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Antibiotics 337
Uses: It is used in the treatment of bacterial eye infections and typhoid fever caused by S. typhi.
The most serious adverse effect of chloramphenicol is bone marrow depression and fatal blood
dyscrasias.
Preparation: Injectable solution: 1000 mg/vial.
Storage and Stability: It should be stored at 20°C to 25°C. Chloramphenicol sodium succinate
sterile powder for injection should be stored at 15°C to 25°C. Keep container tightly closed in a
dry and well-ventilated place. It is stable for several years at room temperature.
Officials:
➢ Chloramphenicol Capsules, I.P., B.P.
➢ Chloramphenicol Ear Drops, I.P., B.P.
➢ Chloramphenicol Eye Ointment, I.P., B.P.
➢ Chloramphenicol Eye Drops, B.P.
➢ Chloramphenicol Palmitate Oral Suspension, I.P.
➢ Chloramphenicol Sodium Succinate Injection, I.P.
12.4.2 Clindamycin
Brand Names: Cleocin HCl, Cleocin Pediatric, Cleocin Phosphate, Cleocin Phosphate ADD-
Vantage, Clindesse, ClindaMax Vaginal
Clindamycin is a broad-spectrum, semi-synthetic antibiotic produced by a 7(S)-chloro-
substitution of the 7(R)-hydroxyl group of the parent compound lincomycin. The structural
formula is represented below:
IUPAC Name: Methyl 7-chloro-6,7,8-trideoxy-6Â(1-methyl-trans-4-propyl-L-2-pyrrolidine
carboxamido)-1-thio-L-threo-α-D-galactoÂoctopyranoside monohydrochloride.
Properties: It occurs as yellow, amorphous solid with characteristic taste; odorless or has faint
mercaptan-like odor. It is freely soluble in water, dimethyl formamide and methanol; soluble in
alcohol; and practically insoluble in acetone.
Mechanism of Infection: Clindamycin may be bacteriostatic or bactericidal in action, depending
on the concentration of the drug attained at the site of infection. It inhibits bacterial protein
synthesis by binding to the 23S RNA of the 50S subunit of the ribosome and suppresses protein
synthesis.
338 Text Book of Pharmaceutical Chemistry
Uses: Clindamycin is an antibiotic used for the treatment of a number of bacterial infections such
as:
➢ It is parenterally used in the treatment of bone and joint infections.
➢ It is used intravaginally as a vaginal cream or suppository or orally for the treatment of
bacterial vaginosis.
➢ It is used topically alone or in conjunction with benzoyl peroxide in the treatment of
inflammatory acne vulgaris.
➢ It is used in the treatment of serious respiratory tract infections, skin and skin structure
infections, or septicemia caused by susceptible strains of S. aureus, Streptococcus
pneumoniae, or other streptococci.
➢ It is used in pelvic inflammatory disease, throat, pneumonia, middle ear infections, and
endocarditis.
Dosage Forms:
➢ Capsule: 75 mg, 150 mg, 300 mg
➢ Injectable solution: 150 mg/mL
➢ Oral solution: 75 mg/5 mL
➢ Intravenous ready-to-use solution: 300 mg/50 mL (5% dextrose), 600 mg/50 mL (5%
dextrose), 900 mg/50 mL (5% dextrose).
Storage: Store it at room temperature and away from excess heat and moisture.
Officials:
➢ Clindamycin Hydrochloride, I.P.
➢ Clindamycin Hydrochloride Capsules, I.P.
12.5 EXERCISE
A. Long Answer Type Questions
1. What are antibiotics? Classify them and give example of each class.
2. Discuss structure, chemical name, brand name, properties and therapeutic uses of
Penicillin G.
3. What are macrolid antibiotics? Give the uses of Erythromycin.
4. Write short notes on:
(a) Azithromycin
(b) Chloramphenicol
5. Write the structure, stability and therapeutic uses of Streptomycin.
Antibiotics 339
6. What are tetracyclines? Give a brief account on tetracyclines.
7. Write the official preparations of: (a) Chloramphenicol (b) Tetracycline (c) Amoxicillin
8. Discus briefly about the beta-lactam antibiotics.
9. Classify Penicillin and give the basic nucleus of penicillin.
B. Short Answer Type Questions
1. Define antibiotics.
2. Give therapeutic uses of Tetracyclines.
3. Write the classification of antibiotics based on chemical structure.
4. Write the official preparations of Amoxicillin.
5. Write the stability and uses of Cloxacillin.
6. Write a short note on Penicillin.
7. Write the official preparations of Streptomycin.
8. Give two examples of aminoglycosides antibiotics.
9. Write structure, properties, uses and stability of Doxycycline.
10. Give the structure and uses of Chloramphenicol.
11. Define macrolid antibiotic with examples.
12. Give four examples of Cephalosporin.
13. Write the difference between broad-spectrum and narrow-spectrum antibiotics.
C. Fill in the Blanks
1. Penicillin belongs to the class _______________.
2. Streptomycin is a _______________.
3. Penicillin G is also called as _______________.
4. Erythromycin is a _______________.
5. Brand name of Cloxacillin is _______________.
6. Gentamycin is an _______________.
7. Structure of benzyl penicillin consists of a _______________, _______________ and
_______________ side chain moiety.
8. Basic nucleus of Cephalosporin is _______________.
9. Neomycine is obtained from _______________.
10. Chloramphenicol is a semi-synthetic, broad-spectrum antibiotic produced initially by
_______________.
11. Erythromycin is produced from _______________.
340 Text Book of Pharmaceutical Chemistry
Answers:
1. β-lactam
2. Aminoglycoside antibiotics
3. Benzyl penicillin
4. Macrolide antibiotic
5. Cloxapen, Tegopen
6. Aminoglycoside antibiotic
7. β-lactam ring, thiazolidine ring and benzyl
8. β-lactam ring
9. Streptomyces fradiae
10. Streptomyces venezuelae
11. S. erythreus
Chapter
13
ANTI-NEOPLASTIC AGENTS
STRUCTURE
13.1 Introduction
13.2 Exercise
OBJECTIVES
Anti-neoplastic Agents: Cyclophosphamide, Busulfan, Mercaptopurine, Fluorouracil,
Methotrexate, Dactinomycin, Doxorubicin Hydrochloride, Vinblastine Sulphate, Cisplatin,
Dromostanolone Propionate
13.1 INTRODUCTION
The human body is made up of billions of cells that can only be seen under a microscope.
These cells are grouped together to form tissues and organs. In normal tissue, the rates of new
growth and old death are kept in balance if the control over cell growth loss, which results in
cancer.
Cancer is a disease in which some of the body’s cells divide uncontrollably and spread into
surrounding tissues. Cancer develops when the body’s normal control mechanism stops working.
Old cells do not die; instead, they grow out of control, resulting in the formation of new,
abnormal cells. These extra cells may form a mass of tissue called a tumor.
Differences between Cancer Cells and Normal Cells
➢ Cancerous Cells: Cancerous cells can invade into nearby areas and spread to other areas
of the body. They grow in the absence of signals telling them to grow.
➢ Normal Cells: Normal cells stop growing when they come across other cells. Most
normal cells do not invade into nearby areas and do not spread to other areas of the body.
Normal cells only grow when they receive such signals.
Types of Cancer
There are various types of cancer and these are generally named for the organs or tissues
where the cancers form. For example, lung cancer starts in the lung, and brain cancer starts in the
brain. There are mainly two types of cancers. These are:
342 Text Book of Pharmaceutical Chemistry
1. Benign Tumors: Benign tumors are non-malignant/non-cancerous tumor. A benign
tumor is usually localized, does not spread to other parts of the body (metastasize) and are
typically slow-growing. Examples of benign tumors include:
➢ Adenomas – A tumor that arise from glandular epithelial tissue.
➢ Papilloma – A projecting mass on the skin, e.g., wart.
➢ Lipomas – A tumor that occurs in the fatty tissue.
➢ Osteoma – A tumor originating in the bones.
➢ Angioma – A tumor derived from cells of the vascular or lymphatic vessel walls.
➢ Myoma – A myoma commonly known as a fibroid, tumor that develops in or around
the uterus.
➢ Hemangiomas – A tumor caused by a buildup of blood vessels in a certain part of the
body. They are most commonly found on the head, neck, or trunk of the body.
➢ Premalignant –A premalignant tumor is not yet cancerous but appears to be
developing the properties of cancer.
2. Malignant Tumors (Cancerous): Malignant tumors are cancerous. It means the tumor is
made of cancer cells. It can spread to other parts of the body through the blood and lymph
systems (called metastasis). Examples of malignant tumors include:
➢ Carcinoma – A cancer that begins in a tissue that lines the inner or outer surfaces of
the body.
➢ Sarcoma – A tumor that begins in cartilage, bones, fat, blood vessels or other
connective tissues and nerves.
➢ Leukemia – A cancer of the blood cells, caused by a rise in the number of white blood
cells in the body.
➢ Blastoma – A tumor formed from embryonic tissue or developing cells is known as
blastoma.
Differences between Benign Tumor and Malignant Tumors
Benign Tumors
Malignant Tumors
• Benign tumor is the type of tumor
that cannot spread to other parts of
the body.
• The rate of growth is slow.
• They are encapsulated and sharply
demarcated from their surroundings.
• They are always well differentiated.
• Typically, they are not life-
threatening
• Malignant tumor can shed cells that travel
through the blood or lymphatic system to other
parts of the body to form new tumors.
• The rate of growth is moderate or fast.
• They are not encapsulated and not demarcated.
• They vary from well-differentiated to
completely anaplastic tumors.
• They can be life-threatening.
Anti-neoplastic Agent 343
Antineoplastic Agents
Antineoplastic agents are the drugs that are used for the treatment of cancer, malignancy,
tumours, carcinomas, sarcomas, leukaemia, and other neoplasms (Greek neo = new, Plasm =
formation).
Chemical Classification of Anticancer Agents
1. Alkylating Agents:
(a) Nitrogen mustards – Mechlorethamine hydrochloride, Cyclophosphamide (Cytoxan),
Chlorambucil, Melphalan, Ifosfamide
(b) Alkyl sulfonates – Busulfan
(c) Nitrosoureas – Carmustine, Lomustine, Semustine, Streptozocin
(d) Ethylenimines – Thiotepa
(e) Triazenes – Dacarbazine
2. Antimetabolites:
(a) Folate antagonists – Methotrexate
(b) Purine analogues – Thioguanine (6-TG), Mercaptopurine (6-MP), Fludarabine,
Pentostatin, Cladribine
(c) Pyrimidine analogues – Cytarabine (cytosine arabinoside, ara-C), Fluorouracil (5-FU)
(d) Vitamin and coenzyme inhibitors – Isoribiflavine, Galactoflavin
(e) Glutamine antagonists – α-glutamine, Azoserine
3. Plant-derived Products:
(a) Vinca alkaloids – Vincristine, Vinblastine
(b) Epipodophyllotoxins – Etoposide, Teniposide
(c) Taxanes: Paclitaxel
4. Antibiotics:
(a) Anthracyclines – Doxorubicin hydrochloride, Daunorubicin, Idarubicin (Idamycin)
(b) Bleomycins – Bleomycin sulfate
(c) Mitomycin – Mitomycin C
(d) Dactinomycin – Actinomycin D, Cosmegen
(e) Plicamycin – Mithracin
5. Enzymes: L-Asparaginase
6. Hormonal agents:
(a) Androgens – Testosterone, Fluoxymesterone
(b) Antiandrogens – Flutamide
(c) Estrogens – Diethylstilbosterol, Ethynyl esteradiol
(d) Antiestrogens – Tamoxifen citrate
(e) Progestins
(f) Luteinizing hormones – Buserelin, Leuprolide
344 Text Book of Pharmaceutical Chemistry
ALKYLATING AGENTS
13.1.1 Cyclophosphamide
Brand Names: Cytoxan, Cytoxan Lyophilized, Neosar
Cyclophosphamide is a type of nitrogen mustard drug which exerts its effects through the
alkylation of DNA. It is not cell-cycle phase-specific drug. It is converted in vivo to an active
metabolite 4-hydroxy cyclophosphamide by liver cytochrome P450 (CYP) enzymes and inhibits
protein synthesis through DNA and RNA crosslinking.
IUPAC Name: N,N-bis(2-chloroethyl)-2-oxo-1,3,2λ
5
-oxazaphosphinan-2-amine
Properties: Cyclophosphamide is a fine white crystalline powder, odorless with a slightly bitter
taste, odorless with melting point 41°C to 45°C. It is slightly soluble in benzene and carbon
tetrachloride; very slightly soluble in ether and acetone; soluble in chloroform, dioxane and
glycols; and insoluble in carbon tetrachloride and carbon disulfide.
Uses:
➢ It is used to treat malignant lymphoma, lymphocytic lymphoma (nodular or diffuse),
multiple myeloma, acute myelogenous and monocytic leukemia, ovarian cancer, breast
cancer, small cell lung cancer, neuroblastoma, and sarcoma.
➢ It is also used to treat cancer as well as autoimmune diseases as an immune suppressor
in nephrotic syndrome, granulomatosis with polyangiitis, and following organ transplant,
among other conditions.
Storage and Stability: Cyclophosphamide should be preserved in tight containers at a
temperature between 2°C and 32°C. During transport or storage of cyclophosphamide vials,
temperature influences can lead to melting of the active ingredient.
Dosage and Strength:
➢ Cyclophosphamide for Injection, U.S.P. (lyophilized powder) is a sterile white cake
available in 500 mg, 1 g and 2 g.
➢ Cyclophosphamide Tablets, U.S.P. are white tablets with blue flecks available in 25 mg
and 50 mg.
Officials:
➢ Cyclophosphamide, I.P.
➢ Cyclophosphamide Tablets, I.P.
➢ Cyclophosphamide Injection, I.P.
Anti-neoplastic Agent 345
13.1.2 Busulfan
Brand Names: Busulfex, Busilvex, Myleran
Busulfan is a synthetic derivative of dimethane-sulfonate that contains 2 labile methane
sulfonate groups attached to opposite ends of a 4-carbon alkyl chain. It has antineoplastic and
cytotoxic properties.
IUPAC Name: 4-methylsulfonyloxybutyl methane sulfonate
Properties: It occurs as a white crystalline powder. It is very slightly soluble in water and
alcohol; and soluble in acetone and acetonitrile. It is used in the treatment of chronic granulocytic
leukaemia.
Uses:
➢ Busulfan is used to treat the symptoms of chronic myelogenous leukemia (a type of blood
cancer), polycythemia and myeloid metaplasia.
➢ Busulfan tablets are also used in combination with other drugs to destroy the bone
marrow and cancer cells in the preparation for a bone marrow transplant.
Dosage Forms and Strengths:
➢ Parenteral: 6 mg/mL (60 mg) Busulfex
➢ Oral: Tablets, film-coated: 2 mg Myleran (Glaxo Smith Kline)
Storage: Busulfan tablets should be stored in well-closed containers at 25°C but may be exposed
to temperatures ranging from 15°C to 30°C. Busulfan Injection diluted in 0.9% Sodium Chloride
Injection, U.S.P. or 5% Dextrose Injection, U.S.P. is stable at room temperature (25°C) for up to 8
hours but the infusion must be completed within that time.
Official:
➢ Busulfan Tablets, I.P., B.P.
13.1.3 Mercaptopurine
Brand Names: Purixan, Purinethol
Mercaptopurine (6-mercaptopurine 6-MP) is a member of the class of thiopurine that is 6,7-
dihydro-1H-purine carrying a thione group at position 6. It is an antimetabolite with
antineoplastic and immunosuppressive activities.
346 Text Book of Pharmaceutical Chemistry
IUPAC Name: 3, 7-dihydropurine-6-thione
6-MP is similar to the purine bases in DNA. When used in DNA replication, it prevents cell
division. This also leads to inhibition of DNA synthesis and function, as 6-MP incorporates
thiopurine nucleotides. 6-mercaptopurine (6-MP) causes remissions in childhood leukemia cases
without severely harming normal cells.
Properties: Mercaptopurine occurs as a yellow crystalline powder, nearly odorless that
decomposes at 313°C to 314°C. Oral tablets are pale yellow to buff. It is soluble in hot alcohol
and dilute alkali solutions; slightly soluble in dilute sulfuric acid; and insoluble in water, acetone
or ether.
Uses:
➢ 6-MP is used to slow the growth of cancer cells.
➢ It is also used to treat certain types of leukemia:
• Acute lymphocytic leukemia (ALL) (especially in childhood cases)
• Acute myelogenous and myelomonocytic leukemias
• Chronic myeloid leukemia (CML) (type of inflammatory bowel disease)
➢ It is used in ulcerative colitis.
➢ For acute lymphocytic leukemia, it is generally used with methotrexate.
Storage: Store the drug in a closed container at room temperature, away from heat, moisture, and
direct light. Keep away from freezing. Once opened, use the oral liquid within 8 weeks. Throw
away any unused medicine after 8 weeks.
Officials:
➢ Mercaptopurine, I.P.
➢ Mercaptopurine Tablet, I.P.
13.1.4 Fluorouracil
Brand Names: Actikerall, Carac, Efudex, Fluoroplex, Tolak, Occlusion Pack
Fluorouracil (5-FU) is a pyrimidine analogue. 5-FU converted to the active metabolite
5-fluoroxyuridine monophosphate (F-UMP); replacing uracil, F-UMP incorporates into RNA and
inhibits RNA processing, thereby inhibiting cell growth.