Drugs Used for Hypertension Philip Marcus, MD MPH

Drugs Used for Hypertension

Philip Marcus, MD MPH

Hypertension: Epidemiology

Elevation in Blood Pressure High Prevalence in US population

Affects up to 24% of adults Over 50 million people affected in US

Untreated in a large percentage Only 53% treated

Lack of treatment may result in irreversible damage

Primary (Essential) Hypertension:

No identifiable cause Accounts for 95%+/- of cases Clusters in families Chronic and progressive Populations at risk:

Elderly Postmenopausal females African-Americans Obese

Drug therapy lowers BP Does not eliminate underlying pathology Treatment generally lifelong

Smoking and Obesity are cofactors

Primary Hypertension: Pathophysiology

Increased sympathetic activity Increased production of sodium retaining

hormones and vasoconstrictors Long term sodium intake Inadequate potassium/calcium intake Increased renin secretion Deficiency of endogenous vasodilators

Prostaglandin, Prostacyclin Nitric Oxide

Obesity and Insulin resistance

Classification of Hypertension:

Category Systolic DiastolicNormal <120 <80Pre-hypertension

120-139 80-89

Stage I 140-159 90-99Stage II ≥160 ≥100

JNC7:Classification and Management of Blood Pressure for Adults Aged 18 Years or Older, 2003

Secondary Hypertension: Chronic Renal Disease 4% Renovascular Disease 2% Coarctation of Aorta 0.3% Primary Aldosteronism 0.2% Cushing’s Syndrome 0.1% Oral Contraceptive Use 1% Pheochromocytoma 0.1% Sleep Apnea

50% have significant hypertension

Consequences of Hypertension: Untreated hypertension leads to increase in

morbidity and mortality Heart Disease

LV Hypertrophy and Congestive Heart Failure Coronary Artery Disease

Renal Disease Increased prevalence despite available treatment

Retinal Disease Cerebral Vascular Disease

Stroke

Benefits of Antihypertensive Treatment Greater in elderly than in younger patients over short

term (5 years) Older persons at higher immediate and absolute risk

of developing cardiovascular events Prevalence of preexisting cardiovascular disease greater

Systolic hypertension is associated with greater cardiovascular risk than diastolic

Systolic hypertension more prevalent in elderly Smoking less common in older persons

Smokers respond less well to antihypertensive treatment Most large trials involving elderly are more recent

than those involving younger patients Use treatment regimens with fewer adverse effects

Benefits of therapy increase over time Long-term benefits may be greater in younger patients

Non-Drug Management of Hypertension: Lifestyle Modification

Weight reduction Sodium restriction Alcohol restriction Smoking cessation Exercise Maintenance of dietary potassium(>100 mEq/day)

and calcium intake Dietary Approaches to Stop Hypertension (DASH)

Reductions in BP in persons on diet rich in fruits, vegetables, and low-fat dairy products

Lowered BP in all subgroups Appel, et al, NEJM 1997; 336:1117

Physiologic Control of Blood Pressure

BP = C.O. x SVR C.O. = H.R. x Stroke Volume Factors to be considered:

Heart Rate Blood Volume Contractility Arteriolar Constriction

Arterial Pressure

Cardiac

Output

Peripheral

Resistance

= X

1. Heart Rate 2. Contractility 3. Blood Volume 4. Venous Return

Arteriolar Constrictio

n

HR x SV

Mechanisms Regulating Blood Pressure:

Sympathetic Nervous System Baroreceptors Medullary vasomotor center

Renin Angiotensin System Angiotensinogen

2 globulin Activated by Renin

Produced by JG cells Increased by decreased renal blood flow Increased with stimulation Observed clinically with renal artery stenosis,

hypotension

Mechanisms Regulating Blood Pressure:

Renin Angiotensin System Angiotensin I

Product of renin action on angiotensinogen Converted by Angiotensin-Converting Enzyme

Primarily in vasculature and lung Angiotensin II

Acts on Angiotensin Receptors (AT1) Causes vasoconstriction Causes release of Aldosterone

Converted to Angiotensin III in adrenal Aldosterone

Results in Na retention and K loss Expands extracellular fluid volume

Action of Angiotensin II and Aldosterone results in decrease in renin secretion

Sites of Antihypertensive Drug Action Central Nervous System

Vasomotor center Suppresses sympathetic outflow

Cardiac Resistance Vessels (arterioles) Results in:

Reduction in Heart Rate Decrease in Contractility Vasodilatation

Typical drugs: Clonidine, Methyldopa

Sites of Antihypertensive Drug Action Sympathetic Ganglia

Ganglionic blockade reduces sympathetic stimulation to heart and blood vessels

Cause vasodilatation and reduction in HR Rarely used anymore Trimethaphan last remaining agent

Adrenergic Nerve Terminals Decreases NE release Results in decreased stimulation of heart and

blood vessels Guanethidine, reserpine

Sites of Antihypertensive Drug Action Cardiac Receptors

Results in decrease in HR and contractility Vascular Receptors

Results in vasodilatation Prazosin, Terazosin, Labetalol

SA node and myocardium Calcium channel blockers Verapamil and Diltiazem

Renal tubules Diuretic agents Furosemide, Hydrochlorothiazide

Diuretics Used in the Treatment of Hypertension

Sites of Antihypertensive Drug Action Receptors on juxtaglomerular cells

Reduces renin release Vascular Smooth Muscle

Direct vasodilators Hydralazine

Angiotensin-Converting Enzyme Inhibitors Decreases formation on Angiotensin II Captopril, Enalapril

Angiotensin II Receptor Blockers Results in blockade of AT1 receptors Losartan, Candesartan Similar in action to ACE inhibitors

D1 (dopamine) Receptor Agonists

Hypertensive Crisis: Severe Increase in BP

Diastolic BP > 120 Rate of rise more important than

absolute BP in determining need for EMERGENCY treatment

Usually occurs in noncompliant or under-medicated patients

In absence of evidence of acute or ongoing target organ damage, no need for acute, aggressive BP reduction

Hypertensive Crisis: What constitutes the Hypertensive Emergency?

Encephalopathy Myocardial Infarction or Unstable Angina Congestive Heart Failure Subarachnoid hemorrhage, stroke or

intracerebral hemorrhage Dissecting Aortic Aneurysm Cocaine overdose Acute renal insufficiency Post-operative hypertension

Centrally Acting Antiadrenergic Agents:

Act in CNS to reduce firing of sympathetic neurons

Effects are the result of decreased stimulation of receptors in periphery

Stimulate central inhibitory receptors Acts on post-synaptic receptors Exerts inhibitory influence on regions of brain

that regulate sympathetic nervous activity Primary site of action in medulla

Centrally Acting Antiadrenergic Agents: Clonidine (Catapres ®)

2-imidazoline derivative Results in decrease in BP, HR and CO

Decreases renal vascular resistance Renal blood flow unchanged

Lipid soluble Enters CNS

Side effects common Dry mouth, dizziness, drowsiness Gynecomastia, rebound hypertension

Oral and Transdermal route Also used in drug, alcohol and nicotine withdrawal


Clonidine HCl Recently introduced in epidural form Useful in this formulation for neuropathic pain

Primarily used in patients with neoplastic disease Produces analgesia at presynaptic and

postjunctional adrenergic receptors in the spinal cord

Prevents pain signal transmission to the brain Pain relief additive to morphine

Duraclon ™


Methyldopa (Aldomet ®) Analog of L-dopa Action similar to clonidine Requires uptake into CNS neurons

Converted to methyl-norepinephrine Results in decrease in BP with little cardiac effects Large 1st pass effect

Low bioavailability Oral and IV administration Side Effects

Positive Coombs test, Hemolytic Anemia Hepatotoxicity Sedation, Lactation

Adrenergic Neuron Blocking Agents:

Act in presynaptic location to reduce NE release from sympathetic neurons

Rarely used in therapy because of side effects

Previously major agents used in treatment

Reserpine and Guanethidine

Rauwolfia serpentina

Reserpine

Rauwolfia alkaloid Causes depletion of NE from postganglionic

sympathetic neurons Decreases stimulation of all adrenergic receptors Effects resemble blockade

Blocks uptake of dopamine into vesicles which prevents NE synthesis Interferes with ATP and Mg++ dependent uptake

Displaces NE from vesicles causing degradation of NE by MAO

Acts peripherally and in CNS

Reserpine Physiologic Effects

Bradycardia Decreased Cardiac Output Vasodilatation End result is reduction in Blood Pressure

Side Effects Sedation and Depression Nasal stuffiness Orthostatic hypotension Extrapyramidal effects GI hypersecretion

Diarrhea, cramps, Increased gastric Acid

Guanethidine Acts presynaptically to inhibit the release of

NE from sympathetic neurons Must first be taken up into terminals of

sympathetic nerves Uptake via active transport for NE After uptake, will prevent further NE release Can promote NE release initially

Polar compound Highly basic Nitrogen Does NOT enter CNS

Oral route, t1/2 = 5 days

Guanethidine Physiologic Effects

Bradycardia Decreased Cardiac Output Vasodilatation

Side Effects Resemble those of pharmacologic sympathectomy

Orthostatic Hypotension Diarrhea Defective ejaculation

Effects decreased by compounds that interfere with uptake

Tricyclic Antidepressants Cocaine Phenothiazine drugs

Adrenergic Blockers: Useful in hypertension and

pheochromocytoma Selective inhibitors of receptor

Contrast with phenoxybenzamine and phentolamine

Cause blockade of receptors Used also for urinary obstruction in BPH

Alternative to surgery Results in decrease in tone in smooth muscle

of bladder neck and prostate Improves urine flow

Adrenergic Blockers:

Physiologic Effects: Decrease peripheral vascular resistance Relax arterial and venous smooth

muscle Results in decrease in Blood Pressure Minimal changes in Cardiac Output,

renal blood flow and GFR

Used orally


Side Effects Orthostatic Hypotension

Results from blockade of venous receptors causing pooling when upright

Reflex tachycardia, generally not long-term Nasal Congestion Impotence Interference with ejaculation Sodium retention and edema

Frequently used with a diuretic First-dose effect

Exaggerated hypotensive effect Results in syncope Adjust first dose to 1/3 to ¼ usual dose at bedtime


Prazosin (Minipress ®) Initial agent Short half-life

Terazosin (Hytrin ®) Longer acting Half-life = 12 hours

Doxazosin (Cardura ®) Longest half-life, 20 hours

Tamsulosin: Flomax®

Alfuzosin

Uroxatral®

Vasodilators:

Direct Vasodilators Hydralazine Minoxidil

Angiotensin-Converting Enzyme Inhibitors

Angiotensin II Receptor Blockers

Vasodilators: Traditionally not used as primary drugs for

hypertension Produce relaxation of vascular smooth muscle,

predominantly arteriolar Decreases SVR Decreases Blood Pressure

Result in reflex tachycardia and increased contractility

May precipitate angina Increase myocardial oxygen consumption

Also result in increase in plasma renin concentration Sodium and water retention

Hydralazine (Apresoline ®) Hydrazine derivative Direct arteriolar smooth muscle dilator Rapidly and almost totally absorbed from GI

tract Significant 1st-pass effect Peak levels in ½ to 2 hours

Correlates with peak hypotensive effects t-1/2 2-4 hours, duration of action 6-8 hours

Acetylation Slow vs. Fast acetylators

87% protein-bound

Hydralazine (Apresoline ®)

Side Effects: Headache Nausea, vomiting Tachycardia, dizziness Fluid retention Lupus syndrome

Occurs in up to 10% of patients Generally with >400 mg/day Generally reversible upon discontinuation

Minoxidil: Selective arteriolar dilator

? Effect on opening of K channels Antagonizes action of intracellular cAMP on K channels Opens K channels causing relaxation of muscle

No effect on capacitance vessels (veins) Rapidly and completely absorbed Extensive metabolism Eliminated in urine Hypertrichosis

Occurs in 80% receiving drug > 4 weeks Used topically to stimulate hair growth (Rogaine®)

Reserved for use in severe hypertension

Sodium Nitroprusside (Nipride ®): Causes arterial and venous smooth

muscle relaxation Decreases preload and afterload Action more pronounced in upright patient

Increased venous pooling occurs Renal blood flow and GFR maintained Increased plasma renin activity No tachycardia occurs

Mechanism similar to nitrates Results in increase in cGMP

Sodium Nitroprusside

Sodium Nitroprusside (Nipride ®):

Used exclusively via intravenous infusion Onset of action with 1 to 2 minutes t1/2 of minutes

Used for hypertensive emergencies and severe CHF

Used also for aortic dissection

Sodium Nitroprusside (Nipride ®): Fe++ reacts with –SH compounds in RBC CN- produced

Reduced to SCN- in liver (rhodanase) Sodium thiosulfate (S donor) facilitates metabolism of CN-

Hydroxy-cobalamin also combines with CN- (cyanocobalamin)

SCN- excreted in urine Half-life 3 to 4 days May accumulate after prolonged use

Causes toxic psychosis Predisposing factors include renal disease and hyponatremia Monitor levels >3 days [0.1 mg/ml]

Acute toxicity Excess vasodilatation and hypotension

Diazoxide Thiazide compound

No diuretic effect Selective arteriolar dilator

Results in decrease in SVR and BP Compensatory increase in HR and contractility Increase Na and water retention

Pharmacokinetics Administer via bolus IV injection Extensively bound to albumin Effects in minutes, half-life = 24 hours

Adverse Effects Hyperglycemia

Suppresses insulin release Hyperuricemia

Decreases renal uric acid excretion

Fenoldopam mesylate (Corlopam®):

Selective D1 dopamine receptor agonist D1 receptors located on smooth muscle of renal, coronary,

cerebral and mesenteric arteries Vasodilator effect strongest in renal arteries

Causes diuresis and natriuresis Maintains renal perfusion ( Increases renal blood flow)

D2 peripheral receptors located on presynaptic adrenergic nerve terminals and on sympathetic ganglia

Inhibit norepinephrine release Used via intravenous infusion Used in hypertensive emergencies Adverse effects related to excess vasodilatation

Flushing Hypotension

Recent trial to evaluate for prevention of contrast-induced nephropathy


Block action of angiotensin-converting enzyme (ACE) Inhibit cleavage of Angiotensin I Prevents formation of Angiotensin II Interfere with bradykinin degradation

Via inhibition of kininase II Bradykinin stimulates PG synthesis

Causes vasodilatation by: Decreased amounts of Angiotensin II Increased amounts of bradykinin Decreased secretion of aldosterone


Causes decrease in SVR Results in decrease in Blood Pressure

Causes venodilation in CHF Relatively selective action on renal vasculature

Decreases afferent and efferent arteriolar resistance

Decreases glomerular capillary hydrostatic pressure

No effect on cardiovascular reflexes Minimal orthostatic hypotension No CNS effects Effects enhanced by diuretic/Na restriction

Angiotensin-Converting Enzyme Inhibitors: Therapeutic Use

Hypertension Useful for initial therapy Most effective in younger patients and elderly Efficacy enhanced with diuretics

Congestive Heart Failure Decrease in rate of sudden death and progressive heart

failure Left ventricular dysfunction

May lead to regression of LV hypertrophy Following myocardial infarction

To improve survival, particularly with LV dysfunction Administer with 24 hours of MI

Diabetic nephropathy

Assessment of LV Function

(Echocardiogram, Radionuclide Ventriculogram)

EF < 40%

Assessment of Volume Status

Signs and Symptoms of

Fluid Retention

Diuretic (Titrate to Euvolemic

State)

No Signs and Symptoms of Fluid

Retention

ACE Inhibitor

-Blocker

Digoxin

Recommended Approach to the Patient with Heart Failure

Angiotensin-Converting Enzyme Inhibitors: Chemical Classification

Peptide structure Direct-acting ACE inhibitors

Captopril, lisinopril, enalaprilat Prodrugs

De-esterified in liver to active diacid forms Three subgroups

Sulfhydryl-containing Captopril

Di-carboxyl-containing Enalapril

Phosphorus containing Fosinopril


Captopril (Capoten®) Initial agent in class

Only agent available generically 70% bioavailable

Reduced to 40% in presence of food Half-life 3 hours Primarily excreted in urine

40 to 50% unchanged Active metabolites eliminated by kidney


Remainder of agents differ in terms of: Half-life Duration of action Protein binding Route of elimination

Fosinopril Renal = hepatic elimination

Captopril, Lisinopril (enalaprilat derivative) active forms Benazepril, Enalapril, Moexipril, Ramipril require de-

esterification

Angiotensin-Converting Enzyme Inhibitors: Adverse Reactions

Rash Dysgeusia Angioedema

Potentially fatal Macroglossia typical Also, swelling of mouth, pharynx, larynx Seen with all ACE inhibitors May be related to increase in kinin levels Susceptible patients may have subclinical

deficiency of complement 1-esterase inactivator Urticaria


Cough Dry, hacking cough develops in 3 to 20% Usual begins within 1 to 2 weeks of therapy Women affected more than men Resolves within one week after discontinuation,

can take up to 4 weeks Recurs upon repeat challenge Not more frequent in asthmatics Mechanism unknown Worse in supine position

Neutropenia


Hypotension More prominent in patients with hypovolemia Begin with low doses

Acute Renal Failure Most severe in bilateral renal artery stenosis Also occurs in hypertensive nephrosclerosis and

polycystic kidney disease ACEI relax efferent arteriole, cause lowering of

intraglomerular pressure and reduce GFR Angiotensin II levels rapidly reduced Serum creatinine rises within few days of therapy


Hyperkalemia Results from reduction in aldosterone

secretion Impairs efficiency of urinary K excretion Incidence approaches 10%

Proteinuria Primarily with underlying renal disease Seen with high doses of Captopril

Angiotensin-Converting Enzyme Inhibitors: Use in Pregnancy

Not teratogenic in first trimester Category C Discontinue as soon as pregnancy discovered

Fetopathic in second and third trimesters Category D Causes fetal injury

Skull hypoplasia Anuria

Renal failure (Reversible/Irreversible) Oligohydramnios Intrauterine growth retardation

Angiotensin II Receptor Antagonists Saralasin

Peptide analog of Angiotensin II Partial agonist Parenteral administration Short duration of action Not used clinically

New agents; introduced first in 1995 Non-peptide selective blockers of binding of Angiotensin

II to type 1 (AT1) angiotensin receptors on cell membrane

Primarily imidazole compounds Represent third class of agents that antagonize

renin-angiotensin-aldosterone system

Angiotensin II Receptor Antagonists Blockade of action of Angiotensin II leads to

elevations in plasma levels of: Renin Angiotensin I Angiotensin II

Agents block effects of Angiotensin II Vasoconstrictor Aldosterone secretion

Build-up of precursors does not overwhelm receptor blockade

Comparative efficacy in hypertension to ACEI

Angiotensin II Receptor Antagonists

Losartan (Cozaar ®) Irbesartan (Avapro ®) Candesartan (Atacand ®) Telmisartan (Micardis ®) Valsartan (Diovan ®) Eprosartan (Teveten ®) Olmesartan (Benicar ®)

Agents differ in half-life, duration of action, bioavailability and metabolic fate

Approved only for use in hypertension

Angiotensin II Receptor Antagonists: Side Effects

Generally well tolerated May cause changes in renal function Effects in pregnancy same as for

ACEI Category C first trimester Category D second and third trimesters

No cough noted Hyperkalemia

Lifestyle Changes: Weight Reduction Sodium Restriction Alcohol Restriction Exercise Smoking Cessation

Inadequate Response

Continue Lifestyle Changes and initiate drug therapy:

Preferred Initial Drug: Diuretic or -blocker

Alternative Initial Drug: ACE inhibitor or calcium channel blocker, -1-blocker or blocker

Inadequate Response

Increase drug dose or Substitute another drug

Or Add a second drug from a different class

Results from recent clinical trials ALLHAT

Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack

Major Outcomes in High-Risk Hypertensive Patients Randomized to ACE Inhibitor or Calcium Channel Blocker vs Diuretic

Chlorthalidone Amlodipine Doxazosin Lisinopril

JAMA, Dec. 18 2002, 288: 2981-2997 Thiazide-type diuretics are superior in

preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy

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Drugs Used for Hypertension Philip Marcus, MD MPH