1b.pharmacyantihypertensives

Antihypertensive Drugs

PHR 242: Pharmacy Pharmacology

William B. Jeffries, Ph.D

Room 570A Criss III

280-4092

Email: [email protected]

flap.creighton.edu

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)

Mortality Is Related to Blood Pressure

JNC VI Stages of Hypertension

Stage Diastolic Range (mm Hg)

Systolic Range (mm Hg)

High Normal

85-89 130-139

Stage 1 90-99 140-159

Stage 2 100-109 160-179

Stage 3 > 109 >179

Treatment Rationale

Short-term goal of antihypertensive therapy:

Reduce blood pressure

• Primary (essential) hypertension• Secondary hypertension

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

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

Major Risk Factors That Increase Mortality in Hypertension

Smoking Dyslipidemias Diabetes Mellitus Age >60 Gender: men, postmenopausal women Family history

"Individualized Care"

Risk factors consideredMonotherapy is institutedNon pharmacological therapy tried firstConsiderations for choice of initial

monotherapy: Renin status Coexisting cardiovascular conditions Other conditions

Treatment Thresholds for Essential Hypertension

Stages Risk group A(no major risk factors, no target organ damage)

Risk Group BOne or more major risk factors (except diabetes), no organ damage

Risk Group CTarget organ damage and/or diabetes

High Normal

Lifestyle Modification

Lifestyle Modification

Lifestyle Modification and Drug Therapy

Stage 1 Lifestyle Modification (up to 12 months)



Stages 2 and 3




Monotherapy for Hypertension

• ACE inhibitors and ATII antagonists• Diuretics• ß-adrenoceptor blockers• α1-adrenoceptor blockers

• Ca2+ channel blockers

Benzothiazide Diuretics

Mechanism of action Indications

– Monotherapy for mild-moderate HTN– Adjunct agent– Usually necessary in severe HTN

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

ß-Adrenoceptor blockers

Mechanism of Action:ß-adrenoceptor antagonism

Why blood pressure reduction?– Reduction of Cardiac output– Reduction of renin release– Central nervous system - reduction of sympathetic

outflow

Types of ß-blockers:

Non selectivePrototype: Propranolol (others: nadolol, timolol, pindolol,

labetolol)

CardioselectivePrototype: Metoprolol (others: atenolol, esmolol, betaxolol)

Non selective and cardioselective ß-blockers are EQUALLYEQUALLY effective in reducing blood pressure

Other Properties Relevant to Antihypertensive Effect:

Intrinsic sympathomimetic activity. Mixed antagonism.

Therapeutic Use in Hypertension

Monotherapy most effective in high renin

hypertension hypertension with coronary

insufficiency low cost to patient

Administration

Blah Blah Blah

Adverse Effects

Bradycardia Heart failure Bronchospasm Coldness of extremities Withdrawal effects Glucose metabolism

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 – Ca2+channel blockers Conduction effects on heart

are additive w/ ß blockers.

α-Adrenoceptor Blockers

Mechanism of action: blockade of vascular α−adrenoceptors

Non selective (α1 and α2) blockers: Phentolamine, phenoxybenzamine and dibenamine

Selective (α1) prototype: prazosin (others: terazosin, doxazosin, trimazosin)

Therapeutic Use in Hypertension

Non selective (α1 and α2) blockers: used for treatment of hypertensive crises in pheochromocytoma

Selective (α1) blockers Monotherapy Adjunctive therapy

Administration of α1-Adrenoceptor Blockers

Read The Book

Side effects of α1-adrenoceptor blockers

First dose phenomenon Tachycardia GI effects (rare)

Adverse Effects of Non Specific α-Adrenoceptor Blockers

Postural hypotension Reflex tachycardia Fluid retention

Other Sympatholytics

Guanethidine Ganglionic blockers

Guanethidine

Mechanism of action Therapeutic use

Ganglionic Blockers (Trimethaphan)

Mechanism of action Therapeutic use

Drugs Interacting With the Renin-angiotensin System

ACE inhibitors ATII antagonists

Physiology of Renin-Angiotensin System

Details: Katzung, Chapter 17

Receptor Subtypes for Angiotensin

AT1

– AT1A

– AT1B

– Prototype antagonist: Losartan

AT2 Primary antagonist available is PD123177

AT3?AT4

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.

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

Types of ACE Inhibitors

Active molecules: Captopril, Lisinopril, Enalaprilat

Prodrugs: Enalapril, Benazepril, Fosinopril, Quinapril, Ramipril, Moexipril, Spirapril

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

Administration

Captopril Prodrugs: inactive prodrug is hydrolyzed

in vivo to active compound, e.g., enalapril to enalaprilat

Lisinopril

ACE Inhibitor Adverse Reactions

Hypotension Renal insufficiency Cough Hyperkalemia Hyperreninemia

Minor Adverse Effects of ACE Inhibitors

Ageusia Skin rash Proteinuria Neutropenia

Pharmacology of AT-Receptor Antagonists

Losartan Valsartan Candesartan *sartan

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

Clinical Indications for ATII Antagonists

Hypertension Heart failure Prevention of restenosis following angioplasty

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

Hydralazine

Direct acting vasodilator: liberates NO from vascular endothelium which stimulates the production of cGMP in vascular smooth muscle, resulting in relaxation (arterioles > 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

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 (>24 hours)

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

Centrally Acting Sympatholytics: α2-Adrenoceptor Agonists

α−Methyldopa Clonidine Guanabenz Guanfacine

α2-Adrenoceptor Agonists Mechanisms of Action

Central Action: Stimulation of α2 adrenoceptors in the brainstem reduces sympathetic tone, causing a centrally mediated vasodilatation and reduction in heart rate

Prejunctional action: Stimulation of α2 adrenoceptors located prejunctionally on peripheral neurons reduces norepinephrine release

Vascular smooth muscle: α2 adrenoceptors located on vascular smooth muscle open Ca2+ channels and cause vasoconstriction. Not evident clinically unless given intravenously

Mechanisms of Action (cont.)

Clonidine, guanabenz and guanfacine: Direct acting α2 adrenoceptor agonists.

α-methyldopa: Prodrug taken up by central adrenergic neurons and converted to the α2 adrenoceptor agonist α-methylnorepinephrine.

Therapeutic Uses in Hypertension

Not generally used for monotherapy of mild to moderate hypertension

Considerations– fluid retention: must use diuretic

– Direct acting α2 adrenoceptor agonists: effective in lowering blood pressure in ALL patients.

– Direct acting α2 adrenoceptor agonists are equally efficacious but more efficacious than α-methyldopa

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.

Administration: α−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

Administration: Clonidine, Guanabenz and Guanfacine

• Orally active, good absorption, usually given twice daily

• Clonidine: available as a sustained release transdermal patch (avoids withdrawal syndrome)

Adverse Effects of α 2-Adrenoceptor Agonists

Hypotension especially in volume depleted patients

Sedation: more prominent for direct acting α2 adrenoceptor agonists - 50% of patients

Withdrawal syndrome: hypertension, tachycardia, nervousness and excitement.

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

Adverse Effects of Clonidine, et al:

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

α 2-Adrenoceptor Agonist Drug Interactions

Diuretics enhance hypotensive action Tricyclic antidepressants inhibit clonidine's

action

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

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

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