Drugs Used in Chronic Ischemic Heart Disease -DSA

Question 1

Approach to treating angina pectoris

Answer 1

1 - increase coronary blood flow

2 - reduce myocardial oxygen demand

Question 2

Determinants of myocardial oxygen demand

Answer 2

Heart rage
contractility
preload
afterload

Question 3

Drug classes used in chronic IHD

Answer 3

Nitrates - nitrovasodilators
CCB
Beta blockers
Ranolazine

Question 4

Nitrovasodilators

Answer 4

Nitroglycerin
Isosorbide dinitrate
Isosorbide mononitrate - active metabolite of dinitrate

Question 5

Nitrovasodilator pharmacokinetics

Answer 5

Significant first-pass metabolism - high nitrate reductase activity in the liver (Nitrate reeducates activity in saturable)
Bioavailability with oral route is low - other routes avoid first pass metabolism
partially denigrated metabolites have activity and longer half-lives
Isosorbide mononitrate is poor substrate of nitrate reductase - high bioavailability

Question 6

Nitrovasodilator pharmacodynamics - MOA

Answer 6

– Unknown enzymatic reaction releases NO (or other active metabolite – nitrosothiol?)
• The role of mitochondrial aldehyde dehydrogenase 2 (ADH2)

– Thiol compounds are needed to release NO from nitrates

– Vascular smooth muscle relaxation by NO

– Sensitivity of vasculature to nitrate-induced vasodilation:
Veins > Large arteries > Small arteries and arterioles

– No “coronary steal” phenomenon

– Inhibit platelet aggregation

Question 7

Beneficial action of nitrovasodilators in angina

Answer 7

decreased myocardial oxygen demand

Relaxation of vascular smooth muscle - dilation of veins (major effect) and dilation of arteries

Question 8

Dilation of veins with nitrovasodilators for treatment of angina

Answer 8

major effect

increased venous capacitance

reduced ventricular preload

Question 9

Dilations of arteries with nitrovasodilators for treatment of angina

Answer 9

higher concentrations of nitrates are needed compared to venous dilation

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

Question 10

Nitrate effects in angina of effort

Answer 10

decreased preload

decreased oxygen demand

Question 11

Nitrate effects on vasospastic angina

Answer 11

relaxation of coronary artery vascular smooth muscle

Relieving coronary artery spasm

Question 12

Clinical use of nitrovasodilators

Answer 12

short-acting formulations used to relieve angina attack

Long-acting preparations may be used to prevent attacks

Question 13

Development of nitrate tolerance

Answer 13

• 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

Question 14

Adverse effects of nitrates

Answer 14

• Headache (meningeal vasodilation)
• Orthostatic hypotension

• Increased sympathetic discharge
– Tachycardia
– Increased cardiac contractility

• Increased renal Na+ and H2O reabsorption

Question 15

Nitrate drug interactions

Answer 15

ED treatment:

– Sildenafil, vardenafil, tadalafil
• Inhibit cGMP-phosphodiesterase-5, increases cGMP
• Minimal effects on hemodynamics when administered alone in men
with coronary artery disease
– Combination with nitrates causes severe increase in cGMP and a dramatic drop in BP

– Acute myocardial infarction cases have been reported

Question 16

Non-cardioactive calcium channel blockers (dihydropyridines)

Answer 16

Amlodipine - long acting (t1/2 30-50 h)
Nifedipine - short acting (t1/2 4 h)
Nicardipine - short acting (t1/2 2-4 h)

Question 17

Cardioactive calcium channel blockers (non-dihydropyridines)

Answer 17

Diltiazem

Verapamil

Question 18

Calcium channel blockers MOA

Answer 18

• Ca2+ mediates smooth muscle contraction; enters cells via voltage-dependent
calcium channels

• CCBs block Ca2+ entry to relax vascular smooth muscle

Question 19

Anti-Anginal mechanisms of CCBs - decreased myocardial oxygen demand

Answer 19

– Dilation of peripheral arterioles
• Decreased PVR and afterload, decreased blood pressure
• Arterioles more affected than veins (less orthostatic hypotension)
• Dihydropyridines are more potent vasodilators

– Decreased cardiac contractility and heart rate (observed with cardioactive CCBs)

Question 20

Anti-antinal mechanisms of CCB - increased blood supply

Answer 20

Dilation of coronary arteries relieves local spasms (this mechanism may operate in vasospastic (Prinzmetal) angina and NOT in atherosclerotic angina)

Question 21

Major adverse effects of CCB

Answer 21

Cardiac depression, cardiac arrest, acute heart failure (cardioactive CCBs)

Bradyarrhythmias, AV block (cardioactive CCBs)

Short acting dihydropyridine CCBs - vasodilation triggers reflex sympathetic activation

Nifedipine - immediate release: increases risk of MI in patient with HTN, slow release and long acting dihydropyridines better tolerated

Question 22

Minor adverse effects of CCB

Answer 22

Flushing, HA, anorexia, dizziness
Peripheral edema
Constipation

Question 23

Beta blockers indicated in angina

Answer 23

Propranolol
Nadolol
Metoprolol
Atenolol

Question 24

Beta blocker MOA in angina

Answer 24

decreased myocardial oxygen demand

– Decrease in HR leads to improved myocardial perfusion and reduced
oxygen demand at rest and during exercise

– Decrease in contractility

– Decrease in blood pressure leads to reduced afterload

Question 25

Adverse effects of beta-blockers

Answer 25

– Reduced cardiac output – Bronchoconstriction – Impaired liver glucose mobilization – Produce an unfavorable blood lipoprotein profile (increase VLDL and decrease HDL) – Sedation, depression – Withdrawal syndrome associated with sympathetic hyperresponsiveness

Question 26

Contraindications of beta-blockers

Answer 26

``` – Asthma – Peripheral vascular disease – Raynaud’s syndrome – Type 1 diabetics on insulin – Bradyarrhythmias and AV conduction abnormalities – Severe depression of cardiac function ```

Question 27

Effects of nitrates alone on heart rate, arterial pressure, end-diastolic volume, contractility, and ejection time in angina pectoris

Answer 27

Heart Rate: Reflex increase (not desirable) Arterial pressure: Decrease End-diastolic Volume: Decrease Contractility: Reflex increase (not desirable) Ejection time: Decrease

Question 28

Effects of Beta Blockers or CCBs on heart rate, arterial pressure, end-diastolic volume, contractility, and ejection time in angina pectoris

Answer 28

``` Heart Rate: Decrease Arterial pressure: Decrease End-diastolic Volume: Increase (not desirable) Contractility: Decrease Ejection time: Increase (not desirable) ```

Question 29

Effects of nitrates with beta blockers or CCBs on heart rate, arterial pressure, end-diastolic volume, contractility, and ejection time in angina pectoris

Answer 29

``` Heart Rate: Decrease Arterial pressure: Decrease End-diastolic Volume: none or decrease Contractility: None Ejection time: None ```

Question 30

Ranolazine MOA

Answer 30

– Inhibits late Na+ current 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 repolarization abnormalities – Ranolazine normalizes repolarization of cardiac myocytes and reduces mechanical dysfunction

Question 31

Ranolazine does not affect...

Answer 31

* Heart rate * General inotropic state of myocardium * Coronary blood flow * Peripheral hemodynamics

Question 32

Clinical use of Ranolazine

Answer 32

– Stable angina which is refractory to standard medications | – Decreases angina episodes and improves exercise tolerance in patients taking nitrates, or amlodipine, or atenolol

Question 33

Adverse Effects of Ranolazine

Answer 33

``` – QT interval prolongation – may trigger polymorphic ventricular arrhythmias – Constipation – Nausea – Dizziness – Headache ```

Question 34

Drug interactions of Ranolazine

Answer 34

– Metabolized by CYP3A4/5 – interaction with drugs that modulate the activity of these enzymes • Do not combine with strong CYP3A inhibitors: antifungal azoles, verapamil – Ranolazine inhibits CYP2D6 • Increases half-life of Amitriptyline, Fluoxetine, Metoprolol, opioid drugs – Drugs that prolong QT interval – certain antiarrhythmic (Quinidine) and antipsychotic drugs (Thioridazine) – may trigger ventricular arrhythmias