Cv Pharm - Angina Pectoris Part 1

Front 1

What is angina pectoris

Back 1

-Used to describe the symptoms associated with chronic ischemic heart disease
-Result of a failure of the oxygen supply to the heart carried by the coronary blood flow to meet th oxygen demands of the ventricular myocardium
-Describes a sense of "strangling" in the chest often accompanied by "angor animi" (fear of death)

Front 2

Describe chronic stable angina

Back 2

1. Characterized by discomfort in the chest during effort. ST segment depression occurs on the ECG, indicating subendocardial ischemia. Also, there may be abnormalities in ventricular wall motion indicating a contraction deficit

2. Caused by fixed obstruction in a coronary artery (70-90% obstruction) as a result of atherosclerosis. MI occurs when oxygen demand increased because of increased work of the heart.

3. Pain results from release of adenosine, bradykinin, and histamine which stimulate sensory endings of afferent cardiac sympathetic nerves

Front 3

Describe unstable angina

Back 3

1. Angina pain at rest as well as with minimal exertion. There are often severe and prolonged episodes. Usually represents a worsening of preexisting chronic stable angina

2. Ischemia is often precipitated by a decrease in oxygen supply caused by transient and reversible formation of platelet aggregates in a region of coronary artery narrowing caused by atherosclerosis. Platelets can released thromboxane A2 that constricts coronaries

3. Associated with ST segment changes on ECG and ventricular arrhythmias

4. Often a precursor of MI

Front 4

Describe variant angina (Prinzmetal's Angina)

Back 4

1. Anginal pain that occurs at rest

2. ST segment elevation occurs on ECG indicating transmural ischemia. Ischemia may precipitate ventricular tachycardia and fibrillation.

3. Caused by vasospasm (contraction of arteriolar smooth muscle) of a large coronary artery. Can occur in normal (10-15%) or disease (85%) coronary arteries. In diseased arteries it occurs in a region adjacent to atherosclerotic narrowing.

Front 5

What is the primary goal of drug therapy for angina pectoris?

Back 5

To restore the balance between oxygen supply and the needs of the ventricular myocardium (oxygen demand)

Front 6

What are the two mechanisms by which drugs can restore the balance between oxygen demand of the myocardium and supply delivered by coronary blood flow

Back 6

-Drugs can act on the heart to decrease the oxygen demand
-Drugs can act on the coronary arteries to increase coronary flow and the oxygen supply

Front 7

Describe how drugs can act on the heart to decrease the oxygen demand

Back 7

a. Alter (slow) heart rate
b. Reduce hte afterload
c. Decrease preload and LV diameter
d. Decrease the inotropic state of myocardium

Front 8

Describe how drugs can act on the coronary arteries to increase coronary flow and the oxygen supply

Back 8

a. Decrease EDP of the LV
b. Decrease coronary artery vascular tone

Front 9

What organic nitrates are available for clinical use?

Back 9

-Amyl nitrite
-Glyceryl Trinitrate (nitroglycerine)
-Isosorbide denitrate
-Isosorbide mononitrate

Front 10

Describe the cellular mechanism of action for nitrates

Back 10

-Formation of free radical NO activates guanylate cyclase in smooth muscles and increases the synthesis of cGMP
-Biochemical effect is the same as EDRF (endothelium derived growth factor) which relaxes smooth muscle

Front 11

Describe the mechanisms of anginal action for nitrates

Back 11

a. Systemic vasodilation by direct action. Reduces venous return to the heart, decreases ventricualr EDP and V (preload) and heart size, thereby decreasing systolic wall stress and oxygen consumption

b. Peripheral arteriolar dilation occurs but is less important than venous dilation. This effect reduces afterload on the ventricle and oxygen consumption

c. Cause dilation of large epicardial coronary arteries to increase oxygen supply. Occurs without dilation and impairment of autoregulation in small coronary arterioles. Coronary flow is redistibuted to inschemic areas where resistance vessels are maximally dilated by the local metabolic demand and there is no coronary "steal". Net effect is redistribution of blood to needy areas.

d. Coronary flow is also improved as a result of a decrease in EPD caused by decreased preload

Front 12

Describe the absorption and administration of nitrates

Back 12

i. Due to extensive 1st pass metabolism in the liver, nitroglycerin given sublingually to abort an anginal attack. Time to peak: 4 min, t1/2: 3 min

Isosorbide dinitrate when given sublingially: time to peak: 6 minutes, t1/2: 45 min

ii. High doses of isosorbide dinitrate or isosorbide mononitrate can be effective when given orally

iii. Nitroglycerin ointments and patches are also used for absorption from the skin

iv. IV nitrates are used in emerg setting

Front 13

Describe the elimination of nitrates

Back 13

-Degraded by reductive hydrolysis catalyzed by hepatic glutathione organic nitrate reductase, an enzyme with large caralytic capacity
-Long acting nitrates (isosorbide dinitrate and others) are denitrated at about 1/10 the rate of glyceryl trinitrate (nitroglycerine)
-Isosorbide mononitrate, which is used therapeutically is a metabolite of isosorbide dinitrate

Front 14

Describe nitrate tolerance and dependence

Back 14

i. Tolerance develops to continuous use because of down regulation of guanylate cyclase. Dosing strategy to prevent this requires periods off nitrates

ii. Dependence develops to prolonged continuous use caused by down regulation of guanylate cyclase. Coronary vasoconstriction after withdrawal.

Front 15

Describe the clinical use of nitrates

Back 15

Main clincal uses are to terminate anginal attacks or to prevent anginal attacks

Front 16

Describe the undesirable effects of nitrates

Back 16

a. Throbbing headache caused by vasodilation of arteries leading to brain

b. Flushing of the skin.

c. Postural hypotension, dizziness

d. Reflex tachycardia caused by fall in BP may offset beneficial effect by increasing oxygen demand

Front 17

Describe the mechanisms of action for beta-adrenergic blocking drugs

Back 17

Decrease myocardial demand by the following actions
a. Decrease HR (esp during stress)
b. Decrease myocardial contractility
c. Decrease arterial BP and afterload
d. Beta blockers may increase coronary blood flow by slowing HR (block of β2 receptors in coronaries may constrict)

Front 18

Describe the clinical pharmacology of beta-adrenergic blocking drugs

Back 18

-Nonselective beta blockers (propranolol, timolol) block β1 and β2 receptors which may be a disadvantage in a patient with asthma
-Atenolol and metoprolol are cardioselective beta blockers-Pindolol is a partial agonist which does not cause a decrease in HR at rest but prevents sympathetically induced increases in HR

Front 19

Which beta blockers are most useful for angina pectoris

Back 19

THe onces that can be given once or twice a day

Front 20

Describe how beta blockers are used clinically for angina

Back 20

-Used orally on a chronic basis with the objective of decreasing myocardial oxygen demand and thereby preventring anginal attacks
-Not used acutely like nitroglycerine
-Often used in conjunction with organic nitrates or combined with Ca channel blocking drugs

Front 21

Describe the undesirable effects of beta blockers

Back 21

a. Exacerbation of angina if ventricular contraction is depressed too much leading to an increase in EDV and decrease in coronary flow. Also β2 receptor blockade may lead to some coronary vasoconstriction
b. Aggravation of HF
c. Sinus bradycardia, AV block
d. Fatigue and depression (beta block that can enter the CNS)
e. Hypoglycemia
f. Bronchospasm
g. Rebound angina pectoris on stopping therapy resulting from upregulation of beta receptors in the heart

Front 22

Describe the chemistry of calcium channel blockers

Back 22

Subdivided into 3 categories:
-Phenylalkylamines (verapamil)
-Dihydropyridines (nifedipine, amlodipine)
-Benzothiazepines (diltiazem)

Front 23

Describe the actions of Ca channel blockers on vascular smooth muscle

Back 23

i. Peripheral vasodilation and decrease in system arterial pressure decrease the afterload. There is little or no effect on venous smooth muscle and preload

ii. These drugs dilate coronary arteries nad prevent coronary vasospasm. This effect is not selective for the epicardial arteries so coronary steal may occur

Front 24

Describe the actions of Ca channel blockers on the myocardium

Back 24

Variable effects on HR:
-Verapamil decreases HR, which may be beneficial
-Diltiazem causes no change
-Nifedipine increases HR which may be deleterious

Verapamil and diltiazem decrease myocardial contractility which is beneficial. Nifedipine may cause a reflex increase in contractility which may increase oxygen demand and be deleterious

Front 25

Describe the clinical pharmacology of Calcium channel blockers

Back 25

a. The bioavailability of calcium channel blocking drugs is relatively poor
b. All the calcium channel blocking drugs are extensively metabolized and their half-lives are relatively short, e.g., 3-4 hours
c. The calcium channel blocking drugs can be given orally or IV. There is a sublingual formulation for nifedipine

Front 26

Describe the clinical use of Calcium channel blockers for angina pectoris

Back 26

-Oral formulation are given to treat chronic effort angina or vasospastic angina
-Sublingial formulation of nifedipine can be used to abort an attack of coronary vasospasm
-Often used in conjunction with another antianginal drug. Nitroglyceroin and verapamil or beta blockers and nifedipine are good combinations
-Diltiazem can be used with either nitrates or beta blockers.
-Nifedipine and nitroglycerine (both increase HR) or verapamil and beta blockers (both decrease HR) are more likely to cause adverse effects

Front 27

What are the adverse effects associated with calcium channel blockers?

Back 27

a. Excessive systemic vasodilation leading to hypotension, dizziness, headache, flushing
b. Aggravation of myocardial ischemia caused by coronary steal, decrease in coronary perfusion if hypotension is excessive, or reflex tachycardia (nifedipine)
c. Aggravate ventricular failure
d. GI effects (verapamil)
e. Ankle swelling (nifedipine)

Front 28

Describe Ranolazine

Back 28

-For chronic stable angina
-Inhibits late I_Na to reduce Ca overload of smooth muscle
-Only for patients who are symptomatic on standard therapies (prolongs QT)

Front 29

Describe verapamil's effect on the heart and vasculature

Back 29

Heart: ++++
Vasculature: +++++

Decreases HR
Slows AV conduction
Increases AVN ERP

Front 30

Describe Diltiazem's effect on the heart and vasculature

Back 30

Heart: +++
Vasculature: ++++

Slows HR
Slows AV Node conduction
Increase AV node ERP

Front 31

Describe Nifedipine's effect on the heart and vasculature

Back 31

Heart: +
Vasculature: +++++++

Increases HR
Speeds AV node conduction
Decreases AV node ERP