Type Here to Get Search Results !

Antihypertensive Drugs

Chapter 40

Antihypertensive Drugs

Antihypertensive Drugs

These are drugs used to lower BP in hypertension.

Hypertension is a very common disorder, particularly past middle age. It is not a disease in itself, but is an important risk factor for cardiovascular mortality and morbidity. The cutoff manometric reading between normotensives and hypertensives is arbitrary. For practical purposes ‘hypertension’ could be that level of BP at or above which long-term antihypertensive treatment will reduce cardiovascular mortality. The JNC 7* (2003) and WHO-ISH@ guidelines (2003) have defined it to be 140 mm Hg systolic and 90 mm Hg diastolic, though risk appears to increase even above 120/80 mm Hg. Epidemiological studies have confirmed that higher the pressure (systolic or diastolic or both) greater is the risk of cardiovascular disease.

Majority of cases are of essential (primary) hypertension, i.e. the cause is not known. Sympathetic and renin-angiotensin systems may or may not be overactive, but they do contribute to the tone of blood vessels and c.o. in hypertensives, as they do in normotensives. Many antihypertensive drugs interfere with these regulatory systems at  one level or the other. Antihypertensive drugs, by chronically lowering BP, may reset the barostat to function at a lower level of BP.

Antihypertensive drug therapy has been remarkably improved in the last 50 years. Different classes of drugs have received prominence with passage of time in this period. Before 1950 hardly any effective and tolerated antihypertensive was available. Veratrum and Sod. thiocyanate could lower BP, but were toxic and difficult to use. The ganglion blockers developed in the 1950s were effective, but inconvenient. Reserpine was a breakthrough, but produced mental depression. The therapeutic potential of hydralazine could not be tapped fully because of marked side effects when it was used alone. Guanethidine introduced in 1961 was an improvement on ganglion blockers. The antihypertensives of the 1960– 70s were methyldopa, β blockers, thiazide and high ceiling diuretics and clonidine. The status of β blockers and diuretics was consolidated in the 1970s and selective α1 blocker prazosin broke new grounds. The antihypertensives of the 1980–90s are angiotensin II converting enzyme (ACE) inhibitors and calcium channel blockers. Angiotensin receptor blockers (losartan) are the latest antihypertensives. With the development of many types of drugs, delineation of their long-term benefits and complications, and understanding of the principles on which to combine them, hypertension can now be controlled in most cases with minimum discomfort.

* JNC 7—The seventh report of Joint National Committee (of USA) on prevention, detection, evaluation and treatment of high blood pressure. @ WHO-ISH—World Health Organization and International Society of Hypertension.

CLASSIFICATION

1. Diuretics 

Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide High ceiling: Furosemide, etc. K+ Sparing: Spironolactone, Amiloride.

2. ACE inhibitors 

Captopril, Enalapril, Lisinopril, Perindopril, Ramipril, Fosinopril, etc.

3. Angiotensin (AT1 receptor) blockers

Losartan, Candesartan, Irbesartan, Valsartan, Telmisartan.

4. Calcium channel blockers 

Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine, etc.

5. β Adrenergic blockers 

Propranolol, Metoprolol, Atenolol, etc.

7. α Adrenergic blockers 

Prazosin, Terazosin, Doxazosin Phentolamine, Phenoxybenzamine.

8. Central sympatholytic 

Clonidine, Methyldopa.

9. Vasodilators Arteriolar:

Hydralazine, Minoxidil, Diazoxide Arteriolar + venous: Sodium nitroprusside.

Adrenergic neurone blockers (Reserpine, Guanethidine, etc.) and ganglion blockers (Pentolinium, etc.) are only of historical importance, though reserpine is still marketed.

DIURETICS

Diuretics have been the standard antihypertensive drugs over the past 4 decades, though they do not lower BP in normotensives. Their pharmacology is described in Ch. 41.

Thiazides and related drugs (chlorthalidone, etc.) are the diuretic of choice in uncomplicated hypertension. The proposed mechanism of antihypertensive action is:

1. Initially, the diuresis reduces plasma and e.c.f. volume by 5–15% → decreased c.o. 

2. Subsequently, compensatory mechanisms operate to almost regain Na+ balance and plasma volume; c.o. is restored, but the fall in BP is maintained by a slowly developing reduction in t.p.r.

3. The reduction in t.p.r. is most probably an indirect consequence of a small (~5%) persisting Na+ and volume deficit. Decrease in intracellular Na+ concentration in the vascular smooth muscle may decrease stiffness of vessel wall, increase their compliance and dampen responsiveness to constrictor stimuli (NA, AII). Similar effects are produced by salt restriction; antihypertensive action of diuretics is lost when salt intake is high. A mild slowly developing vasodilator action of thiazides due to opening of smooth muscle K+ ATP channels and hyperpolarization has been proposed, but does not appear to be real.

The fall in BP develops gradually over 2–4 weeks. During long-term treatment with thiazides, the heart rate and c.o. are unaffected, while t.p.r. is reduced despite compensatory increase in plasma renin activity, which confirms persisting Na+ deficit. They have no effect on capacitance vessels, sympathetic reflexes are not impaired: postural hypotension is rare. Thiazides are mild antihypertensives, average fall in mean arterial pressure is ~10 mm Hg. They are effective by themselves in ~ 30% cases (mostly low grade hypertension) but they potentiate all other antihypertensives (except DHPs) and prevent development of tolerance to these drugs by not allowing expansion of plasma volume. They are more effective in the elderly and maximal antihypertensive efficacy is reached at doses equivalent to 25 mg of hydrochlorothiazide/day, though higher doses produce greater diuresis.

High ceiling diuretics Furosemide, the prototype of this class, is a strong diuretic, but the antihypertensive efficacy does not parallel diuretic potency. Furosemide is a weaker antihypertensive than thiazides: fall in BP is entirely dependent on reduction in plasma volume and c.o. The explanation to this paradox may lie in its brief duration of action. The natriuretic action lasting only 4–6 hr after the conventional morning dose is followed by compensatory increase in proximal tubular reabsorption of Na+. The Na+ deficient state in vascular smooth muscle may not be maintained round-the-clock. The t.p.r. and vascular responsiveness are not reduced. 

Moreover, the high ceiling diuretics are more liable to cause fluid and electrolyte imbalance, weakness and other side effects. They are indicated in hypertension only when it is complicated by:

(a) Chronic renal failure: thiazides are ineffective, both as diuretics and antihypertensives.

 (b) Coexisting refractory CHF.

 (c) Resistance to combination regimens containing a thiazide, or marked fluid retention due to use of potent vasodilators.

Desirable properties of diuretics as antihypertensives are:

1. Once a day dosing and flat dose-response curve permitting simple standardized regimens. 

2. No fluid retention, no tolerance.

 3. Low incidence of postural hypotension and relative freedom from side effects, especially CNS, compared to sympatholytics. 

4. Effective in isolated systolic hypertension (ISH). 

5. Lessened risk of hip fracture in the elderly due to hypocalciuric action of thiazides. 

6. Low cost

Current status of diuretics as antihypertensives

The popularity of diuretics as antihypertensive has had ups and downs. In the 1960–70s they were almost routinely prescribed alone or in combination to nearly all hypertensive patients. The usual dose used was hydrochlorothiazide 50 mg/day or equivalent. Soon a number of drawbacks were highlighted:

Hypokalemia—muscle pain, fatigue and loss of energy.

Erectile dysfunction in males. 

Carbohydrate intolerance: due to inhibition of insulin release (probably secondary to K+ depletion which interferes with conversion of proinsulin to insulin), precipitation of diabetes.

Dyslipidemia: rise in total and LDL cholesterol and triglycerides with lowering of HDL. This could increase atherogenic risk, but no direct evidence has been obtained. 

Hyperuricemias: by inhibiting urate excretion—increased incidence of gout. 

Increased incidence of sudden cardiac death: attributed to episodes of torsade's de pointes and ischemic ventricular fibrillation precipitated by hypokalemia.

Consequently, prescribing of diuretics fell. Over the past 20 years thiazides have been used at lower doses (12.5–25 mg/day hydrochlorothiazide or equivalent) alone and in combination with a K+ sparing diuretic.

The multiple risk factor intervention trial (1982), the Medical research council trial (1987, 1992), the systolic hypertension in the elderly programme (SHEP, 1991) and a case control study (1994) demonstrated that increased incidence of death associated with thiazide diuretic use in the elderly was dose-dependent, and that 25 mg/day hydrochlorothiazide (or equivalent) yielded the best benefit-risk ratio. Favourable results obtained with ≤ 25 mg/day in the above and subsequent studies, including ALLHAT (2002) and a meta-analysis (2003) have reinstated thiazide diuretics as the first choice antihypertensive.

Findings with low dose thiazide therapy are:

Though serum K+ falls a little, significant hypokalemia does not occur.

 Continuous ECG recording studies have failed to document increased incidence of arrhythmias during low-dose thiazide therapy.

Impairment of glucose tolerance or increase in serum cholesterol or hyperuricemia over long-term are unlikely.

 Whereas earlier data had failed to document reduction in the incidence of MI with thiazides, analysis of recent trials has found them to reduce fatal and nonfatal MI by 27–44%. The incidence of stroke is reduced by 31–49%. Overall mortality and morbidity is reduced in long-term trials. 

Though not as effective as ACE inhibitors, some recent trials in mild to moderate hypertension have found thiazides to reduce left ventricular mass.

The JNC 7 recommends instituting low-dose (12.5–25 mg) thiazide therapy, preferably with added K+ sparing diuretic, as a first choice treatment of essential hypertension, especially in the elderly. Higher doses are neither more effective nor safe. If the low dose (25 mg/day) fails to reduce BP to desired level, another antihypertensive should be added, rather than increasing dose of the diuretic. However, in the treatment of severe hypertension when potent vasodilators/ sympatholytics have induced fluid retention, higher dose of thiazide or a loop diuretic may be appropriate. Not withstanding the above, there are subsets of patients in whom other antihypertensives are more suitable. Some patients complain impairment of quality of life with diuretics.

Potassium sparing diuretics Spironolactone or amiloride themselves lower BP slightly, but they are used only in conjunction with a thiazide diuretic to prevent K+ loss and to augment the antihypertensive action.

Indapamide It is a mild diuretic, chemically related to chlorthalidone; reduces BP at doses which cause little diuresis. Electrolyte disturbances and K+ loss are minimal at antihypertensive doses. In post-stroke patients, indapamide, with or without ACE inhibitor, reduces the risk of further stroke. It probably has additional vasodilator action exerted through alteration of ionic fluxes across vascular smooth muscle cell. Indapamide is well absorbed orally, has an elimination t½ of 16 hr. Single daily dose (2.5 mg) is enough.

LORVAS, NATRILIX 2.5 mg tab, NATRILIX-SR 1.5 mg SR tab

It is well tolerated: side effects are minor g.i. symptoms and fatigue. Hypokalaemia is infrequent.

ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS

The ACE inhibitors are one of the first choice drugs in all grades of essential as well as renovascular hypertension (except those with bilateral renal artery stenosis). Most patients require relatively lower doses (enalapril 2.5–10 mg/day or equivalent) which are well tolerated. 

Used alone they control hypertension in ~50% patients, and addition of a diuretic/β blocker extends efficacy to ~90%. Because of supraadditive synergism, only a low dose of diuretic (12.5 mg of hydrochlorothiazide, rarely 25 mg) needs to be added. The pharmacology and use of ACE inhibitors in hypertension are described in Ch. 36. Of particular mention are their renal blood flow improving action, their potential to retard diabetic nephropathy and their capacity to regress left ventricular/vascular hypertrophy. They are the most appropriate antihypertensives in patients with diabetes, nephropathy (even nondiabetic), left ventricular hypertrophy, CHF, angina and post MI cases. Several large prospective studies including AIRE (1993), HOPE (2000), ALLHAT (2002) have confirmed the antihypertensive and cardioprotective effects of ACE inhibitors. They appear to be more effective in younger (< 55 year) hypertensives than in the elderly. Dry persistent cough is the most common side effect requiring discontinuation of ACE inhibitors.

ANGIOTENSIN RECEPTOR BLOCKERS

The pharmacology of losartan and other angiotensin receptor blockers (ARBs) is described on p. 488. In a dose of 50 mg/day losartan is an effective antihypertensive. Action manifests early and progresses to peak at 2–4 weeks. Addition of 12.5 mg/day hydrochlorothiazide further enhances the fall in BP. The newer ARBs—valsartan, candesartan, irbesartan and telmisartan have been shown to be as effective antihypertensives as ACE inhibitors, while losartan may be somewhat weaker than high doses of ACE inhibitors. ARBs are remarkably free of side effects. Because they do not increase kinin levels, the ACE inhibitor related cough is not encountered. Angioedema, urticaria and taste disturbance are also rare. Though effects of ACE inhibitors and ARBs are not identical, the latter have all the metabolic and prognostic advantages of ACE inhibitors. 

Several interventional endpoint reduction trials like LIFE (2002), VALUE (outcomes in hypertensive patients with valsartan or amlodipine, 2004), SCOPE (study on cognition and prognosis in the elderly; stroke prevention with candesartan in elderly with isolated systolic hypertension, 2004), JLIGHT (Japanese losartan therapy intended for global renal protection in hypertensive patients, 2004) have attested to the favorable effects of ARBs on morbidity and mortality in hypertensive patients. 

The value of combining ARBs with ACE inhibitors is discussed on p. 489.

CALCIUM CHANNEL BLOCKERS

Calcium channel blockers (CCBs) are another class of first line antihypertensive drugs. Their pharmacology is described in Ch. 39. All 3 subgroups of CCBs, viz. dihydropyridines (DHPs, e.g. amlodipine), phenylalkylamine (verapamil) and benzothiazepine (diltiazem) are equally efficacious antihypertensives. They lower BP by decreasing peripheral resistance without compromising c.o. Despite vasodilatation, fluid retention is insignificant.

Ankle edema that occurs in some patients is due to increased hydrostatic pressure across capillaries of the dependent parts as a result of reflex constriction of post capillary vessels in these vascular beds.

The onset of antihypertensive action is quick. With the availability of long acting preparations, most agents can be administered once a day. Monotherapy with CCBs is effective in ~ 50% hypertensives; their action is independent of patient’s renin status, and they may improve arterial compliance. Other advantages of CCBs are:

1. Do not compromise haemodynamics: no impairment of physical work capacity. 

2. No sedation or other CNS effects; cerebral perfusion is maintained. 

3. Not contraindicated in asthma, angina (especially variant) and PVD patients: may benefit these conditions. 

4. Do not impair renal perfusion. 

5. Do not affect male sexual function.

6. No deleterious effect on plasma lipid profile, uric acid level and electrolyte balance.

7. Shown to have no/minimal effect on quality of life. 

8. No adverse foetal effects: can be used during pregnancy (but can weaken uterine contractions during Laboure).

In the past few years large amount of data from controlled trials (HINT, TRENT, SPRINT I, II) and metaanalysis has consistently indicated increased mortality/reinfarction in patients treated with standard nifedipine (or other shortacting DHP) formulations. This increase in mortality is dose-related. Worsening of unstable angina and CHF has also been noted. The CCBs do not decrease venous return. DHPs may even increase it and jeopardise haemodynamics in patients with diastolic dysfunction. DHPs (especially short-acting) also tend to increase HR and c.o. by invoking reflex sympathetic stimulation. The increased mortality among coronary heart disease patients has been attributed to repeated surges of adrenergic discharge and marked swings of BP attending each dose of rapidly acting DHP. However, this risk cannot be extrapolated to verapamil/ diltiazem as broughtout by DAVIT I, II and other controlled studies, as well as to slow acting DHPs (amlodipine type) including nifedipine GITS (gastrointestinal therapeutic system).

In the past few years large amount of data from controlled trials (HINT, TRENT, SPRINT I, II) and metaanalysis has consistently indicated increased mortality/reinfarction in patients treated with standard nifedipine (or other shortacting DHP) formulations. This increase in mortality is dose-related. Worsening of unstable angina and CHF has also been noted. The CCBs do not decrease venous return. DHPs may even increase it and jeopardise haemodynamics in patients with diastolic dysfunction. DHPs (especially short-acting) also tend to increase HR and c.o. by invoking reflex sympathetic stimulation. The increased mortality among coronary heart disease patients has been attributed to repeated surges of adrenergic discharge and marked swings of BP attending each dose of rapidly acting DHP. However, this risk cannot be extrapolated to verapamil/ diltiazem as broughtout by DAVIT I, II and other controlled studies, as well as to slow acting DHPs (amlodipine type) including nifedipine GITS (gastrointestinal therapeutic system).

The JNC 7 have considered CCBs to be less suitable for monotherapy in hypertensives with no other risk factors, because they appear to afford less prognostic benefits than thiazides, β blockers and ACE inhibitors/ARBs. However, CCBs are still widely used as one of the first line monotherapy options because of their high efficacy and excellent tolerability. They are preferred in the elderly hypertensive. Also there is convincing evidence of their stroke preventing potential (syst EUR, ALLHAT studies). The long-acting DHPs are next to ACE inhibitors in reducing albuminuria and slowing disease progression in hypertensive/diabetic nephropathy. They are the most useful antihypertensives in cyclosporine induced hypertension in renal transplant recipients.

Use of rapid acting oral nifedipine for urgent BP lowering in hypertensive emergencies is out moded. In fact, there is currently no therapeutic indication for rapid and short-acting oral DHPs in hypertension.

Other concerns in the use of CCBs as antihypertensive are:

(i) The negative inotropic/dromotropic action of verapamil/diltiazem may worsen CHF and cardiac conduction defects (DHPs are less likely to do so). 

(ii) By their smooth muscle relaxant action, the DHPs can worsen gastroesophageal reflux.

(iii) CCBs (especially DHPs) may accentuate bladder voiding difficulty in elderly males.

β-ADRENERGIC BLOCKERS

The pharmacology and mechanism of antihypertensive action of β blockers is described in Ch. 10. They are mild antihypertensives; do not significantly lower BP in normotensives. Used alone they suffice in 30–40% patients—mostly mild to moderate cases. In the large majority of the rest, they can be usefully combined with other drugs.

The hypotensive response to β blockers develops over 1–3 weeks and is well sustained. Despite short and differing plasma half lives, the antihypertensive action of most β blockers is maintained over 24 hr with a single daily dose.

All β blockers, irrespective of associated properties, exert similar antihypertensive effect. Drugs with intrinsic sympathomimetic activity (ISA) cause less reduction of HR and c.o. but lower vascular resistance by β2 agonism. The nonselective β blockers slightly reduce renal blood flow and g.f.r., but this is minimal in the β1 selective ones and those with ISA.

There are several contraindications to β blockers, including cardiac, pulmonary and peripheral vascular disease. The nonselective β blockers have an unfavourable effect on lipid profile (raise triglyceride level and LDL/HDL ratio). They have also fared poorly on quality of life parameters like decreased work capacity, fatigue, loss of libido and subtle cognitive effects (forgetfulness, low drive), nightmares and increased incidence of antidepressant use. However, most of these drawbacks are minimized in the β1 selective agents and in those which penetrate brain poorly. Thus, there are several reasons to prefer a β1 selective hydrophilic drug like atenolol over propranolol.

Because of absence of postural hypotension, bowel alteration, salt and water retention; a low incidence of side effects, low cost; once a day regimen and cardioprotective potential, β blockers continue to be among the first choice drugs recommended by JNC 7 and WHO-ISH, especially for relatively young nonobese hypertensives, those prone to psychological stress or those with ischaemic heart disease—particularly postinfarction. β blockers and ACE inhibitors are the most effective drugs for preventing sudden cardiac death in postinfarction patients; all cause mortality has been lowered in long-term trials. Hypertensives with stable heart failure should be treated with a β blocker that has been shown to be effective in retarding CHF progression (metoprolol/bisoprolol/carvedilol) along with an ACE inhibitor/ARB (CIBIS, 1999; MERIT-HF, 1999, COPERNICUS, 2002 studies). β blockers are considered less effective and less suitable for the older hypertensive. The LIFE (2002) and ALLHAT (2002) trials have found β blockers to be inferior to low-dose thiazide or ACE inhibitor/ARB (losartan) or a combination of these in preventing stroke, as well as in diabetic patients. As monotherapy, ACE inhibitors/ARBs and CCBs appear to compromise quality of life less than β blockers. Rebound hypertension has occurred on sudden discontinuation of β blockers.

β+α ADRENERGIC BLOCKERS

Labetalol (see Ch. 10). It is a combined α and β blocker; reduces t.p.r. and acts faster than pure β blockers. It has been used i.v. for rapid BP reduction in cheese reaction, clonidine withdrawal, etc. Oral labetalol therapy is restricted to moderately severe hypertension not responding to pure β blocker. Side effects of both α blocker and β blocker occur with it.

Carvedilol This nonselective β + selective α1 blocker produces vasodilatation and has additional antioxidant/ free radical scavenging properties. Whether these ancillary properties confer any superiority is not known. It has also been used in CHF. Side effects are similar to labetalol; liver enzymes may rise in some.

α-ADRENERGIC BLOCKERS

Prazosin (See Ch. 10)

This prototype selective α1 antagonist dilates both resistance and capacitance vessels; effect on the former predominating. The haemodynamic effects—reduction in t.p.r. and mean BP with only slight decrease in venous return and c.o. are similar to that produced by a direct acting vasodilator. However, there is little reflex cardiac stimulation and renin release during long-term therapy. Tachycardia does not compensate for the fall in BP, because release inhibitory α2 (presynaptic) receptors are not blocked: autoregulation of NA release remains intact. It probably decreases central sympathetic tone also.

Renal blood flow and g.f.r. are maintained but fluid retention may attend hypotension. Cardiovascular reflexes are not appreciably impaired by chronic therapy, but postural hypotension and fainting may occur in the beginning—called ‘first dose effect’, and with dose increments. This disappears with continued therapy, but may persist in the elderly. For this reason, prazosin is always started at low dose (0.5 mg) given at bedtime and gradually increased with twice daily administration till an adequate response is produced (max. dose 10 mg BD). Patients who develop marked first dose effect generally require lower maintenance doses (2–6 mg/ day). An oral dose produces peak fall in BP after 4–5 hours and the effect lasts for nearly 12 hours, though plasma t½ is only 3 hours. This may be due to generation of active metabolites.

Other advantages of prazosin are:

1. Improves carbohydrate metabolism; suitable for diabetics, but not if neuropathy is present —postural hypotension is accentuated. 

2. Has favourable effect on lipid profile: lowers LDL cholesterol and triglycerides, increases HDL. 

3. Affords symptomatic improvement in coexisting PVD or benign prostatic hypertrophy.

MINIPRESS XL: Prazosin GITS 2.5 mg, 5 mg tabs.; PRAZOPRESS 1, 2 mg tabs.

Adverse effects Prazosin is generally well tolerated at low doses. Apart from postural hypotension related symptoms (to which tolerance frequently develops), other side effects are headache, drowsiness, dry mouth, weakness, palpitation, nasal blockade, blurred vision and rash. Ejaculation may be impaired in males: especially with higher doses. Fluid retention attending prazosin monotherapy may precipitate CHF. Prazosin is a moderately potent antihypertensive with many desirable features, but is not used as a first line drug because fluid retention and tolerance gradually develops with monotherapy—necessitating dose increase—more side effects and risk of CHF. It may be added to a diuretic + β blocker in those not achieving target BP. 

Terazosin, Doxazosin These are long-acting congeners of prazosin with similar properties and suitable for once daily dosing (see p. 134). In the ALL HAT (2002) study doxazosin monotherapy has doubled the incidence of CHF; but this can occur with any α1 blocker. A higher incidence of stroke relative to patients receiving a thiazide diuretic was also noted.

Nonselective α blockers (Phentolamine, Phenoxybenzamine)

The conventional α blockers have been disappointing for routine treatment of hypertension, because fall in t.p.r. is compensated by increased HR and c.o. They block both α1 and α2 receptors—NA release is accentuated. They are reserved for special situations like pheochromocytoma, clonidine withdrawal, cheese reaction, etc., where circulating CAs are responsible for the rise in BP.

CENTRAL SYMPATHOLYTICS

Clonidine

It is an imidazoline derivative having complex actions. Clonidine is a partial agonist with high affinity and high intrinsic activity at α2 receptors, especially α2A subtype in brainstem. The major haemodynamic effects result from stimulation of α2A receptors present mainly postjunctionally in medulla (vasomotor centre) → decrease sympathetic out flow → fall in BP and bradycardia (also due to enhanced vagal tone). Plasma NA declines. Though clonidine is capable of reducing NA release from peripheral adrenergic nerve endings (release inhibitory prejunctional α2 action), this is not manifest at clinically used doses. Clonidine is a moderately potent antihypertensive.

Presence of Imidazoline receptors which are distinct from α2 receptors has now been confirmed both in the brain as well as periphery. These are activated by clonidine and related drugs but not by NA. Experimental evidence suggests that clonidine may first stimulate central imidazoline receptors which then trigger medullary α2A receptors to reduce sympathetic outflow. Clonidine also appears to directly stimulate α2A receptors to produce hypotension and sedation. Rilmenidine and moxonidine are selective cerebral imidazoline receptor agonists with low α2 receptor affinity. Therefore, they have low sedative property but equivalent antihypertensive action.

Rapid i.v. injection of clonidine raises BP transiently due to activation of peripheral postsynaptic vasoconstrictor α2B receptors at the high concentrations so attained. Oral doses producing lower plasma clonidine levels cause only fall in BP, because clonidine has lower intrinsic activity on α2B receptors which predominate in vascular smooth muscle. Probably for the same reason clonidine exhibits the therapeutic window phenomenon: optimum lowering of BP occurs between blood levels of 0.2–2.0 ng/ml. At higher concentrations fall in BP is less marked.

On chronic administration of clonidine decrease in c.o. contributes more to the fall in BP than decrease in t.p.r. Cardiovascular reflexes are affected little. Decreased sympathetic flow to the kidney results in reduced renin release. It does not alter plasma lipid levels.

Pharmacokinetics Clonidine is well absorbed orally; peak occurs in 2–4 hours; 1/2 to 2/3 of an oral dose is excreted unchanged in urine, the rest as metabolites. Plasma t½ is 8–12 hours. Effect of a single dose lasts for 6–24 hours.

Dose: Start with 100 μg OD or BD, max. 300 μg TDS, orally or i.m.

CATAPRES 150 μg tab, ARKAMIN 100 μg tab.

Adverse effects Side effects with clonidine are relatively common.

Sedation, mental depression, disturbed sleep; dryness of mouth, nose and eyes (secretion is decreased by central action), constipation (antisecretory effect on the intestines).

Impotence, salt and water retention, bradycardia (due to reduced sympathetic tone). 

Postural hypotension occurs, but is mostly asymptomatic. 

Alarming rise in BP, in excess of pretreatment level, with tachycardia, restlessness, anxiety, sweating, headache, nausea and vomiting occur in some patients when doses of clonidine are missed for 1–2 days. The syndrome is very similar to that seen in pheochromocytoma: plasma catecholamine (CA) concentration is increased. 

This is due to: 

(a) Sudden removal of central sympathetic inhibition resulting in release of large quantities of stored CAs. 

(b) Super sensitivity of peripheral adrenergic structures to CAs that develops due to chronic reduction of sympathetic tone during clonidine therapy. 

A combination of α blocker with a β blocker, or a potent vasodilator or clonidine itself can be used to treat the syndrome.

Interactions Tricyclic antidepressants and chlorpromazine abolish the antihypertensive action of clonidine, probably by blocking α receptors on which clonidine acts.

Use Clonidine was a popular antihypertensive in the late 1960s and 1970s, but frequent side effects, risk of withdrawal hypertension and development of tolerance to its monotherapy have relegated it to a 3rd or 4th choice drug. At present, it is occasionally used in combination with a diuretic.

Other indications

1. Opioid withdrawal: Opioid and α2 adrenergic systems converge on the same effectors in many systems; both activate the Gi regulatory protein. Clonidine suppresses sympathetic overactivity of opioid withdrawal syndrome and reduces craving to some extent. Clonidine has also facilitated alcohol withdrawal and smoking cessation. 

2. Clonidine has analgesic activity. It has been used to substitute morphine for intrathecal/epidural surgical and postoperative analgesia. 

3. Administered preoperatively, it diminishes an aesthetic requirement. 

4. Clonidine attenuates vasomotor symptoms of menopausal syndrome. 

5. Clonidine has been used to control loose motions due to diabetic neuropathy—may be acting by α2 receptor mediated enhancement of salt absorption in gut mucosa. 

6. Clonidine suppression test for pheochromocytoma: clonidine reduces plasma NA concentration to < 0.5 ng/ ml in patients of essential hypertension but not in those with pheochromocytoma.

Methyldopa It is the α-methyl analogue of dopa, the precursor of dopamine (DA) and NA. The α methyl-NA (a selective α2 agonist) formed in the brain from methyldopa acts on central α2 receptors to decrease efferent sympathetic activity. Because methyldopa decreases t.p.r. more than HR or c.o., it may be acting on a different population of neurons in the vasomotor centre than clonidine. In large doses, methyldopa inhibits the enzyme dopa decarboxylase in brain and periphery → reduces NA synthesis and forms the false transmitter methyl-NA in periphery as well. These mechanisms were considered to be responsible for the antihypertensive effect; but it was demonstrated that neither responses to stimulation of sympathetic nerves nor their NA content was reduced at clinically used antihypertensive doses. Moreover, α methyl NA is as potent vasoconstrictor as NA. The primary central site of action of methyldopa has been confirmed. 

Methyldopa is a moderate efficacy antihypertensive. Circulating levels of NA and renin tend to fall due to reduction in sympathetic tone. Inhibition of postural reflexes is mild.

Pharmacokinetics Though methyldopa is transported actively by intestinal amino acid carrier, less than 1/3 of an oral dose is absorbed. It is partly metabolized and partly excreted unchanged in urine. Antihypertensive effect develops over 4–6 hours and lasts for 12–24 hours. Dose: 0.25–0.5 g BD–QID oral.

EMDOPA, ALPHADOPA 250 mg tab

Adverse effects Sedation, lethargy and reduced mental capacity are common side effects. 

Cognitive impairment may develop. Dryness of mouth, nasal stuffiness, headache, fluid retention, weight gain, impotence. Postural hypotension is generally mild but more common than with clonidine; occurs especially in the elderly patients and in those receiving a diuretic.

Positive Coomb’s test occurs in 1/6 patients, few develop haemolytic anaemia. Fever, rash, hepatitis, ‘flu’ like illness, thrombocytopenia and rarely lupus syndrome occur. Rebound hypertension on sudden withdrawal of methyldopa is mild and less common.

Interactions Tricyclic antidepressants reverse its action by blocking its active transport into the adrenergic neurones.

Use Methyldopa was a widely used antihypertensive, especially in combination with a diuretic. However, it is infrequently used now, except to treat hypertension during pregnancy wherein it has a long track record of safety, both for the mother as well as the foetus.

VASODILATORS

Hydralazine/Dihydralazine It is a directly acting arteriolar vasodilator with little action on venous capacitance vessels; reduces t.p.r. It causes greater reduction of diastolic than systolic BP. Reflex compensatory mechanisms are evoked which cause tachycardia, increase in c.o. and renin release → increased aldosterone → Na+ and water retention. The disproportionate cardiac stimulation appears to involve direct augmentation of NA release and myocardial contractility as well. Thus, a hyperdynamic circulatory state is induced—angina may be precipitated due to increased cardiac work as well as steal phenomenon. There is no reduction in renal blood flow despite fall in BP. However, fluid retention and edema may occur by the above mechanism. Tolerance to the hypotensive action develops unless diuretics or β blockers or both are given together to block the compensatory mechanisms.

The mechanism of vascular smooth muscle relaxant action of hydralazine is not clearly known. It is partly endothelium dependent: may involve generation of NO (nitric oxide) and stimulation of cGMP. Direct effects on membrane potential and on Ca2+ fluxes have also been proposed.

Pharmacokinetics Hydralazine is well absorbed orally, and is subjected to first pass metabolism in liver. The chief metabolic pathway is acetylation which exhibits a bimodal distribution in the population: there are slow and fast acetylators. Bioavailability is higher in slow acetylators, but these patients are more prone to develop the lupus syndrome. 

Hydralazine is completely metabolized both in liver and plasma; the metabolites are excreted in urine, t½ 1–2 hours. However, hypotensive effect lasts longer (12 hours), probably because of its persistence in the vessel wall.

Dose: 25–50 mg OD–TDS; NEPRESOL 25 mg tab.

Adverse effects are frequent and mainly due to vasodilatation.

1. Facial flushing, conjunctival injection, throbbing headache, dizziness, palpitation, nasal stuffiness, fluid retention, edema, CHF. 

2. Angina and MI may be precipitated in patients with coronary artery disease.

 3. Postural hypotension is not prominent because of little action on veins: venous return and c.o. are not reduced. 

4. Paresthesia's, tremor, muscle cramps, rarely peripheral neuritis. 

5. Lupus erythematosus or rheumatoid arthritis like symptoms develop on prolonged use of doses above 100 mg/day. It is more common in women and in slow acetylators. It is slowly reversible on stopping treatment. 

Use Hydralazine is used in moderate-to-severe hypertension not controlled by the first line drugs. Usually, low doses are added to the diuretic and β blocker already being administered. It is not used alone. Large doses are not recommended for long periods. Hydralazine is used in moderate-to-severe hypertension not controlled by the first line drugs. Usually, low doses are added to the diuretic and β blocker already being administered. It is not used alone. Large doses are not recommended for long periods.

Hydralazine can be used in patients with renal involvement, but is contraindicated in older patients and in those with ischaemic heart disease. It is one of the preferred antihypertensives during pregnancy because of decades of experience and record of safety. It can also be used parenterally in hypertensive emergencies. 

The arteriolar dilator action of hydralazine can be employed in the management of CHF (see p. 504–505).

Minoxidil It is a powerful vasodilator, the pattern of action resembling hydralazine, i.e. direct relaxation of arteriolar smooth muscle with little effect on venous capacitance. Marked vasodilatation elicits strong compensatory reflexes: increased renin release and proximal tubular Na+ reabsorption → marked Na+ and water retention → edema and CHF may occur; increased sympathetic activity → palpitation, increased c.o. To offset these, it has to be used along with a loop diuretic and a β blocker

Minoxidil is a prodrug—converted to an active metabolite (by sulfate conjugation) which is an opener of ATP operated K+ channels; acts by hyperpolarizing smooth muscle. 

Minoxidil is indicated only rarely in severe or lifethreatening hypertension.

Use in alopecia Oral minoxidil increases growth of body hair. Applied topically (2% twice daily) it promotes hair growth in male pattern baldness and alopecia areata. The response is slow (takes 2– 6 months) and incomplete, but upto 60% subjects derive some benefit, albeit for short periods. Baldness recurs when therapy is discontinued. 

The mechanism of increased hair growth is not known; may involve:

(a) Enhanced microcirculation around hair follicles. 

(b) Direct stimulation of resting hair follicles.

(c) Alteration of androgen effect on genetically programmed hair follicles.

Local irritation, itching and burning sensation are frequent. Dermatological reaction and systemic side effects (headache, dizziness, palpitation) occur in 1–3% cases.

MINTOP, GROMANE 2% scalp lotion, MULTIGAIN 2% topical solution and metered spray, MANEXIL 5% gel; apply twice a day.

Diazoxide This K+ channel opener dilator of arterioles was used in the past for rapid reduction of BP in hypertensive emergencies. It is administered by rapid i.v. injection in fractional doses (50–100 mg) repeated every 5–10 min, as required. Slow i.v. injection or infusion is less effective because it binds tightly to plasma proteins before binding to vessel wall.

The duration of action is long (6–24 hours) because of tight binding to plasma and tissue proteins. It is employed in place of nitroprusside when regulated i.v. infusion or close monitoring is not possible. 

Sodium nitroprusside It is a rapidly (within seconds) and consistently acting vasodilator; has brief duration of action (2–5 min)—vascular tone can be titrated with the rate of i.v. infusion. It relaxes both resistance and capacitance vessels: reduces t.p.r. as well as c.o. (by decreasing venous return). Myocardial work is reduced ischemia is not accentuated, as occurs with selective arteriolar dilators (hydralazine). Little reflex tachycardia is produced in supine posture. Plasma renin is increased. In patients with heart failure and ventricular dilatation, nitroprusside improves ventricular function and CO by reducing cardiac preload and afterload.

Endothelial cells, RBCs (and may be other cells) split nitroprusside to generate NO which relaxes vascular smooth muscle. The enzymes involved are different from those that produce NO from glyceryl trinitrate. Moreover, nitroprusside is nonenzymatically converted to NO (and CN) by glutathione. This may be responsible for the different pattern of vasodilator action compared to nitrates, as well as for the fact that no nitrate like tolerance develops to nitroprusside action.

Nitroprusside has gained popularity in the management of hypertensive emergencies; 50 mg is added to a 500 ml bottle of saline/glucose solution. The infusion is started at 0.02 mg/min and titrated upward with the response: 0.1–0.3 mg/min is often needed. It decomposes at alkaline pH and on exposure to light: the infusion bottle should be covered with black paper.

Nitroprusside is split to release cyanide. The latter is converted in liver to thiocyanate which is excreted slowly. If larger doses are infused for more than 1–2 days, excess thiocyanate may accumulate and produce toxicity, including psychosis.

Side effects mainly due to vasodilatation are— palpitation, nervousness, vomiting, perspiration, pain in abdomen, weakness, disorientation, and lactic acidosis (caused by the released cyanide).

Nitroprusside has also been used to produce controlled hypotension, in refractory CHF, pump failure accompanying MI and in acute mitral regurgitation.

SONIDE, PRUSIDE, NIPRESS 50 mg in 5 ml inj.

ADRENERGIC NEURONE BLOCKERS

Reserpine It is an alkaloid from the roots of Rauwolfia serpentina (sarpgandha) indigenous to India which has  been used in ‘Ayurvedic’ medicine for centuries. The pure alkaloid was isolated in 1955 and later found to act by causing CA and 5-HT depletion. It was a popular antihypertensive of the late 1950s and early 1960s, but is now used only as a pharmacological tool.

Reserpine acts at the membrane of intraneuronal granules which store monoamines (NA, 5-HT, DA) and irreversibly inhibits the active amine transporters → the monoamines are gradually depleted and degraded by MAO. The effects last long after the drug is eliminated (hit and run drug) because tissue CA stores are restored only gradually.

Higher doses deplete CAs and 5-HT in the brain as well; cause sedation and mental depression. Antipsychotic effect (mild) and extrapyramidal symptoms are produced due to DA depletion.

SERPASIL 0.25 mg tab; 1 mg/ml inj.

Guanethidine It is a polar guanidine compound which is taken up into the adrenergic nerve endings by active amine transport, and has three important facets of action:

(a) Displaces NA from storage granules stoichiometrically. 

(b) Inhibits nerve impulse coupled release of NA.

(c) Engages and blocks NA uptake mechanism at the axonal membrane. Guanethidine has gone out of use now due to marked side effects.

TREATMENT OF HYPERTENSION

The aim of antihypertensive therapy is to prevent morbidity and mortality associated with persistently raised BP by lowering it to an acceptable level, with minimum inconvenience to the patient. Both systolic and diastolic BP predict the likelihood of target organ damage and complications such as: 

(a) Cerebrovascular disease, transient ischaemic attacks, stroke, encephalopathy.

(b) Hypertensive heart disease—left ventricular hypertrophy, CHF.

(c) Coronary artery disease (CAD), angina, myocardial infarction, sudden cardiac death.

(d) Arteriosclerotic peripheral vascular disease, retinopathy.

(e) Dissecting aneurysm. 

(f) Glomerulopathy, renal failure.

The JNC 7 (2003) has reclassified BP readings as:

Since the risk of complications depends not only on the level of BP, but also on other risk factors (see box) and existing target organ damage (TOD), these have also to be considered in deciding when to start drug therapy, in selection of drugs and in devising therapeutic regimens.

The JNC7 have also identified compelling indications (see box) which may mandate use of specific antihypertensive drugs even in patients with BP values in the ‘prehypertension’ range. Moreover, presence of compelling indications may suggest fixing a lower target BP value to be attained by drug therapy.

Beneficial effects of lowering BP has been established in all patients having BP above 140/ 90 mm Hg, and even in the 120–139 (systolic) or 80–89 mm Hg (diastolic) range in those with compelling indications or cardiovascular risk factors; e.g. in diabetics, lowering diastolic BP to 80 mmHg was found to reduce cardiovascular events more than reducing it upto 90 mm Hg.

If the cause of hypertension can be identified (hormonal, vascular abnormality, tumours, renal disease, drugs) all efforts should be made to remove it. Nonpharmacological measures (life style modification—diet, Na+ restriction, aerobic activity or exercise, weight reduction, moderation in alcohol intake, mental relaxation, etc.) should be tried first and concurrently with drugs. The level to which BP should be lowered is uncertain. A value of < 140 systolic and < 90 mmHg diastolic is considered adequate response, because it clearly reduces morbidity and mortality, though risk reduction may continue upto 120/80 mmHg in terms of CAD, heart failure, stroke, etc. When significant cardiovascular and/or renal damage has already occurred, lowering BP to normotensive level may not be tolerated: edema, CHF, angina, rise in blood urea and syncope may be precipitated: reduce BP gradually and only to the level tolerated.

The Swedish trial in old patients with hypertension-2 (STOP-2, 1999) conducted over 5 years in 6614 hypertensives aged 70–84 years has shown that conventional therapy with diuretic and/or β blockers is as effective in reducing BP and risk of major cardiovascular events as are ACE inhibitors or CCBs. The ALLHAT (2002) study comparing chlorthalidone, lisinopril and amlodipine has also found no difference in the primary outcomes of death and MI. The results convey that efficacy wise there is little to choose among the 4 classes of drugs; choice of initial drug has to be guided by associated features/contraindications and acceptable side effects in individual patients.

With the establishment of at least five groups (ACE inhibitors; AT1 antagonists, CCBs, β blockers, diuretics) of first choice drugs and their evaluation in large multicentric trials, an ‘individualized care approach’ can be adopted for the selection of initial monotherapy, followed if needed, by stepped combination therapy. The principle of this approach is to match the lifestyle issues, tolerability and concomitant medical conditions of individual patients with the pharmacological and clinical properties of an appropriate antihypertensive drug. For each class of antihypertensive drugs, certain patients can be identified who are best suited to be treated with that drug as first choice therapy, and those in whom it should be avoided (see box). 

The general principles of antihypertensive therapy enunciated in JNC7 and WHO-ISH guidelines may be summarized as:

1. Except for stage II hypertension, start with a single most appropriate drug which for majority of patients is a thiazide. However, a β blocker, ACE inhibitor, ARB or CCB may also be considered. The CCBs may be less suitable for monotherapy due to less convincing prognostic benefits, except in the elderly and for stroke prevention.

2. Initiate therapy at low dose; if needed increase dose moderately. Thiazide dose should be 12.5–25 mg/day hydrochlorothiazide or equivalent.

3. Majority of stage II hypertensives are started on a 2 drug combination; one of which usually is a thiazide diuretic.

4. If only partial response, add a drug from another complimentary class or change to low dose combination.

5. If no response, change to a drug from another class, or low dose combination from other classes.

6. In case of side effect to the initially chosen drug, either substitute with drug of another class or reduce dose and add a drug from another class.

With the above approach 50–70% stage I hypertensives can be successfully treated, at least initially, with Monod rug therapy. A simple regimen with once or twice daily drug dosing is most likely to be complied with. Because most stage I and some stage II hypertension patients are asymptomatic, a drug which makes them symptomatic (one or the other side effect) is not likely to be accepted for prolonged periods. Effect of the drug on quality of life measured by sense of wellbeing, energy level, mental acuity, drive, libido, sleep, life satisfaction, etc. is an important criterion in drug selection.

Combination therapy Though both JNC 7 and WHO-ISH emphasise on single drug therapy, the addition of a second (and third) drug when monotherapy fails or is not tolerated, is also highlighted. In practice, a large majority of hypertensives ultimately require 2 or more drugs. In the HOT study 70% patients who achieved target BP were being treated with 2 drugs.

Since BP is kept up by several interrelated factors, an attempt to block one of them tends to increase compensatory activity of the others. It is rational in such cases to combine drugs with different mechanisms of action or different patterns of hemodynamics effects: 

(a) Drugs which increase plasma renin activity— diuretics, vasodilators, CCBs, ACE inhibitors may be combined with drugs which lower plasma renin activity—β blockers, clonidine, methyldopa. 

(b) All sympathetic inhibitors (except β blockers) and vasodilators cause fluid retention: used alone tolerance develops. Addition of a diuretic checks fluid retention and development of tolerance.

(c) Hydralazine and DHPs cause tachycardia which is counteracted by β blockers, while the initial increase in t.p.r. caused by nonselective β blockers is counteracted by the vasodilator. 

(d) ACE inhibitors/ARBs are particularly synergistic with diuretics; this combination is very good for patients with associated CHF and left ventricular hypertrophy.

(e) Other useful combinations are: ACE inhibitor/ARB + CCB ACE inhibitor/ARB + β blocker β blocker + prazosin.

Combination therapy with low doses of each component allows BP reduction in nonresponsive patients with fewer side effects: antihypertensive action of the components adds up, while side effects being different do not. Use of combined formulation improves compliance and lowers cost.

A three drug combination therapy may be needed in a few patients (of severe or nonresponsive hypertension). Commonly used triple drug combinations are:

CCB + ACE inhibitor/ARB + diuretic CCB + β blocker + diuretic

ACE inhibitor/ARB + β blocker + diuretic Combinations including prazosin or clonidine or hydralazine are infrequently used. Patients who fail to reach the goal BP despite being adherent to full doses of an appropriate 3 drug (including a diuretic) regimen, have been labelled by JNC7 as ‘resistant hypertension’. In them even 4 drug therapy may have to be given to achieve the target BP. However, the patient must be reevaluated and factors like non-compliance, pseudo tolerance, need for a loop diuretic, drug interactions, secondary hypertension, etc. must be first excluded.

Combinations to be avoided

1. An α or β adrenergic blocker with clonidine: apparent antagonism of clonidine action has been observed.

2. Nifedipine (or other DHPs) with diuretic: synergism between these drugs is unproven.

 3. Hydralazine with a DHP or prazosin: similar pattern of hemodynamics action. 

4. Verapamil or diltiazem with β blocker: marked bradycardia, A-V block. 

5. Methyldopa with clonidine or any two drugs of the same class. 

Some antihypertensive combinations

1. Amlodipine 5 mg + Lisinopril 5 mg—AMLOPRES-L, LISTRIL-AM 

2. Amlodipine 5 mg + Atenolol 50 mg—AMCARD-AT, AMLOPIN-AT, AMLOPRES-AT 

3. Amlodipine 5 mg + Enalapril 5 mg—AMACE, AMTAS-E 

4. Atenolol 25 mg or 50 mg + chlorthalidone 12.5 mg— TENOCLOR, TENORIC 

5. Enalapril 10 mg + Hydrochlorothiazide 25 mg— ENACE-D, VASONORM-H 

6. Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg— CARDACE-H 

7. Losartan 50 mg + Hydrochlorothiazide 12.5 mg— LOSAR-H, TOZAAR-H, LOSACAR-H 

8. Lisinopril 5 mg + Hydrochlorothiazide 12.5 mg— LISTRIL PULS, LISORIL-HT 

9. Losartan 50 mg + Ramipril 2.5 mg or 5 mg— TOZAAR-R, LAPIDO-R 

10. Losartan 50 mg + Amlodipine 5 mg—AMCARD-LP, AMLOPRESS-Z, LOSACAR-A 

11. Losartan 50 mg + Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg—LOSANORM-HR 

12. Irbesartan 150 mg + Hydrochlorothiazide 12.5 mg— IROVEL-H, XARB-H.

When the BP has been well controlled for > 1 year, stepwise reduction in dose and/or withdrawal of one or more components of a combination may be attempted to workout a minimal regimen that will maintain the target BP. However, in most patients of essential hypertension, drug therapy is usually life-long.

Hypertension in pregnancy A sustained BP reading above 140/90 mm Hg during pregnancy has implications both for the mother and the foetus: reduction of BP clearly reduces risks. Two types of situations are possible:

(a) A woman with preexisting essential hypertension becomes pregnant. 

(b) Pregnancy induced hypertension; as in toxaemia of pregnancy—preeclampsia.

Toxaemic hypertension is associated with a hyperadrenergic state, decrease in plasma volume (despite edema) and increase in vascular resistance.

In the first category the same therapy instituted before pregnancy may be continued. However, one of the ‘safer’ drugs listed below may be substituted if one of the ‘drugs to be avoided’ was being used.

Antihypertensives to be avoided during pregnancy

Diuretics: Tend to reduce blood volume— accentuate uteroplacental perfusion deficit (of toxaemia)—increase risk of foetal wastage, placental infarcts, miscarriage, stillbirth. ACE inhibitors, AT1 antagonists: Risk of foetal damage, growth retardation. Nonselective β blockers: Propranolol has been implicated to cause low birth weight, decreased placental size, neonatal bradycardia and hypoglycaemia. Sod. nitroprusside: Contraindicated in eclampsia.

Antihypertensives found safer during pregnancy

Hydralazine Methyldopa (a positive Coombs’ test occurs, but has no adverse implication). Dihydropyridine CCBs: discontinue before labour as they weaken uterine contractions. Cardioselective β blockers and those with ISA, e.g. atenolol, metoprolol, pindolol, acebutolol: may be used if no other choice. Prazosin and clonidine—provided that postural hypotension can be avoided.

Hypertensive emergencies and urgencies

Systolic BP > 180 or diastolic BP > 120 mm Hg with evidence of active end organ damage is labelled ‘hypertensive emergency’, while the same elevation of BP without signs of endorgan damage is termed ‘hypertensive urgency’.

Controlled reduction of BP over minutes (in emergencies) or hours (in urgencies) is required to counter threat to organ function and life in:

1. Cerebrovascular accident (haemorrhage) or head injury with high BP. 

2. Hypertensive encephalopathy. 

3. Hypertensive acute LVF and pulmonary edema. 

4. Unstable angina or MI with raised BP. 5. Dissecting aortic aneurysm. 

6. Acute renal failure with raised BP. 

7. Eclampsia. 

8. Hypertensive episodes in pheochromocytoma, cheese reaction or clonidine withdrawal.

Nifedipine (10 mg soft geletine cap) orally every ½–1 hr was widely employed for rapid BP reduction in urgencies. This practice has now been discarded because of inability to control rate and degree of fall in BP as well as serious adverse consequences/mortality. Other rapidly acting oral drugs like captopril (25 mg) or clonidine (100 μg) every 1–2 hours have also been found unsatisfactory. Parenteral drugs with controllable action are now used. Mean BP should be lowered by no more than 25% over minutes or a few hours and then gradually to not lower than 160/100 mmHg. Drugs employed are:

1. Sodium nitroprusside (see p. 548) Because of predictable, instantaneous, titratable and balanced arterio-venous vasodilatory action which persists without tolerance till infused, nitroprusside (20–300 μg/min) is the drug of choice for most hypertensive emergencies. However, it needs an infusion pump and constant monitoring, but is the most effective drug.

2. Glyceryl trinitrate (see p. 525) Given by i.v. infusion (5–20 μg/min) GTN also acts within 2–5 min and has brief titratable action. Its predominant venodilator action makes it particularly suitable for lowering BP after cardiac surgery and in acute LVF, MI, unstable angina. Tolerance starts developing after 18–24 hours of continuous infusion.

3. Diazoxide (see p. 548) Given as fractional i.v. bolus doses—BP once lowered remains so for > 6 hours; constant monitoring is not required.

4. Hydralazine (see p. 547) 10–20 mg i.m. or slow i.v. injection; acts in 20–30 min and keeps BP low for 4–8 hours. It has been especially used in eclampsia. It is to be avoided in patients with myocardial ischaemia or aortic dissection.

5. Esmolol (see p. 141) This β blocker given as 0.5 mg/kg bolus followed by slow i.v. injection (50–200 μg/kg/min) acts in 1–2 min; action lasts for 10–20 min. It is particularly useful when cardiac contractility and work is to be reduced, such as in aortic dissection (nitroprusside may be given concurrently) and during/after anaesthesia. The BP lowering action is weaker. Excess bradycardia is to be guarded.

6. Phentolamine (see p. 134) This α1 + α2 blocker is the drug of choice for hyperadrenergic states—hypertensive episodes in pheochromocytoma, cheese reaction, clonidine withdrawal. Injected i.v. (5–10 mg) it acts in 2 min and action lasts 5–15 min. Tachycardia and myocardial ischaemia may complicate its use. A β blocker may be added.

7. Labetalol Injected i.v., it is an alternative to α + β blockers for lowering BP in pheochromocytoma, etc. but has only weak α blocking action. It has been used to lower BP in MI, unstable angina, eclampsia also. Concomitant CHF and asthma preclude its use.

8. Furosemide (20–80 mg oral or i.v.) It may be given as an adjunct with any of the above drugs if there is volume overload (acute LVF, pulmonary edema, CHF) or cerebral edema (in encephalopathy), but should be avoided when patient may be hypovolemic due to pressure induced natriuresis (especially in eclampsia, pheochromocytoma).   

Post a Comment

0 Comments
* Please Don't Spam Here. All the Comments are Reviewed by Admin.