CVS Part1 PDF

CVS part1 Prepared by Abdallah E. Abdallah, PhD Associate Professor of Pharmaceutical Chemistry Positive inotropic drugs Cardiac glycosides (Congestive heart failure treatment) Hydroxyl groups can be attached to C12...

CVS part1 Prepared by Abdallah E. Abdallah, PhD Associate Professor of Pharmaceutical Chemistry Positive inotropic drugs Cardiac glycosides (Congestive heart failure treatment) Hydroxyl groups can be attached to C12 12 and C16 according to 17 R Lacton ring the type of a glycon H 13 14 16 10 H OH 3 HO O H O O O The sugar moiety links via a glycosidic linkage to 3-OH In of the aglycone In Bufadienolides Cardenolides (animal origin) (plant origin) Toxic, not used medically  O O O OH O O O H H H OH H OH H OH H OH HO HO H HO H H Digitoxigenin Gitoxigenin Digoxigenin  O Site of metabolism Digoxin Increase hydrophilicty and hence renal clearance OH O About 80% oral bioavailability Relatively short duration of action Half life: 1-2 days H Excreted unchanged in the urine H OH OH O O O HO O O H O OH OH O Digoxin O H Digitoxin H OH OH About 98% oral bioavailability O O O Half life: 5-7 days HO O O H Metabolized by the liver to be O excreted OH OH Digitoxin The sugar moiety is polysaccahride of D-digitoxose with beta-1,4-glycosidic linkage  O Improve oral OH O bioavailability, H leading to rapid and complete absorption, OH H OH then O-delkylation O O O O O H O occurs inside the O OH OH body, however, about half of the given dose is excreted unchanged Metildigoxin in the urine Mechanism of action The cardiac glycosides inhibit the Na+/K+-ATPase pump, leading to an increase in the intracellular Na+ concentration. So Na+/Ca2+ exchange is altered to increase intracellular Ca2+ concentrations and as a result, positive inotropic effect is obtained. Potassium level is crucial for therapeutic and toxic effects of cardiac glycosides. Non glycoside positive inotropic agents Phosphodiesterase 3 (PDE3) inhibitors PDE3 inhibitors give H2N positive inotropic effect NH2 N N N N N N PDE N N O HO O HO OH O OH O P O P HO O OH O AMP cAMP Certain calcium channels and storage sites for calcium must be activated by cAMP-dependant protein kianases. As a result, cAMP plays indirect role in increasing levels itracellular calcium and hence cardiac contractility  Bipyridine derivatives Site of metabolism H H O N O N H2N N N N 5-amino-[3,4'-bipyridin]-6(1H)-one 2-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-5-carbonitrile Amrinone (Inamrinone) Milrinone drug of choice Side effect higher selectivity Thrombocytopenis less toxic shorter duration Selective inhibitors for PDE3, leading to positive inotropic and vasoldilatation. They are used intravenous for short term management of CHF cases not respond to digitalis hese agents are not used for long term therapy of chronic CHF. ong term use of these agents leads to increasing mortality in heart failure patien Non glycoside positive inotropic agents Beta agonist e.g. Dobutamine Drugs for treatment of angina pectoris The drugs used for treatment of angina pectoris can be classified to 1- organic nitrates 2- beta blockers 3- calcium channel blockers  Organic nitrates They are esters of alcohols (simple or polyols) with nitric acid. O + N O O O - O H O N+ O N+ - O H O O- N O - - O O O - O +O O +O H O N N O N+ O H O O O OH Amyl nitrite Glyceryl trinitrate Isosorbid dinitrate Isosorbid mononitrate (Nitroglycerin) Low moleular weight esters have low melting point and easily volatile, however they are highly lipophilic giving good penetration and rapid action in acute attacks of angina.  Organic nitrates They give NO which is responsible for vasodilatation of coronary artery. They are administrated by inhalation, as sublingual, chewable tablet, sustained release tablets, capsules, transdermal patches, ointments, and by infusion. For treatment of both chronic and acute attacks of angina pectoris. Also for prevention.  O N+ O O O - O H O N+ O N+ - O H O O- N O - - O O O - O +O O +O H O N N O N+ O H O O O OH Amyl nitrite Glyceryl trinitrate Isosorbid dinitrate Isosorbid mononitrate (Nitroglycerin) inhalation sublingual oral sublingual onset about 20 seconds onset about 3 minutes onset about 2 minutes duration one minute duration 4-6 hours duration half an hour oral spray dermal patch oral sustained release Nicorandil Molecualr hybridization Vasodilator nicotinamide Vasodilator organic nitrate O O N NO2 H N Nicorndil 2-(Nicotinamido)ethyl nitrate Dual effect leading to vasodilatation of coronary artery and peripheral vessels Beta blocker Limited to treatment of exertion induced angina. Example: Propranolol, atenolol, and metoprolol Often used in combination with nitrate or calcium channel blockers Calcium channel blockers It was proven that inhibition the influx of calcium ions into the myocardium is advantageous in preventing angina. They are classified according to chemical structure into Dihydropyridine derivatives: Benzothiazepine derivatives Aralkylamine derivatives  Electron withdrawing group at ortho position Cl O O O2N O2N N O O O O O N O O H O O O N H N H2N H Nifedipine Amlodipine Nicardipine oral bioavailability 60% 75% 35% 2-7 h according to formulation 35-50 h 2-4 h Half life Dihydropyridine based Ca+2 channel blockers Penta substituted dihyropyridine, to position 4, substituted phenyl ring is attached in a way makes the two aromatic rings are not in the same plane but perpendicular to each other as the free rotation is restricted due to steric hinderence. Ester functionality, which means very good absorption with low oral bioavailability due to extensive first pass metabolism.  Cl Dichlorophenyl perpendicular on the pyridine ring Felodipine O Cl O Ester O O N H Felodipine It is more selective for vascular muscle than cardiac muscle. Effective vasodilator Used for angina and hypertention. Oral bioavailability: 10-25% (drug interaction with CYP3A4 inhibitors available as sustained release formulation Half life : 10-18 h 3D image of nifedipine Nifedipine Amlodipine Nicardipine  Benzothiazepine derivatives Metabolized by esterase,the deacetylated metabolite is still active (about half potency of the parent drug) O N-delkylation by CYP3A4 O HN O Cl N O-delkylation by CYP2D6 S O Diltiazem hydrochloride Chiral copmpound, dextrorotatory isomer is more potent than levorotatory. absorbed well, but experienced extensive first pass metabolism, oral bioavailability is about 40%. Drug drug interaction with compounds metabolized by either CYP3A4 or CYP2D6 Diltiazem is CYP3A4 inhibitor. Aralkylamine derivatives O O N O NH Cl O Verapamil hydrochloride Chiral compound  O O O O N N N-demethylation H O N O N CYP3A4 O O Verapamil Norverapamil 30% oral bioavailability has 20% of verapamil potency Drug drug interaction with CYP3A4 inhibitors CYP2D6 O-demethylation coadminstration leads to increase verapamil toxicity O O N HO N O inactive metabolite  Which calcium channel blockers are highly affected by CYP3A4 inhibitors such as grape fruit and some drugs as ketoconazole? Why? Other coronary vasodilators used for angina HO OH N O N N N O N O N N N O N HO OH Papaverine Dipyridamole Benzylisoquinoline alkaloid found in PDE5 &3 inhibitor causes coronary opium causes generalized nonspecific dilataion and prevent platelet aggregation. arteriodilatation Other calcium channel blockers (dihydropyridine derivatives) O NO2 NO2 O O O O O O O O N N H H Nisoldipine Nimodipine Has greater potency on It specifically dilates the cerebral blood vascular smooth muscle vessels more effectively than other than on cardiac muscle candidtaes of the same group. This drug used for hypertention is mainly indicated for vasospam following subarachnoid hemorrhage Antiarrhythmic drugs They are classified into four classes Class I: Sodium channel blockers Class II: Beta blockers Class III: Potassium channel blockers Class IV: Calcium channel blockers Class I: Sodium channel blockers It is subdivided to Class IA: Intermediate rate of dissociation from sodium channel. Class IB: Rapid rate of dissociation from sodium channel Class IC: slow rate of dissociation from sodium channel Class IA N OH O O N N H N H2N quinidine procainamide  C3 quinuclidine ring Tertiary basic nitrogen pKa is about 11 N C8 N C4 OH C9 OH O O N N quinoline less basic nitrogen Quinine Quinidine quinidine sulfate quinidine gluconate (suitable for injection) both can be used oral bioavilability is about 80% metabolized by CYP3A4 in the liver Absolute configuration Absolute configuration 3R:4S:8S:9R 3R:4S:8R:9S Effects of these two diasteriomers on the cardiac muscle is widely different.  O O lead modification N N N O H Bioisoteric replacement H2N H2N Procainamide procaine More stable chemically and metabolically Discovered first to show short Longer duration of action antiarrhythmic activity Oral effective O O N N N-acetyltransferase O N N H H N H2N genetic factor H Procainamide N-acetylProcainamide active metabolite one third of the parent drug activity Class IB O N H N O NH NH O Lidocaine Phenytoin  O NH O N extensive first pass metabolism NH NH Lidocaine Active metabolite but rapidly hydrolyzed Drug of choice for emergency treatment of ventricular Amidase arrhythmia due to its intravenous infusion rapid effect. Also this effect disappears rapidly after infusion termination + O NH NH2 HO so lidocaine is not effective orally in treatment of arrhythmia Class IC O O N H OH Propafenone Local anesthetic and antiarrhythmic agent. It can be used oral or intravenous Can you expect another pharmacological activity to propafenone?  O Aryloxypropanolamine a pharmacophore for O N beta blocking properties H OH Propafenone Class II antiarrhythmic drugs (beta blockers) OH H N  HN O S O Sotalol It contains a chiral center and is marketed as them racemic mixture. Because of its enantiomers, its mechanism of action spans two of the antiarrhythmic drug classes. The l(-) enantiomer has both -blocking (class II) and potassium channel-blocking (class III) activities. The d(+) enantiomer has class III properties similar to those of the (-) isomer, but its affinity for the -adrenergic receptor is 30 to 60 times lower. Class II antiarrhythmic drugs (beta blockers) O N H OH Propranolol  OH Class III: H N Potassium methansulfonamide group HN O S O Sotalol channel The toxicity on thyroid gland and other organ is attributed to the two iodine atoms. blockers O Reduce lipophilicity and hence reduce toxicity S NH O I O O O N O I O N O Amiodarone Dronedarone Approved for treatment of life threating structurally similar to amiodarone in ventricular arrhythmias that are resistant to that it is a benzofuran based molecule. other drugs. but it carries no iodine, instead it this refelcts its severe toxicity that make it contains methansulfonamide moiety. the last choice. also it contains relatively bulky alkyl half life several weeks groups attached to the nitrogen atom. less lipophilic than amiodarone. half life: 24 hour Class IV: Calcium channel blocker O O O HN O Cl N O N S O NH O Cl O Diltiazem hydrochloride Verapamil hydrochloride