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152 Pharmaceutical Chemistry
Colestipol, which forms a non-absorbable complex with bile acids. Thus, these drugs help
to reduce the bile acid level from the gut and inhibit their reabsorption ability and they are
similar in the mode of action. Cholestyramine and Colestipol are also examples of anion
exchange resins which remain undigested and non-absorbable in the gastrointestinal tract
(GIT).
*
*
Cholestyramine
*
NMe3Cl
Fig. 6.29: Bile acid sequestrants
n
*
N
CHOH
CH
2
N
*
Colestipol
NMe
NMe
n
2
2
These resin drugs are used among patients suffering from high LDL levels and in
hypercholesterolemia in combination with cholestyramine and nicotinic acid. These resins
have anionic nature, thus these can be bound with other drugs, viz., thyroxine, vitamin C,
digitalis glycosides, iron and Warfarin, etc. (Fig. 6.29).
6.2.7.1.4 Inhibition of LDL Oxidation
Macrophages help to convert oxidised LDL into foam cell which is a hallmark of
atherosclerosis. Probucol is the most potent cholesterol lowering agent of a series of
alkylidenedithiobisphenols (Fig. 6.30) apparently through stimulation of non-receptor
mediated clearance pathways. It is an antioxidant that partitions into lipophilic media
such as LDL particles, where it can prevent or terminate the oxidative process.
HO
CMe
3
Me
Me
CMe
3
OH
Me3C S S
Fig. 6.30: Probucol
CMe
3
6.2.7.1.5 Miscellaneous Agents (Fig. 6.31)
(a) Nicotinic acid: It is generally given with bile acid binding resin and used in the
treatment of hyperlipoproteinemia, however it lacks hypolipidemic activity. It
helps to enhance the activity of lipoprotein lipase, resulting into low circulating
VLDL level which finally leads to low circulating LDL level.
(b) E-Sitotsterol: It has the structural similarity with cholesterol, thus it may help to
replace the cholesterol easily resulting in the reduction of cholesterol level.
Cardiovascular Drugs 153
(c) Acipimox: Acipimox is nicotinic acid derivative and 20 times more active than
nicotinic acid. It acts by inhibiting adipose tissue lipolysis.
(d) Neomycin: It is an amino glycoside antibiotic and exerts its hypolipidemic activity
only if it is subjected to oral administration.
(e) Metformin (N,N-dimethyl biguanidine): It has no effect on cholesterol biosynthesis
but it affects the lipoprotein composition. It produces about 50% reduction in the
serum triglyceride level. It is also a hypoglycemic agent and lowers blood glucose
level.
(f) Dextrothyroxine: It increases the hepatic catabolism of LDL and thus lowers the
plasma concentration of LDL particles.
(g) Other agents having hypolipidemic activity include sucrose polymers,
eicosapentaenoic acid, propranolol and pindolol. Similarly, estrogens also interfere
in the fat metabolism resulting into a decrease in plasma LDL concentration and an
increase in plasma HDL concentration. These metabolic effects of estrogens are
partly opposed by progestin.
COOH
N
Nicotinic acid
Me
Me
Me
HO
b− Sitosterol
Fig. 6.31: Miscellaneous antihyperlipidemic agents
Me
Me
HO
I
I
O
I
I
D-Thyroxine
NH
2
COOH
6.2.8 Hypoglycaemic Agents
Hypoglycaemic agents are also known as blood sugar lowering agents and are used in the
treatment of diabetes mellitus. Irregular food habits, irregular functioning of organs and
genetic disorders, abnormal metabolism of carbohydrates, fats and proteins generally
cause diabetes. Pancreas secrete three peptide hormones and specifically play a key role in
the metabolism of carbohydrates, lipids and amino acids which insulates the glucagons
and somatostatin. There are two types of conditions of diabetic patient: one is
hyperglycaemia (when sugar level is more than the normal range—70-90 mg per 100 mL)
and the other is hypoglycaemia (when sugar level is less than the normal range—70-90 mg
per 100 mL). High sugar level is generally characterized by sugar present in the blood and
also by checking the presence of sugar in the urine (condition is called glucosuria).
6.2.8.1 Types of Diabetes
Under current clinical terms, diabetes mellitus can be sub-categorised as under:
(a) Insulin-dependent, type I (IDDM or juvenile or brittle or unstable diabetes),
(b) Non-insulin dependent type II (NIDDM or adult onset or maturity onset diabetes),
154 Pharmaceutical Chemistry
(c) Other types include
(i) Insulin receptor abnormalities
(ii) Hormonal etioloy, e.g., acromegaly
(iii) Pancreatic disease
(iv) Genetically related abnormalities
(v) Drug-induced conditions.
6.2.8.1.1 Insulin Dependent Diabetes Mellitus (IDDM)
IDDM arises when cells fail to produce insulin in the required quantity and this insufficient
amount of insulin fails to metabolise, specially carbohydrate as the energy source. Thus, to
overcome this problem of energy production in the body, body always attempts alternative
pathways such as metabolism of fats and proteins, thereby the amounts of nitrogenous
and ketonic waste material both travel to the blood and urine. This problem can cause
specific symptoms, viz., major infection, poor wound healing, nausea, vomiting, tiredness
and drowsiness, etc. It is believed that the viral attack on genetically susceptible host (who
have diabetic history genetically) could be a good platform or environment to increase the
diabetic condition. Recent studies on mice revealed that ‘encephalomyocarditis’ virus is
responsible to produce diabetes. It is postulated that a viral attack may trigger an auto
immune reaction which destroys some of the pancreatic E-cells which result in the overall
reduction of E-cells while D, D and PP cells are unaffected. Reduction in E-cells may occur
due to the patient’s exposure to certain chemicals or other miscellaneous environments.
The E-cells help in secretion of insulin in the liver, thus, if E-cells are reduced then there is
more probability of reduction in insulin secretion. There are a few drugs which can destroy
E-cells, viz., alloxan, uric acid, dehydroascorbic acid, quinolones and streptozocin.
6.2.8.1.2 Non-Insulin Dependent Diabetes Mellitus (NIDDM)
NIDDM is specific towards genetic and hereditary diabetes and generally found in old
people while it is more common in women. The patient suffering from NIDDM retains a
considerable population of functioning cells (especially D-cells are increased in population)
which makes insulin deficiency less severe and ketosis does not occur. Thus, patients
suffering from NIDDM may not need any treatment except a strict dietary restriction.
6.3 ORGANIC NITRATES
Organic nitrates are useful therapeutic agents for the symptomatic treatment of angina
pectoris. Their duration of activity may be related to their prerequisite metabolism to show
the circulatory effects. Organic nitrate biotransformation was ablated by CYP450 inhibitors
and biotransformation of glyceryl trinitrite was catalyzed by isoenzymes induced by
phenobarbital. Organic nitrates are classified into short acting (amyl nitrate, isosorbide
dinitrite) and long acting (erythrityl tetranitrate, pentaerythritol tetranitrate). Nitroglycerine
may be short or long acting based on the pharmaceutical formulation. Most of the clinical
toxicity of nitrates is derived from circulatory effects, including methemoglobinemia.
Cardiovascular Drugs 155
Significant paucity of liver toxicity is reported with these agents. However, since these are
combined usually with other vasodilators, including Ca-channel blockers or E-adrenoceptor
antagonists, hepatic reactions may emerge due to metabolic interactions.
There is hepatic CYP450 dependent biotransformation of organic nitrates. When glyceryl
trinitrate (GTN) was incubated with aortic supernatant and rat hepatic microsomes, there
were concentration-dependent increases in guanylyl cyclase activity pointing to a role of
nitric oxide (NO). The guanylyl cyclase was increased with phenobarbital induced
microsomes and reduced by metabolic inhibitors. GTN is mutagenic to Salmonella TA1535
and the mechanism of DNA damage may be via NO generation due to metabolic reduction.
GTN also induces hepatocellular carcinoma in rats. NO-P53 mutations were found in the
tumour but K-ras point mutations occurred in half of the tumours. Sodium nitrate given
to Wistar rats caused liver tumours including hepatocellular carcinoma and haemangiosarcoma, whereas in another study in F-344 rats, sodium nitrite did not cause tumours. In
contrast, pentaerythritol tetranitrate administered to F-344 rats and B6C3F1 mice was
essentially non-toxic and did not induce liver neoplasia. These studies do not provide
sufficient evidence to confirm a liver neoplastic potential upon long-term use of these
agents.
6.3.1 Glyceryl Trinitrite (GTN, Nitroglycerin; 1,2,3-Propanetriol Trinitrate; Glonoin;
Trinitrin)
Glyceryl trinitrate ointment is an effective epicutaneous vasodilator.
H2C–ON
එ
HC–ONO
එ
H
C–ONO
2
2
2
2
6.3.1.1 Specifications
Name : 1,2,3-Propanetriol
Molecular formula : C
3H5N3O9
Molecular weight : 227.09 g/mol
Physical state : Colourless or white to pale yellow, thick odourless, flammable,
explosive liquid having sweet taste
Solubility : Slightly soluble in water and soluble in most of the organic solvents.
6.3.1.2 Synthesis of GTN
Glyceryl trinitrate (nitroglycerin; nitro glycerol; trinitrin; trinitroglycerin) is the nitric acid
ester of glycerin, and may be prepared by treating dehydrated glycerin with a mixture of
fuming nitric acid and sulphuric acid. Concentrated glyceryl trinitrate solution is a 9–11%
solution of propane-1,2,3-triol trinitrate in ethanol (96%). It is a clear, colourless to pale
yellow solution.
CH2OH
CHO
CH2OH
3HNO
H
H2SO
3
4
CH2ONO
CHONO
CH2ONO
1,2,3-Propanetriol
2
2
2
+
3H
O
2
156 Pharmaceutical Chemistry
6.3.1.3 Metabolism of GTN
The classical organonitrate was the drug of choice for the treatment of angina pectoris.
After oral administration, it is metabolised rapidly in the intestinal wall and liver, and red
blood cells to less active dinitrates, mononitrates and nitrites. Kinetic studies in patients
with renal failure have not been reported, but no significant changes should be anticipated.
The sustained release forms are not recommended since oral bioavailability is so poor and
tolerence is favoured. Bioavailability is much greater by the buccal and the sublingual
routes. By the sublingual routes, the vasodilator effects of the the drug appear in 2-3
minutes and lasts for about 20 minutes, but exercise tolerance may be increased for as long
as an hour in some patients. Buccal tablets, if retained in the mouth, release nitroglycerine
for 3-5 hours. Sustained release of oral capsules and tablets maintain plasma levels for 8-12
hours. A nitroglycerine ointment can provide therapeutic blood levels for 2-12 hours per
application. Transdermal preparations may sustain plasma levels for 24 hours or longer.
An intravenous formulation is available but has a short life of 1-5 minutes and, therefore,
must be administered via continuous infusion.
Cerebral vasodilation may cause transient headaches. Paradoxical angina occurs when
the dose is too large and blood pressure falls too low to sustain coronary flow. Dizziness,
nausea, and other symptoms of hypertension also occur. High, respective doses can cause
methemoglobinemia. Generally, GTN is increasingly used in hypertensive emergencies
(including renal hypertension) such as dissecting aneurysm and acute left ventricular
failure and to control the blood pressure during and after open heart surgery.
6.3.1.4 Mode of Action
Most clinicians are aware that GTN acts as a dilator of coronary arteries and venous
capacitance vessels, and as such it finds use in the treatment of angina pectoris and left
ventricular failure. However, it is perhaps less widely appreciated that GTN at higher
doses dilates both resistance arterioles and veins. Variable absorption and rapid metabolism
preclude the use of oral dosage, and sublingual and percutaneous routes are more suited
to low dose administration.
GTN has dose related antihypertensive effects when given by continuous intravenous
infusion. The onset and offset are rapid (within minutes) and this facilitates rapid titration
of dose against effect. Infusion may be continued for days or weeks if necessary. GTN
infusion may be accompanied by an increase in the heart rate, whereas myocardial oxygen
consumption may decrease.
Vasodilator agent, anginine is used as a pain reliever in angina pectoris and coronary
arteries which may be the result of myocardial ischaemia, secondary to coronary artery
disease. Anginine helps to increase blood flow to ischemic area by distributing blood flow
from collateral channels and epicardial to endocardial regions. Anginine plays a major role
by reducing oxygen demand by increasing venous capacity in the peripheral veins and
thus, reduce ventricular volume. The overall effect of the mode of action of anginine results
Cardiovascular Drugs 157
in the reduction of arterial pressure which will help in reduction of myocardial oxygen
demand.
Vasodilator agent, anginine has similar mode of action as GTN. It activates guanylate
cyclase in vascular smooth muscle cells by free radical nitric oxide and thus results in an
increased synthesis of cGMP. cGMP is involved in the activation of its dependent protein
kinase with resultant phosphorylation of smooth muscle proteins and subsequent
dephosphorylation of the myosin light chain and consequent relaxation of smooth muscles.
6.3.1.5 Adverse Effects
Acute toxicity which has not yet been reported, but some adverse effects have been
reported, viz., decreased systemic and diastolic blood pressure and cardiac output with
resulting pallor, weakness, dizziness and activation of compensatory sympathetic reflexes.
Abrupt withdrawal from chronic exposure in industrial workers has been considered to
cause ischemic cardiac injury.
QUESTIONS
1. What are cardiovascular drugs?
2. What are cardiac glycosides? Explain the mode of action.
3. Which drugs are useful for patients affected by abnormal rhythm and heart rate?
4. Write down the classification of antiarrhythmic agents.
5. What are the differences between Class-IA/IB/IC antiarrhythmic drugs?
6. How are Class-I/II/III/IV/V antiarrhythmic drugs different from each other?
Explain.
7. What are antianginal agents? Specify their classification.
8. What are antihypertensive agents?
9. What are D-adrenergic antagonists? Explain with a suitable example.
10. What are the drugs responsible for depleting neurotransmitter?
11. What are vasodilators? Explain with an example.
12. What are diuretics? Explain with an example.
13. What are anticoagulants? Explain how Heparin acts as an anticoagulant?
14. What are antihyperlipidemic agents?
15. What is the difference between high density lipoproteins (HDLs) and low density
lipoproteins (LDLs)?
16. What are hypoglycaemic agents?
17. How can diabetes be categorised?
18. Write a note on organic nitrates.
19. How can glyceryl trinitrite be synthesized?
20. What are organic nitrates and how glyceryl trinitrite acts on the host?
7
Anti-Leprosy Drugs
7.1 INTRODUCTION
Leprosy is one of the ancient diseases known to man and it was the first disease for which
an invading microorganism was proposed as the causative agent. It is presently one of the
six major world diseases which are the target of World Health Organization’s (WHO)
special programmes. Leprae, is a rod-shaped bacillus that is an obligate intracellular (only
grows inside of certain human and animal cells) bacterium. Mycobacterium leprae is termed
an “acid fast” bacterium because of its chemical characteristics. Leprosy, a chronic infectious
disease caused by M. leprae, was identified by G. H. A. Hansen in 1873. The causative agent
is M. leprae, a noncultivable but close relative of M. tuberculosis which is the other major
mycobacterial human pathogen. M. leprae is an obligate intracellular parasite which has a
tendency to skin and peripheral nerves. It is described as an organism of high infectivity
but low pathogenicity. This means that only a relatively small proportion of people infected
by the bacillus go on to develop the disease. The disease itself is probably transmitted by
mucosal discharge from the nose and mouth, spitting, nose blows, etc. It has a long
incubation period, generally 2-5 years, and is described as a bipolar disease. At one end of
the bipolar scale is lepromatous leprosy (LL, the patient has large number of bacilli present
and large number of antibodies to the bacilli but a compromised cell mediated immune
response (CMI) which cannot effectively kill and clear the parasite). On the other end of
the scale is tuberculoid leprosy (TL, the patient has a few bacilli and an efficient CMI).
Between the two poles of the disease spectrum, there are various intermediate states which
are characterized by bacteriological, immunological and clinical features.
The bacteriological classification of the disease/organism includes the bacteriological
index (BI), which is simply the number of bacilli (expressed on a logarithmic scale), and the
morphological index (MI). The MI attempts to express the viability of the bacilli based on
the staining characteristics: solid staining bacilli are regarded as viable while those with
obvious fragmented staining are thought to be nonviable. The MI is expressed as the
percentage of solid staining to nonstaining bacilli. Such assessments obviously require
skilled operators but even then the MI, which is often low or very low, varies enormously.
This is important in both in vitro and in vivo drug testing systems as the viability of the
innocula used is crucial for a successful test. More recently, the viability of bacilli has been
assessed by alternative staining and counter-staining techniques using fluorescein diacetate,
Anti-Leprosy Drugs 159
which is hydrolysed by esterases in the live bacilli to give a green fluorescence, and ethidium
bromide, which only penetrates dead bacilli and provides an orange background. Rhodamine
123, and cationic dye, has been used to identify viable cells which have an intact
transmembrane potential along which the dye passes and accumulates in the cell.
Leprosy is known as a great ‘mimic’ of other diseases. Its diagnosis, particularly in the
early stages, requires careful and perceptive clinical judgement. Unless early diagnosis is
made and prompt therapy given the subsequent damage to peripheral sensory, motor, and
secretion controlling nerves leads inexorably to extensive tissue damage and disfigurement,
paralysis, blindness, and loss of fingers and toes.
7.2 THE ORGANISM
The organism M. leprae is a large cigar-shaped bacillus, 6-8 Pm u 0.5 Pm. Until the recent
discovery of the nine-banded North American armadillo as a suitable alternative host, the
only reliable source of the bacilli was the human leprosy patient. The supply of M. leprae is
very limited. The use of most of the laboratory supplies of M. leprae in vaccine preparation
means that little is available for other studies. Nevertheless some studies of the biochemistry
of the organism in both the whole and broken cell systems have been carried out. In line
with the variable viability of the bacilli, its slow growth, and the present inability to maintain
the organism for any length of time (~14–20 days) in any culture medium, only quite low
levels of metabolic activity have been observed. Some of the claims concerning unusual or
unique metabolic activity in M. leprae remain highly contentious, particularly the presence
of a unique dihydroxyphenylalanine (DOPA) oxidase enzyme. The structure and chemistry
of the distinctive cell wall and the identification of a unique phenolic glycolipid with
pronounced immunostimulant properties provide somewhat more secure grounds for
new drug development.
7.3 DRUG TESTING SYSTEMS
The classical and now universally accepted in vivo system is the mouse footpad test;
however it is debatable. The mouse, a very poor host for M. leprae, will allow the
bacilli to multiply following a injection into the hind footpad. Growth is very slow.
Drugs under screening are administered at various well-planned dose levels, as a
percentage by weight, in the mouse feed. After six months, the first measurements
of growth (by counting bacilli present) in control mice are made. Further counts are
made at 2–4 weeks interval over the next six months. The results are usually complete
after twelve months. A number of variations in the procedures allow drugs to be
classified as bacteriostatic or bactericidal. Both the Armadillo (mouse-like animal)
and the severely immuno-compromised mouse (nude Athymic mouse) will allow
more extensive growth of M. leprae, but these are not generally used for drug testing.
The footpad test is time consuming and expensive so other cultivable mycobacteria
have been used as in vitro model systems to test drug candidates; the organisms used
160 Pharmaceutical Chemistry
include M. tuberculosis, M. smegmatis, and other mycobacteria, and the so-called ‘M.
lufu’. Such models have some value but even M. tuberculosis, the most widely used,
is sensitive to some drugs which do not affect M. leprae (e.g., isoniazid, pyrazinamide,
and ethambutol) and has only little or no susceptibility to drugs which are active
against M. leprae, e.g., Dapsone.
The inadequacies of both the footpad and other cultivable mycobacteria to provide
a rapid and accurate assessment of new candidate drugs has led to the use of a
variety of alternatives in vitro systems which utilize M. leprae either alone or after
incorporation into human or mouse macrophage, a host cell occupied by the bacillus
in vivo. These tests rely on the measurement of the uptake and/or utilization of radio
labelled substrates (e.g., DOPA, thymidine) or changing levels of a key intracellular
indicator, e.g., adenosine triphosphate, or on changes in macrophage cell membrane
expression associated with the presence of live bacilli. These tests are currently under
evaluation by the WHO but, at present; seem only capable of providing an
approximate identification of activity. Recently, laser microbe mass analysis
(LAMMA) has been used to study intracellular
23Na+/39K+
ratios in single cellsuntreated (1:10) and dapsone treated (10:4). In addition, the fingerprint mass spectra
arising from the organic material in the cells were also analysed by non-linear
mapping techniques and could be divided into treated and untreated groups. The
cation ratios correlated with ATP content are measured on the same cells.
7.4 CHEMOTHERAPY
Chemotherapy for leprosy treatment started in 1940s with the introduction of sulphones.
Dapsone is a sulfone derivative, mostly used for the treatment of leprosy. However, the
widespread emergence of dapsone-resistant strains of M. leprae in lepromatous leprosy
patients on dapsone monotherapy has forced leprologists to develop a rationally sound
combination chemotherapy involving companion antileprosy drugs. The bacteriological
and pharmacological activities of these drugs have been evaluated and compared by
Colston, et al., dapsone, clofazimine (a phenazine derivative), rifampicin and ethionamide/
prothionamide are the only bactericidal drugs being considered for limited duration
multidrug regimens. Thiacetazone (thiosemicarbazone) and acedapsone (diacetyl
dapsone), which exerts its antibacterial activity on conversion to dapsone, are reported to
be useful in treating leprosy patients. The usefulness of pyrazinamide may prove helpful
for the treatment of ‘persister’ bacilli in multi-bacillary leprosy cases. The drugs presently
used to treat leprosy can be divided into two main groups, first-line and second-line which
are as follows:
First-fine drugs: These drugs are dapsone, rifampicin and clofazimine. Until recently,
extensive and often life-long monotherapy, particularly with dapsone, the first
effective anti-leprosy drug, was commonplace. The emergence of resistant organisms
as secondary (occurring during therapy) or primary (the original infection) resistance
Anti-Leprosy Drugs 161
coupled with the recognition that short-term therapy gains wider patient compliance
has led to the current use of multi-drug treatment regimens. The proposed drug
regimens vary somewhat with the clinical classification of the disease. Standard
regimens proposed by the WHO THELEP (Therapy of Leprosy) panel are now being
evaluated worldwide, but other regimens are also being used. Generally, for
lepromatous leprosy, rifampicin (the most potent bactericidal drug) is used with
dapsone and clofazimine or prothionamide over a five-year period. For tuberculoid
leprosy, two drugs, rifampicin and either dapsone or clofazimine, over two to three
years are recommended. The in vivo interactions of these drugs are an important area
of investigation.
Second-fine drugs: These include the thioamides prothionamide and ethionamide,
the thiosemicarbazone thiacetazone, and the (little used) thiourea thiambutosine.
Other drugs: The principal new compound is deoxyfructoserotonin. The activity of
a number of known antimicrobial agents against M. leprae has been studied.
7.5 CLASSIFICATION OF LEPROSY AND THE CLINICAL SYMPTOMS
Leprosy is classified into several types based on the bacterial load present in the lesions,
the extent of skin and nerve involvement and based on the presence of deformities. Several
types of classification like Madrid classification, Ridley & Jopling classification, Indian
classification, WHO classification, Field Worker’s classification, etc.
Based on the two commonly used classifications, leprosy is classified into six types
based on the clinical features (Ridley & Jopling classification). This type of the disease is a
reflection of the immune status of the host.
The first sign of the disease is the feeling of numbness or loss of sensation for temperature
(heat) followed by touch and pain which usually begins at the extremities. The skin lesions
appear later during the course of the disease. Leprosy diseases with clinical features are
described in Table 7.1.
Table 7.1: Leprosy diseases with clinical features
Disease Clinical Features
Indeterminate
leprosy
Paucibacillary
(tuberculoid
leprosy)
Borderline
borderline leprosy
They are the first type of skin lesions characterized by hypo-pigmented spots, and the
lesions undergo healing spontaneously.
A large red patch with well-defined raised borders or a large hypo pigmented asymmetrical
lesion.
Lesion is dry and hairless,
Infectivity is minimal at this stage,
Loss of sensation is observed,
Nerves become thick followed by loss of function,
It either progresses to the borderline stage or spontaneously gets cured.
Characterized by small and numerous skin lesions,
The disease goes back to the tuberculoid stage or progresses to the next stage.
Contd...