Text books

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1. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, J.N.Delgado and W.A.Remers eds., 11th edition, Lippincott-Raven, Philadelphia, (2004).

2. Lemeke, T. L. and Williams, D. A., Foye’s Principle of Medicinal Chemistry, Lippincott Williams & Wilkins, Philadelphia, PA., 6th Edition, (2008).)

Cardiovascular DrugsCardiovascular Drugsare those ofCardiovascular drugs: are those used for prevention or treatment of cardiovascular diseases diseases

Cardiovascular drugs: are grouped according to their therapeutic application into the following categories:

1- Antianginal Drugs - Coronary Vasodilators 2- Antihypertensive Agents 3- Antiarrhythmic Agents 4- Drugs used in Congestive Heart Failure 5- Anti-hyperlipidemic Agents 6- Anticoagulants

2

1. Antianginal Drugs - Coronary Vasodilators

Angina pectoris is the disease of the coronary artery, the principal supplier of blood carrying oxygen from

the left ventricle to all heart tissues including the ventricles themselves.

Angina is the principal symptom of an ischemic heart. It is characterized by a sudden, severe pain originating in the chest, radiating through the left shoulder and running down the arm. The symptom has been described since 1772

Anti-anginal drugs mainly alleviate and prevent anginal attacks by dilating the coronary artery. Such action replenishes the left ventricle tissues of fresh blood carrying oxygen and relieves anginal pain.

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• Three classes of drugs are found to be efficient in this regard:

1.1. Organic nitrates.1.2. Calcium channels blockers. 1.3. β-Adrenergic blockers.

1.1. Organic Nitrates (Nitrovasodilators)

They are esters of simple organic alcohols or polyols with nitric acid. This class was developed after the anti-anginal effect of amyl nitrite was first observed in 1857. They include:

Amyl nitrite: Mixture of isomeric amyl nitrite but principally isoamyl nitrite

Nitroglycerin: Glyceryl Trinitrate

Erythrityl tetranitrate  

Isosorbide dinitrate: 1,4:3,6-Dianhydro-D-glucitol dinitrate   

Pentaerythritol tetranitrate: 2,2-bis(hydroxymethyl)-1,3-propandiol tetranitrate

4

Except for amyl nitrite, all are nitrate esters (R-ONO2). 5

StructureStructure

Nitrate Esters

RO H + OH N O RO N O + H2O

alcohol nitrous acid alkyl nitrite water

RO H + OH N

O

O+ H2O

alcohol nitric acid alkyl nitrate water

+

_

RO N

O

O

+

_

• Some nitrate esters are wrongly named, e.g., amylnitrite is actually isoamylnitrite, nitroglycerin is not a nitro compound

• Nitrate esters are susceptible to hydrolysis!

Shelf life is a concern. 6

The chemistry of these molecule is easily predicted based on the structures presented above as follow:

i. They are small molecules ii. They all are non-polar.iii. They are ester derivatives with susceptible C-O

bond. This leads to ease of hydrolysis. Thus moisture should be avoided to minimize the loss in principal active component.

iv. They are nitrate esters, therefore these compounds may be explosive, especially in pure concentrated form. Thus these compounds should be packaged in variety of diluents with excipients .

v. The number of nitrate ester groups may vary from two to more than four, however, there is no direct relationship between them. number of nitrate groups and the level of activity.

vi. The higher the lipophilicity of the drug, the greater the potency and the longer the vasodilatory response. 7

vii. The structure of the organic nitrates determines the onset and duration of action as shown in the following table:

8

Pharmacokinetics of Nitrate EstersPharmacokinetics of Nitrate Esters

33020Pentaerythritol tetranitrate

18015Erythrityl tetranitrate

Active603Isosorbide dinitrate

302Nitroglycerin

10.25Amyl nitrite

MetabolitesDuration of Action (min)Onset

(min)

• Nitrite esters act fast! Think about the size of these molecules.

• They are rapidly metabolized in the liver (glutathione-nitrate reductase). Yet, can be used in oral prophylactic therapy.

• Number of nitrate groups does not linearly correspond to potency

• Nitrate esters and possibility of explosion!

• Nitrovasodilators decrease the blood pressure of patients!!

9

10

Synthesis of isosorbide dinitrate:

CHO

OHH

HHO

OHH

OHH

CH2OH

CH2OH

OHH

HHO

OHH

OHH

CH2OH

O

O

OH

H

OH

H

O

O

ONO2

H

ONO2

HH2/pt H2SO4

H2SO4

HNO3

1,4:3,6-Dianhydro-D-glucitol dinitrate

Metabolism

Organic nitrates are metabolized rapidly after oral administration, they generate nitric oxide (NO) in situ that forms the basis of their pharmacological action. The mechanism of release of NO from nitrites and nitrates is not clear.

Mechanism of Action

Nitric oxide has been shown to be an important messenger in many signal transduction processes.  This free radical gas is naturally produced endogenously from arginine in a complete reaction that is catalyzed by nitric oxide synthetase (NOS).

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1.2. Calcium Channel BlockersCalcium channel blockers available for anti-anginal action are heterogeneous group of compounds. On the basis of structural features three main subgroups can be differentiated:

1.2.1. Phenylalkylamines Verapamil and Bepridil

1.2.2. Dihydropyridines Nifedipine and others

1.2.3. Benzothiazipines Diltiazem

1.2.1. Phenylalkylamines

They are structurally characterized by central basic nitrogen to which alkyl and aralkyl groups are attached. Representative example for this class is Bepridil and Verapamil

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N CH3

CH3

CH3

OMeMeO

CN

MeO

MeO

Verapamil

Bepridil

N

N O

Ph CH3

CH3

NOR: ~20% Active

O-deMegives inactivespecies

– VerapamilVerapamil is a synthetic compound possessing structural similarity to papaverine. It is a chiral compound where the (+)-isomer is more potent than the (-)-isomer as a calcium channel blocker.

– The essential structural features of this class of drugs are:

i. The benzene ring.ii. A 3ry amino nitrogen, which is almost completely

charged at physiological pH.iii. The isopropyl group is not essential for activity.14

1.2.2. The 1,4-dihydropyridines.

The 1,4-dihydropyrines form a rather extensive group of calcium channel antagonists. They are possessing the following general structure:

N

R1

R2

H3CO2C

H3C

CO2R3

CH2R4

H

H

R1R2R3R4Generic Name

HNO2

H

ClH

NO2

C2H5

CH2CH2N(CH3)CH2Ph

CH3

OCH2CH2NH2

HH

AmlodipineNicardipineNifedipine

Nifedipine: Dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl) pyridine-3,5-dicarboxylate.15

Synthesis:

It is synthesized by condensation of 2 mol of methylacetoacetate with 1 mol each of ammonia and 2-nitrobenzaldehyde.

O

O O

O

O O

O H

NO2

NH3 +

+

HN

OO

HOONO2

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The structural features essential for activity are :

1. The 1,4-dihydropyridine ring2. The 2ry nitrogen in the ring which remains uncharged at

physiological pH.3. A bulky substituent (almost phenyl) in the 4 position of

dihydropyridine.4. Nitro group and ester moieties are not essential.

N

R'

COOR''

CH2R'''

H

CH3

H3COOC

X

R' R'' R''' XNifedipine NO2 CH3 H HAmlodipine Cl C2H5 O-)CH2(2-NH2 XNicardipine H -)CH2(2-N)CH3()CH2-Ph( H NO2

Extensive hydroxylation to inactive species

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1.2.3. Benzothiazepines

Diltiazem

The 3ry basic nitrogen is essential for activity. N-demethyl derivative as well as quaternization products are either less active or not active compared to the parent compound.

S

N

O

O

N CH3

CH3

O

CH3

HH

Diltiazem

Des-Acgives

~50%

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Protein Binding of Calcium Channel BlockersProtein Binding of Calcium Channel Blockers

24 h>90%Bepridil

6 h iv~80%Diltiazem

phenyl hydroxylations, inactive24 h>95%Amlodipine

MetabolitesDuration of ActionProtein Binding

8 h90%Verapamil

desacetyl derivative, ~ 50 % active

Extensive inactive metabolites

N-demethyl derivative, ~ 20 % active

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Biochemical Mechanism of ActionBiochemical Mechanism of Action

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Metabolism

First-pass metabolism occurs extensively, especially for verapamil, leading to low bioavailability. The primary metabolites are N-demethylated and deacetylated products. These metabolites are inactive.

The duration of action of these calcium channel blockers ranges from 4 - 8 h. However, amlodipine and Bipridil is the only agent that is active over a 24 h range.

Why?

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PropranololPropranolol

Nonselective Nonselective BlockersBlockers

11--Isopropylamino-3-(1-naphthyloxy)-propan-2-olIsopropylamino-3-(1-naphthyloxy)-propan-2-ol

– It is the prototype non-selective competitive antagonist at both 1 and 2 receptors.

– Relatively high lipid solubility allows distribution to the CNS (some drowsiness)

O

NH

HO

1.3. -Adrenergic blockers

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OH

O

Cl+

O

O

NH2

Propranolol

Naphthol Epichlorohydrine

Synthesis:

Major Metabolites:

OH

O

NH

HO

O

COOHHO

4-Hydroxy propranolol Naphthoxylactic acid(Potant -blocker)23

Nonselective Nonselective antagonistsantagonists

11-Selective -Selective antagonistsantagonists

PropranololPropranololMetoprololMetoprolol

NadololNadololAtenololAtenolol

TimololTimololEsmololEsmolol

PindololPindololAcebutalolAcebutalol

LabetololLabetolol

CarvedilolCarvedilol24

Selective Selective 11 Blockers Blockers (CardioselectiveCardioselective))

AtenololAtenololNH2

O NH

OH

O

– It is the prototype Selective 1 Blocker

– Its half-life is twice that of propranolol– It is used in hypertension, angina pectoris associated with coronary atherosclerosis and acute myocardial infarction.

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• Atenolol also differs from propranolol in that only a small amount (6%-16%) is bound to proteins in the plasma

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EsmololEsmolol

O NH

OH

O

O

– Very rapid onset & short duration of action (WHY?)–1-selective– Used as IV infusion for pri-operative tachycardia and hypertension, arrhythmias– Used in electroconvulsive therapy

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Agents Used to Treat Hypertension:

2. Antihypertensive Agents

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What is Hypertension?

• A serious disease affecting 1 in 3 adults in the United States

• More commonly known as High Blood Pressure

• Occurs when blood is forced through the heart and arteries under excessive pressure

http://www.beauregard.org/bldpress.htm

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What is Blood Pressure?• Blood pressure

readings have two components:– Systolic pressure

• Heart muscles contracted

– Diastolic pressure• Heart muscles relaxed

• With hypertension:– Arteries narrow thereby

increasing pressure– Fluid volume in arteries

increases which can increase pressure

http://www.everybody.co.nz/page-3f71418a-d1e1-43d7-9ac0-fdcb4a79a3e3.aspx30

Classifying Blood Pressure by Readings

Blood Pressure CategorySystolic (mm Hg)

Diastolic (mm Hg)

Normal<120<80

Prehypertension120-13980-89

High: Stage 1140-15990-99

High: Stage 2160 +100 +

• High Blood Pressure = Elevated systolic pressure and/or elevated diastolic pressure

• The highest reading dictates classification

• Elevated readings must occur on multiple occasions to be diagnosed

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Classifying Hypertension by Causes

• Primary or Essential Hypertension– 90-95% of hypertension cases– Causes are unknown, but linked to

risk factors

• Secondary Hypertension– 5-10% of hypertension cases– Caused by disease states

• Some causes include: kidney disease, atherosclerosis, hormone imbalances, pregnancy, and some medications

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Risk Factors

• Controllable– Alcohol use– Excess sodium– Lack of exercise– Stress– Smoking– Obesity due to

inactivity/overeating

– Medications

• Uncontrollable– Age– Race– Gender– Family history– Medical condition– Obesity due to

medical condition– Medications

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Who is Affected by Hypertension?

Race and GenderPrevalen

ce

White Female19.3%

White Male 24.4%

African-American Female34.2%

African-American Male 35.0%

Hispanic Female22.0%

Hispanic Male 25.2%

Race and GenderDeath Rate

White Males14.4%

African-American Males49.6%

White Females13.7%

African-American Females40.5%

• Affects 1 billion people worldwide• Affects 65 million Americans age 6+• 30% of people with hypertension

don’t know they have it

(Death rates per 100,000 people)

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Why Should I Care?

• Hypertension can elevate your risk for:– Stroke

• Blood clots• Bleeding

– Heart attacks– Heart enlargement– Heart failure– Kidney failure– Atherosclerosis

http://member.rivernet.com.au/balehirs/drHt2.jpg35

Treatment Options for Hypertension

• Normal blood pressure cases:– Prevent hypertension

• Reduction of controllable risk factors

• Prehypertension cases:– Reduction of controllable risk factors– Careful monitoring

• Stage 1 & Stage 2 hypertension cases:– Reduction of controllable risk factors– Close monitoring– Drug therapies

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Available Drug Therapies

• Drug therapies available:– ACE (angiotensin-converting enzyme)

inhibitors– Alpha blockers– Alpha-2-agonists– Angiotensin II receptor blockers– Beta blockers– Calcium channel blockers– Combined alpha and beta blockers– Combined ACE inhibitors and diuretics– Diuretics

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2. Antihypertensive Agents

The available antihypertensive drugs can be classified on the basis of their mechanism of action as follows:

2.1.1. Centrally acting agents.2.1.2. Agents with both central and peripheral actions.2.1.3. Ganglionic blocking agents.2.1.4. β-adrenergic blocking agents.2.1.5. α-adrenergic blocking agents2.1.6. Combined α-and β-adrenergic blocking agents2.1.7. Agents that block catecholamine synthesis

2.1. Sympathetic Depressant Agents

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2.1.1. Centrally acting agents.Methyldopa

HO

HO

CH2 C

NH2

CH3

CO2H

It is postulated that α-methylnorepinehrine, (α-methyldopa metabolite) lowers arterial pressure by stimulating central adrenoreceptors which causes a reduction in sympathetic nervous outflow.

3-Hydroxy--methyl-L-tyrosine

Clonidine

N

N

N

Cl

Cl

H

H

It stimulates the central a–adrenoreceptors which lead to inhibition of central sympathetic tone, resulting in a lowering of arterial pressure and of heart rate.

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The renin-angiotensin system of blood pressure control

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2.2 .Angiotensin Converting Enzyme (ACE) Inhibitors

Angiotensinogen

Angiotensin I

Angiotensin II

Renin

Inactive decapeptide

Octapeptide (A very potent vasoconstrictor)

ACE (dipeptidyl carboxypeptidase)

– ACE inhibitors inactivate angiotensin–converting enzyme (ACE) thereby preventing the formation of peptides angiotensin II and III, agents that mediate the signal for increasing the systemic blood pressure.

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The first substance developed in this sense was Teprotide, a nonapeptide isolated from the venom of Bothrops jararaca.

With the recognition that ACE was a metallo-enzyme, inhibitors of ACE had been developed.

CaptoprilCaptopril

It is the first orally active ACE inhibitor, used in severe essential and renovascular hypertension. However it introduces some side effects such as rashes and loss of taste.

1(-3-mercapto-2-methyl-oxopropyl-)L-proline43

Interaction of ACE with the normal substrate

Inhibition of ACE with Captopril

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EXTENSIONEXTENSION

Hydrophobic pocketHydrophobic pocket

Bindingsite

NH

N

O CO2

O

O

CH3

Bindingsite

NH

N

O CO2

O

O

CH3

(I)

Hydrophobic pocketHydrophobic pocket

VacantVacant

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Lisinopril

H

H

NH

H

O

N

CO2H

HO2C

NH2

, 2 H 2O

N-[N-[(1S)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline

– It is a lysine derivative of enaliprilate, see next, non-thiol-containing ACE inhibitor. Like all ACE inhibitors it is an active site-directed inhibitor of the enzyme using the Zn ion in an effective binding interaction at a stoichiometeric ratio of 1:1.

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ACE Inhibitor Prodrugs

Enalapril Maleate

NH

CO2H

ONH

H CH3H

O

O

H3C

CO2H

CO2H

,

1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline . Maleate

It is a long acting ACE inhibitor (prodrug), it requires activation by hydrolysis of its ethyl ester to form the di-acid of enaliprilate.

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Fosinopril Sodium

N

H

CO2NaH

P

OO

O

OCOC2H5

It is a phosphorus – containing ACE inhibitor. It is inactive but serves as a prodrug, being completely hydrolyzed by intestinal and liver enzymes to the active diacid Fosinoprilate.

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General characters of ACE Produrgs 1. They are non-thiol-containing ACE inhibitors devoid

of the side effects of rashes and loss of taste seen with captopril.

2. It is interesting to observe that the loss in affinity caused by the replacement of the mercapto function by a carboxyl rest was compensated with the help of additional hydrophobic interaction.

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3. With the exception of the phosphorus-containing Fosinopril, they have a 2-(S)- aminophenylbutyric acid ethyl ester moiety differing only in the substituents on the amino group.

4. They have the common property of acting as prodrugs, being hydrolyzed by intestinal and liver enzymes to the active di-acid.

5. They are used, as the prototype drug Captopril, in the treatment of mild to moderate hypertension.

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2.2.2. Angiotensin II AntagonistsInhibition of Angiotensin II to produce a vasoconstrictor effect can be achieved by administration of competitive antagonists such as Saralasin. The newly introduced class of hypotensive drugs known as Sartans.

LosartanN

NN

N

N

N

Cl

OH

K

It is an orally active non-peptidic hypotensive agent acting through its high affinity for Angiotensin II receptor sites of the smooth muscles, kidney and adrenal glands. It does not inhibit ACE, therefore avoiding the serious side effects of ACE inhibitors.

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Olmesartan Medoxomil

NH

NN

N

N

NH3C

OH

H3C

H3C

O

O

O

OCH3O

It was introduced to market in 2002 in the US as an orally administered treatment for hypertension. It is rapidly and completely bioactivated by ester hydrolysis to its active metabolite, Olmesartan, thus it is an ester prodrug of Olmesartan.

NH

NN

N

N

NH3C

OH

H3C

H3C

O

O

O

OCH3O

NH

NN

N

N

NH3C

OH

H3C

H3C

OH

O

Hydrolysis

Olmesartan MedoxomilOlmesartan

52

Olmesartan is a new selective and competitive non-peptide angiotensin II type 1 (AT1) receptor antagonist and potentially inhibits the Ang.II-induced pressor responses.

Olmesartan Medoxomil was also shown to reduce blood pressure significantly more effectively than losartan and the ACE inhibitor captopril and as effectively as the β–blocker atenolol.

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2.3 .Direct-Acting VasodilatorsHydralazine. HCl

N

N

NHNH2

.HCl

1-Hydrazinophthalazine

It lowers arterial pressure in many experimental models of hypertension. It acts on vascular smooth muscle to cause relaxation, however, its precise mechanism of action is still controversial.

Essential structure requirements necessary for maximal activity are:

1. The presence of a free amino group.

2. Position of the hydrazino-group in phthalazine moiety (position 1) is optimal for duration of action.

3. Unsubstituted phthalazine moiety, substitution of phthalazine or its replacement with other nucleus (e.g. pyridine or benzene) greatly affect the activity.

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Sodium Nitroprusside

[Na+]2 Fe

CN

CN

CNNCCN

ON

.2H2O

Pentakis(cyano-C)nitrosylferrate(II) disodium dihydrate

– It is one of the most potent blood pressure lowering drugs, its use is limited to hypertensive emergencies due to its short duration of action.

–The hypotensive effect of the drug is due to the formation of NO in situ, elevating cellular levels of cGMP.

– Thiocyanate is the final metabolic product of Sodium Nitroprusside and to which the toxicity is attributed.55

Potassium Channel Agonists

– They called “potassium channel openers”. They activate ATP-sensitive potassium channel, which leads to a decrease of intracellular Ca+ and reduces the excitability of smooth muscle.

– The primary action of these drugs is to open potassium channels in the plasma membrane of vascular smooth muscle. An efflux of potassium from the cell follows, resulting in hyperpolarization of the membrane that produces an inhibitory influences on membrane excitation and subsequent vasodilation.

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Diazoxide

N

NHSCl

CH3

OO

7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide

• It is a des-sulfamoyl analogue of the benzothiazine diuretics and has a close structural similarity to chlorothiazide.

• It was developed intentionally to increase the antihypertensive action of the thiazides and to minimize the diuretic effect.

• It is used as sodium salt by i.v. injection as rapidly acting hypotensive drug for emergency reduction of blood pressure.

SNH

NCl

H2NO2S

O O

57

Minoxidil N

N N

H2N

H2N

O6-(piperidin-1-yl)pyrimidine-2,4-diamine 3-oxide

It is the only direct-acting vasodilator that requires metabolic activation to produce hypotensive effect. It is converted to minoxidil sulfate in the liver by a sulfotransferase enzyme.

N

N

N

H2N NH2

O

N

N

N

H2N NH2

OSO3

Sulfotransferase

58

Selective Selective -BlockersBlockers

N

NH3CO

H3CO

N

N R

O

NH2

Quinazoline ring

Piprazine ring

Acyl moiety

R Gen. Name

O

Prazosin

O

Terazosin

O

O

Doxazosin

59

Clinical UsesClinical Uses::

– HypertensionHypertension

– Benign prostatic hypertrophy - reverses smooth muscle Benign prostatic hypertrophy - reverses smooth muscle contractioncontraction

60

3. Antiarrhythmic AgentsThey are classified into 4 classes based on their mechanism of action or pattern of electrophysiological effects produced on heart tissue.

61

A representation of the membrane action potential. Phase 0 corresponds to rapid depolarization (inward movement of Na+ ions), while phases 1 through 4 are repolarizations through movement of K+, Ca+2 and Cl- ions. Repolarization is completed during phase 4, the resting phase. The duration of action potential is the total time for 0-3 segment.

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63

Phase 0: The permeability of the membrane for sodium ions increases, and sodium rapidly inters the cells causing them to become depolarized

Phase 1: Reduce the rate of sodium influx but favors the influx of chloride and efflux of potassium.

Phase 2: the plateau phase, results from slow inward movement of calcium and efflux of potassium that balances the influx of calciumThus resulting in little or no change in membrane potential.

Phase 3: slowing the calcium influx coupled with a continued efflux ofPotassium.

Phase 4: Continued efflux of potassium from the cell restores the membrane potential to normal resting potential levels. During phase 4, Na+, K+-ATPase pump restores the ions to their proper local concentrations.

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3.1. Class I: Sodium Channel Blockers

All class I antiarrhythmic agents (Ia, Ib and Ic) decrease the rate of rise (upstrocke velocity) of phase 0 of the action potential by inhibiting the rapid sodium influx. Under suitable conditions these agents also can block the sodium channels of nerve fibers, which explains the local-anesthetic effect of class I agents.

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Class IA antiarrhythmic agents )QUINIDINE, NORPACE, PRONESTYL(

• Lengthens refractory period, decrease automaticity, slows overall conduction via:

• inhibition of the fast sodium channels

• prolongation of the action potential by inhibiting the repolarizing K+ current

• Indications:

• treatment of supraventricular arrhythmias and supraventricular tachycardias

• conversion of atrial fibrillation and atrial flutter to sinus rhythm

• prevention of PSVT )Paroxysmal supraventricular tachycardia)

• prevent recurrent ventricular tachycardia

Myocardial Action Potential

Quinidine Effect

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– Quinidine is a dextrorotatory diastereoisomer of quinine. Both quinidine and quinine are obtained from many species of Cinchona plant. – Quinidine contains two basic nitrogens, of which the quinuclidine nitrogen has a pKa of ~10 and is thus more basic. –Quinidine is a prototypic anti-arrhythmic drug that reduces Na+ ion current by binding to the open ion channel resulting in depression of automaticity of ectopic foci. –It is used to treat supraventricular and ventricular ectopic arrhythmias, atrial and ventricular tachycardia, atrial flutter and atrial fibrillation.

Quinidine

It is the prototype of class I anti-arrhythmics (class Ia), therefore substances in this group also called “Quinidine-like”.

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Procainamide HCl

NH2C

O

NH

N

4-amino-N-(2-(diethylamino)ethyl)benzamide

A class Ia antiarrhythmic agent, has all the electrophysiological effects of quinidine.

It is commonly prescribed by clinicians for ventricular tachycardias while quinidine for atrial arrhythmias .

The major metabolite is N-acetylprocainamide (NAPA) which possesses only 25% activity of the parent compound.

NH

C

O

NH

N

O

NAPA68

N-Substituted carboxamides

N-Substituted carboxamides have three common features:

1. A lipophilic aromatic group.2. An aliphatic spacer group3. A substituted amino group

Lipophilicity is crucial for nonspecific interaction with the alkyl chains of the membrane’s phospholipids. Together with the amino group which can be protonated at physiological pH values. This seems to be the molecular requirement for antiarrhythmic activity of this group of compounds.

Disopyramide (Class 1a)C

N

O

NH2N(RS)-4-[bis(1-methylethyl)amino]-2-phenyl-2-(pyrid-

2-yl)butyramide

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Class I B antiarrhythmic agents ) XYLOCAINE )LIDOCAINE(, MEXITIL, DILANTIN (

• Depresses automaticity in ectopic beats via:

• inhibition of fast sodium channels, decrease action potential duration

• works especially well in hyperkalemic )ischemic( myocardium & during MI

• sometimes given prophylactically in acute MI

• Indications:

• first line of treatment for acute ventricular arrhythmias

• along with Class III drug Amiodarone – sometimes administered first

• also used in ventricular arrhythmias associated with cardiac surgery

Myocardial Action Potential

Lidocaine Effect

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CH3

CH3

NH

N

OLidocaine HCl

2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide

•A class Ib antiarrhythmic agent with a different effect on electrophysiological properties of myocardial cells from that of quinidine and procainamid.

• Its administration is limited to the parenteral route.

• Its half-life ranging from 15-30 minutes and has a rapid onset of

action.

• It is rapidly metabolized in first pass metabolism. The monoethylglycinexylidide metabolite, resulting from partial de-ethylation of the N-diethyl group, is an effective anti-arrhythmic agent.

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72

Phenytoin

N N

O

O

HH

5,5-diphenylimidazolidine-2,4-dione

It is a class Ib antiarrhythmic agent used in treatment of digitalis-induced arrhythmias. Its action is similar to that of lidocaine.

Mexiletine.HCl

(RS)-[2-(2,6-dimethylphenoxy)-1-methyl-ethyl]- amine hydrochloride

A class Ib antiarrhythmic agent which is effective both parenterally and orally. It may be used for chronic treatment.

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Flecainide (Benzamide derivative)OF3C

NH

O CF3

HN

O

N-[(RS)-(piperidin-2-ylmethyl)]-2,5-bis(2,2,2-trifluoroethoxy)benzamide

It is a class Ic antiarrhythmic agent which is effective both parenterally and orally.

Aprindine

N NIt is a class Ic antiarrhythmic agent which has a sustained activity, however, due to the serious side effects (agranulocytosis) it should only be used for life-threatening arrhythmias

3.2. Class II antiarrhythmic agents (-receptor blockers)

PropranololAcebutololEsmololSatalol

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3.3. Class III antiarrhythmic agents

Agents in this class prolong the duration of action potential without changing its rate of rise.

AmidaroneO

OI

I

ON

A class III drug used only in the treatment of documented life-threatening recurrent ventricular arrhythmias refractory to other agents.

Bretylium tosylate

Br

N

H3C SO3 2-Bromobenzyl(ethyl)dimethylammonium toluene-4-sulfonate

It is an adrenergic neuronal blocking agent that accumulates in the neurons and displaces norepinephrine. Because of this it was earlier used as an antihypertensive agent, but its use was discontinued due to development of tolerance and pain related side effects. 75

3.4 .Class IV: Calcium Channel Blockers

They are applied chiefly in coronary heart disease. Some of these substances also are used as antiarrhythmic therapy.

Their antiarrhythmic effect is based on prolongation of the impulse conduction in the AV node and to a lower degree on inhibition of the impulse generation in the sinus node.

Bepridil

In addition to class IV effects, it also shows class I effect.

DiltiazemVerapamil

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4. Drugs used in Congestive Heart Failure

Congestive Heart Failure• Cardiac failure can be described as the inability of the heart to pump blood effectively at a rate that meets the needs of the metabolizing tissues. • Increasing the force of contraction of the heart (positive inotropic activity) is very important for most heart failure patients.

• There are several mechanisms by which this could be achieved including:

1. Cardiac glycosides which are the most useful. 2. Phosphodiesterase inhibitors, such as amrinone and

milrinone.3. Direct adenylate cyclase stimulants, such as

forskolin (will not be discussed). 77

4.1. Cardiac GlycosidesCardiac Glycosides. .

Mode of Action

The most widely accepted mechanism involves the ability of cardiac glycosides to inhibit the membrane bound Na+-K+-ATPase pump responsible for Na+-K+ exchange.Structure

78

The R group at the 17-position defines the class of cardiac glycoside. Two classes have been observed in Nature:

1. The cardenolides have an unsaturated butyrolactone ring.

2. The bufadienolides have an -pyrone ring (not used therapeutically due to high toxicity). 

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Nomenclature :

The term 'genin' at the end refers to only the aglycone portion (without the sugar). Thus the word digitoxin refers to a agent consisting of digitoxigenin (aglycone) and sugar moieties (three).

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The aglycone moiety:

Rings A/B and C/D are cis fused while rings B/C are trans fused. Such ring fusion give the aglycone nucleus of cardiac glycosides the characteristic 'U' shape.

81

18-CH3 is cis to 14-OH and 19-CH3 is cis to 5-H whereas 8 and 9-Hs are trans to each other.

–The steroid nucleus has hydroxyls at 3- and 14- positions of which the sugar attachment uses the 3-OH group. 14-OH is normally unsubstituted. –Additional hydroxyl groups at 12- and 16- positions are greatly affect the duration of action.

– The lactone moiety at C-17 position is an important structural feature.

– Plant sources provide a 5-membered unsaturated lactone– Animal sources give a 6-membered unsaturated lactone.

Sugar moiety :

– One to 4 sugars are found to be present in most cardiac glycosides attached to the 3-OH group.

– The sugars most commonly used include L-rhamnose, D-glucose, D-digitoxose, D-digitalose, D-digginose, D-sarmentose, L-vallarose, and D-fructose.

HOH

OH

RIII RI

RIIRIV

12

34

56

7

89

10

1112

13

14 1516

17

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1. The sugar moiety appears to be important only for the partitioning and kinetics of action. It possesses no biological activity.

SARSAR

2. The "backbone" U shape of the steroid nucleus appears to be very important. Structures with C/D trans fusion are inactive.

3. Conversion to A/B trans system leads to a marked drop in activity. Thus although not mandatory A/B cis fusion is important.

4. The 14 -OH groups is now believed to be dispensible. A skeleton without 14 -OH group but retaining the C/D-cis ring fusion was found to retain activity.

5. Lactones alone, when not attached to the steroid skeleton, are not active. Thus the activity rests in the steroid skeleton. 83

6. The unsaturated 17-lactone plays an important role in receptor binding. Saturation of the lactone ring dramatically reduced the biological activity.

SAR SAR (Cont.)(Cont.)

7. The lactone ring is not absolutely required. For example, using ,-unsaturated nitrile (C=C-CN group) the lactone could be replaced with little or no loss in biological activity.

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4.2. Phosphodiesterase inhibitorsPhosphodiesterase inhibitors

– Phosphodiesterases are responsible for the degradation of cyclic adenosine monophosphate (cAMP). Inhibition of these enzymes lead to increase the concentration of cAMP and the Ca2+ level in the myocardial cell.

– Phosphodiesterase inhibitors have positive inotropic and vasodilatory properties thus they are effective in the treatment of acute cardiac failure.

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Amrinone

N

NH

NH2

O

5-Amino-(3,4’-bipyridine)-6(1H)one

– It improve cardiac performance by enhancing cardiac contractility. It is used through i.v. route with strong restrictions.

Side Effects: Thrombocytopenia, hepatotoxicity, arrhythmia, nausea, vomiting and may lead to mortality due to heart failure by long term administration.

Milrinone

N

NH

CN

O

H3C

5-Cyano-2-methyl-(3,4’-bipyridine)-6(1H)one

– It is about 10-30 times more potent than amrinone with a higher level of side effects that limit its use to acute therapy.

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