direct agonist: directly activates adrenoceptors or

indirect agonist: stimulates catecholamine release or inhibits reuptake of released catecholamines

any sybstance capable of being stored and released in place of the substance normally serving as the transmitter in a given neuron

Transmission will be altered if the effect of the false transmitter on postjunctional receptors differs significantly from that of the normal neurotransmitter

e.g. Methyldopa

acts as "false transmitter" (met by same enzymes as those that make NE from dopa)

Action: agonist at presynaptic alpha 2 adrenergic receptor (eg of autoreceptor on preseynaptic fiber: inbitory action); Thus inhibits adrenergic neuronal outflow from the brainstem-->decreases NE release-->reduces output of vasoconstrictor adrenergic signals to SNS

Mechanism: synthesized to methylNE (by dopa decarboxylase and dopamine hydroxylase)

Sympathetic transmission: BLOCKED

Clinical Use: HYPERTENSION(esp during pregnancy)

Problems: SERIOUS RARE side effecs (hepatotoxicity and hemolytic anemia) limit use outside of pregnancy (in pregnancy: safe and effective for both mom and baby)

Action: a)specific blocker of vesicular pump in monoaminergic neurons (irreversible inhibition of VMAT: vesicular monoamine transporter)

Effect: decrease NE released into terminal (bc less loaded into vesicles)-->sypathetic transmission=BLOCKED

Clinical Use: HYPERTENSION (peripheral and central mechanisms)

Adverse effects: Because of adverse effects, RARELY USED ANYMORE; peripheral adverse effects (orthostatic hypotension, increased GI activity); CNS effects: sedation, SEVERE DEPRESSION (suicide in susceptible indviduals)

"Uncoupler" of NE stimulus/secretion

Actively transported into neuron via NET (NE transporter); Concentrates in vesicles so therefore displaces NE; gradually depletes NE (occurs gradually so MAOs in cytoplasm not get overwhlemed: can break down NE as its displaced gradually from the vesicles by drug); does not stimulate adrenoceptros directly

Mech: Block NET; displace NE from from vesicle

Effect: Deplete NE (after gradual release)

Sympathetic transmission: BLOCKED

Use: HYPERTENSION but now OBSOLETE

Prob: Loss of sympathetic reflexes (produced postural hypotension)

takes NE up into presynaptic cleft from synaptic cleft (one way of termination NE action on postsynaptic receptors); NE then in cytoplasm of presynaptic cleft: concentrated into vesicles via VMAT

NET=aka UPTAKE 1 --> recycles NE (unlike COMT - uptake 2: takes NE up into postynaptic cleft: limits extracellular spread of NE that is not recycled by NET), and MAO -breaks down NE in presynaptic cytoplasm)

Efficiency of NE recycling (via NET) depends on location:

Heart: 90% of released NE removed via NET

Vasculature: 60% of released NE removed via NET

Inhibits NET/UPtake 1 (therefore less NE taken back into presynaptic cleft fom synaptic cleft: NE stays there, having an effect on postsynaptic receptors, longer)-->Enhances NE signaling-->decreases uptake for vesicular recycling (therefore more NE must be made from scratch from tyrosine, dopa, dopamine rather than from recycled NE); noes NOT affect NE already stored in presynaptic cleft

Peripheral effects: increased BP, HR (potential for stroke, arrythmias, MI, sudden death, other sns hyperactivity)

Central effects: Euphoria, inc alertness, arousal (central action on dopamine, serotonin, NE - all have inc effects bc stay in synaptic cleft longer, less uptake bc NET is inhibited)

Medical use: topical local anesthetic for surg involving nasal mucosa/lacrimal ducts (causes vasoconstriction: less bleeding: keeps local anasthetic in isolated area and has some intrinsic anesthetic effect also)

No direct effect on adrenoceptors; must be transported into nerve terminal and synaptic vesicles (eg. a drug that is taken up into presynaptic cleft by NET, then taken up by VMAT to store in versicles-->displaces NE from the vesicle-->if NE is dumped into cytoplasm as result in high enough conc, then MAO is overwhlemed and NET acts in reverse to release NE from the presynptic cleft into the synaptic cleft, where it can have an effect on the postsynaptic receptors: therefore the drug that displaced NE from the vesicles has an indirect SYMPATHOMIMETIC effect; however this effect is only transient, because eventually the NE displaced from the vescicles runs out and is replaced by the drug that has no direct effect on adrenoceptors, the MAO's are no longer overwhelmed so can breakdown any NE they come across in presynaptic cytoplasm: no more NE released into synaptic cleft: diminished sympathetic activity at that synapse.

Acute/initial action: sympathomimetic

Chronic/longer term: sympathoLYTIC

produced by fermentation and bacterial met; high levels in beer, wine, cheese, processed meats/sausage

Normally metabolized in GI tract and liver by MAO

In presence of MAO-I can accumulate and displace NE from vesicles

(Tyramine is poorly retained in synaptic vesicles but its metabolite octapamine can be stored at high concentrations)

Displacement of NE from vesicles results in a large increase in cytoplasmic NE which is not at all metabolized in cytoplasm due to inhib of MAO: NET reverses and transports the NE displaced into cytoplasm out into synaptic cleft: increased sympathetic activity on postsynaptic receptors - a HYPERTENSIVE crisis

*amphetamine - narcolepsy

 *methamphetamine

*ephedrine - decongestant

*pseudophedrine - decongestant

*methylphenidate - ADHD

COMT: highest activity in LIVER; inhibited by entacapone

MAO: surface mem protein of mitochondria; high levels in monoamine-containing nerve terminals in liver, kidney, gut; Inhibitors used as antidepressants (iproniazid) - can cause potentially lethal wine and cheese syndrome.

Lower levels of both COmT and MAO found in wide variety of other tissues

While transport back into presynaptic nerve terminal (via NET/Uptake-1) is primarily responsible for terminating the action of neuronally released catecholamines, MAO and/or COMT may play a key role in inactivation of circulating catecholamines, catecholamine-like drugs, etc

inhibitor of COMT (therefore less inactivation of synaptic catecholamines, esp NE)

Used as adjunt drg therapy of PARKINSONS

Minimal effect on sympathetic transmission

Prob: adverse effects assoc with increased DA

MAO-I  = MAO inhibitor (therefore less breakdown of catecholamines like NE: can increase at synaptic cleft, and also natrually occuring substances like Tyramine: more tyramine around, can displace NE from presynaptic vesicles: act as indirect sympathomimetic)

Use: Depression, parkinson's

Prob: increased TYRAMINE levels; Serotonin syndrome with SSRIs

Indirect sympathomimetics

decongestants

aka RITALIN

Indirect sympathomimetic

ADHD

Indirect sympathomimetic

narcolepsy

contraction in: vascular smooth muscle, uterine sooth muscle, radial muscle of pupil, GI inhibition

Relative potency: EPI>NE>>>ISO (not v effective)

Signal via Gq pathway; mobilize Ca from intracellular stores; activates PKC (both result in protein phosphorylation); Found on vascular smooth muscle, GU sm muscle, intestinal sm muscle, heart, liver; mediates VASOCONSTRICTION

Key responses: vasoconstriction (innervated), pupillary dilation, ejaculation, inhib micturation, GI inhib

Clincal uses: nasal decongestants, adjunct to local anesthetic action, maintain BP (ie. shock), treat paroxysmal atrial tacy, eye drops for red eye, mydriatic (dilate pupil)

Signals thru Gi: inhibits adenylyl cyclase: activates certain K+ channels, inhibits neuronal Ca2+ channels: (results in decreased protein phosphorylation) + decreased transmitter release; Found PREsynaptically and function as UTORECEPTORS to INHIBIT sympathetic output; On pancreatic beta cells ot inhibit insulin release; on platelets to inhibit platelet aggregation; (this is neg feedback when NE is released to prevent further NE release)

Key responses mediated: vasoconstriction (UNinnervated), prejunctional INHIBITION of NE release (autoreceptors)

Signal through Gs: activate adenylyl cyclase: inc cAMP and PKA: increaed Phosphorylation of ion channels etc

 Beta r agonist:

Action - relax bronchial sm muscle and decrease airway resistance

clin use: asthma, COPD

probs: cardio effects (beta1 rs have cardiac effects); solution to prob: give via AEROSOL - deliver to bronchi where want action; rapid response; challenge: only get 10% of dose into lungs, must master technique

found in: Heart (increased inotropy, chronotropy, conduction velocity in AV node); Kidney: inc renin release

Key responses mediated: Cardiac stimulation (innervated), secretion of renin

Found in: Smooth muscle (relaxes contractile apparatus; esp for relaxation of bronchial smooth muscle); Liver (glycogen phosphorylase activation and glycogen catabolism; increase plasma glucose); skeletal muscle (stimulate glcogenolysis; promotes K+ uptake)

Key responses mediated: Cardiac stimulation (UNinnervated, minor), BRONCHODILATION, uterine relaxation, GI inhibition, vasodilation (UNinnervated)

aka EPIPEN; stimulated ALL alpha and beta receptors (but usually see vasoconstriction - vasodilator effects usually masked);

"all purpose" catecholamine bc agonist at all alpha and beta r's

Clinical Use: treatment of acute anaphylaxis or cardiac arest; adjunt with local anesthetics (bc vasoconstricts the area - keeps local anasthetic from leaving set area); (also was in OTC bronchodilator, primatene mist, via B2 activation, but no longer sold)

prob: activates ALL alpha, beta receptors --> excessive cardiac stimulation

EPI REVERSAL: unmask epi vasoconstriction effects by giivng phentolamine: blocks alpha receptors, so only beta receptors are activated by epi: has vasodilatory effects now instead

aka ISUPREL; stimulates beta 1 and 2 (NOT alpha);

i.e. acts on heart: cardiac stimulation (via Beta 1) - increaed HR; did use for asthma but not anymore due to excess cardiac stim.

alpha (1) receptor agonist (causes vasoconstriction-->increased BP)

Action: alpha1 r agonist; constricts vascular sm muschle

Clinical use: nasal congestion (topical), ophthalmic hyperemia (topical), shock (iv)

probs: bradycardia (reflex brady response to increase in BP caused by drug)

(egs visine, afrin)

direct effect on alpha, beta

Mostly act as Indirect Sympathomimetics (IS)

(similar structure as epinephrine, but different PK and PDs:)

PKs: more sustained action bc of resistance to both MAO and COMT--> ORALLY active

PKs: some direct action at beta rs (less on alpha); STRONG INDIRECT action on noradrenergic nerve endings in periphery and similar effect in CNS

(don't take with MAO-I: will have increased effect - less NE broken down by MAO when displaced from vesicles: more reaches synaptic cleft)

Medical uses: decongestant in OTC cold remedies acting thru direct and indirect stim of alpha r's in periph bl vessels to cause vasoCONSTRICITON and thus relieve swelling in nasal mucosa

Non-med use: "ephedra" products as dietary supplements for wht loss and strength training

CNS effects though to result from amphetamine-like action in brain

Adverse effects: 1) increased BP, stroke (alpha 1: vasoconstriction) 2) arrhythmia, MI (Beta 1: cardiac stimulation), 3) CNS stimulation, seizures [similar to adverse effects of AMPHETAMINES - similar structure)

One of most potent Indirect Sympathomimetic of CNS

eg. Adderall

treat ADHD

10-30 mg oral: wakeful, alert, elevated mood, increased concentration ability

higher dose: depression, fatigue, palpitation, dizzy agitated, confused

Prob: tolerance develops, potential for abuse, adverse reactions can be lethal (arrhythmia, angina, stroke, psychosis, convulsions)

eg. Phen-fen was appetite suppressant - caused heart valve damage (unknown mech); weight loss mech due to RED FOOD INTAKE (effect on lat hypothal feeding center); due to rapid tolerance you develop, not ideal for wght loss!!

Toxicity: rare when dose < 15 mg (acidify urine to increase elimination, take sedative for CNS sx, alpha antagonist for sever HTN)

aka RITALIN

"amphetamine like" CNS stimulant

Treatment of ADHD

aka catapres, duraclon

action: alpha2 receptor agonist; acts in CNS to dec sns activity to heart and vessels

clin use: HTN

probs: sedation, dry mouth; withdrawal syndrome after long term use (probs due to long term suppression: body compensates by becoming more sensitized: HTN, tachy, angina, mi) - can treat hypertensive crisis with labetalol (competetive antag at alpha, beta r's)

Beta agonist

tx asthma - long acting but slow onset (contrast to albuterol: fast onset)

kidney: DA acts instead of NE

action: stimulate DA rs (esp in kidney) - dilation of bl vessels in kidney; also direct A, B r agonist and IS activity

clin use: SHOCK; also CHF

prob: must give IV

ipsi, unilateral: ptosis, miosis, anhidrosis; results from interruptino of sympathetic ns to face

Diagnosis (pre v postganglionic lesion):

Phenylephrine = A1 agonist: give in both cases, acheive puilarry dilitation (bc directly activates r's on radial m's that dilate puil by constricting)

Hydroxyamphetamine: taken up by NET, VMAT: displaces NE from vesicles: NE accum in cytoplasm, leaves presyn terminal via NET acting in reverse: achieve dilation only in situation where lesion is PREganglionic (bc still has NE available at postsyn cleft bc no lesion/prob at this level); when lesion is postganlionic, not have NE available, so get no NE release despite presence of IS (NO dilation: pupil stays constricted)

aka REGITINE, ORAVERSE

phentolamine = Competetive alpha blocker

phenoxybenzamine = NON competetive alpha blocker

clin use: mgmt of pheochromocytoma; NOT useful fo htn

prob: excess cardiac stim, MORE so than just a baroreceptor reflex: these are A antagonists - BOTH a1 and a2 - so blocks vasoconstrictino med by a1 but ALSO blocks prejunctional inhibi of NE release: when the a1 antagonism effect decreaes BP, baroreflex kicks in to increase sns activity at heart level-->inc HR to compensate (reflex tachy); normally the a2 r's wld help control this reflex and make sure not too much NE wld be released at heart level, but bc these alpha antagonists are non-selective for BOTH a1 and a2, a2 is blocked from giving its normal feedback: miss the blockade of excess NE release at heart level-->escess cardiac stimulation

alpha 1 selective antagonists

action: competitive antagonists selective for alpha 1 r's (avaoids excess cardiac stim prob); dec TPR and reduction of sympathetically-mediated stim of smooth muscle

clin use: HTN, CHF, BPH

prob: "1st dose phenomenon" = severe hypotension/syncope; impotence

aka FLOMAX

alpha 1a selective antagonist

relatively selective effect on urinary flow; ts BPH w less incidence of orthostatic hypotension :)

action: mixture w one isomer a potent a1 blocker and another a potent b blocker (blocks vasoconstriction, cardiac stimulation via b1, respectively)

clin use: HTN in PREGNANCY

probs: postural hypotension, bronchoconstriction (bc also blocks b2 responsible for bronchodilation)

noncovalent inhibitors of cholinesterase mech: occlude active site short acting clin use: DIAGNOSTIC Does not enter cns (edro doesnot; don does)

Another use for Donepezil: AD

Reversible substrate inhibitors of cholinesterase; Carbamates Mech: serves as substrate and forms more stable (but still reversible) enzyme-substrate complex Medium acting physo enters cns; neo does not

clin use: MYASTHENIA GRAVIS

cholinesterase inhibitor: IRREVERSIBLE substrate inhibitor; Organophosphate Mech: serves as substrate and forms stable and for all practical purposes PERMANENT enzyme-substrate complex Long acting topical use only *key difference: enzyme is phosphorylated and that form is very stable - undergoes "aging": breaking of one of the oxygen-phosphorous bonds of inhibitor in favor of stronger bonds between enzyme and inhibitor; must treat wit hstrong nucleophile prior to aging to "regenerate" enzyme (i.e. to cure a pt poisoned by this drug)

clin use: GLAUCOMA

Organophosphates  - irreversible substrate inhibitors of choinesterase

Used as military "nerve gas"

Action at Nicotinic rs: depolarizing blockage; target = nmj: muscle weakness, resp failure, death

at Muscarinic rs: HYPERACTIVITY:

target 1: periph psns: bradycardia or escess airway secretion leading to death

target 2: cns: dec resp drive or gen seizures leading to death

DUMBELS - used to recognize immed effects of toxicity (diarrhea, urination, miosis, bronchospasm/bradycardia, emesis, lacrimation, salivation/sweating)

selectively activate nicotine r's at nmj, ganglia EFFECTS OF NICOTINE OR ANY NI R AGONIST MAY REFLECT STIMULATION OR BLOCKADE OF NICOTINIC RECEPTORS Effect on BP, HR: first see decrease, then increase (once Ach all broken down and vagal dominance no longer applies, then Epi takes over at heart and blood vessels)

produces tolerance; physical dependence; withdrawal

successful smoking cessation: reduce craving, inhib reinfrocing effects

curare-like; neuromuscular blocker (non-depolarizing blockade) action: competetive antagonist at nicotnic receptors of nmj mn use: induce paralysis in major surg procedures probs: fall in arterial pressure

-reverse action with neostigmine but need to co admin with atropine (to prevent effects at muscarinic rs - only want effect on nic rs)

Calcium +150 mV, sodium 70, potassium -98

cardiac cells are selectively perm to K+ at rest:

If extracellular K+ DECREASES, the cell HYPERPOLARIZES (K+ will leave the cell, which makes the cell less +/more -)

If extracellular K+ INCREASES, the cell DEPOLARIZES (K+ will enter the cell, which makes the cell more +/less-)

Occurs in atrial, ventricular muscle and purkinje fibers (resing membrane potential around -90 mV)

Phase 0: rapid depolarization (sodium enters through fast sodium channels)

Phase 1: rapid initial repolarization (closure of soidium channels)

Phase 2: neutral plateau (calcium and some sodium enters; potassium exits)

Phase 3: final repolarization (potassium exits)

Phase 4: resting membrane potential (potassium exits)

Normal in SA and AV node (resting potential of around -65 mV)

Only 3 total phases (versus 5 in Fast response AP)

Phae 0: Rapid depol (calcium enters)

Phase 3: repolarization (potassium exits)

Phae 4: slow depolarization = AUTOMATICITY (slow decrease in potassium exit, increase in sodium and calcium entrance)

Early afterdepolarizations; interruptions of phase 3 repolarization, esp when the ap is abnormally prolonged (i.e. the case of LONG QT intervals); thought to be responsible for TORSADE DE POINTES caused by some antiarrhythmic drugs

esp during very SLOW HR, low ec K+, drugs that prolong AP duration

Delayed afterdepolarizations; occurs during phase 4 (resting membrane potential); sometimes see when intracellular CALCIUM is increased (i.e. when myocytes are damaged or in presence of DIGITALIS)

esp when heart rate is very HIGH

Na channel blockers bind when na channel is in the open or inactivated state, drugs dissoc when the channel is back to rested.

IA - dissociate intermediate rate (Na block modestly enhanced at faster rates)

IB - dissociate rapidly (Na block enhanced at faster HR)

IC - dissociate slowly (Na block best when HR is normal or even slow)

Class IA antiarrhythmics

Block fast Na channels - SLOWS conduction by dec slope (and rate) of phase 0 of fast response AP in atria, ventricles, purkinje fibers

Also: Increases AP DURATION and REFRACTORY PERIOD (bc BLOCKS K+ channels for phase 3 repolarization)

Both meds may cause "QUINIDINE SYNCOPE" - which may lead to TORSADE DE POINTES: AP duration is increaed threfore QT interval is prolonged (only the NAPA version of Procainamide - acetylated version - has K+ blocking properties like Quinidine, and therefore prolongs AP, QT and can cause Torsades)

Current indication: post Mi v tach; emergency treatment of v tach or fib

Class IB antiarrhythmic

Unbinds Na channels rapidly-->beat to beat ACCUMULATION of blocked Na channels

mn effect: blocks fast Na channels-->slows conduction by dec slope of phase 0 of fast respnse APs in atria, ventricles, Purkinje fibers

Especially effective during FAST HRs when Na channels spend more time in open/inactivated state

Limited use: emergency setting for post MI pt with repeated v tach

(decrease AP duration and refractory in contast to IA drugs that lengthen both)

Current indication: emergency setting to suppress v tach post MI

Class IC antiarrhytmia

Unbinds Na channels SLOWLY during channel resting state

mn effect: block fast NA+ channels-->SLOWS conductino by dec slope of phase 0 fo fast response APs in atria, ventricles, Purkine fibers

Most effective AT NORMAL (to slow) HRs (bc of SLOW unbinding)

Usually Class IC's have Little effect on AP duration or refractoriness but Flecainide is an acception: blocks K+ current involved in repolarization (shares this in common with Class IA drugs Quinidine and Procainamide)--> prolongs AP duration (and refractory period I assume...can it therefore lead to Torsade similar to that seen in Quinidine syncope?)

Current indication: USE WITH CAUTION - DO NOT GIVE TO PT POST MI - only for a fib or svt in pt without evidence of structural heart disease

Class II antiarrhythmics

Beta Blockers

Block cascade caused by beta receptor activation (i.e. inreased cAMP, phosphorylationf of Ca channels, Ca influx):

Effects: 1)dec rate of phase 4 depolarization in automatic cells (SA, AV, Purkinje - bc largely depend on Ca influx for phase 4 slow depolarization/automaticity)-->dec HR, ectopic automaticity

2) SLOW conduction thru AV node - enhances AV block (esp good to treat supraventricular tachy)

3) Reduce myocardial contractility

**Beta Blockers are the only class shown to decrease sudden death from arrhythmias in post MI pts!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Class III antiarrhythmic drug

Mn mech: PROLONGS AP duration (PROLONGS refractory period/delays repolarization) via blockage of K+ channels responsible for PHase 3 repolarization in atria, ventricles, Purkinje fibers (good for blocking re-entry)

***Amniodarone in particular has characteristics of ALL FOUR CLASSES of antiarrhythmic drugs!!!!!!!!!!!

(blocks Na channels like Class I - decreases Vmax of fast response APs, blocks Beta r's like Class II, blocks K+ channels like it should since it is considered a Class III, and blocks Ca channels like Class IV)

Problem: potentially fatal PULMONARY FIBROSIS, hypo/hyperthyroidism

Like Class IA Quinidine, Procainamide as well as IC Flecainide, Amiodarone prolongs the AP and therefore prolongs the QT interval-->risk of TORSADES DE POINTES

Main current indications: a) atrial fib (dec ventricular response), 2) acute MI with V tach refractory to other drugs

Class IV antiarrhythmic drug

Block L-type Ca2+ channels in myocardial and smooth muscle (potentially can dec HR and BP...)

Mn effects are on SLOW response APs (SA, AV nodes):

1) decrease slope of phase 4 depolarization (depends on Ca influx) - DECREASE HR

2) Decreae in rate of depolarization and amplitude of phase 0 in slow reponse cells (also depends on Ca influx majorly) - SLOW AV CONDUCTION (manifests as a prolong PR interval)

Like with Na blockers, Ca blockers exhibit "use dependence" - more effective at FASTER rates - esp IB Na blocker eg. Lidocaine

Current indication: supraventircular tachy

Activates a K+ current in Av nodal cells which decreases the conduction across the AV node and can potentially stop the tachy

Problem: v short half life: must give quickly and IV only

-very good for treating supraventricular tachy

An organic nitrate;

mech: act as an exogenous NO doner

-->NO activates Guanylate cyclase, activates cGMP, activates PKG (protein kinase G), activates Ca SPARK pathway (Ca enters SR from cytoplasm, RyR releases Ca right next to voltage gated L-type Ca channels in vasc sm muscle cell membrane, membrane hyperpolarizes, dec Ca enters cell thru L type channels, cytoplasmic Ca drops, decreased contractility: RELAXATION of vascular smooth muscle cells

Main Cardiac effect: DECREASED LVEDV (aka PREload)--> Improves CORONARY BLOOD FLOW (because an elevated LVEDV impedes coronoary circulation in the inner layers of myodardium which occurs during diastole)

Treats: Ischemic heart disease (helps deliver inc FLOW to heart to help optimize the supply/demand balance)

(Isosorbide dinitrarte also an organic nitrate, but different kinetics:)

Kinetics: acts quickly and briefly; half life is only a few seconds

 *Effects of this drug, due to relaxation of vascular smooth muscle cells and subsequent decreases in BP, triggers a REFLEX TACHY which increases myocardial O2 demand, which is the opposite effect we want for pt with IHD (may therefore somewhat negate the drugs effect)

-->Consider giving organic nitrates in COMINATION WITH B BLOCKERS to decrease this reflex tachy effect

-May also cause NITRATE TOLDERANCE

Adverse effects: Orthostatic hypotension, tachy (mech stated above), H/A, TOLERANCE, dizziness, flushing, syncope

-May also consider prescribing IN COMBINATION WITH DIURETIC - to counteract the neg effects of nitrates on circulating volumes)

Organic Nitrate (like Nitroglycerin)

Used to treat Ischemic Heart Disease

Longer half life than Nitroglycerin; takes longer to have effect and has effect a longer duration

Compared to isosorbide monohydrate, this drug has a large first pass effect in the liver and therefore a much LOWER BIOAVAILABILITY

Type I Ca channel blockers: electrophysiologic effects in add to vascular effects (unlike type II - ie Nifedipine - only see vascular effects)

Can be used to treat Ischemic HD

 Mn adverse effect = conduction abnormalities

Class II Calcium Channel blocker

Primarily vascular effects (rather than electrophysio, which is more Class I like verapamil, Diltiazem)

Can use to treat Ischemic HD

mn side effect: Peripheral edema

1) inc o2 delivery to ischemic myocardium by vasodilating coronary arteris (CA SPARK PATHWAY)

2) Reduce myocardial oxygen consumption by reducing afterload (dec systemic arterial pressure - dec wall tension - dec o2 demand)

3) reduce myocardial o2 consumption by red HR, contractility

**These drugs specifically bind to L-type Voltage gated Ca channels in memb of smooth muscle cells rather than cardiac myocytes due to their preferential affinity for membranes closer the the resting potential of a smooth muscle cell (which is more DEpolarized than a cardiac myocyte, which has a rmp that is more negative and threfore comparatively HYPERpolarized)

a Beta Blocker

can be used to treat IHD

Mech: DEC myocardial oxygen DEMAND by dec HR (mn effect) (and dec myocardial contractility, and dec Afterload - aka systolic BP)

esp good for treating a pt POST MI - considering that Beta blockers are the only antiarrhythmic drug proven to dec risk of sudden death in post MI patients)

aka Viagra

Phosphodiesterase 5 (PDE5) inhibitor

This blocks the action of PDE5 which results in smooth muscle relaxation and erection

(bc PDE5 breaks down cGMP, which is necessary for activating PKG which is part of the CA SPARK cycle responsible for decreasing cytosolic Ca and threfore decreasing sm m cell contractility)

DO NOT PRESCRIBE WITH NITRATE - this may cause a potentially fatal reduction of arterial pressure (since they both amp up the Ca Spark pathway which causes relaxation of smooth muscle cells, one effect being dec BP)

Change in membrane potential of cardiac myocyte (ie a rapid upstroke of the AP) allows Ca to enter the cell throught the L-type voltage gated Ca channel; Ca then enters the RyR thats close to the membrane and sits in the SR membrane - then signals Ca to leave the SR to entre the cytoplasm which causes a global inc in cytoplasmic Ca which increases the contractility of the cell

Reuptake of Ca fro the cytosol back into the SR is the main way to STOP CONTRACTION and for the cell to be ready for the next contraction, which is regulated by PLB*****

Epi/NE can bind Beta receptors and, via second messengers, activate the EC cascade that results in increased global cytoplasmic Ca and resulting contraction (POSITIVE INOTROPY - note: inotropy = contractility)

Effects of B adreenergic receptor stim on cardiomyocyte force:

INCREASED: 1) rate of CONTRACTION, 2) PEAK force, 3) Rate of RELAXATION

Phospholamban

= Membrane protein of the SR

key mediator in the B receptor induced contracility in cardiomyocytes: withut B adrenergic stimulation, PLB inhibits the activity of the pump that brings Ca from the cytosol back into the SR lumen (thus inhibiting contractility); B receptor stimulation DISINHIBITS the effects of PLB and activates the pumping of Ca from the cytosol back into the SR lumen so the cell is ready for the next contraction

ability of the heart ot increase SV (force) in response ot increased EDV/PRE-load (via changes in fiber LENGTH)

**Differs from the mechanism of the heart by which the heart ejects more blood against an increased aortic pressure by increasing CONTRACTILITY/inotropy of its fibers

1) changes in fiber length (Frank Starling)

2) Changes in contactility (related to changes in intracellular second messenger levels that increase cytosolic Ca)

The inability of the heart to deliver enough blood to peripheral tissues to meet metabolic demands; esp due to defect in myocardial contraction i.e. myocardial failure resulting in decreased ejection fraction which decreases CO (CO=SV x HR, and dec EF means a dec SV and therefore a dec CO)

Myocardial failure may be caused by loss of functional cardiomyocytes, altered activation of contractile proteins, alterations in contractile apparatus, ventricular remodeling, etc

symptoms: pulmonary edema, pleural effusion, peripheral edema, ascites, tired, SOB, cough

1) CO = SV x HR: dec EF means dec SV, therefore HR increases to compensate

2) BP = CO x TPR: dec CO  (due to dec SV due to dec EF) therefore TPR increases to compensate

The sympathetic nervous system amps up to increase both HR and TPR; incidentally, other things happend too due to chronic NE exposure (i.e. increased renin - increased aldo secretion - increased Na reabs and K excretion; increased PVR via vasoconstriction); worst consequence: APOPTOSIS OF CARDIOMYOCYTES

1)potent vasoconstrictor

2) increases secretion of Aldo from adrenal cortex, which increases reabs of Na and excretion of K at the proximal tubules

-excreted by the liver and made into AngI by renin and AngII by ACE which is bound to the endothelial cell memb of pulmonary vessels

Mn cardiovascular effects: 1) increased peripheral resistance, 2) altered renal fxn (inc Na reabs, inc K excretion), 3) cardiac hypertrophy and remodeling (i.e. fibrosis)

1)  Altered myocyte biology (EC coupling; Hypertrophy)

EC coupling FAILS: prolonged AP duration, prolonged repolarization, dec peak of AP

2) Myocardial changes (myocyte loss: APOPTOSIS; fibrosis)

3) Alterations in LV chamber geometry (LV dilation)

Chronic NE and AT exposure can lead to both concentric and eccentric hypertrophy

RAAS: fluid retention-->increased wall stress-->hypertrophy-->decreased contractility

Adrenergic (NE, Epi): increased HR and contractility-->increased o2 demand-->myocyte damage-->decreased contactitiy

Both cause vasoconstriction and direct cardiotoxicity which contributes to dec contractility too

ACE inhibitors

ACE INHIBITION IS CONSIDERED MANDATORY TRATMENT OF CHF***

-Effect BOTH preload and afterload

-Studies show an increase in survival when CHF pts take ACE inhibitors over simple vasodilators

mech: inhib conversion of angiotensin I to angiotensin II

Also: increases BRADYKININ (a vasoDILATOR) by inhibiting Kininase II (an advantage of ACE inhibitors over ACE receptor blockers)

Effects: Vasodilation (bc Angiotensin (AT) II is a potentent vasocontrictor), dec aldo levles (bc AT increases aldo secretion from the adrenal cortex), dec sympathetic activity (bc AT increased NE release at presyn nerve terminals), reduced interstitial fibrosis (bc AT increases prolif of fibroblasts and their products), dec myocardial (hypertropy, dilation) and vascular (sm muscle prolif) remodeling, anti-apoptotic

first ACE inhibitor

side effects: persistent cough (due to circulating bradykinin)- fairly common (switch to AT receptor blocker); ANGIOEDEMA (potentially fatal!!!); HYPERKALEMIA (bad bc 1)depolarizes cardiomyocytes, 2) prolongs AP duration-->long QT syndrome-->inc risk of fatal ventricular arrhythmias)

ACE inhibitor

similar to Captopril, except LONGER half-life - only a concern if pt has renal insufficiency (bc the drug is renally excreted)

Angiotensin II AT1 receptor blockers (ARBs)

-effect BOTH preload and afterload

why use: 1) all adverse effects relevant to a failing heart (apoptosis, hypertrophic growth) involve activation of AT1 receptors, 2) ACE inhibitors alone do not fully antagonize TISSUE based RAAS (bc different enzymes other than ACE - which only works systemically- mediate RAAS in local tissues)

ARBs are about as effective as ACE inhibitors in reducing mortalitiy, morbidity in HF

ARBs do not produce the most common side effect associated with ACE inhibitors: COUGH (bc do NOT increase circulating Bradykinin, a vasodilator, as ACE inhibitors do - therefore ARBs will not have as much of an effect on lowering BP as ACE inhibitors will)

side effects similar to ACE inhibitors (ie lethal ANGIOEDEMA) except no cough

Effects of Aldosterone: 1) increased Na and water retention, 2) renal K and Mg loss, 3) promotion of myocardial fibrosis and ventricular arrhythmias (esp due to dec serum K levels: makes cells hyperpolarized)

Aldosterone receptor blockers:

1) dec plasma volume and change elctrolyte excretion, 2) beneficial effects of aldo receptor blockers in CHF most likely results from their ANTIFIBROTIC and ANTIARRHYTHMIC properties

egs: spironolactone (side effects: Hyperkalemia, Gynecomastia), Eplerenone (hyperkalemia)

-lots of evidence showing they decrease cardiovascular mortality in CHF ps, improve HF sx, dec need for heart transplant

-A bit surprising that Beta blocking would help CHF: EC coupling responsible for cardiomyocyte contractility (via the Ca cycle with cAMP, Ryr, SR, etc) can be activated directly by binding of Epi/NE to Beta r's (so wouldn't a block on B rs cause a dec in contractility and thus worsen HF?)

Short term adrenergic effects (esp Beta1****) seem good (increased contractility, HR), but CHRONICALLY the effects are BAD: *MYOCYTE APOPTOSIS*, pathologic myocyte growth, proarrhythmia, fetal (myosin) gene induction

Because most of the bad effects are mediated by Beta1 r's, Beta1 r's should esp be blocked in CHF pts (eg Metoprolol, Bisoprolol are both highly selective B1 blockers)

Carvedilol is minimally B1 selective, and has an additional alpha1 blocking ability (caues vasoldilation); another benefit: blocks spontaneous Ca release from SR which thereby decreases fatal arrhythmias (bc CA DISREGULATION is the MAIN CAUSE OF FATAL ARRHYTHMIAS IN A FAILING HEART)***

Limits: Obstructive airway disease (bc will cause bronchoconstriction - ie not good for asthma), Decompensated HF (ie less contractility, HR may be deleterious as one might assume; can give Phosphodiesterase 3 inhib first to recompensate, then initiate B blocer), Sinus node or conduction system disease (can impland a pacemaker to normalize conduction prior to B blocer tx initiation)

Chronic tx of HF with non neurohormonal vasodilators does NOT improve mortality (as ACE inhibitors and ARBs does), but ACUTE tx with them is key for acute DEcompensated HF

Rationale:

1) venous dilation-->decreased venous return (bc bl pools in large vessels)-->dec diastolic wall stress-->dec EDV/PREload

2) arteriolar dilation-->dec vascular resistance (dec TPR)-->dec AFTERload-->(increased EF)-->increased SV

 eg. nitroglycerin, isosorbide dinitrate

Drugs that alter myocardial contractility - Inotropic

Used for short term mgmt of severe HF; IV only

prob: arrhythmogenic (give under constant supervision)

Phosphodiesterase type THREE inhibitors

(type 3 is specifically in cardiomyocytes)

Inotropic effect (increased contractility due to less cGMP breakdown in the Ca cycle - more Ca in cytoplasm)

Use: short term mgmt of severe HF; IV only

prob: arrhythmogenic (aka "KILLRINONE") - give under constant supervision

Inotropic effect

Digoxin, Digitoxin

Mech of action: INHIBITION OF NA/K PUMP (normally 3 Na out; 2 K in): inreased intracell Na-->more Na in cell: Na/Ca exchanger (normally 1 Ca out for 3 Na in) has less gradient with which to pump Ca out of cytoplasm - may work in reverse: more Ca in cytoplasm: increased contractility

Other mechs: 1) increased vagal tone (dec HR: dec O2 consumption. 2) dec Na reabs: dec circulating plasma vol: dec EDV: dec wall tension: dec PREload :)

Like vasodilators for Tx of CHF: does not improve longterm mortality, but may improve short term cardiac performance, relieve sx

Only of Digitalis glycosides to be tested

Inotropic for CHF tx

NARROW therapeutic index: therapeutic dose very near toxic dose; can treat digitalis toxicity (ie arrhythmias) with digoxin specific abs, to bind and inactivate digoxin