Transcript 313-1A (1)

Text books
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).)
1
Cardiovascular Drugs
are those of
Cardiovascular 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.
3
•
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
4
tetranitrate
tetranitrate:
2,2-bis(hydroxymethyl)-1,3-propandiol
Except
for amyl nitrite, all are nitrate esters (R-ONO2).
5
Structure
Nitrate Esters
RO H
+
alcohol
RO H
alcohol
+
HO N O
RO N O
nitrous acid
alkyl nitrite
+
HO N
_
O
nitric acid
O
+
RO N
+
H2O
water
_
O
O
alkyl nitrate
+
H2O
water
•
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
7 potency and the longer the vasodilatory response.
vii. The structure of the organic nitrates determines the
onset and duration of action as shown in the following
table:
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Pharmacokinetics of Nitrate Esters
Amyl nitrite
Onset
(min)
0.25
Duration of Action (min)
Nitroglycerin
2
30
Isosorbide dinitrate
3
60
Erythrityl tetranitrate
15
180
Pentaerythritol tetranitrate
20
330
Metabolites
1
Active
•
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!
•
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Nitrovasodilators decrease the blood pressure of patients!!
Synthesis of isosorbide dinitrate:
CH2OH
CHO
H
HO
H
OH
H
H2/pt
HO
H
H
OH
H
OH
H
OH
H
OH
CH2OH
OH
OH
CH2OH
H2SO4
H
O
ONO2
O
H
HNO3
H2SO4
OH
H
O
O
H
ONO2
1,4:3,6-Dianhydro-D-glucitol dinitrate
10
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 Blockers
Calcium 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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NOR: ~20% Active
CH3
MeO
N
CH3
CH3
MeO
O-deMe
gives inactive
species
– Verapamil is a synthetic
CN
MeO
OMe
Verapamil
N
Ph
CH3
O
N
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.
CH3
Bepridil
– The essential structural features of this class of drugs are:
The benzene ring.
A 3ry amino nitrogen, which is almost completely charged
at physiological pH.
iii. The isopropyl group is not essential for activity.
i.
ii.
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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
R1
structure:
R2
H
H3CO2C
H3C
CO2R3
N
CH2R4
H
R1
R2
R3
R4
Generic Name
H
NO2
H
Cl
H
NO2
C2H5
CH2CH2N(CH3)CH2Ph
CH3
OCH2CH2NH2
H
H
Amlodipine
Nicardipine
Nifedipine
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.
NH3
O
+
O
H
N
O
O
O
+
O
O
O
H
O
H
NO2
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O
O
NO2
The structural features essential for activity are :
1. The 1,4-dihydropyridine ring
2. 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.
X
Extensive hydroxylation to inactive species
R'
R''
R'''
R'
Nifedipine
NO2
CH3
H
COOR''
Amlodipine Cl
C2H5
O-(CH2)2-NH2
Nicardipine H
-(CH2)2-N(CH3)(CH2-Ph) H
H3COOC
H3C
N
H
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CH2R'''
X
H
X
NO2
1.2.3. Benzothiazepines
Diltiazem
3ry
The
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.
O
H
H
S
O
N
N
O
CH3
H3C
Diltiazem
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CH3
Des-Ac
gives
~50%
Protein Binding of Calcium Channel Blockers
Protein Binding
Duration of Action
Metabolites
Amlodipine
>95%
24 h
phenyl hydroxylations, inactive
Diltiazem
~80%
6 h iv
desacetyl derivative, ~ 50 % active
Bepridil
>90%
24 h
Verapamil
90%
8h
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Extensive inactive metabolites
N-demethyl derivative, ~ 20 % active
Biochemical Mechanism of Action
20
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?
21
1.3. -Adrenergic blockers
Nonselective  Blockers
HO
N
H
Propranolol
O
1-Isopropylamino-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)
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Synthesis:
NH2
O
Propranolol
+ Cl
O
OH
Naphthol
O
Epichlorohydrine
Major Metabolites:
HO
N
H
HO
COOH
O
O
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OH
4-Hydroxy propranolol
(Potant -blocker)
Naphthoxylactic acid
Nonselective
antagonists
1-Selective
antagonists
Propranolol
Metoprolol
Nadolol
Atenolol
Timolol
Esmolol
Pindolol
Acebutalol
Labetolol
Carvedilol
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Selective 1 Blockers (Cardioselective)
O
N
H
OH
Atenolol
NH2
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.
25
• Atenolol also differs from propranolol in that only a small
amount (6%-16%) is bound to proteins in the plasma
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Esmolol
O
N
H
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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2. Antihypertensive Agents
Agents Used to Treat Hypertension:
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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
http://www.beauregard.org/bldpress.htm
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• Occurs when blood is
forced through the
heart and arteries
under excessive
pressure
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
30
http://www.everybody.co.nz/page-3f71418a-d1e1-43d7-9ac0-fdcb4a79a3e3.aspx
Classifying Blood Pressure by Readings
Blood Pressure Category
Systolic
(mm Hg)
Diastolic
(mm Hg)
Normal
<120
<80
Prehypertension
120-139
80-89
High: Stage 1
140-159
90-99
High: Stage 2
160 +
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
–
–
–
–
–
–
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• Uncontrollable
Age
Race
Gender
Family history
Medical condition
Obesity due to
medical condition
– Medications
–
–
–
–
–
–
Who is Affected by Hypertension?
• Affects 1 billion people worldwide
• Affects 65 million Americans age 6+
• 30% of people with hypertension don’t
know they have it
Race and Gender
34
Prevalence
White Female
19.3%
Race and Gender
White Male
24.4%
White Males
14.4%
African-American
Female
34.2%
African-American Males
49.6%
African-American Male
35.0%
White Females
13.7%
Hispanic Female
22.0%
African-American Females
40.5%
Hispanic Male
25.2%
Death Rate
(Death rates per 100,000 people)
Why Should I Care?
• Hypertension can
elevate your risk
for:
– Stroke
• Blood clots
• Bleeding
–
–
–
–
–
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Heart attacks
Heart enlargement
Heart failure
Kidney failure
Atherosclerosis
http://member.rivernet.com.au/balehirs/drHt2.jpg
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
36
Available Drug Therapies
• Drug therapies available:
–
–
–
–
–
–
–
–
–
37
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
2. Antihypertensive Agents
The available antihypertensive drugs can be classified on
the basis of their mechanism of action as follows:
2.1. Sympathetic Depressant Agents
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 agents
2.1.6. Combined α-and β-adrenergic blocking agents
2.1.7. Agents that block catecholamine synthesis
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2.1.1. Centrally acting agents.
Methyldopa
HO
It
is
postulated
that
αmethylnorepinehrine,
(αmethyldopa
metabolite)
lowers
arterial pressure by stimulating
central
adrenoreceptors which
causes a reduction in sympathetic
nervous outflow.
NH2
HO
CH2
C
CO2H
CH3
3-Hydroxy--methyl-Ltyrosine
Clonidine
Cl
N
H
N
N
Cl
39
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.
The renin-angiotensin system of blood pressure control
40
41
2.2. Angiotensin Converting Enzyme (ACE) Inhibitors
Angiotensinogen
Renin
Angiotensin I
Inactive decapeptide
ACE (dipeptidyl
carboxypeptidase)
Angiotensin II
Octapeptide (A very potent vasoconstrictor)
– 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.
42
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.
Captopril
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-proline
43
Interaction of ACE with the
normal substrate
44
Inhibition of ACE with Captopril
Hydrophobic pocket
Hydrophobic pocket
Vacant
CH3
CH3
EXTENSION
N
O
O
N
H
Binding
site
45
O
O
(I)
CO2
N
N
H
Binding
site
O
O
CO2
Lisinopril
H2 N
HO 2C
H H
, 2 H 2O
N
N
H
O
H
CO2 H
N-[N-[(1S)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline
– It
is a lysine derivative of enaliprilate, see next, nonthiol-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.
46
ACE Inhibitor Prodrugs
Enalapril Maleate
H3C
O
O
H H
CH3
CO2 H
O
N
H
N
,
CO2 H
CO2 H
H
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 diacid of enaliprilate.
47
Fosinopril Sodium
OCOC2H5 H
O
N
P
O
O
H
CO2Na
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.
48
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.
49
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.
50
2.2.2. Angiotensin II Antagonists
Inhibition 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.
Cl
Losartan
N
N
OH
N
N K
N
N
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.
51
Olmesartan Medoxomil
H3C OH
H3C
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.
H3C
N
O
N
N
N
O
N
NH
O
O
CH3
O
H3C OH
H3C
H3C
H3C OH
N
H3C
O
N
N
N
O
H3C
N
N
O
NH
Hydrolysis
N
OH
O
O
O
CH3
Olmesartan Medoxomil
52
N
N
Olmesartan
N
NH
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.
53
2.3. Direct-Acting Vasodilators
Hydralazine. HCl
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.
NHNH2
N
.HCl
N
1-Hydrazinophthalazine
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.
54
Sodium Nitroprusside
CN
+
[Na ]2 NC
ON
Fe
CN
CN .2H2O
CN
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
Nitroprusside
and to which the toxicity is attributed.
55
of
Sodium
Potassium Channel Agonists
– They
called “potassium channel openers”. They activate ATPsensitive 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.
56
Diazoxide
O
Cl
Cl
N
O
S
NH
NH
H2NO2S
S
O
O
N
CH3
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.
57
H2N
Minoxidil
N
6-(piperidin-1-yl)pyrimidine-2,4-diamine 3-oxide
O
N
N
H2N
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
Sulfotransferase
N
H2N
N
N
O
58
NH2
H2N
N
OSO3
NH2
Selective 1-Blockers
O
Acyl moiety
Quinazoline ring
H3CO
N
N
R
N
Piprazine ring
N
H3CO
R
Gen. Name
NH2
Prazosin
O
Terazosin
O
O
Doxazosin
O
59
 Clinical Uses:
– Hypertension
– Benign prostatic hypertrophy - reverses smooth muscle
contraction
60
3. Antiarrhythmic Agents
They 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.
62
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 calcium
Thus resulting in little or no change in membrane potential.
Phase 3: slowing the calcium influx coupled with a continued efflux of
Potassium.
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.
63
64
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 localanesthetic effect of class I agents.
65
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
Myocardial
Action
Potential
Quinidine Effect
• 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
66
Quinidine
It is the prototype of class I antiarrhythmics (class Ia), therefore
substances in this group also
called “Quinidine-like”.
– 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.
67
Procainamide HCl
NH
N
C
NH2
O
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.
O
NH
N
C
O
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NAPA
N
H
N-Substituted carboxamides
N-Substituted carboxamides have three common features:
1. A lipophilic aromatic group.
2. An aliphatic spacer group
3. 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)
O
C
(RS)-4-[bis(1-methylethyl)amino]-2-phenyl-2-(pyrid-
2-yl)butyramide
69
N
NH2
N
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:
Myocardial
Action
Potential
Lidocaine Effect
• 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
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CH3
Lidocaine HCl
O
N
N
H
CH3
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.
• It
is rapidly metabolized in first pass metabolism. The
monoethylglycinexylidide metabolite, resulting from partial deethylation of the N-diethyl group, is an effective anti-arrhythmic
agent.
• Its half-life ranging from 15-30 minutes and has a rapid onset of
action.
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Phenytoin
O
H
N
N
H
It is a class Ib antiarrhythmic agent
used in treatment of digitalisinduced arrhythmias. Its action is
similar to that of lidocaine.
O
5,5-diphenylimidazolidine-2,4-dione
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)
O
F3C
N-[(RS)-(piperidin-2-ylmethyl)]-2,5-bis(2,2,2trifluoroethoxy)benzamide
O
N
H
HN
O
CF3
It is a class Ic antiarrhythmic agent which is effective both
parenterally and orally.
Aprindine
N
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N
It 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)
Propranolol
Acebutolol
Esmolol
Satalol
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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.
Amidarone
O
A class III drug used only in the treatment of
documented life-threatening recurrent ventricular
arrhythmias refractory to other agents.
I
O
N
O
I
Bretylium tosylate
Br
H3C
N
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.
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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.
In addition to class IV effects, it also shows class I effect.
Bepridil
Diltiazem
Verapamil
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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.
2.
Cardiac glycosides which are the most useful.
Phosphodiesterase inhibitors, such as amrinone and
milrinone.
3.
Direct adenylate cyclase stimulants, such as forskolin (will
not be discussed).
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4.1. Cardiac 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).
80
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.
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.
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–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 :
RIII
12
RIV
11
13
14
2
3
HO
17
16
15
RII
9
1
10
4
RI
5
6
8
7
OH
H
– 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.
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SAR
1. The sugar moiety appears to be important only for
the partitioning and kinetics of action. It possesses
no biological activity.
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
SAR (Cont.)
6. The unsaturated 17-lactone plays an important role in receptor
binding. Saturation of the lactone ring dramatically reduced the
biological activity.
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 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.
–
85
Amrinone
NH2
N
O
NH
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.
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Milrinone
CN
N
O
NH
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.
–
87