ANTI- ANGINAL DRUGS

CONTENT

Anti anginal drugs Angina pectoris Types Classification Nitrates Calcium channel

blockers b blockers Combination therapy

ANTI-ANGINAL DRUGS

Antianginal drugs may relieve attacks of acute myocardial

ischemia by increasing myocardial oxygen supply or by decreasing myocardial oxygen demand Three groups of pharmacological agents have been shown to be effective in reducing the

frequency, severity, or both of primary or secondary angina. These agents include the nitrates, adrenoceptor

antagonists, and calcium entry blockers. To understand the beneficial actions of these

agents, it is important to be familiar with the major factors regulating the balance between

myocardial oxygen supply and demand.

ANGINA PECTORIS

It is the principal symptoms of patient with ischemic heart disease.

Manifested by sudden, severe, pressing substernal pain that often radiates to the left shoulder and along the flexor surface of the left arm.

Usually precipitated by exercise, excitement or a heavy meal.

TYPES OF ANGINA PECTORIS

NITRATES

Classification of nitrates:1. Rapidly acting nitrates

* used to terminate acute attack of angina * e.g.- Nitroglycerin and Amyl nitrate * usually administered sublingually

2. Long acting nitrates * used to prevent an attack of angina * e.g. – tetra nitrate, Iso sorbide di nitrate,

Penta erythrytol tetra nitrate * administered orally or topically

ORGANIC NITRATES

Organic nitrates & nitrites are simple nitric & nitrous esters of glycerol.

These agents cause a rapid decrease in myocardial oxygen demand leading to rapid resolution of symptoms.

Nitrates are effective for all types of angina.

Activation of guanylate cyclase increases cGMP activating a cGMP kinase leading to dephosphorylation of myosin light chains decreasing contractile force.

1ST MECHANISM OF ACTION

Coronary artery dilatation

Decrease coronary bed resistance (Relieved coronary vasospasm)

Increase coronary blood flow

Increase oxygen supply

2ND MECHANISM OF ACTION

Reduction on peripheral resistance(Secondary to dilatation of aorta)

Decrease blood pressure

Decrease after load

Decrease workload

Decrease oxygen consumption

3RD MECHANISM OF ACTION

Reduced venous return(Due to dilatation of the veins)

Decrease left ventricular volume

Decrease preload

Decrease workload

Decrease oxygen consumption

ROUTE OF ADMINISTRATION

1. Sublingual route – rational and effective for the treatment of acute attacks of angina pectoris. Half-life depend only on the rate at which they are delivered to the liver.

2. Oral route – to provide convenient and prolonged prophylaxis against attacks of angina

3. Intravenous Route – useful in the treatment of coronary vasospasm and acute ischemic syndrome.

4. Topical route – used to provide gradual absorption of the drug for prolonged prophylactic purpose.

Drug Usual single dose Route of administration

Duration of action

Short actingNitroglycerin

0.15-1.2 mg sublingual 10 - 30 min

Isosorbide dinitrate 2.5-5 mg sublingual 10 – 60 min

Amyl nitrite 0.18 – 3 ml inhalation 3 – 5 min

Long actingNitroglycerin sustained action

6.5 – 13 mg q 6-8 hrs oral 6 – 8 hrs

Nitroglycerin 2% ointment

1 – 1.5 inches q hr topical 3 – 6 hrs

Niroglycerin slow released

1 –2 mg per 4 hrs Buccal mucosa 3 – 6 hrs

Nitroglycerin slow released

10 – 25 mg /24hrs (one patch/day}

transdermal 8 –10 hrs

Isosorbide dinitrate 2.5 – 10 mg per 2 hrs sublingual 1.5 – 2 hrs

Isosorbide dinitrate 10 –60 mg per 4-6 hrs oral 4 – 6 hrs

Isosorbide dinitrate chewable

5 – 10 mg per 2-4 hrs oral 2 – 3 hrs

Isosorbide mononitrate 20 mg per 12 hrs oral 6 –10 hrs

EFFECTS

1. Coronary artery dilatation2. Reduction of peripheral arterial

resistance – decrease after load3. Reduce venous return – decrease

preload

PHARMACOKINETICSThe difference between nitrate preparations is

mainly in time of onset of action. Nitroglycerin suffers marked 1st pass

metabolism so administration is sublingual. t1/2 ~10 minutes. Occasionally as nitroglycerin is metabolized

anginal symptoms will return. Transdermal administration either as patch or

paste provides a depot of agent for a steady availability.

Nitro-Bid is an oral or topical preparation which saturates the hepatic catabolic pathways allowing a prolonged level of nitroglycerine.

Isosorbide mono nitrate & Isosorbide di nitrate are long acting nitrates that are relatively resistant to hepatic catabolism ……t1/2 ~ 1 hour.

ADVERSE EFFECTS

1. Throbbing headache2. Flushing of the face3. Dizziness – especially at the

beginning of treatment4. Postural Hypotension – due to pooling

of blood in the dependent portion of the body

CONTRAINDICATIONS

1. Renal ischemia2. Acute myocardial infarction3. Patients receiving other

antihypertensive agent

BETA- BLOCKERS

β-Blockers decrease oxygen demands of the myocardium by lowering the heart rate and contractility (decrease CO) particularly the increased demand associated with exercise.

They also reduce PVR by direct vasodilatations of both arterial & venous vessels reducing both pre- and after load.

These effects are caused by blocking β1 receptors, selective β1 antagonists (atenolol, metoprolol ) lose their selectivity at high doses and at least partially block β2 receptors.

β1 antagonists reduce the frequency and severity of anginal episodes particularly when used in combination with nitrates.

β1 antagonists have been shown to improve survival in post MI patients and decrease the risk of subsequent cardiac events & complications.

There are a number of contraindications for β blockers: asthma, diabetes, bradycardia, PVD & COPD.

β-Blockers in combination with nitrates can be quite effective

HEMODYNAMIC EFFECT

1.  Decrease heart rate2. Reduced blood pressure and cardiac

contractility without appreciable decrease in cardiac output

MECHANISM OF ACTION

Decrease heart rate & Contractility

Increase duration of diastole Decrease

workload Increase coronary blood flow Decrease

oxy.consumptionIncrease oxygen supply

CONTRAINDICATIONS

1. Congestive heart failure2. Asthma3. Complete heart block

CALCIUM CHANNEL BLOCKERS Ca+2 channel blockers protect tissue by inhibiting the

entrance of Ca+2 into cardiac and smooth muscle cells of the coronary and systemic arterial beds.

All Ca+2 channel blockers produce some vasodilation (↓ PVR) and (-) inotropes.

Some agents also show cardiac conduction particularly through the AV node thus serving to control cardiac rhythm.

Some agents have more effect on cardiac muscle than others but all serve to lower blood pressure.

CHF patients may suffer exacerbation of their failure as these are (-) inotropes.

They are useful in Prinzmetal angina in conjunction with nitrates.

AGENTS

Nifedipine: This Ca+2 channel blocker works mainly on the

arteriolar vasculature decreasing after load it has minimal effect of conduction or HR.

It is metabolized in the liver and excreted in both the urine & the feces.

It causes flushing, headache, hypotension and peripheral edema.

It also has some slowing effect on the GI musculature resulting in constipation.

A reflex tachycardia associated with the vasodilatation may elicit myocardial ischemia in tenuous patients, as such it is generally avoided in non-hypertensive coronary artery disease.

VERAPAMIL

The agents has its main effect on cardiac conduction decreasing HR and thereby O2 demand.

It also has much more (-) inotropic effect than other Ca+2 channel blockers

It is a weak vasodilator. Because of its focused myocardial effects it is

not used as an antianginal unless there is a tachyarrhythmia. It is metabolized in the liver.

It interferes with digoxin levels causing elevated plasma levels; caution and monitoring of drug levels are necessary wit concomitant use.

DILTIAZEM

This agent function similarly to Verapamil however it is more effective against Prinzmetal angina.

It has less effect on HR. It has similar metabolism and side

effects as Verapamil.

Drugs Onset of action Peak of action Half-life

Nifedipine 20 minutes 1 hour 3-4 hours

Verafamil 1-2 hours 5 hours 8-10 hours

Diltiazem 15 minutes 30 minutes 3-4 hours

Nicardifine 20 minutes 45 minutes 2-4 hours

Felodipine 2-5 hours 6-7 hours 11-16 hour

pharmacokinetics

ADVERSE EFFECT

Nausea and vomiting Dizziness Flushing of the face Tachycardia – due to hypotension

CONTRAINDICATIONS

Cardiogenic shock Recent myocardial infarction Heart failure Atria-ventricular block

COMBINATION THERAPY

1. Nitrates and B-blockers The additive efficacy is primarily a

result of one drug blocking the adverse effect of the other agent on net myocardial oxygen consumption

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

CALCIUM CHANNEL BLOCKERS +BETA BLOCKERS

Useful in the treatment of exertional angina that is not controlled adequately with nitrates and B-blockers

B-blockers – attenuate reflex tachycardia produce by nifedipine

These two drugs produce decrease blood pressure

CALCIUM CHANNEL BLOCKER+NITRATES

Useful in severe vasospastic or exertional angina (particularly in patient with exertional angina with congestive heart failure and sick sinus syndrome)

Nitrates reduce preload and after load Ca channels reduces the after load Net effect is on reduction of oxygen

demand

TRIPLE DRUGS:-NITRATES+CALCIUM CHANNEL BLOCKERS+BETA BLOCKER

Useful in patients with exertional angina not controlled by the administration of two types of anti-anginal agent

Nifidipine – decrease after load Nitrates – decrease preload B-blockers – decrease heart rate &

myocardial contractility

ANJALI KOTWAL5TH SEMESTER B.PHARMACYSHOOLINI UNIVERSITY

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