Basic and Clinical Pharmacology

C11 ANTIHYPERTENSIVE AGENTS

A. Q. Sangalang, MD, MHPEd, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

• Classification of hypertension on the basis of blood pressure

§ Strategies for treating high blood pressure are based on determinants of arterial
pressure

§ Strategies include reduction of

o Blood volume
o Sympathetic tone
o Vascular smooth muscle tone
o Angiotensin effects
§ Baroreceptor reflex and renin response to lower blood pressure (BP)
§ Compensatory homeostatic responses to these drugs may be significant (See
Table in Katzung)
§ Compensatory mechanisms can be counteracted by
o Tachycardia- beta blockers, reserpine
o Salt and water retention-diuretics, angiotensin antagonists

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DIURETICS
§ Lower BP by reduction of blood volume and direct vascular effect
§ Compensatory responses to BP lowering are minimal

THIAZIDES
• HYDROCHLOROTHIAZIDE
o Adequate in mild hypertension
o Maximum antihypertensive action is achieved with doses below those
required for maximum diuretic effect

LOOP DIURETICS
• FUROSEMIDE
o Used in moderate, severe, and malignant hypertension

SYMPATHOPLEGICS
§ Interfere with sympathetic nerve functions
§ Compensatory mechanisms and adverse effects are marked for some of these
agents
§ Reduction of the following
o Venous tone
o Heart rate
o Contractile force of the heart
o Cardiac output (CO)
o Total peripheral resistance (TPR)

CLASSIFICATION
A. Baroreceptor sensitizing – No drug available
B. CNS Active
C. Ganglion Blocking Drugs
D. Post-ganglionic sympathetic blocker
E. Adrenoceptor blockers

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B. CNS-ACTIVE AGENTS

ALPHA2-SELECTIVE AGENTS

CLONIDINE
• Decrease sympathetic outflow by activation of α2-receptors in the CNS
• Readily enter the CNS when given orally
• Reduce BP by reducing cardiac output, vascular resistance, or both
• Major compensatory mechanism is salt retention
• Can cause sedation
o Rebound hypertension
Ø Sudden discontinuation causes elevated BP due to loss of
antihypertensive effect

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 Ø Controlled by reinstitution of the drug or administration of α2
blockers (phentolamine)
METHLYDOPA
• Prodrug converted to methlynorepinephrine in the brain
• Causes hematologic immunotoxicity (+ Coombs test) ---hemolytic anemia
• Sedation is more pronounced

C. GANGLION-BLOCKING DRUGS

HEXAMETHONIUM and TRIMETHAPHAN

• Very efficacious
• Adverse effects are severe
• Obsolete
• Major compensatory mechanism is salt retention
• Toxicities reflect parasympathetic blockade
o Blurred vision
o Constipation
o Urinary hesitancy
o Sexual dysfunction
o Orthostatic hypotension

D. POSTGANGLIONIC SYMPATHETIC NERVE TERMINAL BLOCKERS

• Very efficacious in high doses
• High incidence of side effects
• Long duration of action (days to weeks)
• Compensatory response is salt retention

RESERPINE
• Depletes the adrenergic nerve terminal of norepinephrine (NE) stores
• Adjunct to other agents in low doses
• Readily enters the CNS
• Toxicity
o Behavioral depression
o May require discontinuation of the drug

GUANETHEDINE
• Blocks the release of stores of NE
• Rarely used
• Does not enter the CNS
• Requires the catecholamine reuptake pump (uptake 1) to reach its intracellular site
of action
• Toxicity
o Orthostatic hypotension
o Sexual dysfunction
• Drugs that inhibit the pump (cocaine, tricyclic antidepressants) will interfere with
its action

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MAO INHIBITORS
• Formation of octopamine, a false transmitter released during normal nerve action
potential results to diminished vascular and cardiac response---lower BP
• Large doses of indirect-acting sympathomimetics (tyramine) may cause release of
large amounts of NE and lead to a hypertensive crisis
• No longer used for hypertension
• Occasionally used for treatment of severe depressive disorder

E. ADRENOCEPTOR BLOCKERS
• Effective antihypertensive agents

PRAZOSIN
• Alpha1-selective blockers
• Reduce vascular resistance and venous return
• Free of severe adverse effects

PHENTOLAMINE, PHENOXYBENZAMINE
• Nonselective α-blockers
• No value in chronic hypertension
• Excessive compensatory responses especially tachycardia

BETA-BLOCKERS
• Initially reduce cardiac output
• Decrease vascular resistance, it reduces renin release from the kidneys that
results to reduce angiotensin levels
• Most heavily used antihypertensive
• Associated with
o Slightly elevated glucose, LDL, triglyceride,
o Diminished levels of HDL

CALCIUM CHANNEL BLOCKERS

• NIFEDIPINE, VERAPAMIL, DILTIAZEM
• Effective vasodilators
• Orally active
• Chronic use
• Used in hypertension of any severity
Fewer compensatory responses

VASODILATORS
• Dilate blood vessels by acting directly on the smooth muscle cells through
nonautonomic mechanisms
• Compensatory responses maybe marked and include salt retention and
tachycardia

§ FOUR MAJOR MECHANISMS

o Release of nitric oxide
o Opening of potassium channels
o Blockade of calcium channels
o Activation of D1 dopamine receptors

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HYDRALAZINE
• Older vasodilator
• More effect on arterioles than veins
• Orally active
• For chronic therapy
Acts through release of nitric oxide from endothelial cells
• Rarely used at high dosage because of toxicity
• Efficacy is limited
• Toxicity
o Compensatory responses (tachycardia, salt and water retention)
o Drug-induced lupus erythematosus (reversible upon stopping the drug
(uncommon at doses below 200 mg/d)

MINOXIDIL
• Older vasodilator
• Prodrug
• Minoxidil sulfate, its metabolite is a potassium channel opener that hyperpolarizes
and relaxes vascular smooth muscle
• Extremely efficacious
• Reserved for severe hypertension
• Toxicity
o Severe compensatory responses
o Hirsutism
o Pericardial abnormalities

NITROPRUSSIDE and DIAZOXIDE

§ IV vasodilators used in hypertensive emergencies

NITROPRUSSIDE
• Short-acting (duration is a few minutes)
• Infused continuously
• Release of nitric oxide from the drug which stimulates guanylyl cyclase
and increase cGMP in the muscle
• Toxicity
• Excessive hypotension
o Tachycardia
o Accumulation of cyanide or thiocyanate in the blood if infusion is
continued for several days
DIAZOXIDE
• Given as IV boluses or as an infusion (duration of action of several hours)
• Opens potassium channels, hyperpolarizes and relaxes smooth muscles
• Reduces insulin release
• Used to treat hypoglycemia caused by insulin-producing tumors
• Toxicity
o Hypotension
o Hyperglycemia
o Salt and water retention

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FENOLDOPAM
• Dopamine D1 receptor activation cause marked arteriolar vasodilation
• Given IV
• Used for hypertensive emergencies

ANGIOTENSIN ANTAGONISTS
• Two primary groups

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS

• Captopril, enalapril
• More extensively used
• Inhibit the enzyme ACE, kininase II, and peptidyl dipeptidase
• Reduction in blood levels of angiotensin II and aldosterone
• Increase in endogenous vasodilators (bradykinin)
• Low incidence of serious adverse effects when given in normal doses (except in
pregnancy)
• Minimal compensatory responses
• Toxicity
o Cough (30% of patients)
o Renal damage in patients with preexisting renal vascular disease (protect
the diabetic kidney)
o Renal damage in fetus

ANGIOTENSIN II RECEPTOR BLOCKERS

• Losartan, valsartan, irbesartan, candesartan and other analogs
• Orally active
• Competitively inhibit angiotensin II at AT1 receptor site
• Toxicity
o Lower incidence of cough
o Fetal renal toxicity
o Contraindicated in pregnancy
o Reduce aldosterone levels
o Causes potassium retention and lead to accumulation
Ø Patients with renal impairment
Ø High-potassium diet
Ø Taking drugs that conserve potassium

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CLINICAL USES
“STEPPED CARE”
• Use of multiple drugs at lower dosage to reduce overall toxicity and minimize
compensatory responses
• Used in patients with severe hypertension
• Drugs are added to a patient’s regimen in stepwise fashion
• Additional agent is chosen from a different subgroup until BP control is achieved
• Lifestyle measures (salt restriction and weight reduction
• Diuretics
• Sympathoplegic (beta-blockers)
• ACE inhibitors
• Vasodilator (calcium-channel blockers)

MONOTHERAPY
• Many patients do well on a single drug
• Simple
• Better patient compliance
• Low incidence of toxicity

AGE
• Older patients respond better to diuretics and beta-blockers

MALIGNANT HYPERTENSION
• Accelerated phase of severe hypertension
• Rising BP and rapidly progressing damage to vessels and end organs

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• Deterioration of
o Renal function
o Encephalopathy
o Retinal hemorrhages
• Angina, stroke or myocardial infarction
• Management
o Emergency
o Vasodilators (nitroprusside, fenoldopam, diazoxide) combined with
diuretics and beta-blockers
o Lower BP to 140-160/110 mm Hg
o Further reduction is pursued more slowly

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