Antihypertensive Drugs

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Antihypertensive Drugs

• PHR 242 Pharmacy Pharmacology
• William B. Jeffries, Ph.D
• Room 570A Criss III
• 280-4092
• Email wbjeff_at_creighton.edu
• flap.creighton.edu

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Definition

• Elevation of arterial blood pressure above 140/90
  mm Hg. Can be caused by
• an underlying disease process (secondary
  hypertension)
• Renal artery stenosis
• Hyperaldosteronism
• pheochromocytoma
• idiopathic process (primary or essential
  hypertension)

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Mortality Is Related to Blood Pressure
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JNC VI Stages of Hypertension
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Treatment Rationale

• Short-term goal of antihypertensive therapy
• Reduce blood pressure
• Primary (essential) hypertension
• Secondary hypertension

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Treatment Rationale

• Long-term goal of antihypertensive therapy
• Reduce mortality due to hypertension-induced
  disease
• Stroke
• Congestive heart failure
• Coronary artery disease
• Nephropathy
• Peripheral artery disease
• Retinopathy

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Ways of Lowering Blood Pressure

• Reduce cardiac output (ß-blockers, Ca2 channel
  blockers)
• Reduce plasma volume (diuretics)
• Reduce peripheral vascular resistance
  (vasodilators)

MAP CO X TPR
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Major Risk Factors That Increase Mortality in
Hypertension

• Smoking
• Dyslipidemias
• Diabetes Mellitus
• Age gt60
• Gender men, postmenopausal women
• Family history

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"Individualized Care"

• Risk factors considered
• Monotherapy is instituted
• Non pharmacological therapy tried first
• Considerations for choice of initial monotherapy
• Renin status
• Coexisting cardiovascular conditions
• Other conditions

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Monotherapy for Hypertension

• ACE inhibitors and ATII antagonists
• Diuretics
• ß-adrenoceptor blockers
• a1-adrenoceptor blockers
• Ca2 channel blockers

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Benzothiazide Diuretics

• Mechanism of action
• Indications
• Monotherapy for mild-moderate HTN
• Adjunct agent
• Usually necessary in severe HTN

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Thiazide diuretics considerations

• Long-term hypokalemia appears to increase
  mortality.
• K-sparing diuretics are superior to K
  supplementation when diuretics used.
• Most efficacious in low renin or
  volume-expanded forms of hypertension

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ß-Adrenoceptor blockers

• Mechanism of Actionß-adrenoceptor antagonism
• Why blood pressure reduction?
• Reduction of Cardiac output
• Reduction of renin release
• Central nervous system - reduction of sympathetic
  outflow

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Types of ß-blockers

• Non selective
• Prototype Propranolol (others nadolol, timolol,
  pindolol, labetolol)
• Cardioselective
• Prototype Metoprolol (others atenolol, esmolol,
  betaxolol)
• Non selective and cardioselective ß-blockers are
  EQUALLY effective in reducing blood pressure

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Other Properties Relevant to Antihypertensive
Effect

• Intrinsic sympathomimetic activity.
• Mixed antagonism.

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Therapeutic Use in Hypertension

• Monotherapy
• most effective in high renin hypertension
• hypertension with coronary insufficiency
• low cost to patient

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Administration

• Blah
• Blah
• Blah

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Adverse Effects

• Bradycardia
• Heart failure
• Bronchospasm
• Coldness of extremities
• Withdrawal effects
• Glucose metabolism

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5. Adverse Effects (Cont)

• CNS effects
• Pregnancy
• Rise in plasma triglyceride concentration
  decrease in HDL cholesterol
• Drug interactions
• NSAID'S - can blunt effect of ß-blockers
• Epinephrine - causes severe hypertension in
  presence of ß-blockade
• Ca2channel blockers Conduction effects on heart
  are additive w/ ß blockers.

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a-Adrenoceptor Blockers

• Mechanism of action blockade of vascular
  a-adrenoceptors
• Non selective (a1 and a2) blockers
  Phentolamine, phenoxybenzamine and dibenamine
• Selective (a1) prototype prazosin (others
  terazosin, doxazosin, trimazosin)

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Therapeutic Use in Hypertension

• Non selective (a1 and a2) blockers used for
  treatment of hypertensive crises in
  pheochromocytoma
• Selective (a1) blockers
• Monotherapy
• Adjunctive therapy

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Administration of a1-Adrenoceptor Blockers

• Read
• The
• Book

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Side effects of a1-adrenoceptor blockers

• First dose phenomenon
• Tachycardia
• GI effects (rare)

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Adverse Effects of Non Specific a-Adrenoceptor
Blockers

• Postural hypotension
• Reflex tachycardia
• Fluid retention

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Other Sympatholytics

• Guanethidine
• Ganglionic blockers

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Guanethidine

• Mechanism of action
• Therapeutic use

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Ganglionic Blockers (Trimethaphan)

• Mechanism of action
• Therapeutic use

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Drugs Interacting With the Renin-angiotensin
System

• ACE inhibitors
• ATII antagonists

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Physiology of Renin-Angiotensin System

• Details Katzung, Chapter 17

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Receptor Subtypes for Angiotensin

• AT1
• AT1A
• AT1B
• Prototype antagonist Losartan
• AT2 Primary antagonist available is PD123177
• AT3? AT4

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Angiotensin Converting Enzyme (ACE) Inhibitors

• Mechanism of Action Inhibition of angiotensin
  II formation
• Competitive inhibition of angiotensin converting
  enzyme reduces circulating ang II, reducing
  vascular tone.

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Systemic Effects of ACE Inhibitors

• Reduction in systemic arteriolar resistance,
  systolic, diastolic and mean arterial pressure.
• Regional hemodynamic effects
• Increased regional blood flow in proportion to
  ang II sensitivity of the vascular bed
• Increased large artery compliance
• Cardiac output and heart rate unchanged
• Aldosterone secretion reduced

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Types of ACE Inhibitors

• Active molecules Captopril, Lisinopril,
  Enalaprilat
• Prodrugs Enalapril, Benazepril, Fosinopril,
  Quinapril, Ramipril, Moexipril, Spirapril

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Therapeutic Uses in Hypertension

• One of the initial choices for monotherapy of
  mild to moderate hypertension
• Well tolerated as monotherapy. Drugs of choice
  in diabetes mellitus with hypertension
• Most effective in high renin hypertension
• More effective in white vs. Black patients
• Excellent for patients with concomitant
  congestive heart failure, LVH, cardiac
  arrhythmias or diabetes mellitus, consider in
  asthma instead of ß-blockers
• Efficacy enhanced by diuretics

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Administration

• Captopril
• Prodrugs inactive prodrug is hydrolyzed in vivo
  to active compound, e.g., enalapril to
  enalaprilat
• Lisinopril

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ACE Inhibitor Adverse Reactions

• Hypotension
• Renal insufficiency
• Cough
• Hyperkalemia
• Hyperreninemia

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Minor Adverse Effects of ACE Inhibitors

• Ageusia
• Skin rash
• Proteinuria
• Neutropenia

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Pharmacology of AT-Receptor Antagonists

• Losartan
• Valsartan
• Candesartan
• sartan

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Mechanism of Action of ATII Antagonists

• Molecular Competitive inhibitor of AT1
  receptors. Blocks ability of angiotensins II and
  III to stimulate pressor and cell proliferative
  effects
• Antihypertensive effects
• Cell growth effects
• Lack of bradykinin effects

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Clinical Indications for ATII Antagonists

• Hypertension
• Heart failure
• Prevention of restenosis following angioplasty

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Ca2 Channel Blockers

• One of the initial choices for monotherapy of
  mild to moderate hypertension
• all CEB's are equally effective when used as
  monotherapy for Stage 1 hypertension
• Verapamil and diltiazem are vasodilators that do
  not cause reflex tachycardia due to direct
  inhibition of cardiac automaticity
• Best in low renin hypertension Blacks and
  elderly
• do not cause fluid retention

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Hydralazine

• Direct acting vasodilator liberates NO from
  vascular endothelium which stimulates the
  production of cGMP in vascular smooth muscle,
  resulting in relaxation (arterioles gt veins)
• Can NOT be used for monotherapy
• Bioavailability dependent on genetic factors
  (fast or slow acetylators)
• Tachycardia with palpitations, hypotension OFTEN
• Lupus-like syndrome may occur with chronic use
  that is reversible upon continuation
• Never use as first choice Try in refractory
  hypertension as part of a multidrug regimen

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Minoxidil

• Prodrug of minoxidil N-O sulfate, which is a
  direct acting vasodilator
• Mechanism K channel opener, causes membrane
  hyperpolarization, reducing ability of smooth
  muscle to contract.
• Other K channel openers pinacidil, diazoxide
• refractory hypertension
• Long duration of action (gt24 hours)

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Minoxidil Adverse Effects

• Fluid and water retention can lead to pulmonary
  hypertension
• Tachycardia and increased cardiac output can
  progress to congestive heart failure
• Hypertrichosis Occurs in all patients who take
  therapeutic doses of minoxidil for a prolonged
  time

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Centrally Acting Sympatholytics a2-Adrenoceptor
Agonists

• a-Methyldopa
• Clonidine
• Guanabenz
• Guanfacine

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a2-Adrenoceptor Agonists Mechanisms of Action

• Central Action Stimulation of a2 adrenoceptors
  in the brainstem reduces sympathetic tone,
  causing a centrally mediated vasodilatation and
  reduction in heart rate
• Prejunctional action Stimulation of a2
  adrenoceptors located prejunctionally on
  peripheral neurons reduces norepinephrine release
• Vascular smooth muscle a2 adrenoceptors located
  on vascular smooth muscle open Ca2 channels and
  cause vasoconstriction. Not evident clinically
  unless given intravenously

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Mechanisms of Action (cont.)

• Clonidine, guanabenz and guanfacine Direct
  acting a2 adrenoceptor agonists.
• a-methyldopa Prodrug taken up by central
  adrenergic neurons and converted to the a2
  adrenoceptor agonist a-methylnorepinephrine.

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Therapeutic Uses in Hypertension

• Not generally used for monotherapy of mild to
  moderate hypertension
• Considerations
• fluid retention must use diuretic
• Direct acting a2 adrenoceptor agonists effective
  in lowering blood pressure in ALL patients.
• Direct acting a2 adrenoceptor agonists are
  equally efficacious but more efficacious than
  a-methyldopa

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Other Use

• Clonidine is useful in diagnosis of
  pheochromocytoma. Clonidine (single 0.3 mg dose)
  will reduce plasma norepinephrine concentration
  to below 500 pg/ml in tumor-free patients.

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Administration a-Methyldopa

• Short plasma half life (2 hours) but longer
  action (peak at 6-8 hours, duration 24 hours
• ? Once or twice daily dosing due to long action
• ? Action prolonged in patients with renal
  insufficiency

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Administration Clonidine, Guanabenz and
Guanfacine

• ? Orally active, good absorption, usually given
  twice daily
• ? Clonidine available as a sustained release
  transdermal patch (avoids withdrawal syndrome)

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Adverse Effects of a2-Adrenoceptor Agonists

• Hypotension especially in volume depleted
  patients
• Sedation more prominent for direct acting a2
  adrenoceptor agonists - 50 of patients
• Withdrawal syndrome hypertension, tachycardia,
  nervousness and excitement.

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Adverse Effects Unique to Methyldopa

• Heart block (methyldopa)
• Immunological changes positive Coombs test (20
  after 1 year), lupus like syndrome, leukopenia,
  red-cell aplasia
• Altered liver function 5
• Hyperthermia
• Reduced mental acuity

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Adverse Effects of Clonidine, et al

• Dry mouth, nasal stuffiness
• Contact dermatitis with clonidine patch 20
• Vivid dreams
• Restlessness
• Depression (infrequent)

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a2-Adrenoceptor Agonist Drug Interactions

• Diuretics enhance hypotensive action
• Tricyclic antidepressants inhibit clonidine's
  action

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Reserpine

• Molecular mechanism of action Inhibition of
  noradrenergic function.
• Reserpine binds to storage vesicles and releases
  norepinephrine and serotonin.
• Storage vesicles are destroyed and nerve ending
  loses capacity to store and release
  norepinephrine and serotonin
• Pharmacological consequences reduction of
  cardiac output and TPR

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Reserpine

• Extremely long acting
• Tolerated well (as well as diuretic plus
  propranolol in Veteran's cooperative study)
• CNS effects
• Sedation, loss of concentration
• psychotic depression. Depression insidious
  progression that can lead to suicide