Which of the following formulas are correct for active dihydropyridine derivatives H H H CH3 H C N CH N 3 3 H3C N CH3 H3C CH3 H3C N CH3 ROOC COOR ROOC COOR ROC COR ROOC COOR NO NO2 2 NO2 NO2 a b c d The correct answer is: 1. all ; 2. b and d; 3. c and d; 4. a; 5. b 1 Cardiac glycosides inhibit the membrane-bound Na+/K+-ATPase pump responsible for sodium/potasium exchange. Nonglycosides positive inotropic drugs such as milrinone are PDE3 inhibitors. Dopaminergic and adrenergic agonists stimulate / inhibit the synthesis of cAMP. 2 Milrinone and inamrinone They are the bipiridine/ piridine derivatives. They are selective/non selective PDE3 inhibitors. They are positive inotropes and vasadilatators indicated for the short-term intravenous management of CHF in patients who have not responded adequately to digitalis, diuretics and/or vasodilatators. They are not used as a monotherapy, they are used in conjunction with other treatment modalities (diuretics, β-blockers, ACE –I or cardiac glycosides. Milrinone is 10-fold more potent than inamrinone. The most common and severe side effects of PDE3 inhibitors are ventricular arrhytmias. 3 Drugs for the treatment of angina pectoris - Organic nitrates; they are pharmacologic sources of nitric oxide (NO) for the body. The examples: glyceryl trinitrate, amyl nitrate, pentaerythritol tetranitrate, isosorbide dinitrate. Nicorandil structurally is a hybrid between organic nitrates and potassium channel activators, it combines the smooth muscle-relaxing property of both nitrates and nicotinamide with its ability to increase potassium ion conductance. Molsidomine is an oral NO donor vasodilatator. It is enzymatically metabolized by liver esterases to its active metabolite, linsodimine, which is spontaneously converted in the blood into its nitroso metabolite. NO acts as a cellular messenger, leading to activation of soluble guanylate cyclase to release cGMP and vasodilatation. - Calcium channel blockers: dihydropiridines – nifedipine, amlodipine, nicardipine; benzothiazepine derivative – diltiazem; aryl amine derivative – verapamil; benzazepinone derivative – zatebradine, diaminopropanol ether – bepridil. - β1-Blockers: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, nebivolol. They inhibit receptors (bronchial and vascular) at higher doses. 2 4 Drugs for the treatment of cardiac arrhythmia Class IA: Na+ channel blockade (quinidine, procainamide, disopyramide) Intermediate rate of dissociation from sodium channels; Slows phase o depolarization; Prolongs action potential duration; Slows conduction Class IB: Na+ channel blockade (lidocaine, mexiletine, phenytoin, tocainide) Rapid rate of dissociation from sodium channels; Shortens phase 3 repolarization; Shortens action potential duration Class IC: Na+ channel blockade (flecainide, encainide propafenone, moricizine) Slows rate of dissociation from sodium channels; Markedly slows phase o depolarization; Slows conduction Class II: Blocks sympathetic stimulation of β1-adrenergic receptors: β1-blockers Slows phase 4 depolarization; Slows firing of SA node and conduction through AV node, prolonging repolarization Class III: K+ channel blockade (block delayed rectifirt current): amiodarone, dronedarone, sotalol, bretylium Prolongs phase 3 repolarization; Prolongs duration of action potential , which prolongs refractory period Class IV: Ca2+ channel blockade: verapamil, diltiazem Slows phase 4 depolarization; Slows firing of SA node and conduction through AV node, prolonging repolarization of AV node 5 Seminar 2 6 ACE inhibitors (ACE-I) Currently, there are 11 ACE-I approved for therapeutic use in the US. These compound can be subclassified into three groups base on their chemical composition: * sulfhydryl- containing inhibitors (captopril) * dicarboxylate-containing inhibitors (benazepril, enalapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, trandolapril) * phosphonate-containing inhibitors (fosinopril) 7 ACE-I have been designated as first-line agents for the treatment of hypertension and are effective for a variety of cardiovascular disorders. They are especially usefull in treating patients with hypertension who also suffer from heart failure, left ventricular dysfunction or diabetes. They can be used either individually or with other classes of compounds. Combination products that include an ACE-I ACE-I/Diuretic: benazepril/ hydrochlorothiazide; captopril/ hydrochlorothiazide; enalapril/ hydrochlorothiazide; fosinopril/ hydrochlorothiazide; lisinopril/ hydrochlorothiazide; moexipril/ hydrochlorothiazide; quinapril/ hydrochlorothiazide; ACE-I/Calcium channel blocker: benazepril/amlodipine; enalapril/diltiazem; enalapril/felodipine; trandolapril/ verapamil 8 Angiotensin II receptors blockers (ARBs) All ARBs are currently approved for the treatment of hypertension and, along with ACE inhibitors, diuretics, β-blockers and calcium channel blockers have been designated as first-line agents either alone or in combination with other antihypertensive agents. A numer of other indications have also been approved. • Irbesartan and losartan – for the treatment of nephropathy in type 2 diabetes. • Losartan – for stroke prevention in hypertensive patients with left ventricular hypertrophy. • Candesartan and valsartan – for the treatment of heart failure. • Telmisartan – to reduce the risk of MI (myocardial infarction) and stroke. • Valsartan – to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following MI. 9 Combination products that include an ARB ARB/Diuretic: candesartan/ hydrochlorothiazide; eprosartan/ hydrochlorothiazide; irbesartan/ hydrochlorothiazide; losartan/ hydrochlorothiazide; olmesartan/ hydrochlorothiazide; telmisartan/ hydrochlorothiazide; valsartan/ hydrochlorothiazide; ARB/Calcium channel bloker: olmesartan/amlodipine; telmisartan/amlodipine; valsartan/amlodipine ARB/ Diuretic /Calcium channel bloker: olmesartan/ hydrochlorothiazide /amlodipine; valsartan/ hydrochlorothiazide /amlodipine ARB/ Renin Inhibitor: valsartan/aliskiren Aliskiren directly inhibits renin, thereby preventing the formation of angiotensin I and angiotensin II. 10 There are two potential advantages of inhibiting renin as compared to inhibiting ACE or using an ARB. Inhibition of the renin-angiotensin pathway through any of these mechanisms has been shown to cause a compensatory increase in renin concentrations; however, unlike ACE inhibitors and ARBs, the ability of renin inhibitors to directly bind to the enzyme blocks increase in plasma renin activity seen with ACE inhibitors and ARBs. Additionally, alternate pathways such as the chymostatin-sensitive pathway present in the heart, can convert angiotensin I to angiotensin II. While this alternate pathway could affect the efficacy of ACE inhibitors, it would not alter the effects of direct renin inhibition. Aliskiren is approved for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents. Aliskiren is available alone or in combination with hydrochlorthiazide (a diuretic), amlodipine (a calcium channel blocker) or valsartan (an ARB). 11 Calcium channel blockers – Chemical classification • 1,4-Dihydropyridines: amlodipine, clevidipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine • Phenylalkylamines: verapamil • Benzothiazepines: diltiazem • Diaminopropanol ethers: bepridil (bepridil was indicated for the oral treatment of chronic stable angina pectoris; however, its manufacturer voluntarily removed it from the US market, prmary because of its ability to cause torsades de pointes). 12 Calcium channel blockers – Approved indication 1,4-Dihydropyridines • Amlodipine: angina pectoris (V = vasospastic; CS = chronic stable), hypertension • Clevidipine: hypertension • Felodipine: hypertension • Isradipine: hypertension • Nicardipine: angina pectoris (CS), hypertension • Nifedipine: angina pectoris (V, CS), hypertension • Nimodipine: subarachnoid hemorrhage • Nisoldipine: hypertension Phenylalkylamines • Verapamil: angina pectoris (V, CS, U = unstable), hypertension, atrial fibrilation/flutter, PVST (paroxysmal supraventricular tachycardia) Benzothiazepine • Diltiazem: angina pectoris (V, CS), hypertension, atrial fibrilation/flutter, PVST 13 Seminar 3 14 Pulmonary arterial hypertension (PAH) PAH is defined as a group of diseases characterized by a progressive increase of pulmonary vascular resistance, leading to right ventricular failure. Drugs used to treat PAH Thiazide and loop diuretics Vasodilators Calcium channel blockers Prostaglandins (Epoprostenol, Treprostinil, Beraprost, Iloprost) Endothelin receptor antagonists (Bosentan, Ambrisentan, Sitaxentan) Nitrodilators PDE5 inhibitors (Sildenafil) The endothelin receptor antagonist bosentan is recommended as first-line treatment patients with PAH. Bosentan is teratogenic in animal models and therefore can cause birth defects and is contrindicated in pregnancy. 15 Choose the correct answer. α2 -Adrenergic receptors are blocked by: a) Doxazozin, Prazosin, Terazosin, Alfuzosin b) Minoxidil c) Milrinone, Inamrinone d) Sildenafil e) Clonidine, Moxonidine, Rilmenidine, Agmatine 16 Choose the correct answer. α2 -Adrenergic receptors are blocked by: a) Doxazozin, Prazosin, Terazosin, Alfuzosin (α1 -Adrenergic receptor blockers) b) Minoxidil (Potassium channel oppener) c) Milrinone, Inamrinone (PDE3 inhibitors) d) Sildenafil (PDE5 inhibitors) e) Clonidine, Moxonidine, Rilmenidine,