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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5648_Библиотеки_им_академика_М_И_Перельмана.pdf
142 Pharmaceutical Chemistry
(e) Agents depleting neurotransmitter stores: Reserpine is used in mild to moderate
hypertension and in chronic psychoses. Reserpine is metabolized by the liver and
intestine to methyl reserpate and 3,4,5-trimethoxybenzoic acid. Guanethidine
sulphate is another drug used in the treatment of hypertension in case other drugs
prove inadequate, viz., Reserpine, Guanethidine, Guandrel sulphate, etc.
OMe
MeO
N
H
MeO2C
Reserpine
O
O
OMe
Fig. 6.13: Agents depleting neurotransmitter
OMe
OMe
N
Guanethidine
H
N
NH
NH
2
O
O
H2N
Guanadrel
NH
NH
(f) Gaglionic blocking agents: Mecamylamine hydrochloride may be indicated in
severe or malignant hypertension, viz., Pentolinium, Trimethaphan and
Mecamylamine hydrochloride (Fig. 6.14).
NHMe
S O
Trimethaphan
N
N
Fig. 6.14: Gaglionic blocking agents
N N
Pentolinium
MeMe
Mecamylamine
Me
Me
Me
6.2.4.1.2 Agents Acting on Renin-angiotensin System
(a) Angiotensin converting enzyme (ACE) inhibitors: Captopril and enalapril are
prodrugs which on hydrolysis convert to enalaprilate. Lisinopril is the lysine
analogue of enalaprilate and is itself active (Fig. 6.15).
O
NH
COOH
2
H
N
HS
O
Me
Captopril
COOH
O
H
N
EtO2C
Enalapril
Fig. 6.15: Angiotensin converting enzyme inhibitors
Me
COOH
HOOC
Lisinopril
(b) Angiotensin receptor antagonist: Losartan and saralasin are common examples of
this class (Fig. 6.16).
Cardiovascular Drugs 143
N
Cl
OH
Losartan
Sar-Arg-Val-Tyr-V
Saralasin
al-his-pro-Ala
HN
N
N
N
N
Fig. 6.16: Angiotensin receptor antagonist
6.2.4.1.3 Vasodilators
(a) Directly acting vasodilators
(i) Arterial dilators: Sodium nitroprusside is a short-acting hypotensive agent with
duration of action of 1-10 minutes. It may also be employed to produce controlled
hypotension during general anaesthesia and in the treatment of hypertensive
crisis, viz., hydralazine, dihydralazine, sodium nitroprusside, etc. (Fig. 6.17).
NHNH
Hydralazine
Fig. 6.17: Arterial dilators
2
NC
N
N
Fe
NC CN
Nitroprusside
sodium
-2
CNNC
2Na
NO
(ii) Potassiumion ion channel agonist: Diazoxide is given intravenously for the
treatment of hypertensive emergencies and is also used by mouth in the
treatment of intractable hypoglycaemia. Examples, minoxidil and diazoxide
(Fig. 6.18).
OO
Cl
Fig. 6.18: Potassium channel agonist
S
N
Diazoxide
NH
Me
N
N
H2N NH
O
Minoxidil
2
(b) Calcium ion channel blockers (Fig. 6.19)
(i) Alkylamines: e.g., Verapamil,
(ii) Benzothiazepines: e.g., Diltiazem,
(iii) Dihydropyrimidines: e.g., Nifedipine, Felodipine, Amlodipine and Nimodipine.
144 Pharmaceutical Chemistry
MeO
MeO
Verapamil
NO
2
MeO2C CO2Me
N
H
Nifedipine
Me
N
Me2HCO2C CO2CH2CH2OMe
Fig. 6.19: Calcium channel blockers
CHMe
NC
N
H
Nimodipine
2
NO
MeMe
OMe
OMe
2
Me
N
O
Diltiazem
N
H
Amlodipine
Me2N
MeO2C CO2Et
S
O
O
Cl
CH2OCH2CH2NH
OMe
Me
2
Thus, the practolol (propranolol) is selective and the most potent E-blocker inhibitor
among the series. The E-blockers have found a wide use in treating hypertension.
6.2.4.1.4 Diuretics (Fig. 6.20)
(a) Thiazides: e.g., Hydrochlorothiazide
(b) Loop diuretics: e.g., Furosemide
(c) Potassium sparing diuretics: Spironolactone is employed in the treatment of
refractory oedema associated with congestive heart failure, cirrhosis of the liver, or
the nephrotic syndrome, malignant asides and in the treatment of essential
hypertension. It is used in conjunction with other diuretic agents to prevent
excessive loss of potassium ions. Example: Triamterene, Spironolactone, etc.
O
Me
O
SCOMe
Cl
H2NO2S
Hydrochlorothiazide
H
N
S
O O
NH
Cl
H2NO2S
COOH
Furosemide
Fig. 6.20: Diuretics
NH
O
N
H2N NH
N
Triamterene
2
N
N
2
Me
O
Spironolactone
6.2.4.1.5 5-HT Antagonists
It is used clinically as an antihypertensive agent and study of the serotonin system;
specifically, the 5-HT
receptor, e.g., Ketanserine (Fig. 6.21).
2A
Cardiovascular Drugs 145
O
O
N
N
O
N
H
Fig. 6.21: 5-HT antagonist
Ketanserine
F
6.2.5 Anticoagulants (Antiplatelets and Thrombolytics)
These drugs are sometimes referred to as “blood thinners”, but this term is not factually
accurate. They have inhibiting ability for blood to clot, preventing clots from forming in
blood vessels and from getting bigger. Under a number of different circumstances, it
becomes necessary to stop clotting. A heparin antagonist is one example of this class.
Anticoagulants have specific indications and medicinal uses, for example, patient needs
lifelong oral administration of anticoagulants who has replaced heart valve with a
mechanical valve. They help to prevent clots forming on the valve and also used in
rhythmic disturbance, in the treatment and prophylaxis of thromboembolic occlusive
vascular diseases (venous thrombosis after operation, pulmonary embolism and cardiac
infarction). Patient suffering from thrombophlebitis (an inflammation of the veins in the
legs or pelvis) is generally prescribed with oral anticoagulants. Sometimes these clots may
travel to the lungs resulting in pulmonary emboli.
Blood clots are removed from the vascular system by breaking down the fibrin by
proteolytic enzyme plasmin, which is formed from its inactive precursor plasminogen by
the action of streptokinase, urokinase and tissue plasminogen activator.
Coagulation normally does not occur in an intact blood vessel. It is prevented by several
regulatory mechanisms requiring a normal vascular endothelium. Antithrombin, a plasma
protein, inhibits coagulation factors. Prostacyclin (PGI
inhibits platelet aggregation.
Heparin can be the best asset in the retardation of coagulation because it inhibits the
activity of thrombin and activates factor X. Heparin is not absorbed orally while given
parentally. The other class of drugs is anticoagulants which act by depressing the synthesis
of vitamin K-dependent coagulation factors.
), synthesized by endothelial cells,
2
6.2.5.1 Classification of Anticoagulants
6.2.5.1.1 Heparin
Heparin is a water-soluble mucopolysaccharide or a complex anionic linear polysaccharide
of mammalian origin with irregular sequence. It was first discovered by W.H. Howell
(1922). Heparin, also known as glucosaminoglycan, consists of alternating unit of
D-glucuronic acid (or its epimer L-iduronic acid) and D-glucosamine residues, most of
which are sulphated. Complete hydrolysis of heparin results in D-glucosamine,
D-glucuronic acid, L-iduronic acid, acetic acid and sulphuric acid. The pentasaccharide
portion of heparin is involved in the binding with antithrombin (Fig. 6.22).
146 Pharmaceutical Chemistry
CH
OSO
2
O
OH
O O
COO
3
O
OH OH
O
CH2OSO
O
O
COO
3
O
CH
OSO
2
3
O
OH
O
O3SO
NHSO
a
Fig. 6.22: Heparin (a = N-acetylglucosamine, b = glucuronic acid, c = N-sulphated glucosamine-3,6-disulphate,
d = iduronic acid 2-O-sulphate, e = N-sulphate glucosamine 6-O-sulphate)
OH
3
b
NHSO
c
OSO
3
3
d
NHSO
e
3
Heparin is often used in a person suffering from thrombophlebitis and thrombolytic
therapy due to heart attack. Heparin has the ability to immediate catalytic action on the
addition of an inhibitor and protease, resulting in an increase in the rate of thrombinantithrombin reaction. Thus, heparin exerts its anticoagulant effect by inhibiting the
activity of thrombin. High doses of heparin (Na and Ca salt) may prolong the bleeding
time. Most of the times platelet blood cells are responsible for blood clotting, thus it is very
difficult to remove the clot from the coronary artery (responsible for heart attack) and it
needs strong anticoagulants to remove this clot. Aspirin is not an anticoagulant but has the
ability to inhibit the clotting action of platelets, thus it acts as an antiplatelet and is frequently
prescribed in patients who have recovered from a heart attack, in order to prevent clots
from forming in the veins used for coronary bypass surgery.
Recently, thrombolytic drugs have been used by the people with major heart attacks.
These agents are given intravenously to dissolve the clot in a coronary artery. The three
most commonly used thrombolytics are tissue plasminogen activator (t-PA), streptokinase,
and anisoylated plasminogen streptokinase activated complex (APSAC). They are
generally used only in emergency situations in hospitals.
6.2.5.1.2 Dicoumarol (Dicouman) and Other Related Derivatives
Orally active anticoagulant drugs belong to the chemical categories of coumarins and
indanedione family (Fig. 6.23). In 1939, Campbell & Link identified dicoumarol as
O
O
O
OH
Tromexan
O
OH
OHO
O O
OH
Warfarin (R = H)
Nicoumalone (R = NO
R
Me
O
)
2
O
O
O
OMe
Me
Cyclocoumarol
O O
O
OH
Dicoumarol
Fig. 6.23: Dicoumarol and related derivatives
O
OH
O O
OH
Phenprocoumon
Me
OH
Cardiovascular Drugs 147
haemorrhagic agent. It is used as injection in cattle to prevent excessive and persistent
bleeding (haemorrhage), and also used as a prophylactic against post-operative thrombosis
and embolism. It retards the rate of coagulation by blocking the enzyme system responsible
for the synthesis of prothrombin in the liver. Other examples of this class are warfarin,
nicoumalone, cyclocoumarol, phenprocoumon, coumachlor, snitrom, marcoumar,
tromexan (pelentan), etc.
6.2.5.1.3 Indanedione
Indanedione derivatives (i.e., phenindione and anisindione) were conceived as ring
contracted analogues of coumarins. Like coumarins, they also act as oral anticoagulants by
inhibiting the synthesis of prothrombin (Fig. 6.24).
O
O
Phenidione (R = H)
Anisidione
(R =
R
Delphenadione
OCH3)
Fig. 6.24: Indanediones
O
O
6.2.5.1.4 Miscellaneous Drugs (Fig. 6.25)
(a) Sodium citrate, when taken orally, gets metabolized to citrate ion in vivo, which is
2+
a soluble complex with Ca
. This complex thus converts prothrombin to thrombin
and thus citric acid prevents the formation of clot.
(b) Sulphanilamidoquinoxaline is a potent anticoagulant and thrombodyn is also
used for the treatment of thrombosis.
NH
H
N
N
N
Sulphanilamidoquinoxaline
S
O
O
Fig. 6.25
2
COOH
SO3Na
N
Thrombodyn
Thus, in conclusion we can say warfarin is a chiral compound having racemic mixture.
Isomer (S)-warfarin is 4-fold more potent than the (R)-warfarin as an anticoagulant by
inhibiting the synthesis of active clotting factors VII, IX, X and plasma prothrombin.
1,3-Indanedione analogues also act as anticoagulants having the similar mechanism as
warfarin.
148 Pharmaceutical Chemistry
6.2.6 Vasodilators
Vasodilators are an important class of drugs especially for cerebral and peripheral
vasodilating effects. These drugs include arterial vasodilators, arterial venous dilatators,
muscle relaxants and some E-adrenoceptor stimulators.
6.2.6.1 Classification of Vasodilators
6.2.6.1.1 Arterial Vasodilators
This class of antihypertensive drugs decreases peripheral vascular resistance and arterial
blood pressure. These drugs are also used to control expansion of the extra-cellular fluid
and plasma volume in the cell by promoting the salt and water retention thus, these drugs
can also be used as E-blockers for patients in conjunction with diuretic difficulty. Examples:
hydralazine hydrochloride (Apresoline), minoxidil (Loniten), diazoxide (Hyperstat), etc.
(Fig. 6.26).
N
H
2
N
N
N
O
Minoxidil
N
Cl
NH
2
Fig. 6.26: Arterial vasodilators
S
O O
Diazoxide
NH
Me
Cl
O O
3-Hydroxymethyl-
Diazoxide
CH2OH
N
NH
S
Cl
O O
3-Carboxy-
Diazoxide
COOH
N
NH
S
NHNH2.HCl
N
N
Hydralazine
hydrochloride
Hydralazine is prescribed to the patients suffering from moderate to severe hypertension
because of its relaxant ability to the vascular smooth muscle. It has some side effects as
well, such as reflex tachycardia and fluid retention; thus, it should always be given in
combination with a E-adrenergic receptor blocker and diuretics. Hydralazine has similar
action as sodium nitroprusside and organic nitrites, because they all produce nitric oxide.
For patients suffering from severe hypertension, no other drug, but minoxidil is prescribed
to help in relaxing arterial smooth muscle. It also forms an active metabolite known as
Minoxidil NoO sulfate, which again helps to release vascular smooth muscles and increase
the permeability of the cell membrane to K
+
resultant hyperpolarization. Diazoxide is used
as an antihypertensive drug in emergencies and lacks sulfonamido group thus causes Na
retention. It has rapid onset of action (3-5 minutes) and it lowers blood pressure when
administered intravenously and gets metabolised easily in 3–hydroxymethyl and 3-carboxy
derivatives of diazoxide. Diazoxide helps to activate ATP-sensitive K
+
channels which
result in hyperpolarization in arterial smooth muscle cells. Diazoxide has some side effects
such as severe hypotension.
+
Cardiovascular Drugs 149
6.2.6.1.2 Arterial and Venous Dilatators
Sodium Nitroprusside (Nipride): It is a non-selective vasodilator used for short-term, and
rapid reduction of blood pressure in hypertensive emergencies. Sodium nitroprusside
forms glutathione and nitrosothiol in the vascular endothelium which helps to increase the
cyclic guanosine monophosphate (cGMPI), thereby causing vasodilation. A metabolic
product of nitroprusside is cyanide, which is quickly metabolized to thiocyanate.
6.2.7 Antihyperlipidemic Agents
Antihyperlipidemic agents or hypocholesterolemic agents or lipid lowering agents are
used to reduce the concentration of plasma lipids. Increased cholesterol level (or
plasmalipid) is a major problem in industrial suburbs and responsible alone for one-third
deaths around the globe. When lipid content increases in the plasma of the cell, the
condition is known as hyperlipidemia (or hyperlipoproteinemia). This condition is
involved with arterial damage (or atherosclerosis) which might lead to severe cerebral
vascular failure and ischaemic heart diseases.
Water insoluble lipids are present in the plasma in the form of lipoproteins. Lipoproteins
consist of two units, one is the central core of hydrophobic lipid (for example, triglycerides
or cholesteryl esters) and another is hydrophilic coat of polar substances (for example,
phospholipids, free cholesterol and associated proteins or apoproteins). Lipoproteins
generally depend on the varied content of lipids and apoproteins, hence can be categorized
in following five categories:
(a) High density lipoprotein (HDL): HDLs contain low lipid content and can be
sub-classified on the basis of the density of the lipoproteins. Someone having low
HDL value (value falls below normal) may be diagnosed with atherosclerosis. HDL
apparently enhances the removal of cholesterol from the arterial wall. Elevated
levels of VLDL, IDL and LDL are considered to increase the risk of atherosclerosis.
(b) Very low density lipoprotein (VLDL): Globular shaped VLDLs are synthesized in
the liver with diameter of 30–80 nm and consist of apoproteins B, C and E. They
help in transport of endogenous lipid from the liver to the plasma.
(c) Intermediate density lipoprotein (IDL): IDLs are 20–30 nm in diameter and
synthesized on the partial digestion of triglyceride content of VLDL, by the action
of extrahepatic lipoprotein lipase.
(d) Low density lipoprotein (LDL): LDLs are 18–28 nm in diameter and synthesized
when apoproteins C and E are digested from the triglyceride content of IDL. They
consist of phospholipids, cholesterol, B-100, B-74 and B-26 apoproteins. LDL plays
a major role in the cell formation by delivering it to hepatic and certain extrahepatic
tissues for further lysosomal degradation to release the cholesterol. It has 1.5 days
half-life, longest amongst the lipoproteins.
(e) Chylomicron: Lipoproteins are rich in triglycerides and contain A and B-48
apoproteins and secreted into the lymph. They are generally involved in the
transportation of dietary fat from gut.
150 Pharmaceutical Chemistry
The main aim of antihyperlipidemic agents or lipid lowering agents is to decrease the
plasma cholesterol level in the plasma. The mode of action of these drugs can be either by
increasing the removal of lipoprotein from the blood or reducing the production of
lipoproteins. High ratio of HDL:LDL and high level of plasma cholesterol have high risk
of atherosclerosis. Many groups around the globe are working at different pharmacological
lipid lowering agents and trying to understand their mode of action and how cholesterol
metabolizes and how lipoproteins help to carry cholesterol into the plasma. A few
explanations for metabolism of cholestrol are as follows:
(i) Cholesterol synthesis inhibition (e.g., 3-Hydroxy-3-methylglutanyl-CoA (HMG-
CoA) reductase inhibition. Lovastatin can be a good medicine).
(ii) Alter the relative levels of different plasma lipoproteins (e.g., clofibrate, gemfibrozil,
nicotinic acid and possibly probucol, thyroid hormone, and androgens can be good
medicines).
(iii) Sequester bile acids formation in the intestine (e.g., cholestyramine and colestipol
can be good medicines).
(iv) Inhibit cholesterol absorption in the intestine (e.g., neomycin and plant steroids,
such as E-sitosterol can be good medicines).
6.2.7.1 Classification of Antihyperlipidemic Agents
6.2.7.1.1 HMG-CoA-reductase Inhibitors: e.g., Lovastatin, Simvastatin and Pravastatin.
6.2.7.1.2 Fibric acid derivatives: e.g., Clofibrate, Fenofibrate, Ciprofibrate, Bezafibrate
and Gemfibrozil.
6.2.7.1.3 Bile-acid sequestrants: e.g., Cholestyramine, and Colestipol.
6.2.7.1.4 Inhibition of LDL oxidation: e.g., Probucol.
6.2.7.1.5 Miscellaneous agents: There are few miscellaneous examples such as
E-Sitosterol, Nicotinic acid, Acipimox, Neomycin, Dextrothyroxine and
Metformin.
6.2.7.1.1 3-Hydroxy-3-methylglutanyl-CoA (HMG-CoA) Reductase Inhibitors
A new class of antifungal and lipid lowering agents are potent inhibitors of the enzyme
HMG-CoA reductase, which includes Compactin and Mevinolin. HMG-CoA reductase
plays a key role in the rate determining step of the endogenous synthesis of cholesterol. In
1976, Endo isolated Compactin from the culture of Penicillium species, while Mevinolin
(or monacolin K) was isolated from the cultures of Aspergillus and Monascus species. These
drugs are very effective in decreasing the hepatic cholesterol synthesis and finally help to
reduce the LDL cholesterol level.
Three statins, lovastatin, simvastatin (prodrug) and pravastatin are examples of this
class. The eliminating half-life of these is relatively short (1-3 hr), but duration of enzyme
inhibition is much longer. The first drug of this class, Mevastatin (1976) was isolated in
Japan from Pencillium species. But the first drug to be marketed from this class was
Cardiovascular Drugs 151
Lovastatin (1987) which was isolated from cultures of Aspergillus and Monascus (Fig. 6.27).
The success of Lovastatin, therefore, has prompted the development of additional synthetic
HMG reductase inhibitors resulting in the marketing of Pravastatin (epstatin) and
Simvastatin (synvinolin). Pravastatin was isolated from Absidiacoerulea.
O
Me
S
)
3
Fig. 6.27: HMG-CoA-reductase Inhibitors
HO
CoA
Pravastatin (R
Me
COOH
OH
1
O
= OH, R
HO
O
Me
F
Et
R
2
R
1
= H)
2
COO Na
OH
N
Fluvastatin
HO
Me
Lovastatin (R1=CH
Simvastatin (R
Mevastatin (R
O
O
1
1
O
O
= CH
= H, R
O
HO
R
R
1
, R2= H)
3
, R2= CH
3
= H)
2
HO
HMG CoA
Me
Et
2
6.2.7.1.2 Fibric Acid Derivatives
A series of Aryloxy-isobutyric acids was effective in reducing plasma concentrations of
triglyceride and cholesterol. Clorfibrate was the first compound of this class and clinically
effective for the treatment of hypertriglyceridemia. Several chemical analogs, congeners
and homologs, collectively referred to as fibric acids have been prepared with lesser
toxicity. One of these, Gemfibrozil, has been widely used (Fig. 6.28).
Me Me
O
Me
Me
Me
O
Me
Cl
Clorfibrate
O
O
Fig. 6.28: Fibric acid derivatives
O
Me
Fenofibrate
Cl
6.2.7.1.3 Bile Acid Sequestrants
Bile acids are the metabolic end-products of cholesterol which are secreted by the liver and
released into the intestine. About 98% of bile acids released into the gut are reabsorbed
through the enterohepatic circulation and suppresses the microsomal hydroxylase enzyme.
The microsomal hydroxylase enzyme is used in the synthesis of bile acid from the
cholesterol. Finally, enterohepatic reabsorptioin of the bile acids takes place and cholesterol
level is reduced. There are some bile acid-binding resins, viz., Cholestyramine and