Pharmacology Part 2

1. Pharmacology Part 2 IMEC INC. Quick Learning Technique

2. Treatment of Congestive Heart Failure

3. Cardiac Glycosides • Digitalis • Mode of Action: Regulation of cytosolic calcium-inhibiting pump activityby reversibly binding with sodium-potassium ATPase • Increasing the Contractility of the Cardiac Muscle • Therapeutic uses include-CHF caused by ischemia or congenital heart disease • Digoxin/Digitoxin- digoxin has a shorter ½ life and is eliminated unchanged in the urine, whereas digitoxin is extensively metabolized by the liver and may be contraindicated in hepatic disease • Adverse affects: severe toxicity causes V-Tach • Anti dig (FAB) fragments are given • CNS-headache, confusion, color perception and halos on dark objects

4. Digitalis Toxicity • Factors predisposing • Electrolyte disturbances-HYPOKALEMIA • HYPO K is most observed in patients using Thiazide diuretics • Hypernatremia, hypermagnesemia, and alkalosis are also factors • Drugs: Quinidine reduces renal clearance of digoxin and and alters renal clearance-corticosteroids, and any potassium clearing diuretics can alter this

5. Antiarrythmics • Amrinone-Amrinone is a rapid-acting inotropic agent that increases cardiac output following IV administration. It is a phosphodiesterate (Class III) inhibitor that increases myocardial contractility and produces systemic vasodilations without stimulating either alpha or beta adrenergic receptors. Amrinone’s net hemodynamic effects are similar to those of dobutamine, however, because the drug does not stimulate beta adrenergic receptors, it may be effective in patients with CHF who do not respond to dobutamine or other inotropic agents.

6. Vasodilators • The vasodilator of choice for CHF is the ACE INHIBITOR- Captopril • Other vasodilators such as nitroprusside are also useful in CHF because it opens both venous and arterial beds • The outpatient vasodilator of choice with an equivalent to nitroprusside is Prazosin

7. Antiarrythmic Drugs

8. Actions of Antiarrythmic Drugs • Class Mechanism Comment IA Na Channel Blocker Slow Phase Zero Depolar IB Na Channel Blocker Shortens phase 3 Repolar IC Na Channel Blocker Slows Phase Zero Depolar II B Adrenergic Blocker Suppresses phase 4 Depolar III K channel Blocker Prolongs Phase 3 Repolar IV Ca Channel Blocker Shortens Action Potential

9. Myocardial Action Potential

10. Action Potential

11. CLASS (1A) antiarrhythmic • Quinidine • Procainamide • Disopyramide

12. Quinidine— • Prototype class 1A , bind to open and inactivated sodium channel to prevent sodium influx.Thus slowing the rapid influx during Phase O • It also decreases the slope of phase 4 • It inhibits ectopic arrhythmias and ventricular arrhythmias caused by increased automaticity • Also prevents re-entry arrhythmias • Used for A-V Junctional, Ventricular Tachycardia • Effects are increased by hyperkalemia, can increase digoxin levels. It also has a mild alpha effect, and atropine like effect

13. Procainamide • Class 1A, a derivative of anesthetic Procaine-shows action similar to Quinidine • Can be given orally • Procainamide has a relatively short half life • Acetylated in the liver to NAPA-which has properties of a CLASS III drug • NAPA is eliminated in via the kidney, therefore doses may need to be adjusted in renal failure. • With chronic use reversible SLE-Syndrome has been noted • Used mainly for Ventricular Arrhythmias ACLS

14. Disopyramide • Class 1A similar to Quinidine • Has a greater negative iontropic effect, decreasing myocardial contractility • Can cause peripheral vasoconstriction • ½ is excreted unchanged by the kidney, and about 30% is converted by the liver to a less active metabolite • Used for Ventricular arrhythmias as an alternative to procainamide or quinidine • Adverse effects-shows anticholinergic effects-dry mouth urinary retention-blurred vision-constipation

15. Class 1B • Lidocaine • Mexiletene • Tocainide • Phenytoin

16. Lidocaine • Lidocaine, an anesthetic also causes reduction in Phase O. Therefore shortens action potential, • Lidocaine abolishes Re-entry • Lidocaine is useful in treating ventricular arrhythmiasarising during myocardial ischemia • Lidocaine is given IV, because of extensive first-pass metabolism by the liver • Therefore patients with hepatic disease may need adjustments in dosage • Lidocaine has a fairly wide toxic to therapeutic ratio • No negative Ionotropic effect

17. Mexiletine and Tocainide • Class 1B similar to Lidocaine • MEXILETINE • Used in chronic treatment of ventricular arhrythmias associated with previous MI • TOCAINIDE • Treatment of V-Tach • Has pulmonary toxicity, which may lead to pulmonary fibrosis

18. Phenytoin • This antiepileptic drug has antiarrhythmic properties similar to lidocaine • Phenytoin is useful in Digatilis induced arrhythmias. • Also used sometimes in children with ventricular arrhythmia

19. Class 1C • Flecainide • Encainide • Propoferone

20. Flecainide • This Class 1C, slowly dissociates from resting sodium channels and shows prominent effects, even at normal heart rates • These drugs are approved only for refractory ventricular arrhythmias • Can suppress PVC’s • Has a negative iotropic effect, and can aggravate CHF • Flecainide is absorbed orally and undergoes very little biotransformation ½ life 16-20 hours • Like other Class 1C, it can aggravate pre-existing arrhythmias or can induce life threatening ventricular tachycardia, resistant to treatment

21. Encainide and Propoferone • Class 1C—slows conduction in all cardiac tissue and are considered broad spectrum antiarrhythmics

22. Class II ANTIARRHYTHMICS • BETA-BLOCKERS • Review Beta blockers • Propanolol (MI) • Metaprolol (B1 specific, reduces risk of bronchospasm) • Pindolol (may decrease frequency of cardiac failure) • Esmolol (IV)

23. Class III Antiarrhythmics • Bretylium • Amiodarone

24. Bretylium • Class III agents block potassium channels and thus diminish the outward potassium current, which leads to repolarization of Cardiac Cells. • These agents prolong the duration of the action potential without altering Phase O of depolarization

25. Bretylium(cont) • Bretylium differs from Class I in does not slow the rise of Phase 0 of the Action Potential and does not reduce the slope of phase 4-spontaneous depolarization • The most prominent is the prolongation of the refractory period and raising of the the electrical current necessary to induce ventricular fibrillation in the His-Purkinje system • Reserved for life-threatening ventricular arrhymias, especially recurrent V-fib and V-tach • Must be given parental, do to poor oral absorption • Can cause postural Hypotension

26. Amiodarones • Contains Iodine (Blue discolored skin) and is structurally related to Thyroxine • It has complex action and show actions of Class I, II, III, IV • Amiodarone is effective in the treatment Severe Refractory V-tach or SVT • It is limited to toxicity • Has a very long ½ life • SE-Interstitial Pulmonary Fibrosis, Liver Toxicity, GI intolerance, Hyper-hypothyroidism, liver toxicity, photosensitivity, neuropathy, blue-skin

27. Class IV Antiarrhythmic Drugs • Verapamil • Diltiazem

28. Verapamil & Diltiazem • Calcium Channel blocker • Action: calcium enters the cells by voltage-sensitive channels and by receptor operated channels that are controlled by the binding of agonist, such as catocholamines, to membrane receptors. • Therefore are effective are more effective against voltage sensitive channels, which cause a decrease in the slow inward current that trigger cardiac contraction. • Therefore usefulness is with SVT • USEFUL in ATRIAL ARRHYTHMIAS • Can be given via oral route • ***Contraindicated In preexisting depressed Cardiac Function**

29. ANTI-ANGINAL DRUGS

30. Organic Nitrates • Nitroglycerin • Isosorbide Dinitrate • Amyl Nitrate

31. Nitroglycerin/ Isosorbide • Nitroglygerin converts Nitrite to Nitric Oxide, which activates Guanylate Cyclase and increase cGMP levels. This in turn leads to dephosphorylating of the myosin light chain and smooth muscle relaxation. • AT Low doses Veins dilate and this reduces PRELOAD. Little effect on arterioles exists, and the stroke output is compensated by tachycardia • At Higher doses, Arterioles are dilated, causing a decrease in peripheral resistance. This then effects AFTERLOAD. • NITROGLYCERIN HAS FIRST PASS METABOLISMSO IT CAN BE GIVEN SUBLINGUALLY/TRANSDERAML • ISOSORBIDE is a oral form that is not as readily metabolized by the liver, it does the same thing but has a lower potency than nitroglycerin

32. Calcium Channel Blockers • Verapamil-slow cardiac conduction and thus decreases heart rate. It should be used cautiously in digitalis patients, and in patients with AV conduction problems. • Nifedapine- arteriolar vasodialator, it is administered orally • Diltiazem,-is similar to other calcium channel blockers, specifically used for spasms, therefore useful in variant Angina.

33. Antihypertensive Drugs

34. Hydochlorothiazide • Thiazide diuretics work specifically on inhibiting reabsorption of sodium and chloride in ascending loop of Henle and early distal tubules • Decreasing extra cellular fluid volume and decreasing CO • Thiazide diuretics decrease blood pressure whether in a supine or standing position • Useful in combination with beta blockers and ACE inhibitors • Thiazide diurectics can induce hypokalemia and hyperuricemia 70% of the time and hyperglycemia 10% of the time • Serum Potassium levels should be monitored closely, especially in those patient with left ventricular hypertrophy, CHF, or ischemic heart. • Diuretics should be avoided in hypertensive diabetics and hyperlipidemia. • Expect decreased K+ and Mg+, and increased Ca+

35. Spirolactone • Spirolactone inhibits aldosterone mediated reabsorption of Na+ and secretion of K+ • Often used with thiazide diuretics to prevent loss of K+

36. ACE inhibitors • Angiotensin-converting enzyme inhibitors lower blood pressure by reducing peripheral vascular resistance without reflective increases in cardiac output , rate,or contractility. • These drugs block to cleavage of angiotensin I, therefore stopping the production of Angiotensin II a potent vasoconstrictor. • It also inhibits bradykinin inactivation a vasodilator • This combined effects lowers vasoconstriction and enhances vasodilation • ACE works well in CHF • SE: ACE can cause acute renal failure, and sever bilateral renal artery stenosis

37. Alpha adrenergic blocker • Clonidine- a2 agonist that diminishes central adrenergic outflow • For mild to moderate hypertension • Because it causes Na and water retention it is administered with diuretic • AE- sedation and drying mucosal membranes • A-Methyldopa • Reduces total peripheral resistance, but cardiac output remains normal

38. Direct acting vasodilators • Hydrazaline • Directly to arteries and arterioles, prompt decrease to total peripheral resistance • Moderate to severe hypertension • In combination with b-blocker and diuretic • SE-lupus like syndrome • Minoxidil • Directly on arterioles but not venule capacitance • Also used for alopecia

39. Sodium Nitroprusside • Nipride works directly on veins, it has a very short T ½, and decreases preload- • Requires continuous infusion • Cyanide ion production can occur but toxicity is rare • Rhodanase combines this with a thiosulfate to produce a thiocyanate, which can be eliminated by the kidneys

40. Diazoxide • Used in Hypertensive Emergencies • Malignant Hypertension • Hypertensive encephalopathy • Hypertensive ecclampsia • Toxicity--Hypotension

41. Drugs Affecting Blood

42. Heparin • Heparin is an injectable, rapid acting anticoagulant • It acts indirectly by binding to anti-thrombin III, Its effects are within minutes • Antithrombin III is considered a cofactor and inhibits serine proteases, including several clotting factors • However, Chronic or intermittent administration of heparin can lead to reduction in antithrombin III. • Because of this low dose heparin is usually employed.

43. Heparin (cont) • Heparin abolishes fibrin formation and thus limits the formation of thrombi • Surgery-post operatively to prevent venous thrombosis • Deep vein thrombosis • Heparin works rapidly • Thrombocytopenia (reduced platelets can happen 8 days after initiation) • Some patients develop a formation of antiplatelet antibodies • If thomboembolism occurs with heparin therapy, another anti coagulent should be substituted • Heparin is reversed by protamine sulfate

44. Warfarin • Warfarin and Dicumerol have action to the ability to antagonize the cofactor functions of Vitamin K • Cofactors 1972 • Unlike heparin-effects are not observed until 8-12 hours after drug is administered • The drug is 99% plasma bound, therefore it does not diffuse into CSF, urine, or breast milk • Can be displaced by Sulfonamides

45. Problems with thrombosis Local thrombosis is an important part of the normal hemostatic response that limits hemorrhage from microscopic or macroscopic vascular injury. Physiologic thrombosis is counterbalanced by physiologic anticoagulation and physiologic fibrinolysis. Under normal conditions, thrombus is confined to the immediate area of injury and does not obstruct flow to critical areas. Under pathological conditions, thrombus can propagate into otherwise normal vessels. Thrombus that has propagated where it is not needed can obstruct flow in critical vessels and can obliterate valves and other structures that are essential to normal hemodynamic function. Abnormal thrombosis can occur in any vessel at any location in the body. The principal clinical syndromes that result are acute myocardial infarction (MI), deep vein thrombosis, pulmonary embolism, acute nonhemorrhagic stroke, acute peripheral arterial occlusion, and occlusion of indwelling catheters.

46. RETEPLASE Seems to work more quickly and to have a lower bleeding risk than the first-generation agent alteplase. • Reteplase is a synthetic nonglycosylated deletion mutein of tissue plasminogen activator containing 355 of the 527 amino acids of native tissue plasminogen activator. The drug is produced in Escherichia coli by recombinant techniques. Reteplase does not bind fibrin as tightly as native tissue plasminogen activator, allowing the drug to diffuse more freely through the clot rather than binding only to the surface the way tissue plasminogen activator does. In high concentrations, reteplase does not compete with plasminogen for fibrin-binding sites, allowing plasminogen at the site of the clot to be transformed into clot-dissolving plasmin. These 2 modifications help explain the faster clot resolution seen in patients receiving reteplase than in those receiving alteplase. • The modifications also resulted in a molecule with a faster plasma clearance and shorter half-life (about 11-19 min) than alteplase. Reteplase undergoes renal (and some hepatic) clearance. The shorter half-life makes the drug ideal for double-bolus dosing. The result is more convenient administration and faster thrombolysis with reteplase than with alteplase, which is given by a bolus followed by an intravenous (IV) infusion.

47. ALTEPLASE (t-PA) Alteplase (t-PA, Activase) was the first recombinant tissue-type plasminogen activator and is identical to native tissue plasminogen activator. In vivo, tissue-type plasminogen activator is synthesized and made available by cells of the vascular endothelium. It is the physiologic thrombolytic agent responsible for most of the body's natural efforts to prevent excessive thrombus propagation. Alteplase is the fibrinolytic agent most familiar to emergency departments and is the lytic agent most often used for the treatment of coronary artery thrombosis, pulmonary embolism, and acute stroke. HIGHEST FIBRIN SPECIFICITY • In theory, alteplase should be effective only at the surface of fibrin clot. In practice, however, a systemic lytic state is seen, with moderate amounts of circulating fibrin degradation products and a substantial systemic bleeding risk. • The agent may be readministered as necessary, as it is not antigenic and almost never is associated with any allergic manifestations.

48. UROKINASE Urokinase (Abbokinase) is the fibrinolytic agent most familiar to interventional radiologists and the one that has been used most often for peripheral intravascular thrombus. At the time of this writing, urokinase is not available from the manufacturer. Its availability in the immediate future is not known. In the meantime, the FDA has encouraged the off-label use of reteplase and alteplase for local-regional lysis of venous and arterial thrombus at any location. • Urokinase is a physiologic thrombolytic agent that is produced in renal parenchymal cells. Unlike streptokinase, urokinase directly cleaves plasminogen to produce plasmin. When purified from human urine, approximately 1500 L of urine are needed to yield enough urokinase to treat a single patient. Urokinase is also commercially available in a form produced by tissue culture, and recombinant DNA techniques have been developed for urokinase production in E coli cultures. • In plasma, urokinase has a half-life of approximately 15 minutes. Allergic reactions are rare, and the agent can be administered repeatedly without antigenic problems • GOOD WITH PULMONARY EMBOLI

49. Streptokinase Streptokinase is the least expensive fibrinolytic agent, but unfortunately it is highly antigenic and produces a high incidence of untoward reactions. This drawback limits the usefulness of streptokinase in the clinical setting. • Streptokinase is produced by beta-hemolytic streptococci. It was first isolated in 1933 and entered clinical use in the mid-1940s. Streptokinase by itself is not a plasminogen activator, but it binds with free circulating plasminogen (or with plasmin) to form a complex that can convert additional plasminogen to plasmin. Streptokinase activity is not enhanced in the presence of fibrin. • The principal plasma activity half-life of streptokinase is about 20 minutes, but an unbound fraction (about 15%) has a half-life of 80 minutes. Since it is produced from streptococcal bacteria, it often causes febrile reactions and other allergic problems. Streptokinase usually cannot be administered safely a second time within 6 months, because it is highly antigenic and results in high levels of antistreptococcal antibodies.

50. Drugs to treat Anemia • Iron • Folic Acid • Cyanobalmin (B-12) • Erythropoietan