Antianginal Drugs

Question 1

Fixed (Stable, Classic) Angina

Answer 1

• Precipitated by exercise and/or excitement. Stable angina is relieed by rest. It is caused by obstruction in one or more of the coronary arteries, and the lesion is usually artherosclerotic.

Question 2

Variant Angina (Prinzmetal’s Angina)

Answer 2

• Occurs at rest or even during sleep and is unpredictable. It is caused by vasospasm of an artery that is probably injured.

Question 3

Unstable Angina (Acute coronary syndrome)

Answer 3

• Rapidly progressing of the frequency and severity of angina attack, and in the initial stages, indistinguishable from impending myocardial infarction. The condition is believed to be caused by combination of atherosclerotic plaque and thrombosis and spasm. Symptoms may occur during resting state and are unpredictable. It should be treated as a medical emergency.

Question 4

Silent Ischemia

Answer 4

• Ischemia of myocardium w/o pain or symptoms. ECG detects the episode of angina.

Question 5

Nitrates/Nitrites pharmacological effects

Answer 5

• Increase coronary blood flow; increasing O2 supply
• Vasodilators; increases blood velocity and flow rate in normal vessels, but less of a response in stenotic vesses, which shunt blood from the ischemic area to an already adequately perfused area of the heart. This “steal effect” will exacerbate tha angina attack.
• Decrease cardiac work; decrease preload (venodilation- primary effect, decreases left ventricular filling pressure) and afterload (arteriolar dilation- reduces peripheral resistance and impedance to left ventricular outflow); decreasing O2 demand
• Relieve coronary artery spasm
• Anti-platelet aggregation

Question 6

Calcium Channel Antagonist Pharmacological Effects

Answer 6

• Increase coronary blood flow; increasing O2 supply
• Vasodilators; increase blood velocity and flow rate in normal vessels, but less of a response in stenotic vessels, which shunt blood from the ischemic area to an already adequately perfused area of the heart. This “steal effect” will exacerbate the angina attack
• Decrease cardiac work; decrease afterload, heart rate and contractility; decreasing O2 demand

Question 7

Beta-adrenergic Blockers Pharmacological Effects

Answer 7

• Decrease heart rate and contractility; decreasing O2 demand

Question 8

Nitrates and Nitrite Drugs

Answer 8

Rapidly acting agents used to terminate an acute attack of angina

• Nitroglycerin- given sublingual (0.15-0.6mg), IV, and oral spray (0.4mg)
• Isosorbide Dinitrate- given sublingual

Agents w/ prolonged action used to prevent attacks of angina and are given orally and topically

• Oral, sustained release of nitroglycerin
• Nitroglycerin Transdermal (2.5-15mg/24hrs)
• Isosorbide Dinitrate

Question 9

Nitrates and Nitrites MOA

Answer 9

• Nitric Oxide activates guanylyl cyclase to produce cGMP (second messenger) to promote dephosphorylation of myosin light chain resulting vascular smooth muscle relaxation (i.e., vasodilation)

Question 10

Nitrates and Nitrites Pharmacokinetics

Answer 10

• Low oral bioavailability (10-20%) extensive hepatic metabolism; t1/2 = 2-8min.; however, active metabolites (eg dinitroglycerins) of nitroglycerin have a t1/2 = 3hrs.

Question 11

Nitrates and Nitrites Tolerance

Answer 11

• Repeated administration leads to tolerance manifested by the need of higher doses to produce the same effect. there is also cross tolerance b/w various compounds of this class. Ensure nitrage-free interval (at least 8h) to prevent tolerance
• Mechanism: depletion of cysteine stores in vessels during the conversion to S-nitrosothiol, but may be reversed w/ sulfhydryl-regenerating agents
• “Rebound phenomenon”: should use a graduale withdrawal after chronic therapy to avoid myocardial ischemia and death
• “Monday Disease”: industrial disease caused by chronic exposure to organic nitrates in the workplace; characterized by headache, dizziness, and tachycardia on Monday when workers reture to work afte 2 day absence, then develop tolerance duing the work week

Question 12

Nitrates and Nitrites Adverse Reactions

Answer 12

• Throbbing headache (meningeal artery vasodilation), flushin, postural (orthostatic) hypotension (venodilator effect)
• Reflex tachycardia
• Caution: nitrates/nitrites w/ sildenafil can cause severe hypotension, even myocardial infarctions. It is recommended that at least 6hrs pass b/w use of a nitrate and the ingestion of sildenafil.

Question 13

Nitrates and Nitrites Therapeutic Uses

Answer 13

• Terminate acute attackes of angina: sublingual nitroglycerin (or sublingual isosorbide dinitrate)
• Stable angina
• Variant angina
• Unstable angina

Question 14

Calcium Channel Blockers Pharmacological Effects

Answer 14

• Decrease myocardial contractility to reduce O2 requirement (mainly verapamil, diltiazem)
• Decreased arteriolar tone results in decreased afterload
• Dilate coronary and relief of coronary artery spasm
• Principally used as prophylactic

Question 15

Calcium Channel Blocker Drugs

Answer 15

• Non-dihydropyridine: Verapamil, Diltiazem
• Dihydropyridine: Nifedipine, Amlodipine (avoid short-acting dihydropyridine agents for angina)

Question 16

Calcium Channel Blockers MOA

Answer 16

• Inhibition of L-type calcium channels (heart and smooth musle). Dihydropyridines (eg, nifedipine) are more potent vasodilators and have less inhibition on cardiac contractility compared to verapamil and diatiazem; also may produce reflex tachycardia

Question 17

Calcium Channel Blockers Adverse Effects

Answer 17

• Flushing, dizziness, nausea, constipation (common for verapamil), peripheral edema; high doese of non-dihydropyridine Ca channel blocker may cause cardiac depressant effects, such as heart failure (particular caution w/ combining w/ beta blockers), AV blockage and sinus node depression

Question 18

Calcium Channel Blockers Therapeutic Uses

Answer 18

• Variant angina and stable angina

Question 19

Beta adrenergic Blockers Pharmacological Effects

Answer 19

• Not vasodilators (except carvedilor and nebivolol)
• Decreased myocardial contractility and heart rate to reduce myocardial oxygen requirement at rest and during exercise
• Lower heart rate is assoc. w/ an increase in diastolic perfusion time leading to an increase in myocardial perfusion thereby reducing symptoms
• Principally used as prophylactic

Question 20

Beta adrenergic Blocker Drugs

Answer 20

• Propranolol
• Metoprolol
• Atenolol

Question 21

Beta-adrenergic Blockers MOA

Answer 21

• Inhibition of beta adrenergic receptors (heart muscle)

Question 22

Beta-adrenergic Blockers Adverse Effects

Answer 22

• Undesirable effects: increase in end-diastolic volume and increase in ejection time tend to increase myocardial oxygen demand
• Fatigue, impaired exercise tolerance, insomnia, erectile dysfunction, cardiac depressant effects when combining w/ non-dihydropyridine Ca channel blocker

Question 23

Beta-adrenergic Blockers Therapeutic Uses

Answer 23

• Stable and unstable angina
• B1-selective agents preferred (i.e., atenolol, metoprolol), avoid agents w/ intrinsic sympathomimetic activity (i.e., pindolol)

Question 24

Nitrates, Nitrates with Beta Blocker and Nitrates w/ Calcium Channel Blockers in Angina Pectors Chart

Answer 24

Question 25

Ranolazine

Answer 25

• Inhibitor of late phase of the sodium current; reduces intracellular sodium and calcium overload, thereby improving diastolic function. Also may modify fatty acid oxidation.
• Has antianginal as well as antiarrhythmic properites. It is indicated for the treatment of chronic angina and may be used alone or in combination w/ other antianginal therapies.
• Can prolong the OT interval and should be avoided w/ other drugs that cause QT prolongation

Question 26

Trimetazidine

Answer 26

• Metabolic modulator
• pFOX inhibitors which partially inhibit the fatty acid oxidation pathway in myocardium to reduce oxygen requirement per unit of ATP production
• Demonstrate efficacy in stable angina but not approved for use in USA

Question 27

Ivabradine

Answer 27

• Inhibits If sodium current in SA node to reduce heart rate and consequently decreases cardiac work

Question 28

Summary Chart

Answer 28