11 Antihypertensive Agents

DRUGS USED IN
DRUGS USED IN
HYPERTENSION
HYPERTENSION
A. Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
12/23/17
DRUGS USED IN HYPERTENSION
 Strategies for treating high blood pressure
are based on determinants of arterial
pressure
12/23/17
VASOMOTOR CENTERS
Parasympathetic Sympathetic ANS

Baroreceptor ANS
`
Peripheral Vascular Contractile
Heart rate Venous tone
Resistance forces
Cardiac Stroke Venous Blood

Mean return volume
output volume
Arterial
Pressure
Aldosterone
Renal
blood RENIN Angiotensin
flow
 Strategies include reduction of
 Blood volume
 Sympathetic tone
 Vascular smooth muscle tone
 Angiotensin effects
 Baroreceptor reflex and renin response to lower blood
pressure (BP)
 Compensatory homeostatic responses to these drugs may
be significant (Table 111 Katzung)
12/23/17
 Compensatory mechanisms can be counteracted by
 Tachycardia beta blockers, reserpine
 Salt and water retentiondiuretics, angiotensin antagonists
12/23/17
12/23/17
DIURETICS
 Lower BP by reduction of blood volume
and direct vascular effect
 Compensatory responses to BP lowering
are minimal
12/23/17
DIURETICS
THIAZIDES
HYDROCHLOROTHIAZIDE
 Adequate in mild hypertension
 Maximum antihypertensive action is achieved with doses
below those required for maximum diuretic effect
LOOP DIURETICS
FUROSEMIDE
 Used in moderate, severe, and malignant hypertension
12/23/17
SYMPATHOPLEGICS
 Interfere with sympathetic nerve functions
 Compensatory mechanisms and adverse
effects are marked for some of these agents
12/23/17
SYMPATHOPLEGICS
 Reduction of the following
 Venous tone
 Heart rate
 Contractile force of the heart
 Cardiac output (CO)
 Total peripheral resistance (TPR)
12/23/17
SYMPATHOPLEGICS
CLASSIFICATIONS:
A.Baroreceptor sensitizing – No drug available
B.CNS Active
C.Ganglion Blocking Drugs
D.Postganglionic sympathetic blocker
E.Adrenoceptor blockers
12/23/17
SYMPATHOPLEGICS
B. CNSACTIVE AGENTS
 ALPHA2SELECTIVE AGENTS
 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
12/23/17
SYMPATHOPLEGICS
B. CNSACTIVE AGENTS
CLONIDINE
 Rebound hypertension
 Sudden discontinuation causes elevated BP due to
loss of antihypertensive effect
 Controlled by reinstitution of the drug or
administration of α2 blockers (phentolamine)

12/23/17
SYMPATHOPLEGICS
B. CNSACTIVE AGENTS
METHLYDOPA
 Prodrug converted to methlynorepinephrine in the
brain
 Causes hematologic immunotoxicity (+ Coombs test)
hemolytic anemia
 Sedation is more pronounced
12/23/17
SYMPATHOPLEGICS
C. GANGLIONBLOCKING DRUGS
HEXAMETHONIUM and TRIMETHAPHAN
 Very efficacious
 Adverse effects are severe
 Obsolete
 Major compensatory mechanism is salt retention
 Toxicities reflect parasympathetic blockade
 Blurred vision
 Constipation
 Urinary hesitancy
 Sexual dysfunction
 Orthostatic hypotension
12/23/17
SYMPATHOPLEGICS
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
12/23/17
SYMPATHOPLEGICS
D. POSTGANGLIONIC SYMPATHETIC NERVE
TERMINAL BLOCKERS
RESERPINE
 Depletes the adrenergic nerve terminal of
norepinephrine (NE) stores
 Adjunct to other agents in low doses
 Readily enters the CNS
 Toxicity
 Behavioral depression
 May require discontinuation of the drug
12/23/17
SYMPATHOPLEGICS
TERMINAL BLOCKERS
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
 Orthostatic hypotension
SYMPATHOPLEGICS
D. POSTGANGLIONIC SYMPATHETIC
NERVE TERMINAL BLOCKERS
GUANETHEDINE
 Drugs that inhibit the pump (cocaine,
tricyclic antidepressants) will interfere with
its action
12/23/17
SYMPATHOPLEGICS
TERMINAL BLOCKERS
MAO INHIBITORS
 Formation of octopamine, a false transmitter
released during normal nerve action potential
results to diminished vascular and cardiac
responselower BP
 Large doses of indirectacting sympathomimetics
(tyramine) may cause release of large amounts of
NE and lead to a hypertensive crisis
12/23/17
SYMPATHOPLEGICS
TERMINAL BLOCKERS
MAO INHIBITORS
 No longer used for hypertension
 Occasionally used for treatment of severe
depressive disorder
12/23/17
SYMPATHOPLEGICS
E. ADRENOCEPTOR BLOCKERS
 Effective antihypertensive agents
Alpha1selective blockers
Prazosin
 Reduce vascular resistance and venous
return
 Free of severe adverse effects
12/23/17
SYMPATHOPLEGICS
D. ADRENOCEPTOR BLOCKERS
Nonselective αblockers
Phentolamine, phenoxybenzamine
 No value in chronic hypertension
 Excessive compensatory responses
especially tachycardia
12/23/17
SYMPATHOPLEGICS
D. ADRENOCEPTOR BLOCKERS
Betablockers
 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
 Slightly elevated glucose, LDL, triglyceride,
 Diminished levels of HDL
12/23/17
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
12/23/17
VASODILATORS
 FOUR MAJOR MECHANISMS
 Release of nitric oxide
 Opening of potassium channels
 Blockade of calcium channels
 Activation of D1 dopamine receptors
12/23/17
VASODILATORS
A. HYDRALAZINE and MINOXIDIL
 Older vasodilators
 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
 Compensatory responses (tachycardia, salt and water
retention)
 Druginduced lupus erythematosus (reversible upon
12/23/17
stopping the drug)
(uncommon at doses below 200 mg/d)
VASODILATORS
A. HYDRALAZINE and MINOXIDIL
MINOXIDIL
 Prodrug
 Minoxidil sulfate, its metabolite is a potassium channel
opener that hyperpolarizes and relaxes vascular smooth
muscle
 Extremely efficacious
 Reserved for severe hypertension
 Toxicity
 Severe compensatory responses
 Hirsutism
 Pericardial abnormalities
VASODILATORS
B. CALCIUM CHANNEL BLOCKERS
NIFEDIPINE, VERAPAMIL, DILTIAZEM
 Effective vasodilators
 Orally active
 Chronic use
 Used in hypertension of any severity
 Fewer compensatory responses
12/23/17
VASODILATORS
C. NITROPRUSSIDE and DIAZOXIDE
 IV vasodilators used in hypertensive emergencies
NITROPRUSSIDE
 Shortacting (duration is a few minutes)
 Infused continuously
 Release of nitric oxide from the drug
which stimulates guanyl cyclase
and increase cGMP in the muscle
12/23/17
VASODILATORS
NITROPRUSSIDE
 Toxicity
 Excessive hypotension
 Tachycardia
 Accumulation of cyanide or thiocyanate in the blood
if infusion is continued for several days
12/23/17
VASODILATORS
DIAZOXIDE
 Given as IV boluses or as an infusion
(duration of action of several hours)
 Opens potassium channels, hypepolarizes
and relaxes smooth muscles
 Reduces insulin release
 Used to treat hypoglycemia caused by
insulinproducing tumors
12/23/17
VASODILATORS
DIAZOXIDE
 Toxicity
 Hypotension
 Hypergylcemia
 Salt and water retention
12/23/17
VASODILATORS
D. FENOLDOPAM
 Dopamine D1 receptor activation cause
marked arteriolar vasodilation
 Given IV
 Used for hypertensive emergencies
12/23/17
ANGIOTENSIN ANTAGONISTS
 Two primary groups
ANGIOTENSINCONVERTING 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)
12/23/17
ANGIOTENSINCONVERTING ENZYME
(ACE) INHIBITORS
 Low incidence of serious adverse effects
when given in normal doses (except in
pregnancy)
 Minimal compensatory responses
 Toxicity
 Cough (30% of patients)
 Renal damage in patients with preexisting renal vascular disease
(protect the diabetic kidney)
 Renal damage in fetus
12/23/17
ANGIOTENSIN II RECEPTOR BLOCKERS
 Losartan, valsartan, irbesartan, candesartan
and other analogs
 Orally active
 Competitively inhibit angiotensin II at AT1
receptor site
 Toxicity
 Lower incidence of cough
 Fetal renal toxicity
12/23/17 Contraindicated in pregnancy

ANGIOTENSIN II RECEPTOR
BLOCKERS
 Toxicity
 Reduce aldosterone levels
 Causes potassium retention and lead to accumulation
 Patients with renal impairment
 Highpotassium diet
 Taking drugs that conserve potassium
12/23/17
CLINICAL USES
A. “ 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
12/23/17
CLINICAL USES
A. “ STEPPED CARE”
 Lifestyle measures (salt restriction and
weight reduction
 Diuretics
 Sympathoplegics (betablockers)
 ACE inhibitors
 Vasodilator (calciumchannel blockers)
12/23/17
CLINICAL USES
B. MONOTHERAPY
 Many patients do well on a single drug
 Simple
 Better patient compliance
 Low incidence of toxicity
C. AGE
 Older patients respond better to diuretics and
betablockers
12/23/17
CLINICAL USES
D. MALIGNANT HYPERTENSION
 Accelerated phase of severe hypertension
 Rising BP and rapidly progressing damage
to vessels and end organs
 Deterioration of
 Renal function
 Encephalopathy
 Retinal hemorrhages
 Angina, stroke or myocardial infarction
12/23/17
CLINICAL USES
D. MALIGNANT HYPERTENSION
 Management
 Emergency
 Vasodilators (nitroprusside, fenoldopam, diazoxide)
combined with diuretics and betablockers
 Lower BP to 140160/110 mm Hg
 Further reduction is pursued more slowly
12/23/17

11 Antihypertensive Agents

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DRUGS USED IN

Parasympathetic Sympathetic ANS

Cardiac Stroke Venous Blood

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