Antihypertensive drugs – Clinically hypertension is persistently raised arterial pressure which is primarily due to increased vascular resistance in the systemic circulation. In due course of time, heart undergoes hypertrophy and subsequently failure because it has to work against a permanently increased after load. If the condition remains untreated and uncontrolled for a long period, there occurs irrepairable damage to other vital organs of the body such as brain, heart, kidney and eyes.
In essential or primary hypertension (90%), the underlying cause is not known. In 10% of the cases, hypertension is secondary to some recognizable pathological condition and can be treated by removing or treating that condition. On the other hand, essential hypertension is treated by antihypertensive drugs.
Classification of Antihypertensive Drugs
Based on the mode of action, the antihypertensive drugs can be classified as follows:
1. Diuretics: Hydrochiorothiazide, chlorthalidone, frusemide.
2. Antihypertensive drugs which lower sympathetic tone:
• Centrally acting: Clonidine, alphamethyldopa, guanfacine, moxonidine
• Autonomic ganglionic blockers: Trimetaphen
• Post ganglionic adrenergic neuron blockers:
Guanethidine, guanadrel, bethanidine, debrisoquin, reserpine
• Beta-adrenoceptor blockers: Propranolol, atenolol, metoprolol, labetalol
• Alpha-adrenoceptor blockers: Prazosin, terazosin, indorarnin
• Mixed adrenoceptor blockers: Labetalol, carvediol
• Smooth muscle relaxant:
i. Arteriolar: Hydralazine, indapamide, zipamide
ii. Arteriolar-venular: Sodium nitroprusside
• Calcium channel blockers: Verapamil, diltiazem, nifedipine, felodipine, amlodipine, nitrendipine, lacidipine
• Potassium channel openers: Minoxidil, pinacidil, diazoxide
4. Inhibitors of renin-angiotensin system:
• ACE-inhibitors: Captopril, enalapril, lisinopril, ramipril, perindopril
• Angiotensin II subtype-i (AT1) receptor blocker: Saralasin, losartan
Antihypertensive Drugs which act by Lowering Sympathetic Tone
Centrally acting drugs: Clonidine and alphamethyldopa, stimulate alpha-2 receptors on the vasomotor centre of the brain and thus decrease sympathetic outflow from the CNS to the peripheral vessels. Due to this, there occurs decrease in cardiac output and heart rate and thus fall in blood pressure. Clonidine acts as such while alpha-methyldopa gets converted intraneuronally into methyl noradrenaline which is responsible for antihypertensive drugs effect. Abrupt withdrawal of both drugs may lead to severe rebound hypertension. These drugs are used in moderate hypertension. When used alone there occurs tolerance to their anti- hypertensive effect due to retention of sodium and increase in plasma volume. This can be overcome by simultaneous administration of a diuretic.
Clonidine: It is well absorbed on oral administration. It is mostly excreted in urine as unchanged drug. Important side effects are dry mouth, drowsiness, constipation, gastric upset and impotence. It should not be given to patients who are at risk of depression. The antihypertensive drugs effect of clonidine is blocked on concomitant treatment with tricyclic antidepressants.
The usual oral dose of clonidine is 0.1 mg twice a day. The dose may be increased up to 0.6 mg 3 times a day.
Alpha-methyldopa: The antihypertensive drugs action to methyl dopa develops slowly. On oral administration, peak effect on blood pressure is seen after 2—6 hours. It is excreted in urine both as an unchanged drug and a conjugated metabolite. Important side effects are sedation, drowsiness, nasal congestion, orthostatic hypotension and impotence.
Dose: 250 mg 2 to 3 times a day. In hypertensive emergencies, it is given i.v. (250— 500 mg).
Guanfacine is related to clonidine and has actions similar to clonidine. However, its duration of action is prolonged.
Moxonidine: It is a selective imidazole receptor (I receptor) agonist. It stimulates I receptor in the medulla. So it reduces central sympathetic drive and peripheral vascular resistance. Concentrations of catecholamines and rennin in plasma are decreased. Due to these actions, it produces fall in blood pressure. It is particularly beneficial in obese hypertensive patients with co-existing glucose intolerance and/or dyslipidemia due to its ability:
• To have beneficial effect on lipid and carbohydrate metabolism
• To improve insulin-mediated glucose disposal in obese patients
Ganglion blocking agents: Except trimetaphan, other ganglion blocking agents are no more used as antihypertensive drugs being non-selective. Trimetaphan is a rapidly acting drug. It is given i.v. for hypertensive emergencies and to induce controlled hypotension for neurosurgery.
Adrenergic neuron blocking agents:
Guanethidine and reserpine lower blood pressure by interfering with the release of adrenergic transmitters from postganglionic sympathetic neurons and other tissues. Guanethidine is a synthetic compound. It is incompletely absorbed from the gut, and does not cross blood—brain barrier. It is slowly excreted from the body and produces cumulative effect. Like noradrenaline, it is taken up from the plasma by the adrenergic neurons and causes adrenergic blockade. So these antihypertensive drugs causes:
• Inhibition of release of norepinephrine at the sympathetic nerve endings
• Blockade of re-uptake of norepinephrine by the sympathetic nerve endings
• Depletion of norepinephrine stores at the sympathetic nerve endings and tissues. Cocaine and tricyclic antidepressants prevent the neuronal uptake of guanethidine by competing for the same uptake mechanism.
Guanethidine is given orally in severe hypertension, usually in combination with diuretic and vasodilators. Important adverse effects are orthostatic hypotension, nasal stuffiness, p arotid tenderness, diarrhoea, muscle pain, supersensitivity of adrenergic receptors and retention of water and electrolytes.
Guanadrel, bethanidine, and debrisoquin are related to guanethidine and have similar mechanism of action.
Reserpine: It is an alkaloid. It is obtained from the roots of Rauwofia serpentina. It is readily absorbed on oral administration. It slowly depletes catecholamines and serotonin from brain, adrenergic neurons and all other tissues. This results in loss of transmitter and fall in arterial pressure. However, it is no more used because of its toxicity related to CNS and gut and availability of more selective and less toxic antihypertensive drugs.
Beta-adrenoceptor blockers: Many clinicians consider that beta-adrenoceptor blockers are the drugs of first choice for the treatment of essential hypertension. Several mechanisms are involved in their hypotensive effect. Their hypotensive effect, therefore, is due to following reasons:
On prolonged administration, blood pressure gradually falls in hypertensives but not in normotensives. Initially, total peripheral resistance (t.p.r.) is increased due to blockade of f32-mediated vasodilatation and cardiac out put is reduced due to blocked of 13-receptors of the heart. So there occurs little change in blood pressure. However, with continued treatment, resistance vessels gradually adapt to chronically reduced cardiac output so that t.p.r. decreases and both systolic and diastolic blood pressure falls.
• Reduction of sympathetic out flow from central nervous system due to blocked of presynaptic 3-receptors centrally to peripheral blood vessels.
• Blocked of peripheral facilitatory presynaptic f32-receptors to reduce sympathetic vasoconstrictor nerve activity.
• Reduction of renin release due to blocked of receptors of the juxtaglomerular cells of the renal cortex.
• An increase in biosynthesis of prostacycline in vascular beds.
• Increase in natriuretric peptide secretion caused by beta blockers.
Propranolol is contraindicated in bronchial asthma and diabetes mellitus being a non- selective beta blocker. Further, it is to be given 2—3 times a day.
Atenolol: It is a selective beta blocker. It can, therefore, be given to patients suffering from bronchial asthma and diabetes mellitus. Since the drug is given once a day the patient compliance is better.
Metoprolol is a cardio-selective 31-receptor blocker. So it is given to hypertensive patients with diabetes.
Aipha-adrenoceptor blocker: Prazosin is an alpha-adrenoceptor blocker. Its antihypertensive drugs effect is due to its ability to selectively block a1 receptors. It allows nor-adrenaline to continue to act on a2 receptors arid inhibit its own release. So it causes less tachycardia than the non-selective alpha-blockers. Renal blood flow is not impaired and it increases HDL level in blood. Initi4lly it is given 1 mg 3 times a day. The dose is gradually increased up to 20— 30 mg a day. The first dose is given at bedtime because fainting or syncopal attack may occur after the first dose due to precipitous fall in blood pressure while standing. This does not occur in long-term treatment with prazosin.
Terazosin and doxazosin are the analogues of prazosin which are used as antihypertensive drugs. They are preferred over prazosin because of their longer duration of action. They are either used alone in mild hypertension or in combination with other drugs.
Excessive hypotension, arrhythmias and accumulation of cyanide are reported as side effects.
Calcium channel blockers: These drugs block voltage operated slow L-type Ca channels of vascular smooth muscles. So they reduce the frequency of their opening in response to depolarization. This results in a marked decrease in transmembrane Ca current in vascular smooth muscle. They, therefore, dilate peripheral arterioles by inhibiting calcium influx in the arteriolar smooth muscle and reduce total peripheral resistance and blood pressure. Important side effects are headache, hypotension and dizziness.
Among the three prototype drugs, verapamil is relatively cardioselective, nifidipine is relatively vascular smooth muscle selective, while diltiazem exhibits intermediate selectivity. So for the treatment of hypertension, nifedipine and its analogues are preferred over the other two groups. The other important features of nifedipine group (dihydropyridines) are:
• These drugs block Ca channels of vascular smooth muscle at a concentration b e 10 w that required for cardiac depressant effects. So these are less cardiac depressant than verapamil and diltiazem.
• However, reflex tachycardia with nifedipine (though to a lesser degree with long acting dihydropyridines such as felodipine and amlodipine) in therapeutic doses is more common as compared to diltiazem and verapamil due to their direct negative chronotropic effect.
Calcium channel blockers are among first choice antihypertensive drugs because of:
• Convenient dosage schedule
• Better patient compliance
• Stroke preventing benefits
These are very useful in patients with low renin hypertension and in geriatric people with stiff blood vessels.
Nifedipine is used in a dose of 10—20 mg in hypertension, hypertensive emergencies and hypertension associated with pregnancy, diabetes mellitus and renal impairment.
Felodipine is administered in doses of 5 to 10mg once daily. Amlodipine is given in doses of 5 to 10 mg once daily.
Potassium channel openers: They cause vasodilatation by opening voltage-gated K channels of blood vessel and membrane hyperpolarization. They dilate arterioles with no effect on venules.
Minoxidil: It is given orally in a dose of 5 mg 1 to 2 times a day. The dose may be increased up to 50 mg per day. It is used to treat moderate to severe hypertension which are refractory or do not respond to conventional drug therapy. It is usually given in combination with a beta-blocker and a loop diuretic to minimize the dose of the drug, tachycardia, and retention of water and electrolytes. It causes serious side effects such as pericardial effusion, hirsutism, fatigue, tachycardia, angina pectoris, and retention of fluid.
Diazoxide: It has structural resemblance with thiazide diuretic, but it causes retention of sodium and water instead of diuresis. It is a K channel opener. Oral absorption is erratic, soit is given rapidly i.v. It causes fall in blood pressure within 3—5 minutes and the effect lasts for 8—12 hours. It promptly decreases the tone of resistance vessels without an effect on capacitance vessels. It is used in the treatment of hypertensive emergencies. Reflex tachycardia can be prevented by beta blocker. It is also used to treat hypoglycaemia secondary to insulinoma because it inhibits insulin release from the pancrease.
Pinacidil and cromakalim are also K channel openers which are being tried in hypertension.
4. Renin-angiotensin System Inhibitors
High plasma renin activity leads to:
• Increased formation of angiotensin-II (potent arteriolar vasoconstrictor)
• Stimulation of aldosterone secretion (promotes retention of Na and water)
• Release of catecholamines
All these factors cause increase in the total peripheral resistance and ultimately essential hypertension. Renal ischaemia, adrenergic over activity and hyponatraemia may stimulate renin release.
Angiotensin converting enzyme (ACE) inhibitors: These drugs competitively inhibit ACE and thereby reduce the synthesis of angiotensin-Il. Since ACE metabolizes bradykinin, they also preserve the concentration of bradykinin (potent vasodilator). So they reduce peripheral vascular resistance and lower the blood pressure. The other factors responsible for hypotensive effect may be via prostaglandin synthesis and reduction in adrenergic activity. These antihypertensive drugs can be used safely in patients with ischaemic heart disease because they do not change significantly heart rate and cardiac output. Further, they also reduce both preload and after load without the side effects of other hypotensive drugs.
Captopril: It is given 25 mg 3 times a day orally one to two hours before food. The dose may be increased at 1—2 week intervals to 150 mg per day.
Enalapril: It is a prodrug. Food does not interfere with its absorption from gastrointestinal tract. On oral administration 70% of the drug is absorbed. In the liver, it is converted into the active drug enalaprilat (half life 11 hours). It is given in doses of 10—20 mg once daily.
Lisinopril: It is a lysine derivative of enalaprilat which is given in doses of 10—80 mg once daily orally. It is slowly absorbed and its half-life is 12 hours.
Ramipril and perindopril are the other ACE inhibitors in use. They are given orally once a day.
Therapeutic uses antihypertensive drugs:
• Mild to moderate hypertension with or without high plasma renin activity. The drug can be used alone or with a thiazide diuretic.
• Malignant hypertension.
• Congestive cardiac failure.
Adverse reactions of antihypertensive drugs are uncommon, but may be serious in some cases such as:
• Hypotension after the first dose in sodium depleted patients.
• Bone marrow depression and proteinuria.
• Minor side effects are cough, headache, dizziness, fatigue, allergic skin rash, drug fever, alteration in taste sensation.
They are contraindicated in patients with bilateral renal artery stenosis because they may precipitate acute renal failure.
Angiotensin receptor blocken Saralasin is an analogue of angiotensin-II. It is a competitive inhibitor of angiotensin-II at vascular receptor site. However, it also has significant partial agonist property. It is used to diagnose renal cause of hypertension by blocking the pressor effects of circulating angiotensin-il and lowering the blood pressure in high renin states. It is given by Lv. infusion at a rate of 20 mg/kg/mm because it has a very short half-life (4 mm).
Losartan: It is phenyl tetrazone substituted imidazole compound. It is selective angiotensin-Il receptor type-1(AT1) antagonist. Unlike saralasin, it does not have intrinsic agonist property. Its side effects are skin rashes and neuropsychiatric disturbances(insomnia, confusion, nightmare, agitation and depression). It is useful in the treatment of essential hypertension.
Valasarten, irbesartan and candesartan are the newer analogues of losartan.
At present, clinical uses of angiotensiri-il subtype 1 (AT1) receptor antagonists are kept reserved by many clinicians for patients with hypertension in whom ACE inhibitor is indicated, but who are unable to tolerate this because of dry cough. This side effect is not caused by AT1 antagonists.
Other possible indication is heart failure which is currently being explored in clinical trials.
PRESENT DAY STATUS OF ANTIHYPERTENSIVE DRUGS
• Drug treatment of hypertension is carried out with those drugs which have proven benefit and least likely to produce side effects. At present, ganglion blockers, adrenergic neuron blockers, and reserpine are no more used because they produce fearsome array of adverse effects.
• Thiazide diuretic or 3-adrenoceptor blockers are commonly used as starting points for the treatment of mild hypertension. They abolish the excess risk of stroke and reduce the risk of myocardial infarction. There adverse effects are much less severe in comparison to methyldopa or guanethidine.
• To control moderate or severe hypertension without causing side effects, use combination of low doses of different drugs with complementary mechanism of action, e.g. diuretic with angiotensin converting enzyme inhibitor(ACEI). The efficacy of diuretic is limited by the increased plasma rennin activity that it causes.
This side effect is controlled by ACET. Further, high doses of antihypertensive drugs are often not very effective in chronic administration due to homeostatic mechanisms and they cause side effects also.
• ACEI and calcium channel blockers are used alone or in combination to control moderate or severe hypertension. AT1 receptor antagonist is especially indicated if patient is unable to tolerate ACEI because of cough. One of the following antihypertensive drugs is added(in case of severe hypertension) or substituted (in case of moderate hypertension) if the above mentioned treatment is not sufficient to control the blood pressure. In both groups, when target blood pressure (140/ 85 mm Hg) is reached and consistently maintained, try to step down the antihypertensive drug treatment to the initial drugs.
• During pregnancy, toxaemic hypertension may develop. It is associated with a hyperadrenergic state, decrease in plasma volume (despite oedema) and increase in vascular resistance. Selection of antihypertensive drugs should be made from the following drugs: Hydrallazine, Methyldopa, Dihydropyridine calcium channel blockers, Cardio-selective 3-blockers and those with sympathomimetic activity, Prazocin and clonidine-provided postural hypotension can be avoided.
In hypertensive emergencies, one of the following drugs is used:
In hypertensive urgencies, one of the following drugs can be used:
Points for Dental Students
During history taking, find out whether patient is suffering from hypertension. If so dentist must be aware of medications which are being administered to the patient due to following reasons:
1. This is important because these antihypertensive drugs have drug interactions with other drugs which may be prescribed by the dentist, e.g.
2. If blood pressure in hypertensive patient is fluctuating, use a local anaesthetic without a sympathomimetic.
3. Commonly used antihypertensive drugs may have intraoral changes that are of importance to the provision of dental care such as:
4, Before initiating dental care, assess hypertension and determine presence of target organ disease. Dental treatment for patients with elevated blood pressure is determined as under:
Treatment of hypertension
Non pharmacologic measures
Reduced saturated fat
Sometime syncope may be precipitated due to anxiety during dental procedures. It is defined as a transient loss of consciousness and postural tone due to inadequate cerebral blood flow. This is mediated by the Bezold-Jarisch reflex. It is usually triggered by a reduction in venous return due to a stressful and painful experience. Concomitant sympathetic activation then leads to vigorous contraction of the relatively under filled ventricles. In turn this leads to the reflex by stimulating ventricular mechanoreceptors.
This reflex produces parasympathetic (vagal) activation and sympathetic withdrawal causing bradycardia, vasodilatation or both. Premonitory symptoms such as nausea, diaphoresis, tachycardia, and pallor are usual. Episode can be aborted by head-up-tilt method. It involves asking the patient to lie down on a table that is then tilted to an angle of 70° for up to 45 minutes. Drug treatment is often un-necessary but in severe cases 3-blockers (which inhibit the initial sympathetic activation) or disopyramide (a vagolytic agent) may be helpful.
Some antihypertensive drugs (e.g. prazosin, terazosin, labetalol, guanethidine, etc.) cause postural hypotension. So a patient on these antihypertensive drugs should not stand suddenly upright on being in a supine position for some time on a dental chair to avoid postural hypotension.
1. Clinically, hypertension is persistently raised arterial pressure which is primarily due to increased vascular resistance in the systemic circulation.
2. Hydrochiorothiazide is commonly used to treat mild or moderate hypertension either alone or in combination with sympatholytic and/or vasodilator antihypertensive drugs.
3. Frusemide causes severe reduction of blood volume and electrolyte imbalance, so it is not used in routine, It is indicated in hypertensive emergency, congestive cardiac failure and renal insufficiency.
4. Clonidine and alpha methyldopa cause fall in blood pressure by stimulating alpha-2 receptors on the vasomotor centre of the brain and thus decreasing sympathetic outflow from central nervous system to the peripheral vessels.
5. Except trimetaphan, being non-selective, other ganglionic blocking agents are no more used. Trimetaphan is used i.v. for hypertensive emergencies and to induce controlled hypotension for neurosurgery.
6. Because of frequent and disturbing side effects, guanethidine has practically gone out of use now.
7. Because of frequent side effects and limited efficacy, reserpine is seldom used now.
8. To treat mild hypertension, a thiazide or a beta blocker is used initially. Combined (2-drug) therapy may be given if response is not satisfactory.
9. To treat moderate or severe hypertension, use ACEI or calcium channel blockers alone or in combination. Add or substitute additional antihypertensive drugs, if patient is not responding to therapy.
10. To treat hypertension emergency, sodium nitroprusside or diazoxide is used parenterally. Alternatively, nifedipine sublingually or parenterally or hydralazine parenterally may be used.