
| hypothalamus - it stimulates TRH (thyrotropin releasing hormone) that acts on anterior pituitary to stimulate TSH release |
|
|
Term
| What mediates the actions of T3 & T4? |
|
Definition
| THR (thyroid hormone receptor) - a hormone regulated transcription factor (member of the steroid receptor class) |
|
|
Term
Effect
T3 or T4 binding THR |
|
Definition
| induces the transcription of particular hormone-responsive genes via binding of the receptor to specific DNA sequences |
|
|
Term
| Does THR have a preference for one thyroid hormone over ther other? |
|
Definition
| yes, T3 has 10x higher binding affinity |
|
|
Term
| Is there a difference if T3 or T4 binds to THR? |
|
Definition
| yes, T3 only seems to activate THR |
|
|
Term
| Does THR have a preference for one thyroid hormone over ther other? |
|
Definition
| yes, T3 has 10x higher binding affinity (b/c T3 is the active hormone where T4 is the prohormone) |
|
|
Term
| Does thyroid hormone regulate the body minute to minute like insulin? |
|
Definition
| no, effects are long term |
|
|
Term
| What reflects the long-term effects of T3 & T4? |
|
Definition
| long half lives & large steady-state pools or hormone available in tyroid & circulation |
|
|
Term
| How are large quantities of thyroid hormone stored in the thyroid? |
|
Definition
| as thyroglobulin (biosynthetic precursor) |
|
|
Term
| When released, is more T3 or T4 released from the thyroid? |
|
Definition
| T4 (~80% of all released hormones) |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| How do both T3 & T4 circulate the blood? |
|
Definition
| >99% are bound to TBG (thyroxine binding globulin) - accounts for the long half lives since when bound, not subject to metabolic degradation (T4 is 10x more tightly bound to TBG ∴ longer half life) |
|
|
Term
| Is free or bound thryoid hormone able to enter cell? |
|
Definition
|
|
Term
| What enzyme converts T4 to T3? |
|
Definition
| deiodinase enzymes in target tissue |
|
|
Term
| What enzymes convert T4 to reverse T3 (inactive T3)? |
|
Definition
| deiodinase enzymes in target tissues |
|
|
Term
| Where is tyroxine synthesized? |
|
Definition
|
|
Term
| Where is triiodothyronine synthesized? |
|
Definition
| hyroid & peripheral tissues |
|
|
Term
|
Definition
|
|
Term
| What is the key element in thyroid hormone synthesis? |
|
Definition
| iodine (I- iodide form needed) |
|
|
Term
| How is I- uptaken into thyroid follicles? |
|
Definition
| energy-dependent direct & rapid uptake from circulation (can handle [250x] of circulating iodide) |
|
|
Term
| What damaging form of iodine is aslo readily uptaken by the thyroid? |
|
Definition
| resioisotopes (common by products of nuclear reactor accidents) |
|
|
Term
| What inhibits iodide uptake? |
|
Definition
| thiocyanate (SCN-) & perchlorate (ClO4-) |
|
|
Term
| What is the main natural source of dietary iodine? |
|
Definition
|
|
Term
Effect
dietary iodine insufficiency |
|
Definition
|
|
Term
|
Definition
| enlargement of thyroid gland that occurs as the gland tried to scavenge more iodide from circulation |
|
|
Term
| What happens to iodide once it is absorbed by the thyroid follicles? |
|
Definition
| further oxidized & attached to tyrosine |
|
|
Term
| What enzyme is needed for the oxidization & attachment to tyrosine of iodide in the thyroid follicle? |
|
Definition
|
|
Term
| Where do the tyrosine substrates of iodination come from? |
|
Definition
| tyrosine residues resident in the protein thyroglobulin |
|
|
Term
| How many tyrosine residues are available in thyroglobulin? |
|
Definition
|
|
Term
| How many T4 molecules are produced per molecule of tyroglobulin? |
|
Definition
|
|
Term
| What is the 2 step process of iodination of tyrosine? |
|
Definition
1) iodine added at the 3 position to make MIT (monoiodotyrosine)
2) second iodine added to the 5 position to give DIT (diiodotyrosine) |
|
|
Term
| What is the target of the thioureylenes? |
|
Definition
| the steps of iodination of tyrosine |
|
|
Term
|
Definition
| from 2 DIT residues combining in a condensation reaction (takes place while residues remain attached to thyroglobulin backbone) |
|
|
Term
| Where is the iodine modified thyroglobulin stored? |
|
Definition
| secreted into an enclosed extracellular space (colloid) |
|
|
Term
| How is T3 synthesized in the thyroid? |
|
Definition
| MIT + DIT combine in a condensation reaction |
|
|
Term
| What happens to the newly formed T3 & T4 moieties in the thyroid? |
|
Definition
| remain attached to the thyroglobulin stored in colloid |
|
|
Term
| How are T3 & T4 excreted? |
|
Definition
| uptake of colloid from lumunal space via phagocytosis => iodinated thyroglobulin hydrolyzed down to component aa & resident T3 & T4 molecules released & secreted into the blood stream |
|
|
Term
| What is the role of TSH in hormone production/release? |
|
Definition
stimulated all aspects:
iodide uptake & organification
lysosomal release from thyroglobulin
growth of thyroid gland itself (=> goiter in hypo- & hyper- thyroidism) |
|
|
Term
|
Definition
1) TSH stimulation
2) stimulatory TSH mimetic Abs (Graves' disease) |
|
|
Term
| What can induce the hypothalamust to produce more TRH? |
|
Definition
|
|
Term
| Where do T3 & T4 exert their FBI? |
|
Definition
|
|
Term
| where do thioureylenes exert their anti-thyroid effects? |
|
Definition
|
|
Term
| What are the 3 thyroid function tests? |
|
Definition
1) free T3 & T4 levels
2) FTI (free thyroxine index)
3) TSH level |
|
|
Term
| Which thyroid function tests are easily measured? |
|
Definition
|
|
Term
def
free thyroxine index (FTI) |
|
Definition
| indirect assessment to determine amount of free T4 (hypo- & hyper- thyroidism both have small deflections of FTI) |
|
|
Term
| What is the advantage to TSH level testing? |
|
Definition
TSH levels are tightly & quantitively related to free T4
small changes in FT4 are amplified into large deflections of TSH level (best measure of tyroid function) |
|
|
Term
Thyroid Function Test Results
hyperthyroidism |
|
Definition
|
|
Term
Thyroid Function Test Results
hypothyroidism |
|
Definition
|
|
Term
| What are the most common forms for hypo- & hyper- thyroidism resultant from? |
|
Definition
|
|
Term
|
Definition
1) lack of facial affect
2) cold & dry skin
3) lowered CO
4) hisky, low-pitched speach
5) weakness
6) diminished appetite
7) impaired mentation
8) cold intolerance
9) cretinism |
|
|
Term
| When is cretinism observed? |
|
Definition
| when hypothyroidism is present from birth |
|
|
Term
| When are thyroid hormones more important in development? |
|
Definition
| weeks prior & weeks after delivery |
|
|
Term
| What are the 3 causes of hypothyroidism? |
|
Definition
1) Hasimoto's thryoiditis (most common cause) - autoimmune
2) dietary deficiency
3) destruction of thyroid (surgey, trauma, radioactive iodine, long-term progression of grave's) |
|
|
Term
|
Definition
Dietary deficiency: supplementation with sodium iodide
Other: tyroxine replacement (PO) |
|
|
Term
|
Definition
1) maternal or post-natal iodide insufficiency
2) athyreosis (failed thyroid development)
3) pituitary or hypothalamic defect
4) genetic defect in thyroid hormone biosynthetic pathway |
|
|
Term
|
Definition
1) newborn screening (w/in 1-4 days of birth)
2) T4 replacement
3) maternal pre-natal screening |
|
|
Term
|
Definition
|
|
Term
|
Definition
| synthetic T3 (tho not generally used) |
|
|
Term
| Why is T4 typically given over T3? |
|
Definition
1) cheaper
2) makes T3 peripherally
3) longer half life
4) less doses needed (once daily) |
|
|
Term
|
Definition
| hypothyroidic coma (due to greater potency) |
|
|
Term
|
Definition
| OD of T4 => hyperthyroid Sx |
|
|
Term
Sx
thryotoxicosis (hyperthyroidism) |
|
Definition
1) exopthalamus (protrusion of eyes)
2) goiter
3) skin is warm, flushed, & moist
4) tachycardia
5) muscle tremor
6) insomnia, anxiety, apprehension
7) "thyroid storm" |
|
|
Term
|
Definition
sudden acute exacerbation of thyrotoxicosis.
Life threatening & may include severe tachycardia with atrial fibrillation => heart failure |
|
|
Term
| What are the 3 causes of hyperthyroidism? |
|
Definition
1) Graves' disease (most common cause) - autoimmune Ab to TSH R
2) toxic adenoma (tumor of pituitary TSH secretion)
3) toxic multinodular goiter |
|
|
Term
| What causes ecopthalmus in hyperthyroidism? |
|
Definition
| autoimmune infiltration of periorbital tissue (may worsen upon control of hyperthyroidism) |
|
|
Term
|
Definition
1) anti-thyroid drugs (block hormone synthesis)
2) ablation of thyroid gland with radioactive iodide
3) surgical resection of thyroid |
|
|
Term
|
Definition
| moving patient to hypothyroid state, but this SE can easily be treated with T4 |
|
|
Term
| What are the 3 main thioureylenes? |
|
Definition
1) methimazole
2) peopylthiouracil |
|
|
Term
|
Definition
| decrease synthesis of thyroid hormones thru inhibition of tyrosyl iosination via competitive inhibition of thyroid perioxidase |
|
|
Term
Is methimazole or propylthiouracil the DOC?
Why? |
|
Definition
| methimazole due to once daily dosing and long duration of action (40 hr) |
|
|
Term
| What is the advantage of propylthiouracil? |
|
Definition
| added MOA of inhibiting peripheral de-iodination of T3 to T4 |
|
|
Term
|
Definition
thyroid storm
long-term stabilization of hyperthyroidism |
|
|
Term
|
Definition
PO administration
1) rapid inactivation of hormone biosynthesis
2) long lag b/w administration & relief of Sx (2-3 months) |
|
|
Term
| What causes the long lag of Sx relief in anti-thyroid therapy? |
|
Definition
1) slow turnover of pre-existing circulating thyroid hormone
2) large thyroid stores of pre-existing hormone
=> Sx relief only after stores are depleted |
|
|
Term
|
Definition
| reversible cholestatic jaundice |
|
|
Term
|
Definition
severe hepatic toxicity
hepatic failure |
|
|
Term
| What is the current preferred & most common Tx for Graves' Disease? |
|
Definition
| partial thyroid destruction with radioactive iodine |
|
|
Term
|
Definition
| PO 131I is used.
It emits both β particles & γ rays with a radioactive half life of 8 days => specific thyroid destructive effects with little or no peripheral tissue destruction
no established cancer, infertility, or birth defects (tho still not used in children or women of child bearing age) |
|
|
Term
|
Definition
| anti-thyroid drugs (will inhibit the incorporation of iodine into the thyroglobulin) |
|
|
Term
|
Definition
| may induce hypothyroidism depending on amount of thyroid destruction (Tx by T4) |
|
|
Term
| What is a paradoxical Tx of hyperthyroidism? |
|
Definition
|
|
Term
MOA
high dose iodide for hyperthyroidism |
|
Definition
1) rapid inhibition of thyroid hormone release
2) reduces size & vascularity of thyroid |
|
|
Term
SOA
high dose iodide for hyperthyroidism |
|
Definition
acute only (transient effect long-term)
thyroid storm |
|
|
Term
| What medication can be used off label to elicit some relief of hyperthyroidism Sx? |
|
Definition
| propranolol & other β blockers |
|
|
Term
| What Sx particularly are relieved of hyperthyroidism from β blockers s.a. propranolol? |
|
Definition
1) tachycardia
2) arrythmias
3) tremors
4) general agitation |
|
|
Term
SOA
β blockers s.a. propranolol in hyperthyroid Tx |
|
Definition
1) prolonges lag perioid following initiation of thioureylene therapy
2) immediate control of Sx of thyroid storm |
|
|
Term
|
Definition
| arrythmias (can be fatal) |
|
|
Term
Tx
symptomatic bradyarrythmias |
|
Definition
|
|
Term
Tx
ectopic beats & short episodes of tachycardia |
|
Definition
none
unless symptomatic - β blockers DOc |
|
|
Term
| What causes regular narrow complex tachcardias? |
|
Definition
| AV nodal reentry or AV reentry dues to an accessory pathway |
|
|
Term
Tx
regular narrow complex tachycardias |
|
Definition
AV nodal blockade using adenosine
iv verapamil
diltiazem
β blocker |
|
|
Term
|
Definition
anticoagulation
ventricular rate control
drug therapy to maintain sinus rhythm (amiodarone DOC or sotalol)
To prevent reoccurance:
ACEIs
angiotensin receptor blockers
statins |
|
|
Term
Tx
ventricular tachycardia |
|
Definition
transthoracic defibrillation
IV drugs
DC cardioversion
ICD (implantable cardioverter/defibrillator) |
|
|
Term
|
Definition
infection
painful discharges
potential malfunction => potential major complications of removal of implant |
|
|
Term
def
RF (radiofrequency) catgeter ablation |
|
Definition
| small area of tissue responsible for genesis or mainentance of an arryhtmia are identified & destroyed |
|
|
Term
DOC
prevention of atrial fibrillation & ventricular tachycardia or fibrillation |
|
Definition
|
|
Term
| what has amiodarone surpassed as the DOC in cardiac arrest situations? |
|
Definition
|
|
Term
Effect
amiodarone on an atrial fibrillation |
|
Definition
| converts it to a sinus rhythm & slows ventricular response |
|
|
Term
|
Definition
CYP3A4 inhibitor
CI: in drugs that prolong QT interval |
|
|
Term
SOA
β blockers in arrythmias |
|
Definition
1)control ventricular rate in atrial fibrillation or flutter
2)terminate & prevent recurrences of paryoxysmal supraventricular tachycardias
3) safer, tho less effective in suppressing aymoptomatic premature ventricular complexes |
|
|
Term
| Which β blocker is used to control the ventricular response in atrial fibrillation or flutter (esp. after cardiac surgery) |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Why should caution be given when withdrawing β blockers from a patient with angina pectoris? |
|
Definition
| may precipitate a myocardial ischemia or cardiac arrythmia |
|
|
Term
| Which arrythmatic syndrome are β blockers CI? |
|
Definition
| wolff-parkinson-white syndrome |
|
|
Term
Effect
Ca Channel blockers on arrythmias |
|
Definition
| prolong AV nodal refractoriness |
|
|
Term
SOA
Ca Channel blockers for arrythmias |
|
Definition
10terminating & preventing recurrant reentrant supraventricular tachycardias
2)slowing the ventricular rate in atrial fibrillation or flutter |
|
|
Term
|
Definition
hypotension
bradycardia
(esp. in concurrent cardiodeppressants, underlying heart disease, sustained ventricular tachycardia) |
|
|
Term
| Which 2 Ca Channel blockers can raise Digoxin levels? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| Wolff-Parkinson-White syndrome |
|
|
Term
SOA
dihydropyridine Ca Channel blockers in arrythmias |
|
Definition
| no antiarrythmic activity |
|
|
Term
SOA
adenosine in arrythmias |
|
Definition
terminating superventricular arrythmias
(not multifocal atrial tachycardia or atrial fibrillation/flutter0 |
|
|
Term
|
Definition
heart block
hypotension
transient atrial fibrillation
nonsustained ventricular tachycardia |
|
|
Term
| Why is adenosine preferred to diltiazem & verapamil (despite SE)? |
|
Definition
| disappears within seconds |
|
|
Term
| What happens when a person with Wolff-Parkinson-white syndrome is given adenosine while in atrial fibrillation/flutter? |
|
Definition
| extremely rapid ventricular rates |
|
|
Term
Effect
sotalol, dofetilide, ibutilide |
|
Definition
prolong cardiac refractoriness
increase QT interval |
|
|
Term
SE
sotalol, dofetilide, ibutilide |
|
Definition
|
|
Term
| What other MOA does sotalol use? |
|
Definition
| non-selective β blocker effective in prevention of recurrent atrial fibrillation |
|
|
Term
|
Definition
β blockade Sx & dose related prolongation of QT interval
risk of torsades de pointes
(caution with renal disease) |
|
|
Term
|
Definition
convert atrial fibrillation & to maintain sinus rhythm after cardio convertion
(NOT ventricular arrythmias or paroxysmal atrial fibrillation) |
|
|
Term
|
Definition
torsades de pointes
QT prolongation
changes in renal function |
|
|
Term
|
Definition
many - esp. others that prolong QT interval
CI: verapamil (increases [plasma]) |
|
|
Term
|
Definition
| termination of atrial fibrillation/flutter |
|
|
Term
|
Definition
|
|
Term
Effect
flecainide & propafenone |
|
Definition
| decrease cardiac conduction velocity |
|
|
Term
SOA
felcainide & propafenone |
|
Definition
1) ventricular arrythmias
2) prevent episodes of paroxysmal supraventricular tachycardia & atrial fibrillation |
|
|
Term
SE
flecainide & propafenone |
|
Definition
| aggrevate or precipitate arrythmias (esp. in patients with underlying heart disease & sustained ventricular tachycardia) |
|
|
Term
Additional MOA
propafenone |
|
Definition
| low-degree β blocking activity |
|
|
Term
| What is usually given prior to flecainide or propafenone? |
|
Definition
| AV nodal blocking agents s.a. digoxin, verapamil, or a β blocker (due to increased centricular response by fle & porp) |
|
|
Term
|
Definition
| digoxin (raises to toxic levels) |
|
|
Term
SOA
quinidine, procainamide, disopyramide |
|
Definition
| patients not tolerating other agents (frequent toxicity0 |
|
|
Term
|
Definition
fever
diarrhea
nausea
granulomatous hepatitis
QT prolongation
torsades de pointes
thrombocytopenia
lupis-like syndrome (rare) |
|
|
Term
|
Definition
|
|
Term
|
Definition
hypotension
fever
rash
ANAs => lupus-like syndrome (disappears upon discontinuation)
agranulocytosis
torsades de pointes
CI; reduced renal function |
|
|
Term
|
Definition
aggrevate heart failure
anticholinergic effects
urinary retention (requires discontinuation)
torsades de pointes |
|
|
Term
| when is digoxin used in arrythmias? |
|
Definition
adjunctive agent to control ventricular response in atrial fibrillation/flutter
terminate some paroxysmal supraventricualr arrythmias (other drugs more effective) |
|
|
Term
|
Definition
| may accelerate ventricular response during atrial fibrillation in patients with bypass tracts => CI: wolff-parkinson-white syndrome |
|
|
Term
SOA
Magnesium sulfate for arrythmias |
|
Definition
preventing recurrent drug-induces torsades de pointes & some arrythmias related to digitalis toxicity
alternative to amiodarone for shock-refactory cardiac arrest (esp. for suspended torsades de pointes or hypomagnesemia0 |
|
|
Term
SOA
lidocaine for arrythmias |
|
Definition
| alternative to amiodarone as a first line therapy for ventricular arrythmias causing cardiac arrest |
|
|
Term
|
Definition
| orally effective cogener of lidocaine |
|
|
Term
|
Definition
Nausea
termor
(reduced when given with food) |
|
|
Term
| What causes chronic systolic heart failure? |
|
Definition
| left ventricular ejection fraction <40% (symptomatic is usually higher) |
|
|
Term
|
Definition
|
|
Term
| What comorbid conditions are patints with heart failure and preserved systolic function treated for? |
|
Definition
|
|
Term
Tx
chronic systolic heart failure |
|
Definition
ACEI + β blocker 9unless special CI)
9+diuretic if volume overload) |
|
|
Term
|
Definition
chronic systolic heart failure
MI Hx
patients with high risk for heart failure b/c of atherosclerotic disease, obesity, DM, or HTN |
|
|
Term
|
Definition
1)co-administration with a diuretic in patients with fluid retention
2)low systolic Bp (<90)
3)creatinine levels high
4)potassium levels high
5)cI: Hx of angioedema or bilateral renal artery stenosis or pregnancy |
|
|
Term
|
Definition
cough
angioedema
hyperkalemia
hypotension
renal insufficiency
9caused by inhibition of breakdown of kinis, suppression of angiotensin II, and reduced aldosterone production) |
|
|
Term
| What drug type also has comparable efficacy to ACEIs? |
|
Definition
| angiotensin receptor blockers |
|
|
Term
| when should β blockers be given in addition to ACEIs? |
|
Definition
sympotmatic systolic heart failure
asymptomatic patients with Hx of MI |
|
|
Term
Cautions
β blockers in heart failure |
|
Definition
fatigue
hypotension
fluid retention
worsening heart failure |
|
|
Term
| Which β blocker is least effective? |
|
Definition
|
|
Term
|
Definition
| asthma or severe bradycardia |
|
|
Term
| what are the 2 aldosterone antagonists? |
|
Definition
1) spironolactone
2) eplerenone |
|
|
Term
SOA
aldosterone antagonists |
|
Definition
co-administered for severe systolic heart failure
acute MI from left ventricular systolic dysfunction & heart failure |
|
|
Term
SE
aldosterone antagonists |
|
Definition
hyperkalemia (esp. with renal impairment, ACEIs, potassium supplements)
anti-adronergic activity => painful gynecomastia & erectile dysfunction and menstrual irregularities (less so with eplerenone) |
|
|
Term
| What are the 2 vasodilators that can be used for pateitns who cannot tolerate an ACEI or angiotensin receptor blocker? |
|
Definition
hydalazine
isosorbide dinitrate |
|
|
Term
SE
hydralazine/isosorbide dinitrate |
|
Definition
headache
dizziness
tachycardia, peripheral neuritis, lupus-like suyndrome(hydralazine) |
|
|
Term
CI
hydralazine/isosorbide dinitrate |
|
Definition
| phosphodiesterase inhibitor due to risk of additive hypotension |
|
|
Term
| Why are diuretics usually given concurrently in heart failure? |
|
Definition
| most patients with heart failure have fluid retention => Sx relief |
|
|
Term
| Which 3 diuretics work on the loop of henle? |
|
Definition
furosemide
bumetanide
torsemide |
|
|
Term
| Are diuretics that work of the loop of henle or thiazide diuretics more effective in heart failure? |
|
Definition
|
|
Term
| Where do thiazide diuretics (s.a. hydrochlorothiazide) work? |
|
Definition
|
|
Term
| When can a person experience diuretics resistance? |
|
Definition
| consume large amounts of sodium or medications DDI (s.a. NSAIDs0 or if heart failure progresses |
|
|
Term
|
Definition
concurrent use of 2 diuretics
addition of aldosterone antagonist |
|
|
Term
|
Definition
|
|
Term
Effect
digoxin on heart failure |
|
Definition
decrease Sx
increase exercise tolerance
(doesnt increase survival) |
|
|
Term
|
Definition
conduction disturbances
cardiac arrythmias
nausea
vomiting
confusion
visual disturbances |
|
|
Term
|
Definition
|
|
Term
| What are the 2 most widely used thiazide diuretics? |
|
Definition
1) hydrochlorothiazide
2) chlorthalidone |
|
|
Term
| Which thiazide diuretics is more potent with a longer duration of action? |
|
Definition
|
|
Term
| Which thiazide diuretic is safe in those with renal failure? |
|
Definition
|
|
Term
| When are loop diuretics s.a. furosemide more effective in lowerin BP? |
|
Definition
| moderate to severe renal insufficiency |
|
|
Term
| What diuretic can be used in those allergic to sulfonamides? |
|
Definition
|
|
Term
| What are the 4 potassium sparing diuretics? |
|
Definition
1) amiloride
2) triamterene
3) spironolactone
4) eplernone |
|
|
Term
| When are potassium sparkin diuretics s.a. amiloride & triamterene used for HTN? |
|
Definition
| to prevent/correct hypokalemia with other diuretics |
|
|
Term
Caution
potassium sparing diuretics |
|
Definition
renal impairment
decrease aldosterone secretion (ACEIs & ARBs, β blockers, & direct renin inhibitors) |
|
|
Term
|
Definition
|
|
Term
|
Definition
| mineralcorticoid receptor antagonist |
|
|
Term
|
Definition
|
|
Term
| What must β blockers be combined with to be more effective in african american patients? |
|
Definition
| thiazide diuretic or Ca Channel blocker |
|
|
Term
| Are ARBs (angiotensin receptor blockers) more or less effective than ACEIs? |
|
Definition
| as effective (with fewer SE) |
|
|
Term
|
Definition
1_ irbesartan
2) isartan
3) valsartan
4) candesartan
5) telmisartan
("-sartans") |
|
|
Term
| What is the first direct renin inhibitor? |
|
Definition
|
|
Term
|
Definition
| can be monotherapy, but more effective when combined with other agents of HTN |
|
|
Term
| When are β blockers a good choice for hTN Tx? |
|
Definition
When another use of a β blocker is indicated s.a.:
migrane
angina pectoris
MI
heart failure |
|
|
Term
| Are β blockers as effective in HTN Tx as other anti-hypertensives? |
|
Definition
|
|
Term
| Which β blocker has participated in most β blocker studies on HTN? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Which 3 β blockers have intrinsic sympathomimetic activity? |
|
Definition
pindolol
acebutolol
penbutolol |
|
|
Term
| When are β blockers with intrinsic sympathomimetic acitivity preferred? |
|
Definition
| patients with symptomatic bradycardia or postural hypotension (since less decrease in HR) |
|
|
Term
|
Definition
| nonselective β blocker with α blocking properties |
|
|
Term
Function
Ca Channel blockers |
|
Definition
| vasodilation => decrease peripheral resistance |
|
|
Term
| Which Ca Channel blockers have an initial reflex tachycardia? |
|
Definition
| dihydropyridines (non-dihydropyridines decrease heart rate) |
|
|
Term
| Why should the non-dihydropyridines s.a. verapamil & diltiazem be used with caution with β blockers? |
|
Definition
1) decrease hR
2) affect AV conduction |
|
|
Term
| What 3 α adrenergic blockers may be used for HTN? |
|
Definition
1) prazisin
2) terazosin
3) doxazosin |
|
|
Term
| Why would an α adrenergic be given over another direct vasodilator (s.a. hydralazine or minoxidil)? |
|
Definition
|
|
Term
|
Definition
postural hypotension
heart failure
stroke
combined CVD
stress incontinence in women |
|
|
Term
| why might a centrl α agonist be used for HTN? |
|
Definition
| decrease sympathetic outflow (tho cant inhibit felex response completely) |
|
|
Term
| What are the 4 central α agonists? |
|
Definition
1) clonidine
2) guanabenz
3) gunafacine
4) methyldopa |
|
|
Term
SE
central α adrenergic agonists |
|
Definition
sedation
dry mouth
erectile dysfunction |
|
|
Term
|
Definition
reflex tachycardia
rare - orthostatic hypotension |
|
|
Term
What should be co-administered with a direct vasodilator to minimize the reflex in heart rate & CO?
to avoid sodium & water retention? |
|
Definition
β blocker or a centrally acting drug to minimize HR & CO increase
diuretic to avoid sodium & water retention |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| Why should minoxidil be reserved for severe refractory HTN? |
|
Definition
potent & rarely fails to lower bp
causes hirsutism, tachycardia, & severe fluid retention |
|
|
Term
| What peipheral adrenergic neuron antagonist is an effective antihypertensive? |
|
Definition
| reserpine, tho seldom used b/c can cause depression |
|
|
Term
| Why are combination products convenient antihypertensives? |
|
Definition
| many people need more than one drug to control BP |
|
|
Term
| What are good potential first line therapies for HTN? |
|
Definition
1) thiazide diuretic (chlorthalidone)
2) Ca channel blocker or ACEI or ARB |
|
|
Term
| What needs to be managed when treating atrial fibrillation? |
|
Definition
1) ventricular rate control
2) anticoagulation
3) conversion to normal sinus rhythm
4) maintenance of sinus rhythm |
|
|
Term
| What is the first line therapy for anchronic atrial fibrillation? |
|
Definition
| β blockers, non-dihydropyridine Ca Channel blockers and digoxin for ventricular rate control |
|
|
Term
CI
β blockers for atrial fibrillation |
|
Definition
asthma (use a Ca channel blocker instead0
heart failure |
|
|
Term
| How are verapamil & doltiazem effective in slowing ventricular rate? |
|
Definition
| prolong AV nodal refractoriness |
|
|
Term
|
Definition
hypotension
bradycardia
(esp. with concurrent use with other cardiodepressants)
CI: wolff-parkinson-white syndrome since can cause accelerated ventricular response in atrial fibrillation in patients with bypass tracts |
|
|
Term
SOA
digoxin for atrial fibrillation |
|
Definition
as an adjunct to help control ventricular response
DOC for systolic heart failure
CI: wolff-parkinson-white |
|
|
Term
| Why are anticoagulants administered with atrial fibrillation? |
|
Definition
| increased risk of thromboembolic stroke with atrial fibrillation |
|
|
Term
| What anticoagulant is used in patients with atrial fibrillation who've had a previous stroke, transient ischemic attack or non-CNS embolus, or have two or more other risk factors for stroke? |
|
Definition
| warfarin (at this point, the benefits surpass the risk of major bleeding) |
|
|
Term
| What anticoagulant should be used in patients with atrial fibrillation with no history of stroke, TIA or non-CNS embolus, and only one additional risk factor? |
|
Definition
|
|
Term
| What anticoagulant should be given to patients with atrial fibrillation who are ≤75 years old and have no risk factors of stoke? |
|
Definition
|
|
Term
| What is the main drawback of warfarin? |
|
Definition
| need for close monitoring |
|
|
Term
| What accounts for the variability of warfarin potency? |
|
Definition
| genetic variation in the C1 subunit of vitamin K epoxide reductase (VKORC1) & CYP2C9 |
|
|
Term
|
Definition
many
most important for atrial fibrillation:
amiodarone
acetaminophen |
|
|
Term
| Why aren't direct thromin inhibitors given more frequently than warfarin to prevent thromboembolic events with atrial fibrillation when they do not require monitoring or dose adjustments? |
|
Definition
| must be given parenterally |
|
|
Term
| What other anticoagulant can be used to control throboemboli, but has not been approved in the US yet? |
|
Definition
|
|
Term
| What is the DOC for urgen conversion of atrial fibrillation to normal sinus rhythm? |
|
Definition
|
|
Term
| What are used to maintain normal sinus rhythm? |
|
Definition
| antiarrythmic drugs & catheter ablation |
|
|
Term
Function
antiarrythmics for atrial fibrillation |
|
Definition
| prevent episodes of paroxysmal atrial fibrillation & to maintain sinus rhythm after cardioversion |
|
|
Term
| Which antiarrythmics are used for patients with structurally normal hearts? |
|
Definition
|
|
Term
| Which antiarrythmic is used to maintain normal sinus rhythm in patients with vagally-induced atrial fibrillation? |
|
Definition
|
|
Term
| Which antiarrythmic is used in patients with compromised left ventricular function? |
|
Definition
|
|
Term
| Which antiarrythmic is most effective for maintaining sinus rhythm? |
|
Definition
|
|
Term
|
Definition
| many (some severe) as well as many DDIs |
|
|
Term
| What is the safer, non-iodinated analog of amiodarone? |
|
Definition
| dronedarone (tho less effective) |
|
|
Term
|
Definition
maintains sinus rhythm
imporves Sx, exercise capacity & QOL
(better than antiarrythmics) |
|
|
Term
| What is needed after AV node ablation? |
|
Definition
| permanent pacemaker & anticoagulation therapy |
|
|
Term
| What is often the source of ectopic beats that trigger paroxysmal atrial fibrillation? |
|
Definition
| pulmonary veins (thus ablation here too) |
|
|
Term
SE
pulmonary vein ablation |
|
Definition
pulmonary vein stenosis
left atrial flutter
Rare: atrial performation, cardiac tamponade, thromboembolism, atrioesophageal fistula |
|
|
Term
| What is the standard post-ablation care? |
|
Definition
hospitalized overnight & terted with heparin infusion.
Antiogaulation with warfarin is continued for 2-3 months ± antiarrythmic drug |
|
|
Term
| What is the first priority in treatment of atrial fibrillation? |
|
Definition
|
|
Term
| What are the most commonly used drugs for rate control in atrial fibrillation? |
|
Definition
| β blockers, verapamil, diltiazem, & digoxin |
|
|
Term
| What is the second prioroty in treatment of atrial fibrillation? |
|
Definition
| reduction of thromboemolic risk |
|
|
Term
| When is rhythm control important in atrial fibrillation? |
|
Definition
| persistently symptomatic patients |
|
|
Term
| What are the 3 options for rhythm control for persistantly symptomatic patients with atrial fibrillation? |
|
Definition
antiarrythmic drugs
electrical cardioversion
RF ablation |
|
|
Term
| What 2 hormones play a vital role in the female reproductive tract? |
|
Definition
|
|
Term
| What is the principal hormone in males? |
|
Definition
|
|
Term
Function
estrogen & progesterone |
|
Definition
preparing the female reproductive tract for reception of sperm & implantation of the fertilized ovum.
many other features of female habitude |
|
|
Term
| Where is testosterone produced in males? |
|
Definition
|
|
Term
| Where are small amounts of testosterone produced in females? |
|
Definition
|
|
Term
| Where are the gonodal hormones subject to FBI thru? |
|
Definition
| hypothalamus & pituitary gland |
|
|
Term
| What drug was the prototype treatment for esttogen receptor-positive breast cancer patients requiring adjuvant Tx after surgical removal of tumor? |
|
Definition
|
|
Term
Function
adjuvant Tx after surgical removal of breast tumor |
|
Definition
| prevent the original breast cancer from returning 7 the development of new cancers in the other breast |
|
|
Term
| What is another adjuvant Tx option for estrogen receptor-positive breast cancer patients? |
|
Definition
|
|
Term
| When are aromatase inhibitors used as an adjuvant? |
|
Definition
| women who have reached menopause |
|
|
Term
| When is tamoxifen used as an adjuvant? |
|
Definition
|
|
Term
| What is the precursor of both corticosteroids & sex hormones? |
|
Definition
|
|
Term
| What is the most potent, naturally occuring estrogen? |
|
Definition
|
|
Term
| What are naturally occuring estrogens conprised of? |
|
Definition
| steroid of 18 C with a phenolic A ring, hydroxy at C3 and β-hydroxy or ketone at position 17 of ring D |
|
|
Term
| What is the principal requirement for selective, high affinity binding to estrogen receptor? |
|
Definition
|
|
Term
| Why is estradiol ineffective when given orally? |
|
Definition
|
|
Term
| How are PO estrogens given if first pass metabolism makes estradiol ineffective? |
|
Definition
| modified derivative s.a. ethinyl estradiol are protected from hepatic inactivation |
|
|
Term
| What was the first synthesized, non-steroidal estrogen? |
|
Definition
|
|
Term
| What is the most important feature of non-steroidal synthetic estrogens? |
|
Definition
| increased bioavailability following PO dose |
|
|
Term
| What are estrogens formed from? |
|
Definition
| androstenedione or testosterone |
|
|
Term
| What catalyzes androstenedione or testosterone -> estrogen reaction? |
|
Definition
| aromatase (CYP-dependent MOA) |
|
|
Term
| Where is the source of estrogen (estradiol) in pre-menopausal women? |
|
Definition
|
|
Term
| Where is the principal source of estrogen in men & postmenopausal women? |
|
Definition
|
|
Term
| What can also produce large quantities of estrogen in pregnancy? |
|
Definition
|
|
Term
|
Definition
| enter cells by passive diffusion, distributes thru the cell & binds nuclear estrogen receptor => binding of specific DNA sequences => regulating transcription of genes |
|
|
Term
| What tissues are estrogen receptors found? |
|
Definition
| estrogen responsive tissue |
|
|
Term
| What happens in female puberty to that is responsible for the physical changes associated with puberty? |
|
Definition
| initial small amount of GnRH, FSH, LH, & estrogen |
|
|
Term
| How are the hormones released at puberty for females? |
|
Definition
| hypothalamus releases gnRH (gonadotropin releasing hormone) in a pulsatile fashion => stimulation of FSH (folicle stimulating hormone) & LH (leutinizing hormone) release => estrogen release |
|
|
Term
| How long after onset of puberty is there sufficient estrogen to produce endometrial changes & menstrual bleeding? |
|
Definition
|
|
Term
| What exerts a FBI on the hypothalamus to limit GnRH => suppression of FSH release from pituitary? |
|
Definition
|
|
Term
| What effect does estrogen have on pituitary LH release? |
|
Definition
| biphasic => midcycle surge of LH (critical for ovulation) |
|
|
Term
| How can menstrual bleeding be induced when the ovaries are non-functional or have been surgically removed? |
|
Definition
administration & subsequent withdrawl of estrogen
1) single large dose or sever weeks of sm. dose
2) threshold dose => mestrual flow even in the absence of estrogen withdrawl
3) induction by preogesterone administration, in absence of estrogen withdrawl |
|
|
Term
| Are estrogens or androgens stronger anabolic agents? |
|
Definition
|
|
Term
| What causes moderate water retention at the latter half of the menstrual cycle? |
|
Definition
| estrogen (can cause water & salt rentention at high doses) |
|
|
Term
| What effect do estrogens have on serum lipids? |
|
Definition
decrease LDLs
increase HDLs |
|
|
Term
| What bad cardio effects are seen due to estrogen? |
|
Definition
| increased HTN due to water & sodium retention |
|
|
Term
| Where are therapeutic estrogens absorbed from? |
|
Definition
| skin, mucous membrane, GI - tho limited effectiveness PO of natural estrogens (1st pass metabolism) |
|
|
Term
| What are the therapeutic uses of estrogen therapy? |
|
Definition
1) oral contraception
2) post menopausal hormone replacement therapy (HRT)
3) primary hypogonadism
4) dysmenorrhea
5) prostate cancer |
|
|
Term
| Does estrogen secretion continue from the ovary following menopause? |
|
Definition
| yes, slow & gradual decline for several years |
|
|
Term
| What are the indications of HRT in postmenopausal women? |
|
Definition
host flashes
sweating
atrophic vaginitis
high risk osteoporosis |
|
|
Term
| Who has the highest risk for osteoporosis? |
|
Definition
| smokers who are think, Caucasian, inactive, with low Ca intake & family Hx |
|
|
Term
| How are estrogen HRT administered? |
|
Definition
| cyclic fashion (3 weeks on, 1 week off - like oral contraceptives) in the smallest dose possible to relieve Sx |
|
|
Term
| What is estrogen HRT after co-administered with? |
|
Definition
|
|
Term
| When are prophylactic effects of estrogen HRT most effective in osteoporosis? |
|
Definition
| Tx started before significant bone loss |
|
|
Term
| Why is prophylactic estrogen HRT not justified prior to significant bone loss? |
|
Definition
1) only ~35% of postemenopausal women affected
2) exercise & Ca also effective
3) potential SE
(more justified in women who have undergone oophorectomy & hysterectomy since endometrial cancer is not an issue) |
|
|
Term
| Why would estrogen be used in primary hypogonadism? |
|
Definition
These patients are estrogen deficient due to ovarian dysgenesis or castration.
Used to stimulate development of secondary sex characteristic areound 11-13y |
|
|
Term
Though dysmenorrhea can be treated by estrogen replacement, what is the DOC?
Why? |
|
Definition
| NSAIDs since the cause is thought to be due to uterine production of prostaglandins |
|
|
Term
| Why might eastrogen (diethylstilbestrol) be used in prostate cancer treatment? |
|
Definition
| In palliative Tx since it can inhibit androgen secretion by its actions on the hypothalamus |
|
|
Term
What is the better alternative to estrogen in the palliative care of prostate cancer?
Why? |
|
Definition
| leuprolide (GnRG analog), same efficacy with less side effects |
|
|
Term
|
Definition
1) most common cause of postmenopausal bleeding (also a Sx of endometrial cancer, so give in cyclic fashion so bleeding occurs on withdrawl)
2) Nausea, breast tenderness, hyperpigmentation, migranes, cholestasia, HTN
3) estrogenic effect in male offspring
4) vaginal tumors in adult female offspring
5) increased risk endomettrial cancer (postmenopausal - decreased with coadministration of progestinal agent)
6) breast cancer (with oral contraceptives)
7) CV risk
8) dementia
9) blood clots |
|
|
Term
| What hormones cease production by ovaries in menopause? |
|
Definition
|
|
Term
|
Definition
1) estrogen dependent neoplasms (s.a. uterine cancer, breast cancer, etc.)
2) undiagnosed genital bleeding, liver diseases, Hx of thromboembolic disorder
3) pregnancy (esp. first trimester) |
|
|
Term
| What are the 2 types of estrogen drug prototypes? |
|
Definition
|
|
Term
| What are the 2 "natural" estrogens? |
|
Definition
1) Estradiol
2) Estradiol salts
3) Conjugated estrogens |
|
|
Term
| What are the 2 synthetic estrogens? |
|
Definition
1) diethylstilbestrol
2) ethinyl estradiol |
|
|
Term
| What are the alternative therapies for managing menopause? |
|
Definition
| botanical products containing or acting like estrogens may provide some benefit (s.a. soy, hops, flax seed, etc) |
|
|
Term
|
Definition
1) competitive antagonist for estrogen receptor
2) inhibitor of estrogen synthesis
3) agents exerting opposite effect (s.a. progestins & androgens) |
|
|
Term
| Of the anti-estrogens, which are the most specific & mostly used for infertility & breast cancer? |
|
Definition
|
|
Term
| What are the 2 most widely used competitive estrogen receptor antagonists? |
|
Definition
1) Tamoxifen
2) clomiphene |
|
|
Term
| How are both tamoxifen & clomiphene metabolically activated? |
|
Definition
| hydroxylation of C4 on the A ring |
|
|
Term
| How can you convert an antiestrogen antagonist like tamoxifen or clomiphene to an agonist? |
|
Definition
trans = antiestrogen
cis = agonist |
|
|
Term
| Why aren't in vitro effects of antiestrogens always predictive of in vivo activity? |
|
Definition
| isomerization can occur after metabolic activation |
|
|
Term
|
Definition
|
|
Term
|
Definition
| diruption of FBI of estrogen on hypothalamus & pituitary => increased ovarian gametogenesis & steriodogenesis |
|
|
Term
DOC
estrogen receptor positive breast cancer |
|
Definition
|
|
Term
| Why is tamoxifen the DOC for estrogen receptor positive breast cancer? |
|
Definition
| low incidence of toxic effects |
|
|
Term
|
Definition
| increased endometrial or uterine cancer |
|
|
Term
| t1/2/absorption
tamoxifen & clomiphene |
|
Definition
5-7 days
readily absorbed from GI |
|
|
Term
| Why is Leuprolide sometimes used as an antiestrogen? |
|
Definition
| [gonadotropin] remain elevated initially, but with continued use, GnRH receptors are desensitized on pituitary gonadotrophs => reversible suppression of gonadotropin & steroid release |
|
|
Term
| What 3 antiestrogens are aromatase inhibitors? |
|
Definition
1) Anastrozole
2) letrozole
3) exemestane |
|
|
Term
|
Definition
| substrate analog that acts as a suicide inhibitor to irreversible inactivate aromatase |
|
|
Term
MOA
letroxole & anastrozole |
|
Definition
| interact reversibly with the heme groups of CYPs |
|
|
Term
Is exemestane steroidal or non-steroidal?
anastrozole?
letrozole? |
|
Definition
exemestane is steroidal
anastrozole & letrozole are non-steroidal |
|
|
Term
| Why is the concentration of E2 in breast carcinoma 10x that of plasma in postmenopausal women? |
|
Definition
| intratumoral aromatase (therefore need for aromatase inhibitors in breast cancer) |
|
|
Term
| What are aromatase inhibitors s.a. letrozole used for in premenopausal women? |
|
Definition
| induction of ovulation in infertility |
|
|
Term
| What is needed to bind to the progesterone receptor? |
|
Definition
|
|
Term
| Where on progentins do substituents greatly affect the biological activity? |
|
Definition
|
|
Term
| What induces progesterone synthesis & secretion? |
|
Definition
| corpus lutem response to LH during 2nd half of menstrual cycle (just prior to ovulation) |
|
|
Term
| How is the corpus luteum sustained if ovum in fertilized? |
|
Definition
| implantation occurs within 7 days & developing trophoblast begins secretion of HCG (humor chorionic gonadotropin) |
|
|
Term
| When does the placenta take over & begin secreting estrogen & progesterone? |
|
Definition
| 2nd or 3rd month of pregnancy |
|
|
Term
|
Definition
1) development of secretory endometrium
2) abrupt withdrawl => menstruation (estrogen also needed)
3) maintaining pregnancy - suppressing menstruation & uterine contractility
4) proliferation of the mammary gland acini in pregnancy
5) increased body temp by 1°C midcycle (prior to ovulation) |
|
|
Term
|
Definition
| diffuse freely into cells => interaction with nuclear progesterone receptor => binding of specific hormone responsive elements => modulation of gene transcription |
|
|
Term
| Where are prgesterone receptors found? |
|
Definition
| primarily in the female resproductive tract (narrow distribution) |
|
|
Term
| Why are prostestins not given PO? |
|
Definition
| readily absorbed, but extensive 1st pass metabolism (tho several are not, and therefore are effective PO) |
|
|
Term
|
Definition
1) Oral contraceptives
2) HRT
3) Dysfunctional uterine bleeding
4) Dysmenorrhea
5) premenstrual syndrome (no evidence of efficacy, tho still used)
6) endometriosis
7) metastatic endometrial carcinoma |
|
|
Term
| How are progestins used to treat endometriosis? |
|
Definition
Mild case: ~ to dysmenorrhea
more severe (painful extraneous masses & infertility): aimed to cause regression of ectopic endometrial growth - may be continuous for 6-9 mo. |
|
|
Term
| What are the 4 prototypical progestins? |
|
Definition
1) Medroxyprogesterone
2) norethidrone
3) norgestrel
4) ethynodiol |
|
|
Term
| What has the focus of antiprogestins as a MOA been? |
|
Definition
| competitive antagonist (~ to antiestrogen) |
|
|
Term
| What abtiprogestin is a derivatriv of noethindrone? |
|
Definition
|
|
Term
|
Definition
1) suppression of mid-cycle surge of gonadotropins=> prevents ovulation when administered during follicular phase & prevents follicular development
2) blocks release of prostaglandins from endometrium during luteral phase of cycel => blocks menstrual bleeding
3) binds glucocorticoid receptor (also an antiglucocoricoid) => inhibiton of adrenocortical-mediated hypoathalamic feedback => increase adrenal steroidogenesis |
|
|
Term
| Avialability/t1/2
mifepristone |
|
Definition
~25% available PO
half life: ~ 20 hrs |
|
|
Term
|
Definition
1) abortifacient in early pregnancy when co-administered with prostaglandins
2) post-coital contraceptive
3) possible use on progesterone sensitive tumors |
|
|
Term
| What are the 4 types of oral contraceptives? |
|
Definition
1) combination preparations with estrogen & progesterin
2) biphasic & triphasic preparation where estrogen is combined with low amounts of progestin that vary in the cycle
3) subq progestin implants with norgesrtel
4) single-entity preparations (progestin alone or estrogen alone) |
|
|
Term
| What are the disadvantages to subq progestin implants? |
|
Definition
surgical insertion/removal
irregular bleeding typical of progestin alone preparation |
|
|
Term
| Why are progestin alone preparations less popular than other contraceptives? |
|
Definition
lower efficacy (from 99 to 97%)
more irregular cycle |
|
|
Term
| When are estrogen alone preparations still used (i.e. diethylstilbesterol)? |
|
Definition
| "morning after" pill - effect 72 hours post coitus |
|
|
Term
| What has replaces diethylstilbesterol as the "morning after pill"? |
|
Definition
norgestrel/ethinyl estradiol
norgestrel alone
mifepristone |
|
|
Term
| Why was diethylstilbestrol replaced as the "morning after pill"? |
|
Definition
SE (N/V)
potential danger (if ineffective, aborption recommended due to high liklihood of vaginal carcinoma in female offspring) |
|
|
Term
|
Definition
| suppress plasma concentrations of FSH & LH => inhibit ovulation |
|
|
Term
|
Definition
(take with a grain of salt since studies were done on older preparations)
1) CV problems (increased risk with additive factors s.a. smoking, age, HTN)
2) induction/promotion of tumors |
|
|
Term
| Why are the increases in CV risks ok with PO contraceptives? |
|
Definition
| pregnancy is also associated with increased risk |
|
|
Term
| What is the principal androgen? |
|
Definition
|
|
Term
| Where is testosterone synthesized? |
|
Definition
male: testis
female: ovary & adrenal cortex |
|
|
Term
| What 2 classes of steroids can testosterone serve as prohormone for? |
|
Definition
1) 5α-reduced androgens
2) estrogens |
|
|
Term
| What is the net effect of endogenous androgens? |
|
Definition
| sum of testosterone + 5α-reduced androgen + estrogen effects |
|
|
Term
| Why PO testosterone ineffective? |
|
Definition
| extensive 1st pass metabolism |
|
|
Term
| What 2 chemical modifications were made to testosterone to retard the catabolism &/or enhance the androgenic potential? |
|
Definition
1) esterification of 17β-hydroxy => more soluble => slows release & prolongs action (hydrolyzed prior to action)
2) alkylation of 17α => inhibition of hepatic metabolism |
|
|
Term
| What are the 3 periods of life when testosterone is high in males? |
|
Definition
1) embryogenesis when male phenotypic development takes place @ 8 weeks
2) during neonatal period
3) at time of male puberty |
|
|
Term
| What causes the testosterone surge in males at puberty? |
|
Definition
| unknown stimulus => secretion & release of GnRH from hypothalamus => pituitary to secrete LH & FSH in a pulsatile fashion => testicular growth, spermatogenesis & steroidogenesis |
|
|
Term
Function
LH in male puberty |
|
Definition
1) stimulate Leydig cells to stimulate steroidogenesis
2) testosterone produced is needed for spermatogenesis & sperm maturation |
|
|
Term
Function
FSH on male puberty |
|
Definition
1) act on Sertoli cells of seminiferous tubules to promote spermatogenesis
2) augment LH effects on Leydig cells |
|
|
Term
| Is there a FBI for testosterone secretion? |
|
Definition
| yes, testosterone (like estrogen) can suppress LH & FSH release via inhibition of GnRH from hypothalamus |
|
|
Term
Function
testosterone in embryonic development |
|
Definition
| virilize the UG tract => critical role in development of male phenotype |
|
|
Term
Function
testosterone in neonatal period |
|
Definition
|
|
Term
Function
testosterone in male puberty |
|
Definition
| development of male habitus |
|
|
Term
| What anabolic effects (Nitrogen retaining activity) does testosterone have? |
|
Definition
1) decreased urinary excretion of N, K, Na, Cl
2) short induced +Nitrogen blanace that's short lived (1-2 mo) |
|
|
Term
|
Definition
| androgenic steroids that have anabolic effect & adrogenic effect, but response varies dependent on tissue |
|
|
Term
|
Definition
| action mediated thru androgen receptor => binding of specific DNA sequences => modulation of gene transcription |
|
|
Term
|
Definition
1) hypogonadism
2) catabolic states
3) athletic performance
4) stimulation of erythropoiesis
5) carcinoma of the breast |
|
|
Term
| How is hypogonadism recognized? |
|
Definition
| delayed onset of puberty (tho patients should be evaluated for pituitary & gonadal dysfunction) |
|
|
Term
| How should hypogonadism be treated? |
|
Definition
| prolonged therapy with long acting testosterone esters starting at expected time of puberty (may need growth hormone supplementation too) |
|
|
Term
| What happens if hypogonadism therapy is delayed long after expected puberty? |
|
Definition
| variable/incomplete results |
|
|
Term
| What happens if hypogonadism occur post-pubertal? |
|
Definition
| androgen therapy will generally result in return to normal sexual activity |
|
|
Term
| When is a -Nitrogen balance observed? |
|
Definition
| during minor injury or surgery |
|
|
Term
|
Definition
anabolic steroids to correct the -N balance, but no significant therapeutic effect is noticed
must be used in well-nourished patients
no effect in acute illness, severe trauma, protein depletion with chronic illness |
|
|
Term
Effect
anabolic steroids on athletic performance |
|
Definition
1) promote muscle growth or immature boys & women of all ages
2) questionable effect on muscle growth of mature men (androgen receptors are saturated prior to dose, so possible mechanism is blocking catabolic effect of glucocorticoids) |
|
|
Term
|
Definition
| too severe to preclude therapy |
|
|
Term
| What is the difference in hematocrits of males & females? |
|
Definition
| stimulatory effect of testosterone on formation of erythropoietin |
|
|
Term
| When can androgens be used for their stumulation of hematopoiesis? |
|
Definition
1) refractory angina
2) bone marrow failure
3) myelofibrosis
4) renal failure (tho recombinant erythropoietin has largely replaced it here) |
|
|
Term
| Why has testosterone preparations been used in palliative care of breast cancer, esp. in postmenopausal women? |
|
Definition
| MOA unknown, but likely acts as an antiestrogen with low remission rates |
|
|
Term
|
Definition
1) virilizing effects
2) feminizing effects
3) toxicity |
|
|
Term
| What virilizing effects are seen in adrogen use? |
|
Definition
1) masculinization of women ( acne, facial hair, coarsening of voice, mentrual irregularities - LH & FSH suppression - reversible)
2) prolonges Tx => male patterned baldness, excessive body hair, prominent musculature, hypertrophy of clitoris (irreversible)
3) chilren have profound virilization & disturbances in growth & bone development (closure of epiphyseal)
4) prolonged Tx => azoospermia due to inhibiton of gonadotropin secretion & coversion of androgens to estrogen |
|
|
Term
| What feminizing effects are seen with androgen use? |
|
Definition
1) gynecomastia
2) due to aromatization to estrogen
3) esp. problematic in children who possess increased extraglandular aromatase activity & men with liver disease that causes decreased androgen clearance |
|
|
Term
| What are the toxic SE of androgens? |
|
Definition
1) edema with sodium retention
2) jaundice
3) hepatic adenocarcinoma (long-term Tx) |
|
|
Term
| What are the 4 androgen drug prototypes? |
|
Definition
1) testosterone salts
2) oxandrolone
3) methytestosterone
4) flyoxymesterone |
|
|
Term
|
Definition
| compounds that block the synthesis or action of androgens |
|
|
Term
|
Definition
hyperplasia & carcinoma of prostate
acne
male-pattern baldness
virilization in females
precocious puberty in boys
inhibition of libido in male sex offenders |
|
|
Term
| What is the most effect MOA for inhibition of testosterone synthesis? |
|
Definition
| continuous GnRH or analog => decreased plasma LH => decreased testosterone secretion & desensitized GnRH receptors |
|
|
Term
| What are the 5 antiandrogens? |
|
Definition
1) Leuprolide
2) Finasteride
3) cyproterone acetate
4) flutamide
5) bicalutamide |
|
|
Term
| What GnRH analog is used to inhibit testosterone synthesis? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| converts testosterone to its active form (dihydrotestosterone) |
|
|
Term
|
Definition
| competitive antagonist of dihydrotestosterone for androgen receptor |
|
|
Term
| What androgen SE is cyproterone acetate the only antiandrogen that can Tx it? |
|
Definition
|
|
Term
| What are the 2 non-steroidal antiandrogens? |
|
Definition
|
|
Term
MOA
flutamide & bicalutamide |
|
Definition
| competitive antagonist of androgen receptor |
|
|
Term
|
Definition
| prostate cancer with leuprolide for GnRH blockade |
|
|
Term
| What is the advantage of bicalutamide over flutamide? |
|
Definition
|
|
Term
|
Definition
| inhibits glucocorticoid & androgen synthesis in adrenal gland |
|
|
Term
|
Definition
| competitive antagonist for androgen receptor |
|
|
Term
| What has spirnolactone been used as an antiandrogen for? |
|
Definition
|
|
Term
| What governs the hypothalamic release of GnRH? |
|
Definition
| hypothalamic neural pulse generator |
|
|
Term
|
Definition
| regulation of synthesis of gonadal steroids thru LH & FSH of the pituitary |
|
|
Term
|
Definition
| growth beyond or outside the uterus of tissue resembling endometrium |
|
|
Term
| What causes endometrosis? |
|
Definition
| excess estrogen created each month |
|
|
Term
|
Definition
lower estrogen levels via:
1) leuprolide (GnRH analog)
2) nafarelin (GnRH analog)
3) cetrorelix acetate (GnRH antagonist) |
|
|
Term
| What is the most common benign neoplasm in females? |
|
Definition
|
|
Term
|
Definition
| benign tumors that grow in the muscle layers of the uterus as a single tumor or cluster |
|
|
Term
| Can uterine fibroids occur with endometriosis? |
|
Definition
|
|
Term
| Why are fibroids estrogen sensitive? |
|
Definition
| contain estrogen receptors |
|
|
Term
When do fibroids decrease due to decreased estrogen?
increase due to increased estrogen? |
|
Definition
decrease: postmenopause
increase: pregnancy |
|
|
Term
|
Definition
decrease estrogen via:
1) leuprolide (GnRH analog)
2) nafarelin (GnRH analog)
3) cetrorelix acetate (GnRH antagonist) |
|
|
Term
| Where is oxytocin secreted from? |
|
Definition
|
|
Term
| When is there an increase in oxytocin receptors? |
|
Definition
| uterine smooth muscle in the second half of pregnancy |
|
|
Term
|
Definition
| stimulate uterine contraction (i.e. induce labor) |
|
|
Term
|
Definition
1) acts thru GPCR & phsphoinositide-calcium second messanger system => uterine smooth muscle contraction
2) stimulates the release of prostaglandins & leukotrienes that also facilitate uterine contraction |
|
|
Term
|
Definition
1) increasing hydration to lower plasma concentration of oxytocin
2) oxytocin antagonist (atosiban) |
|
|
Term
|
Definition
| child born prior to 36 weeks gestational age |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| <8 yr (8+ and pediatric patients have similarities to adult patients) |
|
|
Term
| What lead to a rate & extent of absorption difference b/w infants & adults? |
|
Definition
| anatomical & physiological differences |
|
|
Term
|
Definition
| translocation of a compound from its site of administration (cutaneous, IM or GI) into the blood (IV administration = complete absorption) |
|
|
Term
| What is the only administration route with no significant age-related differences in absorption? |
|
Definition
|
|
Term
Is cutaneous absorption enhanced in infancy or adulthood?
Why? |
|
Definition
infancy due to the
1) development of cutaneous layers, level of hydration & cutaneous perfusion of the epidermis
2) higher proportion of body surface area to mass
3) effect amplified even more so in premature neonates due to non-intact barrier function of integument
therefore infants and children recieve more systemic exposure with topical drugs => toxic effects |
|
|
Term
| When is IM an acceptable alternative administration route in pediatrics? |
|
Definition
| when IV access is poor (generally not preferred) |
|
|
Term
| What is IM absorption dependent on? |
|
Definition
nature of the compound being injected as well as patient related factors
1) must be lipophilic enough to be absorbed thru tissues to capillaries
2) must retain enough water solubility at physiologic pH to revent precipitation at injection site
3) must be adequate blood flow to muscle bed
4) muscle activity is directly proportional to rate of absorption |
|
|
Term
| How are most medications administered to children? |
|
Definition
|
|
Term
| What are the differences that bear consideration in neonatal/infant populations in regards to GI absorption? |
|
Definition
| change in gastric pH, gastric emptying, intestinal motility, bile salt pool, intestinal surface area, integrity |
|
|
Term
Is gastric pH higher in neonates or adults?
How does this affect dosing of acidic drugs? |
|
Definition
neonates - over several months it drops to adult levels
acid-labile drugs = readily absorbed
weak acids = need larger oral doses |
|
|
Term
| Is GI motility faster/more efficient in adults or neonates? |
|
Definition
adults
neonates increases in the first few weeks of life & improved throughout infancy |
|
|
Term
| When might GI integrity be an problem in the pediatric population? |
|
Definition
| infants (esp. premature infants) - may provide less absorptive barrier |
|
|
Term
| Can rectal administration be used in children? |
|
Definition
| yes, tho not as reliable as oral |
|
|
Term
| What drugs can effectively been given to children rectally? |
|
Definition
antipyretics (s.a. APAP)
anticonvulsants (s.a. benzos & barbituates)
rectal diazepam is frequently perscribes for epilepsy at home rescue |
|
|
Term
| What is the difference b/w a solution & a suspension? |
|
Definition
medication in solution is dissolved thruout the liquid
suspention is when the medication is in small particles & "suspended" in the liquid - subject to gravity & will sink ∴ must shake prior to administration
(needed for children since they do not possess the ability to swallow tablets |
|
|
Term
| Does a pill or a suspenstion lead to faster transmucosal transport & potentially shorter lag time to peak concentration? |
|
Definition
| suspension due to larger SA:volume ratio |
|
|
Term
| What does the distribution of most substances in the body depend on? |
|
Definition
1) body compartment size
2) protein binding
3) membrane permeability |
|
|
Term
| What is the most important PK parameter that affects drug distribution? |
|
Definition
| Vd (volume of distribution) - it reflects the apparent space in the body availalbe to contain a drug & the amount of drug in the body to it's concentration in a biological fluid (plasma) |
|
|
Term
| *What does the apparent Vd differ from patient to patient for any given drug based on? |
|
Definition
1) protein binding
2) body composition
significant age-related differences - esp. due to alterations in total body water |
|
|
Term
| Is total body water greater in infants or adults? |
|
Definition
infants (as well as the extracellular compartments)
birth: TBW = 75%
4 mo to adult: TBW = 60%
adult: TBW = 50% |
|
|
Term
| What happens if a water soluble drug is administered to a child with no consideration to the differences in TBW? |
|
Definition
| lower plasma levels of drug |
|
|
Term
| *Do higher or lower concentrations per kilogram body weight need to be given to children to achieve comparable concentration of drug in adults? |
|
Definition
|
|
Term
| Is a drug pharacologically active when protein bound? |
|
Definition
|
|
Term
| What does the degree of protein binding od a drug depend on? |
|
Definition
1) avidity of a protein for certain medication
2) pathophysiologic conditions that affect protein binding |
|
|
Term
| Is there more or less protein binding in infants than adults? |
|
Definition
| less => increased free fraction of the drug => need for therapeutic monitoring for drugs highly protein bound |
|
|
Term
| What does distribution of lipophilic drugs depend on? |
|
Definition
1) TBW
2) fat composition of the body |
|
|
Term
| Do infants have a higher or lower fat composition compared to adults? |
|
Definition
|
|
Term
| *Why do infants have higher Vd for both fat & water soluble medications than adults? |
|
Definition
| higher TBW & fat composition |
|
|
Term
|
Definition
| elminiation of the active drug from the body |
|
|
Term
| What is clearance of a drug a function of? |
|
Definition
| metabolism of the active compound and/or excretion of the drug from the bosy |
|
|
Term
| Do infants generally have increased or decreased drug clearance? |
|
Definition
|
|
Term
| What are the biotransformations of Phase I metabolism in the liver? |
|
Definition
Oxidation, Reduction, Hydrolysis, Hydroxylation
(P450s can do this) |
|
|
Term
| Are CYP450s more or less developed in infants than adults? |
|
Definition
| less (30-60% of adult values, but reach adult values ~1 yr) |
|
|
Term
| Is hepatic metabolism higher or lower in infants than adults? |
|
Definition
| usually lower, but for certain substances can be higher - know the mechanism of each substance |
|
|
Term
| What are the biotransformations of Phase II metabolism in the liver? |
|
Definition
| conjugation reactions => increased water solubility or renal excretion of drugs |
|
|
Term
What conjugation reaction is most important in infant phase II metabolism?
Why? |
|
Definition
| sulfation other conjugation pathways aren't well developed |
|
|
Term
| When does glucuronidation conjugation at adult levels? |
|
Definition
|
|
Term
| *Since the hepatic capacity for glucuronidation is pooly developed early in life, which drugs should be monitored closely? |
|
Definition
drugs that proceed thru glucuronidation s.a.
1) morphine
2) NSAIDs
3) APAP
4) endogenous bilirubin |
|
|
Term
| How are many water soluble drugs & metabolites excreted? |
|
Definition
|
|
Term
| *Why is newborn toxicity high for water soluble compounds renally excreted? |
|
Definition
| immaturity of kidney => limited glomerular & rubular functional capacity => decreased drug elimination & prolonged half life |
|
|
Term
| *How efficacious is neonatal GFR compared to adults? |
|
Definition
|
|
Term
| When do children have a GFR equivilant to adults? |
|
Definition
|
|
Term
| Why are tetracycline CI in children <8 yrs? |
|
Definition
|
|
Term
| Why are fluroquinolones CI in children? |
|
Definition
| tendon problems & poor cartilage development |
|
|
Term
| Why is ceftriaxone rarely used in neonates? |
|
Definition
can displace bilirubin in neonates with hyperbilirubinemia which can result in kernicterus
plus alternatives exist |
|
|
Term
| Do children or adults have a greater propensity for dystonic reactions when given DA agonists? |
|
Definition
|
|
Term
| When might DA infusions be used to precipitate a catecholamine response? |
|
Definition
| critical care for patients in shock b/c of effects on heart & peripheral vasculature |
|
|
Term
| Why do neonates response poorly to DA infusions to increase HR & BP? |
|
Definition
| relative immaturity of catecholamine receptor density & function |
|
|
Term
| Which sedative drugs tend to display a paradoxical & inappropriate hyperexcitability in children? |
|
Definition
antihistamines
benzos
barbituates |
|
|
Term
| Why is the evaluation od the ciochemical & functional maturity of specific metabolic pathways in vivo limited? |
|
Definition
| moral, ethical, & technical concerns |
|
|
Term
| Why is chemotherapy often used in conjunction with surgery or ionizing radition? |
|
Definition
| attempt to eradicate small number of tumor cells that may be missed |
|
|
Term
| When might chemotherapy be the only options? |
|
Definition
| cancers s.a. leukemia that are widely-disseminated |
|
|
Term
| Why do anti-tumor agents lack selective toxicity? |
|
Definition
| tumor cells generally do not differ qualitatively from normal mammalian cell types |
|
|
Term
| Which cells are most often affected by anti-tumor toxicity? |
|
Definition
|
|
Term
MOA
most anti-tumor agents |
|
Definition
| inhibit DNA synthesis ∴ affect any rapidly dividing normal cell types |
|
|
Term
| What type of anti-tumor agents can cause delayed toxicity? |
|
Definition
|
|
Term
| Where are the most rapidly dividing cells in the human? |
|
Definition
|
|
Term
| What later effects can be seen due to DNA damage of anti-tumor agents? |
|
Definition
|
|
Term
| How are appropriate dosages determined with anti-tumor agents? |
|
Definition
pharmacology & toxicology profiles, since they're often used near maximum tolerated levels
variable include:
1) modes of drug administration
2) absorption
3) distribution
4) rate of conversion into active/inactive products
5) modes/rate of drug excretion |
|
|
Term
| Why are SE hard to predict with anti-tumor agents? |
|
Definition
1) delayed toxicity
2) variation in rates of drug metabolism per cell
3) effects caused by local drug concentrations in certain tissues |
|
|
Term
| What do many effects of anti-tumor agents mimic? |
|
Definition
| radiation therapy since drugs disappear from circulation quickly, but toxic effects are delayed |
|
|
Term
| When is clinical success of anti-tumor agents more successful? |
|
Definition
1) tumor target cells are rapidly dividing since they're more sensitive to the drugs
2) malignant cells are damaged (reduced capacity for repair) |
|
|
Term
| What has complicated the evaluation of anti-tumor drug effectiveness? |
|
Definition
1) significant number of spontaneous tumor remissions
2) false diagnoses
3) unexplained results |
|
|
Term
| Where are anti-tumor drug toxicities directed to? |
|
Definition
| cells in S phase (DNA synthesis) |
|
|
Term
| What causes the failure of chemotherapy? |
|
Definition
1) drug resistance
2) host toxicity
3) accumulation of tumors in compartments not readily accessible to particular drug used |
|
|
Term
|
Definition
| with in addition to surgery &/or radiation |
|
|
Term
|
Definition
| compound that can form covalent bonds with DNA |
|
|
Term
|
Definition
| drug that interferes with a biologically-important metabolic process (analogs to some biologic comound s.a. purine or pyrimidine) |
|
|
Term
|
Definition
| property of an agent such that normal cells are transformed into malignant cells |
|
|
Term
|
Definition
| an agent primarily toxic to cells at a certain phase of the cell cycle |
|
|
Term
def
combination chemotherapy |
|
Definition
| simultaneous use of several drugs |
|
|
Term
|
Definition
| substantial 5-10 yr disease-free interval |
|
|
Term
|
Definition
| a tumor or leukemic cell that is not sensitive to the action of one or more drugs |
|
|
Term
|
Definition
| the occurance of cancer cells in the circulating blood, stemming from marrow or lymphatic systems. Cells can also form colonies in host organs |
|
|
Term
|
Definition
| a drug that occurs in nature |
|
|
Term
|
Definition
|
|
Term
|
Definition
| lethal to cells at any phase of the cell cycle |
|
|
Term
|
Definition
| the science or art of research on & Tx of cancer |
|
|
Term
|
Definition
| the end of a remission; clinical Sx of cancer return |
|
|
Term
|
Definition
| clinical Sx of cancer can no longer be detected |
|
|
Term
| What determines the mode of administration of anti-tumor agents? |
|
Definition
function of drug properties i.e.
highly reactive agents, poorly absorbed, relatively unstable - IV |
|
|
Term
| How can host toxicity be minimized? |
|
Definition
| "antidotes" to some anti-tumor agents |
|
|
Term
| What is the first line Tx to neoplasms? |
|
Definition
| surgery or radition (attempt to remove tumor) |
|
|
Term
| When is chemotherapy used? |
|
Definition
1) prior to surgery to try to reduce the size or tumor
2) post surgery/radiation to "mop-up" an tumor cells left |
|
|
Term
| Are leukemias or solid tumors more drug resistant? |
|
Definition
|
|
Term
| What determines the sensitivity of cells to anti-tumor agents? |
|
Definition
| status of DNA synthesis at the time of drug exposure |
|
|
Term
| How long does G1 last in the cell cycle? |
|
Definition
| minutes (rapidly dividing cell) to months (slowly dividing cell) |
|
|
Term
| What phase of the cell cycle in DNA synthesis occuring? |
|
Definition
|
|
Term
| Is there variation of S phase duration like there is G phase? |
|
Definition
|
|
Term
| What is the major different b/w rapid growing & slow growing cells? |
|
Definition
|
|
Term
| When in the cell cycle are proteins & RNA synthesized? |
|
Definition
|
|
Term
| What happens for a cell to move through the cell cycle? |
|
Definition
| different cyclin proteins must activate certain enzymes |
|
|
Term
| What happens when damage to DNA is detected? |
|
Definition
| p53 is activated which activated p21 to freeze the cell cycle via inhibition of cyclin dependent enzymes |
|
|
Term
| What protein that can halt the cell cycle tends to be missing in many neoplastic cells? |
|
Definition
|
|
Term
|
Definition
| targets a particular cyclin => decides whether a cell should divide or not |
|
|
Term
| Why are solid tumors not as susceptible to anti-tumor drugs? |
|
Definition
| remain in prolonged G1 or G0 ∴ escape lethal effects of agents that kill S phase cells |
|
|
Term
| Why is there no advantage in increasing the concentration of an S phase active agent once a lethal drug level has been achieved? |
|
Definition
| cells not in S phase will not be affected |
|
|
Term
| How often do cells in rapidly dividing tumors reach S phase? |
|
Definition
| once every 24 hrs ∴ if levels of drug are maintained for 24 hrs all cells will be effected |
|
|
Term
| Why don't tumors with low growth fraction respind to agents that kill cells in the S phase? |
|
Definition
| concentrations of the drug cannot be maintained for long periods of time due to lethal effects of normal host cells |
|
|
Term
| Is the rate of killing of tumor cells 1st order or 0 order? |
|
Definition
| 1st order (linear on a log scale) |
|
|
Term
| How much of the tumor population must be destroyed for a curative effect? |
|
Definition
|
|
Term
| In tumor cell populations, is 100% effective dose ever reached prior to lethal dose? |
|
Definition
|
|
Term
| What variables determine efficacy of a tumor treatment? |
|
Definition
1) level of drug toxicity (to tumor & host)
2) persistence of drug in circulation
3) rate of absorption & inactivation
4) unexpected drug toxicities |
|
|
Term
| If a 100% effective dose cannot be administered, how is a dosing schedule set up? |
|
Definition
reduced dose to elimiate weight loss & death.
Considered still effective if tumor cell population decreases after each course and if growth occurs, never exceeds originial number |
|
|
Term
| How do cells resistant to anti-tumor agents emerge? |
|
Definition
1) mutational events
2) drug-resistant cells were present at begining of drug Tx |
|
|
Term
| How is drug-resistance avoided in many cases? |
|
Definition
|
|
Term
| What MOA is needed of non cell-cycle specific agents for slowly growing tumors? |
|
Definition
drugs that bind strongly to DNA or otherwise react with DNA to interfere with subsequent DNA synthesis & replication
tend to be less responsive & most toxic |
|
|
Term
| Do the non-specific cell cycle inhibitors exhibit 1st order or 0 order kill kinetics? |
|
Definition
|
|
Term
| Should the dosing schedule of non cell-cycle specific anti-tumor agents be more or less frequent than S phase specific drugs? |
|
Definition
| less to give host cells more time to recover |
|
|
Term
| When is toxicity usually seen with non cell cycle specific agents? |
|
Definition
|
|
Term
| What are the 4 major classifications of anti-tumor agents? |
|
Definition
1) Natural Products/Antibacterial
2) Alkylating Agents
3) Hormonal Agents
4) Antimetabolites |
|
|
Term
| Can S phase specific anti-tumor agents affect cells in G1, G2, & M phases? |
|
Definition
| yes, but they do not kill them |
|
|
Term
| When is an S phase cell cycle specific anti-tumor agent considered self-limiting? |
|
Definition
| drug slows progression thru the cell cycle which limits toxicity |
|
|
Term
| What does the net therapeutic result of a anti-tumor agent depend on? |
|
Definition
1) persistence of a drug at effective levels
2) growth fraction of tumor
3) numbers of drug-resistant cells present
4) other unknown factors |
|
|
Term
| What are the 5 antimetabolite antitumor agents? |
|
Definition
1) methotrexate
2) fluorouracil
3) cytosine arabinoside
4) mercaptopurine
5) thioguanine
(Fluoride Metabolites That xCyte Mermaids) |
|
|
Term
|
Definition
| binds to DHFR => antagonism of the synthesis of thymidylic acid (precursor of DNA) |
|
|
Term
| What is the "antidote" to methotrexate toxicity? |
|
Definition
| folinic acid (reduced folate) |
|
|
Term
Absorption/Excretion
methotrexate |
|
Definition
poor GI (∴ IV administration)
poor CNS penetration
poor benetration in most cell types
rapid urine excretion |
|
|
Term
| Why is methotrexate an effective DNA synthesis antagonist? |
|
Definition
| binding of enzyme is so tight that essentially every drug molecule that enters the cell binds to the enzyme DHFR |
|
|
Term
| How can resistance to methotrexate occur? |
|
Definition
1) impairment of transport system responsible for accumulation of drug (mutations that delete transport system - most common)
2) selection for tumor cells with very high levels of target enzyme
3) methotrexate can udergo an enzymatic coversion to a derivative that contains multiple glutamate residues |
|
|
Term
| What cells are supposedly rescued by folinic acid anti-methotrexate therapy? |
|
Definition
| GI & marrow, tho rarely used since not wholly reversed |
|
|
Term
| Are most antimetabolites S phase or non cell cycle specific anti-tumor agents? |
|
Definition
|
|
Term
| What causes the self-limiting action of methotrexate? |
|
Definition
1) interference with purine synthesis of normal cells => reduced granulocytes, alopecia & immunosuppression
2) slow the cell cycle (as mentioned before - most S phase agents are self limiting in this fashion) |
|
|
Term
| With which patients will drug dose of methotrexate need to be reduced? |
|
Definition
|
|
Term
| What is fluorouracil an alalog of? |
|
Definition
|
|
Term
|
Definition
| activation (via ezymes that attach a ribose sugar, then phosphorylate the ribose group, then reduce to deoxyribose, and add a second phosphate) to FUdRP => inhibition of thymidylate synthesis (component of DNA) ∴ inhibition of DNA synthesis |
|
|
Term
| How can antitumor action of fluorouracil be potentiated? |
|
Definition
| if administered with folinic acid to promote formation of the teriatry complex of FUdRP, reduced folate & thymidylate synthetase (how thymidylate synthysis is inhibited) |
|
|
Term
| What antitumor drug can antagonize fluorouracil's actions? |
|
Definition
| methotrexate (limits folinic acid production) |
|
|
Term
|
Definition
| DPD (some patients are missing this enzyme => dose reduction needed) |
|
|
Term
| What happens to flurouracil efficacy if DPD antagonized by ethynyluracil? |
|
Definition
| reduced degradation, but not increased efficacy |
|
|
Term
| Is fluorouracil an S phase specific or non cell cycle specific agent? |
|
Definition
|
|
Term
| How is fluorouracil self limiting? |
|
Definition
| interferes with RNA synthesis => slows progression thru cell cycle |
|
|
Term
Absorption/Metabolism/Excretion
fluorouracil |
|
Definition
unpredictable PO absorption (∴ IV administration)
inactivated by liver
kidney excretion |
|
|
Term
| What causes resistance to fluorouracil? |
|
Definition
| tumor cell deletes one or more enzymes involved in phosphorylation of the drug (these enzymes are on the salvage pathway of pyrimidine metabolism ∴ loss doesn't affect capacity of cell to synthesize pyrimidines) |
|
|
Term
|
Definition
solid tumors
(ineffective against leukemias) |
|
|
Term
| Why is fluorouracil ineffective against leukemias? |
|
Definition
| they tend to lack one or more of the enzymes needed to "activate" fluorouracil (i.e. convert to FUdRP) |
|
|
Term
| What is different about what increases/varies fluorouracil's toxicity? |
|
Definition
rate of infusion
fast = depressed WBC & GI
slow = pain & swelling of the palms & soles of feet (1/3 of patients) |
|
|
Term
| What is cytosine arabinoside an analog of? |
|
Definition
| cytidine (with one -OH group on the sugar pointing the "wrong" direction) |
|
|
Term
MOA
cytosine arabinoside (Ara-C) |
|
Definition
| phosphorylated to tri-phospate to activate => competitive inhibition of deoxycytidine triphosphase incorportation into DNA & growth inhibitory actions |
|
|
Term
| What causes the rapid deactivation of Ara-C? |
|
Definition
| deaminase present in many cells (esp. kidney) |
|
|
Term
| Is Ara-C S phase specific or non cell cycle specific? |
|
Definition
|
|
Term
| How is Ara-C self limiting? |
|
Definition
| it's not, it has no delay to the cell cycle progression |
|
|
Term
|
Definition
acute leukemias of granulocytic series
sometimes given in high dose for resistant leukemias
(ineffective against solid tumors) |
|
|
Term
| What unexpected adverse reactions can occur when resistant leukemias are given high doses of Ara-C? |
|
Definition
| irreversible damage to CNS |
|
|
Term
| Do the same activating (phosphorylating) enzymes of fluorouracil activate (phosphorylate) Ara-C? |
|
Definition
|
|
Term
| What causes Ara-C resistance? |
|
Definition
| deficiency of the enzyme involved in ara-C phosphorylation |
|
|
Term
| Why is Ara-C strongly immunosuppressive? |
|
Definition
| lymphatic system contains high levels of the phosphorylating enzyme |
|
|
Term
| How is Ara-C administered? |
|
Definition
|
|
Term
| What are both 6-mercaptopurine & 6-thioguanine analogs of? |
|
Definition
|
|
Term
Absorption/Metabolism/Excretion
mercaptopurine & thioguanine |
|
Definition
PO administration
degraded by liver
excreted by kidney |
|
|
Term
| How are 6-MP & 6-TG activated? |
|
Definition
| phosphorylated by cellular enzymes |
|
|
Term
| How can resistance to 6-MP & 6-TG occur? |
|
Definition
| when cells lose the capacity to phosphorylate the drugs, or have enhanced levels of enzymes that degrade the drugs |
|
|
Term
|
Definition
leukemias
seldom: solid tumors |
|
|
Term
What 4 antimetabolite antitumor agents use phosphorylation for activation?
Do any of them use the same enzymes for phosphorylation? |
|
Definition
fluorouracil
Ara-C
6-MP
6-TG
none use the same enzymes |
|
|
Term
| Besides phosphorylation for activation, how are 6-MP & 6-TG similar to Ara-C? |
|
Definition
|
|
Term
| What enzyme degrades the purines & their analogs (i.e. 6-MP)? |
|
Definition
|
|
Term
| What drug inhibits xanthine oxidase? |
|
Definition
|
|
Term
| What happens to the large amounts of nucleic acid released from dying tumor cells? |
|
Definition
| converts purines to uric acid via xanthine oxidase (=> gout, renal calculi) |
|
|
Term
|
Definition
| decrease serum levels of uric acid |
|
|
Term
| What antimetabolite antitumor medication must be decreased forpatients on allopurinol? |
|
Definition
|
|
Term
| Does allopurinol affect catbolism of Ara-C, fluorouracil, or thioguanine? |
|
Definition
| no (Ara-C & fluorouracil are pyrimidines and are not converted to uric acid. Thioquanine is not extensively deaminated is not readily converted to uric acid) |
|
|
Term
| What type of tumor cells can be killed by alkylating agents? |
|
Definition
|
|
Term
|
Definition
| converted via intra-molecular rearrangements to structures highly reactive towars all neucleophilic groups => many cytotoxic consequences (esp. when DNA is alkylated) => non-function DNA replication => inhibition of DNA synthesis |
|
|
Term
| What are the 5 alkylating agents? |
|
Definition
1) Nitrogen Mustard
2) Cyclophosphamide
3) Nitrosoureas
4) Temodar
5) Cis-Platinum
(Cyclone Al kills Them Nitrogen Sources) |
|
|
Term
| What is the largest group of alkylating antitumor agents? |
|
Definition
| nitrogen mustard & it's analogs |
|
|
Term
| What is a severe SE of all alkylating antitumor agents? |
|
Definition
| carcinogenic properties => secondary neoplasia years after use |
|
|
Term
| What was the original purpose for nitrogen mustard? |
|
Definition
|
|
Term
| Why can nitrogen mustard only be given IV? |
|
Definition
| escape into tissues causes sever local toxicity - it alkylates everything it touches (including water molecules) - plus it has 2 sites for alkylating |
|
|
Term
|
Definition
|
|
Term
| Can the 2 sites for alkylation on a molecule of nitrogen mustard alkylate different strands of DNA? |
|
Definition
| yes, which results in a cross linking |
|
|
Term
| What is the most common site for alkylation of the DNA? |
|
Definition
| 7 amino position on the guanine molecule |
|
|
Term
| Can cross-linked DNA (via alkylation) replicate? |
|
Definition
| not until the cross-linked bases are replaced ∴ when nitrogen cross-links DNA of non-dividing cells, cell death can occur later |
|
|
Term
|
Definition
Hodgkin's disease
lymphoma |
|
|
Term
| Why were nitrogen mustard analogs formed (s.a. phenylalanine mustard & chlorambucil)? |
|
Definition
| still given PO with more broad SOA & effective levels persist for days in circulation & tissue |
|
|
Term
SOA
melphalan (phenylalanine mustard) |
|
Definition
myelomas
breat & ovarian tumors |
|
|
Term
|
Definition
chronic lymphocytic leukemias
Hodgkin's disease
other malignant lymphomas |
|
|
Term
|
Definition
cholinergic Sx
bone marrow depression
GI toxicity |
|
|
Term
|
Definition
|
|
Term
| Is the bone marrow toxicity associated with alkylating agents reversible upon cease of administration? |
|
Definition
|
|
Term
| Why alkylating agent was initially synthesized as an analog to nitogen mustard, but with the mistaken idea it would be converted to an alkylating agent when "selectively" cleaved by tumor cells? |
|
Definition
cyclophosphamide
(it turns out tumor cells have no ability to cleave P-N linkages) |
|
|
Term
| What activates cyclophosphamide? |
|
Definition
| enzymes in the liver (not the tumor) |
|
|
Term
|
Definition
| after activation => enters tumor cells and alkylates sensitive sites (inc. DNA) |
|
|
Term
|
Definition
broad spectrum s.a.
Hodgkin's disease
lymphomas
breast & ovarian tumors |
|
|
Term
Administration
cyclophosphamide |
|
Definition
|
|
Term
|
Definition
immunosuppression
alopecia
GI Sx
(less toxic to thrombocytes than other nitrogen mustard analogs) |
|
|
Term
Excretion
cyclophosphamide |
|
Definition
| urine, but may cause severe hemorrhagic cystitis |
|
|
Term
Tx
severe hemorrhagic cystitis from cyclophosphamide |
|
Definition
maintaining increased urine flow
administering MEMSA to neutralize metabolites |
|
|
Term
| What drug analog of cyclofosphamide is more slowly metabolized by the liver? |
|
Definition
|
|
Term
| What are the 3 nitrosoureas? |
|
Definition
|
|
Term
|
Definition
highly lipid soluble (readily penetrate CNS)
given PO (except BCNU)
effective levels persist for ~24 hrs |
|
|
Term
|
Definition
bone marrow & GI toxicities
substanatial toxicity |
|
|
Term
|
Definition
CNS tumors
(may use a coated wafer applied directly to site of glioma infiltration) |
|
|
Term
| What anti-tumor drug is a precursoe of an alkylating agent used in brain tumors? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| converted to alkylating agent => interacts withquanine residues on DNA => product mistaken for adenine => base-pair mismatching => loss of viability |
|
|
Term
SOA
cis-platinum (platinol) |
|
Definition
broad spectrum
variety of solid tumors (esp. testicular neoplasia & ovarian carcinoma) |
|
|
Term
|
Definition
| Cl atoms are lost to form a drug that acts like an alkylating agent => formation of covalent bonds with nucleic acids with little cell specificity |
|
|
Term
| What controls the dose-limiting toxicities of cis-platinum? |
|
Definition
| kidney tubule damage with neurotoxicity |
|
|
Term
| How are the kidney damaging SE of cis-platinum avoided? |
|
Definition
| drug administration in large volume of fluid containing mannitol (diuretic) |
|
|
Term
| What are the drawbacks to drug analogs of cis-platinum with less neurotoxicity? |
|
Definition
| cause bone marrow toxicity & are less useful in combinations |
|
|
Term
| What has to happen for the DNA to proceed thru replication after alkylation? |
|
Definition
| removal of alkylated region |
|
|
Term
| What enzyme can remove alkylated DNA? |
|
Definition
endonucleases
and then DNA is repaired by DNA pol & DNA ligase |
|
|
Term
| Which cells are more sensitive to alkylating agents? |
|
Definition
| those with less ability for DNA repair |
|
|
Term
| How does resistance to an alkylating agent occur? |
|
Definition
1) selection of tumor cells with an enhanced capacity for repair
2) enhanced level of products contain -SH residues (i.e glutathione) to react & inactivate most alkylating agents |
|
|
Term
| Where do the natural product anti-tumor agents come from? |
|
Definition
| occur in nature in plants or microorganisms |
|
|
Term
| What are the 5 natural product anti-tumor agents? |
|
Definition
1) Bleomycin
2) Anthracyclines
3) Vinca alkaloids
4) Taxol
5) Actinomycin D
(Abx Act as A Tax & Bleed the Vines) |
|
|
Term
| Where is actinomycin D isolated from? |
|
Definition
|
|
Term
|
Definition
| (no activation needed) binds tightly to to DNA via intercalation (does NOT covalent bond) => inhibiton of RNA synthesis |
|
|
Term
|
Definition
IV administration
rapidly disappears from circulation and causes toxicity to several hos organs |
|
|
Term
|
Definition
marrow
GI
oral mucosa
hair follicles
(seldom used due to toxicity) |
|
|
Term
|
Definition
|
|
Term
| When should dose modifications of actinomycin D occur? |
|
Definition
| patiens with impaired liver function |
|
|
Term
|
Definition
Wilms' tumor in children (in combination with x-ray therapy)
neuroblastomas |
|
|
Term
| Where is bleomycin obtained from? |
|
Definition
|
|
Term
| What properties make bleomycin a welcome addition? |
|
Definition
1) after parenteral administration, it's detoxified by most normal tissue except lung & skin
2) marrow is spared due to high level detoxifying enzyme |
|
|
Term
|
Definition
|
|
Term
|
Definition
| slows progression thru G2, tho mainly lethal to mitotic cells => considerable DNA damage => breaking in fragmentation of DNA |
|
|
Term
| What is the anthracycline? |
|
Definition
|
|
Term
| How is doxorubicin obtained? |
|
Definition
|
|
Term
|
Definition
| binds to DNA (even non-diving cells) => inhibition of subsequent DNA & RNA synthesis |
|
|
Term
Absorption/Excretion
doxorubacin |
|
Definition
GI absorption unpredictable (∴ IV administration)
drug slowly cleared, levels are detectable for 1-2 days
excretion via liver/bile |
|
|
Term
| When should doxorubacin be dose adjusted? |
|
Definition
|
|
Term
| How do most anthracyclins also tend to inhibit cell viability? |
|
Definition
| interactions with topoisomerase II |
|
|
Term
|
Definition
marrow
GI
other rapidly dividing host cells
cardiac toxicity => HF (due to mitochondrial damage via free radicals) |
|
|
Term
| What enhances the cardiotoxic effects of doxorubacin? |
|
Definition
| any loss of glutathione in cardiac cells (since GSH can interact with free radicals & remove them) |
|
|
Term
|
Definition
| borad spectrum over many solid tumors |
|
|
Term
| When is doxorubacin unstable? |
|
Definition
|
|
Term
| What are the 2 vinca alkaloids? |
|
Definition
1) Vincristine
2) Vinblastine |
|
|
Term
| Where are the vinca alkaloids extracted from? |
|
Definition
|
|
Term
|
Definition
| arrest cell division at metaphase by distrupting microtubule structures => neurotoxicity |
|
|
Term
Absorption/Excretion
vinca alkaloids |
|
Definition
IV administration
disappear rapidly from circulation (minutes)
some via liver/bile |
|
|
Term
|
Definition
|
|
Term
|
Definition
| peripheral nervous system |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| What causes the variation of effectivity of veracristine to verablastine? |
|
Definition
| minor structural alteration |
|
|
Term
|
Definition
| promotes tubulin polymerization & stability of microtubules => inhibition of metaphase & mitosis |
|
|
Term
|
Definition
| refractory ovarian & breast cancer |
|
|
Term
|
Definition
|
|
Term
|
Definition
rapidly dividing cells
neurotoxicity
neutropenia
hypersensitivity reactions (controlled by steroid administration) |
|
|
Term
| Why is taxol prone to hypersensitivity reactions? |
|
Definition
insoluble in water ∴ must be forumulated with a solubilizer (cremophor) that can cause allergic reactions
a more water soluble form was created to circumvent these rxns |
|
|
Term
| What are the similarities b/w most of the natural anti-tumor agents? |
|
Definition
1) no need for activation
2) cycle non-specific (except vinca alkaloids)
3) excreted liver/bile
4) affected by multiple drug resistance |
|
|
Term
| Why are the natural products affected by multidrug resistance? |
|
Definition
resistance is often related to ATP dependent outward transport process that pumps weakly cationic large moleculesout of cells before they reach critical targets.
Since multiple drugs are affected => MDR
(does NOT affect antimetabolites, alkylating agents, & ALL natural products) |
|
|
Term
| What can inhibit the multi-drug resistant process of natural products? |
|
Definition
| several drugs => promotes host toxicity |
|
|
Term
| What 3 antitumor hormone (& anti-hormonal) agents have been used? |
|
Definition
1) corticosteroids
2) tamoxifen
3) aminoglutethamide |
|
|
Term
MOA
corticosteroids
(s.a. hydrocortisone, prednisone, dexamethasone) |
|
Definition
acute & chronic leukemias
Hodgkin's & non-Hodgkin's lymphomas
multiple myeloma
breast cancer |
|
|
Term
| Why are corticosteroids useful in antitumor combinations? |
|
Definition
| do not supress bone marrow |
|
|
Term
Administration
corticosteroids |
|
Definition
|
|
Term
|
Definition
adrenal atrophy
immune suppression
potentiateion of incipient diabetes
growth retardation (in young) |
|
|
Term
|
Definition
| a potent anti-estrogen for estrogen-dependent breat tumors in post menopausal women |
|
|
Term
|
Definition
| antagonizes the estrogen dependent phenomenon of estrogen dependent tumors |
|
|
Term
|
Definition
| rare - leukopenia, retinopathy, & thrombocytopenia |
|
|
Term
|
Definition
|
|
Term
|
Definition
| estrogen-dependent tumors |
|
|
Term
|
Definition
| non-specific inhibitor of the mized function oxidases that are needed for estrogen biosynthesis |
|
|
Term
| What is co-administered with aminoglutethamide in order to prevent systemic toxicity? |
|
Definition
cortisol & aldosterone
(so other host biosynthetic pathways are not impaired) |
|
|
Term
|
Definition
| when one tumor becomes resistant to one drug, it may be found to be reistant to others |
|
|
Term
| When does cross resistance seem to occur? |
|
Definition
1) when a number of drugs use a single activation pathway
2) when a number of drugs can be antagonized by a common factor
3) defective signaling of apoptosis |
|
|
Term
| Why is drug resistance needed for all anti-tumor activity? |
|
Definition
| most host cells must be resistant in order for the drug to be effective |
|
|
Term
| What is an important factor in the responsiveness of neoplastic cells to anti-tumor agents? |
|
Definition
| ability of cytotoxic agent to initiate an apoptotic response |
|
|
Term
|
Definition
| series of enzymes are activated => fragmentation of DNA & ultimately of cells => engulfment by macs |
|
|
Term
| What can delay or remove an apoptotic response? |
|
Definition
| when signaling pathways are impaired |
|
|
Term
| What is the relationship b/w tumor growth rate & resistance? |
|
Definition
| slower growing tumor could contain more mutations => greater resistance |
|
|
Term
| What is the only notable exception to: "the tumor becomes resistant, not the patient"? |
|
Definition
| patient hair follicles become resistant to doxorubicin |
|
|
Term
| What are the major considerations when giving drug combinations in chemotherapy? |
|
Definition
1) no additive host toxicity
2) synergism is found in combination of one drug that inhibits DNA synthesis + another that alkylates or binds to DNA
3) drug resistance is delayed in combination therapy |
|
|
Term
| What cancer types have seen the most marked success in drug therapy? |
|
Definition
| leukemias & lymphomas (esp. in children) |
|
|
Term
| What seems to derive the relative success with leukemias & lymphomas of anti-tumor drugs? |
|
Definition
method of drug screening:
1) testest against mouse leukemias
2) 1st stage to identify modes of drug toxicity & maximum tolerated dose
3) phase 2 are in patients with refractory cancers
4) phase 3 to dermine whether phase I & II are better than any other "standard" therapy |
|
|
Term
|
Definition
| protein-tyrosine kinase inhibitor that inhibits Bcr\Abl protein TK derived from abnormal Philadelphia chromosome => prevention of cancer cells dividing |
|
|
Term
|
Definition
chronic myeloid leukemia
GI stromal tumors |
|
|
Term
|
Definition
| TK inhibitor, more slective for small cell lung cancer |
|
|
Term
|
Definition
Ab against HER2/neu protein
(mammary tumors) |
|
|
Term
|
Definition
Ab against EGFR (epi GF receptor) => inhibition of tumor growth promoter
(advanced colorectal cancers and head & neck cancers) |
|
|
Term
|
Definition
Ab that targets VEGF (vas. endo. GF) => inhibition of attraction of new blood vessels to maintain tumor growth
(colorectal & lung tumors) |
|
|
Term
| Once a target has been identified, what is used to identify tumor cell types likely to respond to a new agent? |
|
Definition
| genetic screens => clinical trials in population os patients likely to respond |
|
|
Term
| Why are slow release options being explored to chemotherapy drug combinations? |
|
Definition
| since combinations of drugs have different half lives - to keep each drug at optimal level for a significant period of time |
|
|
Term
Drugs are often used in combination to produce an optimal anti-tumor effect. Which of these is an important consideration in the design of drug combinations?
A) all drugs should have approximately the same plasma half life
B) drugs that kill cells in S phase should not be given with alkylating agents
C) each drug should evoke a different pattern of host toxicity
D) no drug should be recognized by the transport system associated with multi-drug resistance
E) combinations should be limited to no more than 3 agents |
|
Definition
|
|
Term
MDR occurs when cells develop an outward drug transport system that can pump out weakly cationic agents before they can accumulate in the nucleaus & inhibit DNA synthesis. Administration of drugs designed to circumvent MDR by inhibiting this transport process can also result in:
A) longer persistence of anti-tumor agents in circulation
B) adverse effects on normal cells with MDR phenotype
C) more rapid development of drug resistance in neoplastic cells
D) failure of drugs to reach tumor cell DNA
E) none of the above |
|
Definition
B
(more toxic kidney effects) |
|
|
Term
Fluorouracil is sometimes administered at a very low dose for a long interval. With this protocol, it is common to observe:
A) alkylation og guanine residues in DNA
B) lack of an antitumor effect
C) rapid emergence of drug resistance
D) no significant changes in tumor-response pattern
E) new patterns of drug responses & of host toxicity |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| What parameters are affected by pharmacokinetics? |
|
Definition
absorption
distribution (transport, Vd)
metabolism
excretion |
|
|
Term
| Is absorption affected in aging? |
|
Definition
PO: no
transdermal, transbronchial, SR preparations: unknown
only GI disease/interference from meals/drugs seems to alter absorption |
|
|
Term
| What is the primary plasma binding protein? |
|
Definition
|
|
Term
| What happens to albumin levels as we age? |
|
Definition
| modest reduction with no clinical impact |
|
|
Term
| What impact does a substatial decrease of albumin have? |
|
Definition
| changes the blanace b/w free & bound drugs |
|
|
Term
| What happens to water soluble/fat soluble compartments (Vd) as we age? |
|
Definition
lipid soluble increases
water soluble decreases
(fat increaases, lean body mass decreases) |
|
|
Term
| What is the main metabolic organ? |
|
Definition
|
|
Term
| What happens to phase I & II metabolism as we age? |
|
Definition
phase I decreases
phase II preserved |
|
|
Term
| Is there liver mass reduction with age? |
|
Definition
| after age 50 (45% decreased perfusion by 65) |
|
|
Term
| What is the main excretory organ? |
|
Definition
|
|
Term
| What happens to GFR with age? |
|
Definition
|
|
Term
| What happens to creatinine level with age? |
|
Definition
| remains stable if decreased GFR balanced with decreased muscle mass |
|
|
Term
|
Definition
|
|
Term
| What happens to the t1/2 of lipid soluble drugs with age?
water soluble drugs? |
|
Definition
|
|
Term
| Overall, are most drug sensitivities increased or decreased with old age? |
|
Definition
| increased ∴ need lower doses, longer dosing intervals, longer periods b/w dosing change |
|
|
Term
| How is a dose determined for an older patient? |
|
Definition
| start with low dose, titrate up to the lowest effective dose |
|
|
Term
| When perscribing a new drug for an elderly patient, what must a physician be aware of? |
|
Definition
|
|
Term
| What are the reasons for noncompliance in the geriatric population? |
|
Definition
1) too many medications
2) complex schedule of dosing
3) previous adverse drug event
4) physical barrier
5) expense
6) lack of patient education |
|
|
Term
| What are the risk factors for an adverse drug event? |
|
Definition
1) 6+ concurrent chronic illnesses
2) 12+ medication doses
3) 9+ medications
4) previous adverse drug event
5) low body weight/BMI
6) GFR <50 mL/min |
|
|
Term
A 79 y/o woman with Hx of CAD & CHF presents with N/V & abdominal pain that began 3 days ago.
Current meds include: warfarin, furosemide, digoxin, captopril, vit E, multivitamin.
Regimen had been stable until 2 weeks ago when furosemide was increaed to enhance control of CHF.
PE: CHF appears compensated & abdomen is unremarkable.
What may have caused her Sx? |
|
Definition
increased furosemide => hypokalcemia
hypokalcemia => digoxin toxicity => GI Sx |
|
|
Term
88 y/o man presents with one month Hx of:
1) deteriorating ability to perform activities of daily living
2) urinary incontinance
Medications include: terazosin, timolol ophthalmic drops, temazepan, APAP, & lisinopril. Also takes diphenhydramine as a sleep aid.
PE: mild bladder distention & scored 20/30 on MMSE
What may be causing his Sx? |
|
Definition
dihydramine has anticholinergic effects which cause both:
1) peripherally, urinary retention/incontinence
2) centrally, acute confusional state |
|
|
Term
A 102 y/o woman with osteoarthritis began course of ibuprofen for chronic knee joint pain, no longer responsive to APAP, several weeks ago.
PE: left knee joint changes consistant with osteoarthritis, w/o acute joint inflammation.
Labs, previously normal, are now:
BUNL 36
Creatinine: 1.9
Na: 135
K: 4.5
Cl: 90
Bicarb: 24
What has caused the abnormal lab results? |
|
Definition
| NSAID induced renal toxicity from reduction of renal prostaglandin formation. |
|
|
Term
An extremely malnourished 85 y/o man with Hx of dementia & seizure disorder presents with increased confusion & recent falls associated with an unsteady gait.
Current meds: donepezil & phenytoin
PE: muscle wasting, 17/30 on MMSE, ataxic gait.
Labs show:
albumin 2.2 (low)
phenytoin 15 (normal)
What may be causing his Sx? |
|
Definition
| Total phenytoin level is normal, but free phenytoin level is high due to decreased albumin level |
|
|
Term
An 86 y/o female with a Hx of DM, HTN, CAD, CHF, depression, osteoarthritis, GERD & glaucoma presents with a Hx & PE consistent with an exacerbation of CHF.
Current meds: insulin, enalapril, furosemide, metoprolol, aldactone, digoxin, rantidine, celecoxib, sertraline, ASA, & various opthalmic drops.
What may have caused her Sx? |
|
Definition
|
|
Term
An 86 y/o woman with Hx of DM, seizure disorder, and HTN was recently discharged from the hospital after a cerebral infarct & associated dysphagia with PEG tube placement, presents with a seizure.
Current meds: enalapril, amlosipine, pioglitazone, phenytoin, ASA, & clopidogrel
What may have precipitated her seizure? |
|
Definition
| contents of GI may interfere with absorption of medication => subtherapeutic levels |
|
|
Term
A 79 y/o gentleman with atrial fibrillation, CHF, HTN, & BPH presents with an INR of 4.5
Current meds: warfarin, ACEI/diuretic combo, finesterise, completing a course of sulphamethoxazole for cystitis
What may have caused this? |
|
Definition
| DDI of warfarin & sulphamethoxazone => enhanced anticoagulant effect of warfarin |
|
|
Term
71 y/o woman comes to the office for a routine PE.
Hx includes pedal edema due to venous insufficiency, episodic insomnia due to situational anxiety, and mild acid reflux disease.
She has no fatigue, anorexia, or GI Sx.
Current meds: garlic capsules, ginko biloba, kava, valerian
PE: normal
Lab results: normal, except ALT 210 & AST 230. Previous LFTs were normal.
What may have caused these abnormalities? |
|
Definition
| Kava can cause hepatotoxicity |
|
|
Term
| What should be examined for the cause of new Sx in the geriatric population? |
|
Definition
1) DDIs
2) homeopathic/OTC/Rx medication SE
3) Drug-organ toxicity
4) decreased albumin (in drugs highly bound)
5) non-adherence
6) GI contents (for PO medication) |
|
|
Term
|
Definition
| drugs that targets a biologically important process (measurable) |
|
|
Term
| Is targeted therapy more or less toxic than standard chemotherapy? |
|
Definition
|
|
Term
| What hallmark of cancer (esp. slow growing cancer) has been the recent target for targeted therapy? |
|
Definition
|
|
Term
|
Definition
| binds target => inhibition of TK => inhibition of downstream signals |
|
|
Term
|
Definition
|
|
Term
| What does imantinib bind to? |
|
Definition
| Bcr/Abl of Philadelphia chromosome (9 & 22) |
|
|
Term
| Which 2 GFs are important for angiogenesis? |
|
Definition
|
|
Term
| What is the difference between MAb (monoclonal Abs) & TKIs? |
|
Definition
| MAb:
1) EXTRAcellular
2) long t1/2 (days to weeks)
3) IV
4) more specific
5) NOT P450
TKI:
1) INTRAcellular
2) short t1/2 (hours)
3) PO
4) less specific
5) P450 (lots of DDIs) |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| What is the intracellular signaling pathway that VEGF & EGF use (and that is inhibited via TKI or MAb)? |
|
Definition
|
|
Term
| Do MAb or TKI's recruit host immune function? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
(due to decreased angiogenesis)
GI perforation
poor wound healing (wait 6 weeks to wash out drug prior to surgery)
hemorrhage
thrommboembolic events
HTN
etc |
|
|
Term
| What is needed to activate all TKs? |
|
Definition
|
|
Term
| Why is sunitinib considered a "dirty" drug? |
|
Definition
| many targets (not specific) |
|
|
Term
|
Definition
|
|
Term
|
Definition
rash
hypothyroidism
(+ some bleeding complications due to decreased angiogenesis) |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| rash (good sign, means sensitive to drug) |
|
|
Term
| Which 2 MAb's directly induce apoptosis? |
|
Definition
|
|
Term
|
Definition
lung (non-smokers)
(specific phenotype - asian female non-smokers
specific geneotype - specific genes) |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| What is the HER1 & HER2 TKI? |
|
Definition
|
|
Term
| What intracellular pathway is activated in HER2? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
1) interferes with thymidine synthesis via TS (thymidylate synthase)
2) RNA function via incorporation into RNA (low dose)
3) DNA synthesis via incorporation into DNA (high dose) |
|
|
Term
|
Definition
hand-foot syndrome
palmar-plantar erythrodysesthesia |
|
|
Term
| What 2 drugs can decrease 5-FU toxicity? |
|
Definition
1) uridine
2) thymidine (depending on schedule can also increase toxicity) |
|
|
Term
| Which 2 drugs can increase 5-FU toxicity? |
|
Definition
1) leucovorin
2) Thymidine (depending on schedule can decrease toxicity) |
|
|
Term
| What 3 drugs increase efficacy of 5-FU? |
|
Definition
1) leucovorin
2) MTX (if given second)
3) dipyridamole (blocks thymidine into cell) |
|
|
Term
| What 2 drugs decrease 5-FU efficacy? |
|
Definition
1) MTX (when given first)
2) dipyridamole (increased 5-FU clearance) |
|
|
Term
|
Definition
colon
breast
head & neck
esophageal
stomach
pancreas
(alone or as an adjuvant) |
|
|
Term
| What causes 5-FU resistance? |
|
Definition
1) deletion of enzymes involved in activation
2) increased catabolism
3) deficiency of folate cofactor
4) decreased incorporation into DNA & RNA
5) increased TS or alterations in TS (thymidylate synthase) |
|
|
Term
|
Definition
50% via 1st pass metabolism
80% by liver
20% by kidney |
|
|
Term
| What enzyme catabolizes 5-FU? |
|
Definition
| DPD (dihydropyrimidine dehydrogenase) |
|
|
Term
| Where is DPD highly active? |
|
Definition
|
|
Term
| What happens if DPD is present in intestinal mucosa? |
|
Definition
| interferes with 5-FU absorption |
|
|
Term
| What happens if a patient is DPD deficient? |
|
Definition
| need less dose (can lead to higher toxicity) |
|
|
Term
| What is the most common mutation in DPD (=> deficiency)? |
|
Definition
| G to A point mutation => truncated protein w/o activity (can be homo- or hetero- zygote) |
|
|
Term
| How is DPD deficiency tested for? |
|
Definition
| ingestion of 13C-Uracil => test 13C-CO2 after => results:
1) high peak = normal
2) low peak = partially DPD deficient
3) no peak = profoundly DPD deficient |
|
|
Term
| What does it mean if there is a severe toxicity to 5-FU? |
|
Definition
| not necessarily that 5-FU is not the right drug...just that the dose was too high |
|
|
Term
| What "antidote" is given for severe 5-FU toxicity? |
|
Definition
|
|
Term
| What causes 5-FU toxicity? |
|
Definition
1) misprogrammed pumps
2) transcription errors
3) DPD deficiency |
|
|
Term
| What effect does ethynyluracil on 5-FU? |
|
Definition
| 1) inhibits DPD
2) converts 5-FU to PO active agent
3) prolongs 5-FU t1/2 |
|
|
Term
| What is 5-FU activated to? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| What is the difference b/w capecitabine & 5-FU? |
|
Definition
same effectivity
less toxicity
increased response rate
liver failure does not seem to alter metabolism |
|
|
Term
| What is the 5-FU prodrug? |
|
Definition
|
|
Term
|
Definition
competitive DPD inhibitor => decreased 5-FU degradation
inhibits 5-FU phosphorylation in GI |
|
|
Term
| What happens if TS levels are high? |
|
Definition
|
|
Term
| What happens if there's high levels od DPD? |
|
Definition
| degrade 5-FU very quickly |
|
|
Term
| What happens if there's high level os thymidine phosphorylase? |
|
Definition
| degrade 5FdUMP too quickly |
|
|
Term
| What does 5-FU efficacy & toxicity depend on? |
|
Definition
|
|
Term
| What can alter 5-FU efficacy & toxicity? |
|
Definition
|
|
Term
| What versions of 5-FU are available with advantages? |
|
Definition
|
|
Term
| Why should a patient reciving 5-FU be genetically tested prior to initial drug administration? |
|
Definition
| predict toxicity & efficacy |
|
|
Term
Patient 1:
24 y/o white male admitted to a renad facility post-MVA w/ Dx of generalized weakness, decondition, & pulmonary insufficiency secondary to bilateral fractures & bilateral pneumothoraces. There is an addition Dx of anxiety.
Upon transfer, records indicate the patient is alert, upbeat, denies pain/difficultly breathing, clear lungs, no edema, normal abdomen, RRR, normal BP. He is beginning to attempt to walk. Childhood Dx of bipolar is noted, tho no relavent Sx evident.
Medications: OTC for resp, GI, CV, & nutritional indications. Clonazepam, quetiapine, fluoxetine, clonipramine, duloxetine, oxcarbazepine, carbamazepine, gabapentin, tramadol, topiramate, oxycontin, oxycodone/APAP, APAP, promethazine, xolpidem, & monafinil.
4 months after admission, the patient has stopped participating in PT. He is bed riffen, claims to have suicidal thoughts, and engages in drug-seeking with staff. He is eventually admitted to the hospital wtih Dx of resp. failure, pneumonia, septicemia, renal failure, urosepsis, bed sores, & severe deconditioning. He ends up recieving a colostomy, tracheostomy, & Foley catheter.
After several weeks of medical stabilization, patient is discharged to a long-term nursing care facility. Future of patient is uncertain.
What most likely happened to this patient? |
|
Definition
| Most likely iatrogenic & drug-induced |
|
|
Term
| What are the indications for carbamezapine, oxcarbamazepine, topiramate, or gabapentin? |
|
Definition
| They are anti-seizure medications - tho with many off-label use s.a. anxiety & neuropathic pain |
|
|
Term
| What are the indications for oxycontin & oxycodon/APAP? |
|
Definition
opioid for moderate to severe pain
oxycontin - long-term, usually for terminal patients
oxycodon/APAP - short term only |
|
|
Term
| What are the indications for tramadol? |
|
Definition
| opioid for long-term moderate pain (must watch for DDIs - esp. with antidepressants => seizures) |
|
|
Term
| What are the indications for clonazepam & zolpidem? |
|
Definition
benzodiazepines - for short term use
clonazepam: anxitey & panic
zolpidem: insomnia |
|
|
Term
| What are the indication for promethazine? |
|
Definition
| FG antihistamine for allergies, sedation & nausea |
|
|
Term
| What are the indications for clonazepam & zolpidem? |
|
Definition
benzodiazepines - for short term use
clonazepam: anxitey & panic
zolpidem: insomnia |
|
|
Term
| What are the indications for promethazine? |
|
Definition
| FG antihistamine for allergies, sedation & nausea |
|
|
Term
| What are the indications for modadinil? |
|
Definition
| stimulant for excessive daytime sleepiness |
|
|
Term
| What are the indications for quetiapine? |
|
Definition
| SGA for bipolar or depression |
|
|
Term
| What are the indications for duloxetine, fluoxetine or clonipramine? |
|
Definition
|
|
Term
| How could the downward spiral of patient 1 hace been avoided? |
|
Definition
1) triage Tx priorities
2) coordinate Rx from physicians
3) use rational therapeutics for the high priority conditions
4) pharmacy check |
|
|
Term
Which CNS disorders should have been emphasized in an initial Tx plan for patient 1?
A) depression
B) BPD
C) pain
D) anxiety |
|
Definition
none. His pain & anxiety were well managed when he was admitted to the rehab facility.
He should have been continued on current medication upon hospital release, possible dose reduction considered. |
|
|
Term
Assume paitent 1 was admitted to the rehab facility NOT on any medication.
Of the medications he was perscribed, which were the only ones he should have been? |
|
Definition
oxycodon/APAP maybe clonazepam for anxiety (tho busparone would be better indicated), transition pain meds to NSAIDs
consider an antidepressant if neuropathic pain & anxiety is the issue |
|
|
Term
| Why is co-administration of fluoxetine & tramadol CI? |
|
Definition
Fluoxetine inhibits CYP2D6
CYP2D6 metabolizes tramadol
risk increased for seizures & serotonin syndrome |
|
|
Term
|
Definition
| potentially life threatening syndrome consisting of mental status changes accompanied by combination of fast HR, fever, shivering, diarrhea, muscle spasms, or ataxia |
|
|
Term
|
Definition
supportive measures
5-HT antagonist |
|
|
Term
Patient 2:
72 y/o diabetic white woman, normal BMI. BP 135/85 & total cholesterol 185. She's been living in a privately operated geriatric residence for 3 years.
At time of admission, she was taken off hypoglycemics & Tx with insulin was started. Each day, she was given insulin before breakfast & additional doses based on her blood sugar before lunch & dinner. She suffered from HF & recieved lisinopril, amlodipine, furosemide, digoxin, and potassium supplements. She was also treated with rosuvastatin, clopidiogrel, omeprazole, & an antacid for chronic peptic ulcer, a stool softener & multiple vitamins. Furosemide was given 3x per day & rosuvastatin was given after dinner. Otherwise, all her medications were given in the morning with first dose of insulin. Though, she has a significant deficit in short term memory, she was cheerful & active and had a number of friends.
What were the roles of lisinopril, furosemide, potassium supplements, and amlodipine in her HF? |
|
Definition
Lisinopril: reduces pre-load & after-load by reducing ATII => reduced cardiac work (also reduce cardiac & vascular remodeling)
furosemide: reduces volume => reduces pre-load => reduces cardiac work (short half life, so multiple doses needed)
Digoxin: increases CO w/ minimal increased cardiac work
KCl: to prevent hypokalemia from furosemide => increased cardiac excitability & potentiation of arrythmias with digoxin
amlodipine: decreases preload when ACEI insufficient, but doesnt reduce inotropy |
|
|
Term
| Why was patient 2 given rosuvastatin, clopidogrel, omeprazole, stool softener, & vitamins? |
|
Definition
Rusovastatin to lower cholesterol since diabetics are prone to CAD - given at night since cholesterol synthesis is more active at night
Clopidogrel is an antithrombolytic
Omeprazole (PPI) for chronic peptic ulcer
Stool softener: important since dehydration can occur with diuretics
Vitamins: Why not? |
|
|
Term
| Why wasn't patient 1 given a β blocker? |
|
Definition
| β blockers decrease cardiac work. Since patient 1 has memory deficit & diabetes, if she forgot to eat after taking insulin, β blockers would predispose her to a hypoglycemic event AND mask the Sx |
|
|
Term
She was noticed to be lethargic with a mild temperature. She was Dx with UTI. She was started on 10 days of levofloxacin with maintenance of omeprazole for peptic ulcer. On the 5th day, she complained of nausea. The next morning, she complained the nausea was worse & she had bowel pain, felt disoriented & as if her heart were bumping around in her chest. She had experienced both V/D overnight.
She was given her morning dose of insulin with breakfast, however she did not eat due to lack of appetite. 2 hour later, she summoned the nurse saying she was having a hypoglycemic episode. She was given cola.
At noon, she felt terrible. She was nauseated, weak & afraid. Her blood glucose was 110, so insulin wasn't administered and was tols she'd feel better after lunch.
30 min later, she went into ventricular fibrillation & died. Her death certificate indicated HF due to various conditions.
What happened? |
|
Definition
Digoxin has a very narrow therapeutic window and a long half life.
Levofloxacin is known to inhibit the metabolism => toxicity => Sx & death |
|
|
Term
| Were there indications of glycoside toxicity in patient 2? |
|
Definition
Lot of them:
GI difficulty - N/V/D
anorexia
heart bumping in chest/tachycardia
anxiety |
|
|
Term
| Why were the Sx of glycoside toxicity of patient 2 not handled properly? |
|
Definition
| indifference, confusion, & ignorance |
|
|
Term
| What are the 3 isoforms of endothelins? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| What receptors are acitvated by ET-1? |
|
Definition
|
|
Term
| What can increase ET-1 synthesis by endothelial cells in low shear stress? |
|
Definition
ATII
thrombin
various cytokines |
|
|
Term
| What can decrease ET-1 synthesis by endothelial cells in high sheer stress? |
|
Definition
|
|
Term
|
Definition
| Overall potent VC
ETB: NO & PGI2 release => VD
ETA & ETB: VC
∴ a transient hypotension followed by a prolonged hypertension |
|
|
Term
What is the most important effect of ET-1 in most vacular beds?
coronary arteries? |
|
Definition
|
|
Term
| Where is ET-1 a potent mitogen for? |
|
Definition
vascular smooth muscle
cardiac myocytes
glomerular mesangial cells |
|
|
Term
|
Definition
1) HTN
2) cardiac hypertrophy
3) atherosclerosis
4) CAD
5) MI
6) asthma
7) pulmonary HTN |
|
|
Term
| What are the 2 ET-1 receptor anatagonists? |
|
Definition
1) Ambrisentin
2) Bosentan |
|
|
Term
| Of the 2 ET-1 receptor antagonists, which one blocks only ETA?
both? |
|
Definition
Ambrisentin - A
Bosentan - both |
|
|
Term
SOA
bosentan & ambrisentin |
|
Definition
|
|
Term
| Why shouldn't bosentan nor ambrisentan be given to women? |
|
Definition
| teratogenic, so can't be given til pregnancy ruled out |
|
|
Term
|
Definition
| fatal hepatotoxicity (∴ LFTs needed) |
|
|
Term
| What are the 3 most important members of the family of peptides with natriuretic, diuretic, & vasorelaxant properties? |
|
Definition
ANP (atrial natriuretic)
urodilatin (~ANP)
BNP (brain natriuretic) |
|
|
Term
| Where are ANP & BNP synthesized? |
|
Definition
| ventricular myocardium & other tissues |
|
|
Term
| How are ANP & BNP released from the myocardium? |
|
Definition
| by atrial stretch & reflect volume expasion |
|
|
Term
| What 4 "other" factors can cause release of ANP & BNP? |
|
Definition
| 1) sympathetic activation (α1A receptors)
2) endothelins (ETA receptors)
3) adrenal steroids
4) vasopressin |
|
|
Term
| In what conditions might the plasma levels of ANP & BNP be increased? |
|
Definition
HF
chronic renal failure
primary aldosteronism |
|
|
Term
| What correlates with the severity of HF? |
|
Definition
|
|
Term
| What receptor subtype do the natriuretic peptides act thru? |
|
Definition
|
|
Term
|
Definition
| activation of GC => increased cGMP |
|
|
Term
| How does administration or release of natriuretic induce sodium & water loss? |
|
Definition
1) increase GFR (via dilation of afferent glomerular arteriole & constriction of efferent glomerular arteriole)
2) decreasing proximal tubular sodium uptake |
|
|
Term
| What 3 hormones that increase BP are suppressed via ANP & BNP? |
|
Definition
1) renin
2) aldosterone
3) vasopressin |
|
|
Term
| What direct effect do natriuretic peptides have on BP? |
|
Definition
|
|
Term
| Do natriuretic peptides have long or short half lives? |
|
Definition
|
|
Term
| How are natriuretics peptides cleared from the system? |
|
Definition
| 1) bind to ANPC on endothelial cells => internalization => degradation
2) degraded by extracellular neutral endopeptidases |
|
|
Term
| What is the recombinant form of BNP? |
|
Definition
|
|
Term
| What is the recombinant form of urodilatin? |
|
Definition
|
|
Term
SOA
nesiritide & ularitide |
|
Definition
| IV administration to hospitalized patients with decompensated HF |
|
|
Term
Effect
nesiritide & ularitide |
|
Definition
improved CO
decreased BP
reduced activation of the sympathetic nervous system & renin-angiotensin system
decreased dyspnea & fatigue as hemodynamics improve |
|
|
Term
|
Definition
|
|
