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11 Antihypertensive Agents
11 Antihypertensive Agents
11 Antihypertensive Agents
DRUGS USED IN
HYPERTENSION
HYPERTENSION
A. Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
12/23/17
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
Strategies for treating high blood pressure
are based on determinants of arterial
pressure
12/23/17
VASOMOTOR CENTERS
Aldosterone
Renal
blood RENIN Angiotensin
flow
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
Compensatory mechanisms can be counteracted by
Tachycardia beta blockers, reserpine
Salt and water retentiondiuretics, angiotensin antagonists
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
12/23/17
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
DIURETICS
Lower BP by reduction of blood volume
and direct vascular effect
Compensatory responses to BP lowering
are minimal
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
Interfere with sympathetic nerve functions
Compensatory mechanisms and adverse
effects are marked for some of these agents
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
Reduction of the following
Venous tone
Heart rate
Contractile force of the heart
Cardiac output (CO)
Total peripheral resistance (TPR)
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
CLASSIFICATIONS:
A.Baroreceptor sensitizing – No drug available
B.CNS Active
C.Ganglion Blocking Drugs
D.Postganglionic sympathetic blocker
E.Adrenoceptor blockers
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
B. CNSACTIVE AGENTS
ALPHA2SELECTIVE 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)
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
B. CNSACTIVE AGENTS
ALPHA2SELECTIVE AGENTS
METHLYDOPA
Prodrug converted to methlynorepinephrine in the
brain
Causes hematologic immunotoxicity (+ Coombs test)
hemolytic anemia
Sedation is more pronounced
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
Sexual dysfunction
Orthostatic hypotension
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
D. POSTGANGLIONIC SYMPATHETIC NERVE
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
Sexual dysfunction
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
D. POSTGANGLIONIC SYMPATHETIC
NERVE TERMINAL BLOCKERS
GUANETHEDINE
Drugs that inhibit the pump (cocaine,
tricyclic antidepressants) will interfere with
its action
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
D. POSTGANGLIONIC SYMPATHETIC NERVE
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
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
D. POSTGANGLIONIC SYMPATHETIC NERVE
TERMINAL BLOCKERS
MAO INHIBITORS
No longer used for hypertension
Occasionally used for treatment of severe
depressive disorder
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
E. ADRENOCEPTOR BLOCKERS
Effective antihypertensive agents
Alpha1selective blockers
Prazosin
Reduce vascular resistance and venous
return
Free of severe adverse effects
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
SYMPATHOPLEGICS
D. ADRENOCEPTOR BLOCKERS
Nonselective αblockers
Phentolamine, phenoxybenzamine
No value in chronic hypertension
Excessive compensatory responses
especially tachycardia
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
VASODILATORS
FOUR MAJOR MECHANISMS
Release of nitric oxide
Opening of potassium channels
Blockade of calcium channels
Activation of D1 dopamine receptors
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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)
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
VASODILATORS
B. CALCIUM CHANNEL BLOCKERS
NIFEDIPINE, VERAPAMIL, DILTIAZEM
Effective vasodilators
Orally active
Chronic use
Used in hypertension of any severity
Fewer compensatory responses
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
VASODILATORS
C. NITROPRUSSIDE and DIAZOXIDE
NITROPRUSSIDE
Toxicity
Excessive hypotension
Tachycardia
Accumulation of cyanide or thiocyanate in the blood
if infusion is continued for several days
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
VASODILATORS
C. NITROPRUSSIDE and DIAZOXIDE
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
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
VASODILATORS
C. NITROPRUSSIDE and DIAZOXIDE
DIAZOXIDE
Toxicity
Hypotension
Hypergylcemia
Salt and water retention
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
VASODILATORS
D. FENOLDOPAM
Dopamine D1 receptor activation cause
marked arteriolar vasodilation
Given IV
Used for hypertensive emergencies
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
ANGIOTENSIN ANTAGONISTS
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
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
ANGIOTENSIN ANTAGONISTS
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
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
ANGIOTENSIN ANTAGONISTS
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
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
CLINICAL USES
A. “ STEPPED CARE”
Lifestyle measures (salt restriction and
weight reduction
Diuretics
Sympathoplegics (betablockers)
ACE inhibitors
Vasodilator (calciumchannel blockers)
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DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION
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