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Antihypertensive drugs fall into the following four major categories according to their site of action, but there is considerable overlap: 1. Sympathetic Inhibitors 2. Vasodilators 3. Captopril 4. Diuretics.
1. Sympathetic Inhibitors:
A. Central and Peripheral Inhibitors:
i. Rauwolfia Group of Drugs:
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These are useful in mild to moderate hypertension. Rauwolfia serpentina is used in the form of dried extract, total alkaloids and active alkaloids. Although many alkaloids have been isolated, reserpine is the most potent and is commonly used. The rauwolfia group of drugs is popular in India because of the low cost and easy availability.
Reserpine is also available in various drug combinations, viz. adelphane, terbolan, etc. Injection serpasil is available for hypertensive emergencies. This drug has a tendency to produce mental depression, and therefore, should be avoided in cases with a history of depression. A careful watch of the patient is necessary from time to time to detect this depression.
Action:
This drug depletes the stores of catecholamines centrally as well as peripherally at the sympathetic nerve endings. It has a central sedative as well as a vagotonic effect. This drug also lowers plasma renin.
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Dose:
The oral recommended dose of reserpine varies from 0.1 to 0.1 mg daily in two or three divided doses. Higher doses usually do not lower BP further, while side-effects are more frequent. Injection serpasil can be given intramuscularly in a dose of 1-5 mg in hypertensive emergencies. The injection may have to be repeated every four to six hours.
The disadvantages of this drug, in cases of hypertensive emergencies, are- It takes from a half hour to two hours to act, and it may be unsafe to wait so long in an emergent situation, and it is also not suitable in hypertensive neurological complications because the drowsiness produced by this drug masks the neurological manifestations.
Side-Effects:
The common side-effects are nasal congestion, fatigue, dreams, drowsiness, impotence, and insomina. Depression and Parkinsonism induced by this drug are serious and take several weeks to disappear even after stopping the drug, particularly when the drug is not discontinued at the earliest indication of the side-effect. Vagotonic effect gives to bradycardia and may lead to diarrhoea, hyperacidity, and even peptic ulceration. Recently, breast carcinoma in a few female patients has been reported after prolonged use of this drug, but this has yet to be corroborated.
ii. Alpha-Methyldopa:
It can be given in all grades of hypertension and can be used in the presence of CCF and pheochromocytoma and in patients on tricyclic anti-depressants. It can also be used in hypertensive patients with renal failure.
Action:
The mechanism of action of alpha-methyldopa is not definitely established, although it was supposed to be a dopa-decarboxylase inhibitor.
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It is now hypothesised that the drug acts as a false neurohumoral transmitter. Alpha-methyldopa enters the brain where it is converted into alpha-methyldopamine and alpha-methylnordrenaline. The latter displaces noradrenaline from granule stores. Alpha-methylnoradrenaline is less potent than noradrenaline and is capable of functioning as a false neurohumoral transmitter and its potency produces the relative hypotensive effect.
This drug also directly inhibits the central vasomotor centres and suppresses the renin release from the kidney.
Dosage:
The usual effective dose is 250-500 mg thrice daily. It has a tendency to retain sodium and water and hence it is best used with an oral diuretic agent. Injectable alphamethyl dopa is available (not in India) for hypertensive emergencies and the dose in 500-1000 mg/IV, to be repeated every 4-6 hours.
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Side-Effects:
These are infrequent with dosage up to 1 g a day. The common side-effects are lethargy, depression, and somnolence which usually disappear after a few days. Impotence and postural hypotension are usually seen with higher doses. Fortunately hepatitis and haemolytic anaemia are rare.
iii. Clonidine:
It is the drug of choice when hypertension is associated with migraine. It can also be used in malignant hypertension.
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The drug should be avoided when the patient is on tricyclic antidepressants. It should be avoided when the pulse is slow. The patient should be cautioned not to stop clonidine suddenly, but to reduce it gradually over four or five days before stopping it as there may be rebound phenomena resulting in hypertensive crisis due to sudden withdrawal, especially if the dose administered is above 0.5 mg per day.
Action:
It stimulates the alpha adrenergic receptors in the brain stem with decreased sympathetic discharge to arterioles. It also decreases plasma renin, peripheral resistance, heart rate and cardiac output.
Dose:
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The dose varies from 0 15 mg a day in three or four divided doses. In cases of severe or malignant hypertension, it can be given I.V. or I.M. in doses of 0.1 to 0.45 mg. However there may be a transient initial rise in BP after IV administration, which is followed by a rapid fall of BP.
Side-Effects:
Prominent side-effects are:
a. Dryness of mouth and eyes,
b. Drowsiness, and
c. General weakness.
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These tend to diminish with continued use. Bradycardia and constipation are some of the other side-effects.
B. Adrenoreceptor Blocking Agents:
Alpha receptor blocking agents such as phentolamine, phenoxybenzamine, and hydrogenated ergot alkaloids are only mild antihypertensive agents and, therefore, are of limited value, except phentolamine Phentolamine is indicated in situations associated with excessive amounts of circulating catecholamines, e.g. exogenously administered catecholamines, and for conditions viz. pheochromocytoma, clonfdine Withdrawal hypertension and hypertension resulting from MAO inhibiting drugs.
MAO inhibitors are both hypotensive and mood elevators. However, with these drugs there is danger of acute exacerbation of the hypertensive state if certain drugs, e.g, sympathomimetics or famine-containing substances (cheese, yoghurt, broad beans, yeast extracts, wine, beer etc.) are taken.
i. Beta Receptor Blocking Agents:
These drugs are useful in the management of hypertension but their mode of action is as yet imperfectly understood. The commonly used beta-adrenergic blocking agent is propranolol.
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Propranolol is a useful drug in the treatment of hypertension and has the following advantages:
(1) Postural hypotension and impotence do not usually occur (these are most objectionable side- effects with sympathetic inhibitors).
(2) It does not cause sodium and water retention and therefore, the drug does not lose its efficacy. Yet, it is a good practice to add a diuretic as diuretics potentiate its action.
(3) BP fluctuation in response to exertion, emotion, and tachycardia is minimised by propranolol and therefore, this drug is most useful in labile hypertension.
(4) It is useful for hypertensive patients who in addition have palpitation, tachycardia, arrhythmias, or angina.
(5) The drug is safe in renal failure and is also effective in malignant hypertension.
However, this drug has many drawbacks- It is contraindicated in (1) CCF (overt or impending), (2) heart block; (3) obstructive pulmonary airway diseases (Cor pulmonale or COPD), and (4) should be avoided in the presence of cardiomegaly, sinus bradycardia and peripheral artery disease, and in diabetics who are on antidiabetic drugs, as propranolol masks the warning signs of hypoglycaemia in diabetics.
In our experience in the city of Bombay we have found that about 15% of the hypertensive patients have some degree of obstructive airway disease. In these subjects beta-blockers may aggravate their respiratory symptoms. About 10% of patients cannot tolerate the drug. All these limit the usefulness of this drug.
Action:
It is believed that the action of propranolol is a direct one on renal juxta glomerular cells thereby suppressing renin release. It causes beta-blockade in the heart and thereby decreases heart rate, cardiac output, and stroke output.
Dose:
The usual dose of propranolol is from 40 to 320 mg a day in two or three divided doses. However, higher doses up to 2000 mg have been used. It is desirable to start with smaller doses (20 mg twice daily) and to increase it gradually according to response and/or side-effects. Heart rate should not fall below 55 per minute. It is desirable not to stop the drug suddenly as it may produce tachycardia, arrhythmia, or angina, or may even precipitate myocardial infarction.
Side-Effects:
Side-effects are seen in 15 to 20% of the cases. In about five to 10% it may become necessary to discontinue the drug. The main side-effects are bronchospasm, fatigue, headache, vivid dreams, insomnia, dizziness, unsteadiness, undue bradycardia, nausea, vomiting, flatulence, skin rashes, etc. Patients may complain of cold extremities as a result of constriction of the vessels due to unopposed action of the alpha receptors.
ii. Combined alpha and beta receptor blocking agents:
Labetalol Hydrochloride (Normadate, Tab. 50 mg, 100 mg, and 200 mg.)
Action:
This most modern drug lowers the blood pressure, by blocking the alpha adreno-receptors in peripheral arterioles, thereby reducing peripheral resistance, and also by its beta adreno-receptor activity, which protects the heart from the reflex sympathetic drive normally induced by peripheral vasodilatation. Cardiac output is not significantly reduced at rest or after moderate exercise.
Increase in systolic pressure during exercise is reduced after Labetalol, while corresponding changes in the diastolic pressure are essentially normal. All these effects can benefit the hypertensive patient. As the alpha and beta blockade are incomplete, the barostatic reflexes remain sufficiently active to prevent postural hypotension in most patients. However, postural hypotension may occur with higher doses.
Dose:
The drug should be started with a dose of 50 mg two or three times a day and gradually increased to 200 mg two or three times a day. Severe cases may require a dosage as high as 2 gms daily. Patients can usually be maintained on twice daily regime.
Precautions:
Labetalol should not normally be given to patients who are in chronic digitalis resistant heart failure or atrioventricular block, and to those who are prone to bronchospasm.
It is not necessary to discontinue Labetalol in patients requiring anaesthesia, but they should be given intravenous atropine prior to induction. Avoid in pregnancy.
Side-Effects:
Postural hypotension may occur if the initial dose is too high or the dose is increased too rapidly or when the daily dose is high. The patient may get skin rashes, dry eyes, headache, tiredness, epigastric pain, nausea, and vomiting. A tingling sensation in the scalp may occur, but this is usually transient. Blurring of the vision, eye irritation, cramps and lichenoid rash have been reported.
Labetalol does not adversely affect renal function and is particularly suitable in hypertensive patients with renal disease. Metabolites of the drug are excreted in the feces and urine and so the drug is unlikely to accumulate in blood even in renal failure.
iii. Ganglion Blocking Agents:
Guanethidine, bethanidine, debrisoquine, pentolinium, trimethaphan, and hexamethonium are also sympathetic inhibiting agents. They are potent but cause severe side-effects, such as orthostatic (postural) hypotension, sexual dysfunction, etc. Of these, guanethidine and trimethaphan are sometimes used. When guanethidine 5-10 mg a day is given in addition to an alphamethyldopa-diuretic-vasodilator regimen, some hypotensive effect can be achieved with minimal side-effects.
These drugs should be prescribed with caution in the presence of renal failure, cerebrovascular insufficiency, or angina, and are also contraindicated when a patient has pheochromocytoma or is on tricyclic antidepressants or phenothiazines. Guanethidine gives rise to marked postural hypotension, sexual dysfunction, and other side-effects. Therefore, this drug has hardly any place in the management of hypertension, more so as many better drugs are available.
Treatment is used in hypertensive emergencies and the indications for this drug are similar to sodium nitroprusside. It is favoured in patients of acute aortic dissection because aortic flow and ventricular ejection are minimally increased. It is administered in concentration of 1 mg/ml (0.1%) intravenously at a rate of 1.0 to 4.0 mg/min. Reduction in BP is achieved within minutes, and as soon as the drop is discontinued BP starts rising. Thus it is a rapidly acting drug and the duration of action is also brief.
2. Vasodilators:
These are commonly used as part of a three-drug regimen in combination with serpena or methyldopa or propranolol and a diuretic. They are mainly indicated in chronic and severe cases and in the presence of renal failure. Besides synergistic effect with propranolol, these increase adrenergic activity and counteract bradycardia produced by propranolol and other drugs.
All vasodilators act by lowering the peripheral resistance. The vasodilators in common use are hydralazine, prazosin, sodium nitroprusside, minoxidil, and diazoxide.
i. Hydralazine:
The only dose of hydralazine is from 25 to 200 mg thrice daily. Side-effects during a triple drug regimen using hydralazine are unusual. Although headache, palpitation, and tachycardia can occur due to increased adrenergic activity, these are minimised by concomitant use of propranolol.
Sodium and water retention is counteracted by the diuretic in the triple regimen. A delayed but serious side-effect, lupus erythematosus-like syndrome may occur with large doses (more than 400 mg/day). Tolerance to hydralazine may be acquired rapidly. This drug should be avoided in angina and AMI.
ii. Prazosin:
The hypotensive effect of prazosin is due to the vasodilator action mainly on the arterioles. It also interferes with the peripheral sympathetic function at a site distal to the alpha adrenergic receptor, without blocking it; a diuretic greatly enhances the action of prazosin.
The side-effects of this drug include giddiness, weakness, dryness of the mouth, postural hypotension, and abdominal cramps. These are not common and are usually not serious enough to require discontinuation of the drug. In some cases, the initial response is abnormal and there is a marked fall of BP.
However, the abnormal BP response usually does not recur. The addition of a beta blocker helps in counteracting some of the undesirable effects and also helps to further reduce BP. The dose is from 1 to 60 mg a day (average, 5 to 10 mg/day) in three divided doses. Always start with 0.5 to 1 mg/day as postural hypotension may occur with the first dose.
iii. Minoxidil (Tab. 5 mg):
Minoxidil is an orally effective, direct acting peripheral vasodilator which reduces elevated systolic and diastolic pressure by decreasing peripheral resistance. It is rapidly absorbed from the gastrointestinal tract and is mainly excreted by the kidneys. It does not interfere with the vasomotor reflexes and, therefore, does not produce orthostatic hypotension. The drug does not affect CNS function in man. It usually increases renin secretion.
With an oral dose, blood pressure starts decreasing within 30 minutes, maximum fall occur within two to three hours, and the total duration of action of a single dose is approximately 75 hours. The drug can be administered once or twice a day.
The side-effects are reflex tachycardia, intractable oedema and right-sided failure, change in the colour of hair, itching of eyes, etc. It is desirable to counteract the reflex tachycardia with drugs which produce bradycardia, e.g. propranolol, reserpine, etc. Diuretics are necessary to counteract the water retention.
The dose of minoxidil varies from 2 to 40 mg per day in divided doses.
iv. Sodium Nitroprusside:
It is a vasodilator drug which relaxes both arteriolar and venous smooth muscles. Thus, it reduces the pre-load and after-load. It is available as a reddish brown lympholized power in a vial. 50 mg or 100 mg of the drug should be dissolved in 2-3 ml of dextrose. The bottle should be promptly wrapped in aluminium foil or some opaque material to prevent degradation to cyanogen by light.
The freshly prepared solution has a very faint brownish tint; if it is high coloured it should be discarded. If possible, it should be given by an infusion pump microdrip regulator. The rate of administration should be adjusted according to BP; the usual rate of administration is 6-120 drops/min. (10-200 mcg/min).
Since the end product of sodium nitroprusside metabolism is thiocynate, it is extremely important to estimate blood thiocynate levels as frequently as possible. The blood thiocynate level should not be allowed to go beyond 10 mg/100 ml. As thiocynate inhibits the uptake and binding of iodine, the drug should be used with caution in patients with hypothyroidism and severe renal impairment.
Minor adverse reactions such as nausea, retching, headache, muscle twitching, dizziness, palpitation, tachycardia, flushing of face, sweating, and abdominal pain may occur, but these symptoms disappear rapidly on slowing the rate of infusion or by temporary discontinuation of infusion. Methemoglobinaemia following nitroprusside infusion has also been reported.
v. Diazoxide:
It acts directly on the smooth muscle producing relaxation. Although related chemically to chlorothiazide, it causes sodium retention and, therefore, diuretics should be used with it. It is especially useful in cases of malignant hypertension and hypertensive crisis. When given intravenously (5 mg/kg body weight), there is a fall of BP, within a few minutes.
The pressure remains low for a few hours. The drug should be injected rapidly since it binds with circulating albumin in the blood and thereby loses much of its hypotensive and vasodilating effect. Injections may be repeated every 6-8 hours during the acute phase.
Administration of diazoxide to patients with hypertensive crisis can cause an angina-like syndrome and even myocardial infarction as shown in a recent study of this drug. Some patients who are refractory to treatment with oral drugs respond to intravenous injection of diazoxide, and the BP can then be controlled with oral antihypertensive drugs.
If the drug is not injected properly into the vein it gives a severe local reaction in the tissues. It also produces sodium retention and hyperglycaemia.
Diazoxide should not be used in the treatment of compensatory hypertension such as that associated with coarctation of aorta or arterio-venous fistula. It should be avoided in patients with cardiac failure, angina pectoris, myocardial infarction, and dissecting aortic aneurysm.
vi. Verapamil:
If the above drugs are not available, verapamil could be used in hypertensive emergencies. The dose of verapamil is 300 mg added to 200 ml of 5% dextrose and is given by a slow IV drip and the rate of drip should be regulated according to the fall of BP. Within a few hours BP can be reduced to moderate level. Orally, verapamil has only a mild antihypertensive action.
3. Captopril – Drugs which interfere with the renin-angiotensin mechanism:
This orally effective agent inhibits the enzyme responsible for both conversion of the inactive angiotensin I to the potent vasopressor angiotensin II and the breakdown of vasopressor bradykinin. The beneficial effect of this drug is due to elimination of angiotensin II and accumulation of bradykinin. Initial dose is 10 mg a day which can be gradually increased at intervals of 48 hours. Captopril can be safely given up to 1 gm/day.
Seralcin:
It is a potent antihypertensive agent and is administered by IV infusion. It is used in malignant (accelerated) hypertension and as a diagnostic agent to determine the angiotensin component in hypertension. It was believed to be angiotensin II antagonist, but probably it is rather a weak competitive agonist.
There is no hypotensive response until there is high renin activity or sodium is depleted. During high rates of seralacin infusion or after injection of a large bolus, there may be rise of BP in hypertensive subjects with low renin activity. In such hypertensive patients with low renin activity BP can be reduced by depleting sodium with a diuretic.
4. Diuretics:
As can be seen from Table II almost all the antihypertensive drugs have sodium and water retaining properties (as seen by increase in plasma volume) which can be counteracted by diuretics. Diuretics are also indicated in the presence of increased intravascular volume as seen in renal failure and congestive cardiac failure.
The choice of the diuretic is of little importance if renal function is normal, but when creatinine clearance is reduced to 20-30% of normal, furosemide, bumetanide, or ethacrynic acid are mainly used as potentiating agents with other antihypertensive drugs.
When diuretics are used on alternate days (two or three days a week), usually it is not necessary to supplement potassium chloride, but when used daily the patient should be advised to take potassium chloride orally or encouraged to take orange juice, tomato juice, coconut water, and bananas as these foods are rich in potassium (see Table-18.3).
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Potent (loop) diuretics in comparison with the thiazide group are more effective and retain their effectiveness even in the presence of serum electrolyte imbalance.
If secondary hyperaldosteronism, induced by diuretics, has occurred, aldosterone antagonist (spironolactone) is administered in addition to thiazides or potent diuretics. These should also be given when the patient complains of weakness which is often due to hypokalemia.
Precautions:
It is essential to evaluate renal function by estimating serum creatinine. When creatinine is elevated, serial values should be estimated every two or three days while the blood pressure is being regulated. If increase in creatinine is observed, the BP should be allowed to increase slightly by reducing the dose of the anti-hypertensive and diuretic agents until the creatinine again returns to the pre-treatment level.
Hypertensive Emergencies:
The aim of treating hypertensive emergencies is- prompt recognition and rapid reduction of blood pressure, though not necessarily to normotensive levels and not with the same urgency in every case.
There is no ideal antihypertensive agent which can be selected as the first choice.
In fact, the choice of an antihypertensive drug to be used for a particular emergency would depend upon various factors:
1. Aetiology of the hypertension
2. Complicating diseases such as ischaemic heart disease.
3. Age of the patient
4. Rapidity of onset, duration of action, and antihypertensive potency of the drug.
In patients with a history of angina pectoris or myocardial infarction, lowering of BP to normotensive or hypotensive levels might precipitate a myocardial infarct or a cerebrovascular episode. Therefore, in these patients the diastolic BP should be reduced to 100-110 mmHg. initially and subsequently reduced further.
If there is undue reduction of blood pressure while treating with antihypertensive drugs, a direct pressor agent such as levarteranol bitartrate (4 mg/litre) or mephantine (15 mg) may be employed.
In hypertensive emergencies, oral antihypertensive drugs should be started with parenteral drugs, so that subsequently the patient may be controlled only with oral drugs.
