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Cardiovascular Medications February 2002. Introduction Pharmacology versus Therapeutics Diseases –HTN –CAD –AMI –CHF –Arrhythmias –Thromboembolic.

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Presentation on theme: "Cardiovascular Medications February 2002. Introduction Pharmacology versus Therapeutics Diseases –HTN –CAD –AMI –CHF –Arrhythmias –Thromboembolic."— Presentation transcript:

1 Cardiovascular Medications February 2002

2 Introduction Pharmacology versus Therapeutics Diseases –HTN –CAD –AMI –CHF –Arrhythmias –Thromboembolic

3 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

4 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

5 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)

6 Hypertension Medications Diuretics –Reduce blood volume Inhibitors of angiotensin –Reduce SVR and blood volume Sympatholytic agents –Reduce SVR and CO Direct vasodilators –Reduce SVR

7 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

8 Diuretics

9 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

10 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

11 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

12 Thiazide Hydrochlorothiazide, chlorthalidone, indapamide, metolazone Inhibits NaCl cotransporter in epithelial cells of distal convoluted tubule

13 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

14 Diuretics

15 Clinical Uses Hypertension –Thiazide, thiazide with potassium sparing CHF –Loop –Spironolactone Edema –Loop

16 Adverse Effects Thiazide –Hypokalemic metabolic alkalosis –Hyperuricemia –Impaired carbohydrate tolerance –Hyperlipidemia –Hyponatremia Loop –Hypokalemic metabolic alkalosis –Ototoxicity –Hyperuricemia –Hypomagnesemia

17 Adverse Effects Potassium Sparing –Hyperkalemia –Hyperchloremic metabolic acidosis –Gynecomastia –Acute renal failure –Kidney stones

18 Diuretic Mechanisms Effect transport proteins of tubular cells –Loop, thiazide, amiloride, triamterene Prevent water reabsorption –Osmotic Inhibit enzymes –Acetazolamide Interfere with hormone receptors –Spironolactone

19 ACE Inhibitors GenericBrand BenazeprilLotensin CaptoprilCapoten EnalaprilVasotec FosinoprilMonopril LisinoprilPrinivil MoexiprilUnivasc PerindoprilAceon QuinaprilAccupril RamiprilAltace TrandolaprilMavik

20 Angiotensin Receptor Blockers GenericBrand CandesartanAtacand IrbesartanAvapro LosartanCozaar TelmisartinMicardis ValsartanDiovan

21 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 11

22 Clinical Uses HTN CHF Diabetic Nephropathy Post-MI

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

24 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

25 Beta Blockers Cardioselective ISA MSA Mixed First pass Renal Half life

26 Beta Blockers Clinical Uses Adverse Effects

27 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

28 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

29 CCB Dihydropyridine –Amlodipine –Felodipine –Isradipine –Nicardipine –Nimodipine –Nisoldipine –Nitrendipine Miscellaneous –Bepridil –Diltiazem –Verapamil

30 CCB Clinical Uses Adverse Effects

31 Central Alpha 2 -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

32 Central Alpha 2 -Receptor Agonists Effects –Decreased heart rate –Decreased peripheral resistance –Decreased renin activity –Blunted baroreceptor reflexes

33 Central Alpha 2 -Receptor Agonists Sedation and dry mouth Depression Rebound hypertension

34 Methyldopa Catecholamine type molecule Stimulates central inhibitory alpha- adrenergic receptors Decreases peripheral vascular resistance, decreases systolic and diastolic BP, decreases heart rate

35 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%)

36 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

37 Clonidine Weekly patch for improved compliance and fewer side effects Disadvantages – cost, skin irritation, 2-3 day delay of effect

38 Clonidine Uses –Hypertensive urgency –Adjunctive pain therapy –Withdrawal – alcohol, BZD, nicotine, opiate –Adjunct to prolong anesthesia –Migraine prophylaxis –Menopausal symptoms –Anxiety-related disorders

39 Alpha 1 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.

40 Alpha 1 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

41 Alpha 1 Blockers CNS side effects – lassitude, vivid dreams, depression First dose phenomenon – dizziness, faintness, palpitations, syncope ALLHAT

42 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

43 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)

44 Vasodilator Hydralazine – lupus-like syndrome, dermatitis, drug fever, peripheral neuropathy, hepatitis, vascular headache Minoxidil – greater compensatory effects (HR, CO, renin, sodium retention), hypertrichosis

45 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

46 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

47 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

48 Digoxin Increased calcium improves myocardial contractility Indirect effect of vagal stimulation on SA and AB nodes, decreases sinus rate

49 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

50 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

51 Digoxin Adverse effects –GI- N/V, abdominal pain, anorexia –CNS- headache, hallucination, delirium, –Vision changes –Gynecomastia –Arrhythmias Hypokalemia Hypercalcemia Hypomagnesemia

52 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

53 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

54 Nitrates Pharmacokinetics –Large first-pass effect –Short half lives (except isosorbide mononitrate) –Large interindividual variations in blood concentrations

55 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

56 Nitrates Tolerance Adverse effects – postural hypotension, headaches, flushing, nausea

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