Which of the following formulas are correct for active dihydropyridine derivatives

HCH3NH3C

COORROOC

NO2

HCH3NH3C

COORROOC

NO2

HCH3NH3C

CORROC

NO2

CH3

CH3NH3C

COORROOC

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 2 receptors (bronchial and vascular) at higher doses.4

5

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-blockersSlows 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, bretyliumProlongs phase 3 repolarization; Prolongs duration of action potential , which prolongs refractory period

Class IV: Ca2+ channel blockade: verapamil, diltiazemSlows phase 4 depolarization; Slows firing of SA node and conduction through AV node, prolonging repolarization of AV node

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

8

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

9

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.

10

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.

11

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).

Calcium channel blockers – Chemical classification

12

• 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).

13

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

14

Seminar 3

15

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.

16

Choose the correct answer.

α2 -Adrenergic receptors are blocked by:

a) Doxazozin, Prazosin, Terazosin, Alfuzosinb) Minoxidilc) Milrinone, Inamrinoned) Sildenafile) Clonidine, Moxonidine, Rilmenidine, Agmatine

17

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)

N

N

N

NO

OH3C

OH3C

NH2

O

HO

HO

COOH

H2NCH3

Which of the following formulas are correct for

a) Guanfacine

b) Prazosin

c) Minoxidil

d) L-Methyldopa

e) Hydralazine

f) Milrinone

Cl

ClO

N NH2

NH

H

1 2

3

N

NN

NH2

NH2

O

4

N

N

N NH2H

5

N

NNC

CH3

O

H

6

Seminar 4

19

20

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.

21

Therapeutic applications

• Bile acid sequestrants are indicated for the treatment of hypercholesterolemia in patients who do notadequately respond to dietary modifications. They may be used either alone or in combination withHMGRIs 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 combinedhyperlipidemia or mixed dyslipidemia (Fredrickson type IIa and IIb) in patients who have not respondedto diet, exercise and other pharmacologic methods. They may be used alone or in combination with bileacid sequestrants, ezetimide or niacin.Inhibitors of HMG-CoA reductase are contrindicated in pregnancy ans should not be used by nursingmothers.

• Ezetimide is indicated as monotherapy or in combination with HMGRI for the reduction of elevated totalcholesterol, 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 onthe dose of the HMGRI.Ezetimide is also indicated for combination use with fenofibrate to treat hypercholesterolemia in patientswith mixed hyperlipoproteinemia.

22

• Fibrates are approved to treat hypertriglyceridemia and familial combined hyperlipidemia (Fredricksontypes IIa, IIb, IV and V) in patients who are at risk of pancreatitis and have not responded to dietaryadjustment or in patients who are at risk of CHD and have not responded to weight loss, dietaryadjustments 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 elevatedchylomicron levels (Fredrickson Type I).

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

Therapeutic applications

23

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.

24

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.