Drugs used in Chronic IHD

Question 1

What are the two approaches to treat angina pectoris?

Answer 1

1) Reduce O2 demand by decreasing cardiac work.

2) Increase oxygen supply by increasing blood flow through coronary arteries.

Question 2

What are ways to increase coronary blood flow?

Answer 2

1) Surgical or non-surgical revascularization approaches

2) Vasodilators

Question 3

What type of angina are vasodilators useful for? Not useful for?

Answer 3

Useful - Vasospastic (Prinzmetal) angina.

Not useful for atherosclerotic (classic) angina.

Question 4

What is the significance of coronary steal phenomenon?

Answer 4

Explains why vasodilators are not useful in atherosclerotic angina. Arteriolar dilation (i.e. Dipyridamole) of normal vessels diverts blood away from ischemic/stenotic areas.

Question 5

What are the determinants of myocardial oxygen demand that are used to reduce O2 demands of heart in tx of angina?

Answer 5

HR, contractility, preload, afterload

Question 6

What are three nitrovasodilators?

Answer 6

1) Nitroglycerin
2) Isosorbide dinitrate
3) Isosorbide mononitrate

Question 7

Where is there high nitrate reductase activity?

What else is special about nitrate reductase activity?

Answer 7

Liver - first pass metabolism.

Nitrate reductase activity is saturable.

Question 8

What is EDRF?

Answer 8

Nitric Oxide: Endothelium-Derived Relaxing Factor - released by ACh when endothelium is PRESENT. NO] relaxes smooth muscle of blood vessels.

Question 9

What does endothelial NOS produce? And what is the ultimate result?

Answer 9

Produces endogenous NO, resulting in vasorelaxation (of vascular smooth muscle).

Question 10

What acts as an extracellular NO donor?

Answer 10

An organic nitrate (i.e. Nitroglycerin) that gets metabolically activated to NO.

Question 11

What physiologically results from NO inside a vascular smooth muscle cell?

Answer 11

NO activates GC, which turns GTP to cGMP, which then activates PKG, which then causes:
1) hyperpolarization of cell and reduced Ca entry (opens K channel) AND 2) smooth muscle relaxation

Question 12

Sensitivity of vasculature to nitrate-induced vasodilation.

Answer 12

veins > large arteries > small arteries and arterioles

Question 13

What two things does nitrate-induced relaxation of vascular smooth muscle result in?
What change in coronary blood flow in atherosclerotic angina?

Answer 13

Dilation of veins (major)
Dilation of arteries (needs higher concentration of nitrates). No significant increase in coronary blood flow to ischemic area in atherosclerotic angina.

Question 14

What effects do nitrates have in angina of effort/atherosclerotic angina (2)?

Answer 14

1) Decreased preload/volume heart has to pump, therefore deceased O2 demand.

Question 15

What effects do nitrates have in vasospastic angina (2)?

Answer 15

1) Relaxation of coronary artery vascular smooth muscle, relieving coronary artery spasm

Question 16

Clinical use: short v. long acting nitrovasodilators.

What is the duration of short v. long?

Answer 16

Short acting used to relieve angina attack (10-90min)

Long acting used to prevent attacks (3-10hrs)

Question 17

Which nitrovasodilators are short acting? Long acting? Formulation?

Answer 17

BOTH:
1) Nitroglycerin - short (subL, spray shortest duration) and long (oral, ointment, patch)
2) Isosorbide dinitrate - short (subL, spray) and long (oral)
ONLY LONG:
3) Isosorbide mononitrate - long (oral longest duration)

Question 18

How is NO depleted in tissue?

Answer 18

Increased generation of superoxide radicals deplete tissues of NO.

Question 19

What occurs in development of nitrate tolerance (4)?

Answer 19

Depletion of thiol compounds, increased oxygen radical generation, REFLEX ACTIVATION of SNS (tachycardia, decreased coronary blood), retention of salt and water

Question 20

What are the ADVERSE EFFECTS of nitrates?

Answer 20

1) HA (meningeal vasodilation)
2) Orthostatic hypotension
3) Increased sympathetic discharge*

Question 21

What are the adverse effects of increased sympathetic discharge due to nitrates (and tolerance)?

Answer 21

Tachycardia, increased cardiac contractility, Increased renal salt and water reabsorption.

Question 22

What is the major class of drug interaction with nitrates (3 drugs) and what is this class used for? What two adverse effects can occur?

Answer 22

Drugs used for ED - sildenafil, vardenafil, tadalafil.

(1) Severe cGMP increased and a dramatic drop in BP and (2) acute MIs have been reported.

Question 23

What two classes of CCBs are used in angina, and what drugs in each class?

Answer 23

1) Non-cardiactive (DHPs) - amlodipine, nifedipine, nicardipine.
2) Cardioactive (non-DHPs) - diltiazem, verapamil

Question 24

What two tissues have L-type calcium channels that CCBs interact with and what does intracellular calcium do?

Answer 24

Vascular smooth muscle (L-type) and Cardiac muscle (L-type). Calcium mediates smooth muscle contraction

Question 25

What do CCBs do for anti-angina (A, B)?

Answer 25

A. Decrease myocardial O2 demand (vasodilation of arterioles) B. Increased blood supply - via dilation of coronary arteries (for VASOSPASTIC ANGINA only)

Question 26

How do CCBs decrease myocardial O2 demand (2)?

Answer 26

A: (1) Dilation of peripheral arterioles (dec. afterload and PVR) (2) Decreased cardiac contractility and HR (cardioactive DHPs)

Question 27

What type of angina can CCB-induced increased blood supply be used for (B)? What is it not used for?

Answer 27

B: Vasospastic (Prinzmetal) angina - dilation of coronary arteries relieves local spasms. NOT used for atherosclerotic angina.

Question 28

Are DHPs or non-DHPs more potent vasodilators (of arterioles?

Answer 28

DHPs (non-cardioactive CCBs)

Question 29

MAJOR adverse effects of CCBs (4)

Answer 29

1) Cardioactive CCBs - cardiac depression, cardiace arrest, AcuteHF 2) Cardioactive CCBs - bradyarrhyth, AV block 3) Short active DHPs - vasodilation triggers reflex sympathetic activation 4) Nifedipine (immediate release) - increases risk of MI in people with HTN.

Question 30

What is better tolerated for tx of angina than Nifedipine, that will not increase risk of MI in patients with HTN?

Answer 30

Slow release and long acting DHPs.

Question 31

MINOR adverse effects of CCBs

Answer 31

Flushing, HA, anorexia, dizziness Peripheral edema Constipation

Question 32

What four beta-blockers are indicated in angina?

Answer 32

Propranolol Nadolol Metoprolol Atenolol

Question 33

MOA of b-blockers in angina.

Answer 33

Decrease myocardial O2 demand: (1) Dec. HR leading to better perfusion and dec. O2 demand at rest+excercise. (2) Dec. contractility. (3) Dec. afterload

Question 34

Adverse effects of b-blockers

Answer 34

Reduced CO, Bronchoconstriction, Impaired liver glucose mobilization, Inc. VLDL/dec. HDL, Sedation and depression, Withdrawl.

Question 35

Contraindications of b-blockers

Answer 35

ASTHMA, PVD, Type1 DM on insulin, bradyarrhythmias, AV abnormalities, severe depression of cardiac function

Question 36

AE of admin of Nitrates alone for angina.

Answer 36

Reflex increase in HR and contractility.

Question 37

AE of Nitrates + b-blocker or CCBs for angina.

Answer 37

Increased end-diastolic volume and increased ejection time.

Question 38

Physiological action of Ranolazine

Answer 38

Inhibits late Na+ current in cardiomyocytes

Question 39

MOA of ranolazine in angina.

Answer 39

Normalizes the repolarization of myocytes and reduces mechanical dysfunction (it inhibits the Na+ current that is enhanced in ischemic myocardium, which results in Ca overload and repol abnormalities)

Question 40

What four things does ranolazine NOT affect?

Answer 40

HR, inotropic state of myocardium, coronary blood flow, peripheral hemodynamics.

Question 41

What is the clinical use of ranolazine? (When is it used and what does it do?

Answer 41

Use for stable angina that is refactory to standard meds. | It decreases angina episodes and improves excercise tolerance in people taking NITRATES, AMLODIPINE, OR ATENOLOL.

Question 42

Adverse effects of ranolazine.

Answer 42

``` QT prolongation (may trigger vent arrhythmias) Constipation, nausea, dizziness, HA. ```

Question 43

What two types of drugs should not be used with ranolazine?

Answer 43

Do not use with CYP3A inhibitors (bc its metab by CYP3A4/5). Do not use with drugs that prolong QT interval (Quinidine=antiarrhythmic or antipsychotic=thioridazine). Triggers vent arrhythmias.

Question 44

What CYP does ranolazine inhibit (and consequently, should not be used with what drugs)?

Answer 44

Inhibits CYP2D6, which increase half life of amitriptyline, fluoxetine, metoprolol, and opioid drugs

Question 45

What two things do nitrates alone increase?

Answer 45

Reflex increase in contractility | Reflex increase in HR

Question 46

What do BB or CCB alonge increase?

Answer 46

Increase EDV and Ejection time.

Question 47

Combined, what do nitrates and BB/CCB cause?

Answer 47

Decreased HR and Decreased arterial pressure.