OBJECTIVES

By the end of the lecture, you should:

• Know the different antihypertensive drugs regarding their

pharmacological effects, therapeutic uses and adverse effects.

• Be oriented with the lines of management of hypertensive

cases.

• Be aware of the drugs used in hypertension with concomitant

diseases.
 Drug therapy of hypertension

Definition:
- Hypertension is a disease in which arterial blood pressure is elevated above
normal. The patient is considered hypertensive when blood pressure is above 140/90
mmHg.

- Hypertension is diagnosed by measuring the blood pressure and finding an

elevated pressure on at least three different readings on different occasions.

Types of hypertension:
1. Essential (primary or idiopathic) hypertension:
It is the most common type (90% of the cases of hypertension). The cause of this
type is unknown. Predisposing factors include genetic factor, obesity, smoking, high
salt intake, atherosclerosis.
2. Secondary hypertension:
• It represents about 10% of the cases. Hypertension occurs secondary to other
disease conditions.

• Causes of secondary hypertension are either renal (renal artery stenosis, acute and
chronic glomerulonephritis, diabetic glomerulsclerosis, congenital polycystic
kidney), endocrinal (pheochromocytoma, Cushing's syndrome, toxemia of
pregnancy), drug-induced (oral contraceptives, corticosteroids).

• Treatment of the underlying cause is essential to cure hypertension.

3. Gestational hypertension (during pregnancy).

Grades of hypertension:
Hypertension is classified according to the level of diastolic blood
pressure into:

Grade Diastolic Pressure

(mmHg)
Mild hypertension 90-105
Moderate hypertension 105-115
Severe hypertension 115
Hypertension emergency 130
Complications of uncontrolled hypertension:
• CVS: heart failure and ischemic heart diseases.

• Kidney: renal impairment.

• CNS: cerebral hemorrhage (cerebrovascular stroke).

• Eye: papillidema and retinal damage

 Classification of antihypertensive drugs
I. Diuretics:
1. Thiazides and thiazide-like diuretics: hydrochlorothiazide and indapamide.
2. Loop diuretics: furosemide.
3. Potassium-sparing diuretics: spironolactone and amiloride.

II. Sympathoplytic drugs:

1. β-adrenergic receptor blockers.
2. Central α2-agonists: α-Methyldopa.

III. Vasodilators:
1. Direct vasodilators: hyralazine, minoxidil and diazoxide, sodium nitroprosside.
2. Calcium channel blockers: verapamil, diltiazem and dihydropyridines.

IV. Inhibitors of angiotensin:

1. ACE inhibitors: captopril, enalapril and lisinopril.
2. Angiotensin II-receptor antagonists: losartan and valsartan.
 I. Diuretics
Diuretics are useful antihypertensive agents when used alone or in combination
with other antihypertensive drugs. They are more effective in elderly and obese
hypertensive patients..

1. Thiazide diuretics:
• They lower the elevated blood pressure by initial diuretic action and on long-term
use they produce direct arteriolar dilatation with reduced peripheral resistance.

• Thiazides are useful for long-term therapy of hypertension They are used alone
(monotherapy) and in combination with other antihypertensive drugs.

• They have more effective antihypertensive action than loop diuretics.

• They produce effective antihypertensive action at lower doses (25-100 mg/day,

orally) than the maximal diuretic doses (100-200 mg/day).
2. Loop (high-ceiling) diuretics:
• They decrease the blood pressure only through the diuretic action (no effect on
peripheral vascular resistance). Although they produce more effective diuretic
action than thiazides, they have less effective antihypertensive activity.

• They are used mainly in hypertensive emergency (IV) because they have rapid
onset and powerful diuretic effect. Unlike thiazides, they can be used for
hypertension associated with renal impairment because they increase RBF and
GFR.

3. Potassium Sparing Diuretics:

• They have weak diuretic and antihypertensive actions and are used in combination
with thiazides or loop diuretics to prevent the development of hypokalemia.
 II. Sympatholytic drugs
1. β-adrenergic receptor blockers:
• They are used alone (monotherapy) and in combination with other
antihypertensive drugs.

• They are more effective in younger patients, hypertension associated

with IHD and in high renin-hypertension.

• No reflex tachycardia and no postural hypotension.

- Propranolol (Inderal) is a non-selective ß-blocker can be given orally (10-40
mg/tds).

- Atenololol (Tenormin) is a selective β1-blocker available in 50 and 100 mg tablets.

The initial dose is 50 mg/day given once daily and increased at weekly intervals till
reaching the maximal dose (100 mg/day).

2. Central α2-agonists:
• α-Methyldopa.
• These agents reduce the sympathetic outflow from the CNS by stimulating the
presynaptic α2-receptors, preventing the release of NE from the central adrenergic
neurons.
• α-Methyldopa (Aldomet) is the drug of choice for treatment of hypertension during
pregnancy (gestational hypertension).
 III. Vasodilators

A). Direct vasodilators

• Arteriodilators: hydralazine, minoxidil and diazoxide.

• Arterio-venous dilators: sodium nitroprusside.

1. Arteriodilators
• Hydralazine increases the release of NO from the vascular endothelium.

• Minoxidil and diazoxide act as K+-channel activator in the vascular smooth muscles
leading to K+ efflux and cell membrane hyperpolarization.
• They cause marked arteriodilatation leading to hypotension with reflex
sympathetic stimulation. This leads to reflex tachycardia, increased
COP, increased peripheral resistance and salt and water retention.
Therefore, rapid tolerance develops to their antihypertensive effect if it is
used alone in treatment of hypertension.

• This is avoided by combining these drugs with a ß-adrenergic receptor

blocker for treatment of hypertension.
Therapeutic uses:

• Hydralazine and minoxidil are used orally for long-term therapy of

hypertension in combination with a ß- blocker.

• Diazoxide is used in hypertensive emergencies (used IV).

Adverse effects:
• Excessive vasodilatation and hypotension leading to reflex tachycardia, palpitation,
anginal pain in patients with IHD, salt and water retention.

• Headache (cerebral vasodilatation), flushing (cutaneous vasodilatation) and nasal

stuffiness.

• Hydralazine may cause lupus erythematosus-like syndrome after long-term therapy

with large doses. It is due to disturbance in the immune system and is usually reversible
after drug discontinuation.

• Minoxidil may cause hirsutism.

• Diazoxide may cause hyperglycemia and hyperuricemia.

 2. Sodium nitroprusside
• Sodium nitroprusside is an effective arterio-venous dilator leading to
reduced peripheral resistance (cardiac afterload) and venous return
(cardiac preload).

• It acts by activation of guanylate cyclase through the release of nitric

oxide (NO donor). This results in increased intracellular cGMP and
dephosphorylation of myosin light chains and vasodilatation.

• Its vasodilator effect is endothelium-independent.

Pharmacokinetices:
• Sodium nitropruside is not used orally (only IV infusion).

• It is rapidly metabolized after its uptake into red blood cells with
release of cyanide ion (CN-).

• CN- is metabolized by the liver in the presence of sulfur donor to

thiocyanate ion (SCN-). The latter ion is much less toxic and excreted by
the kidney.
Therapeutic uses:
• It the drug of choice for hypertensive emergencies as IV infusion.

• In severe cases of congestive heart failure.

Adverse effects:
• Excessive vasodilatation and hypotension leading to reflex tachycardia, palpitation,
anginal pain in patients with IHD, salt and water retention.

• Headache (cerebral vasodilatation), flushing (cutaneous vasodilatation) and nasal

stuffiness.
• Cyanide poisoning in hepatic impairment leading to pink color,

metabolic acidosis, cardiac arrhythmias and death.

• This can be prevented by co-administration of sodium thiosulfate

(sulfur donor) which converts cyanide ion to thiocyanate ion.

 B). Calcium Channel Blockers (CCBs)
• These group of drugs inhibit Ca2+ influx into the cardiac and smooth muscle cells

(vascular and extravascular) by blocking certain type of Ca2+ channels.

Types of voltage-gated Ca2+ channels:

They open in response to cell membrane depolarization. They can be subdivided

into three subtypes:
• N-channels (Neuronal): present only in neuronal cells.

• T-channels (Transient): carry a small transient current and rapidly inactivated.

• L-channels (Long lasting): carry large current and slowly inactivated.

• Only the L-type channel is sensitive to Ca2+ channel blockers. The
selectivity of CCBs to the cardiac and smooth muscles is due to the
abundance of L-type channels in these organs.

• N-type and T-type channels present in neurons and most secretory

glands are not sensitive to these agents, so CCBs have no effect on
the release of neurotransmitters and the secretion of exocrine glands.
Classification of CCBs:
• Verapamil and diltiazem.

• Dihydropyridines include nifedipine, amlodipine, nimodipine.

Pharmacological actions:

Heart:
• Verapamil and diltiazem have direct cardioinhibitory action (negative
chronotropic, inotropic effects and decrease AV conduction).

• Dihydropyridines have no cardioinhibitory action.

Blood vessels:
• Dihydropyridines have more prominent vasodilator action (mainly arteriodilators)
than verapamil and diltiazem.

• Dihydropyridines decrease arterial blood pressure causing reflex sympathetic

stimulation and reflex tachycardia.

• Verapamil and diltiazem do not cause reflex tachycardia due to their direct cardiac
inhibitory action.

• CCBs cause coronary vasodilatation and increase coronary blood flow.

Extravascular smooth muscles:

CCBs cause relaxation of bronchi, GIT and uterus but to a lesser extent than the

vascular smooth muscles due to abundance of of L-type channels in the vascular

smooth muscles.

Special characters:

• Nimodipine has a selective cerebral vasodilator action.

• Amlodipine causes less reflex tachycardia than nifedipine.

Therapeutic uses:
1. Hypertension:
CCBs are effective when used alone or in combination with other antihypertensive
drugs. They are more effective in elderly patients.

2. Angina Pectoris:
• CCBs decrease in myocardial O2 demand (due to cardiac depression) and an
increase in the coronary blood flow (due to coronary vasodilatation).

• The combination of dihydropyirdines with -blockers is recommended in treatment

of angina to abolish the reflex tachycardia of dihydropyridines.
• However, it is contraindicated to combine verapamil or diltiazem with -blockers
because excessive cardiac depression may occur (severe bradycardia, heart block,
heart failure).

3. Supraventricular arrhythmias:

Verapamil is used to reduce ventricular response to supraventricular tachycardia,

atrial fibrillation, atrial flutter.

4. Peripheral vascular diseases: dihydropyridines are used.

5. Nimodipine is a selective cerebral vasodilator. It is used to relief cerebral

vasospasm following subarachnoid hemorrhage and prevents cerebral infarction.
Adverse effects:
• Verapamil and diltiazem: excessive cardiac depression as cardiac
arrest, severe bradycardia, AV block and heart failure.

• Verapamil causes constipation.

• Dihydropyridines: excessive vasodilatation leading to hypotension,

reflex tachycardia, headache, flushing, and edema.
 IV. Inhibitors of angiotensin

1. Angiotensin-converting enzyme (ACE) inhibitors

Chemical classification:

• Sulfhydryl-containing ACE inhibitors as captopril.

• Non-sulfhydryl-containing ACE inhibitors as enalapril and

lisinopril.
Mechanism of action:
• They are competitive inhibitors of ACE which results in:
• Inhibition of angiotensin II synthesis and this leads to vasodilatation of both
arteries and veins (mixed arterio-venous dilators). Arterial dilatation reduces
cardiac afterload, while venous dilatation reduces cardiac preload.

• Also, inhibition of angiotensin II synthesis reduces synthesis and release of

aldosterone with increased salt and water excretion.

• ACE is a nonspecific enzyme which is also responsible for degradation of

bradykinin. ACE inhibition leads to accumulation of bradykinin which is a
powerful vasodilator reducing blood pressure.
Therapeutic uses:

1- Hypertension:
ACE inhibitors are more effective in young and white patients and less effective in
elderly and black patients.

Advantages of ACE inhibitors over other antihypertensive drugs:

• No reflex tachycardia due to increased parasympathetic activity.

• No postural (orthostatic) hypotension because sympathetic reflexes are preserved.

• No effect on blood glucose, uric acid or cholesterol levels (unlike thiazide

diuretics), so ACE inhibitors can be used for patients with diabetes mellitus, gout or
hyperlipidemia.
2- Chronic congestive heart failure:
ACE inhibitors are now the first-choice (standard therapy) for chronic congestive
heart failure due to:
• They cause arteriodilatation which reduces cardiac afterload, and also
venodilatation which reduces cardiac preload. Reduced cardiac afterload and
preload reduces cardiac work.

• They decrease aldosterone secretion increasing salt and water excretion and so
reduces peripheral edema.

• They reduce pulmonary congestion and edema and so relieving dyspenea.

3- Diabetic nephropathy:
• In hypertensive or non-hypertensive patients.

• ACE inhibitors reduce glomerular capillary pressure due to

vasodilatation of efferent glomerular arterioles.

• This reduces proteinuria and glomerular injury and retard the

development of renal failure.
Adverse effects:
• First-dose effect: marked hypotension with the initial dose in patients with
hyponatremia (on diuretic therapy or salt-restricted diet).

• Chronic dry cough (common, 5-15% of patients) due to bradykinin accumulation in

the respiratory mucosa.

• Skin rash and alteration of taste sensation due to the SH groups in captopril (not
with other ACE inhibitors).

• Hyperkalemia in patients with renal impairment.

• Should not be used during pregnancy as they may cause fetal hypotension, renal
failure, congenital abnormalities.

• Should not be used with K+-sparing diuretics as this leads to hyperkalemia (used
with thiazides or loop diuretics which cause hypokalemia).
 Captopril (Capoten) Enalapril (Vasotec)

-Active drug -Prodrug converted by liver to

active enalaprilat
-Rapid onset -Slow onset

-Short duration of action -Long duration of action

-Less potent (larger dose) -More potent (smaller dose)

-GI absorption is reduced by food -Absorption not affected by food

- Contains SH groups with high - No SH groups with minimal

incidence of skin rash and incidence of skin rash and
alteration of taste sensation alteration of taste sensation
 2. Angiotensin II-receptor antagonists

- Losartan is a selective competitive antagonist at AT1-receptors.

- It is a mixed arterio-venous dilator which reduces cardiac afterload and preload.

- It is used in treatment of hypertension, chronic congestive heart failure, diabetic

nephropathy.

- It may cause all adverse effects of ACE inhibitors except chronic dry cough
because there is no bradykinin accumulation.
 Management of hypertension

The aim of treatment is to reduce blood pressure to normal levels (i.e. <140/90
mmHg) with minimal side effects.

General measures (non-drug therapy):

• Diet: sodium restriction and rich in potassium. Avoid atherogenic diet.
• Weight reduction in obese patients.
• Stop smoking and alcohol intake.
• Physical and mental rest.
• Avoid agents which increase blood pressure as sympathomimetics,
glucocorticoids, NSAIDs, xanthines.
Drug therapy of hypertension:
Mild to moderate hypertension:

Step 1. Start treatment with monotherapy with one of the following:

- A thiazide diuretic
- A β-blocker
- An ACE inhibitor
- A Ca2+ channel blocker

• The choice of the first line therapy should be based on the age, race of the patient
and the presence of concomitant disease.

• Thiazide diuretics and β-blockers are the most commonly used drugs for initial
therapy in patients with mild to moderate hypertension.
Step 2:

If monotherapy is inadequate, a second drug with a different mechanism of action is

added (to obtain synergism). Most commonly used combinations are:
• a thiazide diuretics + a β-blocker

• a thiazide diuretic + an ACE inhibitor

Step 3:

If step 2 therapy is inadequate in controlling BP, a third drug is added (triple therapy)
e.g. a thiazide diuretic + a β-blocker + a vasodilator (direct vasodilator or CCB).

Severe Hypertension:
• Start by triple therapy with a combination of three drugs e.g. a thiazide diuretic + a β-
blocker + a vasodilator.
Drug Treatment in Special Cases of Hypertension:

• Hypertensive emergency: Furosemide or Sodium nitroprusside (IV).

• Hypertension in pregnancy (gestational hypertension): α-Methyldopa.

• Hypertension + COPD: Calcium channel blockers.

• Hypertension + peripheral vascular disease: Calcium channel blockers.

• Hypertension + Diabetes mellitus: ACE inhibitors.

• Hypertension + Renal failure: Furosemide.

• Hypertension + IHD: β-blockers.