Verapamil

It is a diphenylalkylamine.

Action:
It causes a decrease in the AV conduction of the heart leading to decreased heart rate and demand for oxygen. It also causes a decrease in the firing time of the sinus node pacemaker.

It has more negative inotropic effect as compared to nifedipine but has weak vasodilation effect.

Verapamil may also produce local anesthetic action (due to less effective blockade of sodium channels).

Verapamil also cause inhibition of insulin release.

Pharmacokinetics:
The drug shows hepatic metabolism.

Administration:
Orally, Intravenously

Therapeutic uses:
It is used for supraventricular tachyarrhythmias.

Adverse effects:
Constipation

Contraindications:
It is contraindicated in:
1. Patients with already decreased cardiac function.
2. Patients with abnormalities of atrioventricular conduction.

Precautions:
It should be used with caution in patients with liver function abnormalities.
It should also be used with caution in patients taking digoxin as it may increase digoxin level.

Nifedipine

It is a dihydropyridine derivative.


Actions:
It causes vasodilation of the arteries. It may cause peripheral vasodilation resulting in the decrease of total peripheral vascular resistance, resulting in decline of blood pressure declining oxygen requirement of the heart muscles.

It rarely affects on cardiac conduction or heart rate.

It may also decrease insulin secretion.


Dosage and administration:
It is administered orally and is available as extended release tablets.

Pharmacokinetics:
It undergoes hepatic metabolism and the metabolites (metabolism products) are excreted in urine and feces.

Therapeutic uses:
It is Useful in the treatment of variant angina (due to spontaneous coronary spasm).

Adverse effects:
Flushing, headache, hypotension, reflex tachycardia, peripheral edema, constipation,

Amlodipine

It does not affect the heart rate or cardiac output.

Structure:

Credit: Rxlist

Other names:

• Amlodipine Benzenesulfonate
• Amlodipine Besilate
• Amlodipine Besylate
• Amlodipine Free Base
• Amlodipino [Spanish]
• Amlodipinum [Latin]

Pharmacokinetics:
Its half life is 34 hours.

Therapeutic uses:
It is used for vasospastic chronic stable angina and hypertension.

Brand Names:

• Amlip (Venezuela)
• Amlocard (AWD (Germany))
• Amlodis (Eczacibasi (Turkey))
• Amlomed
• Amlopick
• Amvaz (Reddy (Malaysia))
• Coroval (Sandoz (Argentina))
• Lipinox  (Commonly misspelled Lipinok, Lepenox,Lilinox,Lipinux)
• Norvasc (Pfizer)

Also available in the following brands:

• Azor (amlodipine + olmesartan)
• Caduet (amlodipine + atorvastatin)
• Coroval B (amlodipine + benazepril)
• Exforge (amlodipine + valsartan)
• Lotrel (amlodipine + benazepril)

 
References:
Amlodipine on http://www.drugbank.ca/drugs/DB00381  Updated on November 10, 2010. Accessed April 17, 2011.

Calcium

Role of calcium:

Calcium is one of the essential components for contraction of muscles. Calcium is also responsible for the excitation-secretion coupling in exocrine and endocrine glands.

Calcium channels:

Calcium got entry into cells through pores in the membrane. These particular pores are named as calcium channels.

Types of calcium channels:

Action of calcium:

The calcium influx is elevated in ischemia as a result of membrane depolarization that is caused by reduced oxygen supply. This depolarization is voltage operated and is done by L- type channels. This increase results in the rise of activity of many ATP-consuming enzymes resulting in the reduction of energy stores. This leads in increase of ischemic effects.

Sometimes channels are opened by receptors for neurotransmitters and therefore this activation is referred to as receptor operated.

Mechanism of action of calcium entry blockers:

Calcium entry blockers get stick to receptors on voltage gated calcium channels resulting in blockage of these channels and saving tissues by preventing the entry of calcium into smooth muscle cells of the systemic arterial beds and muscle cells of coronary arteries (of the heart). Thus they reduce myocardial oxygen demand by saving ATP of muscles of the heart.

Some of the calcium entry blockers cause arteriolar dilatation; resulting from the decreased oxygen demand of the heart muscles, by affecting the heart directly i.e. causes the heart to beat slowly. They are, therefore, also working as vasodilators resulting in the decrease in smooth muscle tone and vascular resistance.

Actions:

Calcium entry blockers work better when the tissue is depolarized. At therapeutic doses, these agents affect on the resistance of vascular smooth muscle and the muscles of the heart.

They also decrease blood pressure.

They have negative chronotropic and inotropic effect resulting in less oxygen demand.

The prominent effect (anti-anginal) in angina caused by exercise and unstable angina is achieved by the reduction in cardiac afterload. On the other hand, vasospastic angina is relieved by dilatation of the coronary arteries and arterioles.

Calcium plays essential role in


1. contraction of muscles of the heart
2. regulating the firmness of the smooth muscles

Calcium get entry to the muscle cells through special channels namely voltage gated calcium channels. As a result, the release of calcium from the sarcoplasmic reticulum and mitochondria is initiated. This causes an additional elevation in the level of calcium in the fluid part of the cytoplasm (cytosol).
Therapeutic Uses:
They are also used in:
1. Systemic hypertension
2. Peripheral vascular disease
3. Hypertrophic subaortic stenosis
4. Stroke
5. Migraine
6. Suppression of atherogenesis

Adverse effects:
Hypotension, Headache, flushing, dizziness (These are caused by vasodilatory effects of calcium entry blockers).
Bradycardia (This is caused by less SA automaticity).
Heart block (This may be caused by reduced AV conduction).
Congestive heart failure (may be due to reduced contraction of the heart muscle).

Constipation (may be due to gentle excitation-contraction uncoupling in GI smooth muscle).

Calcium entry blockers

Much of the calcium entry blockers are dihydropyridines.

Clacium entry blockers include Amlodipine, Bepridil, Diltiazim, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine, Verapamil

Mechanism of action:

They get bind to receptors present on L-type calcium channels (voltage gated calcium channels) resulting in the blockage of calcium channels in the heart and in the smooth muscles of the coronary and peripheral vessels. This causes inhibition of calcium inflow to the cardiac and smooth muscle cells resulting in relaxation of muscles.

Actions:

Calcium channel blockers cause relaxation of the arterioles and veins but relaxation is more pronounced in arterioles than in the veins.

Calcium channel blockers causes dilatation of the coronary arterioles and coronary arteries and reduction of coronary artery spasm. This results in elevated oxygen supply to the muscles of the heart in patients with variant angina.

On the other hand, dilatation of the peripheral arterioles causes a decrease in total peripheral vascular resistance leading to decreased blood pressure. This affect is mainly caused by nifedipine. This causes a decrease in oxygen requirement of the muscles of the heart.

All of these factors are responsible for less oxygen requirement in patients with angina:

1. Reduced generation of impulses in SA node and reduced conduction in AV node

2. Reduced cardiac contractility and output

Verapamil and diltiazim show more pronounced effects on the heart.

Verapamil blocks release of insulin.

Verapamil blocks sodium channels less effectively, so that is why it has slight local anesthetic activity.

Pharmacokinetics:
They have a half life of about 2.5-8 hours, when used orally.

Therapeutic uses:
In hypertension when accompanied by angina, diabetes and/or asthma.

They are also used for angina pectoris, hypertrophic cardiomyopathy, migraine and atherosclerosis.

Verapamil is used to treat migraine, angina and supraventricular tachyarrhythmias.

Adverse effects:
They may cause dizziness, bradycardia, cardiac arrest, hypotension, nausea, constipation (in about 10% of patients), flushing and headache.

Contraindications:
These are contraindicated in patients with
1. cardiogenic shock
2. severe hypotension

Classification of Anti-Anginal Drugs

Classification according to differences in agents/groups:

Organic nitrites and nitrates:
Nitrites:
Amylnitrite,

Nitrates:
Erythrityl tetranitrate, Isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, Pentaerythritol tetranitrate

β adrenoceptor blockers:
Nonselective β adrenoceptor blockers:
        Propranolol, Timolol, Nadolol
Selective β1 adrenoceptor blocker:
        Acebutolol, Atenolol, Metoprolol, Esmolol

Ca2+ entry blockers:
Amlodipine, Bepridil, Diltiazim, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine, Verapamil

Other vasodilator agents:
Dipyridamole, Nylidrin

Miscellaneous agents:
Camphotamide, Prenylamine

Plant products:
Papaverine

Classification according to types of angina pectoris:
Stable angina:
Nitroglycerin,

Variant angina:
Nitroglycerin, calcium entry blockers

Angina

It refers to a severe type of pain from any cause usually angina pectoris is considered.

Angina pectoris:
It is type of condition in which heart lacks blood supply resulting in severe constricting pains in the chest. The pain of angina pectoris often develops and spreads from the precordium of the heart to a shoulder (usually left) and down in the arm (of left side).

Cause of angina:
It may be due to ischemia of the myocardium usually produced as a result of coronary heart disease.

Types of angina:
It may be of different types:

1. Classical angina:
This is also referred to as angina of effort or exercise induced or stable angina or typical angina.
Symptoms:
It is marked by feeling of squeezed chest as well as burning in the chest.
Mechanism:
It may be due to blockage of the large coronary vessels leading to reduced coronary perfusion. This blockage may be caused by lipid deposits in the vessels.

2. Variant angina:

It is also called as vasospastic or prinzmetal’s angina. This often occurs at rest.

Mechanism:
1. It is caused by coronary artery spasm.
2. It also occurs as a result of less flow of blood to the muscles of the heart.

3. Unstable angina:

It occurs fewer than other types of angina and its cause is not among other causes of angina. It is in between stable angina and myocardial infarction. This often occurs at night in bed.

Stable Angina ---------- Unstable Angina ----------- Myocardial Infarction

Treatment of angina:

Angina is treated by any/both of the following mechanisms:
1. Promote perfusion of the muscles of the heart
2. Less metabolic demand of the muscles of the heart

Less requirement of oxygen in patients with angina is done by one of the following mechanisms:
1. Less generation of impulses in SA node
2. Reduced conduction velocity in AV node and Purkinje cells
3. Reduced contractions of the heart muscles
4. Reduced cardiac output.

Classification of Anti-Anginal Drugs