Cardiovascular Medications

February 2002

Introduction

• Pharmacology versus Therapeutics• Diseases

–HTN–CAD–AMI

–CHF–Arrhythmias–Thromboembolic

Goals and Objectives• To provide general information about

cardiovascular medications• Learn pharmacologic properties including

mechanism of action, adverse effects, and clinical use of the following medications:

–Diuretics–ACE inhibitors–ARBs–Beta blockers

–CCBs–Vasodilators–Nitrates–Digoxin

Hypertension• BP=CO X SVR• CO

– Myocardial contractility, heart rate, venous return

• Venous return – Total blood volume

• Kidney

– Percentage of blood volume circulating centrally • Venous tone

• SVR– Arteriolar smooth muscle tone

Hypertension

• Kidney– Production of renin– Regulation of blood volume

• Sympathetic nervous system– Regulation of cardiac output and peripheral

resistance

• Renin-angiotensin-aldosterone– Vasoconstriction (angiotensin II)– Increased cardiac output secondary to

sodium retention (aldosterone)

Hypertension Medications

• Diuretics– Reduce blood volume

• Inhibitors of angiotensin– Reduce SVR and blood volume

• Sympatholytic agents– Reduce SVR and CO

• Direct vasodilators– Reduce SVR

Diuretics• General mechanism of action

– Decrease blood volume– Long-term effects from decreased PVR

• Specific mechanisms– Effect transport proteins of tubular cells– Prevent water reabsorption– Inhibit enzymes– Interfere with hormone receptors

Diuretics

Carbonic Anhydrase Inhibitors

• Acetazolamide, methazolamide • CA leads to reabsorption of

bicarbonate• Inhibition leads to a sodium

bicarbonate diuresis and reduction in bicarbonate stores

• Not used for hypertension– Glaucoma, urinary alkalination (uric acid

elimination, ASA), acute altitude sickness

Osmotic

• Mannitol, glycerin• Large, non absorbed molecule

passing through highly water permeable proximal tubule and descending limb of Loop decreases reabsorption of water

• Not used for hypertension – Reduce intraocular, intracranial pressure

Loop

• Furosemide, bumetanide, ethacrynic acid, torsemide

• Inhibition of Na/K/Cl transport in the ascending limb of the Loop of Henle, increases excretion of Na and water.

• CV uses primarily in CHF, also edema, renal failure

Thiazide

• Hydrochlorothiazide, chlorthalidone, indapamide, metolazone

• Inhibits NaCl cotransporter in epithelial cells of distal convoluted tubule

Potassium Sparing

• Spironolactone – competitive antagonist binds to aldosterone receptors, increases Na excretion

• Amiloride, triamterene – acts on the collecting tubule to inhibit sodium transport through ion channels

Diuretics

Clinical Uses

• Hypertension– Thiazide, thiazide with potassium

sparing

• CHF– Loop– Spironolactone

• Edema– Loop

Adverse Effects• Thiazide

– Hypokalemic metabolic alkalosis– Hyperuricemia– Impaired carbohydrate tolerance– Hyperlipidemia– Hyponatremia

• Loop– Hypokalemic metabolic alkalosis– Ototoxicity– Hyperuricemia– Hypomagnesemia

Adverse Effects

• Potassium Sparing– Hyperkalemia– Hyperchloremic metabolic acidosis– Gynecomastia– Acute renal failure– Kidney stones

Diuretic Mechanisms• Effect transport proteins of tubular

cells– Loop, thiazide, amiloride, triamterene

• Prevent water reabsorption– Osmotic

• Inhibit enzymes– Acetazolamide

• Interfere with hormone receptors– Spironolactone

ACE Inhibitors

Generic Brand

Benazepril Lotensin

Captopril Capoten

Enalapril Vasotec

Fosinopril Monopril

Lisinopril Prinivil

Moexipril Univasc

Perindopril Aceon

Quinapril Accupril

Ramipril Altace

Trandolapril Mavik

Angiotensin Receptor Blockers

Generic Brand

Candesartan Atacand

Irbesartan Avapro

Losartan Cozaar

Telmisartin Micardis

Valsartan Diovan

Angiotensinogen

Angiotensin I

Angiotensin II

Vasoconstriction

Increased peripheral vascular resistance

Increased blood pressure

Aldosterone secretion

Increased sodium and water retention

Kininogen

Bradykinin

Inactive

Increased prostaglandin synthesis

Vasodilation

Decreased peripheral vascular resistance

Decreased blood pressure

Renin Kalikrein

Converting Enzyme

2 2

1 1

Clinical Uses

• HTN• CHF• Diabetic Nephropathy• Post-MI

Adverse Effects

• Hypotension• Acute renal failure• Hyperkalemia• Dry cough• Angioedema• CI in 2nd and 3rd trimester

Beta Blockers

• Competitively antagonize the effects of catecholamines at B-adrenergic receptors.

• Decrease heart rate, stroke volume and cardiac output

• Initial increase in peripheral resistance from blockade of B-receptors in vessels that promote vasodilation, leaving unopposed alpha vasoconstriction

Beta Blockers

• Cardioselective• ISA• MSA• Mixed• First pass• Renal• Half life

Beta Blockers

• Clinical Uses

• Adverse Effects

Calcium Channel Blockers

• Inhibition of calcium influx into arterial smooth muscle cells

• Nifedipine and other dihydropiridine agents are more selective as vasodilators, with less cardiac depressant effects than diltiazem and verapamil

CCB

• Smooth muscle – long lasting relaxation

• Cardiac muscle – reduction in contractility throught the heart and decrease in sinus node pacemaker rate and AV node conduction velocity

CCB

• Dihydropyridine– Amlodipine – Felodipine– Isradipine– Nicardipine– Nimodipine– Nisoldipine– Nitrendipine

• Miscellaneous– Bepridil– Diltiazem– Verapamil

CCB

• Clinical Uses

• Adverse Effects

Central Alpha2-Receptor Agonists

• Clonidine, guanabenz, guanfacine, and methyldopa

• Decrease sympathetic outflow from the vasomotor center in the brain and increase in vagal tone.

• Peripheral activity plays a lesser role– Stimulation of presynaptic a2-receptors

decreases sympathetic tone

Central Alpha2-Receptor Agonists

• Effects– Decreased heart rate– Decreased peripheral resistance– Decreased renin activity– Blunted baroreceptor reflexes

Central Alpha2-Receptor Agonists

• Sedation and dry mouth• Depression• Rebound hypertension

Methyldopa

• Catecholamine type molecule• Stimulates central inhibitory alpha-

adrenergic receptors• Decreases peripheral vascular

resistance, decreases systolic and diastolic BP, decreases heart rate

Methyldopa

• Sodium and fluid accumulation lead to tolerance of hypotensive effect, therefore diuretic use is needed

• Rare hepatitis and hemolytic anemia– Coombs' positive (20%)– Coombs' positive HA (1%)

Clonidine

• Reduces sympathetic outflow from the brain secondary to direct stimulation of alpha-receptors in the medulla

• Increased vagal tone leads to decreases in peripheral vascular resistance and heart rate

• Baroreceptors are blunted, leading to orthostatic hypotension and tachycardia

Clonidine

• Weekly patch for improved compliance and fewer side effects

• Disadvantages – cost, skin irritation, 2-3 day delay of effect

Clonidine

• Uses– Hypertensive urgency– Adjunctive pain therapy– Withdrawal – alcohol, BZD, nicotine,

opiate– Adjunct to prolong anesthesia– Migraine prophylaxis– Menopausal symptoms– Anxiety-related disorders

Alpha1 Blockers

• Prazosin, terazosin, doxazosin• Selective alpha-1 blockade

decreases total peripheral resistance and venous return.

• Inhibition of alpha-1 receptors in the periphery prevents vasoconstriction from adrenergic stimulation, allowing vasodilation without affecting heart rate or cardiac index.

Alpha1 Blockers

• Benign Prostatic Hypertrophy– Prevent stimulation of alpha-1

receptors and subsequent smooth muscle contraction in the bladder neck and prostatic urethra

– Significantly increase urinary flow rates and decrease outflow obstruction and irritation symptoms

Alpha1 Blockers

• CNS side effects – lassitude, vivid dreams, depression

• First dose phenomenon – dizziness, faintness, palpitations, syncope

• ALLHAT

Vasodilators• Hydralazine, minoxidil• Relax arteriolar smooth muscle by

increasing the intracellular concentration of cyclic GMP

• Decrease peripheral vascular resistance

• Activate baroreceptor reflexes, increasing sympathetic outflow

• Activate RAA system

Vasodilator

• Hypotensive effect diminishes over time without concomitant use of a diuretic and sympathetic inhibitor.

• Angina can be exacerbated if vasodilators are used without sympathetic inhibitor (B blocker)

Vasodilator

• Hydralazine – lupus-like syndrome, dermatitis, drug fever, peripheral neuropathy, hepatitis, vascular headache

• Minoxidil – greater compensatory effects (HR, CO, renin, sodium retention), hypertrichosis

Vasodilators• Nitroprusside• IV used for hypertensive emergency• Decreases PVR without increasing CO,

unless there is left ventricular failure• Continuous IV infusion, effect is

immediate and lasts 2-5 minutes• Thiocyanate levels should be

measured if infusion lasts longer than 72 hours

Vasodilators

• Diazoxide• Direct acting arteriolar vasodilator

decreases PVR, increases cardiac output, and maintains or increases renal plasma flow

• IV use for HTN emergency• SE – nausea, vomiting, tachycardia,

hyperglycemia• Use with diuretic

Cardiac Glycosides - Digoxin

• Positive inotropic effect• Inhibits active transmembrane

transport of sodium and potassium• Binds to membrane-bound sodium-

potassium ATPase enzyme, disabling the pump

• Increase of intracellular sodium activates sodium-calcium pump, increasing intracellular calcium

Digoxin

• Increased calcium improves myocardial contractility

• Indirect effect of vagal stimulation on SA and AB nodes, decreases sinus rate

Digoxin

• Loading dose 10 mcg/kg IV or PO• 75% oral bioavailability• Oral maintenance dose 0.125 to

0.5 mg• Renal function, baseline cardiac

function, size, age affect dosing• Monitor drug levels

Digoxin

• Used in heart failure with supraventricular tachyarrhythmias – Early in therapy to control ventricular

response

• Used in HF with NSR– No survival benefit– Reduces symptoms and improves

quality of life

Digoxin

• Adverse effects – GI- N/V, abdominal pain, anorexia– CNS- headache, hallucination, delirium,– Vision changes– Gynecomastia– Arrhythmias

• Hypokalemia• Hypercalcemia• Hypomagnesemia

Nitrates

• Used in ischemic heart disease• Reduces myocardial oxygen

demand secondary to venodilation and arterial dilation, causing a reduction in wall stress from reduced ventricular volume and pressure

• Direct dilation of coronary arteries

Nitrates

• Mechanism– Smooth muscle relaxation

• Nitric oxide stimulates guanylyl cyclase which increases cGMP leading to relaxation

– Preload and afterload are reduced– Cardiac output and blood pressure

are reduced– Oxygen requirement is reduced

Nitrates

• Pharmacokinetics– Large first-pass effect– Short half lives (except isosorbide

mononitrate)– Large interindividual variations in blood

concentrations

Nitrates

• Short, intermediate, long• Acute attack v. prophylaxis• IV, sublingual, PO, transdermal• Half life 1-5 minutes• Isosorbide dinitrate is well

absorbed and has half-life of 5 hours

Nitrates

• Tolerance• Adverse effects – postural

hypotension, headaches, flushing, nausea