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 Venous return SVR
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 Sympathetic nervous system
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 Specific mechanisms
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 CHF Edema
Thiazide, thiazide with potassium sparing
CHF
Loop
Spironolactone
Edema

16. Adverse Effects Thiazide Loop Hypokalemic metabolic alkalosis
Hyperuricemia
Impaired carbohydrate tolerance
Hyperlipidemia
Hyponatremia
Loop
Ototoxicity
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 Generic Brand Benazepril Lotensin Captopril Capoten
Enalapril
Vasotec
Fosinopril
Monopril
Lisinopril
Prinivil
Moexipril
Univasc
Perindopril
Aceon
Quinapril
Accupril
Ramipril
Altace
Trandolapril
Mavik
ACE Inhibitors

20. Angiotensin Receptor Blockers
Generic
Brand
Candesartan
Atacand
Irbesartan
Avapro
Losartan
Cozaar
Telmisartin
Micardis
Valsartan
Diovan

21. Renin 1 Converting Enzyme 1 2 2 Angiotensinogen Kininogen
Kalikrein
Increased prostaglandin synthesis
Angiotensin I
Bradykinin 1
Converting Enzyme 1
Angiotensin II
Inactive 2 2
Vasoconstriction
Aldosterone secretion
Vasodilation
Increased sodium and water retention
Decreased peripheral vascular resistance
Increased peripheral vascular resistance
Increased blood pressure
Decreased blood pressure

22. Clinical Uses
HTN
CHF
Diabetic Nephropathy
Post-MI

23. Adverse Effects Hypotension Acute renal failure Hyperkalemia Dry cough
Angioedema
CI in 2nd and 3rd 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 Miscellaneous Amlodipine Felodipine Isradipine
Nicardipine
Nimodipine
Nisoldipine
Nitrendipine
Miscellaneous
Bepridil
Diltiazem
Verapamil

30. CCB
Clinical Uses
Adverse Effects

31. 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

32. Central Alpha2-Receptor Agonists
Effects
Decreased heart rate
Decreased peripheral resistance
Decreased renin activity
Blunted baroreceptor reflexes

33. Central Alpha2-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. 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.

40. 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

41. Alpha1 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 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