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53 Cards in this Set

  • Front
  • Back
Define angina.
Angina pectoris is caused by myocardial ischeia, w/ ischemia resulting from an imbalance btwn cardiac oxygen demand and the suppl;y of oxygen to the heart.

What are the clinical syndromes of angina?
1. classic or exertional angina

2. variant angina

3. stable angina

4. unstable angina

5. "silent" ischemia
Describe classic or exertional angina.
-- results from inability of the coronary arteries to dilate in face of increasing myocardial oxygen demand during exercise

-- coronary arteries cannot dilate b/c they are impaired by atherosclerotic plaques = CAD
Describe variant angina.
(Prinzmetal's angina)

-- believed to resulg from spasm of an epicardial coronary artery causing a decrease in myocardial blood flow and oxygen delivery
Stable angina vs. unstable angina
STABLE -- symptoms are unchanged and reproducible

UNSTABLE -- angina increasing in severity, that appears at lower levels of exercise or occurs at rest
Describe "silent" ischemia.
The ECG shows typical changes caused my myocardial ischemia
- depression of S-T segment OR
- T-wave inversion

But the patient does not feel any chest pain
What determines cardiac oxygen demand and supply?
1. Increase in HR, dp/dt, and/or left ventricular wall tension INCREASE cardiac oxygen demand

2. Lapace's law

3. Left ventricular wall tension during diastole (determines radius)

4. Left ventricular wall tension during systole

5. The large coronary arteries (supply)

6. The heart rate-pressure double product
Explain the importance of left-ventricular wall tension during diastole.
-- determined by left ventricular end diastolic volume = venous return = cardiac preload

-- increased venous return increases wall tension b/c the left ventricle has larger volume (radius) prior to systole

**radius determinant in
Lapace's law
What determines left ventricular wall tension during diastole?
1. preload -- radius of ventricle at beginning of systole

2. rate of rise of intraventricular pressure (dp/dt) during systole

3. afterload -- determines pressure which must be created in ventricle during systole in order to eject blood into aorta
The large cardiac arteries supply blood to...
the ENDOcardial blood vessels chich sypply the myocytes of the ventricles
Explain the heart rate-pressure double product.
rate-pressure product = HR x BP (systole)

This product is used as a global measurement of myocardial oxygen demand during exercise b/c it incorparates all the major factors which determine oxygen demand

-- patients w/ stable angina will develop anginal pain when they reach a certain threshold for oxygen demand, so they will develop angina when the rate-pressure product achieves some constant value

-- any treatment which decreases the rate of rise of the rate-pressure product increases exercise tolerance
How can we relieve angina?
1. decrease cardiac oxygen demand


2. increase cardiac oxygen delivery
How can we decrease cardiac oxygen demand?
1. prevent symp-mediated increase in HR and dp/dt that occur during exercise

2. decrease wall tension during diastole and systole by decreasing cardiac preload (venous return)

3. decrease wall tension during systole by decreaseing afterload (diastolic blood pressure - DBP)
-- if DBP is decreased the intraventricular pressure req'd to open the aortic valve is less, thus increase in wall tension during systole will be less
How can we increase oxygen delivery?
1. dilation of large epicardial arteries

2. dilation of the endocardial arterioles which provide oxygen to the myocytes
Why is the endocardium always at greater risk for ischemia?
-- blood flow in the endocardium is always impaired by increased wall tension during diastole and systole

-- pressure in ventricle during diasole "squishes" (partially collapses) the endocardial arterioles

-- during high interventricular pressures created by systole, the endocardial arterioles are extremely squished -- NO flow

-- ventricular muscle is perfused during diastole
What are our antianginal drug categories?
1. beta blockers

2. nitrate vasodilators

3. calcium channel antagonists (CCAs)
What are the beta blockers?
atenolol -- cardioselective

propanolol -- non-selective
Beta blockers' MOA?
1. blockade of cardiac B-adrenoceptors prevents cardiac stimulation by the sympth NS

2. All of the B-blockers are equally effective, but the cardioselective drugs are preferred b/c they have less negative effect on pulmonary ventilation
Antianginal effects of B-blockers results from...?
1. decreased HR
2. decreased myocardial contractility
3. decreased cardiac afterload (decreased DBP)
4. increased blood flow to endocardium during diastole (mech unknown)
Adverse effects of B-blockers?
1. bronchoconstriction
2. exacerbation ofheart failure (from decreased dp/dt)
3. sudden w/d of therapy may precipitate MI
What are the nitrate vasodilators?
nitroglycerin (glyceryl trinitrate)

isosorbide dinitrate

isosorbide mononitrate

**these are all organic NO donors
MOA of nitrates?
dilate arteries and veins b/c they are NO donors
-- for unknown reasons, they preferentially dilate VEINS

-- large dose of nitrates can dilate arterioles and thus decrease DBP and produce a baroreflexly-mediated increase in sympth activity in the heart
-- venodilation lasts longer than arteriodilation
isosorbide mono/dinitrate and topical nitroglycerine (paste or transdermal patches)

admin preferentially dilates veins w/ little or no effect on resistance arterioles -- cardiac preload falls but afterload is unchanged

-- major mech by which these drugs prevent angina is via decreaed preload, thus decreased wall tension during diastole and systole

-- decreased diastolic wall tension has two beneficial effects:
1. decreased oxygen demand
2. increased endocardial blood flow

**with selective venodilation, CO is decreased
sublingual nitroglycerine MOA?
-- has acute hemodynamic effects: some immediate effects increase oxygen demand, whereas others decrease oxygen demand
-- sublingual admin allows all of NTG to reach the heart via the SVC and thus be distributed to bother arteries and veins via CO
-- immediate (acute) effect is to dilate both arterioles and venules
-- arteriolar dilation reduces TPR and DBP
-- Body responds to drop in pressure w/ baroreflexly mediated increase in sympath activity - increase HR and dp/dt, which increase oxygen demand
-- b/c DBP falls, patients should take nitro sitting down so they don't faint and fall
The increased oxygen demand w/ nitro should make angina worse, but it is relieved rather quickly. Why?
-- At the same time NTG is dilating resistance vessels, it is also dilating venules to increase venous capacitance and thus decrease venous return (preload)
-- Decrease in preload decreases diastolic wall tension to reduce oxygen demand and increase endocardial blood flow
-- Therefore, the decrease in oxygen demand caused by decreased preload MUST be greater than the increase in oxygen demand caused by tachycardia and increased dp/dt
-- At this point in time, the decrease in afterload (DBP) also decreaseds wall tensino during systole, an effect which also decreases oxygen demand
How long do the effects of sublingual NTG last?
They last less than one hour, and the arteriolar dilation disappears before venodilation.
What is the common theme for the MOA of antianginal nitrates?
1. decreased preload which decreases diastolic and systolic wall tension, which in turn decreases oxygen demand and increases endocardial blood flow

2. If afterload (DBP) is also decreased, the decrease in the intraventricular pressure during systole decreases oxygen demand
Nitrates also increase...
epicardial blood flow (coronary vasodilation)

-- this effect is NOT the major mechanism responsible for the prevention and relief of angina
How do nitrates inhibit platelet aggregation?
-- remember that vascular endothelial cells tonically produce NO which prevents platelet aggregation

-- organic nitrates are NO donors, so they also have this antiplatelet effect

-- effect is good in angina, b/c CAD which causes the angina also predisposes to MI
SUMMARY: antiantinal effects of nitrates result from?
1. venodilation increases venous capacitance and thus decreases venous return to the heart

2. decreased cardiac preload decreases LV wall tension by decreasing LV volume (radius) during diastole and systole

3. Increased blood flow to endocardium during diastole

4. Increased collateral blood flow

5. Anti-anginal effect does NOT result primarily from increased flow through the large (epicardial) arteries
Nitrate tolerance?
-- tolerance develops, but tolerance usually disappears after the drug is withdrawn for a short period of time

-- Tolerance can be lessened by using the approp dosing schedule
1. patches removed at night just before sleep to allow drug-free period when pt is a low risk for ischemia
2. nitrates given p.o. are dosed at 7am and 2pm to lessen development of tolerance
Nitrate adverse effects?

orthostatic hypotension
Other medical uses of nitrates?
1. congestive heart failure
- decreases venous return via dilation of capacitance vessels (veins)

2. myocardial infarction
-- minimize the size of the tissue damaged by infarct
Name the calcium channel antagonists (CCAs)
Describe the L-type calcium channels.
1. channels, which are located in the plasma mbrn, are potential operated (voltage dependent) and open SLOWLY in response to stim (depol)
2. found predom in vascular smooth muscle, cardiac SA and AV nodes, and the cardiac myocytes
3. After channel opens in response to depol, Ca flows down its conc gradient into the cell
4. Increase in free intracellular Ca conc directly activates the calmodulin AND triggers release of addtnl stored Ca from the sarcoplasmic reticulum which also activates calmodulin
5. Ca-calmodulin cmplx activates MLCK which phosphorylates the myosin light-chain, thus allowing it to interact w/ actin and cause contraction of vasc smooth muscle
6. after channel closes, becomes inactive and cannot be opened by another stimulus until some period of time passes
7. exists in three states: open, closed, inactivated
-- block the L-type Ca channels in the vascular smooth muscle of arterioles (little effect on venules), myocardial cells, and cells of SA and AV nodes

-- Each subclass of CCA binds to diff site on the a1-subunit of the channel

-- differences in exact binding site account for some differences in the pharm effects of diff subclasses CCA

-- Unlike other CCAs VERAPAMIL prolings state of inactivation of channel, thus temporarily making it refractory to stim

-- at doses normally used in clinical medicine, CCAs do not block the Ca channels of the SR, which are activated to "trigger" Ca release
Pharmacological effects of CCAs?
1. blockade of L-type Ca channels in the heart decreases:
-- heart rate
-- AV conduction
-- dp/dt

2. Blockade of L-type Ca channels in coronary vessels dilates the epicardial arteries and arterioles of the endocardium

3. Block of channels in vascular smooth muscle of resistance arterioles decreases TPR and thus DBP

4. Relaxation of vasc smooth muscle in the aorta and other large arteries increases arterial compliance and thus lowers SBP more than would be expected from the fall in DBP

5. CCAs do NOT dilate veins, and thus have little effect on venous return
CCAs subclasses?
1. Verapamil and diltiazem primarily affect the heart

2. Dihydropyradines (DHP) primarily affect arterioles
Verapamil and Diltiazem impact?
Verapamil and diltiazem decrease HR, AV conduction and myocardial contractility: both SV and CO are depressed

Cause small decrease in DBP b/c they do cause some relaxation of smooth muscle in resistance arterioles

Fall in BP is too small do produce much of a baroreflexly-mediated increase in symp nerve activity, so their direct inhib effect on the heart predominates
Amlodipine impact
Produces a greater decrease in DBP which causes a baroreflexly-mediated increase in cardiac sympathetic activity

Two counteracting events take place in the heart:
1. Direct effect of the DHPs to block cardiac Ca channels should decrease HR, AV conduction, and contractility
2. Indirect effect of increased sympathetic drive overrides the inhibitory effect of these CCAs

NET CV EFFECT is decreased DBP w/ no change or a small increase in HR, AV conduction, contractility, SV and CO
CCAs and cardiac activity?
verapamil and diltiazem have a depressant effect on cardiac activity, but amlodipine does not
What are the antianginal effects of verapimil and diltiazem?
1. decreased HR and dp/dt
2. decreased wall tension during systole primarily by decreasing cardiac dp/dt
3. dilation of large epicardial arteries to increase coronary blood flow and thus oxygen delivery
4. dilation of endocardial arterioles
5. increased blood flow to endocardium during diastole
6. increased collateral blood flow to myocardium
**antianginal effects result from decreased oxygen demand and increased oxygen delivery
What are the antiantinal effects of amlodipine?
1. decrease wall tension during systole primarily by decreaseing afterload (DBP)
2. dilation of large epicardial arteries to increase coronary blood flow and thus oxygen delivery
3. dilation of endocardial arterioles
4. increased blood flow to endocardium during diastole
5. increased collateral blood flow in the myocardium
6. lack of cardiosuppressant effect of DHPs means that this drug will have antianginal effect w/out decreasing CO
**antianginal effect results from decreased oxygen demand and increased delivery
CCAs and Prinzmetal's angina?
are effective to treat, b/c they prevent the vasospasm in the epicardial arteries
CCA pharmacokinetics?
Good GI absorption, but high first-pass metabolism

diltiazem, verapamil = 2-6h
amlodipine = 30-50h
CCA formulations?
-- All are avb in oral formulations, including slow release preps for diltiazem and verapamil

-- D and V also come in i.v. formulations for trtmt of cardiac dysrhythmias
Adverse effects of V and D?
1. bradycardia - severe and symptomatic brady cardia may respond to i.v. injection
2. SA nodal failure or AV block
3. Heart failure in pts w/ systolic dysfxn
4. Hypotension
5. Paradoxical angina
6. Increaed risk MI
8. Constipation w/ verapamil
Explain he paradoxical angina related to V and D.
-- excessive arteriolar vasodilation which lowers DBP too mych resulting in decreased coronary perfusion
-- "coronary steal" = dilates healthy arteries more than artherosclerotic and thus shunts blood away from ischemic areas to healthy areas
-- increased myocardial oxygen demand from baroreflexly-mediated increase in sympth tone
Explain the increased risk of MI with V and D.
-- large doses of DHPs with short half-lives increase risk of MI in patients w/ CAD
-- CCAs w/ short half lives (V & D) are available in slow release capsules

-- MI probably results from excessive vasodilation and the resulting incerase in sympathetic drive to the heart
Adverse effects of amlodipine?
1. hypotension
2. paradoxical angina
Drug-drug interactions with CCAs?
1. beta-blockers -- overt heart failure or severe bradycardia w/ AV block can be caused by i.v. admin of VERAPAMIL to pts being treated w/ beta blocker
2. Digoxin -- increased plasma conc when treated w/ VERAPAMIL; both combined can potentiate the slowing of AV conduction caused by digoxin
3. Class 1A antidysrhythmic drugs
- procainamide, disopyramide, quinidine
- CCAs (espec V) can cause severe hypotension b/c of combined effects to suppress AV conduction and ventricular contractility
4. Grapefruit juice -- inhibits CYP450 that metabolizes DHPs and thus may potentiate fall in BP
5. Cimetidine -- can increase plasma conc of diltiazem by blocking CYP450 isozyme which degrades these CCAs
Compare MOA of the antianginal effects of the CCAs
See chart
Compare the effects of the isosorbide mono/dinitrate and p.o. NTG patch and paste with the sublingual NTG.
See image