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Cardiovascular II > Drugs for Angina and Ischemic Heart Disease > Flashcards

Drugs for Angina and Ischemic Heart Disease Flashcards

1
Q

Chronic ischemic heart disease is characterized by`

A

the partial occlusion of coronary artery

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2
Q

Classic angina

A
  • angina of effort, stable angina
  • occlusion of the coronary arteries resulting from the formation of atherosclerotic plaque
  • Most common form of angina
  • Symptoms occur during exertion or stress
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3
Q

Variant (Prinzmetal) angina:

A
  • episodes of vasoconstriction of coronary arteries
  • vasospastic
  • Genetic in origin
  • symptoms at rest
  • Less common than classic angina
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4
Q

Angina is the imbalance between

A
  • O2 demand of the heart and oxygen supply via the coronary arteries
  • Heart’s demand for O2>>O2 supply due to partially blocked coronary artery
  • Especially during exertion, stress
  • results in chest pain
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5
Q

Approaches to treat Angina

A
  • Reduce O2 demand by decreasing cardiac work OR
  • increase O2 supply by increasing blood flow through coronary arteries
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6
Q

Ways to increase coronary blood flow to treat angina–surgical and non-surgical approaches

A
  • Coronary artery bypass grafting (most radical)
  • Percutaneous transluminal coronary angioplasty (PTCA)
  • Atherectomy–tip of catheter shears off the plaque–risk of reocclusion
  • Stent–expandable tube used as scafforlding to keep vessel open (drug eluting stents–antiproliferative drugs–cause cell cycle arrest)
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7
Q

To increase coronary blood flow using vasodilators

A
  • useful in vasospastic (Prinzmetal–variant) angina
  • to relieve coronary spasm -to restore blood flow into ischemic area
  • NOT useful in atherosclerotic (classic) angina–can make it worse– due to coronary steal phenomenon
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8
Q

Coronary steal phemomenonen

A
  • redistribution of blood to non-ischemic areas–associated with the dilation of small arterioles
  • Ex: potent arteriolar vasodilators like Dipyridamole
  • vasodilation prevents adjacent arteries from providing collateral blood flow exacerbating symptoms in classic angina!! But vasodilator useful for variant angina!
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9
Q

Determinants of myocardial oxygen demand (targets for treatment)

A
  • Heart rate
  • Contractility
  • Preload
  • Afterload
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10
Q

Tachycardia increases HR and can be harmful. Why?

A
  • Tachycardia affects diastole more than systole
  • decreased length of diastole so blood flow through coronary artery is impeded
  • explains why tachycardia is harmful especially in angina patients
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11
Q

Vasodilator that lacks direct effect on autonomic receptors but may provoke angina attacks

A
  • Hydralazine
  • peripheral vasodilator
  • releases NO
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12
Q

Drug classes used in chronic ischemic heart disease

A
  • Nitrates (nitrovasodilators)
  • Calcium channel blockers
  • Beta-blockers
  • Newer agent: Ranolazine
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13
Q

Nitrovasodilators

A
  • Nitrogylcerin
  • isosorbide dinitrate
  • Isosorbide mononitrate (active metabolite of dinatrate)
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14
Q

Endothelium dependent vascular relaxation

A
  • Release of endothelium-derived relaxing factor (EDRF) by Ach leads to relaxation IF endothelium is present
  • endothelial NOS produces NO, an endogenous vasorelaxing agent
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15
Q

Endothelial Nitric Oxide Synthase

A
  • activated by Ca2+-calmodulin complex
  • then it activates arginine to make citrilline and NO
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16
Q

NO acts on

A

-Guanylyl cyclase–>act cGMP–>act Protein kinase G–> causes relaxation by dephosphorylating myosin light chain or by opening potassium channels and causing hyperpolarization and reduced calcium entry

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17
Q

MOA of nitrates in Variant angina

A

1) Nitrate–>NO via ADH2 (frequently thiols)–>
2) Vascular smooth muscle relaxation–>
3) Coronary artery dilation–>
4) Coronary spasm relief

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18
Q

MOA of nitrates in Classic angina

A

1) 1) Nitrate–>NO via ADH2 (frequently thiols)–>
2) Vascular smooth muscle relaxation–>
3) VENOUS dilation–>
4) Reduced preload–>
5) decreased O2 demand

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19
Q

Multiple effects of NO

A
  • vasodilation
  • Prevents platelet aggregation
  • inhibits interaction of endothelial cells with blood derived cells (leukocytes)–prevents rolling and transmigration and inflammation by leukocytes
  • inhibits smooth muscle proliferation (intimal thickening and reocclusion)
  • prevents oxidation damage -prevents LDL oxidation (protects against atherosclerosis)
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20
Q

Sensitivity of vasculature to nitrate induced vasodilation

A

-veins>large arteries>small arteries and arterioles

21
Q

Nitrovasodilator beneficial action in angina

A
  • decreased myocardial oxygen demand
  • relaxation of vascular smooth muscle
  • dilation of veins (major effect): increased venous capacitance, reduced ventricular preload
  • dilation of arterioles–higher concentrations of nitrates are needed compared to venous dilation
22
Q

Dilation of arteries leads to

A
  • reduced arterial pressure and after load
  • may dilate large epicardial coronary arteries
  • no significant increase in coronary blood flow into the ischemic area in atherosclerotic angina
23
Q

Nitrates in angina of effort

A
  • decreased preload
  • decreased oxygen demand
24
Q

Nitrates in vasospastic angina

A
  • relaxation of coronary artery vascular smooth muscle
  • relieving coronary spasm
25
Q

Nitrate clinical use

A
  • short acting formulations used to relieve the angina attack
  • long acting preparations may be used to prevent attacks
26
Q

Development of nitrate tolerance

A
  • depletion of thiol compounds -increased generation of oxygen radicals
  • reflex activation of sympathetic nervous system (tachycardia, decreased coronary blood supply)
  • retention of salt and water
  • increased generation of superoxide radical depletes tissues of NO
27
Q

Reason to avoid oral administration of nitrates

A

-Rapid denitration by the liver enzymes

28
Q

Adverse effects of nitrates

A
  • headache (meningeal vasodilation)
  • orthostatic hypotension -increased sympathetic discharge
  • tachycardia, increased cardiac contractility
  • increased renal Na+ and H2O reabsorption
29
Q

Nitrate drug interactions

A
  • interaction of nitrates with drugs used for treatment of erectile dysfunction (sildenafil, vardenafil, tadalafil)
  • combination with nitrates causes severe increase in cGMP and a dramatic drop in BP
  • acute MI cases have been reported
30
Q

-Calcium channel blockers

A
  • non-cardioactive (DHP):
  • Amlodipine
  • Nifedipine
  • Nicardipine
  • Cardioactive: Diltiazem, Verapamil
31
Q

CCB MOA

A
  • Ca2+ mediates smooth muscle contraction; enters cells via voltage dependent calcium channels
  • CCBs block Ca2+ entry to relax vascular smooth muscle
  • vasculature does NOT have troponin so acts on Myosin-light chain kinase system (Ca2+-calmodulin sensitive)
32
Q

Anti-anginal mechanisms of CCBs

A
  • Decreased myocardial O2 demand (Classic angina)
  • Dilation of peripheral arterioles
  • Decreased PVR and after load, decreased BP
  • Arterioles more affected than veins (less orthostatic hypotension)
  • DHPs are more potent vasodilaters
  • Decreased cardiac contractility and heart rate (seen with non-DHPs)
  • increased blood supply (operates in variant angina)–dilation of coronary arteries relieves local spasm
33
Q

Major adverse effects of CCBs

A
  • cardiac depression, cardiac arrest, and acute heart failure (cardioactive CCBs)
  • bradyarrythmias, AV block (cardioactive CCBs)
  • short acting DHP CCBs–vasodilation triggers reflex sympathetic activation
34
Q

Nifedipine adverse effects

A
  • immediate release
  • increases risk of MI in patients with HTN–slow-release and long-acting DHPs are better tolerated
  • causes tachycardia due to hypotension and associated baroreflex
35
Q

Minor adverse effects of CCBs

A
  • flushing, headache, anorexia, dizziness
  • peripheral edema
  • constipation
36
Q

Beta-blockers indicated in angina

A
  • Propranolol
  • Nadolol
  • Metoprolol
  • Atenolol
37
Q

MOA of B-blockers in angina

A
  • decreased myocardial O2 demand
  • decrease HR leads to improved myocardial perfusion and reduced O2 demand at rest and during excercise
  • Decrease in contractility
  • Decrease in BP leads to reduced afterload
38
Q

B-blockers adverse effects

A
  • reduced CO
  • bronchoconstriction
  • impaired liver glucose mobilization
  • produce and unfavorable blood lipoprotein profile (increase VLDL and decrease HDL)
  • sedation, depression
  • withdrawl syndrome associated with sympathetic hyperresponsiveness
39
Q

B-blocker contraindications

A
  • asthma
  • peripheral vascular disease
  • Raynaud’s syndrome
  • Type 1 diabetics on insulin
  • bradyarrhthmias and AV conduction abnormalities
  • severe depression of cardiac function
40
Q

Effects of Nitrates alone in treatment of angina pectoris

A
  • reflex increase in HR
  • decrease in arterial pressure
  • decrease EDV
  • reflex increase contractility
  • decrease in ejection time
41
Q

Effects of B-blockers or CCBs alone in treatment of angina pectoris

A
  • decreases HR, arterial pressure, contractility
  • increases EDV and ejection time
42
Q

Effects of combined nitrates with B-blockers or CCBs in treatment of angina pectoris

A
  • decrease HR, arterial pressure
  • no change or decrease in EDV
  • no change in contractility, ejection time
43
Q

Ranolazine MOA

A
  • inhibits late Na+ currents in cardiomyocytes
  • ischemic myocardium is often partially depolarized
  • Na+ channel in cardiomyocytes is voltage-gated
  • Late Na+ current is enhanced in ischemic myocardium and brings about Ca2+ overload and depolarization abnormalities
  • Ranolazine normalizes repolarization of cardiac myocytes and reduces mechanical dysfunction
  • reduce diastolic tension and compression of coronary vessels in diastole and reduces cardiac contractility and O2 demand
44
Q

Ranolazine may reduce

A
  • diastolic tension and compression of coronary vessels in diastole
  • may reduce cardiac contractility and oxygen demand
45
Q

Ranalozaine does not affect

A
  • heart rate
  • general ionotropic state of myocardium
  • coronary blood flow
  • peripheral hemodynamics
46
Q

Ranolazine clinical use

A
  • stable angina which is refractory to standard medications
  • decreases angina episodes and improves exercise tolerance in patients taking nitrates, or amlodipine, or atenolol
47
Q

Ranolazine adverse effects

A
  • QT interval prolongation–may trigger polymorphic ventricular arrhythmias
  • constipation
  • nausea
  • dizziness
  • headache
48
Q

Ranolazine drug interactions

A
  • metabolized by CYP3A4/5–interaction with drugs that modulate the activity of these enzymes
  • do not combine with strong CYP3A inhibitors: anti fungal azaleas, verapamil
  • inhibits CYP2D6–increases half life of Amitriptyline, Fluoxetine, metoprolol, opioid drugs
  • drugs that prolong QT interval–certain anti arrhythmic (Quinidine) and antipsychotic drugs (Thioridazine)–may trigger ventricular arrhythmias

Cardiovascular II (13 decks)

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