 Hypertension is a very common disorder, particularly past middle

age. 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
 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 last 50 year. Before l950 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, b
blockers, thiazide and high ceiling diuretics and clonidine.
The status of b blockers and diuretics was consolidated in the
1970s and selective a1 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.
 =
 Diuretics have been the standard
antihypertensive drugs over the past 4
decades, though they do not lower BP
in normotensives
 Thiazides -(chlorthalidone, etc.)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 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
nd increase their compliance and dampen responsiveness to
constrictor stimuli.
 A mild slowly developing vasodilator action by thiazides due to
opening of smooth muscle K+ channels and hyperpolarization
has been proposed
 High ceiling diuretics Furosemide, 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.
 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.
 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.
 Dyslipidemia: rise in total and LDL cholesterol and triglycerides
with lowering of HDL---increase atherogenic risk.
 Hyperuricaemia: by inhibiting urate excretion- increased incidence of
gout.
 increased incidence of sudden cardiac death: attributed to episodes of
torsades de pointes and ischaemic 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.
 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.
 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.
 ACE inhibitors are:
 captopril, enalapril, lisinopril, benazepril,
ramipril, fosinopril, trandolapril, imidapril and
perindopril are available in India
 Captopril : can also increase plasma kinin levels and potentiate the
hypotensive action of exogenously administered bradykinin.
 elevated kinins (and PGs whose synthesis is enhanced by kinins) may
be responsible for cough and angioedema induced by ACE inhibitors
in susceptible individuals. ACE inhibitors interfere with degradation
of substance P also.
 Captopril lowers BP, but in the short-term.
 Captopril induced hypotension is a result of decrease in total
peripheral resistance. The arterioles dilate and compliance of larger
arteries is increased. Both systolic and diastolic BP fall. It has no
effect on cardiac output.
 Reflex sympathetic stimulation does not occur despite vasodilatation.
They can be safely used in patients with ischaemic heart disease.
 Pharmacokinetics: About 70% of orally administered captopril is
absorbed. Presence of food in stomach reduces its bioavailability.
 Penetration in brain is poor. It is partly metabolized and partly
excreted unchanged in urine. The plasma t1/2 is -2 hours, but actions
last for 6-12 hours
 Adverse effects :The adverse effect profile of all ACE inhibitors is similar.
 • Hypotension: sharp fall in BP occurs ---- in diuretic treated and CHF patients;
 • Hyperkalaemia: more likely in patients with impaired renal function and in those
taking K+ sparing diuretics, NSAIDs or b blockers.
 • Cough: a persistent brassy cough occurs in 4-16% patients within 1-8 weeks,
often requires discontinuation of the drug. It is not dose related and appears to be
caused by inhibition of bradykinin/ substance P breakdown in the lungs of
susceptible individuals.
 • Rashes, urticaria
 • Angioedema
 • Dysgeusia: reversible loss or alteration of taste sensation due to captopril has an
incidence
 of 0.5-3%;
 • Foetopathic: foetal growth retardation, hypoplasia of organs and foetal death may
occur if ACE inhibitors are given during later half of pregnancy
 Interactions
 Indomethacin (and other NSAIDs) attenuate the hypotensive
action. Incidence of renal failure have been reported when a
NSAID was given to patients (especially elderly) receiving
ACE inhibitor + diuretic.
 Hyperkalaemia can occur if K+ supplements /K+ sparing
diuretics are given with captopril.
 Antacids reduce bioavailability of captopril, while ACE
inhibitors reduce Li+ clearance and predispose to its toxicity
 Hypertension: hypertension respond to monotherapy with ACE inhibitors and
majority of the rest to their combination with diuretics or b blockers.
 CHF: ACE inhibitors cause both arteriolar and venodilatation in CHF patients:
reduce afterload as well as preload. Haemodynamic meauserments in severe CHF
patients have shown reduction in right atrial pressure, pulmonary arterial pressure,
pulmonary capillary wedge pressure, systemic vascular resistance, systolic wall
stress and systemic BP
 Myocardial infarction (MI): Several mega trials have established that oral ACE
inhibitors administered while MI is evolving (within 24 hr of an attack) and
continued for 6 weeks reduce early as well as long-term mortality.
 Prophylaxis in high cardiovascular risk subjects:
 Diabetic nephropathy: Prolonged ACE inhibitor therapy has been found to
prevent or delay end-stage renal disease in type I as well as type II diabetics
 Scleroderma crisis: The marked rise in BP and deterioration of renal function in
scleroderma crisis -----ACE inhibitors produce dramatic improvement and are life
saving in this condition
 Over the past 2 decades, several nonpeptide orally active
AT 1 receptor antagonists have been developed as
alternatives to ACE inhibitors. These include
 losartan,
 candesartan,
 valsartan,
 telmisartan
 irbesartan.
 Selective antagonists of AT 2 receptors as well as combined
AT 1 + AT 2 antagonists have also been produced.
 It is a competitive antagonist and inverse agonist of A-II,
10,000 times more selective for AT1 than AT2 receptor;
does not block any other receptor or ion channel, except
thromboxane A2 receptor (has some platelet
antiaggregatory property).
 It blocks all overt actions of A-II. No inhibition of ACE has
been noted.
 Oral absorption of losartan is not affected by food,
 It is partially carboxylated in liver to an active
metabolite (E3174) which is a 10-30 times more
potent noncompetitive AT1 receptor antagonist.
 After oral ingestion peak plasma levels are attainted
1 hr for losartan and at 3-4hours for E3174.
 both compounds are 98% plasma protein bound . Do
not enter brain and are excreted by the kidney. The
plasma t1/2 of losartan is 2 hr, but that of E3174 is 6-
9 hr.
 Candesartan : It has the highest affinity for AT1 receptor and produces
largely unsurmountable antagonism, probably due to slow dissociation
from the receptors or receptor desensitization.
 Irbesartan: The oral bioavailability of this AT 1 antagonist is relatively
high. It is partly metabolized and excreted mainly in bile. The t1/2 is
~12 hours
 Valsartan The AT1 receptor affinity of valsartan is similar to that of
losartan. Its oral bioavailability awrages 23% and food interferes with
its Absorption The t1/2 is 6-9 hours
 Telmisartan The AT1 receptor blocking action of telmisartan is similar
to losartan, but it does not produce any active metabolite
 Hypertension: Losartan and other ARBs are now first line drugs,
comparable in efficacy and desirable features to ACE inhibitors, with
the advantage of not inducing cough and a lower incidence of
angioedema, rashes and dysgeusia.
 CHF The ARBs afford clear-cut symptomatic relief as well as
survival benefit in CHF
 Myocardial infarction The evidence so far indicates that utility of
ARBs in MI, including long-term survival, is comparable to ACE
inhibitors.
 Diabetic nephropathy Several studies have confirmed that ARBs
are renoprotective in type 2 diabetes mellitus
 3 subgroups of CCBs
 1) dihydropyridines (DHPs,e.g. amlodipine),
 2) phenylalkylamine (verapamil)
 3) benzothiazepine (diltiazem)

 All subgroups are equally efficacious antihypertensives.

They lower BP by decreasing peripheral resistance without
compromising c.o. Despite vasodilatation, fluid retention is
insignificant.
 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).
 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.
 The hypotensive response to b blockers develops over 1-3
weeks and is well sustained. Despite short and differing
plasma half lives, the antihypertensive action of most b
blockers is maintained over 24 hr with a single daily dose.
 Labetalol: It is a combined a and b blokage and
reduces t.p.r. and acts faster than pure bblockers
it has been used i.v. for rapid BP reduction in
cheese reaction, clonidine withdrawal, etc ·
 Prazosin: This prototype selective a1 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.
 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.
 Terazosin, Doxazosin These are long-acting congeners of prazosin
 Clonidine: It is an imidazoline derivative having complex actions.
Clonidine is a partial agonist with high affinity and high intrinsic
activity at a2 receptors (a2A subtype in brainstem.)
 The major haemodynamic effects result from stimulation of a2A
receptors present mainly postjunctionally in medulla (vasomotor
centre)-----decrease sympathetic out flow ----fall in BP and
bradycardia

 Methyldopa: It is the a-methyl analogue of dopa,the precursor of

dopamine (DA) and NA. The a methyl-NA (a selective a2 agonist)
formed in the brain from methyldopa acts on central a2 receptors to
decrease efferent sympathetic activity
 Use: Methyldopa was a widely used antihypertensive, especially in
combination with a diuretic
 Hydralazine/Dihydralazine: It is a directly acting arteriolar
vasodilator with little action on venous capacitance vessels;
reduces t.p.r. lt causes greater reduction of diastolic than
systolic BP
 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.
 It is a rapidly (within seconds) and consistently
acting vasodilator 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).