Acute pain: <30 d, identifiable pathology, predictable prognosis, tx typically with analgesics

Subacute pain: Duration of pain between 2-6 mo

Chronic pain: >6 mo, pathology may be unclear, unpredictable prognosis

MOA: Analgesia: not clear. Pos from elevation of pain threshold (stuff with NO, NMDA, & sub P) or pos inhibits COX2 and dec PG activitly. Antipyretic: Endogenous pyrogens produced by WBC cause inc CSF PGE -> fever on preoptic area of ant hypothal to dec heat loss & inc heat gain (APAP shown to inhibit action of pyrogens on heat-reg centers in brain by blocking formation & release of CNS PGs)

Note: Prescription combo limited to 325 mg of APAP per pill (to reduce overdose/hepatotox)

Indications: antipyresis & mild/mod pain

Dosing: Peds: dependent on age for kids (OTC ped doses will be standardized to 160 mg*/5 mL!! Concentrated* infant drops (80 mg/0.8 mL) will be phased* out! Adults: Max = 1000 mg per dose (4 g/d d/t glutathione conj becoming insufficient -> inc acetylimidoquinone -> hepatic cell necrosis possible) - Hidden: vicodin, excedrin, sinutab

-Metab: liver to sulfate to glucoronide metabolites. Small amts by CYP to a highly reactive intermediate (acetylimidoquinone) which is conjugated with glutathione & inactivated

Interactions: additive hepatotoxicity if >1 hepatotoxic meds (INH). 

ADRs: Overall well-tolerated*; hepatotoxicity -> OD can be treated with n-acetylcysteine. More common with chronic concomitant EtOH (>3 drinks/d) or large doses (>4g/d) of APAP. 50% of acute liver failure cases are now d/t APAP poisoning (up fom 28% less than 10 yrs ago) - 50% of APAP overdoses are UN*intentional 

*Preg Cat C = good place to start* for mild-mod pain (since NSAIDs aren't safe) 

More commonly used: Indomethacin* (used for PDA closure only! so don't give to 3rd trim mom!!), Diclofenac* (comes mixed w/ misoprostel to protect stomach from SE; esp used for hemicrania neuralgia, etc), & ketorolac (=as potent as 10 mg of morphine; but can only use for 3-5 d)

Less commonly used: sulindac, etodolac, tometin

Piroxican* & meloxicam* 

Fenamates: meclofenamate

Napthykanones: Nabumetone

Inhibits COX1 &/or COX2. 

COX1 = "housekeeping enzyme" - expressed in most tissues - regulates normal cellular processs via downstream chemicals (gastric cytoprotection (via prostaglandins), vascular homeostasis (via thromboxane), platelet aggregation, & kidney fx); COX2 = usually undetectable in most tissues -> expressed during times of inflam (= inducible; and -> prostaglandins)

*Reversible platelet inhibition. Fx returns when drug elimated. 

Analgesia (ibuprofen >400 mg offer no* more analgesia, but more anti-inflam and more ADRs!); antipyretic; dysmenorrhea; anti-inflammatory (RA, OA, seroneg spondyloarthropathies, localized musculoskeletal syndromes, gout)

Pearls: Ketorolac for "pain" - only commonly used IM/IV formulation. comparable to 12 mg morphine, but longer duration. Limit to <5 d d/t toxicity to kidney (dec afferent -> AIN) 

Misoprostol: PG analog that can prevent gastric ulcers/comps -> causes diarrhea (10%). Contraind w/pregnancy (cat x!!)

H2RAs (famotidine) red risk of NSAID-induced ulcers. PPIs reduce risk of ulcers and* GI bleeding, so they're preferred!

-AHA recommends stopping all NSAIDs except ASA in AMI pts (pts who take NSAIDs within 1 wk of AMI have higher risk of recurrence or death. or use smallest dose for shortest time if can't stop)

-Use warfarin with great caution (d/t NSAID anti-platelet effect & pos cytochrome interact. Inc risk of GI bleed w/ anti-platelet agents, EtOH, & steroids. Interfere w/ antiplatelet* effect of ASA.

Interactions: cytochrome; sodium* and potassium alterations (dec efficacy of diuretics & ACEI/ARBs. Inc lithium concentrations)

Precaution: Pts with HTN (can inc BP by 5), CKD, CHF (antag diuretic), asthma (not making prostaglandins that cause bronchodil); warn of inc risk for CV/GI risks (anyone w/ CAD, CVD, hx TIA, PUD)

Contraind: recent CABG (inc risk of AMI/CVA), Pregnant women** (esp 3rd trim - pos premature closure of PDA)

GI effects: dyspepsia/gastritis (up to 40%) & ulceration/perforation (may dec with taking food, monitor for s/sx of anemia). (indomethacin> naproxen*> ibuprofen* > meloxicam)

-***Risk categor: High = hx of complicated PUD or* >2 of RF (>65, high-dose NSAID hx, hx of uncomp PUD, concurrent ASA, anticoag, or steroid use, pos H. pylori). 

-> risk of thrombosis. COX1 can interfere with ASA antiplatelet effects if they bind to platelet first (so try to use other analgesics first for pain in ASA users. Naproxen>ibuprofen seems to have lowest CV risk). Take regular (not enteric coated) ASA 1 hr before*** NSAID (so ASA can bind to platelet fifrst) and add a PPI if bleeding is a concern

-Thrombosis risk: High = diclofenac, meloxicam, indomethacin; slight inc = piroxicam, ibuprofen; not high = naproxen. See slide 44 if wish. 

-May* precipitate asthma in ASA-sens pt. d/t inhibition of COX1 (shunts down leukotriene path). Not* IgE mediated (=not true allergy). High cross-reactivity with other NSAIDs. 

-Reversible* platelet dysfunction -> inc BT.

-Nephrotoxicity: renal PG inhibition -> dec renal blood flow & inc fluid retention (esp with ketorolac) - may also cause AIN & ATN

Celecoxib, rofecoxib (withdrawn d/t MI/stroke), valdecoxib (withdrawn MI/stroke/bad skin rx)

MOA: selectively binds COX2, doesn't bind platelets

Ind: anti-inflam: RA, OA, gout, seroneg spondyloarhtorpathies, localized MS syndromes (**not more clinically effective than nonselective NSAIDs - maybe less effective?)

-Precautions: same as NSAIDs

-Interactiosn: same. Sub of CYP2C9

1. Antispastic agents for disorders such as MS, SC injury, etc. Ex: baclofen (MS), dantrolene (look at CNS toxicity in 2nd lecture)

2. Antispasmodic agents for musculoskeletal conditions (cyclobenzaprine, carisoprodol, metaxalone, methocarbamol, chlorzoxazone, tizanidine, orphenadrine)

*APS & ACP rec NSAID/APAP first line then muscle relaxant as alt. Limited evidence for effectiveness, yet strong evidence of toxicitiy!

MOA: nearly identical to amitriptyline. appears to act centrally on descending serotonergic pathways to reduce tonic somatic motor activity (no peripheral effects on skeletal muscle fiers or NM jx) - avoud in eldelry/women with QT issue

Ind: tx of muscle spasm ass with acute painful musculoskeletal disorders (modest efficacy)

*Pearls: causes less dizziness & lower abuse than carisoprodol. Has most* evidence for efficacy

Interactions: additive sedation w/ other CNS depressants. Be careful with "depression meds" (not within 14 d of MOAI use); seizure reported with concomitant use of tramadol (so avoid!)

Contraind: pts with arrhtymias, recent AMI or CHF

-ADRs: dose-related sedation, dizziness, & xerostomia m/c. Quinidine-lik effects on heart (QT prolongation)

MOA: don't know. may act as sedative

Ind: short-term use for acute painful musc disorder (modest efficacy) - don't use tho!!

-use <2-3 wks if must. abuse potential since it's metabolized to meprobamate = a controlled substance that has sedative effects similar to barbiturates & alcohol (= scheudle IV)

-Interactions: additive

ADRs: dizziness/sedation; allergic type after 1-4th dose; withdrawal syndrome (abd cramps, HA, insomnia, nausea, seizures); rare idiosyncratic rxn (transient quadraplegia, temporary loss of vision)

Used for spasticity in MS or SC injury pts. Also used for malignant hyperthermia* prevention/management (IV formulation); dose-dependent hepatotoxicity most concerning ADR.

1. Phenanthrenes - Codeine (C-II -never use); codeine + APAP (C-III), hydrocodone (C-III) = (+ APAP = vicodin) (you can write refills)

2. Phenylheptylamines/diphenylheptanes - propoxyphene (removed 11/10 - darvocet)

3. Phenylpiperidines - diphenoxylate (C/V) - can combine with atropine to make sure not abuse. Loperamide (doesn't have analgesic effect - just GI)

1. Phenanthrenes (= "prototypical" opiods) - morphine (CII), oxycodone (CII), oxymorphone (CII), hydromorphone (CII)

2. Phenylheptylamines/diphenylheptanes - methadone (CII) = DEA will look at you if you prescribe this

3. Pnehylpiperidines - meperidine (CII), fentanyl (CII)

Weak Mu: Tramadol (not federally controlled), Tapentadol (CII) - similar to 10 mg of morphine 

Mixed Ag/antag (Partial): Buprenorphine, nalbuphine, butorphanol, petazocine = don't need to know 

Codeine, Codeine/APAP (Tylenol with codeine #3 or 4)

-Codeine (prodrug) -> 2D6 -> morphine (fluox & parox really knock this out). 10% lack this enzyme. 

-Single PO dose >65 mg tend to produce dispor > ADRs than analgesia. 

Hydrocodone+APAP = vicodin. + ibuprofen = vicoprofen (not used tho since we don't want them taking ibu q4-6)

*Hydrocodone (prodrug?) -> 2D6 -> hydromorphone (active metabolite!) - only comes in combo products with APAP/NSAIDs

IR - soln, suppository, tablet, infusion

SR - tablets (MS contin, kadian), 24 hr formulation & morphine/naltrexone (to prevent abuse* of morphine)

IR soln or tab

CR tab (OxyContin*) - reformulated tabs are hard to crush or chew to release all of the drug at once (original formulation - "hillbilly heroin"). They also make it gummy gel that can't be drawn up in a syringe.

-Oxycodone/APAP (percocet!!), oxycodone/ibuprofen & oxycodone/ASA minimally used

Oxymorphone: IR & SR

-Metabolite of oxycodone via CYP2D6

Hydromorphone: "liquid", suppos, tab, IV (= dilaudid!!), ER tab. May cause less** nausea & pruritis than morphine. Metabolite of hydrocodone. 

Soln, tab, IV

-QTc prolongation with inc doses. Has some advantages (long 1/2 life, no active metabolite). Used mostly in pain & opiod rehab clinics -> requires careful dose titration & may raise "red flags"

Soln, tab, IV* (Demerol!)

-Use only for short-term acute pain (24-48 hrs). SQ & IM very irritation to tissue -> IM may lead to muscle fibrosis**. Rneal dysfunction* (including elderly) will lead to accumulation of meatbolites (normeperidine**) -> CNS excitation/seizure. Meperidine & MAOI may -> death 

Transdermal patch* (72 hr) - remember: exposed to heat will release faster -> pos respiratory suppression.

IV, intrathecal, epidural, sublingual, buccal, buccal film, transmucosal lozange, and intranasal spray for breakthrough cancer** pain 

= weak mu-agonist/SNRI

-IR tab or ODT (Ultram) or ER tab. Tramadol/APAP (ultracet).  

-Associated with seizures* in high dose -> avoid in pts with past seizure or stroke, head trauma, alcohol withdrawal, etc. Associated with serotonin* syndrome

IR tab & ER tab

-Similar to tramadol, but stronger** (similar to oxycodone 10-15 mg) 

Buprenorphine, nalbuphine, butorphanol, pentazocine

-Displays partial mu agonist & weak kappa antagonist activity. ISMP lists these drugs as having heightened risk of causing significant pt harm when used in error - many of these drugs have incomplete* reversal with naloxone

Pharmacokineteics: absorbed well from places - most with extensive 1st pass effect -> low bioavailability overall

-CYP3A4 sub (oxycodone, fentanyl, tramadol, methadone) ^Black box warning for oxycontin about interactions! CYP2D6 substrates*:codeine, tramadol (deficient pts or ultra-rapid metabolizers)

-opiod ags at brain & SC. Mu receptor: analgesia, euphoria, resp dep, & physical depedency properties. 

-Alcohol may inc release of some ER products. 

-Watch for tramadol/tapentadol with MAOI d/t adrenergic activity (& serotonin syndrome and seizures)

Constant* pain (less with sharp). 

-Regular fixed dose at a regular time (with prn) is more effective in achieving pain than dosing on demand

-IV morphine relieves SOB with pulm edema! (reduces cardiac preload (reduced venous tone) & afterload (dec PVR), reduces SOB perception, reduces anxiety.

-Cough: cough (constipating tho); dextromethoprhan (free of analgesic/addictive potential, less constipation)

-Diarrhea: Diphenoxylate/atropine & Loperamide (doesn't cross the BBB)

Mild to mod pain: start with codeine (pos not d/t rel efficacy & 10% issue), tramadol, hydrocodone) -> go to morphine or oxycodone if needed

Severe pain: start with morphine, oxycodone, or hydromorphone -> fentanyl if needed

Overall very rare. Many people c/o pseudoallergy -> nonimmune hypersensitivity or anaphylactoid rxn* - very common. Occur when direct stimulation of mast cells release vasoactive mediators like histamine* -> pruritis m/c, also flushing, hives, sweating, and mild hypotension. Not an allergy tho! M/C with codeine & morphine (d/t side chains) & seems to be dose-related. 

-True allergy = angioedema or edema of lips, tongue, face, or mouth; bronchospasm or resp distress; cutaneous rxns other* than hives, flushing, or itching (rash or erythema multiforme). Possible to try another structural class of opioid if true allergy (not a lot of data tho)

Opioids associated with an inc in heart defects & spina bifida when used during 1st trimester.

-Use an opioid if pain during pregnancy can't be managed with other options - oxycodone (B); codeine, hydrocodone, & morphine (C)

If necessary, use low-dose, short*acting agent after** feedings. Watch infant for CNS dep or oversedation. Try to switch to APAP or NSAID within 4 d of delivery before infants begin drinking a lot of milk. 

-Be careful about using codeine, hydrocodone, or oxycodone* during breastfeeding -> these opioids are converted to active metabolites by 2D6 enzymes (babies can OD if mom is ultrarapid 2D6 metabolizer!)

Highest misuse/OD death with men, 20-64 yo, nonhispanic whites, poor & rural populations. 

-FDA will encourage you to participate in Risk Evaluation & Mitigation Strategy (REMS) to reduce misuse of long-acting opioids. (Need REMs plan for oxycodone, ER morphine, hydromorphone, oxymorphone, transdermal fentanyl, & methadone); Prescription drug monitoring programs (PDMPs) will be ramped up so "doctor shoppers" can be ID'd more easily. 

Each agent is roughly equally effective, producing a good response in 30-50%. At least 75% of pts need 2+ drugs to reach BP goals. Combining two synergistic* drugs dec BP about 5x more than doubling the dose of one drug. Start with two* drugs for pts who are >20 mm Hg above their systolic goal or 10 mm Hg or more above their diastolic goal.(remember: RAS = distal in young, AS prox)

-Note: transplnat meds (cyclosporine>others), erytorpoieten, steroids, & neuropsych (SNRI & bupropion) induce HTN.

-1 in 4 stop anti-HTN within 6 mo. 

Proximal convoluted & straight tubule - mannitl & acetazolamide

Thick ascending limb of Henle's loop - bumetanide, furosemide, ethacrynic acid

Distal convuluted tube - thiazide, metolazone

Collecting duct - amiloride, spironolactone, triamterene 

IV or urogenital soln. MOA: nonreabsorbable polysaccharide that acts as an osmotic diuretic, inhibiting Na & H20 reabsorption in proximal tubule & loop of Henle. In contrast to other diuretics, mannitol produces a relative H20 diuresis in which H2O is lost in excess of Na &K. 

-Used to dec ICP of cerebral edema. or GU irrigant in TURP or other transurethral surgical procedures

-Pearls: can produce a big inc in plasma osmolality by 2 mechs: preferential water diuresis -> water deficit* & hypernatremia*. or hypertonic mannitol may be retained in AKI pts -> directly inc plasma osmolality (H20 movement out of cells will lower plasma Na by dilution -> vital to recognize, since tx must be aimed at hyperosmolaity*, not* hyponatremia. 

Monitor: dialy fluid I&O, renal fx & electrolytes, serum & urine osmolality (tx of elevated ICP -> maintain serum osmolality 310 to <320.)

Interactiosn: Anti-HTN & PDE5 inhibitors -> enhanced anti-HTN effect

ADRs: fluid & electrolyte imbalance (hypernatremia!! only one!); dehydration/hypovolemia secondary to rapid diuresis

MOA: reversible inhibition of carbonic anhydrase -> dec H+ secretion at renal tubule & inc renal excretion of Na, K, HCO3, & H20 -- produces both NaCl & NaHCO3 loss. 

Indi: Edematous pt with alkalosis in whom loss of excess bicarb in urine will restore acid-base balance. Or prevention or ameliroation of sx associated with acute mountain* sickness (by dec blood pH, extra breathing is stimulated -> higher oxygen conc blood)

-Net diuresis relatively modest d/t most excess fluid delivered out of proximal tubule is reclaimed. & diuretic action is progressively attenuated by metabolic acidosis from loss of HCO3* in urine

MOA: interferes with Na/K exchange (active transport) in thick segment of Loop of Henle by inhibiting Na/K-ATPase.

Use: Acute pulmonary edema & other edematous states; acute hypercalcemia!!

Monitor: BMP (1st few wks, then periodically), Uric acid (pos. 1st few wks, then period), Ca & Mg prn. 

Pearl: Works better than thiazides for GFR<30mL/min. Enhances calcium excretion -> improvement in hyperCa*. Ethacrynic acid: maybe useful for pts who have not responded to other diuretics; causes more ototox; only loop w/o a "sulfa grp" 

MOA: interferes with K/Na exchange (active transport) in early distal convoluted tubule by inhibiting Na/K-ATPase

-Note: long-term anti-HTN response to thiazides cannot* be reliably predicted by degree of initial reduction in plasma volume, which eventually returns to near-normal levels. A more liklely explanation for persistent antiHTN effects of most thiazides is an overall reduction in SVR (MOA unclear - probs d/t electrolyte changes)

Chlorthalidone is 2x as potent as HCTZ with longer duration of action. Outcome benefits have not* been established for current recommendation of HCTZ (12.5-25). ADRs are equivalent with current doses. 

-Chlorthalidone has a very large Vd owing to its extensive partitioning into* RBCs -> creating a "depot" -> slow streaming effect with subsequent gradual elimination. In spite of apparent superiority of chlorthalidone in currently recommended doses, most fixed-dose combs that include a diuretic use HCTZ!

Use: usually for HTN, low doses usually used, dosed in AM

-Monitoring: BMP (1st few wks, then period), uric acid (same), Ca & Mg prn

-Less* effective when CrCl <30 (except metolazone!!). All enhance calcium* reabsorption! (usually will not cause hypercalcemia but may unmask an underlying condition (hyperparathyroidism, CA, sarcoid); improvement in hypercalcuria* -> dec kidney stones; may be beneficial in osteoporosis.

-Metolazone* may be used with loop diuretics for synergy* in refractory edematous states. 

Interactions: same as loop diuretics 

Volume depletion -> orthostatic HTN; hyponatremia; hypokalemia/hypomagnesemia (hypokalemic metabolic alkalosis, more likely with higher doses); hyperuricemia (enhanced urate reabsorption); hyperlipidemia (inc 5-15%), hyperglycemia, rash (sulfonamide cross-reactivity?)

*Overall, none d/t dose we use. 

MOA: blocks aldosterone effects via direct antagonism of mineralocorticoid receptors at cortical collecting tubule -> dec transcrption of gene for Na/K ATPase - aldosterone inc BP primarily by inducing Na reabsorption. 

*Change transctiption of hormonal factors

-More data & less expensive. Use - mineralcorticoid excess - primary aldosteronism or secondary aldosteronism (m/c - CHF, hepatic cirrhosis, nephrotic syndrome)

MOA: interferes with K/Na exchange (active transport) in distal tubule, cortical collecting tubule & collecting duct by inhibiting Na/K ATPase

-You'd use these to modulate K to grab it back. 

Use: HTN , but outcomes are not great. 

Don't use for K>5.5. Relatively weak* natriuretic effect -> primarily used in combo with a loop or thiazide diuretic (combo dec degree of K loss or may inc net diuresis in pts with refractory edema)

-Monitor: K & BUN/CR

-Interactions: avoid K supplements/salt substitutes; be careful with drugs that retain K (Beta-blockers, NSAIDs, ACEIs, ARBs); anti-HTN & PDE5I

Hyperkalemia (all agents)

Spironolactone: teratogenic* -> male/female concerns in animals; estrogenic effects (painful gynecomastia*, amenorrhea); anti-androgen effects (ED, dec libido)

Triamterene: potential nephrotoxin possibly leading to crystalluria & cast formation (up to 50% of pts) - triamterene stones & possibly ARF from crystal deposition

MOA: vasodilate efferent* arteriole (drains glomerular capillary bed) -> dilating efferent arteriole dec glomerular pressure. (often causes bump in Cr)

Use: LVH, HF with systolic dysfx (m/c), CKD (slows* rate of kidney loss); post-AMI which resulted in dec systolic fx

-Blacks are less sensitive to ACEI monotherapy! ACEI are synergistic with diuretics! ACEI & ARB are not only BP meds, they are renal "protectors"

-Monitoring: BUN/Cr, K

Interactions: Lisonpril (no CYP interactions), enalapril (3A4). Anti-HTN & PDE5I; be careful with other meds that lead to hyperkalemia (ACE, ARB, BB, K sparing diuretic)

MOA: interferes with RAAS by impairing binding of angiotensin II to AT1 receptors - doesn't block AT2 receptors (chronic stim of AT2 receptor may be beneficial -> vasodil by generation of NO). Some agents act as agonsits to PPAR-alpha receptor (dec lipids) & PPAR-gamma (insulin-sensitizing) - Telmisartan mostly. 

-Use: same as ACEI; Data - losartan>valsartan

-Monitoring: BUN/Cr, K

-Interactions: m/c used ARBs are minimally metabolized; other interactions same as ACEIs

-ADRs: same as ACEI without the cough

MOA: binds to catalytic site of renin -> inhibits formation of angiotensin I/II & dec plasma renin activity (inhibits activation* of whole RAAS system

Interactions: P-gp inhibitors may inc aliskiren conc. Anti-HTN & PDE5I

ADRs: well tolerated (so far)

MOA: highly selective antagonist of alpha-1 receptors -> reduces arterial pressure by dilating both resistance & capacitance vessels. Greater BP reduction when upright as compared to supine. Fluid retention common when not paired with a diuretic 

Use: BPH; HTN (ALLHAT trial - less pos data)

-Pearl: causes less tachy than direct vasodilators, but more frequent postural hypotension

-ADRs: postural hypotension common with 1st dose, give 1st few doses at bedtime & titrate slowly; drowsiness/fatigue; nasal congestion*; floppy-iris syndrome - complication during cataract sx, characterized by flaccid iris - relax iris dilator muscle)

(Propranolol, Nadolol, Timolol)

*See Propranolol more with migraines

*Timolol: more bronchospasm; caution in pts with asthma, COPD (but they live longer....), RP (not true)

Agents have partial agonist activity -> dec BP with less dec HR.

Nonselective BB with ISA: pindolol & penbutolol

Selective BB with ISA: acebutolol

Nonselective BB with alpha-1 blocking activity: carvedilol (big one for CHF!!) & labetolol

Selective BB with inc NO release from endothelial cells (via B3 agonism?) - nebivolol

*CHF>HTN

HTN, stable/unstable angina/AMI, HF, certain arrhythmias (A fib), periop - dpends on CV risk & type of surgery; other use: propranolol being studied for pediatric hemangiomas, BB use ass with less breast cancer metastasis & cancer-related death; migraines

-Blacks are less sensitive to monotherpay; pts with ischemic HD shouldn't rapidly d/c therapy -> accelerated angina, AMI, and pos death. Don't** give to pts with cocaine-induced chest pain or AMI (may inc coronary spasm); generally less effective in preventing CV events (esp CVA) c/t ACEI, ARB, & CCBs

Interactions: Propranolol & metoprolol are 2D6 substrates (SSRI affects!), atenonol (minimal), carvedilol (substrate of 2C9 & 2D6). Be careful with other drugs that depress myocardial fx or pacemaker activity (CCB & antirhthm)

ADRs: bradycardia (caution in bock, unless pacemaker); bronchospasm; hyperkalmeia (esp nonselective - since blocks the mvmt of extracellular K into cells); fatigue/exercise intolerance; ED; may mask/delay recovery from hypoglycemia (may not make them feel the anxiety; and epi helps inc glycose - so be careful in diabetics -- education is vital)

Short-acting dihydropyridines: nifedipine

Longer-acting dihydropyridines: felodipine, isradipine, nicardipine, nisoldipine

Long-acting dihydropyridine: amlodipine* 

Non-dihydropyridines: verapamil & diltiazem (cardizem - so use in Afib with AVR; blocks CCB preferentially at heart)

inhibit L-type Ca channel -> no intracellular Ca influx. 

-DHPs: predominant vasodilation by preferentially altering vascular smooth muscle -> dec PVR -> leads to baroreceptor-mediated inc in sympathetic tone, which blunts ionotropic effects of DHPs (little to no effect on cardiac contractility or conduction)

-Non-DHPs: preferentially effects cardiac contractility & conduction (neg ionotropic effect - verapamil>diltiazem) - less potent vasodilators (don't want to dec contractility in CHF)

DHP CCB use: HTN (IR nifedpinine has inc CV mortality; esp in CAD pts), angina, RP; non-DHP: cardiac arrhytmias (SVT, A fib)

-Contraind: non-DHPs best avoided in HF d/t systolic dysfx. If HF pt needs CCB for angina or HTN, use long-acting DHP (ex: amlodipine)

-Interactions: Amlodipine, verapamil, & diltiazem are all substrates of CYP3A4 - data suggests "dirty"* macrolides are problematic with CCBs. Non-DHPs should be used cautiously with BB & digoxin (conduction issues)

-ADRs: DHPs: 10-20% will have >1 sx, all less likely w/ long-acting agents (HA, dizziness, flushing, peripheral edema*, reflex tachycardia*, dyspepsia (relaxation of LES d/t inhibition* of Ca-induced contraction)); gingival hyperplasia (nifedipine>amlopdipine). Non-DHPs: HA, dizziness, flushing, peripheral edema; verpamial = constipation!

Clonidine (transdermal! d/t having rebound HTN if missed dose. Approved for ADHD kids); methydopa (preggo)

MOA: stimulates alpha2 in brain stem. 

*Can use clonidine in HTN urgency as IV. 

ADRs: Methyldopa: overt sedation, lactation (ass with inc prolactin in M & F; pos coombs test (10-20%). Clonidine: most with PO - dry mouth & sedation (may be severe); abrupt withdrawl (1-2 missed doses) may lead to HTN crisis** (nervousness, tachycardia, HA & sweating)

Hydralazine, minoxidil

MOA: relaxes arterial* smooth muscle -> dec PVR -> reflex tachycardia common (then need BB); exact MOA not well-understood. Hydralazine seems to alter cellular Ca metabolism; minoxidil opens ADP-sensitive K channels.

Hydralazine ind: HTN/HTN urgency, pre-eclampsia/eclamp, HF (blacks -- hydralazine plus* isosorbide dinitrate)

-Pearls: should be given with a beta blocker or centrally-acting drug to minimize reflex inc in HR/CO & with a diuretic to avoid Na & H2O retention. Try to avoid in pts with CAD (don't want a potent dec in PVR) 

-ADRs: H= lupus-like rxn (mainly slow acetylators; minimize by using <200 mg/d.) & peripheral neuropathy. Min = hirsutism, severe fluid retention (use w/ loop); reflex tachy (use w/ BB)

Comps of HTN = preterm delivery, fetal growth retardation, & even maternal death. 

-Tx of uncomplicated* HTN usually reserved for systolic BP >160 or diastolic >100. 

-Use: labetalol (C), ER nifedipine (IR has more toxicity = HA & less good CV outcomes), methyldopa (B) is still used sometimes d/t long hx of safety during pregnancy (weak antiHTN with more ADRs, reserve it for women who can't use labetalol or nifedipine); hydralazine is falling out of favor d/t ADRs. 

-Do NOT use ACEI, ARBs, renin inhibitors

Inc stability/raises melting point. Natural trans fatty acids are present in small amounts in dairy/meat products (d/t their diet). 

-Trans inc their shelf life. 

-ave daily intake is 2.6% of total intake. (should be <1%).

-Trans fats are unsaturated, & they - dec HDL, inc LDL, total chole/HDL chol ratio, TG, and lipoprotein(A), causes endothelial dysfx, inc indicators or low-grade systemic inflammation. Inc coronary risk (>sat fats)!!

If 0-1 RF - start drug at 190, goal of 160 or lower

If 2+ RF - start at 160, goal of 130

HD, diabetes - start at 130, goal of 100 or lower (70 usually)

MOA: inhibition of HMG CoA reductase dec intracellular cholesterol conc -> a protease is activated -> cleaves sterol regulatory element-binding proteins (SREBPs) from ER. SREBPs translocate to nucleus where they upregulate expression of LDL receptor gene. Enhanced LDL receptor expression inc receptor-mediated endocytosis of LDL & dec serum LDL. Mevalonate pathway.

-Phys: Dec LDL by 30-60%, dec TG by 20-40%, modest inc HDL of 5% - all agent & dose-depednent.

-Other effects: improve endothelial fx, reduce plasma viscosity, plaque stabilization with dec platelet aggregation & thrombin formation; reduce inflammation

Ind: Primary & secondary prevention!

Pearls: rosuvastatin & pravastatin are hydrophilic -> less myalgias. Lovastatin, fluvastatin & simvastatin should be taken qhs when most* cholesterol synthesis occurs d/t short 1/2 life. Pravastatin, atorvastatin, pitavastin, & rosuvastatin have long half life & can be dosed any time.

-Monitoring: LFTs, CPK (esp with myalgia), FLP (3-4 wks after initiation then qyr once at goal)

-Interactions: Rosuv, pita, & prava minimally CYP metabolized. Sim & ator 3A4 (sim most effected - myopathy risk inc 5x). Some statins are P-gp (sim>ator >prava/rosu). Inhibitors may inc myopathy risk (clarith / erythro, itraconazole, diltaizem/verapmil, cyclosporine, grapefruit juice, amiodarone). Niacin plus* statin -> additive myopathy. Fibrates -> additive hepatotox or myopathy possible. (gemfibrozil inhibits hepatic glucuronidation of statins -> interferes with statin elimin)

Generally well-tolerated -> if unable to tolerate one agent, try another. Reversible dose-dependent hepatotoxicity -> concept of statin-induced hepatotoxicity is no longer valid. 

-Myalgias/weakness (2-10%), rhabdo (0.1%). (risk & severity often secondary to drug interactions or higher doses). Pos check vit D level. 

-Baseline CPK; recheck with complaints -> myalgias may be present with or without* inc CPK conc. Consider continuing statin or lowering dose if sx are tolerable and CK <3-10x ULN. Consider CoQ10. Stop if severe sx or CK >10x ULN. 

-DM- inc A1c - reduce insulin sensitivity in skeletal muscle?

-Cog impairment: statin labeling will mention some pts taking a statin for periods ranging from d-yrs have c/o memory problems that disappeared* when drug was stopped. 

Pk properties, degree of hyperlipidemia.

Presence of renal impairment - atorvastatin & fluvastatin don't require dose adjustment; presence of chronic liver dz - low dose pravastatin or rosuvastatin probably safest. Cost and data = atorvastatin. 

MOA: inhibits intestinal absorption of both dietary and biliary cholesterol by blocking transport at SI brush border (no real effect on TG or fat soluble vit absorption)

Use: dec LDL conc 18%; often combined with statins for additive effect. 

-Monitor: FLP. Minimal drug interactions

-ADRs: generally well-tolerated; mostly diarrhea

MOA: binds bile acids in intestine (usually 90% reabsorbed) -> ensuing dec cholesterol pool dec intrahepatic cholesterol -> promotes synthesis of LDL receptors -> LDL receptors bind LDL from plasma

Use: dec LDL conc up to 20% but may raise TG in pts with hyperTG (not much clinical outcome data!). Monitor FLP.

-Interactions: not absorbed systemically-> no systemic interactions. May bind & impair absorption of other drugs (vanco*, digoxin, warfarin, fat*soluble vitamins; give other meds 1 hr before or 4-6 hrs after)

-ADRs: limited use by GI intolerance (constipation)

IR -> flusihg; SR -> hepatotoxicity; ER (Niaspan) -> least flushing & hepatotoxicity. (can be combined w/ statin)

-MOA: inhibits mobilization of FFA from peripheral adipose tissue to liver -> synthesis & secretion of VLDL are dec and conversion of VLDL to LDL is dec; can also inc HDL via a reduction in lipid transfer of cholesterol from HDL to VLDL & delayed HDL clearance. 

-Use: modifies all* plasma lipoproteins & lipids favorably! Inc HDL 15-35%, dec TG 20-35%, dec LDL 5-25%

Monitoring: CPK (if concurrent statin), FLP, uric acid & glucose (inc baseline fasting flucose & uric acid, at 3 mo, then annually or as clinically indicated)

-Interactions: careful with coadmin of statins or fibrates (overlapping tox profiles - hepatotox & myopathy

-ADRs: flushing*, hepatotox (dose-dependent), may aggravate glucose* and gout (dose dependent)

Reliance on fibrates for high TG is changing! More fish oil use & lifestyle changes being advocated. 

-Modest wt loss can drop TG by 20%. Reducing added sugars, eliminating trans fats, inc fiber & unsat fats, and limiting alcohol can drop it >20%. 

MOA: Fibrates activate the nuclear transcription factor PPAR-alpha - regulates genes that control lipid/glucose metabolism. 

-Use: LDL - min effect, dec TG (25-50%), may inc HDL. 

-Use in pts with hyper TG severe enough to be at risk for pancreatitis (>500, and esp if >1000). HyperTG with low HDL - niacin may be a better choice. 

-Gemfibrozil has the most outcome data (but more interactions & ADRs). Fenofibrate & fenofibric acid have no good clinical outcome data, including when added to statins (less drug interactions & ADRs tho)

Monitoring: LFTs & FLP

Interactions: Gemfibrozil (strong inhibitor of CYP2C9 & 2C19; fenofibrate & fenofibric acid fairly clean. May potentiate oral hypoglycemic agents via PPAR receptor. Use with caution with statins d/t overlapping toxicities. 

ADRs: generally ok. N/V, dyspepsia m/c, reversible hepatotxicity; myositis & rhabdo possible (m/c with gemfibrozil! inhibiting glucoronidation fo statins?), check CPK with muscle complaints

Long-chain unsat omega-3 fatty acid (Lovaza) - each has 840 mg (EPA & DHA). Tx dose = 2-4 g/d

-MOA: reduce hepatic TG prod & inc TG clearance

-Use: dec TG 20-50%, long-term use may* inc HDL conc

-OTC products cost much less than Lovanza, but require taking up to 3x as many capsules. Don't interact with statins to produce myalgias tho. Most are mercury-free direct pts to "USP* verified" products or Lovaza. Seafood allergy is d/t fish protein, not the oil (fish oil capsules may contain some protein however) - advise pt to be careful if they are allergic to seafood. 

Monitoring: FLP (same as statin)

Interactions: high doses of fish oils have antiplatelet effects (not clinically significant so far) - caution with other drugs that effect coagulation

ADRs: generally well tolerated. Eructation (burping), dyspepsia, & an unpleasant aftertaste have been m/c

High LDL: statin +/- niacin or ezetimibe

TG >500-1000: fibrate>fish oils or niacin

TG 200-500: niacin > fish oils or fibrates

low HDL: Niacin >fibrate 

A: assement of CV risk & ASA therapy

B: BP control

C: cholesterol management

D: DM prevention & diet therapy

E: exercise therapy 

Statins: category X; fibric acid derivatives: category C; bile acid sequestrants: cateogry C; ezetimibe: category C; niacin: category A/C (Dose-dependent); omega-3 FAs: Category C

-Take home message -> generally* don't treat lipids in pregnant women. Fetus brain needs lots of cholesterol!

Commonly used: COX inhibitors - ASA; ADP-receptor inhibitors: ticlopidine, clopidogrel, prasugrel, ticagrelor

Less commonly used: PDEI (cilostazol) -> minimal use (mostly intermittent claudication); adenosine reuptake inhibitors (dipyridamole); GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban)

MOA: ASA irreversibly* acetylates COX -> impairing transformation of AA -> PGs, prostacyclin, and thromboxane* A2 -> dec TXA2 conc -> dec platelet aggregation (irreversible platelet effect!)

-Ind: analgesia, anti-pyretic (not in kids with viral syndrome), AMI prophylaxis (secondary>primary); ACS (unstable angina, NSTEMI, STEMI, or PCI) - aspirin (indefinitely) plus* clopidogrel or prasugrel (min 1 mo for bare metal stents; min 1 yr for drug-eluding stents); TIA/CVA.

Monitoring: for anemia, BT sometimes

Interactions: other antiplatelets/anticoags/ NSAIDs 

ADRs: (often dose dep): dyspepsia (enteric coated helps), & GI ulceration (enteric coated doesn't help); bleeding (daily low-dose at least* doubles GI risk -- consider a PPI for high-risk: hx of PUD, NSAID use, clopidogrel, or anticoag; or multi RF - dyspepsia, >60, steroids. Don't use H2RAs - don't prevent ulcers r/t ASA & long-term use may -> tolerance.); hepatotox, SNHL (Salicylism-rining), ARF (blocking vasodil PGs or AIN), bronchospasm in asthma pts (5-30% asthmatics are sensitive); Reye's syndrome

Clopidogrel: Prodrug ->intermed->active -> irreversibly* blocks P2Y12 comp of ADP* receptors -> preents activation of GPIIb/IIIa receptor complex -> prevents fibrinogen binding at that site -> dec platelet aggregation

Prasugrel: Prodrug w/ better absorption & less dependent on CYP -> inc active metab delivered to platelet -> prevents activation > clopidogrel. So more dec in ischemic events, but more bleeding - more efficacious!

Ticlopidine: devel (combined with ASA) facilitated widespread use of coronary-artery stenting* -> no longer used d/t toxicity!

FDA added boxed warning, stating that persons with a CYP2C19 variant encoding a form of enzyme ass w/ low rate of metab might require dose adjustment - so genotyping* endorsed for pts at mod-high risk for CV events who are tx-ed with clopidogrel

-> lower levels of active metabolites. 30% whites affected. Clinical trials have documented diminished platelet inhibition & higher degree rate of major adverse CV events (including stent thrombosis)

Clopidogrel: ACS, TIA/CVA, PAD

Prasugrel: ACS

-PPIs commonly co-admin w/ clopidogrel but saved for HIGH bleeding risk or pts with multiple RF (older age, H. pylori, concomitant ASA/NSAID/steroid/warfarin

-Monitoring: monitor for anemia 

Clopidogrel: Pk - combine with PPI (ome/eso>rabe>lans), cimetidine, fluoxetine, fluconazole. Pd: other bleeders

ADRs: GI intolerance (N/V, dyspepsia, gastritis) - more likely with concurrent ASA; flu-like illness; TTP (ticlidopine>clopidogrel), bleeding (pras>clopid) - m/c in eldelry (>75), frail, & pts with hx of TIA/CVA (remember 20% are non-responders); stop clopid 5d before surgery, pras 7d before. RIsk dec with PPI>H2RA

MOA: same as clopidogrel/pras but has a reversible* anti-platelet effect! 

-Ind: ACS (with concom low-dose ASA)

-Monitor: H/H, renal fx, uric acid conc w/ gout 

-Interactions: 3A4 (but has a short half life, so no biggie)

-ADRs: bleeding, dyspnea (may be r/t ticagrelor-induced stim of adenosine receptors - pts have dc'd ticagrelor b/c of this), bradyarr, inc serum UA and Cr. 

Abciximab, eptifibatide, tirofiban

Ind: ACS - PCI. 

-ADRs: immune-mediated thrombocytopenia; abciximab 1% 1st dose, 10% repeat dose. 

MOA: inhibits adenosine deaminase & PDE -> accum of adenosine/cAMP -> inhibit platelet aggregation (antiplatet!). Direct vascular effect - causes coronary vasodil, pos via prostacyclin or PGD2 (but -> massive HA!)

-Oral form: ASA/dipyrid m/c used for TIA/CVA reduction (not hemorrhagic). IV formulation - historically used as diag agent for CAD. 

-Drug monitoring: oral: nothin unique. IV: BP, HR, ECG drug stress test. 

-ADRs: oral-dizziness, severe* HA; IV - exacerbation of angina, dizziness, HA, hypotension

MOA: antagonizes vit K epoxide reductase complex 1 (VKORC1). Leads to accum of hypofx-al clotting factors and anticoag proteins. 

-Pharmacogenetic: 2C9 (does S warfarin!) -> metabolic clearance of warfarin (variants m/c in asian americans & african americans). VKORC1 -> recycles reduced vit K.

-Ind: prevention & tx of VTE. esp d/t a fib or prosthetic valve (preferred* anticoag for Afib with CAD). May be used for recurrent TIA - pts are often "resistant" to ASA & clopidogrel.  

Start 5*-10 mg/d for first 2 days -> adjust based on INR. Half life of 40 hrs, so takes about 2 days to see effect in PT. Large loading doses create a transient hypercoag state (d/t decline of protein C!!)

-Lower doses may be req for: hepatic impairment, poor nutrition, CHF, elderly*, pts on 2C9 inhibitors/polymorphisms of 2C9. 

-Higher doses may be req for pts on 2C9 inducers (rifampin, phenytoin), polymorphisms of VKOR1

PT/INR - assesses extrinsic pathway (TF & factor VII). Assesses coag factors in common pathway - factors II (prothrombin), V, X, & fibrinogen). Want 2-3 (2.5 in afib)

-prolongation of PT during 1st few days of warfarin therapy is from depression of factor VII. Intrinsic pathway not* initially altered -> not fully anticoagulated until components of intrinsic pathways are reduced (overlap warfarin/UFH or LMWH 5-7d if rapid anticoag needed)

-Monitor daily til stable, then q3-4 wks. or more if unpredictable response. 

Pk: drugs that dec absorption (antacids, bile acid sequestrants); 2C9 substrate - careful with inhibi/inducers. FQ (mech unclear.)

ADRs: bleeding. Graded effect. Don't assume* pts on chronic stable warfarin who develop hematuria is always secondary to anticoagulation! Skin necrosis/gangrene (paradoxical thrombosis occurring in 1st few days; often on extremities, breast, or penis); purple-toe syndrome (cholesterol emboli -> toes); teratogenic*

Porcine intestinal mucosa & bovine lung

-MOA: indirect thrombin* inhibitor, complexes with AT -> converts cirulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa (lesser extent factors XIIa, XIa, & IXa)

-Ind: DVT prophylaxis (5000 u SQ q8-12!). Systemic anticoag (for any reason) -often DVT & PE tx; ACS

-Adv: cheap, familiarty of use, better in renal dysfx (quicker clearance given half-life)

-Limitations: narrow therapeutic window; anticoag response varies widely-> monitor. Reduced ability to inactivate thrombin bound to fibrin as well as factor Xa to activated platelets within a thrombus* -> thrombus may continue to grow. Possibility of HIT. 

Dosing: situation-dependent. Each facility will likely have a "heparin protocol" usually you want your pt 1.5-2.5x baseline aPTT (optimal to get anticoagulated within 24 hr)

-Monitoring: aPTT - for intrinsic pathway (XII, XI, IX, VIII) & final common pathway (II, V, X) - not currently standardized like INR. 

-Monitoring ADRs: Therapeutic dose: qod platelet cts til heparin stopped or d14. Prophyl dose: q2-3d platelt cts til heparin stopped or from d4-14.

30 min half-life

-Nonurgent: turn down/stop

-Urgent: protamine by slow IV infusion - if pts have received protamine previously have a 1% risk for anaphylaxis. Note: FFP doesn't reverse heparin. 

MOA: direct factor Xa inhibitor -> inhibits free & clot-bound factor Xa. 

Ind: prevent DVT in pts undergoing knee* and hip replacement. Prevention of stroke & systemic embolism in pts with non-valvular Afib. 

Pearl: start 6-10 hrs after* surgery. Don't use in pts with CrCl<30. 

-Interactions: Pgp & 3A4. ADRs: protamine doesn't work (c/t LMWH); rivaroxaban is highly protein-bound (not likely dialyzable) - aka can't turn it off. 

MOA: antithrombin-mediated inhibition of factors Xa>IIa

Ind: DVT prophylaxis of hip/knee sx, abdominal sx, & medical pts with restricted mobility. DVT/PE tx; ACS

Lim: cost; harder to dose in renal dysfx & obese pts

Adv: inc SQ bioavailability & anticoag duration (q12-24hr), anticoag correlates with weight* -> fixed dose! No lab monitoring. Less thrombocytopenia, hemorrhage, & bone loss. More effective (dec recurrent VTE, better in cancer), cost effecitive - outpt tx possible.

Dosign: situation & product specific. Need to adjust for CrCl. Pt wt - monitor levels or use UFH (ask pharm!), given by deep SQ AP & LR abdominal wall. 

-Monitor: usually no anticoag monitoring - most helpful for select pts during tx* (monitor anti-Xa levels 4 hrs after sq injection - esp in preg women, renal dysfx, obese pts!!)

-Reversal: protamine sulfate (partially). FFP does NOT reverse LMWH (or unfract heparin)

-ADRs: injection site pain & hematoma; hemorrhage possible less than heparin; thrombocytopenia less than heparin. 

MOA: antithrombin-med inhib of factor Xa

Ind: DVT prophylaxis of hip/knee & abd sx; DVT & PE tx (when initial tx started in hospital)

Lim: not well studies inpts with Cr>1.8. Currently can't be reversed (rFVIIa may help)

Adv: 100% SQ absorption; long half life (qd dosing)

-Dose monitoring: rec to monitor periodic CBC, SCr, stool occult blood (cna't us eif kidney dz!). At therapeutic doses it doesn't alter aPTT, PT, BT, or alter platelet fx or fibrinolysis (monitor with anti-Xa assay)

ADRs: hemorrhage (can't do anythign); pos less likely to cause HIT. 

*No antidote to any of these products!!

-MOA: synthetic, non-peptide, DTI -> inhibits both* clot-bound and circulating thrombin -> dec thrombin-stimulated platelet aggregation. 

-Ind: prevention of VTE stroke in pts w/ non-valvular* Afib (but don't use if CAD! - more AMI)

-Pearls: no antidote, anticoag effect wears off within 2 days; bleedinr risk (warfarin>ICH; dabig>GI bleeds)

Storage: very sensitive* to moisture - only good for 60d after bottle opened; pts should keep meds capped. 

-If a dose is missed, advise taking asap (unless next is <6 hrs due)- pts should not* double up doses. 

-Surgery: stop dabig 1-2d before sx (3-5d for pts with CrCl<50), restart 24 hr after* surgery (longer if high risk of postop bleeding). 

-So switch pts with poor INR control or those who can't be well monitored; wait til INR is <2, then start dabigatran. 

Monitoring: SCr baseline & yearly (elderly & CKD pts), anticoag effect much less variable than that of warfarin - monitoring not required. 

-Reversal: currently unknown. stop dabigatran & initiate supportive measures (saline, RBCs, FFP/rVIIa/PCC, dialysis)

-Interactiosn: sub of P-gp; not metab by CYP!!

ADRs: bleeding, dyspepsia*/gastritis (10%) - tab contains tartaric acid to improve absorption

Synthetic derivative of hirudin; same use as lepirudin

-Monitor aPTT - can't reverse (but has very short half life -30 to 50 min) - probably safest in pt with CKD (with HITTS) -> metabolized by liver

ADR: bleeding 

Recombinant analog of hirudin

-Approved for DVT prophylaxis during Total Hip Arthroplasty (given sq)

-Monitor aPTT - can't reverse!

-ADR: bleeding, anti-desirudin Ab may be generated

Synthetic analog of hirudin

Approved for ACS, pts with or at risk for HIT/HITTS undergoing PCI - both given IV

ADR: bleeding 

Recombinant tissue type plasminogne activator aka tPA. Naturally occuring enzyme rpoduced by a number of tissues - inc endoltheial cells - made recombinantly. Initiates local fibrinolysis by binding to fibrin in a thrombus & converts entrapped plasminogen to plasmin. 

-Ind: STEMI, PE, stroke, catheter clearance, acute peripheral arterial occlusive disease (unlabeled use)

-ADRs: bleeding. Major - IC, RPeritoneal; minor - bleeding at catheter site, GI/GU hemorrhage

Reteplase aka rPA - Same MOA as alteplase but less fibrin selective & has a longer half life. 

Tenecteplase: genetically engineered. 14x more fibrin specific. Same MOA of alteplase with longer 1/2 life than reteplase - single* IV bolus. 

-Both ind: STEMI (same outcomes as alteplase but easier to admin); ADRs - same as old ones. 

Heparin: large molecule that doesn't cross placenta. Cat C (no known teratogenicity & does not anticoagulate the fetus). Admin during preg difficult d/t Pk parameters & HIT, as well as issue of bone loss

LMWH: enoxaparin is cat B (ACOG!); longer lasting, more predictable dosing; less bone loss? switch to SQ heparin 2 wks before delivery - easier issues of surgery/analgesia 

Can be deep (dull/aching, usually well localized) or surface (sharp, burning, "prickly"); caused by activation of pain receptors in cutaneous or MS tissues.

-Etios = metastatic bone pain, incisional pain after surgery, fx, sprain/stain

Poorly localized; often described as pressure, squeezing; pain originating from areas in the body that are encapsulated. Caused by activation of pain receptors resulting from infiltration, compression, extension, or stretching of viscera (abdominal, pelvic, thoracic)

-Common etiologies: pancreatic/liver cancer, abdominal metastases, gastritis, gallstones

Usually severe; described as burning, tingling, lancinating, numbness, stocking glove, "electric shocks"

-Originating from nerve damage from: trauma (stab wound, disc/root injury), chemicals (chemo), disease states (HIV, DM, herpes zoster), surgery, radiation, tumors

Characterized by well-defined pattern of onset - cause usually can be identified (not always). More likely to be accompanied by VS changes (tachycardia, tachypnea, elevated BP). Usually responds to tx by analgesia or reversal of inciting problem. 

-Characterized as 3 mo or less in duration. 

Pain that persists >3 mo.

-Often not accompanied by VS changes. Adaptation of the autonomic nervous system. This makes pts at risk of going undertreated or under recognized. Lack fo VS change does not* = lack of pain.

-May experience periods of control along with periods of "breakthrough"

= transient inc in pain to over moderate intensity occurring on a baseline pain of less than mod intensity.

-Characterization needs to be individualized. Could be marked worsening of pain at end of dosing interval, marked worsening of pain d/t worsening condition, marked worsening of pain d/t tx (dressing change). A pain diary can help the clinician manage these epidodes better.

= level 1-3 (not rigid)

-Start w/ OTCs - Acetaminophen (up to 1000 mg q6hr; max 4 g/d) and ibuprofen (up to 800 mg q8hr; 2400 mg/d) - or another NSAID. 

= 4-6 (or 7). Use single or combo agents.

-Single: codeine 30/60 mg q3-4hrs prn. Dose limited only b/c of SE (prb not good choice because of these!); oxycodone 5 mg q 3-4hrs prn (no dose limits); tramadol 50-100 mg q6hrs prn.

-Combo: Acetaminophen or ASA + narcotic (Percocet q4-6 hr; vicodin q4-6 hrs) - important not to exceed 4 g APAP!

-Potency: oxycodone=hydrocodone > codeine=tramadol > propoxyphene

Pain level 8 or greater.

-IV dosing often used as easier to titrate to effect rapidly. Depending on cause, IV infusions sometimes needed.

-Short acting drugs: morphine, hydromorphone, oxycodone (PO only), meperidine (IV or IM - lots of euporhia) - only use in procedures, <600mg/d d/t accum of toxic metabolites (seizures). IV onset faster (2-15 min vs 15-30 min). So fast onset & short duration.

-Long acting: MS contin or oramorph SR, oxycontin or oxycodone SR, Kadian (another morphine long-acting prep- can be sprinkled on food), transderm fentanyl (duragesic patch, change q2-3d)

30 mg PO morphine = 20-30 mg PO oxycodone = 7.5 mg PO hydromorphone = 10 mg IV/SQ morphine = 2 mg IV/SQ hydromorphone.

-Duragesic patch = 24 hr oral morphine doses / 2.

-2 percocets q4hr = 10 mg PO morphine q 4 hr = 30 mg MS contin q12hr = 1 mg/hr morphine cont IV or SQ = 25 mcg duragesic patch. 

-Always calculate equi-analgesic dosing when switching meds to avoid over or under dosing. Consider 50% dose reduction when switching drugs d/t incomplete cross tolerance.

Oral is preferred rout. If they can eat, try oral. IV/SQ produce same effects if unable. IM route only for unable to eat and no IV access possible/convenient.

-Rectal = oral w/ morphine or hydromorphone

-Use only one long-acting and one short-acting opioid at a time.

-Cont pain req cont meds (long acting morphine, patch)

-Must provide breakthrough med for those on long-acting product (MS contin + oxycodone prn, oxycontin + percocet prn)

Escalate dose 50-100% for severe/uncontrolled. Escalate dose 25-50% for mild/moderate pain. This is irrespective of startign dose!

-Short acting drugs can be escalated as often as 1-2 hrs; long-acting drugs q24hrs. Fentanyl patch q48-72hrs. 

-Constipation - always* prescribe Senna-S scheduled +/- prn suppository when using opiods. Monitor BM frequency, character and add/escalate as needed.

-Nausea: not an allergy. Usually resolves after a few doses. If not, tx nausea with chlorperazine or switch opiod

-Sedation/confusion: usually resolves after a few doses. May need to dec dose if persists.

-Resp suppression: rare with short-acting. RF: rapid IV push, new liver/renal dysfx, rapid dose escalation of fentanyl patch or methadone.

-Pruritis: very common (morphine worst, fentanyl least). Not a true allergy, not a contraindication to opiods. H1 & H2 blockers help a little, can try switching to different opioid if intolerable. 

-Invasive procedures: generally performed by IV radiologist, neurosurgeon, or physical medicine/pain clinicians. Nerve block for radiculitis; vertebroplasty for vertebral compression fx; chemoembolization/radiation for tumors impinging on nerves. 

-Anti-depressants: all TCAs have some analgesic effects (amitriptyline m/c - sedation = m/c SE; anticholinergic SE dissipate); dc if no response in 1 wk at max dose. 

-Anti-convulsants: Gabapentin, phenytoin, carbamazepine, VPA (gabapentin well tolerated & doens't req blood levels.) Use like in seizures; follow blood levels. DC if no response in 1 wk at good blood levels/max tolerated dose.

-Corticosteroids; not longterm. Dexameth or prednisone.

-Lidocaine patch: esp for near surface (shinges, ulcers)

-Capsaicin cream: pain near surface (skeletal muscle)

-Non-harm: acupuncture, PT, biofeedback, meds, heat/cold, TENS

Radiation: bony mets, muscle mets

Bisphosphonate: inhibits bone resorption (osteoclastic/osteolastic activity); pamidronate for bony mets (IV) - fatigue, fever, nausea.

Steroids

Calcitonin nasal spray - antagonizes PTH, inhibits bone resorption; off label except for Paget's dz. 1 spray each nostril daily.

Muscle relaxants - diazepam, cyclobenzaprine

Non-pharm: PT, massage, acupuncture

Breakthrough dose should be 10-20% of 24hr long-acting dose and given q2-3 hrs prn (ex: oxycontin 30 mg bid with 10 mg q2-3 hrs prn breakthrough)

-Avoid morphine in renal pts - inc risk of sedation, seizures, myoclonus; hydromorphone better.

-Otherwise, if you want to use a pure opioid, choose morphine 1st - cheapes, esp long acting form.

-Can shedule anti-emetic if N from opiods (ondansetron)

-Don't crush long-acting opioids or cut fentanyl patches!

Superficial, nonanatomic tenderness; pain with simulated testing; inconsistent responses with distraction; nonorganic regional disturbances (ie nondermatomal sensory loss); overreaction

*Bottom line:  these may suggest* an organic component to the back pain, still use clinical judgment!

1st line: NSAIDs if no contraindications (ibuprofen 800 mg PO q 8; naproxen 550mg q12)

Additional option/in addition: -muscle relaxer (if spasm is an issue): cyclobenzaprine, carisoprodol, diazepam. 

-Opiod combo: hydrocodone + acetaminophen; oxycodone + acetaminophen

-Pure opiod analgesics: oxycodone (all are sedating!)

If mild, can send out with prescription only. If moderate, might try to dull pain in ED prior to discharge. If severe, need to improve enough to ambulate. 

-Options: Ketorlac (toradol) 15-30 mg IM or IV; morphine or hydromorphone; diazepam

With hypokalemia, hypomagnesemia, & bradycardia.

-TdP results from QT prolongation, usually d/t blockade of the Ikr potassium current. 

*Note: all anti-arrhythmic agents can cause arrhythmias, which may be fatal (aka the #1 SE = SCD)

Class I: Ia-slows conduction velocity (less than class Ic) & prolongs AP duration.  Ib - has no effect on conduction velocity & may shorten AP duration.  Ic - slows conduction & may prolong AP duration (mild)

Class II: Beta-blockers

Class III: Prolongs AP duration; no effect on conduction

Class IV: non-DHP CCBs

Other: digoxin

Class I: modulate or block Na channels.  Ia: quinidine, procainamide, disopyramide  Ib: lidocaine, mexiletine  Ic: flecainide, propafenone

Class II: inhibit sympathetic activity - beta blockers

Class III: block K channels - Sotolol, dofetilide, ibutilide, amiodarone*, dronedarone

Class IV: blocks Ca channels. Verapamil, diltiazem

Interactions: avoid other QT prolongators. Most are metabolized by CYP3A4 or 2D6. Drugs that cause hypokalemia/hypomagnesemia (loop diuretics) inc risk

Class ADRs: QT prolongation/proarrhythmic potential; careful in pts with bradycardia/heart blocks

-Quinidine: SE: quinidine syncope (recurrent lightheadedness & fainting secondary to self-terminating TdP. Drug conc usually normal or even subtherapeutic) & cichonism (ass with high drug conc. aka the dry as a bone, etc anti-muscarinic SE)

-Procainamide: SE: Reversible Lupus*-like syndrome (m/c in slow acetylators), potentially severe bone marrow suppression

-Disopyramide: SE: anticholinergic SE (esp urinary retention). Be careful in glaucoma & BPH pts! 

-Mexiletine: SE: CNS toxicity (dizziness/lightheadedness & unsteady gait m/c; tremor 10%)

-Lidocaine: SE: CNS toxicity (tremor m/c; seizures possible)

-Flecainide: SE: Mostly proarrhythmia*, not* in pt with history of AMI = black box warning!

-Propafenone: SE: Dysguesia (altered taste), lupus-like rxn. 

*Note: need Echo to make sure the pt has a structurally normal heart -> black box warning. 

-Sotalol: racemix mix: I-sotolol has class II (nonselective BB) & III activity; D-sotolol has pure class III activity. Avoid concurrent BB & CCB's. Has some BB activity - same precautions (bradycardia, COPD, raynaud, etc)

-Ibutilide: proarrhythmia mostly

-Dofetilide: restricted distribution (REMS program) -> start in hospital! No special ADRs (except dysrhythmias which stretch QT ->torsades -> death)

-Amiodarone, dronedarone 

Iodine-containing cmpd (similar to thyroxine); highly lipid soluble -> stored in high levels in fat, muscle, liver, lungs & skin (very long half life!)

Ind: FDA-approved for life-threatening recurrent VF or hemodynamically unstable VT. Common clin use: AF pharm cardioversion; AF prophylaxis following open heart surgery; recurrent AF

-Pk interactions: Sub of 2C9 & 3A4; inhibits 2C9*, 3A4, 2D6. Pgp inhibitor (inc digoxin conc for up to 3 mo). Pd interactions: additive QTc drugs, additive AV block/bradycardia, drugs that induce dec K or Mg (furosemide, steroids, amphotericin, anything that irritates the kidney)

1. Pulmonary toxicity: pathophys variable (m/c with VT doses); commonly presents like IPF -> ARDS* possible. Interstitial infiltrates on imaging. D/C amiodarone plus* steroids & supportive care. 

2. Thyroid toxicity (hypo>hyper (first tho)) - TFT q6mo

3. Ocular toxicity: corneal deposits (nearly all* pts & affects vision 10% of the time); optic neuropathy/optic neuritis (may lead to blindness; may occur at any time)

4. Derm: photosensitivity; recurrent sun exposure -> bluish skin discoloration; m/c with VT doses

5. Cardiac toxicity: bradycardia & AV nodal block (do ECG at baseline & during loading dose)

Same MOA as amiodarone, but non-iodinated analog; significantly less lipophilic -> substantially smaller Vd -> shorter elim half life & less tissue accumulation

-Ind: AF/atrial flutter - less* effective at maintaing NSR in pts with AF than amiodarone

-Monitoring: all baseline & prn - K, Mg, SCr, LFTs, ECG q3mo (minimum) -> D/C if in AF

-ADRs: Inital: N/V/D; photosensitivy reported, but not blue/gray skin discoloration. Emerging: New warning about possible acute liver & renal failure, exacerbation of HF (FDA issued warning re: liver failure!)

-Contraind: Pts with NYHA class IV HF or II-III with recent decompensation (d/t data of 2x mortality); Dronedarone suppresses sinus node activity & AV conduction -> don't use in: Pts with 2nd/3rd degree AV block, pts with SSS (unless used with pacemaker), pts with bradycardia <50. Pts who can't/will not be converted to NSR or pts who don't stay in NSR (2x risk of CV death, CVA, & HF)

-Interact: CYP3A4 substrate; dronedarone is a mod inhibitor of 3A4 & 2D6 (think metoprolol & statins); drondarone is a Pgp inhibitor. Dronedarone is a moderate QTc prolongator (be careful with other QTc prolongators). Clinicians are seeing INR* elevations w/ warfarin!

-Cardiac glycosides comprise a group of steroid* compounds that can inc CO (ionotrope) & alter eletrical cardiac fx

MOA: depends on use: HF - reversible inhibition of Na/K ATPase pump -> inc intracellular Na -> promotes Ca influx via Na/Ca exchange pump -> inc intracellular Ca -> inc contractivitly.  SV arrhythmias - inc vagal tone -> dec conduction through SA & AV nodes. 

-Uses: Advanced HF (improves sx/dec hospitalzations. does not* alter mortality). 2nd line tx for AF (rate control) in HF pts (only effectively controls HR at rest)

-Baseline & periodic ECG (assess desired & undesired effects); baseline & periodic SCr (renally excreted); periodic K, Mg, Ca (in hx of electrolyte disorders or on meds that induce - ie diuretics)

-Serum trough digoxin conc -> optimally measured prior to next dose (min 6-8 hrs after last dose); 0.8-2 ng/mL generally viewed as "therapeutic" and don't get the toxicity. Check within 5-7d after dose changes.

Interacts with many drugs & toxicity inc* mortality -> monitor levels. 

-Pk: generally Pgp (non-DHP CCBs, amiodarone, & macrolides -> also have additive Pd effects (QT prolongation).  

-Pd: concomitant AV effects (non-DHP CCBs, BB, other anti-arrhythmics)

-Other: oral steroids & diuretics: dec K or Mg -> inc digoxin distribution to heart* and muscles -> inc toxicity!

-Acute: sx dvelop over days - Cardiac effects (arrhythmogenic) are greatest concern. PVCs most common! Others include bradycardia, atrial tachyarrhythmias with AV block, ventricular bigeminy, junctional rhythms, various* degress of AV nodal blockade, VT & VF. GI manifestations (anorexia, N/V, abd pain); neuro manifestations (confusion & weakness). 

-Chronic: More difficult to diagnosis -> sx develop over d-mos. cardiac effects (rhythm disturbances) are greatest concern; neuro (lethargy, delirium, weakness); visual changes may include alterations in color vision (yellow/green), development of scotomas, or blindness -> may occur at or above therapeutic digoxin conc. 

*Note: digoxin toxicity based on clinical & ECG manifestations, not isolated inc serum digoxin conc. 

1. Digoxin conc

2. Serum K conc (inhibition of Na/K ATPase, in both heart & skeletal muscle, leads to an inc in extracellular K -> hyperkalemia is a major manifesation of acute digoxin tox

3. BUN/SCr (volume depletion from diuretics or GI losses can cause prerenal dz contributing to digoxin toxicity)

4. Baseline ECG -> telemetry -> repeat ECG with any telemetry changes/change in clinical status. Know digitalis effect on ECG -- depression or sagging of the ST segment, without J pt depression. ST seg is concave.

M/c sustained cardiac arrhythmia; incidence inc with age; may be asymptomatic -> palpitations, fatigue, dyspnea, & dizziness -> HF & CVA

-Some secondary causes of Afib include: longstanding HTN, sleep apnea, AMI, etc. 

Untreated AF usually ass with rapid, irregular ventricular response - often accomp by sx (palpitation, fatigue, dizzy)

-Widely accepted taht slowing vent response (rest & during activity) w/ drugs that prolong refractory period of AV node ("rate control agents") will result in sx improvement and most likely reduce future risk of adverse CV events

-Guidelines: recommend strict* rate control - resting <80bpm, mod physical activity <110 bpm (studies show it may just lead to more ADRs tho - bradycard, syncope)

BB are first line (ex: metoprolol)

Non-DHP CCBs 2nd line (diltiazem) (verapmail not tolerated d/t constipation)

Digoxin (most often used with above options as its minimall effective for rate control during exercise

*See slide 56 if you wish.

-> more* hospitlizations from adverse CV events; more serious adverse effects from meds; same rate of thromboembolic events compared to pts with rate control

-Rhythm control is an option when rate control is unsuccessful or when sx persist despite rate control!

-Pharm cardioversion & maintenance of NSR are difficut to achieve d/t limited long-term effectiveness of meds, risk of triggering vent arrhythmias, risk of long-term ADRs from med use.

-Paroxysmal & chronic afib tx with rate or rhythm control, require long-term anticoag tx unless risks of anticoag use exceed benefits. 

-Options: ASA, Warfarin (more effective than ASA, but inc bleeding risk; more effective than ASA + clopidogrel with same bleeding risk); dabigatran (new, only non-valvular AF; not in pts with CAD); Rivaroxaban (new, only non-valvular Afib) -- choice depends on CHADS2 score, comorbid dz, choice, cost. Limits of CHADS2 = CAD and sex are not risk factors. compare to HASBLED (>2)

Goals = dec/eliminate pain & disability. Without tx, acute gouty arthritis usually resolves within days-wks -> anti-inflammatories speed resolution.

-Options: NSAIDs (usually naproxen & indomethacin), colchicine, steroids (Methylprednisolone or triamcinolone (intraart); short tapering courses of low-dose systemic corticosteroids (ex: prednisone) effective, particularly for polyarticular* involvement). 

Upon resolution of an acute gouty attack, pt has an "intercrtical" period - variable duration. (Many untreated gout pts experience 2nd episode within 2 yrs)

-Prophylaxis with colchicine or NSAIDs can prevent flares of acute gout during initiation of a urate-lowering agent (6 mo minimum common).  Preventing recurrent gouty arthritis & tophi often requires long-term use of drugs that reduce serum urate conc by: enhancing renal excretion of uric acid -> uricosuric agents (propenecid) & dec urate synthesis (xanthine oxidase inhibitors - allopurinol or febuxostat). 

Available for decades as an unapproved drug -> unapproved products will be taken off market eventually. Tab, IV was removed by FDA d/t toxicity.

MOA: anti-inflam effect not fully understood.

-Ind: used for acute* gout flares

-Dosing: old - 0.6 mg/hr til improvement or until abd pain/diarrhea occured.  New - one dose of 1.2 mg (2 tabs) folllowed by a 2nd dose of 0.6 mg (1 tab) 1hr later (equally effective & less toxicity!)

Substrate of 3A4 (major) & Pgp. Fatal toxicity reported in pts taking colchicine with a strong inhibitor of 3A4 (clarithromycin) or a strong inhibitor of Pgp (cyclosporine). 

-Precautions: FDA recommends that colchicine not be used concurrently with P-gp or strong 3A4 inhibitors in pts with renal or hepatic impairment. FDA recommends dose reduction or interruption of colchicine in pts w/o renal or hepatic impairment. 

-ADRs: Old dosing = diarrhea** (almost everyone). New dosing = about 25% get diarrhea. Myopathy & rhabdo reported in pts taking colchicine with a statin/fibrate.

Uricouric agents = probenecid (like a diuretic - throws urate into the urine!)

Xanthine Oxidase Inhibitors = allopurinol, febuxostat, pegloticase (really a uricase analog that leads to water soluble allantoin.)

Clinical monitoring (start 2-4 wks after initiation): serum urate conc<6; serum urate conc<5 in pts with tophi (always dose urate-lowering drugs to above targets). 

-Lowering serum urate slowly (<0.6 mg/dL per mo during 1st 6 mo) ass with lowest rate of recurrent acute attacks. (d/t paradoxical flares in the beginning if go too fast; also d/t toxicities)

-Most anti-hyperuricemic tx should be initiated once acute intlam event has resolved - initiation during an acute attack may lead to paradoxical worsening! (generally start 2-4 wks after flare resolution.) duration of tx generally indefintie to remain effective.

MOA: weak organic acid promoting renal clearance of uric acid by inhibiting urate-anion exchang in prox tubule that mediates urate reabsorption (net effect = inc excretion).

-Ind: prevention of hyperuricemia secondary to impaired* renal excretion of uric acid ass with gout. (Pts must have adequate renal fx to get optimal response). Prolongation & elevation of beta-lactam plasma levels.

-Monitoring: serum uric acid conc; BUN/Cr 

Contraind: inc urinary Ca excretion in gouty pts -> don't use in pts with prior nephrolithiasis

Interactions: Interference with transport of other organic anions across cell membranes by uricosuric drugs -> numerous drug inteactions possible. (Ex: urinary excretion of beta-lactams dec -> prolongation of drug half life)

-ADRs: pretty well tolerated, but may precipitate* acute gout; uric acid stone* formation (urate nephrolithiasis); rash, N/V/D (dosed multiple/day, but not really used)

MOA: inhibits xanthine oxidase -> inhibition of conversion of hypoxanthine to xanthine to uric acid, without disrupting biosynthesis of vital purines (since it looks like a purine)

-Ind: Prevention of hyperuricemia ass with gout & urate nephrolithiasis (prophylactic tx with concomitant colchicine/NSAID* x 6 mo can dec incidence of paradoxical gout flares during acute** treatment. 

-Dosing: adjust for GRF d/t accumulation of allopurinol & metabolites (low and slow -> titrate to urate levels)

-Monitoring: (esp during initiation): CBC, baseline & periodic LFTs and SCr, serum uric acid conc (serum urate levels begin to fall within 2d & reach stable levels in 1-2 wks -> assess dose titration q2-3 wks.

Interactions: potentiation of IS effects of 6-mercaptopurine, azathioprine, & theophylline (QT or seizures) - metabolized in part by xanthine oxidase -> avoid* allopurinol in these pts

-ADRs: paradoxical* gout flare; simple* rash -> SJS/TEN (severe cutaneous rxns ass with HLA-B*5801) - everyone's afraid of this. If they were to get amox while on this, the chance of rash are dramatically higher); bone marrow suppression; drug fever; special ADRs: Allopurinol Hypersensitivity Syndrome (AHS) - fever, erythematous rash, hepatitis, eosinophilia, & ARF. m/c in CKD pts treated with standard doses of allopurinol & diuretics. Rare (incidence 0.1%) but potentially life-threatening rxn (25%)

MOA: xanthine oxidase inhibitor; not a purine base analogue (unlike allopurinol)

-Ind: Prevention of hyperuriceia ass with gout & urate nephrolithiasis (prophylactic tx with concomitant colchicine/NSAID x 6 mo can dec incidence of paradoxical gout flares during acute* treatment. 

-Monitor: baseline & periodic LFTs. Serum uric acid conc. 

-Interactions: same as allopurinol

-ADRs: paradoxical* gout flare. LFT abnormalities (ALT/AST elevations >3x UNL in 2-3% of pts. Same, but not weird stuff - rash or hypersensitivity syndrome)

Uricase had been lost to man via a missense mutation in gene encoding enzyme - in other species, uricase converts urate to allantoin*, which is 5-10x more water-soluble & more readily eliminated than urate. 

-MOA: reduces serum uric acid conc by catalyzing oxidation of UA -> allantoin, an inert water-soluble purine metabolite that is cleared by kidney

-Ind: IV tx of chronic symptomatic gout in adults who have not responded to maximum* doses of a xanthine oxidase inhibitor (d/t being $20K). 

-IV infusion q2wks -> $20K/yr. Give infusion over 2 hrs; premedicate with diphenhydramine & prednisone before infusion to prevent pos anaphylaxis. Gout flares common -> prophylaxis with a NSAID or colchicine >1wk before starting pegloticase; cont for at least 6 mo. 

-Considered to be a "debulking agent" (can reduce* tophi dramatically) -> emphasize it as an adjunct* followed by another urate-lowering agent. 

-Drug monitoring: serum uric acid conc. (since will go up at first d/t breaking up tophi)

Contraindications: contraindicated in G6PD def pts -> may induce acute hemolysis.

Interactions: none so far

ADRs: paradoxical gout flare*, maybe severe (very frequent). Anti-pegloticase Ab common -> high titers lead to diminished effect. Infusion rxns (urticaria, dyspnea, chest pain/discomfort, erythema, prurirtis) 25%. Anaphylaxis 5%. 

-Used early to prevent irreversible damage to jts & minimize toxicities ass with NSAIDs & corticosteroids. No immediate analgesic effects -> over time can control sxs & may delay/stop progression. NSAIDs have immediate analgesic & anti-inflam effects, but may not* affect dz process. Steroids can rapidly relieve jt sx/control systemic manifestations; chronic use can cause many ADRs. 

-Therapeutic options: "step up" approach common - initiate 1 non-biologic DMARD than add other DMARDs if needed (usually PCP does this). "Step-down" approach may work faster -> initiate 2-3 DMARDs then step down if remission occurs. 

-Nonbiologic: initiate therapy within 3 mo of diagnosis; many pts start MTX* or leflunomide (if can't tolerate MTX - not as much toxicity). Pts with milder RA may start hydroxychloroquine or sulfasalazine.

-Biologic: usually reserved for pts who don't respond well to non-biologic DMARDs or* have moderate-severe dz. May be used alone or in combo with non-biologic DMARDs. Most pts will start a TNF inhibitor. May receive abatacept, rituximab, anakinra, tocilizumab if no response to TNF inhibitors.  

Commonly used: MTX, leflunomide

Less commonly used: Hydroxychloroquine, sulfasalazine

Little clinical use: azathioprine, cyclosporine, minocycline, gold salts, cyclophosphamide

MOA: bind dihydrofolate reductase -> antimetabolite that inhibits DNA synthesis. 

-Ind: Various tumors, RA* (effect may take wks-mos), psoriasis.

-Dosing: often once/wk (then give folate on the other days). Supplement folate* to dec ADRs.

-Monitoring: CBC with diff (baseline & qmo), CMP (baseline & q1-2 mo), CXR (baseline), PFTs (if MTX-induced lung dz suspected), HBV/HCV testing (if at risk) 

Hold* for sick pts in hospital -> more likely to have aplastic crisis. Most flares won't occur for 3-4 wks after cessation. Pts should abstain from EtOH

-Preg issues: teratogenic & abortifacient* (need substantial birth control -> condom plus* ?). Can dec fertility in M/F -> d/c at least 3 mo prior to attempted conception (both sexes) 

-Precaution/contraindications: underlying liver dz (HBV/HCV, EtOH)

-Interactions: other anti-folate drugs (ex: TMP-SMX) may have compound effect; drugs that dec renal fx (ex: NSAIDs) -> dec clearance -> inc risk of toxicity. Other IS (ex: TNF inhibitors)

-ADRs: Low dose (m/c for RA) - usually well tolerated; Possible ADRs include stomatitis, GI intolerance, LFT abnormalities -> hepatitis -> liver fibrosis (continuum possible). Bone marrow suppression -> infections & malignancies (RA is independently ass with lymphoma* -> MTX prevents more than it causes). Pulm hypersensitivity/fibrosis (pulmonary irritation -"MTX lung" is m/c serious ADR)

MOA: inhibits pyrimidine synthesis-> antiprolif & antiinflam

-Ind: RA (main role is for the pt who responded to MTX, but got toxicity from it. 

-Monitoring: CBC & LFTs

-Precautions: Teratogenic: M&F who want to conceive should d/c drug & take cholestyramine to bind & elimiate drug. Plasma levels of active metaboite should then be checked to verify that they are <0.02 mg/L. Same detox protocol can be used for acute toxic effects. 

-Interactions: concom IS (ex: TNF inhibitors)

-ADRs: diarrhea* (may be debilitating), reversible alopecia, bone marrow suppression -> infections? LFT abnormalities

MOA: inhibits mvmt of neutrophils & chemotaxis of eosinophils. impairs complement Ag-AB rxns. 

-Ind: SLE, RA* (moderately effective for mild* RA), often used with other drugs (ex: MTX or sulfasalazine), may req 3-6 mo of tx for clinical effect to become apparent. 

-Felt to be relatively* safe during pregnancy.

-Monitoring: Ophthalmologic exam baseline & q3-12 mo during prolonged therapy -> refer to optho! CBC

-Contraind: anyone with hx of retinal* or visual field abnormalities.

-Interactions - relatively clean. 

-ADRs: usually well-tolerated. Hemolysis may occur in G6PD def pts!! Opthalmic* ADRs: may report immediate blurred vision or difficulty seeing at night -> reverses upon drug d/c. Retinal damage (dose related?) = rare comp avoided by: opthalmologic exam, dosage<6.5 mg/kg/d, drug d/c* promptly when signs of retinal toxicity 1st appear; not used in pts with significant renal insuff. 

MOA: interferes w/ secretion by inhibiting PGE synthesis

Ind: RA (typically req 2-3 mo for clinical effect), IBD* (less- more methalazine). 

-Pearl: probably safe in pregnancy

-Interactions: Fairly clean. 

-ADRs: Common - GI intolerance - less with enteric-coated; sulfa* rash (same class as Bactrim). Serious rxns rare (often occur in 1st 2-3 mo) - hepatitis, bone marrow suppression. Other: lupus-like syndrome; hemolysis* may occur in G6PD def pts (any true sulfa drug can cause hemolysis in these pts)

May be used for pts with refractory RA or systemic involvement such as rheumatoid vasculitis.

-Drug specifics in transplant lecture!

M/C used: TNF inhibitors: Infliximab, etanercept, adalimumab, certolizumab, golimumab

Less commonly used (use when TNF inhibitors don't work): CD20 monoclonal Ab (Rituximab), T cell activation inhibitor (Abatacept), IL1 receptor antagonist (anakinra), IL6 receptor antagonist (tocilizumab)

Infliximab (IV dosing less frequently) & Etanercept (SC more frequently) have most data. 

-Adalimumab (SC), Certolizumab (less dosing SC), Golimumab (less dosing SC)

-MOA: TNF is a pro-inflam cytokine present in synovium of RA pts (so we bind* TNF and block its activity) - biologic activities = induction of proinflam cytokines, ehancement of leukocyte migration, activation of PMNs & eopsinophils, induction of acute phase reactants & tissue degrading enzymes. 

-Mod to severe* RA. Variable indications depending on specific agent - plaque psoriasis/psoriatic arthritis, IBD, AS

-Pearls: act more quickly than nonbiologic DMARDs. No quality clinical trial data that any blocker is more effective than antoher for RA. Don't combine! (Combo can inc ADRs - esp infections without improving outcomes) 

-Make sure pts get appropriate *vaccinations & cancer screenings (lymphoma, melanoma, BCC/SCC), should not* receive live vaccines. Those who don't respond to one TNFI may repsond to another. Synergy with MTX!

Monitoring: TST or IGRA plus* CXR before* tx. Serologic testing for HBV & HCV before* tx. CBC

Contraind: can cause or worsen HF. Interact: IS

-Common ADRs: injection site rxn, URTIs, HA, GI

-Serious ADRs: drug-induced lupus, bone marrow suppression, inc risk of serious infections (serious bacterial infections (esp legionella & listeria), TB reactivation or dissemination; invasive or disseminated fungal infections (commonly missed), other opportunistic infections); inc risk of malignancies (lymphoma mostly)

T cell activation inhibitor: Abatacept - may be used for RA pts who didn't respond to TNF-I (often with MTX)

CD20 monoclonal Ab: Rituximab - may be used for RA pts who didn't respond (with MTX often); also for lymphomas

IL1 receptor antagonists: Anakinra - weakest biologic DMARD - used infrequently

IL6 receptor antagonist: Tocilizumab - may be used for RA pts who didn't respond to TNF-I (often with MTX)

Yeasts: single, small oval cells. Ex: candida spp & cryptococcus. 

Molds: exist as filamentous strands (hyphae). Ex: aspergilus sp. (Worse to get!)

-Dimorphic* fungi: exist as either yeasts or molds depending on external environment. Thermal dimorphism: genetically controlled switch from mold form at ambient temp to yeast form at body temp (ex: Histo. capsulatum - Ohio/KY/TN, Blasto. dermatitidis-WI; breaks free from lungs->skin, & S. schenckii-common in soil; gives purple notches up arms.)

M/C in IC pts: hematological malignancies (lymphoma, leukemia); bone marrow transplant pts; solid organ transplant pts (cryto -> meningitis); pts on corticosteroids or other IS (ex: TNF-alpha inhibitors); burn pts (line infections with candida); AIDS pts (candida & crytococcus)

-Note: classified as either c. albicans or non*-albicans candida (pos resistant to fluconazole or amphotericin B).

Caspofungin*, Micafungin, anidulafungin (all IV since so big that can't be taken in pill form d/t absorption)

-MOA: inhibits synthesis of Beta(1,3)-D-glucan, an essential components of the cell wall* of susceptible fungi. (mamallian cells don't require Beta (1,3)-D-glucan, therefore limited potential for toxicity).

-MOR: relatively rare

-Pharm: drug interactions = minimal; not excreted in urine (broken down before) -> can't generally use for UTI

-Ind: invasive candida infections (including most non-albicans candida); aspergillus infections (lungs or sinuses)

-ADRs: generally well-tolerated

1. Convential amphotericin B products - Ampho B (IV) - creates a pore; inserts itself into the membrane.

2. Lipid amphotericin B = safer & more efficacious. 3 types: Ampho B lipid complex, liposomal* ampho B, & ampho B colloidal dispersion. Pricey tho!

3. Nystatin - usually topical* use (systemic would be way too toxic!!) for OP candidiasis (Nystatin S&S), "intertrigo" (powder)

MOA: binds to ergosterol -> altering cell membrane* permeability & causing leakage of cell components with subsequent cell death. 

MOR: relatively rare

Pharm: interactions with other nephortoxic* drugs!!!!! Directly stimulates monocytes/macrophages to release of proinflammatory cytokines -> F/C/rigors during infusion (=difficult to tolerate)

-Common Ind: Aspergillosis*, Zygomycosis, histoplasmosis, blastomycosis, coccidiodomycosis, crytpococcus, sporotrichosis, candidiasis

Common = F/C/rigors common (transfusion) - HA, N/V, dec BP, & tachypnea also frequently seen. Usually occurs 1-3 hrs into infusion & lasts 1 hr. Pretreat with APAP, diphenhydramine, meperidine +/- hydrocortisone. (& then give it over long periods of times - around 6 hrs)

-Dose-limiting ADR = nephrotoxicity* & electrolyte abnormalities - pre & post-infusion hydration with 500 mL NS may help ameliorate toxicity; avoid other concominant nephrotoxins. cont infusion may dec toxicity as well. Monitor serum creatinine, dec K, & dec mg!!

Clotrimazole* = oral troche 5x/d for thrush or esophagitis

Miconazole = buccal tablet 1x/d

MOA: inhibits fungal CYP enzyme which converts lanosterol -> ergosterol (Ergosterol is a vital part of cell membrane* of fungi -> disruption damages cell wall, inc perm/cell lysis

-MOR: mutations in 14alpha-demethylase or efflux pumps (presence of efflux pumps -> cross-resistance of azoles)

-Pharm: Inhibitor* of 2C9, 2C19, & 3A4 (3A4 also esp ketoconazole & itraconazole!). Renal* excretion (80% as unchanged drug) - only* antifungal that develops appropriate active urinary drug conc! >90% bioavailability. 30 hr 1/2 life. 

-Used for C. albicans (thrush, vaginitis, cutaneous, & "invasive". Some non-albicans are resistant!! (c. krusei is inherently resistant, c. glabrata is relatively resistant). 

-ADRs: fairly well-tolerated

-Pregnancy implications: birth defects ass with long-term, high-dose use. Esp 1st trimester = short, broad head, abnormal face/skullcap, oral cleft, bowing of thigh bones, congenital heart disease. 

Terbinafine (Lamisil)

-MOA: inhibits squalene epoxidase -> ergosterol synthesis inhibition -> deficient cell membrane* -> cell death.

-Strong inhibitor of CYP2D6 (metoprolol)

-Once taken orally, terbinafine concentrates in skin/nail** beds & has relatively low bloodstream conc. 

-Ind: onychomycosis -> oral formulation; cutaneous dermatophyte infections -> topical formulation

-ADRs: occasionally dysgeusia* (may persist for weeks after drug cessation). Hepatotoxicity (baseline LFTs & "periodicially" while on the durg!!)

Hepatic: all azoles, ampho B, echinocandins

Renal: Ampho B

CNS/photoposia: voriconazole

Cutaneous: rash (all), photosens/malignancy (voricon)

-GI: itraconazole

Cardiac: itraconazole

Infusion rxn: Ampho B, echinocandins

Bone marrow suppression: Ampho B

Echinocandins (all = C - no data)

Amphotericin (all = B - d/t probs for mom. Too big to get to baby).

Azoles (most are C - clotrimazole topicalskin/vaginal = B, fluconazole = D except single oral dose)

Allylamines (B since irritates mom's liver)

*Note: mom = IS so fungal infections happen!

Tigecycline (IV) - synthetic derivative of minocycline. 

-MOA: 30S bacterial ribosome inhibition

-Pharm: Drug interactions (minimal), split excretion, bacteriostatic

-ADRs: N/V/D

-Microbial coverage: extremely broad coverage; doesn't* get Pseudomonas aeruginosa

-Common tx indications: mostly nosocomial infections 

Erythromycin, azithromycin* (opthalmic, suspension, tab, IV), clarithromycin (only use for H. pylori!)

-MOA: 50s bacterial ribosome inhibition

MOR: ribosomal binding site alterations; efflux pumps

-Drug interactions: erythromycin/clarithromycin = sub of 3A4; potent inhibitor* of 3A4, not with other QT*-prolonging drugs. Azithromycin = QT prolongation; hepatic excretion, bacteriostatic, potency: C>A>E (even tho clarith is most potent, it has more ADRs, drug interactions & QT prolongation issues)

Erythromycin products activate motilin receptors -> uncoordinated peristalsis -> N/V/D (motilin = gastric hormone that activates duo/jejun receptors to do peristalsis). Erythromycin used off-label as a prokinetic agent in DM gastroparesis acutely (chronic -> dec efficacy)

-Clarithromycin may have metallic taste!

-Azithromycin generally well-tolerated - large doses commonly associated with N/V (ex: 1 g for chlamydia); prolonged use of high-dose IV associated with transient hearing loss (so quickly convert to oral!) 

Coverage: Azithromycin = s. pyogenes, s. pneumoniae, h. influenzae, m. catarrhalis, chlamydia, legionella, mycoplasma

Clarithromycin: as above but tends to be used mostly for H. pylori* in primary care

-Ind of Azithromycin: URTIs (pharyngitis, AOM, sinusitis, AE-COPD), CAP, Gonococcal (2g) & non-gonococcal urethritis.   Clarithro = H. pylori

MOA: inhibits RNA polymerase -> inhibition of protein synthesis

MOR: mutation of the RNA polymerase

-Pharm: minimally absorbed after PO admin -> high intraluminal drug conc (& no real drug interactions) - so bacteriocidal against clostridia species!

-ADRs: N/V (10%), abd pain/GI hemorhage (4%), bone marrow suppression (2%)

-Ind: C. difficile (if failed metro/vanco) - little or no activitiy against organisms other than clostridia -allows for preservation of normal GI flora

Telithromycin (semisyntehtic deriv fo erythromycin)

-MOA: inhibits 50s ribosome. Bacteriostatic

-Interactions: sub of 3A4; potent inhibitor of 3A4!! Don't use with QT-prolonging drugs. Hepatically excreted. 

-ADRs: blurred vision/difficult* focusing. Exacerbates myasthenia gravis (mechanism?) Hepatotoxicity & acute liver failure -> indications for sinusitis & bronchitis have been withdrawn! (only approved for outpt mnmt of CAP!)

-Coverage: S. pneumo, h. influenaze, m. catarrhalis, chlamydia, legionella, mycoplasma, s. pyogenes

-Ind: minimal d/t safety concerns!

Clindamycin (topical, susp, tab, IV - bigger dose)

MOA: inhibits 50S ribosome; bacteriostatic 

MOR: ribosomal target modification; efflux pump

-Pharm: drug interactions (minimal), hepatic excretion

-Microbial coverage: covers most anaerobes (best "above the diaphragm"); often used to cover s. aureus, s. pyogenes, & viridans strep in those w/ serious PCN allergies. Penetrates tissue phenomenally well.

-Ind: Substitute for serious beta-lactam allergy for: SSTIs ("Eagle effect"), strep pharyngitis; anaerobic infections/dental abscesses (plus beta lactam or FQs)

Linezolid!

-MOA: binds ribosomal 50s subunit

-MOR: binding site alterations

-Pharm: drug interactions - concominant serotonergic* drugs -> serotonin syndrome; split excretion; "bacteriostatic" for s. aureus; -cidal for strep. 

-ADRs: reversible thrombocytopenia (monitor plts if >2 wks therapy); reversible MAOI (so watch dietary tyramine); "serotonin syndrome"

-Microbial coverage & tx indications: generally used for MRSA & VRE infections. 

Gentamicin* (most aerobic GNBs - generally used for severe infections; synergistic with cell-wall agents against enterococci sp - generally used for endocarditis), tobramycin* (inhalation-see with CF; most GNBs - including pseudomonas; generally for "severe infections"), streptomycin (2nd line mycobacterial infections), neomycin (minor skin infections- 1/3 get contact dermatitis; "bowel cleansing*"), amikacin (MDR GNBs), kanamycin ("surgical irrigation"), paramomycin (parasite & tapeworm infections), spectinomycin (gonorrhea tx for allergic pts)

-MOA: inhibits 30S ribosome

-MOR: ribosomal binding site alterations, efflux pumps, "aminoglycosidases"

May have additive nephrotoxicity with other nephrotoxic drugs; renal excretion; bacteriocidal*; dependent conc killing; peak conc at 60 min after infusion on the 3rd dose (?); measure trough conc 30 min before next dose.

-Rationale behind once-daily dosing: AG are conc-dependent ABX; AG have an extended postABX effect (often lasting 2-3x longer than the half-life of the drug); toxicities of AG may be time-dependent; uptake into renal tubular cells & into the inner ear is saturable & greater with constant, low serum levels)

-Nephrotoxicity (10-20%) - generally reversible

-Ototoxicity* (gent>tobra) - reversible? Vestibular damage (ex: vertigo, disequilibrium, lightheadedness, N/V, ataxia); cochlear* damage (ex: tinnitus, hearing loss)

-Neuromuscular blockade = rare - contraindicated in Myasthenia Gravis* pts

Non-resp FQ: ciprofloxacin

Resp FQ: levofloxacin & moxifloxacin

-MOA: inhibit bacterial DNA topoisiomerases -> prevent DNA replication. Bacteriocidal.

-MOR: alterations in DNA topoisomerases; efflux pump

-Interactions: Multivalent cations dec* absorption; Cipro - strong inhibitor of 1A2 (theophylline main issue), not with QT-prolonging agents; clinically may raise INR. Levo & moxifloxacin (minimal - not metabolized) - don't use with QT-prolonging agents (esp amiodarone!), may clinically raise INR. Split excretion (levo=all kidney; Moxi=not, so can't use for UTIs). Both time & conc dependent killing. 

Arthropathy: cartilage erosions & noninflammatory effusions (animals). Contraind in kids<18. Tendinopathy (acute Achilles tendon rupture) - m/c in elderly & pts on steroids. "Black box warning". CNS toxicity - HA & dizziness > insomnia/mood alteration > hallucinations/delirium. 

-"Nail-in-the-coffin" ADRs: Photosensitivity (lomefloxacin & sparfloxacin removed d/t this); QT prolongation (sparfloxacin & grepafloxacin removed d/t this); alterations in glucose (gatifloxacin removed d/t this); hepatotoxicity/liver failure (Trova removed d/t this)

Non-resp FQ: Cipro = most aerobic GNBs (including pseudomonas). Ind: think diaphragm to pelvix - upper & lower UTI. Tx of enteric infections/Traveler's diarrhea.

Resp FQ: levo & moxi: inc activity for s. pneumo* and atypical* resp/gential pathogens. Most aerobic GNBs. Ind: upper & lower UTI* (not moxifloxacin); tx of enteric infections/traveler's diarrhea; upper & lower respiratory* tract infections (sinusitis, AE-COPD, CAP)

MOA: sulfa interferes with bacterial folate synthesis by inhibiting dihydrofolic acid synthesis (structural analog of PABA); TMP inhibits dihydrofolic acid reduction to tetrahydrofolate - this results in sequential* enzyme inhibition in folate metabolism!!

-MOR: altered enzyme targets for both TMP & SMX. Dec sulfa accumulation; inc production of PABA.

-Pharm: Both are substrates of 2C9*; both moderately inhibit 2C9! Risk for hyperkalemia* with ACEI/ARB + TMP-SMX! Renal excretion; bacteriostatic.

-ADRs: hypersensitivity rxns (inc with larger doses); reversible myelosuppresion (inc with larger doses); hemolytic anemia in G6PD pts (any sulfa). 

Coverage = s. pneumo, H. influenzae, M. catarrhalis, P. jiroveci (PCP), most e. coli, klebsiella, proteus, MRSA

-Common tx indications: URTIs (AOM, sinusitis, AE-COPD); lower UTIs (generally 2nd line); PCP; MRSA tx/suppression (not serious infections!)

Metronidazole (Flagyl) & Tindazole

-MOA: interacts with DNA to cause a loss of helical DNA structure & strand breakage -> inhib of protein synthesis

-MOR: very little

-Pharm: mod 3A4 inhibitor*, split excretion, bacteriocidal

-Metronidazole ADRs: Metallic* taste, disulfiram-like* rxn, pos fetotoxic in 1st trimester, neurotoxicity* (neuropathy) with several 2 wk pulses.

Coverage: most anaerobes ("best below the diaphragm") including c. diff; various protozoa (Trichomonas, Giardia, Entamoeba)

-Ind: Bacterial vaginosis*, CDI*, amebiasis, Giardiasis*, & Trichomoniasis*

Note: Very high bioavailability! And can give oral (if can-no ileus) b/c absorbed in SI, and c.diff is in colon. Otherwise go to vanco (esp if recurrent) 

MOA: inhibits enzymes including acetyl coenzme A that interferes with metab & possibly cell wall synthesis

MOR: unknown

Pharm: minimal interactions. Renal* excretion -> doesn't penetrate renal tissue. Contraind CrCl<60* (therapeutic levels are not attained) since then not a lot is getting into kidneys - so can't sterilize pyelos. 

-ADRs: acute*-> chronic* pulmonary toxicity/fibrosis. Not in pts with G6PD deficiency. 

-Coverage: PO - covers most urinary pathogens -> GNB & enterococci. Ind: Lower UTI (cystitis)* & prophylaxis of recurrent UTI only. 

Non-absorbed PO ABX derived from rifampin. Inhibits bacterial RNA synthesis.

-Approved for tx of noninvasive straisn of e. coli causing traveler's diarrhea (not effective against infections ass with fever or bloody stool); prevention of hepatic encephalopathy in pts with chronic liver dz (with lactulose)

-Minimal drug interactions; well tolerated. 

Active against H. influenzae, s. pneumoniae, n. meningitidis, & some anaerobes. 

-Reaches therapeutic CNS levels (potentially used as last resort in CNS infections)

-Rarely used because of toxicities - bone marrow suppression & possibly fatal aplastic** anemia. 

MOR: binding site changes

-Pharm: topical ABX compouned in polyethylene glycol (antifreeze, can -->)

-ADRs: local skin rxns/burning

-Coverage: GAS, MSSA, MRSA (staph resistanc inc)

-Ind: impetigo, secondary skin infections, elimination of MRSA colonization (usually nasal)

MOA: inhibit 50s ribosomal subunit

Pharm: topical ABX derived from fungi; compounded in petrolatum - less irritating than PEG

ADRs: local site rxns

Coverage: GAS, MSSA, MRSA

Ind: GAS & MSSA bullous & non-bullous impetigo

1st line: isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), ethambutol (ETH)

2nd line: streptomycin, kanamycin, amikacin, capreomycin, cycloserine, ethionamide, levofloxacin, moxifloxacin, aminosalicyclic acid

MOA: unknown

Pharm: strong inhibitor** of many CYP enzymes - esp 2D6 and 3A4. Genetically controlled acetylation determines blood levels - rapid acetylators more likely to get hepatitis* (esp with EtOH); slow acetylators more likely to get peripheral neuropathy* & drug-induced lupus -> dec risk with vitamin B6* (pyridoxine)

-Ind: Drug of choice for latent* TB - 9 mo. Also a component of active TB tx. 

MOA: inhibits RNA polymerase - inhibits protein synthesis

-Interactions: strong inducer** of most CYP enzymes - remember 2C9 and 3A4. 

-ADRs: "red lobster syndrome", hepatitis, "flu-like illness"

-Ind: component of active* TB tx, alt option for latent TB, meningococcal meningitis prophylaxis. 

ADRs: non-gouty polyarthralgia (up to 40%) - tx with ASA. asymptomatic hyperuricemia. Dose-related hepatitis. 

-Ind: component of active* TB tx

MOA: inhibits cell wall synthesis

-Common ADRs: dose-related optic neuritis** (usually 15 mg/kg dose) - entails dec visual acuity/color discrimination, constricted fields, & scotoma -> irreversible blindness described. Follow with opthalmology for monthly visual acuity & color perception. 

-Common ind: component of active* TB tx. 

-Acyclovir: tab, suspension, tab, IV* (for serious infections - herpes encephalopathy); Cat B; acyclovir is poorly absorbed, so need tid-5x

-Valacyclovir (Valtrex): tab, cat B; val = prodrug - for absorption

-Famciclovir (Famvir): tab, Cat B 

-MOA: competes with deoxyguanosine for viral DNA polymerase & is incorporated into viral DNA -> DNA chain* termination.

-MOR: (rare in immunocomp host) - binding site alterations (if resistant to one, generally resistant to all 3)

-Pearl: initiation in 24-72 hrs = optimal

-Drug interactions = minimal

-Ind: dose & admin route depend on clinical condition - primary & recurrent genital HSV; orolabial HSV, encephalitis** (IV), herpes zoster infections

-ADRs: usually well-tolerated. Large IV doses may -> crystalline nephropathy -> reversible ARF (can -> renal failure)

Pharm: admin orally as a prodrug of acyclovir: 3-5x > bioavailability than oral acyclovir. Drug conc resembes concentrations achieved with IV* acyclovir. Min interact.

-Ind: (Dose depends on condition) Primary & recurrent genital HSV (including suppressive therapy -- dec clinical & subclinical shedding 50-60% -> 50% reduction of transmission to seroneg partner) & herpes zoster infections. (note: HSV2 more likely to reactivate. Also, can have asx-atic shedding, but shedding dec after 2 yr)

-ADRs: generally well-tolerated

Pharm: Admin orally as a prodrug of penciclovir

Interactions: minimal

-Ind/ADR: same as valacyclovir (primary/recurrent genital HSV & herpes zoster infections)

-Ganciclovir: intravitreal insert if CMV retinitis; ophthamlic gel; IV (bone marrow tx)

-Valganciclovir: soln, tab (often transplant pts)

Pharm: MOA & MOR similar to acyclovir (DNA chain termination). 10x more potent against CMV & EBV than acyclovir (equally potent against HSV & VZV). Common ind: (dose depends on conditoin being treated): active retinitis (may need intraocular implant); suppression of retinitis; colitis, esophagitis; prevention of CMV in transplant* patients.

-ADRs: bone marrow suppression (esp neutropenia)

Pharm: admin orally as a prodrug of ganciclovir. Serum drug conc similar to IV ganciclovir

-Ind: usually used for induction & maintenance of CMV retinitis. Prevention of CMV disease following transplant*

-ADRs: similar to ganciclovir (bone marrow sup)

Amantadine (soln, tab) & rimantadine (tab)  

-MOA: blocks viral uncoating of influenza A (not* influenza B) -> prevents viral penetration into host.

-Pharm: admin within 48 hrs in order to be effective - unclear if these drugs dec influenza-related comps or are effective in treating severe influenza pneumonia (doesn't affect lower resp tract probs!). Min drug interactions. 

-Common ind: not really used anymore since the virus is resistant over past few flu seasons (d/t shift); Amantadine = tx parkinsonism* & drug-induced EPS

-ADRs: both teratogenic* in animals. CNS ADRs predominate = nervousness, anxiety, light-headedness, confusion & insomnia (A>R)

-Oseltamivir (tamiflu; liquid, tab); cat C. MOR: AA alteratoins in binding site. Use: prophylaxis & tx of influenza A&B (dec severity & duration of sx (by 1-1.5d) if started within 48 hrs after onset; dec LRT comps. Swine & avian influenza. ADRs: Adults-good. Kids = neuropsych - self injury (with fatalaties), confusion, delirium (Japan) - may be related to flu-ass encephalopathy 

-Zanamivir (relenza; inhalation; cat C) - Same, except ADRs more common - nasal/throat discomfort; *bronchospasm in asthma/COPD pts. Remains active against amant/rimant-resistant & some oseltamivir flu strains.

-Pyrimidines: Thymine-AZT (anemia/neutropenia, myopathy, hyperpigmentation of oral mucosa/nailbeds) & D4T (Pancreatitis, peripheral neuropathy);  Cystosine-3TC (+HBV activity; well tolerated) & FTC* (=emtricitabine* - +HBV activity; well tolerated)

-Purines: Adenine- ddl (Pancreatitis, peripheral neuropathy) & TDF* (tenofovir* - +HBV activity; generally well tolerated. AKI-from fanconi-like syndrome); Guanine-ABC (Hypersensitivity rxn - sx include fever, skin rash, fatigue, GI sx (N/V/D/abd pain), resp sx (pharyngitis, dyspnea, or cough); 3-8% of pts; with HLAB5701 pts 100x more likely to develop hypersens rxn than those who don't have this HLA gene type -> genetic test before initiation of drug!! can dec to 2-3%. Never* rechallenge!

-Note: Combos are popular. 

-AZT inc MCV -> potentially monitors complaince

-d4T & ddl have the most potent metabolic SE (fatal lactic acidosis, lipodystrophy, hyperlipidemia, insulin resistance)

-Nucleoside analogues induce mitochondrial dysfx- drug bind mitocondrial gamma-DNA polymerase - interference of mitochondrial replicaition = mitocon DNA depletion (ddl>d4t>AZT>3Tc/FTC>ABC

-Clin mainfestatoins: neuropathy, myopathy, CMP, pancreatitis, hepatic steatosis, & lactic acidosis.

1. Nevirapine (NVP) - pharm: substrate of 3A4; inducer of 3A4 (strong). ADRs - rash very common - 5-7x m/c in women; hepatotoxicity, hepatic failure, & death (esp with underlying liver disease). 

2. Delavirdine (DLV): not esp effective (limited use)

3. Efavirenz (EFV): pharm: substrate 3A4, induces 3A4 (strong); ADRs: teratogenic in monkeys, rash common; CNS disengagement common (occurs 1-3 hrs after dose (take qhs) - usually dec over a few weeks. Once you mutate to this, it knocks out all other 1st gen. 

Etravirine (ETR) & rilpivirine (RPV) - designed to be active against HIV with mutations that confer resistance commonly prescribed 1st gen NNRTI's (resistance to second gen agents likely confers cross-resistance to other NNRTIs. ADRs = severe rash may occur.

(also a combo product with this - FTC/TDF/EPV = complera)

= -avirs. 

-Ritonavir (low dose) used to inc conc of other PI's d/t 3A4 inhibition -> dec dosage frequency of other PIs. All PIs have CYP450 (3A4 interactions). 

-ADRs: most are ass with N/V/D, hyperglycemia, insulin resistance, & hyperlipidemia (often in conj with fat wasting/reaccum/redistribution), hepatotoxicity

-Indinavir is ass with drug-precipitation stones (diag is with stone-protocol CT, but they don't show up since not Ca)

-Fusion = Enfurviritide (T20) - only commonly used injection HIV med -> injection site rxns (nodules) are m/c SE. Expensive.

-Entry = Maraviroc (MVC): CCR5 inhibitor - need "tropism" assay before initiation (ie test to see if you have CXCR4 vs CCR5 viral type) - assay costs $4000. Generally non-specific ADRs (cough, URI)

Raltegravir (RAL): prevents integration of viral DNA into cellular DNA. Generally well-tolerated.

-It's a SOC drug (option 3 - didn't talk about)

Combo tx with 3 drugs = SOC.

-2NRTIs (FTC + TDF) + 1 NNRTI (EFV) = Atripla

-2 NRTIs (FTC + TDF) + ritonavir + another PI (lopinavir, atazanavir, fosamprenavir, darunavir)

-Before instituting combo tx, genotyping/phenotyping is beneficial in the naiive pt (1% in 92 were resistant to 1+ med, 2001 it was 12%). Goal of tx is to reduce & maintain the viral load below the point of detection (<50 copies/mL - generally)