Contents:
- Classification of antihypertensive drugs
- (I) Drugs acting centrally
- (II) Drugs acting on autonomic ganglia i.e. Ganglion blocking agents
- (III) Drugs acting on post-ganglionic sympathetic nerve endings
- (IV) Drugs acting on adrenergic receptors
- (V) Drugs acting directly on vascular smooth muscles
- (VI) Drugs acting reflexly by stimulating baroreceptors
- (VII) Drugs which block renin-angiotensin aldosterone axis
- (VIII) Oral Diuretics
Classification of antihypertensive drugs
Hypertension is the abnormal elevation in blood pressure. W.H.O has defined hypertension as a state in which systolic pressure is 150 mm of Hg or more and diastolic pressure 95 mm of Hg or more. A diastolic pressure more than 100 mm of Hg is taken as hypertension that needs investigation and treatment with drugs.
The drugs used in the treatment of hypertension act by reducing the cardiac output and/or reducing the total peripheral resistance without correcting the cause. Classification : (According to the site of action)
Antihypertensive drugs can be classified into the following categories on the basis of their site of action :
(i) Drugs acting centrally e.g. Clonidine, methyldopa.
(ii) Drugs acting on autonomic ganglia, i.e. Ganglion blocking agents e.g. Hexamethonium, mecamylamine, pempidine, trimethaphan.
(iii) Drugs acting on post-ganglionic sympathetic nerve endings.
(a) Adrenergic neuron blockers, e.g. Guanethidine.
(b) Catecholamine deplectors, e.g. Reserpine.
(iv) Drugs acting on adrenergic receptors.
(a) α-adrenergic blockers e.g. Phenoxybenzamine, Phentolamine.
(b) β-adrenergic blockers e.g. Propranalol.
(v) Drugs acting directly on vascular smooth muscles i.e. vasodilators e.g. Hydralzine, Diazoxide, Minoxidil, Sodium nitropruside.
(vi) Drugs acting reflexely by stimulating baroreceptor, e.g. Veratrum.
(vii) Drugs which blocks renin angiotensin aldosterone axis. e.g. Saralsin, spironolactone, captopril.
(viii) Oral diuretics e.g. Thiazides.
(ix) Miscellaneous: e.g. MAO inhibitors (pargyline).
(I) Drugs acting centrally
(1) Clonidine:
Pharmacological Actions :
Clonidine is a potent antihypertensive drug. When given within a vein it produces a short, hypertensive response followed by a prolonged hypotension. Hence, it is not suitable drug in hypertensive emergencies. The initial rise in blood pressure is because of its adrenergic agonist action. The major antihypertensive action of clonidine is central. The α-adrenergic receptors in the vasomotor centre are stimulated by clonidine. This inhibits peripheral sympathetic activity. Clonidine also reduces PRA (Plasma Renin Activity). It causes decrease in cardiac output due to both, a decrease in stroke volume and bradycardia. It causes significant reduction in total peripheral resistance in standing position.
Adverse Reactions :
It causes drowsiness and dryness of mouth due to central inhibition of salivation. Besides this, vertigo, constipation, GIT disturbances and allergic reactions can also occur.
Therapeutic Uses :
(i) Antihypertensive
(ii) In migraine: Clonidine hydrochloride administered orally in the dose of 0.025 mg twice daily appears to be prophylatically useful in migraine patients. The drug is more useful in case of patients in whom the attacks are associated with particular foods such as chocolate, cheese, alcohol and citrus fruit. The mechanism of action is not known.
(2) Methyldopa:
Pharmacological Actions :
It decreases heart rate. The fall in blood pressure is more in hypertensive than in normotensive subjects. The hypotensive effect is associated with reduction in cardiac output and in total peripheral resistance. Its hypotensive effect is enhanced by simultaneous use of thiazides. Mechanism of action is not established with certainty. The current evidence suggests that its mechanism of action is similar to that of clonidine.
(II) Drugs acting on autonomic ganglia i.e. Ganglion blocking agents
This class includes the drugs – Hexamethonium, mecamylamine pempidine, trimethaphan etc.
Pharmacological Actions :
These drugs block the transmission of impulses in the sympathetic as well as parasympathetic ganglia. They do not prevent the release of Ach at ganglion but produce ganglionic blockade by occupying the receptor sites on the ganglion cells. This results in the reduction in the amount of noradrenalin released from post ganglionic sympathetic nerve endings and this induce reduction in peripheral sympathetic tone and fall in blood pressure. The normal protective vasomotor reflexes working through baroreceptor mechanism and sympathetic nervous system are also blocked and hence it leads to marked postural hypotension. As a result of venous dilation, venous return is reduced which causes decrease in cardiac output.
Adverse Reactions :
(1) Because of parasympathetic blocked effect, visual disturbances, mydriasis, cycloplegia, constipation, paralytic ileus and urinary retention are some adverse reactions.
(2) Sympathetic blockade: Marked hypotension, disturbances in sexual function in male, sudden pulmonary oedema.
(3) Central actions: Mental confusion tremors and seizures.
(4) Tolerance.
Preparations :
Pentolinium tartarate 10-40 mg tab.
Mecamylamine hydrochloride I.P. – 2.5 mg tablet.
(III) Drugs acting on post-ganglionic sympathetic nerve endings
(a) Adrenergic Neuron Blocking Agents :
These agents act on postganglionic sympathetic neuron and inhibit the ability of nerve impulse to release noradrenaline.
Guanethidine :
Pharmacological Actions :
Guanethidine blocks the adrenergic neuron and thus reduces peripheral sympathetic tone and hence reduction in blood pressure. The reduction in blood pressure by drug is mainly due to reduction in cardiac output, as a result of venous pooling. The heart rate and pulse pressure is usually reduced. It also abolishes the protective cardiovascular reflexes working through baroreceptor mechanism and S.N.S. Hence, it may thus produce postural hypotension. On intravenous administration it produces prominent sympathetic action. Hence, it is to be administered by subcutaneous or intramuscular routes in hypertensive emergencies. Normally it is administered orally.
Adverse Reactions :
Postural hypotension, nasal congestion, decrease in renal blood flow and glomerular filtration rate, nausea, vomitting, diarrhoea and fluid retention leading to congestive cardiac failure are some known adverse reactions.
Guanethidine : 10 mg and 25 mg tab.
(b) Catecholamine Depletors :
Reserpine : It is potent antihypertensive alkaloid.
Pharmacological Actions :
The exact mechanism of drug is not established. However, it is known to deplete catecholamines (NA, Adrenaline, Dopamine). It causes depletion of noradrenaline (NA) stores in the peripheral sympathetic nerve endings. Reserpine acts on both granular uptake and granular amine storage. Thus, it causes both granular NA depletion. The part of intracellur NA is destroyed by enzyme MAO. Reserpine also inhibits the storage of freshly synthesised NA within the granules. Thus, reserpine action leads to depletion of transmitter and consequently the peripheral sympathetic blockade. The transmitter which leaks out from granular storage is inactivated by MAO. Hence, reserpine does not exhibit any sympathomimetic action.
Adverse Reactions :
Salivation, vasodilation, nasal congestion, increased motility of gut, increased appetite, weight gain, mental depression, nightmares, insomnia, suicidal tendency, parkinsonism and endocrine disturbances are some commonly encountered adverse actions.
Preparations : Rauwolfia tab. 1.P. 4 mg.
(IV) Drugs acting on adrenergic receptors
(a) α-adrenergic Blockers :
This class includes the drugs like Phenoxybenzamine and pentolamine.
Phenoxybenzamine: The drug has a long duration of action. It can be given orally and intravenously. The drug controls the hypertension and expands the contracted plasma volume. The drug however is not useful in controlling cardiac arrhythmias.
(b) β-adrenergic Blockers:
Propranolol: These drugs reduces the blood pressure in hypertensive patients. They reduces both systolic and diastolic blood pressure; do not cause tachycardia and do not block baroreceptor mechanism and hence postural hypotension is generally not a problem. Their exact mechanism of action is not known but they reduces peripheral resistance and also reduces cardiac output. They lower the plasma renin. The drugs are Sotalol, Labetalol, Timolol and Propranolol.
(V) Drugs acting directly on vascular smooth muscles
Hydralazine: It is useful in combination with other drugs.
Pharmacological Actions :
Hydralazine directly acts on vascular smooth muscles causing vasodilation. It blocks the peripheral vasoconstrictor action of NA. Diastolic blood pressure is reduced more than the systolic. Decrease in total peripheral resistance is followed by increase in heart rate and cardiac output. The coronary, renal and cerebral blood flow is increased and this is the advantage with hydralazine therapy.
Adverse Reactions :
Palpitation, tachycardia, nausea, vomitting, diarrhoea, anorexia, headache, nasal congestion, flushing and dizziness.
Preparations :
Hydralzine HCl tab., 10, 25, 50, 100 mg.
(VI) Drugs acting reflexly by stimulating baroreceptors
Veratrum :
Pharmacological Actions :
Preparations of veratrum contain several alkaloids protroveratrine A and B being the potent ones. They affect the activity of afferent nerves from the carotid sinus, aortic atrch. There is reflex inhibition of central sympathetic activity, with a resultant parasympathetic predominence, evidenced by slow heart, decreased peripheral vascular resistance. These effects mediated through reflexes via vagus from the larger vessels, may also proceed from the stretch receptors of the alveoli of lung.
Emetic Action :
This action is not due to direct stimulation of the vomitting centre but is a reflex mediated through the sensory fibres of the vagus. Nausea and vomitting are the chief drawbacks of veratrum therapy.
Muscle and Nerves :
The veratrine response of the skeletal muscle tissue is well known. The muscle treated with high dilutions responds to an electric stimulus by a twitch which is higher than normal and is followed by a phase of slow relaxation. The response is tetanic. Denervated muscle responds in the same manner.
Sensory nerve endings are irritated initially on local application to mucosa and this is followed by a temporary loss of sensation.
Veratramine is an amine present in the drug, is antagonistic to the cardiac accelerator action of sympathomimetic amines, the action being exerted on the automatic tissue of the heart itself, predominantly the sinoauricular node.
Toxicity: Heart burn, increased salivation, nausea and vomitting indicate the upper limit of dosage. Symptoms subside when the dose is reduced.
Bradycardia and collapse are among the toxic symptoms often noticed. Atropine and ephedrine may antidotes.
Therapeutic uses :
Veratrum was used in the past for hypertension associated with eclampsia, then receded to the background and has now again come into use. Significant hypotensive effects can be induced if the maximum dose tolerated is taken steadily and in conjuction with rauwolfia. The margin between optimum benefit and early toxicity is Narrow and may amount to no more than 2 mg in a 24 hour period; this narrow margin limits its value. Parenteral veratrum may be very useful in hypertensive encephalopathy, in glomerular nephritis, malignant hypertension and toxaemia and pregnancy.
(VII) Drugs which block renin-angiotensin aldosterone axis
This class includes drugs such as captopril, saralsin etc. The important drug from this class is the diuretic drug spiranolactone. It is well known that diuretics are employed therapeutically as a means of reducing the hypertension by treating the oedema caused due to hypertension.
Spironolactone :
This has a structure similar to that of aldosterone and acts as a competitive antagonist thus promoting renal loss of sodium and retention of potassium. Spironolactone is effective only when there is an increase in the amount of sodium delivered to the distal tubules. So, it is necessary to use it in combination with other diuretics, such as the thiadiazines, which act proximally on sodium reabsorption.
Spironolactone is cumulative in action and the full response may not be seen for some days.
There are few side effects but spironolactone should be used only in cases where there is an excess of aldosterone; such as in hepatic cirrhosis or thrombosis of the inferior vena cava.
(VIII) Oral Diuretics
The diuretics of Benzothiadiazine group are extremely useful in the treatment of hypertension. In addition they enhance the effect of other hypertensive agents.
Pharmacological Actions :
The antihypertensive effect develops slowly. The thiazides probably reduces the blood pressure by several mechanisms. The sodium depletion and consequent reduction in plasma volume and cardiac output. Thiazides reduce the blood pressure probably by a direct action on the arteriolar wall. It has been proposed that thiazides bring about depletion of vascular wall sodium which tends to diminish the sensitivity of the arteriolar wall to circulating catecholamines and angiotensin.
RELATED ARTICLES: