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135 Cards in this Set
- Front
- Back
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What are the prototypical inotropic agents for the following subclasses:
1. glycosides 2. sypathomimetic beta agonists 3. PDE inhibitors |
1. digoxin
2. dobutamine 3. milrinone |
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What are the prototypic agents for the subclasses of vasodilating agents:
1. direct acting agents 2. ACE inhibitors 3. ARBs 4. Nitrovasodilators 5. Ca Ch blockers 6. natriuretic peptides |
1. hydralazine
2. captopril 3. losartan 4. nitroprusside, isosorbide mononitrate 5. amlodipine 6. nesiritide |
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Agents that inhibit cardiac remodeling:
1. Beta blockers 2. ACE inhibitors 3. Mineralocorticoid antagonists |
1. metoprolol
2. captopril 3. spironolactone |
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Agents for myocardial ischemia (anti-anginal)
1. beta blockers 2. nitrovasodilators 3. calcium ch blockers 4. antiplatelet agents "No CAB? don't give yourself chest pain..." |
1. metoprolol
2. isosorbide mononitrate 3. diltiazem 4. aspirin "No CAB? Don't give yourself chest pain...": nitrovasodilator, Ca ch blk, antiplatelet, B blker |
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digoxin
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glycoside, inotropic agent
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dobutamine
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sympathomimetic beta agonist, inotropic agent
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milrinone
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PDE inhibitor, inotropic agent
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hydralazine
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direct acting vasodilating agent
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captopril
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ACE inhibitor, vasodilating agent and inhibits cardiac remodeling
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losartan
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ARB, vasodilating agent
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nitroprusside
isosorbide mononitrate |
nitrovasodilators
isosorbide also used for myocardial ischemia |
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amlodipine
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calcium channel blocker used for vasodilation
(diltiazem is antianginal) |
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nesiritide
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natriuretic peptide vasodilating agent
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metoprolol
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beta blocker to inhibit cardiac remodeling
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spironolactone
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mineralocorticoid antagonist used to inhibit cardiac remodel
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metoprolol
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beta blocker used to inhibit cardiac remodeling and to inhibit myocardial ischemia
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diltiazem
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ca ch blocker used for myocardial ischemia
(amlodipine is a Ca ch blocker used for vasodilating) |
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aspirin
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antiplatelet agent to inhibit myocardial ischemia
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what happens with disease states that involve and damage myocardial tissue?
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they cause a reduction in myocardial contractility or inotropic state
when severe--results in heart failure |
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angina
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the symptom of myocardial ischemia usually resulting from coronary atherosclerosis and stenosis
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arrhythmia
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due ot abnormalities of the heart's electrical system
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inotropic state
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contractile ability of the heart
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what increases contractility?
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Frank-starling: increased length of muscle measured as ventricular vol or vent end diastolic press (LVEDP), causes increase force/pressure development
positive inotropic drugs (digoxin) or symp. stim |
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on a cellular level, how do inotropic drugs or sympathetic stimulation increase contractility?
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increase intracell Ca
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what are some of the reflex mechanisms in reaction to decreased CO and perfusion of vital organs in attempt to restore CO?
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activate SympNS
increase circ catecholamines (increase HR=chronotropy; increase SV=inotropy) |
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what does chronic upregulation of catecholamines cause?
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down regulation of beta receptors (decrease density and responsiveness; decrease effectiveness)
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what are the physiological effects of reduced CO?
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arterial vasoconstriction and increased peripheral vasc resistance
(stimulation of alpha R's; trying to maintain perfusion pressure) activation of RAS (due to decreased renal perfusion) increased salt/water retention increased after and preload |
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what effect does increased afterload have on the heart?
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impairs myocardial contractility b/c of increased work demand placed on damaged heart
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what's the effect of increased preload on the heart?
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increased ventricular volume increases individ. muscle cell length, ventricular diam, ventric end diastolic press.
too much "stretch"--impairs fxn and decreases contract. |
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what are some classes of therapy for treating systolic heart failure?
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inotropes (digoxin, PDE inhib, sympathomimetics)
diuretics and vasodilators -reduce preload/afterload prevent/reverse myocardial remodel (B blk, ACE inh, mineralocorticoid antag) |
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What kinds of drugs would improve inotropy w/ systolic HF?
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drugs w/ + inotropic action:
digoxin PDE inhibitor sympathomimetics |
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How do diuretics/vasodilators reduce preload in systolic HF?
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by either decreasing vascular volume or increased venous capacitance
both: reduce vent end diast vol and press Tx: diuretics, nitrates, venodilators (nitroprusside, ACE inh, natriuretic peptide) |
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How do diuretics/vasodilators reduce afterload in systolic HF?
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decrease BP/arterial vasc resistance (indirectly cause increased inotropy)
Tx: cause sm relaxation (hydralazine ACE inhib, Angiotensin blk, Ca ch blk |
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what drugs are used in systolic HF to prevent/reverse myocardial remodel?
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neurohormonal antagonists
include: beta blkers, ACE inhib, mineralocorticoid agents |
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what are the direct effects of digitalis glycosides (digoxin)?
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inhibit Na/K ATPase pump--increase intracell Na which causes increased cytosolic Ca in exchange
more Ca+2 means more contractility |
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What are the indirect effects of digoxin?
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1. increased vagal tone (baroreceptor sensitivity, stim central vagal nuclei, sens to ACh)
2. withdrawal sympathetic tone (increased barorec. sens causes reflex symp withdrawal) |
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what are the net hemodynamic effects of digoxin in HF?
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1. increase contractility (direct effect), SV, CO, PP
2. decrease symp tone (indirect) and vasc resist (decrease afterload) 3. diuresis (improve renal perfusion) causes decreased preload 4. decrease LV diast/pulm/venous press 5. incr. vagal tone and decrease symp--decr HR 6. decrease heart O2 demand |
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PK of digoxin?
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GI absorption good--depends on preparation
renal excretion t1/2=36 hrs takes ~1 week to reach Steady state levels (give Loading D) |
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what are drug interxns to consider w/ digoxin?
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1. diuretics increase its toxicity by decreasing plasma K+
2. lots of drugs incr its conc in plasma (quinidine, etc) 3. drugs can decrease its absorption (antacid) 4. B blk and Ca Ch blk have additive fx on sinus node 5. gut flora brk dwn to inactive metabolites (10%pts) |
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Therapeutic uses for digoxin?
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1. arrhythmia (due to increased vagal tone--supraventricular tachyarrhythmias)
2. Heart failure--improves quality of life (most effective w/ systolic dysfxn) |
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digitalis glycoside (digoxin) toxicity?
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Low TI--titrate dose carefully
1. cardiac arrhythmia 2. GI: nausea, anorexia, pain 3. neuro: HA, pain, fatigue, delirium 4. visual: yellow-green halos |
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how is digoxin toxicity treated?
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digoxin (Fab) Ab fragments to accelerate elimination and inactivate it upon binding. drug-ab complex cleared renally
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how do sympathomimetic agents help treat HF?
prototype? |
stimulate beta adrenergic R's to increase rate, force contraction by altering Ca+2 handling proteins and myofilament fxn via phosphorylation
prototype: dobutamine |
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how does dobutamine work?
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simulate beta 1,2 and alpha adrenergic R's
increase myo contract, SV, CO minimal effect on BP |
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PK of dobutamine?
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i.v. only-continuous infusion
inotropic effect related to plasma level and infus rate optimal dose det. by response clearance by distribution into tissues where it's metabolized |
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what are the therapeutic uses for dobutamine?
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short term tx of acute exacerbations of chronic HF
low CO following cardiac surgery enhance renal perfusion/urine output |
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dobutamine toxicity?
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higher dose--ventricular arrhythmia
also tachy HTN, nausea, HA, angina, SOB |
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What are positive inotropic agents?
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have direct effects on myocardium, increase contractility and inotropic state
1. digitalis glycosides: digoxin 2. sympathomimetic: dobutamine 3. PDE inhib: milrinone |
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what are 2 PDE III inhibitors for i.v use in HF?
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amrinone, milrinone (30-50x more potent)
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why is there no oral form of PDE III inhibitors (milrinone)?
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b/c long term use increases mortality
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what's the mechanism of action of milrinone/PDE III inhibitor?
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increase myocard cAMP, intracell Ca+2, inotropy and SV
arterial vasodilators-- decrease periph/pulm vasc resist, afterload additive effects to sypathomimetics and digoxin |
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PK for milrinone?
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contin i.v. only
duration of action ~1 hr renal excretion |
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Therapeutic use of milrinone?
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chronic HF refractory to oral Tx w/ digoxin, diuretics, ACE inhib
used when dobutamine ineffective |
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toxicity of milrinone?
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iv:
1. thrombocytopenia 2. GI: nausea, vomit, anorexia 3. increase liver enzymes 4. arrhythmias |
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What are some ways to relax sm and cause vasodilation?
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1. direct action: hydralzine
2. ACE inhib: captopril 3. Ang II R blk: losartan 4. NO generation: nitroprusside 5. Ca Ch blk: amlodipine 6. GC R activator: nesiritide |
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what's hydralazine indicated for?
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anti-hypertensive
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what's the mechanism of the anti-htn drug hydralazine?
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arterial vasodilation by direct smc relaxation
likely mediated by inhibition of Ca+ influx |
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PK of hydralazine
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rapid absorption from GI
peak conc. 30-60 mins 1st pass effect: 90% metabolized to INactive metabolites half-life: .5-2 hrs |
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when is hydralazine indicated?
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2nd line for systolic HF combined w/ long acting nitrates
1st line in African American pts or those w/ renal Dz who can't take ACEI/ARBs |
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whats the point of combining nitrates and hydralazine for systolic HF?
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combined venous and arterial dilation
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which is better ACE inhibitors or nitrates + hydralazine?
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ACEI is 1st line--improved mortality
hydralazine/nitrate=alternative for pts unable to take ARB/ACEIs due to renal insufficiency or renal artery stenosis hydralazine for symptomatic HF in african-american pts now 1st line (maybe due to salt sens low renin HTN) |
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what would you give a pt w/ renal insufficiency or renal artery stenosis to treat systolic HF?
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hydralazine + long acting nitrates
b/c ACEI/ARBs contraindicated w/ renal dz |
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what are the adverse effects of hydralazine?
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flushing, HA, dizzy, increased HR, angina, hypotension, lupus like syndrome
increased renin--maybe increase salt/ water retention |
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what do ACEIs do?
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prevent conversion of angiotensin I to II
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what are the effects of AII?
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potent vasoconstrictor: increase systemic vasc resistance, afterload and BP
stimulates aldosterone secretion |
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what does aldosterone do?
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salt and water retention--increase vasc volume/ preload (indirectly increase BP)
directly increases BP |
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what are the hemodynamic effects of ACEI's?
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arterial vasodilation reduces SVR/afterload, MAP, LV filling pressure
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how do ACEI's affect CO?
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modest effect but sustained action
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what are the effects of ACEI's on bradykinin?
what does bradykinin do? |
reduce the metabolism and degradation of bradykinin
increase PG synth (increase PGII and prostacyclin)--potent vasodilators |
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what are the S/Es of ACEI's?
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hypotension (dizzy, lightheaded)
renal dysfxn (increase BUN, creatinine) - more commonly w/ underlying renal dz cough, angioedema (bradykinin) hyperkalemia some w/ sulfhydryl group (captopril) alter taste, hypersensitivity rxns (rash, neutropenia) |
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what causes renal dysfunction in pts taking ACEI's?
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often have underlying renal vascular dz
decrease in renal perfusion pressure and glomerular filtration pressure |
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what S/E's are specific to captopril?
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it has a sulfhydryl group:
altered taste hypersensitivity rxns (rash, neutropenia) |
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what are some ACEI's?
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captopril, enalapril, lisinopril
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losartan, valsartan
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AII R blockers
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how do ARBs work?
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block binding of AII to ONLY AT1 receptor (ACEI's block activation of both AT1 and AT2 receptor subtypes)
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since ARB's only block the AT1 Receptor subtype, how is their activity different than ACEI's?
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don't affect kinin metabolism:
don't induce cough (infrequent complication of ACEIs) |
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which are preferred for tx of systolic HF: ACEIs or ARBs?
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ACEIs
if pt has persistent HTN on full dose ACEI, can add ARB too. |
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what's nitroprusside?
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potent, rapid vasodilator
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how is nitroprusside administered?
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only by continuous infusion
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how does nitroprusside work?
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stimulates GC which increases cGMP and decreases Ca+2 entry into the cell (vsmc relaxation)
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where does nitroprusside work?
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arteries/ resistance vessels and
veins/ capacitance vessels |
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what are the hemodynamic effects of nitroprusside?
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works on arteries and veins
reduces preload and afterload net increase in SV and CO w/o changing the HR |
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does nitroprusside change HR?
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no, it reduces preload and afterload to increase SV and CO w/o affecting HR
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how is nitroprusside metabolized?
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non-enzymatic cleavage to a cyanide group which reacts w/ thiosulfate in the liver to produce thiocyanate (renal excretion)
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what happens if nitroprusside interacts w/ Hb?
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the interaction releases cyanide which binds metHb to form cyanometHb
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why is nitroprusside not a good idea in renal dz?
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b/c its metabolized to thyocyanate in the liver which is renally excreted.
high levels of thiocyanate can be toxic |
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what are the S/E's of nitroprusside?
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mostly associated w/ Hypotension:
reduced coronary, cerebral, renal BF (hypoperfusion) also nausea, vomit, palpitations, sweating, restlessness, thiocyanate toxicity |
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what are the signs of thiocyanate toxicity?
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dyspnea
nausea vomiting convulsion tremor psychosis |
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when is nitroprusside used?
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chronic HF
reduces afterload: acute mitral regurgitation, VSD, aortic dissection, acute aortic regurg. |
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what endogenous 32AA peptide is nesiritide similar to?
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endogenous b-type (brain) natriuretic peptide (BNP)
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where are ANP and BNP made?
where do they act? |
in the heart
act on R's in vsmc's to cause relaxation via GC and increased cGMP (inhibit Ca+ entry) |
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what are the hemodynamic effects of nesiritide?
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affect arteries and veins
reduces preload and afterload acts on kidney to increase Na+ excretion (natriuretic factor) |
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How is nesiritide cleared?
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same as endog. natriuretic peptides:
1. neutral endopeptidase (blood and tissue interstitium) 2. "clearance receptor" on cell surface of many tissues (removed via internalization and proteolysis) |
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is nesiritide affected by renal or liver dysfxn?
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no, it's cleared by endopeptidase and a "clearance" receptor on cells in many tissues resulting in a T1/2 of about 18 mins
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how is nesiritide given?
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continuous iv infusion (t1/2 ~18 min)
(same administration as nitroprusside) vol of distrib is proportional to body size (dosing weight based) |
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toxicity of nesiritide?
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vasodilator: therefore Hypotension--can lead to organ hypoperfusion, myocardial ischemia, and organ dysfxn (renal, hepatic, cerebral)
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how is nesiritide used therapeutically?
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short term (1-3 days)
acute CHF in hospital pts |
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which drugs are used to prevent and reverse myocardial remodeling?
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ACEI, ARB
B Blocker Aldosterone antagonists |
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how do ACEIs and ARBs prevent chronic remodeling?
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mechanism unclear: may be partly due to AII which can directly stimulate aspects of remodeling (ventricular hypertrophy, myocardial fibrosis)
prevent remodeling more than other vasodilators |
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how do beta blockers given chronically improve LV function and survival?
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not necessarily due to re-sensitization
mechanism related to suppression of adverse effects of chronic beta adrenergic R stimulation (like ACEI and ARB) survival benefit--anti-arhythmic effect (decreased sudden death) |
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what do you need to remember when starting beta blocker therapy?
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start at lower dose than for angina and titrate up
b/c they can cause exertional fatigue in pts w/ systolic dysfxn |
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how do aldosterone antagonists prevent cardiac remodeling?
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RAS increases aldo (salt retention)
aldo may have adverse effects on cardiac structure/fxn evidence of improved pt survival and fxn w/o a diuretic |
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why should high dose spironolactone be avoided?
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hyperkalemia in pts w/ decreased CO---renal hypoperfusion
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what are some primary determinants of oxygen supply to the heart?
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coronary artery BF, number of collaterals, O2 carrying capacity of blood
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what are some determinants of myocardial O2 demand?
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HR
inotropic or contractile state of ventricular myocardium afterload (clinically=BP) myocardial wall stress- related to muscle mass and preload (ventric vol) |
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what's coronary perfusion pressure?
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determinant of O2 delivery
MAP - LVEDP |
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what are some determinants of myocardial O2 demand?
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contractility, HR, wall tension
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what are the determinants of myocardial supply?
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blood flow
O2 content |
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what are the 3 drug classes to prevent myocardial ischemia, angina?
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nitrates (short and long acting)
beta adrenergic blockers Ca+2 channel blockers |
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how do nitrates work?
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relax vsmc and vasodilate VEINS
metabolized to nitrosothiols which increase cGMP to decrease Ca+2 influx (similar to nitroprusside) also increase release of NO, prostacyclin, PGE (vasodilators) |
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what are the effects of NO?
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increase intracell levels of cGMP
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are PDE inhibitors used for angina?
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no, they were tried but unsuccessful.
however, they led to the accidental development of sildenafil for ED |
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pharmacological effect of nitrates?
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Venodilation (increase venous capacitance and decrease return to heart): this slightly reduces SV and CO
at high dose: arterial vasodilatory effects (reduce afterload) |
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pharmacokinetics of nitrates?
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highly lipophilic, rapid absorption from GIT, skin, mucous membranes
tolerance develops w/ time 1st pass effect--avoid by buccal or i.v. route |
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prototype nitrate drug?
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isosorbide mononitrate
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what's the point of a "nitrate free interval"?
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b/c tolerance develops over time and can be diminished by pause in therapy
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what's the metabolism of nitrates?
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1st pass effect
metab rapid by arterial/venous tissue rapid hepatic metab |
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why are nitrates often given by iv, buccal or sublingual?
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b/c of 1st pass effect and rapid onset (less than 3 mins w/ peak effect at 2 mins)
given orally, onset delayed to ~1 hr |
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side effects of nitrates?
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related to vasodilation:
HA, postural hypotension, reflex tachycardia, flushing don't combine w/ viagra: excess hypotension and MI |
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whats a cardioselective beta blocker?
what are they useful for? |
bind to cardiac receptor= b1 R
angina, hypertension, arrhythmia, HF |
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how do beta blockers work in HF?
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reverse "down regulation" of receptors (decreased density/sensitivity) caused by chronic symp stimulation
thus, up-regulation enhances myocardial response to Symp stim |
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pharmacodynamic effects of beta blockers?
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reduce HR and BP
negative inotropic effect: reduce ventricular contract. and SV which results in increase LVEDP and volume |
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what are the differences in PK due to among beta blockers?
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rate of absorption/bioavail
lipo/hydrophilicity metab/elimiination cardioselectivity membrane stabilizing activity intrinsic sympathomimetic activity (ISA) racemic/pure |
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metoprolol
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prototype beta blocker
beta 1 selective |
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toxicity of beta blockers?
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due to sympathetic antagonism:
cardiac toxicity (HF, conduction abnlities) bronchospasm/asthma cold extremities (raynaud's) peripheral vasoconstriction CNS: nightmare, hallucinate, insomnia impotency, decreased libido GI effects: diarrhea/constipation, nausea drug interxns |
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what are the three types of Ca ch blockers?
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1. dihydropyridines: amlodipine
2. phenylalkylamines: verapamil 3. benzothiazipine: diltiazem |
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amlodipine
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primary effect on vsmc, less in myocardium and pacemaker tissue
dihydropyridine type ca ch blker |
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verapamil
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effects in myocardium and pacemaker tissue
less in vsmc's phenylalkylamine type Ca ch blker |
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how do Ca ch blockers work?
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prevent Ca influx causes sm relaxation and vasodilation and decreased SVR and BP
dihyrdropyridine (amlodipine)--vascular effects |
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what can amlodipine cause (dihyrodpyridine type)
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reflex tachycardia due to it s primary vascular effects
diltiazem/verapamil don't b/c they work on automaticity of sinus/AV nodes--reduce SV and CO |
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where do diltiazem and verapamil work?
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on SA/AV node to reduce automaticity (don't cause reflex tachycardia like amlodipine)
reduce SV and CO w/o compensatory symp activation |
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which Ca ch blockers have direct effects on pacemaker tissue (sinus and AV nodes)
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verapamil and diltiazem reduce Ca influx to reduce automaticity and prolong refractory time of SA/ AV nodes
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toxicity of Ca ch blockers?
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mostly due to vasodilation:
HA, periph edema, flushing, fatigue, dizzy, hypotension decrease GI motility--constipation bradycardia/conduction abnlities (verapamil, diltiazem) infrequently cause HF |
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how are Ca ch blockers used clinically?
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HTN, variant angina (vasospasm), angina
some used for HF--amlodipine due to primary vasc effects (limited benefit) |
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what anti-arrhythmic action can Ca ch blockers have?
for what conditions? |
AV nodal blockade
control of ventricular rate and A. fib, a flutter, a tachycardia. can prevent/end supraventricular tachycardias involving the AV node |
