Anti-Anginal Drugs

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Angina pectoris—it is a common disease (ischaemic heart disease) affecting the middle aged persons, usually males.

Angina→ pain, Pectoris→ chest.

Definition—it is a clinical condition where there is chest pain due to transient ischaemia resulting due to imbalance in O2 supply and O2 demand.


Causes of pain—

1. Atherosclerotic narrowing of the epicardial arteries (fat deposition in the sub-endothelial region/tunica intima)

2. Prinz metal angina / variant angina—due to spasm of the epicardial arteries.

3. Severe left ventricular hypertrophy where demand of the hypertrophied myocardium is so great that coronary blood supply fails to meet the demand.

4. Thrombosis.

5. Other less important causes are—

a.    Narrowing of the coronary ostea.

b.   Congenital anomaly and so forth.


*** A transient ischaemia is produced due to underlying disease, as a result myocardial cells suffer from ischaemia and ischaemic pain is felt.


Precipitating factors—

1. Heavy meal

2. Intense physical exercise

3. Intense emotion

4. Cold exertion


Risk factors—smoking, HTN, diabetes, hypercholesterolemia


Basically there are two things to be considered—

1. The requirement that is the O2 demand of the heart.

2. The O2 supply via the coronary blood flow.

Obviously fall of O2 supply or rise of O2 demand or combination of both can precipitate an anginal attack.


Preload—venous return to the heart.

Afterload—arterial side of the heart (the aorta and the branches, blood pumped out)

*** the TPR determines the afterload


Factors determining cardiac output—

1. HR

2. Force of contraction

3. Preload (increases in fluid overload)

4. Afterload (increases in valvular disease and increased PR)

*** if the angina persists for more than 30 min with other sign symptoms such as sweating, palpitation, then it is MI.

*** diabetic patients are sometimes not aware of cardiac pain


Unstable angina—when anginal pain is felt even at rest without any provocation then it is called unstable angina.


Basic steps of treatment—

1. To give symptomatic treatment

2. To cure the underlying cause

3. Remove the risk factors


Pharmacotherapy of atherosclerotic angina / anti-anginal drugs—

These are divided into 3 groups (all drugs basically reduces the O2 demand of the heart)—

a. Nitrates

b. Calcium channel blockers

c.  β-blockers

Nitrates—reduce the O2 demand by venodilatation, thus reducing the preload of the heart. They also dilate epicardial arteries and to some extent reduce the after load.

Calcium channel blockers—cause systemic arteriolar dilatation resulting in ↓ PR. So there is fall of BP and after load decreases. They also dilate the epicardial arteries.


β-blockers—works by reducing the tachycardia and/or contractility—thus work done by the heart is reduced.


*** epicardial arterial dilatation is well marked with calcium channel blockers, so they are popularly used in prinz metals angina where there is spasm of the epicardial arteries.



NITRATES (Nitro-vasodilators)—

Theses are simple nitrous or nitric acid esters of poly alcohol. The prototype is nitroglycerine/GTN


Nitro-vasodilators can be,

1. Nitrites—

Amyl nitrites (almost obsolete)

2. Nitrates—

Glycerin tri-nitrate (GTN)

Iso-sorbide di-nitrate

Iso-sorbide mono nitrate

Erithrityl tetra-nitrate


Nitrates and nitrites with their route of administration—

Amyl nitrate—



Glycerin tri-nitrate—

Sublingual (Angist tab)

Trans-dermal patches

Per cutaneous


Iso-sorbide di-nitrate—





Iso-sorbide mono-nitrate—



Erithrityl tetra-nitrate—





*** in emergency nitrate spray can be given.

*** we usually do not give nitrate orally as there is extensive first pass metabolism→ ↓ bioavailability→↓ efficacy.


Nitrates can be used as anti-anginal drug for the following purpose—

1. To abort an attack (when pain already started), for this purpose short acting nitrate given sublingually is very effective.

2. Just before an anticipated but unavoidable stress which is likely to precipitate angina. Ex—physical exertion, heated argument.

3. Long term prophylaxis, drug is routinely given.


Short acting nitrates—

     i.   GTN

   ii.   Iso-sorbide di-nitrate when given sublingually

iii.   Erithrityl tetra-nitrate when given sublingually


Long acting—

     i.   Iso-sorbide di-nitrate when given orally

   ii.   Iso-sorbide mono-nitrate when given orally

iii.   Nitroglycerine ointment


Mechanism of Action of nitrates (gross organ level)—

Nitrates cause relaxation of the vascular smooth muscles particularly venodilatation, thus reduces the pre-load (venous return to the heart). So there is reduction in the ventricular cavity diameter and reduction in the ventricular wall stretching. As a result there is fall of O2 demand.

Fall of BP due to arteriolar relaxation caused by small or lower dose of nitrates are compensated via sino-aortic reflex which causes tachycardia and vasospasm, thus correcting the BP.

At higher doses the compensatory mechanism cannot prevent fall of BP. So there is fall of afterload.

Nitrates can also dilate epicardial arteries.


Mechanism of Action of nitrates (at molecular level)—

The di-nitrates taken are converted into mono-nitrates in the body (liver). Mono-nitrates within the vascular wall are converted first into nitrous oxide then into nitric oxide which is a potent vasodilator.

{From the vascular smooth muscle the nitric oxide is released and activates the Guanylil cyclase present in the endothelium. Active G cyclase converts GTP into GMP which is a 2nd messenger. GMP causes dephosphorilation of the myosin light chain kinase (MLCK) which causes vasodilatation}

Conversion of nitrous oxide into nitric oxide requires the presence of sulph-hydril (SH) group of glutathione. So if nitrites are used for prolong period the SH group will be used up. So further conversion of nitrous oxide to nitric oxide will not be possible and tolerance will develop.


Because of vasodilatation some adverse effects can be seen—

1. Headache (due to meningeal vasodilatation)

2. Throbbing sensation within the head (intracranial vasodilatation)

3. Flushing of the face

4. Palpitation (due to reflex tachycardia)

5. Orthostatic hypotension (due to peripheral pulling of blood)


Clinical uses of nitrates—

1. angina pectoris

2. heart failure

3. acute hypertension (IV nitroglycerin)

4. acute myocardial infarction (in this case the drug is used cautiously and by specialist)

5. cardiac arrhythmia

6. migraine

7. hyperthyroidism (T3 and T4 increases the number of β1 receptors in the heart)


Nitrate tolerance—it is a condition associated with the use of long acting nitrates (mono and di) in which there may be sustained elevation in the blood concentration of the nitrates. If we give drugs at 6-8 hours interval (drug free period) then we can avoid this phenomena. It is mainly associated with the reduction of vascular smooth muscle SH (sulph-hydril) group.


Individual drugs—



1. Available as tablets (sublingual) 300-600μgm and used as the drug of choice in angina pectoris.

2. Oral (buccal/swallow) formulation of 1-5mg. these are sustained release preparations.

3. Metered oral spray in acute condition (given under the tongue and then mouth is closed).

4. Formulation applied via skin available in patches or ointment, used for prophylaxis.


Iso-sorbide di-nitrate—

1. Oral formulation (½ life is 20min).

2. Used as prophylaxis for angina.

3. Have extreme first pass metabolism and less systemic availability than mono-nitrates.

(Breaks down into mono-nitrates in the body).


Iso-sorbide mono-nitrate—

1. Oral formulation (½ life is 4hrs).

2. Has less extensive first pass metabolism but more systemic availability.

3. Used in prophylaxis of angina.



Afterload reducers—relaxation of the arterial vascular smooth muscle.

Ex—Hydralazine, Diazoxide, Minoxidin, Ca++ channel blockers.


Preload and afterload reducers—relaxes the vascular smooth muscle of both arteries and veins.

Ex—ACE inhibitors, Nitroprusside, Nitrates (mainly relaxation of the veins)


Ca++-channel blocker—

They are used in—angina, hypertension, supra-ventricular tachycardia.



According to the chemical structure—

1.      Phenyl alk-amines—Verapamil.

2.      Di-hydro pyridines—Nifedipine, Amlodipine, Nicardipine, Felodipine, Nimodipine.

3.      Benzodiazepine—Diltiazem.


According to the generation—

1.      First generation (older)—Verapamil, Nifedipine, Diltiazem.

2.      Second generation (newer)—

                                                              i.   Amlodipine (ultra long acting, half life is 36 hrs)

                                                           ii.   Felodipine and Isradipine (intermediate acting, half life is 8 hrs)

                                                         iii.   Nicardipine (short acting, half life is 4 hrs)


*** they differ in pharmacokinetics—they are absorbed well but suffers hepatic first pass metabolism, thus bioavailability is not good. Bioavailability can increase in two conditions—

i.        hepatic damage

ii.     when used in high doses because degrading enzymes are saturated

usually 2nd generation drugs have longer plasma half life.



Mechanism of Action—

1.      At gross level calcium channel blockers cause relaxation of the vascular smooth muscle. It may decrease the myocardial contractility. Influences the development of pace making by SA node and AV node.

2.      At molecular level they act on tissue where the development of action potential is largely dependent on entry of calcium from ECF to ICF.

  There are 2 such tissues—vascular smooth muscle and myocardial cells. (in skeletal muscle Na+ causes contraction)


Hence calcium channel blockers will act on the vascular smooth muscles as well as myocardial cells but have no effect on skeletal muscle.

           In the vascular smooth muscle, the calcium ion enters from the ECF via the calcium channel and forms a complex with a protein called calmodulin within the cytosol. This calmodulin-calcium complex now stimulates the enzyme called myosin light chain kinase (MLKC). MLKC causes phosphorylation of myosin light chain. So that myosin-ATP complex is formed, resulting in contraction of the muscle.

            Ca++ channel blockers primarily cause dilatation of the arterioles but not the veins, so they are afterload reducers. Because arterioles dilate, there is ↓ in the PR and ↓ in BP. So heart will act against less resistance, workload of the heart will be reduced and O2 demand will also be reduced. This less O2 demand will thus relief the ischaemia and angina.

            Ca++ channel blockers also relaxation of the epicardial arteries. So they are very effective in vaso-spastic or prinz metal angina. In myocardial cells the events are as follows—calcium enters the myocardial cells through the channels and activates the sarcoplasmic reticulum, causing release of Ca++ from the sarcoplasmic reticulum then calcium ion concentration in the cytosol rises causing contraction of the myocardial cells.

            Ca++ channel blockers can also cause GIT relaxation producing constipation side effects. Relaxation of the bronchus and the uterus can occur to some extent.

In low therapeutic doses Ca++ channel blockers can affect the vascular smooth muscle only, but not the myocardial cells. Therefore at low doses Ca++ channel blockers can cause vasodilatation but little or no effect on the heart.


Note:-Verapamil and diltiazem can reduce myocardial contractility and HR whereas nifedipine produces tachycardia.


Individual drugs—


Verapamil—it has effects on heart and arterial tree.

            On heart—

a. Myocardial contractility

b. Produces bradycardia by acting on the SA node and AV node. So verapamine is also used in supra-ventricular tachycardia.


*** it cause constipation and ankle oedema.


It is contra-indicated in—

a.   Sick-sinus syndrome

b.   Conduction defect of AV node (heart block)

c.    Myocardial failure

d.  Cannot be used with β-blockers


Nifedipine—more powerful arteriolar dilator than Verapamil, it also dilates the coronary epicardial arterioles better. It has very little negative ionotropic effect on the heart. It can produce reflex tachycardia due to ↓ BP.

It is very popular in prinz-metal angina, it can be used along with β-blockers (nifedipine ↑ HR and β-blockers ↓ HR)


Mechanism of reflex tachycardia—

Nifedipine→ arteriolar dilatation→ ↓ PR→ ↓ BP→ sensed by the sino-aortic receptor (baroreceptor) in the arch of the aorta→ send signal to the vasomotor center (VMS) in the medulla→ VMC increases sympathetic outflow→ secretion of adrenalin and nor-adrenalin→ act on the β1 receptor of the heart→ ↑ HR.


Therapeutic use of Ca++ channel blockers—

  1. Hypertension

  2. Angina

  3. Some of them are used in supra-ventricular tachycardia.

  4. They may be used in Raynaud’s phenomenon

  5. Cardiac myopathy

  6. Prevention of the pre-term labour


As anti-anginal agent they have several advantages—

  1. They are largely a safe drug

  2. Drug of choice in prinz metal angina

  3. Nifedipine can be used along with β-blockers but Verapamil and Diltiazem cannot be used.

  4. They can be used in diabetes whereas β-blockers are not used.

  5. They have no bad effects on lipid profile but β-blockers have.

  6. They do not develop tolerance but nitrates do.


Side effects—

a. Excessive vasodilatation (nifedipine) can lead to headache, dizziness, flushing of the face, syncopal attack.

b. In some persons anginal attack can be aggravated due to reflex tachycardia (nifedipine) and coronary steal.



The objective to use β blockers in angina is to reduce the myocardial O2 demand by reducing the heart rate, blood pressure and myocardial contractility.

The different β blockers differ in their pharmacokinetic properties. Propranolol (lipid soluble) is the prototype.

2nd generation drug is Metoprolol.

Very short acting drug is Esmolol and very long acting is Nadelol.



According to the chemical structure—

1. Very lipid soluble

2. Intermediate lipid soluble

3. Water soluble


According to the receptor selectivity—non selective (β12) and selective β1

*** in liver disease water soluble drug is given and in renal disease lipid soluble drug of correct dose is used.


Mechanism of Action—β-blockers block the β receptor mediated effects of sympathomimetics on the heart. Normally sympathomimetics stimulate the β receptors and increase the cardiac cyclic-AMP. The C-AMP then produces the sympathomimetic effects on the heart. When β blockers are given they block β receptors and decreases the heart rate, cardiac contraction thereby decreasing the myocardial O2 demand.


Mode of action—

1. Reduces the O2 demand of the heart by reducing the sympathetic activity on the heart.

2. Particularly reduces the exercise induced tachycardia, so that chances of angina during exercise reduce.

3. Reduces Renin-Angiotensin axis activity, so Angiotensin-II activity is reduced and ↓ BP.(reducing renin secretion by blocking the β1 receptors of the myoepithelial cells of the juxtra-glomerular apparatus)

4. β-blockers are anti-hypertensive which results in reduction of afterload causing reduction of myocardial O2 demands.


Renin angiotensinogen mechanism—

                                                   Renin ↓                                          ↓ ACE (lung)  

Angiotensinogen (liver)                               Angiotensin I                                          Angiotensin II


Now angiotensin II increases BP by three mechanisms—

  1. ↑ aldosterone → ↑ Na-retention→ ↑ plasma volume→ ↑ CO→ ↑ BP
  2. direct vasoconstriction→ ↑ BP
  3. sympathetic activity→ ↑ BP


Indication of β blockers—

§    Angina

§    Hypertension

§    Arrhythmia

§    Hyperthyroidism

§    Migraine



§    Bronchospasm (asthma)

§    Heart failure

§    A-V block


Adverse effects—

§    Bronchospasm

§    Nightmares

§    Insomnia

§    Hypotension

§    Delayed recovery from hypoglycemia


Advantages over nitrates—

1. No headache, flushing or syncopal attack. (in contrast to nifedipine and nitrates)

2. Less chance of developing tolerance than nitrates, rather with chronic use dose might have to be reduced.

3. (Ca++ channel blockers never develop tolerance)