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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5406_Библиотеки_им_академика_М_И_Перельмана.pdf
122 Pharmaceutical Chemistry
CH
Cl
2
KCN
CH2CN
+
H
EtOH
Esterication
CH2COOEt
COOEt
COOEt
Diethyl oxalate
EtONa
COOEt
COCOOEt
O
HN
HN
Phenobarbital
Et
O
HCl
180°C
-CO
COOEt
COOEt
EtBr
EtONa
Et
COOEt
COOEt
Urea
O
5.3.4.3 Mechanism of Action
The exact mechanism of action of phenobarbital is still an area of discovery. A recent study
shows that phenobarbital may selectively inhibit the spread and suppression firing from
the foci and selectively suppress abnormal neurons. At high concentration of the
administered drugs such as phenobarbital and phenytoin it may suppress high frequency
repetitive firing in neurons in culture through an action on Na
at high concentrations, barbiturates also block Ca
2+
currents (L- & N-type). GABA-
+
ion conductance whereas
benzodiazepine receptor contains allosteric regulator at the active site, thus phenobarbital
binds to these regulatory sites and elevates the GABA receptor-mediated current by
prolonging the openings of the Cl
–
channels. Excitatory responses, induced by glutamate
are also blocked by the phenobarbital that are actually mediated by the activation of the
AMPA receptor. Thus, therapeutic concentrations of phenobarbital may enhance GABAmediated inhibition and the reduction of glutamate-mediated excitation.
5.3.4.4 Metabolism
Phenobarbital, like the other anticonvulsant barbiturates, exhibits anticonvulsant effects
and antiepileptic activity only in doses that usually cause some sedation. These drugs have
low penetration into the blood brain barriers due to hydrophobic nature and it also slows
down renal elimination. Thus, it is excreted in the form of conjugated metabolites (~75%).
Phenobarbital participates very less in the conjugation reactions due to hydrophobic
nature, thus to make more reactive the hydroxyl group is introduced at aromatic side of
phenobarbital by using CYP450 enzyme. Phenobarbital is a potent liver-enzyme-inducing
agent and increases the ability of the liver to metabolize in the microsomal enzyme system
and thus most of metabolites are excreted through urine whereas very less amount through
faeces. Approximately 25–50% of a dose of phenobarbital is unchanged and excreted
through urine. Phenobarbital is metabolized primarily by hydroxylation to
5-p-hydroxyphenyl-5-ethyl-barbituric acid, an inactive metabolic product (Fig. 5.3). This is
Central Nervous System Agents 123
conjugated with glucuronic acid by UDP-glucuronosyl-transferases, and sulfuric acid by
sulfo-transferases which are inactive polar metabolites which are finally excreted through
the kidneys.
O
HN
O
HN
Me
O
O
HN
O
HN
Me
O
Glucuronyl conjugate Sulfuric acid conjugate
5.3.4.5 Side Effects
NADPH + H NADP
O
2
UDP-glucuronide
UDP
HO
O
O
Fig. 5.3: Active metabolites of phenobarbital
OH
OH
COOH
H
O
2
O
HN
O
HN
Me
O
PAPS
3'-P-AMP
O
HN
O
HN
Me
O
OH
O
OH
S
O
O
Common side effects include headache, nausea, vomiting, drowsiness, dizziness, lethargy,
depression, stomach ache, slow heart rate (bradycardia), low blood pressure (hypertension),
breathing problem, polydipsia (increase in thrust) and polyuria (increase in urine output).
Some severe side effects are nosebleeds, joint and muscle pain, seizures, constipation,
fever, skin rashes and nightmares.
Another example: Hexobarbital [5-(1-Cyclohexen-1-yl)-1,5-dimethyl barbituric acid]:
Knoevenagal condensation of cyclohexanone and methyl cyanoacetate gives alkylidene
compounds, which undergo double-bond shift to form cyclohexenyl intermediate. Active
hydrogen is methylated with dimethyl sulphate; this, followed by condensation with
guanidine in the presence of sodium ethoxide, gives the diimino analogue of barbiturate.
N-Methylation followed by hydrolysis affords hexobarbital.
Chlordiazepoxide (trade name librium) is the first benzodiazepine and discovered in 1954
serendipitously by Leo Sternbach (Austrian scientist from Hoffmann-La Roche pharma). Later,
Chlordiazepoxide was synthesized from a dye, quinazolone-3-oxide.
124 Pharmaceutical Chemistry
COOM e
+
O
CN
Base
COOMe
CN
Me2SO
EtONa
NH
2
COOMe
Me
CN
H
N NH
2
EtONa
2
Me
O
Me2SO
NH
N
NHHN
H
N-Methylation
2
Me
O
Me
N
N
NHHN
H
H2SO
4
Hydrolysis
Hexobarbital
O
Me
O
Me
N
N
O
H
5.3.5 Benzodiazepines
It is a fused product of benzene and diazepine ring system. Most of these drugs contain the
5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one substructure.
They include wide range of pharmacological profiles, low toxicity and good therapeutic
quotient thus it is a better drug choice. Benzodiazepines are widely used as muscle relaxants
(anxiolytics/skeletal) and sedatives. They are also used for the symptomatic relief of
anxiety, tension, psychoneurosis, acute alcohol withdrawal, neurosis, skeletal muscle
spasm, and management of status epilepticus. The long term use of benzodiazepines can
cause physical dependence.
Benzodiazepines lead to CNS depression and coma, or paradoxical excitation. Fewer
studies have reported deaths and severe CNS depression when they are administered
alone. The most common adverse effects of benzodiazepines are sedation, intellectual
impairment, dysarthria, somnolence, diplopia and ataxia. Overdose of these drugs can
increase toxicity level in adults while young children or infants and elders are more
susceptible to the CNS depressant action. Hypotension and apnoea may develop after
intravenous administration of benzodiazepines. Having short periods of therapeutic doses
may increase dependency in patients.
5.3.5.1 Mechanism of Action
Benzodiazepine receptors are present in the brain and they form part of a GABAA receptorchloride ion channel macromolecular complex. Binding of benzodiazepines to these
receptors activates GABA
receptor and increases chloride conductance by increasing the
A
frequency of opening chloride channel. These, in turn, inhibit neuronal activity by hyperpolarization and depolarization block. Benzodiazepine binds at the interface of D- and J-
subunit on the GABA
(viz., D
, D2, D3, D4 and D5 containing GABAA receptors) to bind at the D-subunits. Thus
1
benzodiazepines have no affinity for D
receptor. Benzodiazepines require histidine amino acid residue
A
and D
–
4
subunits containing GABAA receptors
–
6
because they contain arginine residue instead of a histidine. Some barbiturates, certain
anaesthetics and neurosteroids can bind to the other sites on the GABA
receptor.
A
Central Nervous System Agents 125
Sometimes, GABAA receptors are sensitive to benzodiazepines then they bind at the
interface of both D- and J-subunits. For example, when benzodiazepine binds to the
GABA
frequency of hyper-polarizing the membrane and opens the available Cl
receptor (receptors those contain higher affinity of neurotransmitter) increases the
A
–
ion channels and
finally exerts anxiolytic and sedatory effects. Thus, we can categorise benzodiazepine
derivatives for their high affinity towards various subunits. If high affinity is associated
towards GABA
associated towards GABA
receptors D1-subunit it results in sedation, whereas if high affinity is
A
receptors D
A
and/or D
–
2
subunits it results in anti-anxiety
–
3
activity.
5.3.6 Diazepam
Diazepam is a benzodiazepine derivative (trade name, Valium) that acts
as CNS depressant and anxiolytic. It is also effective as a sedative and
Me
O
N
mainly used in anxiety states. It is used to treat a wide range of disorders
including anxiety, muscle spasms, seizures, troubled sleeping,
Cl
N
benzodiazepine withdrawal syndrome, alcohol, and restless leg
syndrome.
Diazepam is used in treating convulsions that arise due to a variety of
Diazepam
causes; however benzodiazepines are used in anticonvulsant effects and
sometimes in the long-term treatment of epilepsy. It can be taken orally, intravenously,
inserted into the rectum and injected into the muscle. Long-term use can result in
convulsions, memory loss, habituation and withdrawal syndrome.
In the brain, diazepam is used as an agonist of the GABA
receptor which is used as a
A
tranquilizer in epilepsy. Hydroxylation and demethylation of diazepam are performed
with the help of cytochrome P450 enzymes and results in the metabolite, oxazepam
(Fig. 5.4). Oxazepam usually does not participate in phase-I metabolism and thus it is
eliminated more rapidly than diazepam. Hence, it has some advantage when used as a
sleeping aid.
Me
O
N
Cl
N
CYP450
Cl
H
O
N
OH
N
R
Diazepam Oxazepam
Fig. 5.4: Active metabolite of diazepam
R
Intravenously administered diazepam is the drug of choice for status epilepticus.
Diazepam often provides rapid control of status epilepticus seizures. Because of its high
lipid solubility, intravenously administered diazepam enters the CNS with great rapidity.
126 Pharmaceutical Chemistry
The initial high brain concentration, however is quickly reduced due to redistribution of
the drug, and status epilepticus may return. Concomitant intravenous injection of diazepam
and phenobarbital has been suggested to overcome this difficulty. Orally administered
diazepam is much less effective because tolerance to the anticonvulsant effects of diazepam
develops within a short period of time. On the other hand, when diazepam is effective in
seizure control side effects, particularly sedation are a serious limiting factor.
5.3.6.1 Specification
Name : 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-
2-one or 7-Chloro-1-methyl-5-phenyl-3H-1,4- benzodiazepin-2(1H)-one
Molecular formula : C
16H13
ClN2O
Molecular weight : 284.76 g/mol
Melting point : 131.5–134.5°C
Physical State : White or yellow crystalline solid, odourless, slightly bitter taste
Solubility : Slightly water soluble, soluble in alcohol and chloroform
5.3.6.2 Synthesis of Diazepam
Friedel-Crafts acylation of 4-chloro aniline with corresponding benzoyl chloride in the
presence of Lewis acid affords benzophenone derivative. Acetylation of an amino group
with chloroacetyl chloride gives the chloro acetamide. Heating with ammonia undergoes
cyclization reaction to form nordiazepam; N-methylation from methyl iodide affords
diazepam.
COCl
NH
2
+
Cl
O
Cl
Cl
NH
O
R
R
NH
3
Cyclization
ZnCl
2
Friedel-Crafts
acylation
Cl
Nor-Diazepam
Cl
H
O
N
N
R
NH
CH3I
DMF
2
O
R
Cl
Diazepam (R = H)
ClCH2COCl
Me
N
O
N
R
5.3.6.3 Synthesis of other Benzodiazepam Derivatives
Synthesis of diazepam was first described by Sternbach et al. in 1961. Reaction between
p-chloroaniline and benzoyl chloride led to 2-amino-5-chloro benzophenone which later
Central Nervous System Agents 127
converted to the oxime by reacting with hydroxylamine. Oxime on cyclization in the presence
of chloroacetyl chloride, however ring enlargement can take place in the presence of alkali
and treatment resulting into 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzo-diazepin-2-one-4oxide and finally it is reduced and methylated to benzodiazepine derivatives.
O
NH
2
COCl
ClCH
Cl
Cl
O
R
H
O
N
N
O
R
2
Acylation
(CH
CO)2O
3
Rearrangment
Cl
Cl
NH
Cl
OH
NH
O
OCOCH
2
3
Saponification
Cl
NaOH
O
R
H
N
N
R
O
Cl
NH
NOH
R
Cl
Oxazepam (R = H)
Lorazepam (R = Cl)
Cyclization
Me
N
N
R
O
OH
Examples: Prazepam: Synthesized by alkylating nordiazepam with cyclopropylmethylbromide; Halozepam: Synthesized by alkylating nordizepam with 1,1,1-trifluoroethylbromide (BrCH
diethyl-aminoethylchloride (ClCH
with BrCH
(R = NO
2
followed by the treatment with P2S5 to convert C=S; Clonazepam:
2CF3
) Obtained from nordiazepam; Oxazepam: 7-Chloro-1,3-dihydro-3-hydroxy-5-
); Flurazepam: Synthesized by alkylating nordiazepam with
2CF3
NEt2) and R = F; Quazepam: (R = F) Alkylation
2CH2
phenyl-1,4-benzodiazepine-2-one.
5.3.6.4 Mode of Action
Diazepam has therapeutic and toxic effects on CNS GABA activity. GABA acts as an
inhibitory neurotransmitter that mediates pre- and post-synaptic inhibitions in the whole
CNS. Benzodiazepines and diazepam usually bind to the benzodiazepine receptors that
enhance/facilitate GABA activity which is part of a complex including benzodiazepine
receptor, GABA-receptor and barbiturate receptor. This binding of complex helps to
enhance CNS inhibition by GABA. It is also believed that an anticonvulsant effect due to
diazepam is carried out by a similar mechanism or possibly by involving various subtypes
of the receptor.
There are two different zones at the receptor sites where benzodiazepine binds and is
classified as Type-I (chloride independent) and Type-II (chloride dependent). It is believed
that Type-I receptor stimulants are responsible for anxiolysis whereas Type-II receptors
are responsible for ataxia and sedation. Diazepam is believed to be involved in the
inhibition of a presynaptic-neuronal conduction at GABA mediated sites in the spinal
128 Pharmaceutical Chemistry
cord. Preanaesthetic dose of diazepam is responsible to elevate the anterograde amnesia
that probably arises by disorder of the memory trace in the CNS, however amnesia due to
diazepam is still doubtful but it is suggested that it may also have some anticholinergic
effects. Anticonvulsant effects may be lost due to generation of tolerance due to prolong
therapy usually 6-12 months of therapy, thus it can’t be used for the chronic treatment of
seizure disorders.
5.3.6.5 Metabolism
Hepatic enzymes are mainly responsible for diazepam metabolized, however very little or
no diazepam as such is excreted through the urine. The major active metabolite is
nordiazepam and the minor active metabolites is temazepam. Nordiazepam (or
desmethyldiazepam) is one of most active metabolites of diazepam which is produced by
hepatic N-demethylation. Nordiazepam is generally hydroxylated to produce oxazepam,
which later forms glucose conjugated metabolite known as oxazepam glucuronide. Minor
amount of diazepam and its metabolite nordiazepam (major) is usually found in the blood
through urine at almost the same rate as they are generated. Diazepam was excreted
through urine in the form of glucuronide and sulphate conjugates. Chronic dose of
diazepam may slow down the level of deposition of diazepam and its metabolites.
5.3.6.6 Adverse Effects
Enhanced CNS-GABA activity has been observed and cognitive and psychomotor abilities
may be impaired at therapeutic doses. Some common adverse effects are ataxia, anxiety,
anterograde amnesia, irritation, dizziness, vertigo, motor incoordination, fatigue, mental
confusion, dysarthria, somnolence, and aggressive behaviour while thrombophlebitis and
local phlebitis can occur with intravenous injection. Arterial necrosis can occur with intraarticular injection. Administration of high dose of diazepam and other related
benzodiazepine derivatives can cause physical and psychological dependence for
prolonged periods of time.
QUESTIONS
1. What are central nervous system (CNS) agents?
2. What are analgesics and how are they used in Parkinson’s disease?
3. What are the causes of Parkinson’s disease?
4. What are sedative-hypnotic drugs?
5. What are antipsychotic drugs?
6. What are antidepressant drugs?
7. What are CNS stimulants?
8. What are anti-epileptic drugs?
9. What is anaesthesia?
Central Nervous System Agents 129
10. What are barbiturates? Explain their mechanism of action.
11. What is the general synthesis of barbiturates?
12. What are anticonvulsants and how do they act on human hosts?
13. What is phenobartital? Write down the synthesis.
14. What is the mode of action of phenobarital?
15. How does phenobartital get metabolized?
16. What are the active metabolites of primidone?
17. What are benzodiazepines and what is the mode of action of these drugs?
18. What is diazepam. Write down the synthesis.
19. What is the active metabolite of diazepam?
6
Cardiovascular Drugs
6.1 INTRODUCTION
Cardiovascular diseases and diabetes are among the leading causes of mortality and
morbidity in the civilized world. Therapeutic approaches to these diseases, in general,
require a significant number of drugs and concomitant administration of a large group of
medications that in many instances leads to significant drug interaction and target organ
toxicity. Drugs designed for cardiovascular diseases have effects on the liver in addition to
those organs. For example, hypolipidemic agents can induce systemic adverse reactions in
addition to hepatic changes. Nicotinic acid in a sustained-release formulation causes severe
or fatal liver injury among other symptoms. Elevated phospholipid levels were reported
in the serum and liver, and generalized phospholipidosis developed in patients receiving
a coronary vasodilator agent (diethylaminoethoxyhexestrol) or an antiarrhythmic agent.
Impaired hepatic function can emerge as a result of many drugs taken either singly or
in combination. Thus, it is often difficult to establish a causal relationship between the
applied drug and the development of liver injury. However, the relationship can be
established with certainty when the same liver reaction is observed after a repeat
administration of the drug. When the response pattern is characteristic, such as
phospholipidosis or non-alcoholic steatohepatitis in response to a vasodilator or
antiarrhythmic, the hepatotoxicity can be clearly established.
The morphological, biochemical, and clinical signs of the liver injury brought about by
cardiovascular or antidiabetic drug ranges from mild to severe with acute to chronic
pathological response including steatosis, cholestasis, hepatitis, granulomatous hepatitis,
cholelithiasis and fibrosis, and cirrhosis. Drugs also can cause one or more of these changes
simultaneously. Drug induced hepatic alterations have been reported in 5-35% of patients
receiving cardiovascular or antidiabetic medications. The increasing numbers of these
patients in the world emphasized the importance of recognizing drug-induced adverse
reaction as early as possible in these disease groups.
6.2 CARDIOVASCULAR DRUGS
Cardiovascular drugs encompass a large number of prescriptions that are used to control
heart disorders. These drugs are a complicated group of chemical moieties and used
Cardiovascular Drugs 131
for multiple heart conditions, viz., congestive heart failure (CHF), hypertension and
arrhythmia — lifestyle of patients. For example, Propranolol is a common cardiovascular
drug that can be used to treat hypertension as well as arrhythmias.
The variety and scope of cardiovascular drugs have increased tremendously in the past
few decades. In the 1950s, effective oral diuretics became available which dramatically
changed the treatment of heart failure and hypertension. In the mid-1960s, E-blockers, a
special class of drugs, was discovered which led to major changes in physicians’ ability to
treat patients with hypertension or angina pectoris. In 1980s, Ca-ion channel blockers and
angiotensin-converting enzyme (ACE) inhibitors were widely used in patients having
hypertension, heart failure, and coronary artery disease to be treated more effectively. The
development and use of thrombolytics, the “clot busters,” have revolutionized our ability
to treat patients having a heart attack. After 1990s powerful tools of genetic engineering
produced new and even more effective drugs to prevent and treat the patients with heart
diseases.
In a broad sense cardiovascular drugs include antiarrhythemics, coronary vasodialators
(example: organic nitrates), antihypertensive agents (angiotensin-converting enzyme
inhibitors, D-adrenergic agonists, E-adrenergic blocking agents, Ca-channel blockers), and
lipid-regulating agents (hypolipidemic and cholesterol-lowering drugs).
Cardiovascular drugs can be categorized as follows:
1. Cardiac glycosides
2. Antiarrhythmic agents
3. Antianginal agents
4. Antihypertensive agents
5. Anticoagulants
6. Vasodilators
7. Antihyperlipidemic agents
8. Hypoglycemic agents
6.2.1 Cardiac Glycosides
These is an important class of naturally occurring drugs which are used in the treatment
of CHF. Most glycosides are obtained from leaves of the foxglove, Digitalis purpurea or
Digitalis lanata and from the seed of Strophanthus gratus or Strophanthus kombe. Cardiac
glycosides are generally formed by four units of sugar and an aglycone (or genin).
Aglycones are potent and play a crucial role in cardiac activity while sugar acts as carrier
for aglycone. The effect of glycosides on the heart was first noticed by William Withering
in 1785. This discovery was an example of folk medicine, known to ancient Romans and
Egyptians.