1. Drugs Affecting the Cardiovascular System Heny Ekowati Pharmacy Department Faculty of Medicine and Health Sciences March 2013

2. CARDIOVASCULAR DISEASE CHF Arrhythmias Angina Hipertensi Hiperlipidemia Stroke Etc

3. Congestive Heart Failure The Problem: –Heart cannot pump enough blood –Causes: Htn, arteriosclerosis, valvular disease The Solution(s): Vasodilator Diuretics Inotropes } Goal is to increase cardiac output

4. Vasodilators How do they work? Mechanism 1: –ACE converts Angiotensin I to Angiotensin II –Angio II has effects as shown –ACE inhibitors decrease A II End Results: –Decrease fluid retention, afterload Examples: –Enalapril, Captapril Angiotensin I Angiotensin II ACE ↑ Sympathetic Output Constrict Vascular Smooth Muscle ↑ Na + /H 2 0 Retention ↑ Bradykinin

5. Other Vasodilators: Mechanism 2: –Direct smooth muscle relaxants –Nitrates Venous dilators Reduce preload Eg: sodium nitropruside –Calcium channel blockers Amlodipine, felodipene

6. Diuretics Bottom line: they decrease fluid volumes Four Flavours: –Carbonic anhydrase inhibitors –Loop diuretics –Thiazide diuretics –K + -sparing

7. Diuretics: Sites of Action Na + Cl - K + Na + Cl - HCO 3 - Na + K+K+ Carbonic Anhydrase Inhibitors Eg: Acetazolamide Loop Diuretics Eg: Furosemide Thiazides Eg: Chlorothiazide K + - Sparing Eg: ?

8. Inotropes Increase force of contraction All increase intracellular cardiac Ca ++ concentration Eg: –Digitalis (cardiac glycoside) –Dobutamine (β-adrenergic agonist) –Amrinone (PDE inhibitor)

9. How Digitalis Works Ca ++ Na + K+K+ ATPADP + Pi Out In Digitalis Na +

10. Drugs for Treating Arrhythmias The Problem: –Abnormal cardiac impulse formation/conduction –Can be atrial, supraventricular, ventricular in origin The solution –Several different classes of drugs –All affect cardiac action potentials

11. Cardiac Action Potential Example of effects of Antiarrhythmics Membrane Potential (mV) Time (Seconds) Quinidine (a Class I drug) Sotalol (a Class III drug)

12. Actions of Antiarrhythmic Drugs Class of Drug Action INa + Channel Blocker II Β-Adrenoreceptor Blocker IIIK + Channel Blocker IVCa ++ Channel Blocker

13. Antianginal Drugs What is angina? What causes it?

14. Angina Problem: –Blood flow to myocardium is insufficient –Causes: narrowed artery or arterial spasm Possible Solutions: –Relax vascular smooth muscle –Reduce work of the heart

15. Angina Drugs Organic nitrates –Nitroglycerin Nitrate converted to nitric oxide Calcium Channel Blockers –Diltiazem, Nifedipine Β-Blockers –Propranolol Nitrate NO cGMP Myosin Light Chain Pi Ca ++ Nifedipine Propranolol

16. Antihypertensive Drugs

17. What Determines Arterial Pressure? Arterial PressureCardiac Output Peripheral Resistance ~ ~ X Arteriolar Radius Heart Rate Contractility Filling Pressure

18. Hypertension High blood pressure Normal:Systolic < 130 mm Hg Diastolic < 85 mm Hg

19. Classification of Blood Pressure Category Systemic BP (mm Hg) Diastolic BP (mm Hg) Normal<130<85 High normal130-13985-89 Hypertension Stage 1140-15990-99 Stage 2160-169100-109 Stage 3180-209110-119 Stage 4  210  120

20. Classification of Blood Pressure Primary Hypertension Specific cause unknown 90% of the cases Also known as essential or idiopathic hypertension Secondary Hypertension Cause is known (such as eclampsia of pregnancy, renal artery disease, pheochromocytoma) 10% of the cases

21. Treatment Rationale Short-term goal of antihypertensive therapy: Reduce blood pressure Primary (essential) hypertension Secondary hypertension

22. Treatment Rationale Long-term goal of antihypertensive therapy: Reduce mortality due to hypertension-induced disease Stroke Congestive heart failure Coronary artery disease Nephropathy Peripheral artery disease Retinopathy

23. PharmacologyPharmacology Antihypertensives

24. Antihypertensive Classes diuretics beta blockers angiotensin-converting enzyme (ACE) inhibitors calcium channel blockers vasodilators diuretics beta blockers angiotensin-converting enzyme (ACE) inhibitors calcium channel blockers vasodilators

25. Blood Pressure = CO X PVR Cardiac Output = SV x HR PVR = Afterload Cardiac Output = SV x HR PVR = Afterload

26. BP = CO x PVR Key: CCB = calcium channel blockers CA Adrenergics = central-acting adrenergics ACEi’s = angiotensin-converting enzyme inhibitors cardiac factors circulating volume heart rate contractility 1. Beta Blockers 2. CCB’s 3. C.A. Adrenergics salt aldosterone ACEi’s Diuretics

27. BP = CO x PVR Hormones 1. vasodilators 2. ACEI’s 3. CCB’s Central Nervous System 1. CA Adrenergics Peripheral Sympathetic Receptors alpha beta 1. alpha blockers 2. beta blockers Local Acting 1. Peripheral-Acting Adrenergics

28. Alpha 1 Blockers Stimulate alpha 1 receptors -> hypertension Block alpha 1 receptors -> hypotension doxazosin (Cardura ® ) prazosin (Minipress ® ) terazosin (Hytrin ® ) doxazosin (Cardura ® ) prazosin (Minipress ® ) terazosin (Hytrin ® )

29. Central Acting Adrenergics Stimulate alpha 2 receptors –inhibit alpha 1 stimulation hypotension clonidine (Catapress ® ) methyldopa (Aldomet ® ) clonidine (Catapress ® ) methyldopa (Aldomet ® )

30. Peripheral Acting Adrenergics reserpine (Serpalan ® ) inhibits the release of NE diminishes NE stores leads to hypotension Prominent side effect of depression –also diminishes seratonin

31. Adrenergic Side Effects Common –dry mouth, drowsiness, sedation & constipation –orthostatic hypotension Less common –headache, sleep disturbances, nausea, rash & palpitations

32. Angiotensin I ACE Angiotensin II 1. potent vasoconstrictor - increases BP 2. stimulates Aldosterone - Na + & H 2 O reabsorbtion ACE Inhibitors. RAAS

33. Renin-Angiotensin Aldosterone System Angiotensin II = vasoconstrictor Constricts blood vessels & increases BP Increases SVR or afterload ACE-I blocks these effects decreasing SVR & afterload

34. ACE Inhibitors Aldosterone secreted from adrenal glands cause sodium & water reabsorption Increase blood volume Increase preload ACE-I blocks this and decreases preload

35. Angiotensin Converting Enzyme Inhibitors captopril (Capoten ® ) enalapril (Vasotec ® ) lisinopril (Prinivil ® & Zestril ® ) quinapril (Accupril ® ) ramipril (Altace ® ) benazepril (Lotensin ® ) fosinopril (Monopril ® )

36. Drugs acting on the renin-angiotensin system Brown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120. Angiotensinogen AIAII Renin arteries kidneys adrenal glands Aldosterone Na+Na+

37. Drugs acting on the renin-angiotensin system Brown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120. Angiotensinogen AIAII Renin arteries kidneys adrenal glands Aldosterone Na+Na+

38. Drugs acting on the renin-angiotensin system Brown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120. Angiotensinogen AIAII Renin arteries kidneys adrenal glands Aldosterone A ACE Inhibitors B Beta-blockers AIIRA C Calcium Blockers D Diuretics Spironolactone

39. Calcium Channel Blockers Used for: Angina Tachycardias Hypertension Used for: Angina Tachycardias Hypertension

40. CCB Site of Action diltiazem & verapamil nifedipine (and other dihydropyridines)

41. CCB Action diltiazem & verapamil decrease automaticity & conduction in SA & AV nodes decrease myocardial contractility decreased smooth muscle tone decreased PVR nifedipine decreased smooth muscle tone decreased PVR diltiazem & verapamil decrease automaticity & conduction in SA & AV nodes decrease myocardial contractility decreased smooth muscle tone decreased PVR nifedipine decreased smooth muscle tone decreased PVR

42. Side Effects of CCBs Cardiovascular hypotension, palpitations & tachycardia Gastrointestinal constipation & nausea Other rash, flushing & peripheral edema Cardiovascular hypotension, palpitations & tachycardia Gastrointestinal constipation & nausea Other rash, flushing & peripheral edema

43. Calcium Channel Blockers diltiazem (Cardizem ® ) verapamil (Calan ®, Isoptin ® ) nifedipine (Procardia ®, Adalat ® )

44. Diuretic Site of Action. loop of Henle proximal tubule Distal tubule Collecting duct

45. MechanismMechanism Water follows Na + 20-25% of all Na + is reabsorbed into the blood stream in the loop of Henle 5-10% in distal tubule & 3% in collecting ducts If it can not be absorbed it is excreted with the urine  Blood volume =  preload ! Water follows Na + 20-25% of all Na + is reabsorbed into the blood stream in the loop of Henle 5-10% in distal tubule & 3% in collecting ducts If it can not be absorbed it is excreted with the urine  Blood volume =  preload !

46. Side Effects of Diuretics electrolyte losses [ Na + & K + ] fluid losses [dehydration] myalgia N/V/D dizziness hyperglycemia electrolyte losses [ Na + & K + ] fluid losses [dehydration] myalgia N/V/D dizziness hyperglycemia

47. Diuretics Thiazides: chlorothiazide (Diuril ® ) & hydrochlorothiazide (HCTZ ®, HydroDIURIL ® ) Loop Diuretics furosemide (Lasix ® ), bumetanide (Bumex ® ) Potassium Sparing Diuretics spironolactone (Aldactone ® )

48. Mechanism of Vasodilators Directly relaxes arteriole smooth muscle Decrease SVR = decrease afterload Directly relaxes arteriole smooth muscle Decrease SVR = decrease afterload

49. Side Effects of Vasodilators hydralazine (Apresoline ® ) –Reflex tachycardia sodium nitroprusside (Nipride ® ) –Cyanide toxicity in renal failure –CNS toxicity = agitation, hallucinations, etc. hydralazine (Apresoline ® ) –Reflex tachycardia sodium nitroprusside (Nipride ® ) –Cyanide toxicity in renal failure –CNS toxicity = agitation, hallucinations, etc.

50. VasodilatorsVasodilators diazoxide [Hyperstat ® ] hydralazine [Apresoline ® ] minoxidil [Loniten ® ] sodium Nitroprusside [Nipride ® ] diazoxide [Hyperstat ® ] hydralazine [Apresoline ® ] minoxidil [Loniten ® ] sodium Nitroprusside [Nipride ® ]

51. Antihypertensive Agents: Mechanism of Action Vasodilators Directly relaxes arteriolar smooth muscle Result:decreased systemic vascular response, decreased afterload, and PERIPHERAL VASODILATION

52. Antihypertensive Agents Vasodilators diazoxide (Hyperstat) hydralazine HCl (Apresoline) minoxidil (Loniten, Rogaine) sodium nitroprusside (Nipride, Nitropress)

53. Antihypertensive Agents: Therapeutic Uses Vasodilators Treatment of hypertension May be used in combination with other agents Sodium nitroprusside and diazoxide IV are reserved for the management of hypertensive emergencies

54. Antihypertensive Agents: Side Effects Vasodilators Hydralazine: –dizziness, headache, anxiety, tachycardia, nausea and vomiting, diarrhea, anemia, dyspnea, edema, nasal congestion Sodium nitroprusside: –bradycardia, hypotension, possible cyanide toxicity