ANTIANGINAL AGENTS

Objectives

Describe the pathophysiology of the various forms of angina Explain the pharmacological actions & other indications of various antianginal drugs.

The term angina, or angina pectoris is used to describe a sudden, temporary substernal pain which may radiate to the left shoulder, neck, &/or to the left arm. Imbalance between O2 supply & O2 demand

Oxygen demand

Oxygen supply

Determinants
Heart Rate Contractility Ventricular wall stress BP

Determinants Coronary blood flow

Different clinical entities of Angina

1. Typical Angina (exertional, classic) Most common form (90%) Coronary insufficiency due to vessel occlusion (atherosclerosis) Attacks usually occur during exercise (climbing stairs, etc.) when oxygen demand exceeds supply

2. Variant (Prinzmetals)

Coronary insufficiency due to vasospasm (may be an effect produced by atherosclerosis on vasomotor tone) Attacks often occur during rest (e.g., at night)

3. Unstable

angina (acute coronary syndrome OR rest angina)

Serious problem (impending MI) Increased frequency & severity of attacks Caused by atherosclerotic plaques, platelet aggregation at fractured plaques & vasospasm

AGENTS USED TO TREAT ANGINA 1. Organic Nitrates

Short acting: Nitroglycerin, Long acting: Isosorbide dinitrate, Isosorbide mononitrate

2. 3. 4.

-adrenergic blockers Calcium channel blockers Potassium channel openers- Eg:

Nicorandil, Cromakalim

NITRATES
Mechanism of Action

Nitrates Additional Mechanisms:

Redistribution of coronary blood flow - selectively increase blood flow to ischemic areas although total coronary flow is not increased Nitrates dilate epicardial coronary capacitance vessels thereby increasing blood flow in collateral vessels. A reversal of coronary vasospasm & increased flow has been demonstrated in vasospastic angina. Causes systemic venodilation and therefore reduce myocardial wall tension and oxygen requirements

Uses of Nitrates

Uses of Nitrates Acute attack of angina Chronic prophylaxis of angina CCF Cyanide poisoning low doses (usually sublingual tablets) for acute attacks & for prophylaxis patches used for prolonged prophylaxis Nitrates are the mainstay of therapy for the immediate relief of angina

Nitrates in Angina

Decrease myocardial oxygen requirement by decreasing

ventricular volume Arterial pressure

Relieves coronary vasospasm by causing vasodilation of epicardial coronary arteries Improves perfusion to ischemic myocardium by

Increasing collateral flow Decreasing left ventricular diastolic pressure

Improves subendocardial perfusion by

The role of Nitrates in Cyanide poisoning Nitrates generate methaemoglobin

high affinity for cyanide

forms cyanometheamoglobin
Sodium thiosulate

forms sodium thiocyanate excreted in the urine

MODE OF ADMINISTRATION

SUBLINGUAL - Nitroglycerin & isosorbide dinitrate rapidly & extensively absorbed. Therapeutic effects -observed within 2-4min Treatment of choice for acute angina.

ORAL - Only Isosorbide mononitrate -Prophylaxis TRANSDERMAL - Isosorbide dinitrate & nitroglycerin
- well-absorbed through the skin. Ointments & sustained release patches are often used for prophylaxis of angina

Adverse effects of nitrates

Orthostatic

hypotension Tachycardia Severe throbbing headache Flushing Syncope Tolerance and Dependence

Beta blockers
Mechanism of Action 1) Reduced oxygen consumption (demand) due to reduced heart rate (esp. during exercise), negative inotropic effect & reduced blood pressure (esp. systolic) during exercise. Use: 1) Only for prophylaxis of exertional angina 2) Ineffective (or contraindicated) for variant angina (may make attacks worse) 3) Often combined with other drug types

-blocker Side Effects

Increased end-diastolic volume & ejection time (O2 demand) Fatigue, insomnia, erectile dysfunction, etc. Avoid use in patients with:

Asthma / bronchospastic disorders SAN Dx., AVN Dx.or bradycardia Depression

Calcium Channel blockers

Mechanism -- block calcium influx via L-type channels in cardiac and vascular smooth muscle; produce decreased contractility, vasodilation.

CCBs

Pharmacological Effects

All CCBs vasodilate coronary arterioles & reduce afterload, but each class has different effects on heart rate & cardiac contractility
Verapamil,

diltiazem - have direct negative inotropic, chronotropic & dromotropic effects dihydropyridines have negligible direct effects on heart rate or contractility, but they reflexly increase these which may aggravate angina

The

The desired therapeutic effects of CCBs in treating angina are to:

Reduce

myocardial oxygen consumption by reducing afterload myocardial oxygen consumption by reducing heart rate & contractility (except for dihydropyridines) Improve oxygen delivery to ischemic myocardium by vasodilating coronary arteries

Reduce

COMPARISION BETWEEN CCBs

VERAPAMIL HEART RATE CONTRACTILITY
-------

DILTIAZEM

NIFEDIPINE

A-V Conduction CORONARY VASODILATION

-----

Vascular smooth muscle

++

+++

Pharmacokinetics

All are orally active Exhibit high first-pass metabolism & high protein binding Effects of these are evident within 30 to 60 minutes of an oral dose Dihydropyridines- hypotension, headache, flushing, reflex tachycardia. Verapamil & Diltiazem Depression of contractility, Bradycardia, AV block

Adverse Effects:

Clinical indications, dosage and toxicity of CCBs

Supply vs. Demand

Nitrates, CCBs, -blockers

*
O2 demand

O2 delivery

Normal balance
a ngin A

Nitrates, CCBs, Revascularization

Adapted from Katzung, 9th Ed.

* More often, drugs are used

to decrease O2 demand

Useful Drug Combinations

Nitrate + blocker

Different mechanism of action - additive efficacy blocker can prevent reflex tachycardia & positive inotropic effects caused by nitrates Nitrates can reduce the increase in enddiastolic volume caused by blockers by increasing venous capacitance

Useful Drug Combinations

CCB + blocker + Nitrate

Different mechanisms of action - additive efficacy CCB may cause improvement if there is a vasospastive component to the angina blocker can prevent reflex tachycardia caused by nitrate or dihydropyridine type CCB (& further lower HR & BP)

Unstable Angina

Pts w/ recurrent ischemic episodes at rest Recurrent thrombotic occlusions Platelet aggregation Rx:

aspirin i.v. heparin antiplatelet drugs (clopidogrel, others) nitroglycerin, blockers; CCBs in refractory pts.

Anti-ischemic mechanisms of AntiAnginal drugs

Drug Class Action

Decreased myocardial demand Increased coronary blood supply Prevent coronary spasm Enlarge Coronary stenosis

Nitrates

Blockers

CCBs

++ +++ ++ ++

+++ 0 to + 0 to 0 to +

+ to ++ ++ to +++ ++ to +++ + to ++

Ischemic Heart Disease and Hypertension

IHD is the most common form of target-organ damage associated with hypertension. Beta blockers and long acting CCBs are the first choice in HTN patient with stable angina pectoris. HTN patients with unstable angina or MI should be treated with beta blocker or ACE inhibitor. In patients with post-myocardial infarction, ACE inhibitors, beta blockers and aldosterone antagonists; all reduce progression of left ventricular dysfunction and mortality.