Cardiovascular agents
Moustafa K Soltan
•Cardiovascular agents are the drugs which
act on heart and vascular system
•These drugs are used for treatment of
angina, cardiac arrhythmia, hypertension,
hyperlipidemia, and disorders of blood
coagulation and platelet aggregation .
Antianginal agents
• The English word angina (refers to a painful
choking constriction or tightness somewhere in the
body
• Angina pectoris: chest pain due to ischemia (a lack
of blood and hence oxygen supply) of the heart
muscle
• the principal symptom of Angina pectoris is
characterized by a severe constricting pain in the
chest, often radiating from the pericardium to the
left shoulder and down the arm
Types of angina pectoris
1- stable angina occurs during exercise
2- unstable angina occurs during rest
Treatment of angina pectoris
1- nitrovasodiltors
2- calcium channel blockers
3-drugs with anti platelet aggregation
1- Nitrovasodiltors
Mode of action
Nitrovasodilator
+ cystein or glutathion
R
S
N
O
activate
Guanylate cyclase
GTP
c GMP
c GMP Kinase (activation)
Myosin P
(w hich cause RELAXATION of smooth muscle)
Myosin Lt chain
Glyceryl trintrate
1-used sublingual or transdermal
2- it acts by decreasing cardiac work and reduce oxygen
demands
N.B
Organic nitrates (as glyceryl trinitrate) are preferred
to be taken sublingualy for the following reason :
# Only 15% of the cardiac output is delivered to the
liver , this allows a transient but effective circulating
level of the intact organic nitrate before it is
inactivated .
Metabolism of glyceryl trinitrate in the liver by
reacting with glutathione leads to the conversion of a
potent lipid-soluble vasodilator substance (glyceryl
trinitrate)to a water-soluble metabolite of lower
biological potency (glyceryl mononitrate) that is
readily excreted in the urine .
Amyl nitrite
ONO
Isopentyl nitrite or isoamyl nitrite has onset time (1/4 minute )
and its duration of action is ( one minute ) .
Erythrityl tetranitrate :
Erythritol tetranitrate or ( 1, 2, 3, 4-butanetetrol tetranitrate )
has onset time ( 15 minutes ) , longer duration ( 180 m ) so it is
used in treatment and as a prophylactic agent against angina .
Penta-erythritol tetranitrate :
2, 2-bis (hydroxymethyl)-1, 3-propanediol tetranitrate
Its onset time ( 20 m ) and longer duration ( 5 hours ) ,
and it is used as prophylacting to reduce the severity and
frequency of anginal attacks .
Isosorbide dinitrate:
1,4 : 3,6 – dianhydrosorbitol – 2,5 –dinitrate
Its onset time ( 3 m ) and duration (60 m) and it is effective in
Treatment or prophylaxis of acute anginal attacks.
Calcium channel blockers
Contraction in cardiac m uscle :Stim ulus
Ca
2+
Cell m em brane
Ca
2+
2+
Troponin -C - Ca com plex
Activates
Actin + M yosin inte raction
M us cle contraction
Contraction in vas cular m us cle :2+
Calm oduline Ca
com ple x
prote in k inas e (active )
prote in k inas e (inactive )
w hich activate phos phorization of
M yos in
M yos in-P
inte raction w ith
M us cle contraction
Actin
1- Dihydropyridine derivatives ( 1 , 4- DHP )
Nifedipine , Nicardipine , Nitrendipine ,
Nimodipine , Amlodipine and Felodipine .
2- 1 , 5 –Benzothiazepine derivatives
Diltiazem
3- Aralkylamine derivatives :
Bepridil and Verapamil .
1- Dihydropyridine derivatives ( 1 , 4- DHP )
Nifedipine
3,5-dimethyl2,6-dimethyl-4-(2-nitrophenyl)-1,4dihydropyridine-3,5-dicarboxylate
Nifedipine is the prototype of 1,4-DHP class and is used
in treatment of angina and hypertension .
Nicardipine
2-[benzyl(methyl)amino]ethyl
methyl
2,6-dimethyl-4-(3nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Nicardipine is used in treatment of mild, moderate, and
severe hypertension
It has less negative inotropic effect than Nifedipine .This may
be attributed to: Nicardipine lacks the anticoplannerity of
phenyl and 1,4-DHP rings which is the first riquirement for
fitting on the receptor .
Nitrendipine
ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine3,5-dicarboxylate
Nitrendipine is an effective vasodilator and is used in treatment
of essential hyperetension .
Nimodipine
3-(2-methoxyethyl)5-propan-2-yl2,6-dimethyl-4-(3nitrophenyl)1,4-dihydropyridine-3,5-dicarboxylate .
Nimodipine is used in treatment of subarachnoid hemorrhageassociated neurological deficits, so it dilates the cerebral blood
vessels .
Amlodipine
3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
Amlodipine has greater selectivity for the vascular smooth muscle
than myocardial tissue , it is used in treatment of angina and
essential hypertension.
Amlodipine is used as a non-sustained-release product and can
given once dialy due to its high binding to plasma protein ( more
than 90% ) , andhas a twenty four hours duration of action compared
with other calcium channel blockers
Felodipine
ethyl
5-methyl
4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarboxylate
Felodipine is an effective vasodilator and is used in treatment of
angina and hypertension . It exhibits a high degree of protein
binding and has a half-life ranging from ( 10-18 hrs ) .
2- 1 , 5 –Benzothiazepine derivatives : Diltiazem)
+ )-cis-3-( Acetoxy )-5-( 2-( dimethylamino )ethyl )-2,3-dihydro-2-(
4-methoxyphenyl )1,5-benzothiazepin-4( 5H ) one .
Diltiazem is used in patients with variant angina , and is used as
antiarrhythmic
agent . The first-pass metabolism of Diltiazem resulted in
deacetylation , oxidative O- demethylation or N-demethylation
where the deacetylated metabolite has about 40-50% of the potency
of the parent compound .
(
3- Aralkylamine derivatives
Verapamil
5-( ( 3,4-dimethoxyphenethyl )-methylamino )-2-( 3,4dimethoxyphenyl )-2-isopropylvaleronitrile .
Verapamil is used in the treatment of angina pectoris ,and
arrhythmias .
The levorotatory enantiomer is the most potent .
The first-pass metabolism involves N-demethylation
followed by O-demethylation and the metabolites of
Verapamil have no significant biological activity
Bepridil
N-benzyl-N-(3-isobutoxy-2-pyrrolidin-1-yl-propyl)aniline .
Bepridil is a second generation alkylamine-type channel
blocker, its action is less specific than Verapamil but it is
used for stable angina, and it has a half-life of 33hrs and is
highly bounded to protein ( 99% ) .
Antianginal agent with antiplatelet activity
Dipyridamol
2,6-Bis-( diethanolamino )-4,8-dipiperidino-pyrimido( 5,4-d
)pyrimidine .
its action is selective on the coronary system and is indicated for longterm therapy of chronic angina pectoris . The drug inhibits adenosine
deaminase in erythrocytes and interferes with the uptake of the
vasodilator adenosine by erythrocytes . These actions potentate the
effect of prostacyclin acting as an inhibitor to platelet aggregation (
antithrombotic action ).
Questions
1- Give selective method for analysis
of organic nitrates ?
2- Illustrate synthetic pathway of
Isosorbide dinitrate ?