PH402 Hypertension and Antihypertensives

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PH402 Hypertension and Antihypertensives

• Chris Hague, PhD
• chague_at_u.washington.edu
• Technical Advisor Seth Goldenberg, PhD

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References

• Brodys Human Pharmacology, 4th Edition
• Guyton Human Physiology
• http//www.americanheart.org/presenter.jhtml?ident
  ifier2152
• http//www.nhlbi.nih.gov/health/dci/Diseases/Hbp/H
  BP_WhatIs.html

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Outline
1. Hypertension definitions 2. Diuretics 3. ACE
inhibitors/AT receptor antagonists 4. Adrenergic
receptor antagonists 5. Sympatholytics 6. Ca2
channel antagonists 7. Direct vasodilators
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Hypertension Stats

• 1 in 3 adults have high BP in USA
• 49,707 deaths in 2002
• contributing cause to 261,000 deaths in 2002
• 40 African-Americans have high BP
• 30 of people with high BP dont know it
• no symptoms!

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Diagnosis

• Hypertension an elevation of arterial blood
  pressure above an arbitrarily defined normal value

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Causes of Hypertension

• 90-95, cause unknown
• primary (or essential) hypertension
• 10, cause known
• secondary hypertension
• kidney abnormalities
• congenital heart defects (i.e. aorta)
• narrowing of arteries

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Treatment goals

• Short term goal
• reduce blood pressure
• Long term goal
• reduce mortality due to hypertension-induced
  disease
• stroke
• congestive heart failure
• coronary artery disease
• nephropathy
• retinopathy

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Ways of lowering BP

• Reduce cardiac output
• Beta blockers
• Ca2 channel antagonists
• Reduce plasma volume
• Diuretics
• Reduce Total Peripheral Resistance
• vasodilators
• alpha1-adrenergic receptor antagonists
• ACE inhibitors

MAP CO X TPR
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Summary of Drug Targets
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Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT)

• 42,418 participants
• Findings Chlorthalidone is superior to an ACE
  inhibitor, a calcium channel blocker and an
  alpha1-adrenergic antagonist in preventing one or
  more CVD events.
• Recommendations for antihypertensive treatment
• Use Thiazide-type diuretics as first treatment in
  stage I and II hypertension
• prevent cardiovascular disease better than other
  classes
• lower cost
• drugs of choice for first-step antihypertensive
  therapy.
• Diuretic intolerant patients consider Ca2
  channel blockers and ACE inhibitors
• Most hypertensive patients require more than one
  drug. Diuretics should generally be part of the
  antihypertensive regimen.
• Lifestyle advice should also be provided.
• http//www.nhlbi.nih.gov/health/allhat/index.htm

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Thiazide Diuretics

• mechanism of action
• lower plasma volume
• monotherapy for mild to moderate hypertension
• ALLHAT reduction of CVD superior to other agents
• adjunct agent
• most effective in patients with normal kidney
  function

Hydrochlorothiazide
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Considerations

• long-term hypokalemia increases mortality
• include K sparing diuretic in therapy
• most efficacious in low-renin or
  volume-expanded forms of hypertension
• very effective in African-American patients
• mostly well tolerated
• cheap!

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Drugs interacting with Renin-Angiotensin system

• ACE inhibitors inhibit Angiotensin II formation
• Angiotension receptor antagonists block
  Angiotensin receptor activation

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Systemic Effects of ACE inhibitors

• Reduction in
• total peripheral resistance
• systolic and diastolic pressure
• mean arterial pressure
• aldosterone secretion
• cardiac remodeling
• Increase in
• regional blood flow in vascular beds
• large artery compliance

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Types of ACE inhibitors

• Active Molecules
• Captopril (Capoten)
• Lisinopril (Prinivil)
• Enalaprilat
• Prodrugs
• must be biotransformed for activity by esterases
• Enalapril (Vasotec)
• Fosinopril (Monopril)
• Quinapril (Accupril)
• Ramipril (Altace)

Enalaprilat
Enalapril
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Therapeutic Uses

• initial choice for mild to moderate hypertension
• drug of choice for hypertension due to diabetes
  mellitus
• most effective in high renin patients
• more effective in caucasian patients
• excellent for patients with hypertension
  secondary to CHF, arrhythmias, kidney disease
• efficacy enhanced by diuretics

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Side Effects

• hypotension
• cough
• hyperkalemia
• angioedema
• renal insufficiency
• teratogenic
• skin rash
• neutropenia
• proteinuria (protein in urine)
• ageusia (loss of taste)

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Types of AT1 receptor antagonists

• Losartan (Cozaar)
• competitive antagonist
• Valsartan (Diovan)
• non-competitive
• Candesartan (Atacand)
• non-competitive
• Irbesartan (Aprovel)
• non-competitive

Losartan
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Therapeutic Uses

• same uses as ACE inhibitors
• excellent for inhibiting cell growth
• no bradykinin effects
• no cough
• useful for hypertension secondary to CHF
• used for prevention of re-stenosis after
  angioplasty

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Adrenergic receptor antagonists

• ß-adrenergic receptor antagonists
• ß-blockers
• Non-selective Propranolol, Nadolol, Timolol,
  Pindolol, Labetolol
• Cardioselective Metoprolol, Atenolol, Esmolol,
  Betaxolol
• a1-adrenergic receptor antagonists
• a-blockers
• Non-selective Phentolamine, Phenoxybenzamine,
  Dibenamine
• Selective Prazosin, Doxazosin, Terazosin

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ß-blockers Therapeutic Uses

• Used as monotherapy
• reduce cardiac output
• reduce renin release
• CNS effects reduce SNS outflow
• Most effective in high-renin hypertension
• Used in hypertensive patients with coronary
  insufficiency
• Non-selective and cardioselective drugs are
  equally effective for lowering BP
• Cheap!

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ß-blockers Considerations

• Intrinsic sympathomimetic activity
• Pindolol, Acebutolol, Penbutolol partial ß2-AR
  agonism
• Mixed antagonism
• Labetolol, Carvedilol ß- and a-adrenergic
  receptor antagonists
• Differences in ability to penetrate CNS
• Propranolol readily enters CNS
• Sotalol unable enter CNS

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ß-blockers Side Effects

• Bradycardia
• Bronchospasm
• Coldness of extremities
• Heart failure
• Contraindicated in insulin-dependent diabetes
• CNS effects
• Increased plasma triglyceride concentration
• Decreased plasma HDL concentration
• Do not use in conjunction with Ca2 channel
  blockers, conduction effects in heart
• NSAIDs blunt ß-blocker effects

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a-blockers Therapeutic Uses

• Mechanism of action block vascular
  a1-adrenergic receptors
• inhibit vasoconstriction
• decrease total peripheral resistance
• Non-selective blockers used for treatment of
  hypertensive crisis in pheochromocytoma
• Selective a-blockers used as monotherapy or
  adjunct therapy in resistant patients

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a-blockers Side Effects

• First dose phenomenon
• hypotension
• tachycardia
• baroreceptor reflex
• GI effects
• Fluid retention
• use with diuretic
• ALLHAT study
• http//allhat.sph.uth.tmc.edu/

Graham et al, BMJ, 1976
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Sympatholytics

• Centrally acting sympatholytics
• Clonidine
• a-methyldopa
• Guanfacine
• Guanabenz
• Peripherally acting sympatholytics
• Metyrosine
• Guanethidine, Bretylium
• Reserpine

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CNS Sympatholytics

• a2-AR receptor agonists
• act in CNS to reduce sympathetic neuron firing
  rate
• nucleus of solitary tract
• C1 neurons of rostral ventrolateral medulla
• act on prejunctional sympathetic neurons in
  vascular tissue
• autoreceptor on sympathetic neurons
• prevent NE release
• stimulate post-junctional a2-ARs on vascular
  smooth muscle (I.V. only)

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Pharmacokinetics

• a-methyldopa is a prodrug, converted to
  a-methyl-norepinephrine in brain
• short T1/2 2 hours
• long duration of action 24 hours
• action prolonged with renal insufficiency
• clonidine, guanfacine, guanabenz enter brain
  readily
• orally active
• excellent absorption
• clonidine available as sustained release
  transdermal patch

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Therapeutic Uses

• Reduce BP by lowering TPR and CO
• Peripheral sympatholytics produce marked fluid
  retention and impairment of baroreceptor reflexes
• use with diuretic
• a2-agonists effective in ALL patients
• clonidine used in diagnosis of pheochromocytoma
  reduces plasma NE lt 500 pg/mL in tumor-free
  patients

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Adverse Effects

• Hypotension
• Sedation 50 of all patients
• Dry mouth
• Vivid dreams
• Depression
• Withdrawal
• hypertension
• tachycardia
• nervousness, excitement
• a-methyldopa specific effects
• heart block
• autoimmune Lupus, leukopenia
• hyperthermia
• reduced mental acuity

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Peripheral Sympatholytics

• rarely used
• Metyrosine (or a-methyl-tyrosine)
• inhibits tyrosine hydroxylase
• rate-limiting enzyme for NE synthesis
• Bretylium, Guanethidine
• uptaken into NE vesicle
• prevent NE release from vesicle
• Reserpine
• inhibits accumulation of NE into vesicle

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Ca2 channel antagonists

• an initial choice for monotherapy of mild to
  moderate hypertension
• all antagonists are equally effective for Stage 1
  hypertension
• Verapamil and Diltiazem do not cause reflex
  tachycardia
• directly inhibit cardiac chronotropy
• Effective in low-renin hypertension
• African-americans
• Elderly
• Do not cause fluid retention

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Direct acting vasodilators

• Hydralazine
• liberates NO from vascular endothelium
• decreases TPR
• not used as monotherapy
• bioavailability dependent on genetic factors
• adverse effects tachycardia, hypotension, fluid
  retention, lupus-like syndrome
• only used in severe or refractory hypertension

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Direct acting vasodilators

• Minoxidil
• prodrug of N-O sulfate
• K channel opener, reduces smooth muscle
  contractility
• not used as monotherapy
• long duration of action (24 hours)
• adverse effects tachycardia, fluid retention,
  hypertrichosis
• only used in severe or refractory hypertension

Minoxidil