Drugs Used In Chronic IHD (DSA + Lecture)-Konorev

Question 1

Describe 1st pass metabolism of Nitrovasodilators (i.e., nitroglycerin):

Answer 1

Significant 1st pass metabolism –> High nitrate reductase activity in the liver (nitrate reducatase activity is saturable)

Question 2

___ compounds are needed to release NO from nitrates

Answer 2

Thiol

Question 3

Describe the MOA of nitrovasodilators:

Answer 3

• Unknown enzymatic rxn releases NO (role of mt ADH2)
• Thiol compounds needed to release NO from nitrates
• Vascular smooth m. relaxation by NO
• Inhibit platelet aggregation

Question 4

Describe the sensitivity of vasculature to nitrate-induced vasodilation:

Answer 4

Veins > Large arteries > Small arteries and arterioles

Question 5

What are the effects of nitrates in “Angina of effort”?

Answer 5

• decreased preload

- decreased O2 demand

Question 6

What are the effects of nitrates in “Vasospastic angina”?

Answer 6

• relaxation of coronary artery vascular smooth muscle

- relieving coronary artery spasm

Question 7

Describe what happens to the following with development of nitrate tolerance:

• Thiol compounds?
• O2 radicals?
• Autonomics?
• Salt and water?

Answer 7

• Depletion of thiol compounds
• Increased generation of O2 radicals
• Reflex activation of Sympathetic nervous system (Tachycardia, decreased coronary blood supply)
• Retention of salt and water

Question 8

What are some adverse effects of nitrates?

Answer 8

• headache (meningeal vasodilation)
• orthostatic hypotension
• increased sympathetic discharge –> tachycardia, increased cardiac contractility, increased renal Na and H2O reabsorption

Question 9

The activation of guanylyl cyclase by nitrates and inhibition of PDE5 by ED drugs concurrently causes prolonged activation of what?

Answer 9

cGMP —> Smooth m. relaxation –> erectile tissue and blood vessels

-Combo of nitrates and PDE5 inhibitors causes severe increase in cGMP and a dramatic drop in BP

Question 10

List the Non-cardioactive (DHP) CCBs:

Answer 10

Amlodipine (long-acting)
Nifedipine (short acting)
Nicardipine (short acting)

Question 11

List the cardioactive (non-DHP) CCBs:

Answer 11

Diltiazem

Verapamil

Question 12

What is the MOA of CCBs?

Answer 12

• Ca mediates smooth m. contraction and enters cells via voltage-dependent Ca channels
• CCBs block Ca entry to relax vascular smooth m.

Question 13

What are the anti-angina mechanisms of CCBs?

Answer 13

• Decreased myocardial O2 demand –> dilation of peripheral arterioles (DHP’s more potent vasodilators), and decreased cardiac contractility and heart rate (observed with cardioactive or non-DHP CCB’s)
• Increased bloody supply

Question 14

What are the major adverse effects of CCBs?

Answer 14

• Cardiac depression, cardiac arrest and acute heart failure
• Bradyarrhythmias, AV block
• Short-acting DHP CCB’s –> vasodilation triggers reflex sympathetic activation
• Nifedipine (immediate release) increases risk of MI in pts with HTN-slow release and long-acting DHPs are better tolerated

Question 15

What are some B-blockers indicated in angina?

Answer 15

Propanolol
Nadolol
Metoprolol
Atenolol

Question 16

What is the MOA of B-blockers in angina?

Answer 16

Decreased myocardial O2 demand –> decrease in HR leads to improved myocardial perfusion and reduced O2 demand at rest and during exercise, decrease in contractility, decrease in BP leads to reduced afterload

Question 17

What are some adverse effects of B-blockers for angina?

Answer 17

• reduced CO
• Bronchoconstriction
• Impaired liver glucose mobilization
• Produce unfavorable blood lipoprotein profile (increase VLDL and decrease HDL)
• sedation, depression
• withdrawal syndrome associated with sympathetic hyperresponsiveness

Question 18

What are some contraindications for using B-blockers for angina?

Answer 18

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

Question 19

Describe the effect on heart rate with the use of nitrates alone?

Answer 19

Reflex increase –> baroreceptor reflex

-undesirable effect

Question 20

Describe the effect on contractility with nitrates alone:

Answer 20

Reflex increase –> Baroreceptor reflex

-undesirable effect

Question 21

Describe what happens to end-diastolic volume and ejection time with the use of B-blockers or CCBs:

Answer 21

Both increase

-Undesirable effect

Question 22

This drug normalized repolarization of cardiac myocytes and reduces mechanical dysfunction. It does not affect HR, general inotropic state of myocardium, coronary blood flow, or peripheral hemodynamics:

Answer 22

Ranolazine

Question 23

The clinical use of this drug is for stable angina which is refractory to standard meds. It decreases angina episodes and improves exercise tolerance in pts taking nitrates, or amlodipine, or atenolol:

Answer 23

Ranolazine

Question 24

What are some adverse effects of Ranolazine?

Answer 24

• QT prolongation –> may trigger polymorphic ventricular arrhythmias
• constipation
• nausea
• dizziness
• headache

Question 25

Ranolazine is metabolized by ___

Answer 25

CYP3A4/5 --> DO NOT combine with strong CYP3A inhibitors: antifungal anoles, verapamil

Question 26

Ranolazine inhibits ___

Answer 26

CYP2D6 --> increases 1/2 life of Amitriptyline, Fluoxetine, Metoprolol, opiod drugs

Question 27

Increasing coronary blood flow using vasodilators is useful in __ angina which relieves coronary spasm and restores blood flow into the ischemic area

Answer 27

Vasospastic (Prinzmetal)

Question 28

The use of vasodilators to increase coronary blood flow is not useful in atherosclerotic (classic) angina and can lead to this phenomenon:

Answer 28

Coronary steal phenomenon --> redistribution of blood to non-ischemic areas-associated with the dilation of small arterioles (example-potent arteriolar vasodilators, such as Dipyridamole)

Question 29

Does coronary blood flow occur during systole or diastole?

Answer 29

Diastole

Question 30

Nitrate -----> NO Requires metabolic activation by ___

Answer 30

ADH2 and Thiols

Question 31

In the development of tolerance to nitrates, increased generation of ___ depletes tissues of NO

Answer 31

Superoxide radical

Question 32

Ranolazine inhibits __ current in cardiomyocytes

Answer 32

Late Na+

Question 33

What are 4 drug classes used in chronic IHD?

Answer 33

- Nitrates (nitrovasodilators) - CCB's - Beta blockers - Ranolazine