Antianginal Drugs

Angina PectorisDefinition• A clinical syndrome due to myocardial ischemia characterized

by episodes of precordial discomfort or pressure, typically precipitated by exertion or stress and relieved by rest or drugs.

Types• Exertional angina, (or angina of effort, Stable,) which is

typically triggered by physical activity, persists few minutes and subsides with rest

• Unstable when there is an increased frequency, intensity or duration of attacks, or changes in precipitating factors.

• Vasospastic angina (or Prinzmetal’s angina, or variant angina) which tends to occur regularly at certain times of the day and is characterized by pain at rest.

Pathophysiology of AnginaAngina pectoris occurs when the O2 needs of the heart are not met.The myocardial O2 demand increases when there is an increase in:– heart rate– myocardial contractility– peripheral resistance– ventricular volume– Ejection time

1. Nitrates and nitrites • Amyl nitrite, Nitroglycerine, Isosorbide mononitrateMechanism of action: • Nitrates are denitrated (by glutathione S-transferase),

thereby releasing free nitrite ions (this reaction requires -SH groups).

• Nitrite ion is converted to nitric oxide (NO), which activates a cytosolic form of guanylyl-cyclase (this reaction requires -SH groups).

• cGMP synthesis is increased in smooth muscle.

Nitrate Nitrite NO cGMP

• Effect: 1. Cause smooth muscle relaxation 2. NO stimulates guanylyl-cyclase in platelets and

inhibit platelet aggregation 3. A decreased availability of tissue -SH groups

reduces the action of nitrates (at least partially).

PharmacodynamicsA. Cardiovascular actions1) After therapeutic doses:Marked relaxation of large veins (the main effect) which leads to:

a. Decreased preload and cardiac output (in the absence of cardiac failure).

b. Decreased blood pressure (slightly).c. Improved perfusion of subendocardial regions (due

to the lowering of left ventricular end-diastolic pressure, which reduces subendocardial compression

1) After therapeutic doses: (continued)Relaxation of large arteries (less pronounced than vein relaxation) which leads to increased blood flow in:

a. The skin (face and thorax) and the brain.b. Large epicardial vessels c. Large collateral vessels (perfusion of ischemic

regions is increased)2) After higher doses:

Relaxation of all segment of the vascular system which leads to:

d. Reflex tachycardia and reflex increase in cardiac contractility

e. Postural hypotension

Other actions• Relaxation of smooth muscle of the bronchi, the biliary

system, the GIT and genitourinary tract. • Decreased platelet aggregation (likely due to the

increase in cGMP)• Increased methemoglobin formation (with nitrites,

not with therapeutic doses of nitrates) due to the formation of nitrite ion that can oxidize the ferrous ion of hemoglobin to the ferric state.

PharmacokineticsBioavailability: • Oral: generally low (but isosorbide mononitrate > 95%)• Sublingual: 10-60 %• Transdermal: 50-90 %

Distribution• In all body tissues including brain.Biotransformation• > 99%, mainly in liver (by a high capacity nitrate-

reductase).

Nitrates Tolerance and Dependence• Frequently repeated exposures to nitrates leads to a

decrease in most of their pharmacological effects.• Tolerance to a nitrate results in tolerance (at least partial) to

all other compounds of the class.• The amount of tolerance is a function of the dosage and

the frequency of administration, and it exhibits a very high individual variability.

• Since tolerance appears rapidly (24 hours) and disappears rapidly (6-10 hours), brief periods of no therapy (hours of overnight) can be sufficient to permit recovery.

• Nitrate can cause dependence. In fact sudden death or myocardial infarction have occurred after a few days' break in long-term exposure to an organic nitrate.

Duration of antianginal effect of nitrates

Adverse effects1. Central nervous system– Throbbing headache, Dizziness, vertigo, Syncope

2. Cardiovascular system– Flushing of the face, Palpitations, – Postural hypotension

3. Others– Methemoglobinemia (with nitrite, or with toxic doses

of nitrates) – Withdrawal reactions (digital vasospasm, coronary

spasms, MI)– Drug abuse (with amyl nitrite)

Contraindications and Precautions• Angina due to hypertrophic Cardiomyopathy• Constrictive pericarditis• Increased intracranial pressure• Severe hypotension (systolic < 90 mm Hg)• Hypovolemic states• Hyperthyroidism• Severe hepatic disease• Profound hypotension can occur if taken

concomitantly with sildenafil, a specific cGMP phosphodiesterase-5 inhibitor. The interaction can be life-threatening).

Therapeutic uses 1. Angina pectoris

A. Treatment of the acute attack. • Nitroglycerin (sublingual route) or amyl nitrite

(inhalant route). [pain is relieved; protection lasts 30-40 min].

B. prophylaxis• Nitroglycerin (oral, transdermal), other nitrates

(oral) [attacks are reduced or eliminated].

Main mechanisms of antianginal effects:A. In exertional angina: decreased myocardial O2

demandB. In variant angina: increased myocardial O2 supply

(they are not the treatment of choice)C. In unstable angina: The main mechanism is still

uncertain (decreased myocardial O2 demand, increased myocardial O2 supply, and decreased platelet aggregation, all might contribute to the therapeutic efficacy).

High doses may cause undesirable effects due to:D. reflex tachycardiaE. reflex increase in cardiac contractility

2. Heart failure• Unlike in normal subjects, nitrates can increase stroke

volume and cardiac output in patients with systolic heart failure (the decreased preload lowers the ventricular filling pressure, so allowing a more efficient ventricular contraction).

They are not used routinely in heart failure but can be used when:• Symptoms of pulmonary congestion predominate

(redistribution of blood volume away from the chest relieves the congestion. This improves exercise tolerance even when cardiac output is not increased)

• pulmonary edema occurs or is impending.

3. Myocardial infarction• It has been shown that IV infusion of nitrates lead only to a

minor reduction in short-term mortality.• Therefore they are not recommended for routine use, but it

is reasonable to use IV nitroglycerin in more complicated patients, such as those with impending heart failure or hypertension.

4. Cyanide poisoning• Amyl nitrite and sodium nitrite are sometimes used to

produce methemoglobin which can complex cyanide ion to form cyanomethemoglobin.

• Then IV sodium thiosulphate is used to convert cyanomethemoglobin to thiocyanate and methemoglobin.

2. Beta-blockers

1) Therapeutic doses of beta-blockers are effective in angina because:

a) They decrease cardiac O2 demand (the main mechanism) by:• Reducing heart rate• Reducing cardiac contractility• Lowering blood pressure

b) They increase myocardial perfusion in certain parts of the heart (mainly subendocardial regions) due to an augmented diastolic perfusion time.

Therefore:a) They are effective in chronic prophylaxis of exertional angina and in the acute treatment of unstable angina.b) They are not effective in variant angina (where instead they may be dangerous, by causing coronary vasoconstriction).

2) High doses may cause undesirable effects due to: increased end diastolic volume increased ejection time

NB: • Beta-blockers with sympathomimetic activity have

been clearly demonstrated to reduce mortality in myocardial infarction. They should be given early and continued indefinitely.

• Warning! withdrawal effects after chronic use of beta blockers in ischemic heart disease are well documented. In risk patients abrupt withdrawal may cause hypertension, angina, myocardial infarction, and sudden death.

3. Calcium channel blockers

• Calcium channel blockers bind to the L- type voltage-gated Ca++ channel in blood vessels and heart

Pharmacological effects: A. Cardiac actions(Only verapamil and diltiazem can cause these effects)• Decreased conduction • Increased refractoriness • Decreased automaticity (mainly in ischemic zones, by

preventing Ca++ overload).• Dose-dependent decrease of cardiac contractility.

B. Vascular actions(All Ca++ channel blockers can cause these effects)• Vasodilation (mainly in arterioles, where the calcium-

dependent tone of the smooth muscle is more pronounced).

• Some dihydropyridines have a relative vascular selectivity (nicardipine for cerebral and coronary vessels)

Other Actions

C. Other actions• Relaxation of bronchiolar, gastrointestinal and

uterine smooth muscle (modest).• Inhibition of insulin release (verapamil, nifedipine,

after very high doses)• Inhibition of platelet aggregation (in vitro)• Blockade of P-glycoprotein which is a multidrug

transporter associated with the development of drug resistance in cancer cells (verapamil).

Pharmacokinetics

Biotransformation> 99% in liver and other organs. Some metabolites are active.

Excretion< 1 % excreted by the kidney.

Half-life: very variable(Diltiazem: . 3 hours; amlodipine . 40 hours)

Adverse EffectsCentral Nervous System• Headache, Dizziness, lightheadedness, weakness Cardiovascular System• Flushing , Peripheral edema, Tachycardia, palpitations

Profound hypotension, Aggravation of myocardial ischemia (nifedipine)

• A-V block, bradycardia, arrhythmias (verapamil, diltiazem).• Ventricular fibrillation (verapamil, diltiazem, in patients

with accessory AV pathways)Other systems• Constipation, gingival hyperplasia (verapamil ) • Nausea, heart burn, abdominal pain.

Contraindications and PrecautionsCVS: A. Verapamil, diltiazem• Hypotension• Cardiogenic shock, systolic heart failure• SA and AV block, Ventricular tachycardia • Arrhythmias associated with Wolff-Parkinson-White

syndrome • Digoxin overdose B. Dihydropyridines• Hypotension, Myocardial ischemia Others: • GERD, constipation, fecal impaction

Therapeutic Uses1. Angina pectorisA. Exertional angina: • Mainly because they decrease myocardial O2

demand (due to decreased afterload, heart rate and contractility)

• Verapamil and diltiazem are the preferred drugs.• High doses may cause undesirable effects due to:

• Increased end diastolic volume• The increased ejection time

B. Variant angina • Mainly because they increase myocardial O2

supply (due to coronary vasodilation)• All calcium channel blockers are considered

drugs of choice• High doses of dihydropyridines may cause

undesirable effects due to:• Reflex tachycardia• Reflex increase in cardiac contractility

2. Unstable angina and myocardial infarction• During myocardial ischemia, an increase in Ca++ influx

(due to membrane depolarization) can trigger a secondary cellular damage.

• These drugs can reduce the rate of reinfarction and death in patients without heart failure.

3. Hypertrophic cardiomyopathy and diastolic heart failure• Diltiazem (alone or in combination with beta-blockers)

improves diastolic compliance by reducing myocardial contractility.

4. Cardiac arrhythmias5. Hypertension

6. Subarachnoid hemorrhage• nicardipine dilate cerebral vessels at doses that have

little effects in the periphery. Therefore they inhibit delayed reactive vasospasm arising from hemorrhage.

7. Raynaud's phenomenon

8. Migraine• They are sometimes used for migraine prophylaxis

(mechanism not established).

Antianginal Drug interactions

CI = Clinical importance

Combination Therapy1. Nitrates and B-blockers• Each blocks the adverse effect of the other• B-blockers – blocks the reflex tachycardia associated

with nitrates• Nitrates – attenuate the increase in the left

ventricular end diastolic volume associated with B-lockers by increasing venous capacitance

2. CCBs (dihydropyridines) and B-blockers• These two drugs produce decrease blood pressure• Useful in the treatment of exertional angina that is not

controlled adequately with nitrates and B-blockers• B-blockers – attenuate reflex tachycardia produce by

nifedipine3. Nitrates and CCB (dihydropyridines)• Useful in severe vasospastic 4. CCB, BB, nitrates• Useful in patients with exertional angina not controlled

by the administration of two types of anti-anginal agent.

Drug therapy of acute myocardial infarction

• Oxygen if hypoxic • Relief of pain: Morphine sulfate • Beta-blockers, Nitroglycerin, ACEIs or Angiotensin II

receptor blocker, antiplatelets (clopedogril , aspirin), statin

• Fibrinolytic therapy if STEMI: e.g. Streptokinase, Alteplase • Anticoagulants: low molecular weight heparin • Treatment of complications: (arrhythmias, heart failure

and cardiogenic shock) • Control of risk factors: Stop smoking; control

hypertension, diabetes mellitus and correction of plasma lipids, correct electrolyte disturbace.

Good luck