Drugs for The Treatment of Hypertension pdf - D. Tahsin

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Drugs for the Treatment of Hypertension (HT)

Hypertension is defined as systolic BP ≥140 mm Hg systolic &/or 90 mm Hg
diastolic. It is very common, increasing in incidence in older age, the incidence is
rising worldwide. It is a major cause of morbidity and mortality. The main
complications include stroke, ischemic heart disease, heart failure and renal
failure. However, effective treatment and lowering of blood pressure to normal
levels leads to significant reduction of complications, improve survival and quality
of life

Physics, physiology, and pathophysiology:

Blood pressure equals to the cardiac output time the peripheral vascular
resistance. Cardiac output equals to heart rate multiplied by stroke volume. The
stroke volume is determined by cardiac contractility and left ventricular filling,
which is determined by venous return. This latter is a function of blood volume
and venous tone. Peripheral vascular resistance is determined by the arteriolar
tone. Manipulation of the above mentioned factors is the means of controlling
the blood pressure.

Regulation of blood pressure:

There are 3 mechanisms to control BP:

1. Baro-receptor control: functional in the acute settings (short term): BP is

controlled reflexively by stretch receptors in the carotid sinus and aortic
body. When BP declines it reduces stretching of the receptors, which will
send fewer impulses to the vasomotor centers in the brainstem, causing a
reduced parasympathetic drive and increased sympathetic tone. This will
lead to peripheral vasoconstriction, tachycardia and increased LV
contractility, thereby compensating for the initial reduction of BP

2. Renin-angiotensin-aldosterone system. Intermediate term mechanism.

Renin is released from the juxta-glomerular apparatus in response to β-
receptor stimulation, reduced afferent arteriolar stretching, or reduced
tubular sodium and water load into the proximal convoluted tubule

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(macula densa). Renin activates angiotensinogen (a globulin synthesized in
the liver) into angiotensin I, which is activated via the enzyme ACE into AT
II. This protein has many actions that lead to raising BP: it stimulates a
central sympathetic discharge, stimulates the adrenal medulla to release
catecholamines, provokes the degranulation of sympathetic nerve endings
and release of neurotransmitter, and is a direct vasoconstrictor itself. Also,
it induces aldosterone release from the adrenal cortex. This hormone
induces Na+ and water absorption from DCT, enhancing blood volume.
Another important action of AT II is to act as a direct constrictor of the
glomerular efferent arteriole, which increases the pressure within the
glomerular tuft, increases filtration pressure, and modifying the Starling
forces in the medullary arterioles in favor of more fluid reabsorption in the
renal tubules.

3. Renal mechanism of BP control: Long term mechanism. The kidneys

regulate BP over a wide range of fluid intake.

Drugs that control hypertension act to modify the various factors controlling BP,
e.g. plasma volume, venous return, CO, HR, LV contractility, peripheral resistance
(PR)….

Diuretics: include thiazides, loop diuretics, and potassium sparing diuretics

Thiazide diuretics:

The main class of diuretics used in treatment of HT. include chlorothiazide,
hydrochlorothiazide, chlorthalidone, and metolazone. Initially, they act on the
DCT to decrease Na+ & water reabsorption, leading to plasma volume
contraction. They cause reduction of renal blood flow. Later on, the plasma
volume is restored, but a hypotensive effect persists due to reduction of
vasomotor tone & peripheral vascular resistance.

S.E: hypokalemia, hyperglycemia, hyperuricemia, agranulocytosis, fatigue,
postural hypotension.

Thiazide diuretics are not useful in renal failure (GFR ≤30 ml/min), except
metolazone.

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Loop diuretics:

Include furosemide, bumetanide, ethacrynic acid, & torsemide. They are the most
potent diuretics, blocking Na+ and water reabsorption from the ascending limb of
the loop of Henle. Unlike thiazides, they increase renal blood flow. They are not
used as primary drugs in the treatment of hypertension, but may be used in
combination with other drugs like ACEIs or ARBs to potentiate their effects in
certain clinical scenarios (e.g. congestive failur.

S.E: hypokalemia, hypomagnesemia, hypocalcemia, increased urinary calcium
(hypercalciuria). The latter effect is different than thiazide diuretics, which reduce
urinary calcium and increase serum calcium. Furosemide may cause ototoxicity
(deafness).

Potassium-sparing diuretics:

Include  two  groups:  aldosterone  antagonists,  including  spironolactone  and
eplerinone,  and  drugs  that  inhibit  Na+/k+  exchange  in  the  distal  tutbules  and
collecting  ducts,  which  include  amiloride  and  triamterene.  They  may  cause
hyperkalemia, especially if used in combination with ACEIs or ARBS.

Beta adrenergic blockers:

The non-cardioselective ones block the β1 (heart, kidneys) and β2 receptors
(bronchial and vascular smooth muscles). E.g. propranolol and nadolol

The cardioselective ones: block only β1 receptors, e.g. atenolol, metoprolol, &
bisoprolol. They have little effect on bronchial and peripheral arterial tone.

β-blockers reduce BP by reducing HR and contractility, and also reduce renin
release.

Pharmacokinetics:

β-blockers are orally active. Propranolol has variable first-pass liver metabolism,
so the effective dose can vary from person to person. Intravenous preparations

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exist for propranolol, metoprolol, atenolol, and esmolol. Most of them are
metabolized in the liver. Hydrophilic preparations (e.g. atenolol) don’t cross the
blood-brain-barrier, so they show little CNS effects.

S.E:

 Bradycardia: so they should be avoided in patients with heart block
 Impaired LV contractility: should be avoided in patients with

decompensated heart failure. However, some β-blockers are the drugs of
choice in chronic heart failure.

 Peripheral vasoconstriction: more with the non-selective forms. They

should be avoided in critical limb ischemia.

 Worsening of asthma: especially for non-selective β-blockers. Selective

ones may be used cautiously in asthmatic patients.

 Other non-cardiovascular SE include insomnia (especially with lipid-soluble

agents, nightmares, and erectile dysfunction and reduced libido

 Disturbance of lipid metabolism: occurs with the non-selective agents:

reduced HDL and increased triglycerides

Abrupt withdrawal of β-blockers in patients with IHD may cause worsening of
angina, precipitate acute MI, or even sudden death. Therefore, they should be
withdrawn gradually (tapered) over a period of several weeks in patients with HT
and IHD.

Angiotensin Converting Enzyme Inhibitors (ACEIs):

Include captopril, enalapril, lisinopril, ramipril, & fosinopril. The reduce BP by
inhibiting the activation of Angiotensin II. They also impair the degradation of
bradykinin, which causes an increase in nitric oxide (NO) and prostacyclin, which
are vasodilator substances. They lower plasma aldosterone level, reducing salt
and water reabsorption from the DCT. They prevent efferent arteriolar
constriction, reducing the intra-glomerular pressure; reduce vasomotor tone,
reducing afterload without increasing the cardiac output.

Pharmacokinetics: all ACEIs are orally bioavailable. Captopril and lisinopril are
active drugs, all other ACEIs are prodrugs, i.e. are converted by the liver to an

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active metabolite. Fosinopril is the only drug that is not excreted by the kidneys,
so it doesn’t need dose modification in CKD. Enalaprilat is the only intravenous
preparation.

Clinical uses:

  Very useful in all cases and types of HT, unless contra-indicated
  HT due to unilateral renal artery stenosis
  Hypertensive patients with renal impairment
  Reversal of LV hypertrophy
  Control of proteinuria in diabetic nephtropathy
  Reversal of LV remodeling after acute myocardial infarction
  Standard therapy in all cases of systolic heart failure
  Treatment of acute and chronic IHD and atherosclerosis

SE of ACEIs:

  Dry cough: caused by increased bradykinin in the lung
  Skin rash
  Fever
  Altered taste
  Hyperkalemia: so they should be used cautiously in combination with K+

sparing diuretics or K+ supplements

 Renal impairment: ACEIs may cause reduction in renal function, however,

they are the agents of choice in HT associated with renal impairment, as it
preserves the remaining renal function. In such patients, renal function and
S.K+ should be carefully monitored.

 All ACEIs are contra-indicated in bilateral renal artery stenosis since they

would induce renal insufficiency

 Angio-edema is a rare but serious SE caused by high bradykinin level
 Teratogenic effect: they are absolutely contra-indicated in hypertensive

women who get pregnant.

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Angiotensin Receptor Blockers (ARBs):

Include losartan, valsartan, telmisartan, irbisartan, and candesartan. They block
the AT receptor type 1 and have almost the same action as ACEIs: they reduce the
sympathetic tone leading to vasodilatation, reduce the peripheral vascular
resistance, inhibit aldosterone release, and induce dilatation of the renal efferent
arteriole causing a reduction in the amount of water and Na+ reabsorbed at the
renal tubules and thereby reducing plasma volume. The only difference from
ACEIs is that they don’t inhibit bradykinin metabolism.

S.E.: similar to ACEIs, with the exception of a much less incidence of dry cough.
ARBs should never be administered simultaneously with ARBs. This combination is
ineffective and has more incidence of hyperkalemia. ARBs are also teratogenic,
and should be avoided in pregnancy.

Renin Antagonists (aliskerin):

This drug is not widely used, it has an equivalent anti-hypertensive action to ACEIs
and ARBs. It may cause dry cough and angio-edema. Also it may cause diarrhea.

Calcium Channel Blockers (CCBs):

These are a heterogeneous group of drugs belonging to various compounds:

  Dihydropyridines: nifedipine, amlodipine, nicardipine, isradipine, felodipine
  Diphenylalkylamines: represented by verapamil
  Benzothiazipines: diltiazem

Generally, they are divided into two groups: dihydropyridines and non-
dihydropyridines. These groups have different tissue affinity, different actions,
and different SE profile.

Mechanism of Action: in cardiac muscles and smooth muscles, there are voltage-
sensitive Ca++ channels. When stimulated, Ca++ enters the cells triggering the

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release of intracellular Calcium present in sarcoplasmic reticulum and
mitochondria. This high Ca++ concentration causes contraction of cardiac muscle
(increased contractility) and vasoconstriction (increased peripheral resistance),
ultimately causing an increase in BP. CCBs inhibit this Ca++ mediated effect by
blocking the voltage sensitive channels, thus reducing BP.

CCBs have different mode of action according to the group they belong to:

 Dihydropyridines act mainly on vascular smooth muscle cells causing

relaxation and reduced vasomotor tone. They have little effect on the heart
rate.

 Non-dihydropyridines act mainly on cardiac conductive system and

myocardial cells, inducing slowing of the heart rate and a negative inotropic
effect (reduced contractility).

Also, there is a group difference in SE profile: side effects occur most with the
dihydropyridine group and least with diltiazem.

Pharmacokinetics: All CCBs have short plasma half life except amlodipine, which
can be administered once daily. Otherwise, sustained release preparations are
available for the rest of the group, so that they can be used once or twice daily.

S.E of dihydropyridines: include headache, flushing, leg edema, dizziness (postural
hypotension) and gingival hypertrophy.

S.E of the non-dihydropyridines: include bradycardia, atrio-ventricular block (AV
block), and worsening of congestive heart failure, so they are contra-indicated in
any condition with impaired LV function (unlike the situation with some β-
blockers). The major extra cardiac side effect is constipation, most marked with
verapamil.

α- Adrenergic Blockers:

Include prazocin, doxazocin, terazocin, etc…, they block the α-1 receptors on
arterial and venous smooth muscles, which leads to vasodilatation without
alteration of the cardiac output or renal blood flow. The initial side effect includes
tachycardia and postural hypotension, with continued administration these side
effects disappear, but re-appear each time the drug dose is escalated. These

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drugs are low-efficacy ones, and are no longer used as standard therapy for HT,
but may be used for refractory cases in conjunction with other anti-HT
medications. The major clinical indication for α- Adrenergic Blockers currently is
the relief of congestion in benign prostatic hypertrophy.

Combined α- & β- Adrenergic Blockers:

Include carvedilol and labetalol. They block the α-, β1- & β2 receptors. The main
use of carvedilol is in systolic heart failure, where it improves outcome, preserves
LV function and reduces mortality (other β-blockers in this respect include
bisoprolol and metoprolol succinate). Labetalol is used mainly in the management
of gestational HT and in hypertensive emergencies.

Centrally Acting Anti-HT Drugs:

Include clonidine and methyl dopa. Clonidine acts by stimulating central
sympathetic α-2 receptors in the vasomotor centers in the CNS. This stimulation
leads to inhibition of the peripheral sympathetic tone, reducing the peripheral
vascular resistance without any effect on the kidneys. It’s a drug of low efficacy
and only used as an adjunctive therapy if other drugs fail to control BP. It is
available in oral and transdermal forms. It is well absorbed via the oral route. S.E
include sedation, constipation, and dry mouth. Abrupt cessation of treatment
leads to rise of BP above initial readings (rebound phenomenon), it is rarely used
clinically.

Methyl Dopa: is a centrally acting anti HT drug, stimulating the central
sympathetic α2- adrenergic receptors. It is converted in the CNS into methyl
norepinephrine, which is the active metabolite. It reduces central sympathetic
flow. It is safe in pregnancy, which is the major indication for the drug. S.E include
depression, drowsiness, and an SLE-like syndrome. It requires frequent dosing (2-
3 times daily).

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Peripheral Vasodilators:

Include hydralazine and minoxidil. They are direct arterial and arteriolar smooth
muscle relaxants, so they reduce peripheral resistance, but this is usually
overcompensated by reflex tachycardia and enhanced LV contractility, leading to
increased myocardial oxygen consumption. Thus, they may precipitate angina, MI,
and heart failure. Also they increase plasma renin concentration, this leads to Na+
retention and edema.

Hydralazine is used mainly in pregnancy-induced HT. Injectable forms are used in
HT emergencies. Otherwise, it is only used in combination therapy, usually with a
β-blocker and a thiazide diuretic. S.E include headache, tachycardia, angina,
nausea, sweating, and arrhythmias. Also, high doses may cause an SLE-like
syndrome.

Minoxidil is no longer used to treat HT due to low efficacy and cardiac S.E. a
“useful” S,E is hirsutism, so it is used to stimulate hair growth in androgenic
alopecia as a topical preparation.

Emergency Treatment of HT:

It is rarely necessary or useful to lower BP in an immediate manner. Rapid
lowering of high BP, even to normal levels, may cause CNS catastrophes like
stroke or coma and death. This is due to the phenomenon of auto-regulation: in
chronic HT states, the cerebral vessels constrict to protect the brain from the high
BP and over-perfusion. If pressure is lowered rapidly, the cerebral vessels don’t
dilate immediately but may take several weeks to attain full dilatation. During
that time, brain hypoperfusion occurs because the perfusion pressure is too low
to overcome the cerebral vascular resistance, causing brain damage. So, even in
conditions requiring rapid BP lowering, it should be lowered gradually, cautiously,

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and slowly. Situations requiring rapid lowering of BP include aortic dissection,
unstable angina, STEMI, HT encephalopathy, & eclamptic toxemia.

Intravenous forms are used to achieve rapid lowering of BP, including:

 I.V nitroglycerine: arterial and venous dilator, used mainly in acute

coronary syndrome

 I.V isosorbide di-nitrate, which is mainly an arterial dilator and also is used

in cases of acute coronary syndrome.

 Sodium nitroprusside: a vasodilator with instantaneous effect on BP, so it

can be given as i.v infusion and the rate of infusion is titrated according to
the BP and the desired level. The major SE is methemoglobinemia.

 Labetalol is a combined α and β blocker, and is mainly used in emergency

treatment of HT in pregnancy.

 Intravenous calcium channel blocker: nicardipine
 Hydralazine i.v or i.m