Antihypertensive Drugs
Drug List *
Diuretics
Sympathoplegic
Vasodilators
drugs
Inhibitors and antagonists of the reninangiotensin system
ACE
inhibitors
Captopril
Hydrochlorothiazide
Indapamide
Clonidine
Hydralazine
Methyldopa
Nitroprusside Enalapril
Furosemide
Prazosin
Minoxidil
Spironolactone Propranolol
Enalaprilat
Diazoxide
Labetalol
Fenoldopam
Esmolol
CCBs
* More drugs have been mentioned in other slides
ARBs
Losartan
Renin
inhibitors
Aliskiren
Classification of Antihypertensive Drugs
1) Diuretics
• Thiazides
• Loop diuretics.
• Potassium-sparing diuretics.
2) Sympatholytic drugs
1. Centrally acting antiadrenergic agents.
2. Alpha adrenergic blockers.
3. Beta adrenergic blockers.
4. Alpha-beta adrenergic blockers.
3) Vasodilators
A. Nitric oxide releasers.
B. Potassium channel openers.
C. D1-dopamine receptor agonists.
4) Calcium channel blockers
5) Drugs acting on renin angiotensin system
A. Renin inhibitors
B. Angiotensin Converting Enzyme (ACE) inhibitors.
C. Angiotensin receptor antagonists. (ARB)
1. Diuretics
• Diuretics lower blood pressure but there is no strict
correlation
between
diuretic
efficacy
and
antihypertensive efficacy.
• The fact points out that diuretics do not reduce blood
pressure only by increasing diuresis.
• The initial hypotensive effects of diuretics is associated
with a reduction in plasma volume and cardiac
output. Peripheral vascular resistance is usually
unaffected (or sometimes increased).
• After 4-8 weeks of continuous therapy intravascular volume
and cardiac output return towards normal while peripheral
vascular resistance decreases, due to arteriolar vasodilation
• Mechanisms of this vasodilation are still poorly understood,
but are probably related to:
a. Depletion of body Na+ stores (likely the main
mechanism) which leads to a fall in smooth muscle Na+
concentration. This in turn decreases intracellular Ca++
concentration by activating the Ca/Na exchanger.
b. Induction of renal prostaglandin biosynthesis.
c. Opening of K channels.
 Thiazides and thiazide-like drugs are first choice
antihypertensive agents. They are the most effective
diuretics to reduce blood pressure in patients with
normal renal function.
 The antihypertensive doses are lower that those required
for diuretic effect.
 Loop diuretics are preferable to thiazides only in some
well
recognized
clinical
situations
(malignant
hypertension, concomitant chronic kidney disease etc.)
 Potassium sparing diuretics are only used in combination
with thiazides to counteract hypokalemia. Spironolactone
is used in hypertension due to hyperaldosteronism.
 Diuretics can enhance the hypotensive effects of many
antihypertensive agents.
2. Sympatholytic drugs
A. Centrally acting sympathoplegic
Drugs
Drugs
• Alpha-2 receptor agonists: clonidine
• Indirect acting adrenergic drugs: methyldopa
• Imidazoline receptor agonists: clonidine,
Mechanisms of antihypertensive action
a) Alpha-2 receptor agonists:
• Activation of central alpha-2 receptors (the main
mechanism).
b) Indirect acting adrenergic drugs:
• Methyldopa acts as a false neurotransmitter.
• It is taken up by the adrenergic neurons where it is
transformed into methylnorepinephrine, the
alpha-2 receptor agonist, which acts as described
above.
c) Imidazoline receptor agonists:
• These drugs activates non-adrenergic binding sites
called imidazoline receptors located in medulla,
which is the final common pathway for
sympathetic outflow.
The final effect common to all these drugs is a
decreased of central adrenergic tone
Therapeutic uses in hypertension
• Clonidine and methyldopa (usually given together
with a diuretic) are second choice drugs for therapy
of hypertension.
• Methyldopa is often preferred for the treatment of
hypertension in pregnancy (long experience has
shown that it is not harmful to the fetus).
Adverse effects:
CNS:
• Sedation and drowsiness ,
• Weakness, headache, nightmares
• Risk for depression
CVS:
• Clonidine (and rarely methyldopa) can cause a
hypertensive crisis, when the drug is suddenly withdrawn.
• Bradycardia, A-V block (in risk patients).
Others
• Sexual dysfunction
• Skin eruption (up to 20% with clonidine, when given
transdermally).
• Methyldopa can cause positive Coombs’ test
B. Alpha Blockers
• Prazosin, doxazosin.
Mechanism of action
• Selective blockade of alpha-1 receptors.
• They reduce blood pressure by dilating both resistance
and capacitance vessels
Uses in hypertension
• Hypertension (second choice drugs), often combined
with other antihypertensive drugs.
Adverse effects
1. CVS
• Postural hypotension, mainly after the first dose
"first-dose phenomenon".
• Tachycardia, palpitations, syncope
• Peripheral edema, after chronic treatment (due to
sodium and water retention).
2) Central nervous system
• Fatigue, dizziness, vertigo, drowsiness
3) Others
• Urinary frequency, urinary incontinence.
• Sexual dysfunction
C. Beta-blockers (the “olols”)
Mechanisms of action
• Decrease in cardiac output (blockade of cardiac beta-1
receptors)
• Inhibition of renin release (blockade of beta-1
receptors of juxtaglomerular cells)
Classes of beta blockers
1. Selective (B1): Atenolol, Bisoprolol, Metoprolol
2. Non selective: Propranolol, Penbutolol, Timolol
Pharmacological effects:
• Decrease heart rate.
• Decrease cardiac output.
• Venous tone unchanged.
• Dose not cause postural hypotension
Therapeutic uses of beta blockers
• Supraventricular arrhythmias.
• Hypertrophic obstructive cardiomyopathy.
• Exertional angina.
• Post myocardial infarction.
• Hypertensive emergency (labetalol).
Adverse Effects
• CVS: Bradycardia, hypotension, rebound hypertension
when withdrawn abruptly
• Nonselective compounds devoid of partial agonist
activity are most prone to cause peripheral vascular
disturbances (because of a decreased cardiac output
and associated blockade of vasodilation in skeletal
muscle).
• Respiratory: Bronchoconstriction
• CNS: Insomnia, depression, nightmares
• Hepatic: Impaired ability of the liver for gluconeogenesis
and glycogenolysis causing hypoglycemia
• Sexual dysfunction
Beta blocker with partial agonist
action
Pindolol and acebutolol :
• They bound to beta 1 and 2 and cause partial
stimulation of it but not the full effect and they
inhibit
the
binding
of
more
potent
catecholamine. Thus these drugs are named
blockers with ISA (intrinsic sympathomimetic
action) .
• It used for treatment of hypertension in patients
with moderate bradycardia, because a further
decrease in the heart rate is less pronounced
with these drugs
D. Alpha and beta adrenoceptor blockers
• Labetalol and carvedilol
• They block both α and β receptors
• They cause vasodilation and reduction in the HR and
contractility.
• Uses:
– Treatment of hypertension in black and elderly patients.
– Labetalol is used in treatment of hypertension with
pregnancy.
– IV labetalol is used for treatment of hypertensive
emergencies
– Carvidalol can be used in treatment of heart failure.
• Side effects:
– Orthostatic hypotension and dizziness
3. Vasodilators used in treatment of
hypertension
Drug
Site of action
Mechanism of action
Nitropursside
Arterioles and veins
Production of nitric oxide
Hydralazine
Arterioles
Uncertain
(Perhaps inhibition of Ca++ release
from sarcoplasmic reticulum, and
stimulation of NO release)
Minodoxil
Diazoxide
Arterioles
Arterioles
K+ channel opening
K+ channel opening
Fenoldopam
Arterioles
D1- receptor activation
A. Nitroprusside
Pharmacokinetics
• Rapidly metabolized by red blood cells with liberation of
cyanide, which in turn is metabolized to thiocyanate.
• The half life is about 2 minutes, so the drug must be given
by continuous infusion to be effective.
Adverse effects
• Excessive vasodilation, rebound hypertension, palpitations
• Nausea and vomiting, sub sternal pain
• Accumulation of:
a) Cyanide (with too high doses)
b) Thiocyanate (over prolonged administration)
Therapeutic uses
• Hypertensive emergencies.
• Severe heart failure.
• To induce a controlled hypotension, during
surgery.
B. Hydralazine
• It directly relaxes small arteries and arterioles.
• It is absorbed from GIT, acetylated in the liver.
Adverse effects
a) Due to extension of pharmacological effects:
• Headache, dizziness.
• Palpitations , flushing.
b) Due to immunological reactions
• Lupoid syndrome (up to 20% incidence, with
very high doses).
• Fever, serum sickness, hemolytic anemia,
vasculitis.
Contraindications and precautions
• Coronary artery disease
• Cerebrovascular disease
• Collagen disease
Therapeutic uses
• Hypertension (second choice drug).
• Heart failure (combined with isosorbide
mononitrate)
C. Minodoxil
• Minoxidil is a prodrug which is transformed by the liver
into the active molecule.
Therapeutic uses:
(Not very commonly used because of its toxicity)
• Severe hypertension that responds poorly to other
antihypertensive medications.
• Locally used to treat baldness.
Adverse effects
• Salt and water retention.
• Tachycardia, palpitations, flushing
• Hypertrichosis
D. Diazoxide
• It is a potassium channel opener
• It is similar to thiazide diuretics, but it does not cause
diuresis (apparently because it lacks a sulfonamide
group).
Adverse effects
• Salt and water retention, edema.
• Hyperglycemia
• Excessive hypotension, Flushing and headache
• Hypertrichosis (Hair growth in 20% of patients).
Therapeutic uses
• Hypertensive emergencies.
E. Dopamine D1-Receptor Agonist
Fenoldopam is the only drug on the market.
Administration: IV infusion
Mechanism of action:
• Vasodilation, mainly in renal and mesenteric vascular
beds.
• Increased natriuresis (activation of D1 receptors causes
an inhibition of NA+ reabsorption in the proximal tubule)
Therapeutic uses
• Hypertensive emergencies.
• To induce a controlled hypotension, during surgery.
Adverse effects
• Reflex tachycardia, flushing
• Dose-dependent increase in intraocular
pressure
• Decrease in serum potassium levels (likely due
to natriuresis-induced aldosterone release).
Contraindications
• Angina (tachycardia can trigger an anginal
attack)
• Glaucoma.
• Hypokalemic states.
4. Calcium Channel Blockers
• All calcium channel blockers (dihydropyridines and
non dihydropyridines ‘verapamil, diltiazem’) are
equally effective in lowering blood pressure.
Hemodynamic actions
• Heart rate: increased (dihydropyridines); unchanged
or decreased (verapamil, diltiazem)
• Cardiac output: increased (dihydropyridines);
unchanged (verapamil, diltiazem)
• Peripheral vascular resistance: decreased.
• Postural hypotension: negligible.
• Efficacy of antihypertensive effect: moderate.
Calcium Channel blockers
Uses in hypertension
• Hypertension (first choice drugs, more effective in
African patients).
• Hypertensive emergencies (nicardipine).
• Long term epidemiological studies have reported
an increased risk of mortality when short-acting
nifedipine is used in hypertension. Slow release
formulations apparently do not increase this risk.
5. Drug affecting renin angiotensin system
A. Renin Inhibitors
• Aliskiren is the only drug on the market
Mechanism of action
• Competitive inhibition of renin, the enzyme that
converts angiotensinogen into angiotensin I (the
rate limiting step in angiotensin II biosynthesis).
• The inhibition of renin activity causes a decrease
of angiotensin I, II, and aldosterone and an
increase renin.
Adverse effects
(usually well tolerated)
• Dizziness, fatigue, Diarrhea
• Hyperkalemia (when given with ACE inhibitors
or angiotensin antagonists)
B. ACE inhibitors
• Captopril, lisinopril and enalaprilat are active drugs.
• All other compound (enalapril, benazepril, fosinopril,
etc.) are prodrugs.
Mechanism of action
• The converting enzyme hydrolyzes angiotensin one to
angiotensin II and inactivates bradykinin.
• By inhibiting this enzyme, ACE-inhibitors lead to:
1. Inhibition of the renin-angiotensin system
2. Increased plasma levels of bradykinin
• Both actions lead to a relaxation of vascular smooth
muscle, but the first action is the most important.
• By inhibiting angiotensin II formation ACE
inhibitors decrease the negative feed-back so
causing an increase in renin release.
• This may attenuate the antihypertensive effect of
these drugs).
Pharmacokinetics
• All compounds that are prodrugs are transformed
by the liver into active metabolites.
• All compounds, except enalaprilat (IV), are
administered by oral route only .
Adverse effects
Cardiovascular system
• Hypotension and postural hypotension (mainly
after the initial doses, in 3-5% of patients who are
salt and water depleted, or who have congestive
heart failure).
Respiratory system
• Dry and disturbing cough (it may be mediated by
accumulation in the lungs of bradykinin and
prostaglandins or, more likely, substance P).
Urinary system
• Renal insufficiency (in patients with bilateral renal
artery stenosis or with stenosis of the renal artery of
a solitary kidney)
Other systems
• Hyperkalemia
• Angioneurotic edema. It is rare (up to 0.3%), but may
be fatal (inhibition of bradykinin metabolism can be
involved).
Pregnancy:
• ACE inhibitors are pregnancy category D
Therapeutic uses
• Hypertension (first choice drugs)
• Hypertensive emergencies (enalaprilat IV)
• Myocardial infarction (overall mortality is
reduced when treatment is begun during periinfarction period).
• Chronic congestive heart failure (they decrease
the progression of heart failure, the incidence of
sudden death and myocardial infarction, and
they improve the quality of life)
• Diabetic
glomerulopathy,
hypertensive
nephroangiosclerosis (they decrease the
progression of the disease by preventing the
angiotensin II induced vasoconstriction on
the efferent glomerular arteriole).
• Primary or secondary hyperaldosteronism
(when resistant to conventional therapy).
C. Angiotensin II Receptor antagonists
• Losartan, eprosartan, irbesartan,
• All compounds are administered by oral route
only.
Mechanism of action
• Competitive antagonism at angiotensin II
receptors (these drugs selectively block AT1
receptors)
Pharmacodynamics
• They can prevent and reverse most known actions
of angiotensin II, including:
1. Rapid and slow hypertensive responses
2. Stimulant effect on the peripheral sympathetic
nervous system.
3. All CNS effects (thirst, vasopressin release, etc.)
4. Release of adrenal catecholamines
5. Secretion of aldosterone
6. All growth-promoting actions
• They exert a more complete inhibition of
angiotensin actions compared with ACE
inhibitors (enzymes other than ACE are capable
of generating angiotensin II)
• They have no effect on bradykinin and
leukotriene metabolism.
Main actions are:
• Vasodilation
• Increased salt and water secretion
Adverse effects
[all adverse effects that result from inhibiting
angiotensin II related functions should be expected]
Contraindications
• Bilateral renal artery stenosis, severe stenosis of
abdominal aorta.
• Pregnancy [these drugs are classified by FDA in the
pregnancy risk category D because of their
substantial teratogenic risk].
Therapeutic uses
• Hypertension (first choice drugs)
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