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, , , )  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, Agmatine (α2 -Adrenergic receptor blockers)

17 Which of the following formulas are correct for

O a) Guanfacine O b) Prazosin N HO COOH O N N c) Minoxidil H3C CH H2N 3 H C N HO d) L-Methyldopa 3 O e) Hydralazine NH2 1 2 f) Milrinone

Cl H N N NH2 N NH2 N O NH O Cl NH2 3 4

O HN NH2 NC N NH

N CH3 5 6 N Seminar 4

19 In therapy of hyperlipoproteinemias the following are used:

• Bile acid sequestrants (cholestyramine, colestipol and colesevelam) • HMG-CoA reductase inhibitors (HMGRIs): atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, rosuvastatin, simvastatin • Ezetimide (inhibits the absorbtion of cholesterol from intestine) • Fibrates (bezafibrate, ciprofibrate, fenofibrate, gemfibrozil) • Niacin • Microsomal triglycerde transfer protein (MTP or MTTP) inhibitors: lomitapide • Monoclonal antibody: evolocumab/alirocumab

The succesfull use of these compounds depend on proper identification and classification of the hyperlipoproteinemia affecting the patient.

20 Therapeutic applications

• Bile acid sequestrants are indicated for the treatment of hypercholesterolemia in patients who do not adequately respond to dietary modifications. They may be used either alone or in combination with HMGRIs or niacin. These combinations often can achieve a 50% reduction in plasma LDL levels.

• All HMGRIs are approved for the treatment of primary hypercholesterolemia and familial combined hyperlipidemia or mixed dyslipidemia (Fredrickson type IIa and IIb) in patients who have not responded to diet, exercise and other pharmacologic methods. They may be used alone or in combination with bile acid sequestrants, ezetimide or niacin. Inhibitors of HMG-CoA reductase are contrindicated in pregnancy ans should not be used by nursing mothers. • Ezetimide is indicated as monotherapy or in combination with HMGRI for the reduction of elevated total cholesterol, LDL cholesterol and ApoB in patients with primary (heterozygous familial and nonfamilial) hypercholesterolemia, homozygous familial sitosterolemia or homozygous familial hypercholesterolemia. When used as monotherapy, ezetimide reduces LDL cholesterol by approximately 18%. When used in combination therapy with an HMGRI, LDL levels are reduced by 25% to 65% depending on the dose of the HMGRI. Ezetimide is also indicated for combination use with fenofibrate to treat hypercholesterolemia in patients with mixed hyperlipoproteinemia. 21 Therapeutic applications

• Fibrates are approved to treat hypertriglyceridemia and familial combined hyperlipidemia (Fredrickson types IIa, IIb, IV and V) in patients who are at risk of pancreatitis and have not responded to dietary adjustment or in patients who are at risk of CHD and have not responded to weight loss, dietary adjustments and other pharmacologic treatment.

They can be used either alone or in combination with niacin, bile acid sequestrants or HMGRIs.

Fibrates are not effective in the treatment of hypertriglyceridemia associated solely to elevated chylomicron levels (Fredrickson Type I).

• Nicotinic acid is approved for the treatment of hypercholesterolemia, hypertriglyceridemia and familial combined hyperlipidemia (Fredrickson types IIa, IIb, IV and V) in patients who have not responded to diet, exercise and other nonpharmacological methods

22 Therapeutic applications

Lomitapide (LOJUXTA, UE; JUXTAPID, US) Lomitapide is an MTTP inhibitor. MTTP is present in the liver and intestine. This protein is involved in the binding of chlesterol (VLDL and chylomicrons) and TG to LDL lipoproteins, which are then released into the bloodstream. Mechanism of action. Inhibition of MTTP by lomitapide causes a decrease in the concentration of ApoB containing VLDL lipoproteins and chylomicrons in hepatocytes and enterocytes and, consequently, a decrease in the concentration of TG and LDL cholesterol in the blood. Application. Treatment of adults with homozygous familial hypercholesterolemia in combination with low fat diets and other blood cholesterol lowering drugs. A low-fat diet reduces the risk of side effects (diarrhea). Family HLP is caused by a mutation in one of the genes that codes for a protein important in lipid metabolism (ApoB, LDLR, PCSK9) present in both alleles. This form of HLP is characterized by very high levels of LDL cholesterol in the blood, progressive arteriosclerosis and the occurrence of cardiovascular incidents in young patients. Lomitapide reduces total cholesterol, LDL cholesterol, ApoB, non-HDL cholesterol in patients with homozygous familial hypercholestrrolemia (HoFH). After 26 weeks of treatment, an average reduction of 40% in LDL cholesterol was achieved. Adverse reaction. Lomitapide increases the level of transaminases and causes the accumulation of fat in the liver. 23 Mab: Evolocumab (REPATHA, UE); Alirocumab (PRALUENT, US)

Mechanism of action. Evolocumab / alirocumab selectively inhibits PCSK9 (protein convertase subtilisin / kexin9). PCSK9 binds to LDL receptors, promoting their degradation, resulting in a reduction in the rate of LDL cholesterol elimination from plasma.

The binding of evolocumab / alirocumab to PCSK9 prevents the binding of PCSK9 to LDLR on the surface of hepatocytes and prevents their degradation, resulting in an increase in LDL receptor density and consequently a reduction in serum LDL cholesterol.

Application. • Primary hypercholesterolemia (family and non-familial heterozygous) and mixed dyslipidemia as a dietary supplement in adults - in combination with a statin or statin and other lipid-lowering drugs in patients in whom the LDL-cholesterol target cannot be achieved with the highest-tolerated statin or - as monotherapy or in combination with other lipid-lowering drugs in patients intolerant to statins, or in whom statins are used is contraindicated • homozygous familial hypercholesterolemia in combination with other lipid-lowering drugs in adults and adolescents at least 12 years of age.

24 Seminar 5

25 therapy

• Oral - derivatives (, ) - Indadiones (, ); rarely used because of their significant renal and hepatic toxicities.

They inhibit VKORC1 (vitamin K 2,3-epoxide reductase complex 1) and possibly vitamin K quinone reductase.

• -based anticoagulants - High molecular weight heparin (unfractionated heparin) - Low molecular weight heparin (ardeparin, dalteparin, enoxaparin, tinzaparin) - : it is a synthetic, highly sulfonated pentasacharide.

Fondaparinux is the first selective, indirect inhibitor of activated factor Xa via their activation of III, that is approved for the prophylaxis of DVT (deep vein thrombosis), which may occur in patients undergoing hip fracture sugery or hip or knee replacement sugery.

26 Direct inhibitors (DTIs). The DTIs bind and inactivate both free thrombin and thrombin bound to fibrin. Unlike heparin, DTIs bind directly and reversibly to the active site of thrombin and do not require an activated antithrombin III as a cofactor for their anticoagulant activity. They inhibit only the activity of thrombin, whereas heparin indirectly inhibits factors IIa (thrombin), IXa, Xa, XIa and XIIa. Five DTIs have been approved for clinical use in recent years • : it is now produced by recombinant technology. Hirudin is the lead compound for the design of DTIs. • and desirudin have been approved for the treatment of HIT (heparin-induced thrombocytopenia) and of HIT with thrombotic syndrome. They are bivalent DTIs that bind to both the active site and the exosite-1 of thrombin. • has been approved for use in patients with unstable angina undergoing percutaneus coronary interventioin. It is a rapid-onset, short-acting DTI that binds to both the active site and the exosite-1 of thrombin. • has been approved for the prophylaxis and treatment of thrombosis in patients with HIT. This peptidomimetic binds selectivly to the catalytic site of thrombin as a univalent competitive DTI. • etexilate, a nonpeptidomimetic prodrug, orally active DTI, has recently been approved for the prevention of stroke and blood clots in individuals with atrial fibrillation. The drug is available in UE and Canade, where it is approved for treatment of VTE (venous thromboembolism) in patients undergoing hip or knee replacement surgery and it is being studied for the treatment of DVT (deep vein thrombosis) and PE (pulmonary embolism).

27 Antiplatelet drugs

The major role of antiplatelet drugs is in the prevention of ischemic complications in patients with coronary diseases. These drugs also are effective in combination with moderate-intensity anticoagulants for patients with atrial fibrilation.

COX-1 inhibitors: acetylsalicylic acid (), , indobufen

Phosphodiesterase-3 (PDE3) inhibitors: ,

Platelet P2Y purinergic receptor: , (S)-,

Glycoprotein IIb/IIIa receptor antagonists: , ,

28 Thrombolytic drugs

Early application of reperfusion therapy with thrombolytic agents has significantly improved the outcomes of acute myocardial infarction and other conditions, such as PE (pulmonary embolism), DVT (deep vein thrombosis), arterial thrombosis, acute thrombosis of retinal vessel, extensive coronary embolii and pripheral vascular thromboembolism.

First-generation thrombolytic agents: (at present, it is rarely used), (currently, it is only approved for treatment of PE.

Second-generation thrombolytic agents: , prourokinase

Third-generation thrombolytic agents: rateplase,

29 Coagulants

• Vitamin K

• Protamine

• Thrombopoietin receptor agonists: romiplostim, eltrombopag (they have recently been approved for the short-term treatment of trombocytopenia in patients with chronic ITP (idiopathic thrombocytopenia purpura)

• Antifibrinolytic agents: aminocapronic acid and tranexamic acid (they completely inhibit plasminogen activation). These drugs find clinical utility in settings such as prevention of rebleeding in intracranial hemorrhages, as adjunctive therapy in hemophilia and in treatment of bleeding associated with fibrinolytic therapy. Aprotinin is a inhibitor that blocks kallikrein and plasmin and provides some protection to platelets from mechanical injury.

30