Healthcare in India

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 rnm 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 mayor may not be overactive, but they do contribute to the tone of blood vessels and c.o. in hypertensives, as they do in norrnotensives. 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 1960­70s were methyldopa, _ blockers, thiazide and high ceiling diuretics and clonidine. The status of b blockers and diuretics was consolidated in the 1970s and selective a) 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.

CLASSIFICATION

1.         Diuretics
            Thiazides:                  Hydrochlorothiazide,
Chlorthalidone, Indapamide
High ceiling:             Furosemide, etc.
K+ Sparing:               Spironolactone, Arniloride
2.         ACE inhibitors
Captopril, Enalapril, Lisinopril, Perindopril, Ramipril, Fosinopril, etc.
3.         Angiotensin (A T1 receptor) blockers Losartan, Candesartan, Irbesartan, Valsartan, T elmisartan
4.         Calcium channel blockers
Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine, etc.
5.         b Adrenergic blockers
Propranolol, Metoprolol, Atenolol, etc.
6.         b + a Adrenergic blockers
Labetalol, Carvedilol
7.         a Adrenergic blockers
Prazosin, Terazosin, Doxazosin
Phentolamine, Phenoxybenzamine
8.         Central sympatholytics
Clonidine, Methyldopa
9.         Vasodilators
            Arteriolar:     Hydralazine, Minoxidil, Diazoxide
            Arteriolar + venous: Sodium nitrqprusside
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% -7 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, All). 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:

• Chronic renal failure: thiazides are ineffective, both as diuretics and antihypertensives.
• Coexisting refractory CHF.
• Resistance to combination regimens contain­ing a thiazide, or marked fluid retention due to use of potent vasodilators.

Desirable properties of diuretics as antihyper­tensives are:

• Once a day dosing and flat dose-response-­curve permitting simple standardized regi­mens.
• No fluid retention, no tolerance.
• Low incidence of postural hypotension and relative freedom from side effects, especially CNS, compared to sympatholytics.
• Effective in isolated systolic hypertension (ISH).
• Lessened risk of hip fracture in the elderly due to hypocalciuric action of thiazides.
• Low cost.

Current status oLdiuretics 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:

• Hypokalaemia-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.
• Dyslipidernia: rise in total and LDL cholesterol and triglycerides with lowering of HDL. This could increase atherogenic risk, but no direct evidence has been obtained.
• Hyperuricaernia: by inhibiting urate excre­tion-increased incidence of gout.
• Increased incidence of sudden cardiac death: attributed to episodes of torsades de pointes and ischaernic ventricular fibrillation precipitated by hypokalaemia.

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 :s; 25 mg/ day in the above and subsequent studies, including ALLHA T (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 hypokalaemia 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 hyperuricaemia 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 t? 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 or 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/b 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 favourable 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:

• Do not compromise haemodynamics: no impairment of physical work capacity.
• No sedation or other CNS effects; cerebral per­fusion is maintained.
• Not contraindicated in asthma, angina (especially variant) and PVD patients: may benefit these conditions.
• Do not impair renal perfusion.
• Do not affect male sexual function.
• No deleterious effect on plasma lipid profile, uric acid level and electrolyte balance.
• Shown to have no/minimal effect on quality of life.
• No adverse foetal effects; can be used during pregnancy (but can weaken uterine con­tractions during labour).

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 verapamilj 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 Systolic hypertension in Europe (Syst-EUR) trial has shown that nitrendi'pine (long-acting DHP) reduces cardiovascular morbidity and mortality in elderly hyper­tensives. The Hypertension optimal treatment (HOT), and Sweedish trial in old patients with hypertension-2 (STOP­2) studies have also found CCBs equi-effective as diuretics/43 blockers/ACE inhibitors in reducing cardiovascular/total mortality. No excess mortality with the use of amlodipine in post MI and acute coronary syndrome patients has been noted in the ALL HAT (2002) study. On the other hand, CCBs do not afford survival benefit in post MI patients as 13 blockers, ACE inhibitors or low dose thiazides do. CCBs are also not as effective in suppressing left ventricular hypertrophy (a major risk factor in ischaemic heart disease) as ACE inhibitors.
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, b 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:

• The negative inotropic/ dromotropic action of verapamil/ diltiazem may worsen CHF and cardiac conduction defects (DHPs are less likely to do so).
• By their smooth muscle relaxant action, the DHPs can worsen gastroesophageal reflux.
• CCBs (especially DHPs) may accentuate bladder voiding difficulty in elderly males.