ANTIHYPERTENSIVE Rx MED PHARM 2010

CARDIOVASCULAR DISEASE (CVD) Leading cause of death in the US 36% of deaths, 900,000 per year 52% due to coronary heart disease Mortality declining due to improved Dx & treatment

CVD & Severe Mental Illness Severe mental illness: 5-10% of population Loss of life expectancy: 25 years Due to premature CVD, not suicide

Lenfant C. N Engl J Med 2003;349: Change in U.S. Life Expectancy between 1970 and 2000

Messerli F. N Engl J Med 1995;332: Headlines of the St Louis Post-Dispatch April 13,1945

Messerli F. N Engl J Med 1995;332: Diastolic and Systolic Arterial Pressure of Franklin D. Roosevelt

Chobanian A. N Engl J Med 2009;361: Risk Factors for Hypertension

Adrogue H and Madias N. N Engl J Med 2007;356: Interaction of the Modern Western Diet and the Kidneys in the Pathogenesis of Primary Hypertension

Adrogue H and Madias N. N Engl J Med 2007;356: Molecular Pathways Implicated in the Generation of Increased Arterial and Arteriolar Smooth- Muscle Tone by an Excess of Sodium and a Deficit of Potassium in Primary Hypertension

DRUGS FOR HYPERTENSION DIURETICSDIRECT VASODILATORS Thiazide – Type Hydralazine Hydrochlorothiazide Minoxidil Chlorthalidone Nitroprusside LOOPCENTRAL ALPHA-ADRENERGIC FurosemideAGONISTS Clonidine POTASSIUM – SPARING TriamtereneCALCIUM CHANNEL BLOCKERS Verapamil Diltiazem Amlodopine

DRUGS FOR HYPERTENSION ALPHA-ADRENERGICBETA-ADRENERGICBLOCKERS Prazosin Propranolol Metoprolol ALPHA –BETA BLOCKERS ANGIOTENSIN RECEPTOR CarvedilolANTAGONISTS Labetalol Losartan ACE-Inhibitors RENIN ANTAGONISTS Benazepril Aliskiren

DIURETICS for HYPERTENSION Chlorthalidone Hydrochlorthiazide ADVERSE EFFECTS Fluid & electrolyte imbalance Hypokalemia Dysglycemia

Ernst M and Moser M. N Engl J Med 2009;361: Sites of Diuretic Action in the Nephron

Ernst M and Moser M. N Engl J Med 2009;361: aPotential Complications of DiureticAAAAs nd Their Associated Mechanisms

Landry D and Oliver J. N Engl J Med 2001;345: Regulation of Vascular Smooth-Muscle Tone

CENTRALLY ACTING ANTIHYPERTENSIVE DRUGS CLONIDINE

Central    agonist Hemodynamics Decrease in : Cardiac output Systemic vascular resistance

ALPHA- ADRENERGIC ANTAGONISTS PRAZOSIN Hemodynamics Decrease in systemic vascular resistance ADVERSE RESPONSE first dose hypotension

BETA ADRENERGIC ANTAGONISTS Propranolol non-selective Metoprolol cardioselective,   block Beta blockers are not as effective as the other 4 classes of drugs in reducing stroke, particularly in the elderly

BETA BOCKERS – ADVERSE EFFECTS CNS Cardiovascular Bad dreams Aggravation of severe CHF Depression Aggravation of occlusive arterial disease Slow A-V conduction Pulmonary Bronchospasm in Asthmatics Drug interactions Drugs that impair A-V conduction (digoxin and some calcium channel blockers)

VASODILATORS FOR HYPERTENSION HYDRALAZINE MINOXIDIL SODIUM NITROPRUSSIDE

HYDRALAZINE A direct acting vasodilator May prevent oxidation of NO Hemodynamics- Decrease in systemic vascular resistance

HYDRALAZINE Adverse Effects Fluid retention Lupus-like syndrome in slow acetylators Reflex tachycardia

MINOXIDIL ACTION: HEMODYNAMIC ACTIONS: ADVERSE EFFECTS: Direct acting peripheral vasodilator for resistant hypertension Decrease in systemic vascular resistance Fluid retention, Tachycardia, Angina, Pericardial effusion, Hirsutism, EKG changes

Griffiths, M. J.D. et al. N Engl J Med 2005;353: Regulation of the Relaxation of Vascular Smooth Muscle by Nitric Oxide

Landry D and Oliver J. N Engl J Med 2001;345: Regulation of Vascular Smooth-Muscle Tone

SODIUM NITROPRUSSIDE ACTION Direct relaxation of all vascular smooth muscle Balanced arteriolar and venous dilation Decrease in systemic vascular resistance Intravenous administration USES Hypertensive crisis Heart failure

Murad F. N Engl J Med 2006;355: Endothelium-Dependent Relaxation of Smooth Muscle

Murad F. N Engl J Med 2006;355: Cellular Signaling with Nitric Oxide and Cyclic GMP

RAAS ANGIOTENSIN II FORMATION

A II ACTIONS

Oparil, S. et. al. Ann Intern Med 2003;139: The angiotension II types 1 (AT 1 ) and 2 (AT 2 ) receptors have generally opposing effects

Goodfriend, T. L. et al. N Engl J Med 1996;334: Actions of Angiotensin II

BENAZEPRIL A Long-acting Inhibitor of Angiotensin Converting Enzyme

BENAZEPRIL ACTION: HEMODYNAMIC EFFECT: ADVERSE EFFECTS: Inhibits angiotensin converting enzyme, to reduce formation of angiotensin II and aldosterone, inhibits lysis of bradykinin, may alter prostaglandin metabolism and sympathetic transmission. Decreases total peripheral resistance Heart rate and cardiac output unchanged Cough, angioedema, teratogenic, neutropenia, agranulocytosis, loss of taste, skin rash,& hypotension

ACEI & ARB TERATOGENICITY 1st half ~2.7X increase in malformations CV & CNS 2 nd half oligohydramnios growth retardation pulmonary hypoplasia renal failure hypotension death

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ANGIOTENSIN RECEPTOR ANTAGONISTS ( ARBs) LOSARTAN OTHERS

Goodfriend T et al. N Engl J Med 1996;334: Signal Transduction by Angiotensin AT1 Receptors

Oparil, S. et. al. Ann Intern Med 2003;139: The angiotension II types 1 (AT 1 ) and 2 (AT 2 ) receptors have generally opposing effects

RAAS RENIN ANTAGONIST ANGIOTENSIN II FORMATION

ALISKIREN Renin inhibitor Lowers blood pressure Outcome studies-none

CALCIUM CHANNEL BLOCKERS Verapamil Diltiazem Amlododipine

CALCIUM CHANNEL BLOCKERS ON THE HEART

CALCIUM CHANNEL ANTAGONISTS ADVERSE EFFECTS HypotensionHeart failure HeadacheAV Block ConstipationPeripheral edema DRUG INTERACTIONS: Digoxin or Beta blockers to cause A-V block

Chobanian A. N Engl J Med 2009;361: Advances in the Treatment of Hypertension

Chobanian A. N Engl J Med 2009;361: Changes in the Prevalence and Control of Hypertension in the United States ( )

Chobanian A. N Engl J Med 2009;361: Rates of Awareness, Treatment, and Control of High Blood Pressure in the United States ( )

Chobanian A. N Engl J Med 2009;361: Comparative Drug Trials in Patients with Hypertension

HYPERTENSION & CV DISEASE Hypertension: Increased risk SCD & LVH 3X Risk increases with sbp Independently predisposes to CAD Increases risk of silent MI 63% of coronary events occur in: HTN+ at least 2 other risk factors

ANTIHYPERTENSIVE THERAPY FIRST-LINE DRUGS DIURETICS: THIAZIDE or THIAZIDE TYPE ACE INHIBITOR : LONG ACTING ARB : CCB : LONG ACTING BETA BLOCKERS : NO, absent a compelling indication ( Post - MI, HF,angina)

Algorithm for Management of Hypertension