Cardiovascular Drugs

1. Cardiovascular Drugs Faculty of Pharmacy Department of Pharmacology 5th year Pharmacy Students Drug-Drug Interaction

2. ANTIARRHYTHMICS class I drugs: block the fast sodium channel and divided into three subgroups: Class IA: (quinidine, procainamide, disopyramide) Class IB: (mexiletine, phenytoin, and lidocaine) Class IC: (flecainide, propafenone) Class II drugs: block beta-adrenergic receptors and include: They include propranolol, timolol, metoprolol, and others. Class III drugs: block potassium channels and prolong repolarization. They include sotalol, amiodarone, and bretylium Class IV: drugs block the slow calcium channel and include verapamil, diltiazem.

3. Drug Interactions (Selection; Amiodarone Preferred) 1-Phamacokinetic interactions: • 1-Amiodarone inhibits the activity of two cytochrome P450 enzymes, CYP2D6 and CYP2C9. As a consequence, it reduce the metabolism of certain drugs e.g. anticoagulants. The anticoagulant effects of warfarin is significantly increased when amiodarone is added. 2-Flecainide concentrations increase by an average of 60% with concomitant amiodarone therapy. it is postulated that the hepatic metabolism and/or renal clearance of flecainide may be decreased. 3-Quinidine serum concentrations generally increase by about 33% in patients receiving concomitant amiodarone therapy. it appears that hepatic and/or renal clearance may be diminished and quinidine may also be displaced from tissue- and protein-binding sites.

4. 4-Procainamide and N-acetylprocainamide or NAPA (a pharmacologically active metabolite) concentrations increase approximately 55 % during the concomitant amiodarone therapy due to a reduction in the renal clearance of both parent and metabolite, as well as a reduction in hepatic metabolism seem likely. 5-Amiodarone increases serum levels of digoxin when given concomitantly result from an amiodarone-induced displacement of digoxin from tissue-binding sites, an increase in bioavailability, and/or a decrease in renal clearance. 6-Concurrent administration of amiodarone with coumarin or indandione anticoagulants (warfarin) results in at least a doubling of prothrombin time (PT)

5. 7-Concomitant administration of amiodarone and phenytoin may result in phenytoin Toxicity due to a amiodarone-induced decrease in phenytoin metabolism 8-Two protease inhibitors,ritonavir and nelfinavir, are potent P450 enzyme inhibitors produce a large increase in amiodarone concentrations, due to the inhibition of its metabolism. 9-Paroxetine impairs metabolism of the CYP2D6 (cytochrome P450 isoenzyme 2D6) pathway at therapeutic doses. Competition for hepatic CYP2D6 (cytochrome P450 isoenzyme 2D6) by paroxetine may potentiate the toxicity of these antiarrhythmics.

6. 2-pharmacodynamic interactions 1-Concomitant administration of beta-blockers, or calcium-channel blockers with amiodarone may result in additive electrophysiologic effects including bradycardia, sinus arrest, and atrioventricular block.

7. sympatholytics 1-alpha-Blockers: The selective alpha-1-blockers: such as prazosin, terazosin, and doxazosin are the only class of antihypertensive agents that may have the combined effect of lowering low-density lipoprotein (LDL)-cholesterol, raising highdensity lipoprotein (HDL)-cholesterol levels, and improving insulin sensitivity The alpha -blockers are associated with relatively bothersome side effects, including dizziness (rarely inducing syncope), headache, and weakness. Indications and Usage 1- BENIGN PROSTATIC HYPERPLASIA (BPH) 2- HYPERTENSION

8. Pharmacodynamic interactions: 1- Combined use with other antihypertensive drugs(e.g.,beta -blockers, calcium channel blockers, diuretics, ACE inhibitors) can cause additive blood pressure lowering effects with severe symptomatic hypotension. Pharmacokinetic interaction: 1-Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin mesylate has no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin. There is no information on the effect of other highly plasma protein-bound drugs on doxazosin binding.

9. Beta -Blocking Agents Propranolol, Metoprolol Atenolol, Nadolol ,Pindolol and Labetalol Mechanism of action: binding to beta-adrenergic receptors, which is sufficiently high to antagonize the binding of endogenous agonists like norepinephrine and epinephrine at blood and tissue these agents have been classified according to their: • relative selectivity for the beta-1 or beta-2adrenergic receptors • their ability to bind other adrenergic receptors, usually alpha receptors

10. Drug interactions:

12. DIGITALIS Digoxin and digitoxin Mechanism of action: -Inotropic drug: make positive inotropic effectenhance cardiac muscle contractility as result of increased cytoplasmic calcium concentration and thus increase cardiac output -Improvement of depressed myocardial contractility so, increases cardiac output, promotes diuresis,

13. Drug Interactions Pharmacokinetics • Cholestyramine, colestipol, kaolin-pectin may reduce digoxin absorption. • Metoclopramide may reduce the absorption of digoxin tablets. • Cyclosporine may increase digoxin levels, due to reduced renal clearance. • Erythromycin, clarithromycin, and tetracyclines may increase digoxin (not capsule form) blood levels in a subset of patients. • Itraconazole may increase digoxin blood levels in some patients.

14. • Propylthiouracil (and methimazole) may increase digoxin blood levels by reducing thyroid hormone. • Rifampin reduces the intestinal absorption of digoxin, an effect that probably occurs by the induction of intestinal P- glycoprotein. It is likely that anticonvulsants • Sulfasalazine can decrease digoxin absorption to a variable degree. Pharmacodynamics • Amiloride may reduce the inotropic response to digoxin. • Levothyroxine (and other thyroid supplements) may decrease digoxin blood levels.

15. • Penicillamine has been associated with reductions in digoxin blood levels. • Amiodarone reduces renal and non renal clearance of digoxin and may have additive effects on heart rate. • Succinylcholine administration to patients on digoxin has been associated with an increased risk of arrhythmias • Verapamil , diltiazem increased serum digoxin concentrations.

16. DIURETICS Mechanism of action: Diuretics act by diminishing sodium-chloride reabsorption at different sites in the nephron ,thereby increasing urinary sodium chloride and water loss. The diuretics are generally divided into three major classes, 1.Loop diuretics act in the thick ascending limb of the loop of Henle. 2. Thiazide-type diuretics in the distal tubule and connecting segment (and perhaps the early cortical collecting tubule). 3. Potassium-sparing diuretics in the aldosterone-sensitive principal cells in the cortical collecting tubule. 4. Others: acetazolamide inhibits the activity of carbonic anhydrase, which plays an important role in proximal bicarbonate, sodium, and chloride reabsorption. As a result, this agent produces both NaCl and NaHCO3 loss.

17. Thiazide Diuretics Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in the management of edema and hypertension. In hypertension, thiazide diuretics are often used as initial therapy, either alone or in combination with other agents. Drug Interactions 1-HCTZ can have additive effects when administered with other antihypertensive drugs or diuretics. 2-HCTZ can interfere with the hypoglycemic effects of oral hypoglycemics, which could lead to a loss of diabetic control.

18. 3-HCTZ-induced electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) can predispose patients to digoxin toxicity, resulting in possibly fatal arrhythmias. 4- Administration of HCTZ to patients receiving nondepolarizing neuromuscular blockers can cause prolonged neuromuscular blockade due to HCTZ-induced hypokalemia. .

19. Loop Diuretics • Mechanism of Action • Loop diuretics act by inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle. They inhibit the Na/K/2Cl transport system in the luminal membrane, • resulting in: • 1.Reduction in sodium chloride reabsorption. • 2. loop diuretics increase magnesium and calcium excretion.

20. Drug Interactions 1-The bronchodilator theophylline may be able to reach higher blood levels when used in conjunction with furosemide. 2-Furosemide may lead to displacement of plasma protein binding warfarin and clofibrate 3-Loop diuretics reduce lithium renal clearance and can increase lithium serum concentrations 4-Loop diuretics can increase the risk of digitalis-induced cardiactoxicity 5-Furosemide may increase renal toxicity of cephalosporin antibiotics.

21. 4-Loop diuretics can increase the risk of digitalis-induced cardiactoxicity 5-Furosemide may increase renal toxicity of cephalosporin antibiotics.