Chemotherapy Pharmacology for Dentistry Notes

General Considerations

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Classification Of Antimicrobial Agents

Resistance To Antimicrobial Agents

• It is said to occur when the microorganism does not respond to the antimicrobial agent which would normally kill or inhibit its growth. The resistance may be natural or acquired. Natural resistance is genetically determined, for example, normally, gram-negative bacilli are not affected by penicillin G.
• In acquired resistance, microbes that initially respond to an antimicrobial agent mn(AMA) later develop resistance to the same AMA by mutation or gene transfer, for example, gonococcal resistance to penicillins. Mutation is a permanent alteration in the sequence of DNA.
• Resistance may be due to single-step mutation (for example, the resistance of Staphylococcus to rifampin) or multistep mutation in a gene (occurs in more than one step; the microorganism becomes gradually less sensitive to the drug for example, resistance to erythromycin).
• The transfer of genes for drug resistance occurs by the following mechanisms.

1. Transduction
   • There is transfer of DNA, carrying a gene for resistance, from one bacterium to another through bacteriophage, for example, resistance of strains of Staphylococcus aureus to antibiotics is mediated via transduction.
2. Transformation:
   • The resistance-carrying genetic material that is released into the environment by resistant bacteria is taken up by other sensitive bacteria which then becomes resistant to the AMA, for example, penicillin G resistance in pneumococci.

1. Conjugation:
   • Conjugation is the transfer of genetic material carrying resistance between bacteria by direct contact through sex pilus, for example, Escherichia coli resistance to streptomycin.

• Development of resistance to antimicrobial agents
  • There are several mechanisms by which an organism can develop resistance to an AMA. The important mechanisms are:
    • Production of activating enzymes: For example, staphylococci, gonococci, E. coli, etc. produce β-lactamases that can destroy some of the penicillins and cephalosporins.
    • An efflux pump mechanism: It is a mechanism that prevents the accumulation of drug in the microorganism, for example, the resistance of gram-positive and gram-negative bacteria to tetracyclines, chloramphenicol, macrolides.
    • Decreased entry of antimicrobial agent into the organism due to alteration in the channel/transporter required for its entry into the organism.
    • Alteration of the binding site: For example, change in penicillin-binding proteins (PBPs) in case of certain pneumococci with decreased affinity for penicillins.
    • Absence of metabolic pathway: For example, sulfonamide-resistant bacteria can utilize preformed folic acid without the need for usual metabolic steps.
• Cross-resistance
  • Organisms that develop resistance to an AMA may also show resistance to other chemically related AMAs. The cross-resistance among AMAs could either be one-way or two-way. Cross-resistance among tetracyclines and sulfonamides is usually ‘two-way’.

• • ‘One-way’ resistance is seen between neomycin and streptomycin. Neomycin-resistant organisms are resistant to streptomycin, but streptomycin-resistant organisms may be sensitive to neomycin.

• Prevention of development of resistance to amas is by:

1. Selecting right AMA.
2. Giving right dose of the AMA for proper duration.
3. Using proper combination of AMAs, for example, in tuberculosis (TB), multidrug therapy (MDT) is used to prevent the development of resistance to antitubercular drugs by mycobacteria.

Superinfection (Suprainfection)

• It is defined as the occurrence of a new infection due to antimicrobial therapy for another infection. The causative organism of superinfection should be different from that of the primary disease.
• Most of the AMAs – especially broad-spectrum antibiotics (tetracyclines, chloramphenicol), clindamycin, ampicillin, etc. alter the normal bacterial flora, as a result of which the host-defence mechanism is impaired. Hence, pathogenic organisms invade the host, multiply and produce superinfection.
• The causative organism may be fungi or bacteria.

1. Pathogenesis
   • Superinfection is associated with suppression/change of normal flora in the body following treatment with certain antimicrobials. The pathogenesis of superinfection is described in Fig.
   • The sites involved in superinfection are those body cavities that have direct communication with the exterior, i.e. rectum, oral cavity, vagina, lower urinary tract, upper respiratory tract, etc.

Microorganisms Causing Superinfection and Their Treatment

1. • • 
2. Factors predisposing to superinfection
   • Superinfection is common in immunocompromised conditions, such as diabetes, malignancy and AIDS, and also during prolonged corticosteroid therapy. It can be minimized by
     • Using specific AMAs,
     • Avoiding unnecessary use of AMAs and
     • Use of probiotics, for example, Lactobacillus.

Chemoprophylaxis

Chemoprophylaxis is the administration of AMAs to prevent infection or to prevent the development of disease in persons who are already infected. The ideal time to initiate therapy is before the organism enters the body or at least before the development of signs and symptoms of the disease.

• Chemoprophylactic Regimens

1. Indications and regimens for chemoprophylaxis Chemoprophylaxis is used:
   • To prevent endocarditis in patients with valvular lesion before undergoing dental (manipulation of gingiva or periapical region or perforation of mucosa) or other surgical procedures: Dental procedures → mucosal damage → oral flora enter the bloodstream → bacteraemia → affects damaged heart valve → endocarditis.
   • To protect healthy persons: Chloroquine/mefloquine is used for chemoprophylaxis of malaria for those travelling to malaria-endemic area.
   • To prevent opportunistic infections in immunocompromised patients, for example, cotrimoxazole is used to prevent Pneumocystis jiroveci pneumonia in AIDS patients.
   • Prior to surgical procedures: AMAs are administered to all patients prior to major dental surgical procedures or insertion of dental implants.
     • Diabetics or patients on prolonged corticosteroids undergoing dental procedures which damage mucosa require prophylaxis to prevent wound infection. The selected drug should be effective against oral anaerobes and gram-positive organisms.
   • The effectiveness of chemoprophylaxis depends on the selection of a specific AMA, its dosage, time of initiation and duration of antimicrobial therapy. The suggested chemoprophylactic regimens are listed in Table.
   • Amoxicillin is the preferred drug because it is bactericidal and well-tolerated. Oral drugs are administered 1 h before procedure, whereas parenteral drugs are given just before the procedure.
   • AMA is given before the procedure so that effective plasma concentration of drug is achieved during bacteraemia. If procedures are of long duration, the dose of antimicrobial agent can be repeated.
2. Empirical therapy:
   • It is the use of AMAs before the identification of causative organism or availability of susceptibility test results, for example, combination of ampicillin, ceftriaxone and vancomycin is used as empirical therapy for suspected bacterial meningitis (before test results are available) to cover possible organisms likely to cause meningitis.
3. Definitive therapy:
   • It involves the use of AMA after identification/susceptibility tests of causative organism responsible for the disease.

Combination Of AMAs

It is the simultaneous use of two or more AMAs for the treatment of certain infectious diseases.

1. Indications/advantages of antimicrobial combinations
   • To broaden the spectrum of activity in mixed bacterial infections: Odontogenic infections, brain abscess, etc. are often due to both aerobic and anaerobic organisms. Hence, they require antimicrobial combination therapy.
   • Metronidazole + ampicillin for ulcerative gingivitis.
   • To broaden the spectrum of action in severe infections when the aetiology is not known:
     • A combination of AMAs is used for empirical therapy. Later, the AMA should be selected according to the type of organism, culture and sensitivity results.
   • To increase antibacterial activity in the treatment of specific infections (for synergistic effect).
     • Ampicillin + gentamicin for enterococcal endocarditis.
     • Carbenicillin + gentamicin for infections due to Pseudomonas.
       • Penicillins, by inhibiting bacterial cell wall synthesis, facilitate the entry of gentamicin into the bacterial cell (synergistic effect) resulting in more complete eradication of organisms.
     • Sulfamethoxazole + trimethoprim for P. jiroveci pneumonia.
   • To prevent emergence of resistant microorganisms: In TB, leprosy and HIV infection, combination therapy is used.
   • To reduce duration of therapy: MDT is used in TB and leprosy.
   • To reduce adverse effects: Amphotericin B (AMB) and flucytosine in cryptococcal meningitis: the dose-dependent toxicity (especially nephrotoxicity) of AMB is reduced due to decrease in dose.
2. Disadvantages of antimicrobial drug combinations
3. Increased toxicity, for example, vancomycin with tobramycin may cause enhanced nephrotoxicity.
4. Increased cost.
5. Decreased antibacterial activity due to improper combinations, for example, in pneumococcal meningitis, the activity of penicillin G (bactericidal) against pneumococci will decrease if combined with tetracycline (bacteriostatic).
   • Penicillins act mainly on rapidly multiplying bacteria; tetracycline inhibits multiplication of bacteria because of its static effect.
6. Increased likelihood of superinfection.
7. Irrational combination of AMAs can lead to development of resistance.

List Of Microorganisms

1. Gram-positive cocci: S. aureus, Streptococcus pyogenes, Streptococcus viridans, Streptococcus β-haemolyticus, S. pneumoniae (pneumococcus), Enterococcus.
2. Gram-negative cocci: Neisseria gonorrhoeae, Neisseria meningitides.
3. Gram-positive bacilli: Bacillus anthracis, Corynebacterium diphtheriae, Clostridium tetani, Clostridium perfringens, Clostridium difficile.
4. Gram-negative bacilli: E. coli, Enterobacter spp., Proteus, Pseudomonas, Salmonella, Shigella, Haemophilus influenzae, Haemophilus ducreyi, Klebsiella, Brucella, Vibrio cholerae.
5. Acid-fast bacilli: Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium avium complex (MAC).
6. Spirochaetes: Treponema pallidum, Leptospira.
7. Others: Rickettsia, Mycoplasma pneumoniae, Chlamydia trachomatis, Helicobacter pylori, etc.

Selection Of An Appropriate AMA

1. Patient factors
   • Age: Use of chloramphenicol in premature infants may produce grey-baby syndrome because the metabolic functions of liver and renal excretion are not fully developed. Sulfonamides in neonates can cause kernicterus.
     • Renal function declines with age, hence elderly patients are more prone to ototoxicity and nephrotoxicity with aminoglycosides due to its reduced clearance by kidney.
   • History of allergy: In patients with history of asthma, allergic rhinitis, hay fever, metc. there is an increased risk of penicillin allergy, hence such drugs should be avoided in them.
   • Genetic abnormalities: Primaquine, pyrimethamine, sulfonamides, sulfones, fluoroquinolones, etc. may cause haemolysis in patients with glucose-6- phosphate dehydrogenase (G6PD) deficiency.
   • Pregnancy: Most of the AMAs cross the placental barrier and may affect the developing foetus. The risk of teratogenicity is highest during the first trimester. For example, use of tetracyclines during pregnancy may affect fetal dentition and bone growth. There is an increased incidence of hepatotoxicity with tetracycline in pregnant women.
   • Host defences: In immunocompromised patients (AIDS, leukaemias and other malignancies), normal defence mechanisms are impaired – bacteriostatic drugs may not be adequate; hence, bactericidal agents should be used to treat infection.
   • Hepatic dysfunction: In patients with hepatic dysfunction, drugs like chloramphenicol, erythromycin and rifampin should be avoided or require dose reduction to minimize toxic effects.
   • Renal dysfunction: In renal failure, drugs that are eliminated via kidney can accumulate in the body and cause severe toxic effects. Hence, aminoglycosides, vancomycin, amphotericin B, fluoroquinolones, etc. should be avoided or require dose reduction in patients with impaired renal function.
   • Local factors:
     • The antimicrobial activity of sulfonamides is markedly reduced in the presence of pus.
     • The activity of aminoglycosides is enhanced at alkaline pH.
2. Drug factors
   • Route of administration: Depending upon the severity and site of infection, the AMAs have to be chosen. Some of the AMAs can be administered orally as well as parenterally. For mild-to-moderate infections, oral route is usually preferred, but for severe infections like endocarditis and meningitis parenteral AMAs are preferred during initial stages of therapy.
   • The spectrum ofantimicrobial activity: It is an important factor while selecting an AMA especially during empirical therapy.
   • Bactericidal/bacteriostatic effect: Bactericidal drugs kill the organisms, while static drugs inhibit growth and multiplication. In immunocompromised states, the host-defence mechanisms are impaired; hence, bactericidal drugs are required even for trivial infections.
   • Cost of the AMA: The cost of treatment has to be considered while selecting an AMA. The expensive antimicrobials should not be used routinely when alternative cheaper and effective AMAs are available.
   • Pharmacokinetic/pharmacodynamic considerations.
     • Time-dependent inhibition – This is observed with certain AMAs like β- lactams, glycopeptides, etc. Their antimicrobial action depends on the duration of time the drug concentration remains above the MIC in the dosing interval. Thus, they are administered in multiple doses.
   • Concentration-dependent killing – For aminoglycosides and fluoroquinolones, the antimicrobial effect depends on the ratio of peak plasma concentration to MIC. A single daily dose of aminoglycosides is as/more effective than multiple doses.
   • Ability to penetrate into the infected area –
     • Ability to cross the blood-brain barrier: Clindamycin is effective against anaerobes, but not useful for anaerobic brain abscess as it does not reach cerebrospinal fluid (CSF) and brain. Anaerobic brain abscess can be treated effectively with third-generation cephalosporins or combination of metronidazole and chloramphenicol.
     • Levofloxacin attains good concentration in the lung, skin/soft tissues, urinary tract and produces high cure rates in community-acquired pneumonia, skin infections, etc.
3. Organism-related factors

• In severe infections, empirical therapy with an antimicrobial drug combination should be initiated depending on the clinical diagnosis. Later, the AMA should be selected according to the type of organism, culture and sensitivity reports.
• The bacterial resistance to AMAs and cross-resistance should also be considered while selecting an AMA.

Sulfonamides

Sulfonamides were the first effective AMAs used in the treatment of bacterial infections in man. They are derivatives of sulfanilamide (para-aminobenzene sulfonamide) and are synthetic compounds.

1. Mechanism of action
   • Para-aminobenzoic acid (PABA) is a precursor of folic acid, which is essential for the growth and multiplication of many bacteria. Sulfonamides, being structurally similar to PABA, competitively inhibit folate synthetase enzyme and prevent the formation of folic acid, thereby producing a bacteriostatic effect.
   • Sulfonamides are not effective in the presence of pus as it is rich in PABA, purines and thymidine. Mammalian cells do not synthesize folic acid, but utilize folic acid present in the diet, hence are unaffected by sulfonamides.

1. Bacterial resistance to sulfonamides Most of bacteria have developed resistance to sulfonamides. It could be due to:
   • decreased affinity of folate synthetase for the drug;
   • efflux of the drug by bacteria;
   • development of alternate metabolic pathways for folate synthesis.
2. Pharmacokinetics
   • All systemic-acting sulfonamides are well absorbed from the gut. They are bound to plasma proteins, particularly albumin.
   • Sulfonamides are distributed in almost all tissues of the body including CSF. They cross placental barrier and reach fetal circulation; they are metabolized in liver mainly by acetylation.
   • The acetylated products have no antibacterial activity, but retain the toxic potential of the parent compound. Sulfonamides are excreted partly unchanged and partly as metabolic products.
3. Adverse effects
   • The acetylated products of sulfonamides are poorly soluble in acidic urine and may cause crystalluria, haematuria or even obstruction to urinary tract. This may be avoided by taking plenty of water and alkalinizing the urine.
   • Hypersensitivity reactions include skin rashes, itching, drug fever and exfoliative dermatitis. Stevens–Johnson syndrome is the most severe type of hypersensitivity reaction characterized by fever, erythema multiforme and ulceration of mucous membranes.
   • In patients with G6PD deficiency, sulfonamides may cause acute haemolytic anaemia.
   • Rarely cause hepatitis and suppression of bone marrow.
   • Use of sulfonamides in neonates, especially in premature babies, may cause displacement of bilirubin from plasma proteins. The free bilirubin can cross the blood–brain barrier and get deposited in the basal ganglia resulting in kernicterus.
4. Drug interactions
   • Sulfonamides potentiate the effect of phenytoin, methotrexate, oral anticoagulants and oral hypoglycaemic agents (sulfonylureas) by inhibiting their metabolism and displacing them from plasma protein-binding sites.
5. Therapeutic uses Sulfonamides alone are rarely used now for systemic infections. They are used in combination with other AMAs.
   • Sulfadoxine and pyrimethamine are used in combination with artesunate in the treatment of chloroquine-resistant Plasmodium falciparum malaria.
   • Sodium salt of sulfacetamide is used topically for the treatment of ophthalmic infections.
   • Silver sulfadiazine and mafenide are used topically for preventing infection of burn wound. Silver sulfadiazine is not effective in the presence of pus.

Cotrimoxazole

Cotrimoxazole is a World Health Organization (WHO)-approved–fixed-dose combination of sulfamethoxazole and trimethoprim in the ratio of 5:1.

1. Mechanism of action
   • Cotrimoxazole (sulfamethoxazole and trimethoprim in a dose ratio of 5:1) produces sequential blockade, i.e. two drugs interfere with two successive steps in the same metabolic pathway; hence, their combination produces a supra-additive effect.
   • Sulfamethoxazole inhibits folate synthetase, whereas trimethoprim inhibits folate reductase enzyme. The pharmacokinetic properties of these two drugs match each other almost closely; hence, they are selected for combination.
   • An optimum synergistic effect is seen at a concentration ratio of 20:1 (sulfamethoxazole to trimethoprim) in blood and tissues. The advantages of this combination are:
     • Individually, both are bacteriostatic but the combination has a cidal effect.
     • The chances of the development of bacterial resistance are also greatly reduced.

1. Pharmacokinetics
   • Cotrimoxazole is well absorbed after oral administration and is also available for parenteral use; widely distributed to various tissues including CSF and sputum; metabolized in liver and excreted mainly in urine; hence, dose reduction is needed in patients with renal insufficiency.
2. Adverse effects
   • Cotrimoxazole is well tolerated in most patients. Most of the adverse effects are same as that of sulfonamides. The common adverse effects are skin rashes and gastrointestinal (GI) disturbances.
   • Exfoliative dermatitis, erythema multiforme and Stevens–Johnson syndrome are rare. Gastrointestinal symptoms include nausea, vomiting, glossitis and stomatitis.
   • Megaloblastic anaemia due to folate deficiency may occur rarely, especially in alcoholics and malnourished persons.
   • Bone marrow suppression with leukopenia, neutropenia and thrombocytopaenia occurs rarely. Cotrimoxazole is contraindicated in pregnancy.
     • The preparations of cotrimoxazole are shown in Table.
     • Preparations of Cotrimoxazole
3. Therapeutic uses
   • Urinary tract infection: Cotrimoxazole is effective for the treatment of acute, chronic and recurrent lower urinary tract infections (UTIs) due to gram-negative organisms such as E. coli, Proteus and Enterobacter spp. The usual dose is 800 mg of sulfamethoxazole plus 160 mg of trimethoprim (cotrimoxazole double strength tablet) daily for 3 days.
   • Respiratory tract infections: Cotrimoxazole is effective for acute and chronic bronchitis due to H. influenzae. It is also useful for acute maxillary sinusitis and otitis media.
   • Bacterial diarrhoea: Cotrimoxazole may be used for gastrointestinal infections due to shigella, E. coli and Salmonella spp. But fluoroquinolones are the preferred agents.
   • P. jiroveci infections: Cotrimoxazole is used for the treatment as well as prophylaxis of P. jiroveci pneumonia.Typhoid fever: Third-generation cephalosporins (ceftriaxone) are the treatment of
     choice for typhoid fever. Cotrimoxazole may also be effective.
   • Chancroid: Cotrimoxazole is effective.

Quinolones

• The first quinolone, nalidixic acid, is a urinary antiseptic. It is useful in the treatment of uncomplicated urinary tract infection (UTI) due to gram-negative bacteria and diarrhoea due to Shigella or Salmonella. The most common adverse effects are related to GI tract, central nervous system (CNS) and skin.
• Fluoroquinolones are synthetic, fluorinated analogues of nalidixic acid. The important fluoroquinolones are norfloxacin, ciprofloxacin, pefloxacin, ofloxacin (first generation), levofloxacin, gemifloxacin and moxifloxacin (second generation).
  • Pharmacokinetics, Antibacterial Spectrum, Uses and Drug Interactions of Fluoroquinolones

1. Mechanism Of Action
   • Fluoroquinolones inhibit bacterial DNA synthesis (bactericidal). They inhibit DNA gyrase, thus blocking DNA replication in gram-negative bacteria.
   • Inhibition of topoisomerase 4 in gram-positive bacteria prevents separation of replicated DNA.

1. Antibacterial spectrum
   • Ciprofloxacin is the prototype drug. It is highly effective against aerobic gram-negative organisms – E. coli, Enterobacter, Proteus, Klebsiella, Salmonella, Shigella, H. ducreyi, H. influenzae, N. gonorrhoea, N. meningitidis, Vibrio cholera and Campylobacter jejuni.
   • It has activity against S. aureus, Pseudomonas aeruginosa and M. tuberculosis.
   • Most of the anaerobes – Bacteroides fragilis, C. difficile, etc. – are resistant to ciprofloxacin.
   • Newer fluoroquinolones like levofloxacin, gemifloxacin and moxifloxacin have greater activity against streptococci and some activity against anaerobes.
2. Pharmacokinetics
   • Ciprofloxacin is administered by oral, i.v. or topical routes. It is well absorbed from the gut, but food delays its absorption.
   • It is widely distributed in the body, reaches high concentrations in kidney, lungs, prostatic tissue, bile, macrophages, etc. It is excreted mainly in urine.
3. Adverse effects
   • The common adverse effects are related to GI tract, e.g. nausea, vomiting and abdominal discomfort.
   • CNS effects include headache, dizziness, insomnia, confusion, hallucinations and convulsions.
   • Hypersensitivity reactions include skin rashes, urticaria, itching, eosinophilia and photosensitivity.
   • Tenosynovitis and tendon rupture can occur, especially in athletes.
   • Fluoroquinolones are contraindicated in pregnancy.
   • Fluoroquinolones have caused cartilage damage in immature animals, hence, they should be avoided in young children.
4. Drug interactions
   • Ciprofloxacin increases the plasma concentration of theophylline, warfarin, etc. by inhibiting their metabolism.
   • Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the CNS side effects of fluoroquinolones – confusion, irritability and rarely convulsions may occur.
   • Like tetracyclines, absorption of fluoroquinolones is reduced by antacids, ferrous salts and sucralfate.
   • Other fluoroquinolones have been discussed in Table
5. Uses of fluoroquinolones
   • Urinary tract infections: Fluoroquinolones are one of the most commonly used AMAs for UTI. Fluoroquinolones are superior to cotrimoxazole for the treatment of UTI.
   • Bacterial diarrhoea: Fluoroquinolones are effective for a variety of GI infections caused by E. coli, Shigella, Salmonella, etc.
   • Typhoid fever: Ciprofloxacin (750 mg orally b.d. for 10 days) is useful for treatment mof typhoid.
   • Sexually transmitted diseases: Fluoroquinolones are effective for chancroid and gonococcal infections.
   • Respiratory infections: Newer fluoroquinolones (levofloxacin and moxifloxacin) are highly effective for community-acquired pneumonia and chronic bronchitis.
   • Others: Skin, soft tissue, and bone infection; fluoroquinolones are used in combination with other AMAs in multidrug-resistant (MDR) TB and leprosy.

β-lactam Antibiotics

β-Lactam antibiotics include penicillins, cephalosporins, carbapenems and monobactams. All of them have a β-lactam ring in their chemical structure hence the name β-lactam antibiotics.

Penicillins

Penicillin was the first antibiotic developed and used clinically. It was discovered accidentally by Alexander Fleming. The source of penicillin is the high-yielding Penicillium chrysogenum.

1. Mechanism of action
   • Bacterial cell wall consists of cross-linked peptidoglycans. The enzyme transpeptidase (penicillin-binding protein [PBP]) removes terminal alanine of one strand resulting in its cross-linkage with the adjacent strand. Cross-linking makes the cell wall rigid and stable.
   • β-Lactams, structural analogues of d-alanine, inhibit transpeptidase and thus peptidoglycan synthesis. Cell wall-deficient forms are produced, which undergo lysis (bactericidal action). β-Lactams exert their cidal effect when the bacteria actively multiply and synthesize cell wall.
   • The cell wall in gram-positive bacteria is composed mainly of highly cross-linked peptidoglycan, which is 50–100 layers thick and is near the cell surface. In gram-negative bacteria, the peptidoglycan layer is only one to two molecules thick. In addition, there is an outer lipopolysaccharide layer. Hence, gram-negative organisms are less susceptible to penicillin than gram-positive organisms.

1. Mechanism of bacterial resistance to penicillins Bacteria develop resistance
   • By producing β-lactamases, which destroy the β-lactam ring, for example, S. aureus, E.coli, gonococci, H.influenzae;
   • Due to altered PBPs, which have less affinity for β-lactams, for example, S.pneumoniae;
   • Due to the decreased ability of the drug to penetrate its site of action.
2. Pharmacokinetics
   • Most of the orally administered penicillin G is destroyed by gastric acid (acid labile); hence, penicillin G is usually given by i.v. route. It can also be administered by i.m. route but is painful. Penicillin G is widely distributed in body tissues, but poorly crosses BBB; although during meningitis, adequate amount reaches the CSF.
   • Penicillin G is rapidly excreted in urine mainly by active tubular secretion. Since renal function is not completely developed in infants and neonates, the excretion of penicillins is slow. The action of penicillins can be augmented and prolonged by giving probenecid simultaneously.
3. Preparations of penicillin G The duration of action of penicillin G is increased by combining it with poorly water-soluble compounds, such as procaine (procaine penicillin G) or benzathine (benzathine penicillin G) to yield aqueous suspensions. They are called repository or depot penicillins.
   • Characteristic Features of Preparations of Penicillin G
4. Adverse reactions of penicillin G
   • Penicillins are relatively safe. They may cause hypersensitivity reactions, such as skin rashes, urticaria, fever, dermatitis, bronchospasm, angioedema, joint pain, serum sickness or anaphylactic reaction.
   • The major manifestations of anaphylactic shock are severe hypotension, bronchospasm and laryngeal oedema. It is an immunoglobulin E (IgE) mediated, immediate type of hypersensitivity reaction (Type-1 hypersensitivity).
   • It is not a doserelated adverse drug reaction and can occur with any dosage form of penicillin. Crossreactivity can occur among penicillins and also among β-lactams antibiotics.
     • Treatment of anaphylactic shock
       • Inj. adrenaline 0.3–0.5 mL of 1:1000 solution intramuscularly.
       • Inj. hydrocortisone 200 mg intravenously.
       • Inj. diphenhydramine 50–100 mg intramuscularly or intravenously.
     • Precautions
       • Before giving penicillin, history of previous administration and allergic manifestations, if any, must be noted.
       • In patients with history of asthma, allergic rhinitis, hay fever, etc., there is an increased risk of penicillin allergy; hence, it should be avoided in such cases.
       • Sensitivity test should be performed by an intradermal test on the ventral aspect of forearm. Itching, erythema and wheal formation are watched for. A negative skin test does not ensure absolute safety.
       • Inj. adrenaline and hydrocortisone should be kept ready before injecting penicillin to treat the anaphylactic reaction.
5. Other adverse effects of penicillins are pain and sterile abscess at the site of i.m. injection. Prolonged use of i.v. penicillin G may cause thrombophlebitis.
   • Jarisch–Herxheimer reaction: It is an acute exacerbation of signs and symptoms of syphilis during penicillin therapy due to release of endotoxins from the dead organisms. The manifestations are fever, chills, myalgia, hypotension, circulatory collapse, etc. It is treated with aspirin and corticosteroids.
6. Therapeutic uses of penicillin G Owing to the risk of anaphylaxis as well as availability of better AMAs, the use of penicillin G has declined.
7. Limitations/drawbacks of penicillin G
   • Acid labile – orally not very effective.
   • Short duration of action (to overcome this, repository penicillins have been developed).
   • Narrow spectrum of antibacterial activity (mainly against gram-positive organisms).
   • Destroyed by penicillinase enzyme.
   • Possibility of anaphylaxis.
     • To overcome most of the above drawbacks, semisynthetic penicillins have been developed.
     • Semisynthetic Penicillins The spectrum of action of semisynthetic penicillins, their route of administration and susceptibility to penicillinase is described in Table.
     • Aminopenicillins
       • Adverse effects. The adverse effects of ampicillin are similar to those of penicillin G but skin rashes and diarrhoea are more common.
     • Other penicillins are carbenicillin, carbenicillin indanyl, ticarcillin (carboxypenicillins), mezlocillin and piperacillin (ureidopenicillins).
       • Adverse effects. They are similar to penicillin G. Congestive cardiac failure may be precipitated due to sodium content of carbenicillin sodium. It can also interfere with platelet function and cause bleeding.
   • Classification of Penicillins with Their Spectrum of Activity
8. Therapeutic uses of penicillins
   • In dentistry: Penicillins are used in trench mouth or acute necrotizing ulcerative gingivitis (caused by fusobacteria and spirochaetes), pericoronitis, dentoalveolar abscess, osteomyelitis of mandible, etc. either alone or with metronidazole.
     • Amoxicillin is the commonly used penicillin as drug level in blood is sustained and it is well tolerated. Ampicillin/penicillin V is the alternative for trench mouth. Penicillin G is rarely used as most of the organisms have developed resistance.
   • Upper respiratory infections: Ampicillin and amoxicillin are effective for pharyngitis, sinusitis, otitis media, bronchitis, etc. caused by S. pyogenes, S. pneumoniae and H. influenzae. Among oral β-lactams, amoxicillin is the most effective agent against penicillin-sensitive and penicillin-resistant S. pneumoniae.
   • Subacute bacterial endocarditis: Aminopenicillins in combination with gentamicin have been used for the treatment of subacute bacterial endocarditis (SABE). To prevent bacterial endocarditis in patients with valvular lesions before undergoing dental procedures, amoxicillin is the ideal agent – 2 g given orally, 1 h before the procedure.
   • Bacillary dysentery: Fluoroquinolones are the drugs of choice. Some cases may respond to ampicillin, but many strains have developed resistance to it.
   • Typhoid fever: Ceftriaxone is the drug of choice for typhoid. Ampicillin, cotrimoxazole or ciprofloxacin are useful for eradicating carrier state.
   • Syphilis: Penicillin G is the drug of choice for syphilis. T. pallidum is very sensitive to penicillin and is killed at very low concentrations of the drug. Procaine penicillin G/benzathine penicillin G is used for the treatment of early syphilis.
     • For late syphilis, benzathine penicillin G is used. The alternative drugs are ceftriaxone, azithromycin and doxycycline. Penicillin is the drug of choice for treatment of syphilis in pregnancy.
   • Diphtheria: It is an acute infection of upper respiratory tract caused by C. diphtheriae. It is treated mainly with a specific antitoxin. Penicillin G helps to eliminate carrier state. Patients allergic to penicillin are treated with erythromycin.
   • Clostridial infections (tetanus and gas gangrene): The main treatment is neutralization of the toxin by using human tetanus immunoglobulin. For gas gangrene, penicillin G is used as an adjunct to antitoxin.
   • Gonococcal infections: Penicillin was the drug of choice for gonococcal infections. Ampicillin with probenecid is effective against non–penicillinase-producing gonococcus. Because of the emergence of resistant organisms, penicillins are not preferred at present.
   • Other infections: Leptospirosis, anthrax, listeria infections, Lyme disease, actinomycosis, rat-bite fever, etc. are effectively treated with penicillin G.
   • H pylori infection: Amoxicillin is used in combination with other drugs.
   • Serious infections: Bacteraemias, pneumonia, urinary tract infection, burns, etc. by P. aeruginosa and Proteus are more effectively treated with piperacillin/ticarcillin than carbenicillin. Carbenicillin indanyl is used orally for the treatment of UTI caused by P. aeruginosa and Proteus spp. Ticarcillin is used in combination with a beta-lactamase inhibitor and an aminoglycoside for the treatment of mixed nosocomial infection.
     • Comparison between Ampicillin and Amoxicillin
9. Drug interactions of penicillins
   • Probenecid competes with β-lactams (penicillins and cephalosporins) for active tubular secretion and retards their excretion, thereby increasing the plasma concentration as well as the duration of action of β-lactams.
   • Hence, simultaneous administration of probenecid and penicillin is useful in the treatment of bacterial endocarditis and gonococcal infections to enhance the therapeutic efficacy of β-lactams.

Β-Lactamase Inhibitors

• They are clavulanic acid, sulbactam and tazobactam. They structurally resemble β- lactam molecules. β-Lactamase inhibitors bind to β lactamases and inactivate them.
• Coadministration of these drugs with β-lactams increases the activity of β-lactams by preventing them from enzymatic destruction. Examples are clavulanic acid, sulbactam and tazobactam.

1. Clavulanic acid
   • It competitively and irreversibly inhibits β-lactamases produced by a wide range of gram-positive and gram-negative bacteria. After binding to the enzyme, clavulanic acid itself gets inactivated; hence it is called a ‘suicide’ inhibitor. Details are given in Table
     • β-Lactamase Inhibitors and Their Uses

Cephalosporins

• The first cephalosporins were obtained from a fungus, Cephalosporium acremonium. Later, semisynthetic cephalosporins were developed. Cephalosporins are β-lactam antibiotics.
• The mechanism of action and development of resistance are similar to those of penicillins. Like penicillins, cephalosporins also inhibit the synthesis of bacterial cell wall and produce bactericidal effect. Cephalosporins have been divided into five generations. Features of cephalosporins are listed in Table.
  • Antibacterial Spectrum, Pharmacokinetics and Uses of Cephalosporins

1. Fifth-generation cephalosporins: They are ceftaroline fosamil (i.v.) and ceftobiprole medical (i.v.).
   • Both are prodrugs. They are active against gram-positive and gram-negative bacteria including MRSA, penicillin-resistant S. pneumonia, Enterococcus faecal, etc.
2. Pharmacokinetics
   • Cephalosporins are administered either orally or parenterally. These drugs are excreted mainly unchanged through kidney either by glomerular filtration or tubular secretion. Some cephalosporins are metabolized in the body before their excretion.
   • Cefotaxime is deacetylated in the body before its excretion. Cefoperazone is mainly excreted through bile. Like penicillins, the active tubular secretion of cephalosporins is blocked by probenecid, resulting in higher blood levels and longer duration of action.
3. Adverse effects
   • Hypersensitivity: The most common adverse effects are allergic reactions. They are skin rashes, urticaria and rarely anaphylaxis. Cross-reactivity to penicillin is seen in few patients.
   • Gastrointestinal disturbances – mainly diarrhoea, vomiting and anorexia can also occur.
   • Pain at the site of i.m. injection mainly with cephalothin. Intravenous cephalosporins can cause thrombophlebitis.
   • Nephrotoxicity may occur. Coadministration of cephalothin and gentamicin increases the risk of nephrotoxicity.
   • Intolerance to alcohol (a disulfiram-like reaction) has been reported with cefotetan and cefoperazone.
   • Severe bleeding can occur either due to hypoprothrombinaemia (which responds to vitamin K therapy) or thrombocytopenia and/or platelet dysfunction.

Carbapenems

• Examples are imipenem, meropenem, doripenem, ertapenem and faropenem.
• Imipenem is a semisynthetic β-lactam antibiotic. Imipenem, like other β-lactam antibiotics, acts by inhibiting bacterial cell wall synthesis and produces bactericidal activity.
• It has a wide spectrum of antibacterial activity – gram-positive organisms like streptococci, staphylococci, enterococci, Listeria and C. difficile (anaerobe); gram-negative organisms like P. aeruginosa, Enterobacteriaceae and B. fragilis (anaerobes). It is resistant to most β-lactamases.

• Cilastatin, a dehydropeptidase inhibitor, increases the concentration of imipenem in urine. Hence, it is combined with imipenem. Imipenem–cilastatin combination increases the antibacterial efficacy.
• Imipenem may exhibit cross-reactivity with penicillins and cephalosporins. Nausea, vomiting and skin rashes are the common side effects and, rarely, seizures have also been reported. Dose of carbapenems should be reduced in patients with renal failure.

1. Other carbapenems
   • Meropenem and doripenem
     • Injected intravenously. Not destroyed by dehydropeptidase – does not require cilastatin coadministration.
     • Seizures less likely.
     • Also effective against imipenem resistant P. aeruginosa.
     • Used for treatment of serious nosocomial infections. They are also useful for treatment of serious dental infections.
   • Faropenem
     • Orally effective.
     • Used for respiratory and genitourinary infections.

Monobactams

• Aztreonam is a β-lactam antibiotic with only one ring in its structure, hence the name monobactam. It also acts by inhibiting the bacterial cell wall synthesis.
• It is effective only against gram-negative bacteria, such as Enterobacteriaceae, P. aeruginosa, gonococci and H. influenzae but has no activity against gram-positive bacteria and anaerobes.
• It is resistant to most β-lactamases. It is administered only parenterally (i.m., i.v.). The main advantage with aztreonam is lack of cross-reactivity with other β-lactam antibiotics (except with ceftazidime).
• It is useful for the treatment of hospital-acquired gram-negative infections (genitourinary, intra-abdominal, etc.)

Aminoglycosides

They include streptomycin, gentamicin, tobramycin, amikacin, kanamycin, sisomicin, neomycin, framycetin and netilmicin.

1. Common properties of aminoglycosides
   • They contain two or more amino sugars attached by glycosidic linkage to hexose ring.
   • They are highly polar compounds, hence, poorly absorbed from the GI tract. They are administered by parenteral route (i.m./i.v.) for systemic effect.
   • They are mainly distributed into the extracellular fluid and poorly penetrate into the CSF.
   • They are not metabolized in the body.
   • They are excreted unchanged in urine.
   • They have bactericidal action against gram-negative aerobes and are more active at alkaline pH.
   • They cause ototoxicity and nephrotoxicity.
   • They exhibit partial cross-resistance among them.
   • Transport of aminoglycosides into the bacterial cell requires oxygen; hence, anaerobes are resistant to aminoglycosides.
2. Mechanism of action
   • Aminoglycosides are bactericidal agents – that inhibit protein synthesis.

1. Mechanisms of bacterial resistance
   • Bacterial resistance to aminoglycosides is due to
     • inactivation of the drug by bacterial enzymes
     • decreased entry of drug into bacterial cell and
     • decreased affinity of the drug for the ribosomes.
2. Aminoglycosides exhibit:
   • A concentration-dependent killing effect – higher the plasma concentration, more of the bacteria is killed rapidly.
   • A postantibiotic effect – the bactericidal effect is present even when serum concentration falls below minimum inhibitory concentration (MIC). Therefore, a once-daily dosing regimen is effective.
3. Dosing
   • Once-daily dosing regimen – total daily dose is given as a single injection. It is preferred because it:
     • is as effective as a multiple-dose regimen;
     • is safer than a multiple-dose regimen;
     • is convenient.
   • Multiple-daily-dosing regimen – the total daily dose is administered in two or three equally divided doses.
     • Once-daily dosing regimen is not preferred in bacterial endocarditis and children.
     • Dose adjustment of aminoglycosides is done according to body weight and creatinine clearance.
4. Adverse effects
   • Ototoxicity: Vestibular and cochlear dysfunctions can occur due to VIIIth cranial nerve damage. Aminoglycosides get concentrated in the perilymph and endolymph of the inner ear, which can lead to progressive damage to vestibular and cochlear hair cells.
     • The manifestations are tinnitus and deafness, headache, dizziness, nausea, vomiting, vertigo, nystagmus and ataxia. The adverse effect is reversible if the drug is discontinued early. The important risk factors for ototoxicity are:
       • Elderly patients.
       • Repeated courses of aminoglycosides.
       • Patients with pre-existing auditory impairment.
       • Concurrent use of other ototoxic drugs such as vancomycin, minocycline and loop diuretics.
   • Nephrotoxicity: Aminoglycosides get concentrated in renal cortex and produce nephrotoxicity, which is usually reversible if the drug is quickly discontinued.
     • The risk factors for nephrotoxicity are elderly patients, pre-existing renal disease and concurrent use of other nephrotoxic drugs such as amphotericin B, vancomycin, cisplatin and cyclosporine.
   • Neuromuscular blocking effect: Apnoea and muscular paralysis have been reported. Aminoglycosides inhibit the release of acetylcholine from motor nerve.
   • Hypersensitivity reactions are rare; occasionally skin rashes, drug fever and eosinophilia can occur. Cross-sensitivity between aminoglycosides may occur.
   • Use of aminoglycosides during pregnancy may cause ototoxicity in the foetus.

Streptomycin

Streptomycin was the first aminoglycoside discovered in 1944. The common properties, mechanism of action and adverse effects are explained above.

• Uses
  • Streptomycin is one of the first-line drugs for TB and is used in combination with other\ antitubercular drugs. The other uses include tularaemia, plague and brucellosis.

Gentamicin

• It is the most commonly used aminoglycoside antibiotic for aerobic gram-negativebacillary infections due to E. coli, Klebsiella, Proteus, Enterobacter and P. aeruginosa. It is also effective against gram-positive infections – enterococci, S. viridans and staphylococci but not M. tuberculosis.
• It is available for parenteral and topical administration. Common properties, mechanism of action and adverse effects are discussed above.

Neomycin

• It is highly nephrotoxic, hence never used for systemic effect. It is used only for local effect. The common properties, mechanism of action and adverse effects are as for other aminoglycosides.
• Neomycin is often used topically in combination with bacitracin or polymyxin B for wounds, ulcers, burns and infections of eye and ear.
• It can be used orally (local action) for preparation of the bowel before abdominal surgery and in hepatic encephalopathy.

Framycetin (soframycin)

Like neomycin, framycetin is also highly nephrotoxic, hence not used for systemic administration. The common properties, mechanism of action and adverse effects are similar to other aminoglycosides. Framycetin is widely used topically for skin, eye and ear infections.

Amikacin

Amongst the aminoglycosides, it has the broadest spectrum of activity. It is resistant to aminoglycoside-inactivating enzymes. It is useful for the treatment of nosocomial gramnegative infections and TB.

Tobramycin

All features are similar to gentamicin. It is superior to gentamicin against P. aeruginosa – useful in the treatment of serious infection by this organism.

Netilmicin

It is resistant to aminoglycoside-inactivating enzymes, hence effective against most of gentamicin-resistant bacteria.

• Therapeutic uses of gentamicin and other aminoglycosides
  • Among aminoglycosides, gentamicin is the most commonly used because it is cheap and effective against most of the aerobic gram-negative bacilli.
• In dentistry
  • Prophylaxis of bacterial endocarditis: Gentamicin can be used in combination with amoxicillin/vancomycin for the prophylaxis of endocarditis in highrisk patients before dental or other surgical procedures. Combination broadens the spectrum of activity, produces synergistic effect and decreases emergence of resistance.

Severe aerobic gram-negative bacillary infections

Gentamicin, neomycin, framycetin, etc. are used topically for gram-negative skin, eye and ear infections.

Broad-Spectrum Antibiotics

Tetracyclines and chloramphenicol are broad-spectrum antibiotics. They are called so because of their effectiveness against a wide range of microorganisms such as:

1. Gram-positive and gram-negative cocci – S. aureus, S.pneumoniae, N. gonorrhoea.
2. Gram-negative bacilli – V. cholera, H.ducreyi, H.influenzae, H. pylori, Campylobacter, Yersinia pestis.
3. Gram-positive bacilli – B. anthracis, Listeria, Clostridium, Propionibacterium acnes.
4. Others: Rickettsiae, Mycoplasma, Chlamydia, Actinomyces, Plasmodia, E. histolytica

Tetracyclines

Tetracyclines have four cyclic rings in their structure.

1. Mechanism of action

1. Resistance
   • Bacterial resistance to tetracyclines is due to:
     • Decreased influx or increased efflux of tetracyclines
     • Inactivation of the drug by enzymes.
2. Pharmacokinetics
   • The older tetracyclines are incompletely absorbed after oral administration, but that is adequate to produce antibacterial activity. Food interferes with the absorption of all tetracyclines; doxycycline and minocycline are less affected.
   • Tetracyclines have chelating properties; hence, form stable insoluble and unabsorbable complexes with calcium, magnesium, iron and other metal ions.
   • Therefore, the absorption of tetracyclines is reduced by simultaneous administration with dairy products, antacids, iron, sucralfate and zinc salts.
   • Tetracyclines are widely distributed throughout the body and get concentrated in liver, spleen, bone, dentine, enamel of unerupted teeth but concentration in CSF is relatively low.
   • They cross the placental barrier, are metabolized in liver and excreted in urine. Doxycycline is excreted mainly in the faeces via bile. Therefore, doxycycline is safe for use in patients with renal insufficiency.
   • Doxycycline undergoes enterohepatic cycling.
     • Important Features of Tetracyclines
3. Adverse effects
   • Gastrointestinal: On oral administration, they can cause GI irritation manifested as nausea, vomiting, epigastric distress, abdominal discomfort and diarrhoea.
     • Diarrhoea is more common with tetracycline and oxytetracycline as they are incompletely absorbed → cause alteration of normal flora. Risk of diarrhoea is low with doxycycline.
   • Effects on bones and teeth: Tetracyclines have calcium-chelating property, form tetracycline–calcium orthophosphate complex, which is deposited in growing bone and teeth. Use of tetracyclines in children and during pregnancy can cause permanent brownish discolouration of the deciduous teeth due to deposition of chelate in the teeth. There is increased incidence of caries in such teeth.
     • Tetracyclines also affect the linear growth of bones. The incidence of hepatotoxicity is more in pregnant women. Therefore, tetracyclines are contraindicated during pregnancy in the interest of both foetus and mother. It is also contraindicated in children up to the age of 8 years.
   • Phototoxicity: It is particularly seen with demeclocycline and doxycycline. They may also produce sunburn-like reaction in the skin on exposure to sunlight. They may also produce pigmentation of nails.
   • Superinfection: It is common with older tetracyclines because of their incomplete absorption in the gut; they cause alteration of the gut flora. Superinfection occurs with organisms like Candida, Proteus, Pseudomonas and C. difficile.
     • Pseudomembranous colitis caused by C. difficile is a serious complication. It is characterized by severe diarrhoea, fever, abdominal pain and stool mixed with blood and mucus, which is treated with oral metronidazole.
   • Hepatotoxicity: Acute hepatic necrosis with fatty changes is common in patients receiving high doses (>2 g/day) intravenously. It is more likely to occur in pregnant women.
   • Renal toxicity: Demeclocycline may produce nephrogenic diabetes insipidus by inhibiting the action of antidiuretic hormone (ADH) on collecting duct.
   • Fanconi syndrome: Use of outdated tetracyclines may damage proximal renal tubules – the patient may present with nausea, vomiting, polyuria, proteinuria, acidosis, etc.
   • Hypersensitivity reactions: Skin rashes, fever, urticaria, exfoliative dermatitis, etc. may occur rarely. Cross-sensitivity among tetracyclines is common.
   • Vestibular toxicity: It can occur following use of minocycline. It is reversible – subsides on discontinuation of the drug
4. Therapeutic uses
   • In dentistry: Tetracyclines are useful as an adjuvant in chronic periodontitis resistant to other antibiotics. They attain good concentration in gingival tissues, inhibit Actinobacillus and decrease the free radicals. They inhibit matrix metalloproteinases resulting in decrease in inflammation and bone resorption.
   • Rickettsial infections: Tetracyclines are the first-choice drugs for the treatment of rickettsial infections.
   • M. pneumoniae infections: Doxycycline or macrolides are used to shorten the duration of illness.
   • Chlamydial infections: Lymphogranuloma venereum is a sexually transmitted infection caused by C. trachomatis. Doxycycline is the drug of choice. Macrolides are also effective.
   • Cholera: Fluid and electrolyte replacement is the mainstay of therapy. Single dose of tetracycline or doxycycline is effective in adults. It reduces the stool volume.
   • Plague: Doxycycline is highly effective.
   • Granuloma inguinale: It is a sexually transmitted disease. Doxycycline is effective.
   • Acne: Low doses of tetracyclines are used.
   • Malaria: Doxycycline is used in combination with other antimalarial agents for treatment of chloroquine-resistant P. falciparum malaria. It is used alone for malarial chemoprophylaxis.
5. Advantages of doxycycline over tetracycline
   • It can be administered orally as well as intravenously.
   • It is highly potent.
   • It is completely absorbed after oral administration.
   • Food does not interfere with its absorption.
   • It has a longer duration of action (t1/2–24 h); requires less frequent dosing.
   • Incidence of diarrhoea is rare, as it does not affect the intestinal flora.
   • It can be safely given to patients with renal failure, as it is excreted primarily in bile.

Chloramphenicol

Chloramphenicol, a broad-spectrum antibiotic, was isolated from Streptomyces venezuelae. Even though chloramphenicol has a broad spectrum of antibacterial activity, its use is limited to only a few conditions because of its dangerous side effect – bone marrow suppression.

1. Mechanism of action

1. Chloramphenicol is a bacteriostatic agent, but in high concentration, it can be bactericidal against H.influenzae, N.meningitidis and S.pneumoniae.
   • It can also inhibit mitochondrial protein synthesis in mammalian cells by acting on 70S ribosomes. Resistance to chloramphenicol is caused by:
     • Production of inactivating enzyme – acetyltransferase, for example, H.influenzae, S. typhi, S. aureus.
     • Decreased permeability of the microbial cell wall.
     • Ribosomal mutation.
2. Pharmacokinetics
   • Chloramphenicol is commonly given by oral route and is rapidly absorbed from the gut. It is also available for parenteral and topical administration. Chloramphenicol is widely distributed to all tissues including CSF and brain.
   • It also crosses the placental barrier and is secreted in milk. It gets metabolized in the liver by glucuronide conjugation, and the metabolite is excreted mainly in the urine.
3. Adverse effects
   • Most of the adverse effects of chloramphenicol are due to inhibition of mammalian mitochondrial protein synthesis.

• Hypersensitivity reactions: Skin rashes, drug fever and angioedema may occur rarely.
• Bone marrow suppression: The most serious adverse effect of chloramphenicol is on the bone marrow. Hence, it is not used in dental practice. Bone marrow suppression can occur in two ways:
  • Dose-dependent reversible suppression of bone marrow, which manifests as anaemia, leukopaenia and thrombocytopaenia.
  • Idiosyncratic non–dose-related irreversible aplastic anaemia, which is often fatal.
• Gastrointestinal effects: These include nausea, vomiting and diarrhoea. Prolonged use may cause superinfection due to suppression of gut flora.
• Grey baby syndrome: In neonates, especially in premature babies, chloramphenicol can cause a dose-related grey baby syndrome due to reduced degradation and detoxification of the drug in the liver.
  • The skin appears ashen grey colour, hence the name ‘grey baby’ syndrome. Mortality is high. Therefore, chloramphenicol should be avoided in neonates.

1. Therapeutic uses
   • Typhoid fever: Chloramphenicol was used for typhoid. Antibiotics useful are third-generation cephalosporins, fluoroquinolones, azithromycin, ampicillin, cotrimoxazole, etc. S. typhi has developed resistance to most antibiotics.
   • Now, fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin, etc.) or third-generation cephalosporins (ceftriaxone, cefoperazone) are the drugs of choice for typhoid fever.
   • Bacterial meningitis: Third-generation cephalosporins are the preferred drugs for the treatment of bacterial meningitis caused by H. influenzae, N. meningitidis and S. pneumoniae. However, chloramphenicol can be used alone or in combination with ampicillin.
   • Anaerobic infections: Chloramphenicol is effective against most anaerobic bacteria including B. fragilis. But metronidazole is the preferred drug.
   • Rickettsial infections: Tetracyclines are the drug of choice for the treatment of rickettsial diseases. Chloramphenicol can be used to treat rickettsial infections in children and pregnant women.
   • Eye and ear infections: Chloramphenicol is used topically for eye and ear infections due to susceptible organisms.

Macrolides

Erythromycin was obtained from Streptomyces erythreus. Roxithromycin, clarithromycin and azithromycin are semisynthetic macrolides. Erythromycin is active against S. pyogenes, S. pneumoniae, N. gonorrhoea, C. perfringens, C. diphtheriae, Listeria, Mycoplasma, Legionella and C. trachomatis.

1. Mechanism of action
   • Erythromycin and other macrolides bind to bacterial 50S ribosomal subunit and inhibit protein synthesis. They are bacteriostatic, but can act as bactericidal agents at high concentrations. They are more active in alkaline pH.
2. Pharmacokinetics
   • Erythromycin is adequately absorbed from the upper GI tract. It is destroyed by gastric acid (acid labile), hence must be administered as Enteric-coated tablets to protect it from gastric acid.
   • Food may delay the absorption of erythromycin. It is widely distributed in the body and reaches therapeutic concentration in prostatic secretions but does not cross BBB. It is partly metabolized in liver and excreted in bile. Macrolides can be used safely during pregnancy.
3. Preparations of erythromycin
   • They are erythromycin base, erythromycin Estolate and erythromycin stearate.
4. Adverse effects
   • The common side effects are related to GI tract (Enteral toxicity): Nausea, vomiting, Epigastric pain and diarrhoea. Erythromycin increases GI motility.

1. • Hypersensitivity reactions: Skin rashes, drug fever, eosinophilia and hepatitis with cholestatic jaundice, particularly with erythromycin estolate. The incidence of hepatotoxicity is more in pregnant women.
2. Drug interactions
   • Erythromycin and clarithromycin are Enzyme inhibitors; hence, they increase the blood levels of number of drugs such as theophylline, carbamazepine, valproate, warfarin, digoxin, cyclosporine, etc. and potentiate their effects.
   • Erythromycin and clarithromycin dan precipitate fatal ventricular arrhythmias when given with cisapride, astemizole, terfenadine, etc. – such interactions are not seen with azithromycin.
3. Drawbacks of erythromycin
   • It has a narrow spectrum of antibacterial activity.
   • Its oral bioavailability is low.
   • It has a short duration of action.
   • Poor patient compliance due to GI side effects.
     • To overcome the above drawbacks, semisynthetic macrolides – roxithromycin, clarithromycin and azithromycin – have been developed.
     • Comparative Features of Macrolides
       
       
       
       1. Clarithromycin: Mechanism of action and spectrum of activity is similar to erythromycin. It is administered orally; achieves high concentration inside the cells. It is also used for the treatment of MAC, leprosy and H. pylori infection.
       2. Azithromycin: It can be administered orally and intravenously. Oral administration should be either 1 h before or 2 h after food. It does not cross blood–brain barrier.
          • Azithromycin is more active against H. influenzae than erythromycin and clarithromycin.
          • It has a wide tissue distribution and achieves high intracellular concentration. It is better tolerated and longer acting (single daily dose) than erythromycin.
4. Antibacterial spectrum and therapeutic uses of macrolides
   • In dentistry: Macrolides are alternatives to penicillins to treat orodental infections in patients allergic to β-lactam antibiotics. They can be used for treatment of dental infections – gingivitis, periodontitis, orodental abscess, postextraction infections, etc. due to aerobic as well as anaerobic gram-positive bacteria.
     • Azithromycin is preferred among macrolides because of wider spectrum of activity, high intracellular concentration, better tolerability and single daily dosing (azithromycin 500 mg o.d. orally for 3–5 days).
     • Prophylactic uses: Before dental procedures to prevent bacterial endocarditis in patients with valvular lesion – azithromycin (500 mg p.o. 1 h before the procedure) can be used.
   • As a drug of choice in the following conditions:
     • M. pneumoniae infections: Azithromycin and clarithromycin are often used for the treatment of community-acquired pneumonia. Erythromycin can also be used.
     • Legionnaires’ pneumonia: Macrolides, especially azithromycin, are the drug of choice because of high tissue concentration, excellent activity, better tolerability and single daily dosing.
     • Diphtheria: Erythromycin is very effective for eliminating the carrier state and for the treatment of acute infection.
     • Pertussis (whooping cough): Erythromycin is most effective for the treatment as well as for prophylaxis of close contacts. Clarithromycin and azithromycin are also effective.
   • As an alternative drug in patients who are allergic to penicillin
     • Tetanus: Administration of human tetanus antitoxin, tetanus toxoid, anticonvulsant (for example, diazepam) and debridement of wound are the important therapeutic measures. A course of oral erythromycin for 10 days may be given to eradicate C. tetani.
     • Streptococcal infections: Tonsillitis, pharyngitis, otitis media, cellulitis, pneumonia, etc. respond to azithromycin and erythromycin.

Antipseudomonal Agents (Drugs Used In pseudomonal Infections)

1. β-Lactam antibiotics:
   • Antipseudomonal penicillins: Carbenicillin, carbenicillin indanyl, ticarcillin, piperacillin, mezlocillin
   • Cephalosporins: Cefoperazone, ceftazidime, cefepime
   • Carbapenems: Imipenem, meropenem, doripenem, ertapenem
   • Monobactams: Aztreonam
2. Aminoglycosides: Gentamicin, amikacin, tobramycin, netilmicin, sisomicin
3. Fluoroquinolones: Ciprofloxacin, levofloxacin
4. Sulfonamides: Silver sulfadiazine, mafenide
5. Others: Polymyxin B, colistin

Drugs Used In Anaerobic Infections

1. Nitroimidazoles: Metronidazole, tinidazole, etc.
2. β-Lactam antibiotics:
   • Penicillins: Penicillin G (except for B. fragilis); piperacillin with tazobactam; ticarcillin with clavulanic acid
   • Cephalosporins: Cefoxitin, cefotetan, ceftizoxime
   • Carbapenems: Imipenem, ertapenem, meropenem, doripenem
3. Fluoroquinolones: Moxifloxacin
4. Broad-spectrum antibiotics: Chloramphenicol
5. Sulfonamides: Mafenide
6. Others: Vancomycin, clindamycin

Miscellaneous Antibacterial Agents

• Miscellaneous antibacterial agents have been discussed in Table.

• Miscellaneous Antibacterial Agents

Antitubercular Drugs

• Tuberculosis (TB) is a chronic infectious disease caused by M. tuberculosis. Mycobacterial infections require prolonged treatment.
• Since TB is a chronic infection, it consists of excessive fibrous tissue with central necrosis. So vascularity of the lesion is poor; hence, the penetration of the drug into the lesion is decreased.

1. Classification
   • First-line antitubercular drugs (standard drugs)
     • Isoniazid (H), rifampin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S).
   • Second-line antitubercular drugs (reserve drugs)
     • Para-aminosalicylic acid (PAS), thiacetazone, cycloserine, ethionamide, kanamycin, capreomycin, amikacin, levofloxacin, moxifloxacin, ofloxacin, clarithromycin, rifabutin, rifapentine.

• First-Line Antituberculosis Drugs and Their Daily Doses

First-Line Antitubercular Drugs

They are cheap, more effective, routinely used and less toxic.

1. Isoniazid (isonicotinic acid hydrazide [INH])
   • Isoniazid is a highly effective and the most widely used antitubercular agent. It is orally effective, cheapest and has tuberculocidal activity.
   • It is active against both intracellular and extracellular bacilli. It is a first-line drug for the treatment of TB. It is also used for chemoprophylaxis of TB.
     • Mechanism of action

Isoniazid inhibits the biosynthesis of mycolic acids, which are essential constituents of the mycobacterial cell wall.

1. • • Pharmacokinetics
       • INH is readily absorbed from the gut, distributed well all over the body, tubercular cavities and body fluids like CSF; it also crosses the placental barrier.
       • It is metabolized by acetylation and the metabolites are excreted in urine. The rate of acetylation of INH in either rapid or slow acetylators.
     • Uses
       • Isoniazid (INH) is a first-line drug for the treatment of TB. It is also used for chemoprophylaxis of TB.
     • Adverse effects and drug interactions
       1. Hepatotoxicity: The risk of hepatic damage is higher in chronic alcoholics, elderly patients and rapid acetylators. It is reversible on discontinuation of the drug. Patients receiving INH should be monitored for symptoms like anorexia, nausea, vomiting and jaundice.
       2. Peripheral neuritis: It is dose-related toxicity. INH is structurally similar to pyridoxine; hence, INH competitively interferes with the utilization of pyridoxine. It also promotes the excretion of pyridoxine.
          • Peripheral neuritis is more common in slow acetylators. Pyridoxine 10 mg/day, is generally given along with INH to reduce the risk of peripheral neuritis. It is also used for the treatment of INH-induced peripheral neuritis.
       3. Other side effects are fever, skin rashes, arthralgia, anaemia, GI disturbances, psychosis and rarely convulsions.
          • Isoniazid inhibits the metabolism of phenytoin, carbamazepine, warfarin, etc. → increases plasma levels of these drugs → may result in toxicity.
2. Rifampin (rifampicin)
   • Rifampin, a derivative of rifamycin, is a first-line antitubercular drug. It rapidly kills intracellular and extracellular bacilli including spurters (those residing in caseous lesions).
   • It is the only agent that can act on all types of bacillary subpopulations; hence, rifampin is called a sterilizing agent.
     • Mechanism of action
       • Rifampin binds to bacterial DNA-dependent RNA polymerase and inhibits RNA synthesis. It has a bactericidal effect against mycobacteria, N. meningitidis, H. influenzae, S. aureus, E. coli, Pseudomonas, etc.
     • Pharmacokinetics
       • It is given orally and is rapidly absorbed from GI tract, but presence of food reduces its absorption; distributed widely throughout the body and gets metabolized in liver.
       • The active deacetylated form is excreted in bile and undergoes enterohepatic recycling. The rest of the drug is excreted in urine.
     • Uses
       • Tuberculosis (TB): Rifampin is used along with INH and other antitubercular drugs for the treatment of TB. It is also used for chemoprophylaxis of TB.
       • Leprosy
       • Prophylaxis of meningococcal and H. influenzae meningitis: Rifampin reaches high concentration in the nasopharynx and eradicates the carrier state in case of meningococcal and H. influenzae infections.
       • Rifampin is used with doxycycline for the treatment of brucellosis.
     • Adverse effects and drug interactions
       • Hepatitis is the main adverse effect – the risk of hepatotoxicity is more in alcoholics and elderly patients.
       • Flu-like syndrome with fever, chills, headache, muscle and joint pain.
       • Gastrointestinal disturbances such as nausea, vomiting and abdominal discomfort.
       • Skin rashes, itching and flushing.
         • It stains various body fluids such as urine, tears, saliva, sweat and sputum orange red, which is harmless.
         • Rifampin is a potent microsomal enzyme inducer, hence reduces the plasma levels of drugs such as oral contraceptives (resulting in contraceptive failure), oral anticoagulants, oral antidiabetic drugs, HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs).
3. Pyrazinamide
   • Pyrazinamide is a synthetic analogue of nicotinamide. It is active in acidic pH – effective against intracellular bacilli (has sterilizing activity). It has tuberculocidal activity.
   • Like INH, pyrazinamide inhibits mycobacterial mycolic acid biosynthesis but by a different mechanism. It is given orally, absorbed well from GI tract and is distributed widely throughout the body including CSF.
   • It is metabolized in liver and excreted in urine. The most important adverse effect of pyrazinamide is dose-dependent hepatotoxicity. It impairs the excretion of urates resulting in hyperuricaemia and may also precipitate acute attacks of gout in susceptible individuals.
   • The other side effects are anorexia, nausea, vomiting, fever and skin rashes.
4. Ethambutol
   • It is a first-line antitubercular drug. It inhibits arabinose transferases that are involved in mycobacterial cell wall synthesis.
   • It is a bacteriostatic drug. It is used in combination with other antitubercular drugs to prevent emergence of resistance and for faster sputum conversion. There is no cross-resistance with other antitubercular drugs.
   • Ethambutol is well absorbed after oral administration, distributed widely in the body, metabolized in liver, crosses BBB in meningitis and excreted in urine.
   • Optic neuritis is the main adverse effect seen with ethambutol, which is characterized by decreased visual acuity and colour-vision defects (red–green).
   • Hence, periodic eye examination is necessary when the patient is on ethambutol. The toxicity is reversible if the drug is discontinued early following the onset of symptoms. Other side effects are nausea, vomiting, abdominal pain, skin rashes, itching and hyperuricemia
5. Streptomycin
   • Streptomycin is an aminoglycoside antibiotic. It is a bactericidal drug. It is active against extracellular bacilli in alkaline pH.
   • Streptomycin is not effective orally; it must be injected intramuscularly. The adverse effects are ototoxicity, nephrotoxicity and neuromuscular blockade.
6. Second-line antitubercular agents
   • They are less effective, expensive and more toxic than the first-line drugs; hence, they are reserve drugs for TB.
7. Para-aminosalicylic acid (PAS)
   • It is structurally similar to sulfonamides. Like sulfonamides, PAS also competitively inhibits folate synthetase enzyme and produces a tuberculostatic effect.
   • At present, PAS is a reserve drug for the management of multidrug-resistant TB (MDR-TB). The common adverse effects are GI disturbances – anorexia, nausea, vomiting and abdominal discomfort.
8. Ethionamide
   • It is structurally similar to INH but less efficacious. It inhibits synthesis of mycolic acids.
   • It is a bacteriostatic drug. The adverse effects are nausea, vomiting and epigastric pain.
   • Other side effects are hepatitis, headache, blurred vision and paraesthesia.
9. Cycloserine
   • It is a second-line antitubercular drug with bacteriostatic activity. It inhibits bacterial cell wall synthesis. The common side effects are on CNS and include headache, tremor, psychosis and convulsions.

Other Antitubercular Agents

1. Fluoroquinolones: Moxifloxacin and levofloxacin – bactericidal agents, given orally.
2. Aminoglycosides: Amikacin and kanamycin – bactericidal agents, administered parenterally.
3. Capreomycin: May cause nephrotoxicity and ototoxicity.
4. Macrolides: Azithromycin and clarithromycin – given orally.
5. Rifamycins: Rifapentine and rifabutin – bactericidal agents, given orally.
6. Rifabutin: It is a derivative of rifampin. Rifabutin is preferred to rifampin for the treatment of TB in HIV-infected patients on protease inhibitors (PIs) as rifabutin is a less potent enzyme inducer. Rifabutin is also used for the treatment of MAC infection in combination with clarithromycin and ethambutol.
7. Rifapentine, analogue of rifampin, is also a potent enzyme inducer.

Treatment of tuberculosis

Multidrug therapy (MDT) is used for the treatment of tuberculosis. The objectives of MDT are:

1. To make the patient noninfectious as early as possible by rapidly killing the dividing bacilli and decrease transmission of disease.
2. To prevent the development of drug-resistant bacilli.
3. To decrease morbidity and mortality.

• The regimen recommended for each patient depends on the diagnostic category for each patient. The Revised National Tuberculosis Control Programme (RNTCP) was launched in India in 1997. Under this programme, DOTS (directly observed treatment short course) chemotherapy was implemented.
• In DOTS, patient is administered drugs under the supervision of a health worker or other trained person to ensure that drugs are actually consumed. It is aimed at ensuring patient compliance thus preventing the emergence of drug-resistant TB.
• RNTCP has been renamed National Tuberculosis. Elimination Program in 2020. There is increasing use of technology in monitoring medication intake by patients. The regimens used for the treatment of tuberculosis consist of an intensive phase and a continuation phase.
  • Treatment Regimens for Tuberculosis

Treatment of drug-sensitive tuberculosis involves two phases:

1. Intensive phase: The main objective of the intensive phase is to render the patient noncontagious.
2. Continuation phase: This phase helps to eliminate the remaining bacilli and prevents relapse.

For the treatment of drug-sensitive tuberculosis, oral first-line anti-TB drugs are administered daily as a fixed-dose combination (FDC) based on the body weight of the patient. Streptomycin is administered intramuscularly.

• Doses of Commonly Used Antitubercular Drugs in Adults

Note: E, ethambutol; H, isoniazid; R, rifampin; Z, pyrazinamide. Source: Technical and Operational Guidelines for TB Control in India 201 6. taken during intensive phase; FDC of HRZE contains 75/1 50/400/275 mg, respectively. Taken during the continuation phase; the FDC of HRE contains 75/1 50/275 mg, respectively.

1. Multidrug-resistant tuberculosis (MDR-TB)
   • It is defined as resistance to both isoniazid and rifampicin with or without resistance to any other anti-TB drugs.
   • MDR-TB can be treated by either specially designed standardized or individualized regimens. Patients with or highly likely to have MDR-TB should be treated with regimens containing at least four drugs to which organisms are known or presumed to be susceptible.
   • Conventional treatment of MDR-TB has been for at least 18–24 months beyond culture conversion. Each dose of MDR regimen should be supervised throughout entire duration of treatment.
2. Extensively drug-resistant tuberculosis (XDR-TB)
   • XDR-TB is defined as resistance to INH, rifampicin, fluoroquinolone and one of capreomycin/kanamycin/amikacin. Mortality rate is high.

Treatment In HIV-Positive Patients

Generally, treatment of TB is the same for HIV-infected as for non-HIV-infected TB patients. Rifabutin is preferred over rifampin in HIV-infected patients on antiretroviral drugs such as protease inhibitors, as interaction is minimal.

• Tuberculosis in pregnancy

All first-line drugs (INH, rifampin, pyrazinamide and ethambutol) except streptomycin can be used in pregnancy.

Antileprotic Drugs

Leprosy is a chronic infectious disease caused by M. leprae.

1. Types of leprosy
   • Lepromatous leprosy: The cell-mediated immunity (CMI) is impaired against lepra mbacilli; hence, the course of the disease progresses very rapidly. This is characterized by extensive bilateral skin lesions that contain numerous lepra bacilli.
   • Tuberculoid leprosy: The CMI is intact and is characterized by the predominant peripheral nerve involvement with a single or few skin lesions. The bacilli are seen rarely.
     • Plenty of lepra bacilli are seen in the skin lesions of borderline (BB), borderline lepromatous (BL) and lepromatous leprosy (LL); hence, these groups are called as multibacillary leprosy (MBL).
     • Borderline tuberculoid (BT), tuberculoid (TT) and indeterminate (I) leprosy are referred to as paucibacillary leprosy.
2. Drugs used for the treatment of leprosy

Dapsone (diamino diphenyl sulfone [DDS]), clofazimine, rifampin, ethionamide, ofloxacin, minocycline and clarithromycin are the drugs used in leprosy.

Dapsone Or diamino Diphenyl Sulfone

Dapsone, a sulfone, is the oldest, cheapest and most widely used agent for the treatment of leprosy even today.

1. Mechanism of action
   • Sulfones are chemically related to sulfonamides and have the same mechanism of action. Lepra bacilli utilize para-aminobenzoic acid (PABA) for the synthesis of folic acid, which, in turn, is necessary for its growth and multiplication.
   • Dapsone is structurally similar to PABA; hence, it competitively inhibits folate synthetase enzyme and prevents the formation of tetrahydrofolic acid (THFA). Thus, dapsone produces leprostatic effect.

1. Pharmacokinetics
   • Dapsone is given orally and is almost completely absorbed from the gut; it is bound to plasma proteins, widely distributed in the body and concentrated mainly in the infected skin, muscle, liver, kidney, etc. It is partly secreted in bile and undergoes enterohepatic cycling. Dapsone is metabolized by acetylation and metabolites are excreted in urine.
2. Adverse effects
   • The common adverse effects are dose-related haemolytic anaemia particularly in patients with G6PD deficiency. Other side effects are anorexia, nausea, vomiting, fever, headache, allergic dermatitis, itching and peripheral neuropathy.
   • Dapsone may cause exacerbation of lesions – ‘sulfone syndrome’, which is characterized by fever, dermatitis, pruritus, lymphadenopathy, methaemoglobinaemia, anaemia and hepatitis.

Rifampin

It is the most effective and rapidly acting bactericidal drug for lepra bacilli; it kills most of the bacilli.

Clofazimine

• It is a phenazine dye and has leprostatic activity against lepra bacilli. It has antiinflammatory effect, hence, is also useful in the treatment of type-2 lepra reaction.
• Clofazimine binds to mycobacterial DNA to inhibit its template function. It also has activity against dapsone-resistant organism. It is given orally – fatty meal increases its absorption. It accumulates in tissues – t1/2 is 70 days. It causes reddish–black discolouration of the skin on exposed parts.
• It can cause pigmentation of the conjunctiva and cornea, discolouration of the hair, tears, sweat, urine, etc. Nausea, vomiting, diarrhoea, and abdominal pain are its other side effects.
• Other drugs used are ethionamide, clarithromycin, minocycline and ofloxacin.

Chemotherapy Of Leprosy

The WHO recommends the use of MDT for all leprosy cases. Clinically, leprosy has been classified into two types – multibacillary and paucibacillary leprosy. The objectives and need for MDT are:

• To make the patient noncontagious as early as possible by killing the dividing bacilli.
• To prevent the development of drug-resistant bacilli.
• To prevent relapse.
• To shorten the duration of effective therapy.

1. Treatment schedules of leprosy All drugs are administered orally.
   • For multibacillary leprosy (LL, BL and BB)
     • The duration of treatment is 1 year, and later the patient should be followed up for a period of 3–5 years. If clofazimine is unacceptable, the alternative drug used is ethionamide 250 mg daily, unsupervised.
   • For paucibacillary leprosy (TT, BT and I)
     • For Rifampin 600 mg once monthly (supervised).
     • For Dapsone 100 mg daily (unsupervised).
       • The duration of treatment is 6 months.

Lepra Reaction

These are immunologically mediated reactions that occur during the course of the disease. The exact cause of such reactions is not clear and is usually precipitated by infection, trauma, mental stress, etc. There are two types of reactions:

1. Reversal reaction: It is a delayed type of hypersensitivity in tuberculoid leprosy. There are signs of inflammation in the existing skin lesions – they become red, warm and swollen. New lesions may appear. Nerves are frequently affected. It is treated with prednisolone or clofazimine.
2. Erythema nodosum leprosum (ENL): It occurs in lepromatous leprosy. It is a type-3 hypersensitivity reaction (Arthus-type). There is erythema nodosum – red, painful, tender cutaneous and subcutaneous nodules. Nerves may be affected. Constitutional symptoms are present.
   1. The type-2 reaction may be due to release of antigens from the dying lepra bacilli. Severe form of reaction is treated with thalidomide, but it should not be prescribed during pregnancy. The other drugs used are aspirin, clofazimine, chloroquine and prednisolone.

Antifungal Agents

Most of fungal infections are opportunistic; hence, they are common in diabetes mellitus, cancer, AIDS, pregnancy and in patients on immunosuppressive therapy such as a prolonged course of corticosteroids, broad-spectrum antibiotics and anticancer drugs.

• Fungal Infections/Causative Organisms

1. Classification
   • Polyene antibiotics: Amphotericin B, nystatin, hamycin.
   • Echinocandin antibiotics: Caspofungin acetate, micafungin.
   • Heterocyclic compound: Griseofulvin.
   • Azoles:
     • Imidazoles: Ketoconazole, miconazole, clotrimazole, econazole, oxiconazole.
     • Triazoles: Fluconazole, itraconazole, voriconazole, posaconazole.
   • Allylamine: Terbinafine.
   • Antimetabolite: Flucytosine.
   • Other topical antifungal agents: Whitfield’s ointment, tolnaftate, sodium thiosulfate, selenium sulfide, undecylenic acid, ciclopirox, butenafine.
2. Polyene antibiotics: Amphotericin B (AMB), nystatin and hamycin are polyene antibiotics and have the same mechanism of action.

Amphotericin B

• Amphotericin B (AMB) is a broad-spectrum antifungal antibiotic. It is effective against
• Cryptococcus, Coccidioides, Candida, Aspergillus, Blastomyces, Histoplasma, Sporothrix, fungi causing mucormycosis, etc.

1. Mechanism of action
   • The fungal cell membrane contains a sterol, which resembles cholesterol and is called ‘ergosterol’.

1. Pharmacokinetics
   • AMB is not absorbed from the gut and hence is not suitable orally for systemic infections. It is highly bound to plasma proteins and sterols in tissues, widely distributed to various tissues but does not cross BBB. It is metabolized in liver and excreted slowly in urine and bile.
2. Adverse effects
   • AMB is the most toxic of all the antifungal agents. The acute reactions are fever, chills, headache, dyspnoea, phlebitis at the site of injection, nausea and vomiting.
   • Anaemia and electrolyte disturbances are commonly seen. Anaemia is less with lipid based formulations.
   • Nephrotoxicity with azotaemia is seen in most of the patients on AMB therapy.
   • Hepatotoxicity can occur occasionally.
   • Headache and convulsions may occur on intrathecal administration.
3. Formulations of AMB
   • AMB is poorly water soluble; hence, intravenous preparation is made with deoxycholate–conventional AMB (C-AMB).
   • Liposomal AMB (L-AMB) is a lipid-based formulation of AMB. It is less nephrotoxic than C-AMB.
4. Uses
   • AMB is useful for various systemic fungal infections but is highly toxic; hence, the azoles (fluconazole and itraconazole) have replaced AMB in the treatment of many fungal diseases. AMB is useful topically for oral, cutaneous and vaginal candidiasis.

Nystatin

Nystatin is poorly absorbed from the skin and mucous membranes. It is highly toxic for systemic use. It is used only topically in Candida infections. It is available as suspension, ointment, cream, powder and tablet.

1. Uses
   • In dentistry: Nystatin is used topically for oral candidiasis, angular cheilitis and antibiotic-associated stomatitis. Nystatin oral suspension 5 mL (1 lakh units/mL) to be swished and swallowed four to five times a day for 14 days.
   • Other uses include oropharyngeal, corneal, conjunctival and cutaneous candidiasis.
2. Adverse effects They include nausea and bitter taste.

Hamycin

It was developed in India (Hindustan Antibiotics). Mechanism of action. It is useful topically for cutaneous and vaginal candidiasis. In dentistry, it is used for oral candidiasis and angular cheilitis. It is available as ointment and suspension for topical administration.

Griseofulvin

Griseofulvin is used orally for dermatophytic infections. It is not effective topically.

1. Mechanism of action

1. Pharmacokinetics
   • Griseofulvin is administered orally. Its bioavailability is increased by taking with fatty food and by using ultrafine preparation. It gets concentrated in keratinized tissues such as skin, hair and nails.
   • It is an enzyme inducer; thus, it reduces the effectiveness of warfarin and oral contraceptives. It has disulfiram-like action, hence can cause intolerance to alcohol. It is metabolized in the liver and excreted in urine.
2. Uses
   • Griseofulvin is used in the treatment of dermatophyte infections like tinea (ringworm) infections (tinea capitis, tinea barbae, tinea corporis, tinea pedis).
3. Adverse effects
   • They are headache, rashes, peripheral neuritis, vertigo, blurred vision and GI effects such as nausea, vomiting, diarrhoea and heartburn.

Flucytosine

Flucytosine is a prodrug. It is taken up by susceptible fungal cells and converted into 5- fluorouracil (5-FU) that interferes with fungal DNA synthesis. Flucytosine has narrow spectrum of activity and is effective against Cryptococcus, Chromoblastomyces and Candida spp.

1. Uses
   • Flucytosine is used in combination with AMB for cryptococcal meningitis
2. Adverse effects
   • These include bone marrow suppression with anaemia, neutropenia and thrombocytopaenia. The other side effects include nausea, vomiting, diarrhoea, alopecia, skin rashes, itching and rarely hepatitis.

Azoles

Azole antifungals are broadly divided into imidazoles and triazoles. Both of them are structurally related compounds, have similar mechanism of action and antifungal spectrum.

• Mechanism of action
  • Azoles impair ergosterol synthesis by inhibiting the 14α-demethylase enzyme.

1. Miconazole and clotrimazole
   • They are used topically for dermatophytic and Candida infections. They are available as cream, gel, lotion, solution, spray, vaginal pessary, etc. Clotrimazole troche is also available.
   • Uses
     • Candida infections: Clotrimazole is frequently used for the treatment of oropharyngeal candidiasis – it can be used as gel, lotion or troche (troche 10 mg to be allowed to dissolve in the mouth q.i.d. for 14 days). Miconazole 2% gel can also be used for the treatment of oral candidiasis – 2.5 mL is applied topically four times a day for 14–21 days.
       • Topical clotrimazole is applied at the angle of the mouth in angular cheilitis alternately with topical antibacterial agent (as it could be due to Candida, S. aureus, etc.). For denture stomatitis, clotrimazole, nystatin and miconazole are useful topically.
       • The drug is applied topically as a thin layer over the affected area and tissue side of the denture. The denture should be cleaned and soaked overnight in antiseptic solution like chlorhexidine.
       • Clotrimazole and miconazole are used for the treatment of vulvovaginal and cutaneous candidiasis.
     • Dermatophytic infections: Clotrimazole and miconazole are useful for tinea pedis, tinea cruris, tinea corporis and tinea versicolor.
   • Adverse effects
     • These are local irritation, itching or burning. Miconazole is safe for use during pregnancy.
2. Ketoconazole Ketoconazole (KTZ) is a prototype drug among azole
   • Pharmacokinetics
     • It is orally effective. Acidic environment favours the absorption of KTZ; hence, its bioavailability is reduced by drugs like H2-blockers, proton pump inhibitors or antacids. It is highly bound to plasma proteins, metabolized in liver extensively and excreted mainly in faeces.
   • Adverse effects
     • Ketoconazole is the most toxic among azoles, but it is less toxic than AMB. Anorexia, nausea and vomiting are the most common side effects.
     • It reduces adrenal cortical steroids, testosterone and oestrogen synthesis – thus causes gynaecomastia, oligospermia, loss of libido and impotence in males; menstrual irregularities and amenorrhoea in females.
   • Drug interactions
     • Ketoconazole inhibits the metabolism of sulfonylureas, warfarin, phenytoin, terfenadine, etc.
   • Uses
     • Dermatophytosis: Ketoconazole is used topically.
     • Candidiasis: KTZ is useful for oral, oesophageal and vulvovaginal candidiasis. It is very toxic for systemic use; hence it has been replaced by triazoles.
3. Fluconazole It is a triazole. It is available for oral and i.v. administration as well as for topical use in the eye. It has broad spectrum of antifungal activities.
   • Antifungal Agents and their Uses
   • Pharmacokinetics
     • It is well absorbed from GI tract and has a high bioavailability. Food or gastric pH does not affect its bioavailability. It is poorly bound to plasma proteins, widely distributed in the body, freely crosses BBB and reaches high concentration in the CSF.
     • It is mainly excreted in urine in the unchanged form.
   • Adverse effects
     • The common side effects are nausea, vomiting, diarrhoea and abdominal discomfort. The other side effects include headache, alopecia, skin rashes and hepatic necrosis.
     • It is contraindicated during pregnancy because of teratogenic effect. Fluconazole has enzyme inhibiting property.
   • Uses
     • Candidiasis: Fluconazole is effective in oral (200 mg stat, then 100 mg daily for next 14 days), oropharyngeal, oesophageal, cutaneous and invasive candidiasis.
     • Cryptococcal and coccidioidal meningitis: Intravenous fluconazole is used.

Itraconazole

It is a synthetic triazole. It is administered orally as well as by i.v. route. Gastric acidity favours the absorption of itraconazole. It is highly bound to plasma proteins, does not cross BBB and is metabolized in liver. It has a broad spectrum of activity against many fungi including Aspergillus.

1. Adverse effects
   • These are nausea, vomiting, diarrhoea, headache, hepatotoxicity and hypokalaemia. Itraconazole inhibits CYP3A4 and can increase serum levels of drugs metabolized by this enzyme.
2. Uses Itraconazole is an effective antifungal agent but rarely used in dental practice.
   • It is effective for oesophageal, oropharyngeal and vaginal candidiasis, but not superior to fluconazole. It is useful for the treatment of oral candidiasis refractory to fluconazole.
   • Intravenous itraconazole is the drug of choice in systemic fungal infections like histoplasmosis, blastomycosis and sporotrichosis.
   • In onychomycosis, oral itraconazole is used.
   • It is also effective in aspergillosis and dermatophytosis.

1. Voriconazole It is a triazole. It is used for the treatment of invasive aspergillosis and disseminated Candida infections.
   • Voriconazole is administered orally or intravenously. Adverse effects include visual and auditory disturbances, prolongation of QT interval and skin rashes.
2. Posaconazole, an azole, has broad spectrum of activity against many fungi including Aspergillus and agents causing mucormycosis.
   • It is administered orally; fatty food increases its bioavailability. Adverse effects include headache, sedation and GI disturbances. It is useful for the treatment of oral candidiasis not responding to fluconazole.

Allylamine

1. Terbinafine
   • Terbinafine, an allylamine, inhibits squalene 2,3-epoxidase and blocks ergosterol synthesis. It is available for topical as well as for oral administration. It is well absorbed after oral administration and is concentrated in skin, nails and adipose tissue.
   • It is highly bound to plasma proteins, poorly penetrates the BBB, is metabolized in liver and is excreted in urine. Terbinafine is a fungicidal agent.
   • Adverse effects
     • Terbinafine may cause side effects such as nausea, diarrhoea, dyspepsia and rarely hepatitis. It may cause itching, rashes, local irritation on topical use.
   • Uses
     • Dermatophytosis: Terbinafine is very effective against dermatophytes. It is used topically or orally for tinea pedis, tinea corporis and tinea cruris. In onychomycosis of hands and feet, it is used orally and is more effective than itraconazole.
     • Candidiasis: Terbinafine is less effective in Candida infections.

Echinocandins

1. Caspofungin acetate
   • Caspofungin Acetate is a semisynthetic antifungal agent effective against Candida and Aspergillus. It is administered by i.v. infusion for the treatment of invasive aspergillosis and candidiasis, when the patient is not responding to or intolerant to other antifungal agents.
   • The adverse effects include nausea, vomiting, flushing, fever and phlebitis at the site of injection.

Other Topical Agents

1. Whitfield’s ointment: It contains 6% benzoic acid and 3% salicylic acid. Salicylic acid has keratolytic and benzoic acid has fungistatic effects. It is used in the treatment of tinea pedis.
2. Potassium iodide: It is useful for dermatophytic infection.
3. Butenafine: Its mechanism of action and spectrum of activity is similar to terbinafine.

Antiviral Agents

Classification

1. Drugs used against herpetic infection (antiherpes agents): Acyclovir, valacyclovir, famciclovir, penciclovir, ganciclovir, foscarnet, idoxuridine.
2. Drugs used against HIV infection (antiretroviral agents)
   • Nucleoside reverse transcriptase inhibitors: Zidovudine, stavudine, lamivudine, tenofovir, didanosine, abacavir, emtricitabine.
   • Non-nucleoside reverse transcriptase inhibitors: Nevirapine, efavirenz, delavirdine.
   • Protease inhibitors: Saquinavir, indinavir, ritonavir, lopinavir, nelfinavir, atazanavir, amprenavir.
   • Entry inhibitor (fusion inhibitor): Enfuvirtide.
   • CCR5 receptor blocker: Maraviroc.
   • Integrase inhibitor: Raltegravir, dolutegravir.
3. Anti-influenza agents: Amantadine, rimantadine, oseltamivir, zanamivir.
4. Other antiviral agents: Interferons, ribavirin and sofosbuvir (for hepatitis C), lamivudine, tenofovir, adefovir dipivoxil (for hepatitis B).

Antiherpes Agents

1. Acyclovir
   • It is a synthetic, purine nucleoside analogue that has antiherpes activity. It is more effective against HSV-1 and HSV-2 than Varicella zoster virus (VZV) infections.
   • Mechanism of action
     • Acyclovir is selectively taken up by the herpes virus infected cells and activated to triphosphate derivative, which inhibits viral DNA synthesis.
     • It is available for oral, topical and i.v. administration. It is a highly potent antiherpes drug. It has high therapeutic index with low toxicity to host cells.
     • Its oral bioavailability is poor. It is poorly bound to plasma proteins, widely distributed in the body, freely crosses BBB and is excreted in urine.

• • Uses
    • Mucocutaneous HSV: Acyclovir is used orally or topically in the treatment of gingivostomatitis, herpes labialis and ulcers in mouth (200–800 mg orally five times daily). It is used intravenously in immunocompromised patients.
    • Other uses are genital herpes, herpetic encephalitis, herpes simplex keratitis, chickenpox and herpes zoster.
  • Adverse effects

Acyclovir is usually well tolerated. Nausea, vomiting, diarrhoea and headache are the other side effects. High doses may cause neurotoxicity with tremor, confusion, disorientation and convulsions. On topical use, it can cause irritation and burning.

Other Antiherpes Agents

The important features of some of the antiherpetic agents is given in Table.

• Important Features of the Anti-herpetic Agents

Anti-Influenza Agents

1. Amantadine
   • It is an antiviral drug that has an antiparkinsonian effect as well. It inhibits viral replication. Amantadine is used orally for the prophylaxis and treatment of influenza A virus infection.
2. Oseltamivir
   • It selectively inhibits influenza A and B virus neuraminidases, thus interfering with the release of virus from infected cells.
   • It is used orally in the treatment and prevention of influenza A (avian influenza or bird flu) and B virus infections. Adverse effects are nausea, vomiting and abdominal discomfort.
3. Zanamivir
   • The mechanism of action and uses are similar to oseltamivir. Oral bioavailability is low. It is administered by inhalation.
   • Adverse effects are bronchospasm, headache and dizziness. It should be avoided in patients with airway disease.

Anti-Hepatitis Drugs

Lamivudine, tenofovir and adefovir dipivoxil inhibit hepatitis B virus DNA polymerase. Tenofovir is well tolerated and highly effective for chronic hepatitis B virus infections.

1. Sofosbuvir
   • It is highly effective against hepatitis C.
2. Interferons
   • Interferons are proteins produced by virus-infected cells and also by recombinant DNA technology. There are mainly three types of interferons, namely α, β and γ.
   • The antiviral activity of interferons is due to the inhibition of viral penetration, synthesis of mRNA, translation of viral proteins, assembly of viral particles and their release.
   • They are administered by i.m. and s.c. routes or locally into the lesion.
     • Uses
       • Interferon-α is used for the treatment of herpetic infections in immunosuppressed individuals, chronic hepatitis B and C and Kaposi’s sarcoma in HIV-infected patients.
     • Adverse effects
       • These include fever, headache, myalgia, skin rashes, alopecia, bone marrow suppression and neurotoxicity.
3. Ribavirin
   • Ribavirin monophosphate competitively inhibits cellular enzymes that are needed for the synthesis of guanosine triphosphate (GTP). It also competitively inhibits viral mRNA synthesis. It is administered orally, aerosol or i.v. routes.
   • Ribavirin is effective against a wide range of RNA and DNA viruses. Oral ribavirin is effective in the treatment of chronic hepatitis C infection.

Antiretroviral Agents

Classification:

1. Nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors are effective against both HIV-1 and HIV-2.
2. Non-nucleoside reverse transcriptase inhibitors and entry inhibitors are active against HIV-1.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

These drugs, after entering the HIV-infected cells, are converted to their active triphosphate forms by cellular kinases and competitively inhibit HIV reverse transcriptase. They get incorporated into the growing viral DNA and cause the termination of chain elongation of proviral DNA.

1. Zidovudine (azidothymidine [AZT])
   • Zidovudine was the first antiretroviral drug approved for the treatment of HIV infection. It is the prototype drug of NRTIs. Zidovudine is effective against HIV-1 and HIV-2.
   • It protects the uninfected cells from HIV, but has no effect on HIV-infected cells. Zidovudine is orally effective. It is well absorbed from GI tract, metabolized in liver by glucuronide conjugation and excreted in urine.
   • It crosses placenta and BBB, and is also secreted in milk.
     • Adverse reactions
       • Bone marrow suppression, anaemia and neutropaenia are the common side effects. Nausea, vomiting, abdominal discomfort, headache and insomnia are commonly seen during the initial stages of therapy.
       • Long-term therapy may cause hepatotoxicity, myopathy with fatigue and lactic acidosis.
         1. Zidovudine × paracetamol: Both are metabolized by glucuronide conjugation. Paracetamol competes and interferes with glucuronide conjugation of zidovudine. This leads to a rise in the plasma concentration of zidovudine and its toxicity.
         2. Azoles × zidovudine: Azole antifungal agents are hepatic microsomal enzyme inhibitors. They inhibit the metabolism of zidovudine and increase its blood level resulting in its toxicity.
         3. Zidovudine × stavudine: They should not be combined together because they compete for intracellular phosphorylation leading to antagonism of one drug by other.
            • Zidovudine is used in combination with other antiretroviral drugs for the treatment of AIDS. It is also used for postexposure prophylaxis (PEP) and to prevent vertical transmission of HIV.
2. Didanosine, stavudine, emtricitabine and lamivudine

They are effective orally. The adverse effects are peripheral neuritis, pancreatitis, GI disturbances, lactic acidosis, skin rashes, etc.

• • Lamivudine is a commonly used agent in antiretroviral therapy (ART) because of its efficacy and low toxicity.
  • Tenofovir (nucleotide reverse transcriptase inhibitor): It is a nucleotide analogue of adenosine. It undergoes intracellular phosphorylation and inhibits viral reverse transcriptase enzyme resulting in termination of chain elongation of HIV DNA.
  • It should be cautiously used in patients with renal disease. It is used in combination with other antiretroviral agents for the treatment of AIDS.
  • Abacavir can cause hypersensitivity reactions.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

NNRTIs are highly active against HIV-1 but have no effect on HIV-2. There is no crossresistance with the NRTIs. They are used in combination with NRTIs in the treatment of AIDS.

Adverse effects are skin rashes, fever, nausea, pruritus and CNS disturbances like headache, confusion, insomnia, bad dreams and amnesia. Nevirapine is hepatotoxic. Neuropsychiatric symptoms can occur with efavirenz.

Protease Inhibitors (PIs)

• Examples are indinavir, nelfinavir, atazanavir, saquinavir, lopinavir, ritonavir, fosamprenavir and darunavir.
• Protease inhibitors competitively inhibit the HIV protease enzyme (late step of viral cycle)→ prevent cleavage of viral polyproteins to the final functional, structural and enzymatic components of HIV → immature and noninfectious viral particles are produced.
• Ritonavir inhibits metabolism of lopinavir (LPV), atazanavir (ATV), saquinavir (SQV). Hence, it is combined with these drugs to reduce their dose and frequency of administration. PIs are used orally with reverse transcriptase inhibitors in patients with AIDS.
• They are extensively metabolized in liver. Nausea, vomiting and diarrhoea are common side effects. They also produce skeletal muscle wasting, lipodystrophy, insulin resistance, diabetes, etc.

Other Drugs

• Enfuvirtide (fusion inhibitor) and maraviroc (chemokine receptor blocker) prevent viral entry into the cell. Raltegravir and dolutegravir prevent integration of viral DNA with host DNA.
• They are used as add-on drugs in patients who are not responding to ongoing ART.

Treatment Of HIV Infection

Retroviruses cause selective depletion of CD4 cells leading to a profound decrease in cell-mediated immunity. Hence, the infected person is prone to severe opportunistic infections and lymphoid malignancies.

1. Objectives of anti-hiv therapy
   • To suppress HIV replication and improve immune status of the patient.
   • To prevent the emergence of drug-resistant virus.
   • To prevent or treat opportunistic infections.
2. Principles of therapy
   • ART regimen is used to achieve the above objectives. In ART regimen, drugs with different mechanism of action should be used so that they produce synergistic effect. It usually consists of a combination of two NRTIs with an NNRTI/integrase inhibitor/PI.
3. Criteria for anti-hiv treatment
   • The National AIDS Control Organisation (NACO) has adopted WHO 2016 guidelines for treatment of HIV infection.
   • According to these guidelines, ART should be started in all HIV-infected patients irrespective of CD4 count or clinical stage.
   • Treatment is lifelong. A combination of antiretroviral drugs is used.
4. Regimens
   • First-line ART regimen in adults:
     • 2NRTIs + 1NNRTI/integrase inhibitor (INSTI).
     • Tenofovir +Lamivudine + Efavirenz (fixed dose combination, once daily)
     • Tenofovir + Emtricitabine + Efavirenz
     • Tenofovir (TDF) + Lamivudine (3TC)/Emtricitabine (FTC) + Dolutegravir (DTG) is another first line regimen which can be used
   • Alternate regimens
     • Zidovudine + Lamivudine + Efavirenz or
     • Zidovudine + Lamivudine + Nevirapine or
     • Tenofovir + Lamivudine + Nevirapine
5. Monitoring of therapy Estimation of HIV viral load is preferred.
6. Pregnant women In HIV-positive pregnant women, antiretroviral therapy (tenofovir + lamivudine + efavirenz) is required to prevent vertical transmission to the offspring.
7. Prophylaxis of HIV infection (postexposure prophylaxis)
   • Post-exposure prophylaxis (PEP). It is the use of antiretroviral drugs after exposure has occurred to prevent HIV infection.
   • Individuals who have had exposure which has a risk of transmission of HIV (for example, sexual exposure, needle-prick injury, exposure to blood, breast milk, CSF, pleural, pericardial fluid, etc.) need postexposure prophylaxis (PEP) depending on the risk of transmission and HIV status of the source.
   • Postexposure prophylaxis should be initiated as early as possible, preferably within 72 h of exposure.
   • Preferred regimen for adults and adolescents:
     • Tenofovir (300 mg) + Emtricitabine (200 mg) + Lopinavir/ritonavir (400/100 mg) or
     • Tenofovir (300 mg) + Emtricitabine (200 mg) + Atazanavir/ritonavir (300/100 mg)

The drugs should be administered for 28 days. Postexposure prophylaxis is not required if exposure is to tears, urine or sweat or the source is HIV-negative.

Antimalarial Drugs

• Malaria is a protozoal infection caused by genus Plasmodium and transmitted to man by the infected female Anopheles mosquito.
• The species of malarial parasites are Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and P. falciparum.
• The incidence of malaria is increasing due to the resistance of vectors to insecticides and drug-resistant parasites. In India, P. vivax and P. falciparum are common.
• Classification
  • Chemical classification
    • 4-Aminoquinoline: Chloroquine.
    • 8-Aminoquinoline: Primaquine.
    • Quinoline methanol: Mefloquine.
    • Alkaloids: Quinine, quinidine.
    • Antifolates: Pyrimethamine, sulfadoxine.
    • Antibiotics: Doxycycline.
    • Qinghaosu compounds: Artemisinin, artemether, artesunate.
    • Amino alcohols: Lumefantrine.

4-Aminoquinoline

1. Chloroquine
   • Chloroquine is a 4-aminoquinoline. It is very effective against P. vivax, P. ovale, P. malariae and chloroquine-sensitive strains of P. falciparum.
     • Mechanism of action
       1. Chloroquine is a basic drug, which is taken up by the acidic food vacuoles of susceptible plasmodia and inhibits the conversion of heme to haemozoin.
       2. The ‘drug– haeme’ complex is toxic and kills the parasite. Resistance to chloroquine is common with P. falciparum.
       3. In the acidic vacuole of plasmodia:

• • • Pharmacokinetics
      1. Chloroquine is commonly administered by oral route, but it can also be given by i.m. and slow i.v. routes.
      2. It is well absorbed after oral and parenteral administration. It has strong affinity for melanin-containing tissues.
      3. It gets concentrated in liver, spleen, kidney, lungs, skin, etc. Chloroquine is metabolized in the liver and slowly excreted in urine.
    • Adverse effects and contraindications
      1. Chloroquine in antimalarial doses may cause nausea, vomiting, skin rashes, itching, headache and visual disturbances.
      2. Parenteral administration can cause hypotension, confusion, cardiac arrhythmias, convulsions and even cardiac arrest. It can also cause ototoxicity, retinopathy, myopathy, neuropathy and rarely psychiatric disturbances.
      3. Long-term therapy requires an ophthalmological examination. It is safe for use in pregnancy.
    • Uses
      • Malaria
        1. Chloroquine is the drug of choice for the treatment of acute attack of malaria caused by P. vivax, P. ovale, P. malariae and chloroquine-sensitive P. falciparum.
        2. It is a very effective chemoprophylactic agent for all types of malaria except that caused by chloroquine-resistant strains of P. falciparum (mefloquine or doxycycline can be used).
      • Other uses are as follows:
        1. Amoebiasis – hepatic.
        2. Lepra reaction.
        3. Rheumatoid Arthritis.
        4. Autoimmune disorder – discoid lupus erythematosus.

Note: Uses of chloroquine: Mnemonic – MALARIA

Quinoline Methanol

1. Mefloquine It is a synthetic quinoline methanol. It is a highly effective blood schizontocide.
   • Mechanism of action
     • Similar to chloroquine.
   • Uses
     • Mefloquine is used for prophylaxis of chloroquine-resistant P. falciparum and P. vivax malaria. It is used in combination with artesunate for the treatment of chloroquine-resistant P. falciparum malaria.
   • Adverse effects
     • The common side effects include nausea, vomiting, diarrhoea and dizziness. Nausea and vomiting can be minimized by dividing the dose. Neuropsychiatric symptoms and seizures can occur.

Artemisinin And Its Derivatives (Qinghaosu Compounds)

• Artemisinin is derived from the plant Artemisia annua. The semisynthetic derivatives of artemisinin are dihydroartemisinin, artemether and artesunate.
• Another compound, arteether, was developed in India. They are highly effective against erythrocytic stages of all plasmodia. They also have gametocidal action – reduce transmission of malarial parasite.

1. Uses of artemisinin
   • Artemisinins are used in the treatment of chloroquine-resistant P. falciparum malaria and severe malaria. They have a short half-life. They should not be used as monotherapy because of risk of development of resistance.
   • They are used in combination with other antimalarials – artemisinin-based combination therapy (ACT).
   • The use of ACT improves treatment efficacy, provides faster clinical cure and rapid parasite clearance and prevents the development of resistance.
   • Artemisinin derivatives (short t1/2) can be combined with slowly eliminated antimalarials (long t1/2), for example, sulfadoxine/pyrimethamine or lumefantrine, for the treatment of chloroquine-resistant P. falciparum malaria; duration of the therapy is 3 days.

Nitroimidazoles

Nitroimidazoles are metronidazole, tinidazole, secnidazole, ornidazole, satranidazole, etc.

Metronidazole

Metronidazole is a nitroimidazole derivative, which is highly effective against most anaerobic bacteria and several protozoa such as Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis.

1. Mechanism of action
   • In the presence of oxygen (aerobes), metronidazole cannot be reduced to its active metabolite; hence, it is ineffective against aerobes.

1. Pharmacokinetics
   • Metronidazole is available for oral, i.v. and topical administration. It is usually well absorbed after oral administration and poorly bound to plasma proteins.
   • It diffuses well into the tissues including brain; therapeutic levels are achieved in various body fluids – saliva, semen, vaginal secretion, bile, breast milk and CSF.
   • Metronidazole is metabolized in the liver and the metabolites are excreted mainly in urine.
2. Adverse effects Adverse effects are rarely severe to necessitate the discontinuation of the drug.
   • Gastrointestinal: Anorexia, nausea, metallic taste, dry mouth, epigastric distress, abdominal cramps and occasionally vomiting.
   • Allergic reactions: These include skin rashes, urticaria, itching and flushing. The drug should be stopped.
   • CNS: Dizziness, vertigo, confusion, irritability, headache, rarely convulsions and ataxia may occur. Polyneuropathy may occur on prolonged therapy.
   • Disulfiram-like reaction (nausea, vomiting, abdominal cramps, headache, flushing, etc.) may occur if taken with alcohol; hence, patient should be warned to avoid alcohol during treatment with metronidazole.
     • The teratogenic effect is seen in experimental animals; hence metronidazole should be avoided in pregnant women.
3. Drug interactions
   • Metronidazole potentiates the anticoagulant effect of warfarin and other oral coumarins by inhibiting their metabolism. There is a prolongation of prothrombin time; hence, reduction of warfarin dose may be needed.
   • Metronidazole may potentiate lithium toxicity by decreasing the renal clearance of lithium.
4. Uses
   • Anaerobic infections: Metronidazole is highly effective in most of the anaerobic infections caused by Bacteroides spp., Borrelia vincenti, Fusobacterium, Peptostreptococcus, Clostridium species and other anaerobic organisms.
     • Vincent angina (acute ulcerative gingivitis): It is an anaerobic infection associated with B. vincenti and Fusobacterium. Metronidazole (200–400 mg three times daily for 7 days) is highly effective in Vincent angina as it is secreted in the saliva. It is often used with penicillins (amoxicillin 500 mg t.d.s. for 7 days).
     • Metronidazole is used in the treatment of alveolar abscess, pericoronitis, periodontitis, etc. It is often used in combination with penicillins (penicillin V or amoxicillin).
     • In antibiotic-associated pseudomembranous colitis, metronidazole is effective. It is cheaper and less toxic than vancomycin. In anaerobic brain abscess, metronidazole is often used in combination with third-generation cephalosporin.
     • In the treatment of H. pylori infection, metronidazole is useful in combination with clarithromycin or amoxicillin and a proton pump inhibitor.
   • Amoebiasis: Metronidazole (400–800 mg t.d.s. for 7–10 days) is the drug of choice for the treatment of all forms of amoebiasis. Thus, it is useful in the treatment of both intestinal and extraintestinal amoebiasis.
   • Other uses are trichomonas vaginitis, giardiasis, etc.

Tinidazole

Most of the features are similar to metronidazole. Tinidazole has a longer duration of action and better tolerability than metronidazole.

• Uses

1. Orodental infections: Tinidazole 600 mg twice a day for 5 days or 2 g once daily orally for 3 days is used for anaerobic infections of oral cavity.
2. Amoebiasis: 2 g once daily orally for 3 days or 600 mg twice daily for a week.

Secnidazole

Like metronidazole, secnidazole is a nitroimidazole derivative. The spectrum, side effects and mechanism of action of secnidazole are similar to metronidazole.

Ornidazole And Satranidazole

Both of these are nitroimidazoles with longer duration of action and better tolerability than metronidazole. Satranidazole does not have interaction with alcohol (disulfiram-like reaction).

Anthelmintic Drugs

1. Mebendazole
2. Albendazole
3. Niclosamide
4. Ivermectin
5. Pyrantel pamoate
6. Albendazole
7. Levamisole
8. Praziquantel
9. Diethylcarbamazine citrate

Note: Mnemonic— MANIPAL PD

Mebendazole

It has a broad spectrum of anthelmintic activity. It inhibits microtubule synthesis in the parasite causing immobilization or death of the intestinal parasites. It is administered orally, poorly absorbed from the GIT, highly bound to plasma proteins and metabolized in liver. Most of the oral dose is excreted in faeces.

1. Adverse effects
   • Systemic toxicity of mebendazole is low because of its poor absorption. It is well tolerated and rarely causes GI side effects— anorexia, nausea, vomiting, diarrhoea and abdominal discomfort. Occasionally, it may cause skin rashes, itching, drug fever, etc. It is contraindicated in pregnancy and children below one year of age.
2. Uses
   • It is highly effective against intestinal nematodes— roundworm, hookworm, whipworm, pinworm and mixed worm infestations (dose: 100 mg orally BD for 3 days). It does not require fasting or purging; is well-tolerated and is relatively cheap.
     • Drugs for the Treatment of Helminthiasis

Albendazole

• Albendazole is a broad-spectrum anthelmintic agent. The mechanism of action is similar to mebendazole.
• It is given orally. It is erratically absorbed–fatty food increases its absorption. It is metabolized in the liver, produces an active metabolite, which is widely distributed into various tissues including hydatid cyst.

1. Adverse effects
   • It is very well tolerated. The side effects are rare, but can cause nausea, vomiting, diarrhoea, and epigastric distress.
   • During long-term therapy, it may cause headache, dizziness, fever, weakness, loss of hair and pancytopenia.
2. Uses
   • Nematodes: It is highly effective against intestinal nematodes— roundworm, hookworm, whipworm, pinworm, threadworm and also in mixed worm infestations. It can be taken as a single oral dose of 400 mg (for adults and children above two years of age) at any time of the day, does not require fasting or purging, is cheap and the side effects are rare.
   • Neurocysticercosis: Both albendazole and praziquantel are highly effective in neurocysticercosis. But albendazole is preferred to praziquantel. High doses of glucocorticoids are usually given with albendazole or praziquantel.
   • Hydatid disease: In the Echinococcus hydatid cyst, surgical resection is the treatment of choice, but albendazole is the drug of choice for medical therapy.
   • Filariasis: It is given with diethylcarbamazine (DEC) or ivermectin in the treatment of lymphatic filariasis. It has adjuvant value. It is also very effective in cutaneous larva migrans.

Piperazine

It is effective against roundworms and pinworm. It paralyses the worms that are then expelled by peristaltic movements. It is partly absorbed and most of the drug is excreted unchanged in urine.

• Adverse effects
  • The adverse effects include nausea, vomiting, abdominal pain, headache, skin rashes, itching and dizziness. It occasionally produces convulsions and is contraindicated in epileptics. It is safe for use during pregnancy.

Levamisole

It is effective against roundworm and hookworm infestations. It is used as an adjunct in rheumatoid arthritis and cancer chemotherapy.

Pyrantel Pamoate

• It is highly effective for the treatment of roundworm, pinworm and hookworm infestations. Oxantel pamoate is effective in trichuriasis.
• The mechanism of action is shown in Fig. It is given orally but absorbed poorly, about 80–90% of oral dose is excreted in the faeces.
• It can be taken as a single oral dose of 11 mg/kg, does not require fasting or purging, is well tolerated and relatively cheap.
• Adverse effects
  • These include nausea, vomiting, diarrhoea, headache, dizziness, skin rashes and fever. It is contraindicated in infants.

Diethylcarbamazine (DEC)

• It is the most effective drug used in the treatment of filariasis and tropical eosinophilia caused by Wuchereria bancrofti and Brugia malayi. It is available as citrate salt.
• It acts mainly on microfilariae, but the adult worms are killed slowly only on prolonged treatment. It immobilizes the microfilariae and modifies them so that they are more susceptible to destruction by host–defence mechanisms.
• It is well absorbed from the GIT, widely distributed in the body, metabolized in liver and excreted in urine. It is safe for use during pregnancy.

1. Adverse effects
   • Drug-induced effects: These include anorexia, nausea, vomiting, headache, tiredness and dizziness.
   • Parasite-induced reactions: These are due to the release of proteins from dying parasites. In onchocerciasis, DEC produces a severe reaction. It is characterized by fever, skin rashes, severe itching, nausea, vomiting, headache, cough, chest pain, muscle and joint pain, lymphadenitis, eosinophilia and proteinuria.
     • Hence, it is not recommended in onchocerciasis. In W. bancrofti, the reaction is usually mild which can be minimized by administering H₁-blockers. Severe reactions require steroid therapy.
2. Uses
   • Filariasis: It is the drug of choice for the treatment of filariasis due to W. bancrofti and B. malayi. It is administered orally, 6 mg/kg/day in three divided doses for 3 weeks (diethylcarbamazine citrate 100 mg TDS taken after food for 3 weeks).
     • The addition of single dose of albendazole 400 mg to DEC produces sustained microfilaricidal effect. DEC (300 mg) with albendazole (400 mg) is used to reduce the transmission of filaria.
   • Tropical eosinophilia: It is treated with DEC 100 mg TDS for 3 weeks. Antihistaminics and glucocorticoids may be required to control allergic reactions.

Ivermectin

It causes paralysis and death of the worms. It is given orally, rapidly absorbed, widely distributed, metabolized in the liver and excreted mainly in faeces.

1. Uses
   • It is the drug of choice for onchocerciasis. It kills microfilariae and has little effect on adult worms. It relieves pruritus and skin disease.
   • It is also very effective in strongyloidosis, ascariasis and cutaneous larva migrans.
   • It is used orally in the treatment of scabies and pediculosis.
2. Adverse effects
   • They include itching, skin rashes, oedema, headache, fever, muscle and joint pain. It is contraindicated in pregnancy and children.

Praziquantel

It is effective in the treatment of trematodes and cestodes but not for nematodes. It causes spastic paralysis, disintegration of the tegument and death of the parasite. It is readily absorbed after oral administration, highly bound to plasma proteins, crosses the BBB and is excreted in urine.

1. Adverse effects
   • The most common side effect is dizziness. Other side effects are nausea, vomiting, abdominal discomfort, headache, drowsiness, skin rashes, itching, muscle and joint pain.
2. Uses
   • Schistosomiasis: It is the drug of choice for all species of schistosomes. Praziquantel 40 mg/kg, a single oral dose, usually produces a high cure rate. It is well-tolerated and reasonably cheap.
   • Tapeworm infestation: A single oral dose of praziquantel gives very high cure rate in all tapeworm infestations. In case of Taenia solium, a saline purge is given 2 h after the administration of praziquantel to wash off all mature segments before ova can be released by disintegration to prevent cysticercosis.
   • Neurocysticercosis: It is contraindicated in pregnancy and ocular cysticercosis.

Niclosamide

It is the second drug of choice for T. solium, T. saginata and Diphyllobothrium latum. It is poorly absorbed from the GIT. It rapidly kills adult worms but not the ova. It is given orally in the form of chewable tablets.

• Adverse effects
  • They are nausea, vomiting, diarrhoea, headache, skin rashes, itching and abdominal discomfort.

Anticancer Drugs

• Cancer is a disease of cells characterized by Progressive, Persistent, Purposeless and uncontrolled Proliferation of tissues.
• Both normal as well as cancerous cells must pass through the following phases of cell cycle

1. G₁ phase (synthetic phase): Synthesis of enzymes and other cellular components needed for DNA synthesis.
2. Synthetic phase (S phase): DNA synthesis takes place.
3. G₂ phase (premitotic phase): Synthesis of cellular components for mitosis (proteins and RNA synthesis).
4. Mitotic phase (M phase): Mitotic cell division takes place.
5. G₀ phase (resting phase): Cells stop dividing temporarily or permanently.

Classification Of Anticancer Drugs

1. Alkylating agents
   • Nitrogen mustards: Mechlorethamine, cyclophosphamide, melphalan, chlorambucil.
   • Alkyl sulfonate: Busulfan.
   • Nitrosoureas: Carmustine, lomustine.
   • Platinum-containing compounds: Cisplatin, carboplatin.
   • Triazene: Dacarbazine.
2. Antimetabolites:
   • Folate antagonist: Methotrexate.
   • Purine antagonists: 6-Mercaptopurine (6-MP), 6-thioguanine (6-TG).
   • Pyrimidine antagonists: 5-Fluorouracil (5-FU), cytarabine.
3. Vinca alkaloids: Vinblastine, vincristine.
4. Taxanes: Paclitaxel, docetaxel.
5. Epipodophyllotoxins: Etoposide, teniposide.
6. Camptothecins: Topotecan, irinotecan.
7. Antibiotics: Actinomycin D, bleomycin, mitomycin C, doxorubicin, daunorubicin.
8. Enzyme: L-Asparaginase.
9. Miscellaneous agents: Hydroxyurea, imatinib.
10. Hormones and antagonists: Glucocorticoids, estrogens, antioestrogens, progestins, androgens and antiandrogens.

Toxicity Of Anticancer Drugs (Cytotoxic Drugs)

While destroying cancer cells, anticancer drugs also affect rapidly proliferating normal cells. Bone marrow, skin, hair, GI mucosa, reticuloendothelial (RE) system, gonads, foetus, etc. are most severely affected.

1. General toxicity
   • Oral cavity: Mucositis, oral ulceration, stomatitis, xerostomia, infections (Candida, herpes, etc.), gingival bleeding and mucosal petechiae due to thrombocytopenia.
     • Oral cavity-related toxicity is due to damage to rapidly dividing epithelial cells, immune suppression, decrease in saliva and myelosuppression.
     • Mucositis is common in the movable areas of oral mucosa, for example, lips, tongue and cheeks. It is due to damage to rapidly dividing epithelial cells.
     • Mucositis is ameliorated by oral cooling using ice chips, topical agents like benzydamine (rinse or spray), 2% viscous lignocaine and chlorhexidine mouth rinses. Opioids, for example, morphine and fentanyl (topical/systemic), may be required.
     • For treatment of xerostomia (dry mouth), systemic or topical agents can be used. Pilocarpine and cevimeline are cholinomimetic drugs which increase salivary secretion (sialogogues).
     • Topically, saliva substitutes (liquid, gel, spray) are also useful. Patients should be advised to keep the oral mucosa moist by frequent sips of water.
     • Myelosuppression and decreased immune response results in infections of oral cavity. Oral thrush can be treated with clotrimazole or nystatin or fluconazole (severe cases).
     • For bacterial infections due to Clostridium species, Staphylococcus, P. aeruginosa, etc., systemic antimicrobials will be required. Oral ulceration and perioral vesiculation due to herpes simplex is treated with acyclovir.
     • Oral mucosal bleeding due to thrombocytopenia can be treated with topical thrombin, epinephrine, collagen or systemic agents like epsilon aminocaproic acid. Patients on cancer chemotherapy should be advised to maintain good oral hygiene.
     • Mouth should be rinsed after food. Mouth rinses containing fluorides or povidone-iodine are useful. Alcohol-containing mouth rinses should be avoided, as they cause burning sensation in the oral cavity.
   • Bone marrow suppression: It manifests as leukopenia, agranulocytosis, thrombocytopaenia and aplastic anaemia. In such patients, infection and bleeding are common. Ameliorated/reduced by:
     • Platelet transfusion
     • Granulocyte colony-stimulating factor (G-CSF)
     • Erythropoietin
     • Bone marrow transplantation
     • Using bone marrow-sparing drugs if possible (for example, L-asparaginase, bleomycin, cisplatin, vincristine).
   • Immunosuppression: Decreased lymphocytes result in immunosuppression.
     • Such patients are prone for opportunistic infections with fungi, bacteria, viruses, and parasites (P. jiroveci, Candida, CMV, etc.).
   • GI tract: Nausea and vomiting are due to central action (stimulation of CTZ) and peripheral action in GI tract. Most of cytotoxic drugs cause vomiting. Cisplatin has the most emetogenic potential. 5-HT3 antagonists such as ondansetron and granisetron are the commonly used antiemetics.
     • The other antiemetics are metoclopramide and dexamethasone. Stomatitis, oral mucositis, diarrhoea, GI bleeding and ulcers are due to necrosis of rapidly dividing epithelial cells of gut mucosa.
   • Skin and hair: Alopecia (loss of hair) is due to the damage to hair follicles. Alopecia is usually reversible on stoppage of therapy. Dermatitis and skin rashes too can occur.
   • Gonads: Cytotoxic drugs also affect gonadal cells and cause oligozoospermia and infertility in males, and amenorrhoea and infertility in females.
   • Foetus: Administration of cytotoxic drugs during pregnancy usually causes abortion or teratogenic effects.
   • Hyperuricaemia: Gout and urate stones in the urinary tract are due to excessive cell destruction. They are prevented by good hydration, allopurinol and corticosteroids.
   • Hypercalcaemia: It may be either due to malignancy or certain anticancer drugs. It is treated with adequate hydration, bisphosphonates, corticosteroids, etc.
   • Carcinogenicity (secondary malignancy): These drugs may rarely cause secondary cancers in some patients, for example, the development of leukaemia in patients with prolonged use of alkylating agents.
   • Mutagenicity.
2. Specific toxicity
   • Haemorrhagic cystitis with cyclophosphamide: Ameliorated by administering mesna systemically and acetylcysteine locally.
   • Megaloblastic anaemia with methotrexate: Ameliorated by folinic acid/leucovorin/citrovorum factor.
   • Nephrotoxicity with cisplatin: Infusion of saline and mannitol reduces the incidence of nephrotoxicity.
   • Neuropathy with vincristine and paclitaxel.
   • Pulmonary fibrosis and pigmentation ofskin with busulfan and bleomycin.
   • Cardiotoxicity with doxorubicin and daunorubicin.

1. Alkylating Agents

• • All alkylating agents have alkyl group(s) and are capable of introducing these groups into nucleophilic sites on DNA bases through the formation of covalent bonds.
  • Alkylating agents are CCNS drugs. They also have a radiomimetic effect.

• • Mechanism of action Alkylating agents can also bind to proteins and damage them.

1. Nitrogen mustards
   • Cyclophosphamide
     • Cyclophosphamide is a prodrug and is activated in liver. It has anticancer and immunosuppressant actions.
     • The specific toxicity of cyclophosphamide is severe haemorrhagic cystitis. It is associated with dysuria and haematuria due to irritation of bladder mucosa by acrolein.
     • It is dose-limiting toxicity and can be reduced by adequate hydration and coadministration of i.v. mesna (2-mercapto-ethane-sulfonate).
     • Mesna is also excreted in urine where it binds and inactivates acrolein, thus preventing haemorrhagic cystitis.
     • Ifosfamide is a congener of cyclophosphamide and is administered intravenously.

1. • Chlorambucil Its main action is on lymphoid series, and it produces marked lympholytic effect. It is given orally and was the standard treatment for chronic lymphocytic leukaemia (CLL).
   • Melphalan It is effective in multiple myeloma and is used in combination with other agents.
   • Busulfan It depresses bone marrow with selective action on myeloid series. It was the preferred drug for chronic myeloid leukaemia (CML).
2. Platinum-containing compounds
   • Cisplatin It is a heavy-metal complex with highly effective antineoplastic activity
     • Mechanism of action Inside the cell:
       • Cisplatin is highly effective in the treatment of testicular, ovarian, endometrial and bladder cancer. It is also used in lung and oesophageal cancer. Cisplatin is the most emetogenic anticancer drug.
       • Vomiting can be controlled by 5-HT₃ antagonists such as ondansetron and granisetron. Carboplatin is better tolerated than cisplatin.

Antimetabolites

1. Folate antagonist
   • Methotrexate (MTX) Methotrexate is one of the most commonly used anticancer drugs. It is a cell cycle-specific (CCS) drug and acts during S phase of the cell cycle. It has antineoplastic, immunosuppressant and anti-inflammatory effects.
     • Mechanism of action
       • Methotrexate structurally resembles folic acid. It competitively inhibits dihydrofolate reductase enzyme and prevents the conversion of DHFA to THFA, thus depleting the intracellular THFA.
       • Tetrahydrofolic acid is necessary for the synthesis of purines and thymidylate, which, in turn, are necessary for DNA and RNA synthesis.
       • Methotrexate is the drug of choice for choriocarcinoma. It is also used in acute leukaemias, Burkitt lymphoma and breast cancer.
       • Other adverse effects are megaloblastic anaemia, pancytopaenia and hepatic fibrosis.

1. • Folinic acid rescue/leucovorin rescue
     • The toxic effects of methotrexate on normal cells can be minimized by giving folinic acid. Availability of folinic acid has helped the use of very high doses of methotrexate for better antineoplastic effect.
     • After a few hours of methotrexate therapy, leucovorin is given. Folinic acid is the active coenzyme form. It bypasses the block produced by methotrexate and rapidly reverses the toxicity. This method is called as leucovorin rescue/folinic acid rescue.
2. Purine antagonists: 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG)
   • 6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG) are activated to their ribonucleotides, which inhibit purine ring biosynthesis and nucleotide interconversion.
   • 6-MP also has immunosuppressant action. 6-MP is administered orally and has poor penetration through the BBB. It is metabolized by xanthine oxidase and its metabolite is excreted in urine.
   • Allopurinol interferes with the metabolism of 6-MP by inhibiting the enzyme xanthine oxidase and increases the antineoplastic effect of 6-MP.
   • Therefore, allopurinol is frequently used in cancer patients receiving chemotherapy to prevent hyperuricaemia and to reduce the dose of 6-MP, thus reducing its toxicity. 6-MP is used mainly in acute lymphocytic leukaemia. Bone marrow depression is the major adverse effect of 6-MP.
   • 
3. Pyrimidine antagonists
   • Fluorouracil (5-FU) 5-Fluorouracil interferes with DNA synthesis. It is used in GI tract, breast, ovary, skin, recurrent/metastatic salivary gland tumours, etc.

Plant Products

1. Vinca alkaloids  Vinblastine and vincristine are derived from the periwinkle plant. They are CCS agents and act during M phase of cell cycle. Vinblastine and vincristine have the same mechanism of action but differ in antitumour spectrum and toxicity.
   • Mechanism of action

1. Taxanes Paclitaxel is a taxane derived from the bark of the Western yew tree. Docetaxel is a newer taxane.
   • Mechanism of action
     • Paclitaxel is administered by i.v. infusion. It is useful in advanced breast, ovarian, lung, oesophageal and bladder cancer. The unwanted effects are bone marrow suppression, peripheral neuropathy, myalgia and hypersensitivity reactions.

Anticancer Antibiotics

• Mechanism of action Anticancer antibiotics have direct action on DNA and interfere with cell division.

1. Bleomycin It is used in squamous cell carcinoma of the skin, carcinoma of oral cavity, head and neck cancer. Its main side effects are hyperpigmentation of skin and pulmonary fibrosis. There is very little bone marrow suppression (spares bone marrow).
2. Doxorubicin and daunorubicin Daunorubicin is effective in acute leukaemias; doxorubicin is active against solid tumours. The side effects are bone marrow suppression, GI disturbances and cardiomyopathy with CCF, hypotension or arrhythmias.
3. Actinomycin D It is used in the treatment of Wilms’ tumour and choriocarcinoma. Bone marrow suppression and GI side effects are prominent.
4. Hydroxyurea Hydroxyurea interferes with the conversion of ribonucleotide to deoxyribonucleotide by inhibiting ribonucleoside diphosphate reductase. This results in inhibition of DNA synthesis. It is used mainly in chronic myeloid leukaemia, polycythaemia vera and psoriasis. The common side effect is myelosuppression.

Enzyme

1. L-asparaginase
   • It is an enzyme that is isolated from bacteria, E. coli. Asparagine is an amino acid that is necessary for protein synthesis. Normal cells can synthesize asparagine because they contain asparagine synthetase enzyme. Cancer cells lack this enzyme, so they depend on exogenous source – plasma.
   • L-Asparaginase degrades asparagine to aspartic acid. Hence, neoplastic cells are deprived of asparagine, resulting in cell death. It is used in the treatment of ALL (acute lymphocytic leukaemia).

• • Toxicity
    • Hypersensitivity reaction with skin rashes, itching, urticaria, etc.
    • Hyperglycaemia: Due to insulin deficiency.
    • Headache, Hallucinations, confusion and coma.
    • Haemorrhage: Due to inhibition of synthesis of clotting factors.
    • Pancreatitis.

Hormonal Agents

Hormones produce only palliative effects in cancer.

1. Glucocorticoids: Because of their marked lymphocytic action, they are used in acute leukaemias and lymphomas. Apart from this effect, glucocorticoids:
   • Have an anti-inflammatory effect, decrease oedema associated with the tumour.
   • Produce feeling of well-being.
   • Suppress hypersensitivity reaction due to certain anticancer drugs.
     Control hypercalcaemia.
   • Increase the antiemetic effect of ondansetron/granisetron/metoclopramide.
   • Because of the above effects, glucocorticoids are useful in the treatment of various cancers.
2. Others are oestrogens, progestins, tamoxifen, antiandrogens, finasteride, etc.
   • Anticancer drugs used for targeted therapy is shown below.

Pharmacogenetics

These factors also influence drug metabolism. The study of genetically determined variation in drug response is called pharmacogenetics. For example:

1. Slow and fast acetylation of isoniazid (INH): There is an increased incidence of peripheral neuritis with isoniazid in slow acetylators. The fast acetylators require larger dose of the drug to produce a therapeutic effect.
2. Succinylcholine apnoea: Succinylcholine, a neuromuscular blocker, is metabolized by plasma pseudocholinesterase enzyme. The duration of action of succinylcholine is 3–6 min. However, some individuals have atypical pseudocholinesterase that metabolizes the drug very slowly.
   • This results in prolonged apnoea due to paralysis of respiratory muscles, which is dangerous. This is known as succinylcholine apnoea.
3. Glucose-6-phosphate dehydrogenase (G6PD) deficiency and haemolytic anaemia: G6PD activity is important to maintain the integrity of the RBCs. A person with G6PD deficiency may develop haemolysis when exposed to certain drugs like sulphonamides, primaquine, salicylates and dapsone.