Download Antianginal (Anti-ischaemic) Drugs

Angina pectoris
 Angina pectoris is a clinical
syndrome characterized by
episodes of chest pain.
 It occurs when there is a
deficit in myocardial oxygen
supply (myocardial
ischemia) in relation to
myocardial oxygen demand.
 It is most often caused by
atherosclerotic plaque in the
coronary arteries but may
also be caused by coronary
vasospasm.
Coronary artery disease (CAD)
 The development and
progression of
atherosclerotic plaque is
called coronary artery
disease (CAD).
 Atherosclerotic plaque
narrows the lumen,
decreases elasticity, and
impairs dilation of
coronary arteries.
 The continuum of CAD
progresses from angina to
myocardial infarction.
Ischemic heart disease
 Coronary artery disease (CAD), also known as
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ischemic heart disease (IHD), is a group of diseases
that includes:
angina,
myocardial infarction,
sudden coronary death.
A common symptom is chest pain or discomfort which
may travel into the shoulder, arm, back, neck, or jaw.
Types of angina
There are three main types of angina:
 classic angina (stable, exertional)
 variant angina (Prinzmetal/Vasospastic)
 unstable angina
Stable (exertional) angina
 Attacks are predictably provoked
by exercise, emotion, eating or
coitus.
 is relieved by taking rest and
reducing the myocardial
workload.
 The underlying pathology is—
severe arteriosclerotic affliction of
larger coronary arteries
(conducting vessels)
 Drugs that are useful, primarily
reduce cardiac work (directly by
acting on heart or indirectly by
reducing preload and afterload).
Stable angina
 Classic anginal pain is usually described as substernal
chest pain of a constricting, squeezing, or
suffocating nature.
 It may radiate to the jaw, neck, or shoulder, down the
left or both arms, or to the back.
 The discomfort is usually brief, typically lasting 5
minutes or less until the balance of oxygen supply and
demand is restored.
Variant/Prinzmetal/Vasospastic angina
 Attacks occur at rest or during sleep and are
unpredictable.
 It often occurs at the same time each day.
 They are due to recurrent localized coronary
vasospasm.
 Drugs are aimed at preventing and relieving the
coronary vasospasm.
Unstable angina
 Unstable angina (also "crescendo angina“) this is a form of
acute coronary syndrome
 is defined as angina pectoris that changes or worsens.
 Severe attacks is mostly due to rupture of an atheromatous
plaque attracting platelet deposition and progressive
occlusion of the coronary artery (incomplete coronary
arterial occlusion).
 In contrast with stable angina, unstable angina has at
least one of these three features:
it occurs suddenly at rest (or with minimal exertion)
it is severe and of new onset
it occurs with a “crescendo pattern” (i.e., distinctly more
severe, prolonged, or frequent than before).
CLASSIFICATION
1. Nitrates
 (a) Short acting: Glyceryl trinitrate (Nitroglycerine)
 (b) Long acting: Isosorbide dinitrate (short acting by
sublingual route), Isosorbide mononitrate
2. β Blockers
Propranolol, Metoprolol, Atenolol
3. Calcium channel blockers
 (a) Phenylalkylamine: Verapamil
 (b) Benzothiazepine: Diltiazem
 (c) Dihydropyridines: Nifedipine, Felodipine,Amlodipine
4. Potassium channel opener
Nicorandil
5. Others
Dipyridamole, Trimetazidine, Ranolazine, Ivabradine,
Oxyphedrine
Antianginals
These drugs relieve anginal pain by:
 reducing myocardial oxygen demand
 increasing blood supply to the myocardium.
NITRATES
 Short acting: Glyceryl trinitrate (Nitroglycerine)
 Long acting: Isosorbide dinitrate,
Isosorbide mononitrate
 The only major action is direct smooth muscle relaxation
(vascular smooth muscle).
 Nitrates dilate veins more than arteries → preload on heart
is reduced → decreased cardiac work
 Nitrates also produce some arteriolar dilatation → slightly
decrease afterload on heart
Mechanisms of action
 Nitrates cause venous vasodilation by their conversion
to nitric oxide (NO) which are endothelium relaxing
factor (ERF).
At therapeutic doses, nitrates have two major effects:
 1)they cause dilation of the large veins → this
diminishes preload (venous return to the heart) →
reduces the work of the heart → a decrease in
myocardial oxygen demand
 2) Nitrates dilate the coronary vasculature →
increasing in blood supply to the heart muscle.
Pharmacokinetics
 The time to onset of action varies from one minute for
nitroglycerin to more than one hour for isosorbide
mononitrate.
 Significant first-pass metabolism of nitroglycerin
occurs in the liver.
 Therefore, it is common to give the drug either
sublingually or via a transdermal patch.
NITRATES
 Short-acting nitrates are used to abort angina attacks
that have occurred.
 Longer-acting nitrates are used in the prophylactic
management of the angina pectoris.
 For prompt relief of an ongoing attack of angina
precipitated by exercise or emotional stress, sublingual
(or spray form) nitroglycerin is the drug of choice.
 Used to relieve both exertional and vasospastic angina
Indications
 1. Angina pectoris
 2. Acute coronary syndrome (include unstable angina
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and non-ST segment elevation myocardial infarction)
3. Myocardial infarction
4. CHF and acute LVF
5. Esophageal spasm
6. Cyanide poisoning
Adverse effects
 These are mostly due to vasodilatation:
The most common adverse effect of all
nitrates is throbbing headache(60 % of
patients).
Postural hypotension
Facial flushing
Tachycardia
 Tolerance develops rapidly on continued use.
The most practical way to prevent nitrate
tolerance is to provide nitrate free intervals
everyday. This interval is typically 10-12 hours
usually at night because there is decreased
demand on the heart at that time.
Glyceryl trinitrate (Nitroglycerine)
 The sublingual route – for prompt relief of an attack of
angina (the drug of choice!!!!)
 It acts within 1–2 min (peak blood level in 3–6 min)
 t½ - 2 min
 A sublingual spray formulation acts more
rapidly than sublingual tablet.
 Intravenous infusion of GTN provides rapid, steady
plasma concentration. It has been successfully used for:
 unstable angina,
 coronary vasospasm,
 LVF accompanying MI,
 hypertension.
Nitroglycerine
 Nitroglycerin is indicated for the prophylaxis,
treatment and management of patients with angina
pectoris.
 One tablet should be dissolved under the tongue at the
first sign of an anginal attack.
 The dose may be repeated approximately every five
minutes until relief is obtained.
 If the pain persists after a total of 3-tablets in a 15minute period, it could be a symptom of the MI.
Long-acting nitrates
Isosorbide dinitrate
 is used to reduce the frequency and severity of acute
anginal episodes.
 Sublingually it acts in 2 minutes, and its effects last 2 to 3
hours.
 Therapeutic effects last about 4 hours after oral
administration.
Isosorbide mononitrate
 It is well absorbed after oral administration and almost
100% bioavailable.
 t½ - 5 hours.
 It is used only for prophylaxis of angina; it does not act
rapidly enough to relieve acute attacks.
Choice of Drug
 For relief of acute angina and prophylaxis before events
that cause acute angina, nitroglycerin (sublingual tablets or
translingual spray) is the primary drug of choice.
 Sublingual tablets of isosorbide dinitrate also may be used.
 For long-term prevention or management of recurrent
angina, oral or topical nitrates, beta-adrenergic blocking
agents, or calcium channel blocking agents are used.
 Clients taking one or more long-acting antianginal drugs
should carry a short-acting drug as well, to be used for
acute attacks.
Beta blockers
 Beta blockers are used in the long-term management of
stable (exertional) angina by reducing the myocardial
oxygen demand.
 Not for acute treatment!
 A slower heart rate improves coronary blood flow to the
ischemic area. Beta blockers also reduce blood pressure,
which in turn decreases myocardial workload and oxygen
demand.
 Long term β blocker therapy clearly lowers risk of sudden
cardiac death among ischaemic heart disease patients.
They are contraindicated in:
variant angina (they produce vasospasm)
heart failure
severe asthmatics
Calcium channel blockers
Act on :
 contractile and
conductive tissues of the
heart
As a result:
 myocardial contractility is
decreased, and the
conduction system is
depressed
 vascular smooth muscle.
 coronary and peripheral
arteries are dilated
Calcium channel blockers
Are used in the treatment of :
 chronic stable angina,
 most effectively in the treatment of variant angina (directly
preventing coronary artery vasospasm)
 Hypertension
 Cardiac arrhythmias
 They are not used in the treatment of unstable angina .
 They dilate the coronary and peripheral arteries →
decreasing afterload → reducing heart rate
 Dihydropyridines are vasodilators → more effective in
angina
CALCIUM CHANNEL BLOCKERS
 Nifedipine –functions mainly as an arteriolar
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vasodilator. This drug has no effect on heart rate. The
vasodilation effect of nifedipine is useful in the
treatment of variant angina caused by spontaneous
coronary spasm.
ADR: flushing, headeache, hypotension, and
peripheral edema as side effects of its vasodilation
activity. The drug may cause reflex tachycardia.
Verapamil slows cardiac conduction directly →
decreases heart rate and oxygen demand.
ADR: depressed cardiac function, CHF, AV block.
Diltiazem effects are similar to those of verapamil
and nifedipine
DRUG COMBINATIONS IN ANGINA
I. β blocker + long-acting nitrate combination is rational
in classical angina because:
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(a) Tachycardia due to nitrate is blocked by β blocker.
(b) The tendency of β blocker to cause ventricular dilatation is counteracted by nitrate.
(c) The tendency of β blocker to reduce total coronary flow is opposed by nitrate.
II.Slow acting DHP + β blocker
III. Nitrates (decrease preload)+ CCBs (effect on
afterload) This combination may be especially valuable in severe vasospastic angina,
and when β blockers are contraindicated.
IV. In the more severe and resistant cases of classical
angina, combined use of all the three classes is
indicated:
 Nitrates (decrease preload) + DHP (reduce afterload)
+ β blockers (decrease cardiac work)
POTASSIUM CHANNEL OPENERS
 Nicorandil
 Arterial dilatation is coupled with venodilatation.
 No cardiac effects.
Use:
 in stable angina
 in vasospastic angina
ADR;
 flushing,
 palpitation,
 headache,
 Dizziness
 Large painful aphthous ulcers in the mouth
OTHER ANTIANGINAL DRUGS
Dipyridamole
 It is a powerful coronary dilator
 BUT !!!! It fails to relieve anginal symptoms
 The pharmacological success but therapeutic failure of
dipyridamole has been explained on the basis of
‘coronary steal’ phenomenon. By dilating resistance
vessels in nonischaemic zone as well, it diverts the
already reduced blood flow away from the ischaemic
zone.
Trimetazidine
 The first cytoprotective anti-ischemic agent
 Use just as an additional treatment of angina pectoris in
patients not adequately controlled by first-line
antianginal therapies (nitrate/β blocker/CCB)
 Optimizing cellular energy processes → maintaining
proper energy metabolism during ischaemia (preserving
energy metabolism in cells exposed to hypoxia or
ischaemia)
 Anginal attacks frequency is reduced and exercise
capacity is increased
 For ischaemic heart disease, it is widely used in France,
Spain, some other European countries and India, but not
in the UK or USA.
Ivabradine
 ‘Pure’ heart rate lowering antianginal - an alternative to β
blockers.
 The only significant action is blockade of cardiac pacemaker
(sino-atrial)
 Heart rate reduction decreases cardiac O2 demand
 To improve exercise tolerance in stable angina and reduce
angina frequency.
ADR:
excess bradycardia,
important adverse effect is visual disturbance.
 Ivabradine is indicated in chronic stable angina in patients
with sinus rhythm who are intolerant to β blockers or when
they are contraindicated.
DRUG THERAPY IN MYOCARDIAL
INFARCTION
 Myocardial infarction (MI) is ischaemic necrosis of a
portion of the myocardium due to sudden occlusion of
a branch of coronary artery.
 An acute thrombus at the site of atherosclerotic
obstruction is the usual cause.
 About ¼ patients die before therapy can be instituted.
 The remaining are best treated in specialized coronary
care units with continuous monitoring of the
haemodynamic parameters, biochemical markers and
ECG to guide the selection of drugs and dosage.
 1. Pain
 After pain is not relieved by 3 doses of GTN given 5 min apart, an
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opioid analgesic (morphine/pethidine) is administered
parenterally.
2. Oxygenation
3. Prevention and treatment of arrhythmias -i.v. Lidocaine or
amiodarone
4. Reduce the infarct size -β blockers
5. Bradycardia and heart block - atropine or electrical pacing
6. Pump failure
(a) Furosemide: indicated if pulmonary wedge pressure is > 20
mm Hg. It decreases cardiac preload.
(b) Vasodilators: venous or combined dilator like GTN (i.v.), or
nitroprusside have been mainly used.
(c) Inotropic agents: dopamine or dobutamine i.v.
7. Prevention of thrombosis - Aspirin
Prevention of future attacks
 Platelet inhibitors—aspirin or clopidogrel given on
long-term basis are routinely prescribed
 β blockers—reduce risk of reinfarction, CHF and
mortality. All patients not having any contraindication
are put on a β blocker for at least 2 years.
 Control of hyperlipidaemia—dietary substitution with
unsaturated fats, hypolipidemic drugs especially
statins