Chemotherapy

Antiamoebic drugs

Classification

1.      Tissue amoebicide

a.       For both intestine and extraintestinal amoebiasis

i.                    Nitroimidazoles-metronidazole, tinidazole, senidazole, ornidazole, satranidazole

ii.                  Alkaloids-emetine, dihydroemetine

2.      Luminal amoebicide

a.       Amide:diloxanide furoate, nitazoxamide

b.      8-hydroxyquinolones-iodochlorohydroxyquin, clioquinol, iodoquinol

c.       Antibiotics-tetracyclines

Parasite Life Cycle

An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection. Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in liver. Merozoites are subsequently released from liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness. Repeated cycles of infection can lead to infection of many erythrocytes. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.

In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure these infections. In P vivax and P ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most drugs, and subsequent relapses can therefore occur after therapy directed against erythrocytic parasites. Eradication of both erythrocytic and hepatic parasites is required to cure these infections.

Schematic diagram of Parasite Life Cycle and mechanism of action of Metronidazoleis shown below

Metronidazole

Metronidazole, a nitroimidazole is drug of choice in treatment of extraluminal amebiasis. It kills trophozoites but not cysts of E histolytica and effectively eradicates intestinal and extraintestinal tissue infections.

Mechanism of Action-Metronidazole exerts activity against most anaerobic bacteria and several protozoa. The drug freely penetrates protozoal and bacterial cells but not mammalian cells. Metronidazole can function as an electron sink, and because it does so, its 5-nitro group is reduced. The enzyme, pyruvate-ferredoxin oxidoreductase, found only in anaerobic organisms, reduces metronidazole and thereby activates the drug. Reduced metronidazole disrupts replication and transcription and inhibits DNA repair.

Pharmacodynamics

Antiparasitic and Antimicrobial Effects: Metronidazole and related nitroimidazoles are active in-vitro against a wide variety of anaerobic protozoal parasites and anaerobic. The compound is directly trichomonocidal. The drug also has potent amebicidal activity against E. histolytica.

Metronidazole manifests antibacterial activity against all anaerobic cocci and both anaerobic gram-negative bacilli, including Bacteroides spp., and anaerobic spore-forming gram-positive bacilli. Nonsporulating gram-positive bacilli often are resistant, as are aerobic and facultatively anaerobic bacteria.

Metronidazole is effective in trichomoniasis, amebiasis, and giardiasis, and infections caused by obligate anaerobic bacteria, including Bacteroides, Clostridium, and microaerophilic bacteria such as Helicobacter and Campylobacter spp.

Pharmacokinetics:

Readily absorbed and permeate all tissues by simple diffusion. Intracellular concentrations rapidly approach extracellular levels. Peak plasma concentrations are reached in 1–3 hours. Protein binding of both drugs is low (10–20%); the half-life of unchanged drug is 7.5 hours its metabolites are excreted in urine. Plasma clearance of is decreased in patients with impaired liver function.

Adverse Effects:Nausea, headache, dry mouth, or a metallic taste in the mouth occurs commonly. Infrequent adverse effects include vomiting, diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria, dark urine, vertigo, paresthesias, and neutropenia.

Contraindications:

a.       Taking the drug with meals lessens gastrointestinal irritation, pancreatitis and severe central nervous system toxicity.

b.      Metronidazole has a disulfiram-like effect, so that nausea and vomiting can occur if alcohol is ingested during therapy.

c.       Metronidazole potentiates the anticoagulant effect of coumarin-type anticoagulants.

d.      Phenytoin and phenobarbital may accelerate elimination of drug, while cimetidine may decrease plasma clearance.

Clinical Uses

a.       Amebiasis-Metronidazole is drug of choice in treatment of all tissue infections with E histolytica. They are not reliably effective against luminal parasites and so must be used with a luminal ameobicide to ensure eradication of infection.

b.      Giardiasis-Metronidazole is treatment of choice for giardiasis. The dosage for giardiasis is much lower—and the drug thus better tolerated—than that for amebiasis.

c.       Trichomoniasis-Metronidazole is treatment of choice. A single dose of 2 g is effective. Metronidazole resistant organisms can lead to treatment failures.

Anti-tuberculosis

Classification

1.      First line drugs Ex: Ethambutol, isoniazid, pyrazinamide, rifampicin, streptomycin.

2.      Second line drugs Ex: amino salicylic acid, capreomycin, cycloserine, ethionamide, fluoroquinolones, macrolides, rifabutin, rifapentine.

Isoniazid (isonicotinic acid hydrazide, or INH) is most active drug for treatment of tuberculosis caused by susceptible strains.

Mechanism of Action- it inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase. The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and kills the cell.

Antimicrobial Activity

Isoniazid is bactericidal against actively growing M. tuberculosis and bacteriostatic against nonreplicating organisms. The minimal tuberculostatic inhibitory concentration (MIC) of isoniazid is 0.025 to 0.05 mcg/mL.

Resistance

Mechanism of resistance is mycobacteria’s formation of mutations in catalase– peroxidase KatG, the enzyme that is responsible for activation of isoniazid.

Pharmacokinetics

Isoniazid is water soluble and is well absorbed when administered either orally or parenterally. Oral absorption is decreased by concurrent administration of aluminum-containing antacids. Isoniazid does not bind to serum proteins; it diffuses readily into all body fluids and cells, including tuberculous lesions. The concentrations in CNS and cerebrospinal fluid are about 20% of plasma levels but may reach 100% in presence of meningeal inflammation. Isoniazid is acetylated to acetyl isoniazid by N-acetyltransferase, in liver, bowel, and kidney. Metabolites of isoniazid and small amounts of unaltered drug are excreted in urine within 24 hours.

Drug Interactions

High isoniazid plasma levels inhibit phenytoin metabolism and potentiate phenytoin toxicity when two drugs are coadministered. The serum concentrations of phenytoin should be monitored, and dose should be adjusted if necessary.

Clinical Uses

a.       Isoniazid is safest and most active mycobactericidal agents.

b.      It is considered primary drug for use in all therapeutic and prophylactic regimens for susceptible tuberculosis infections.

c.       It is also included in first-line drug combinations for use in all types of tuberculous infections.

d.      It is preferred as a single agent in treatment of latent tuberculosis infections in high-risk persons having a positive tuberculin skin reaction with no radiological or other clinical evidence of tuberculosis.

e.       Mycobacterium kansasii is usually susceptible to isoniazid, and it is included in standard multidrug treatment regimen.

Adverse Effects

a.       Isoniazid-induced hepatitis and peripheral neuropathy are two major untoward effects. A minor asymptomatic increase in liver aminotransferase, fatal hepatitis is seen. Risk factors for hepatitis include underlying liver disease, advanced age, pregnancy, and combination therapy with acetaminophen. Peripheral neuropathy is observed.

b.      Patients with underlying chronic disorders such as alcoholism, malnutrition, diabetes, and AIDS are at particular risk for neurotoxicity; compared with fast acetylators, neurotoxicity is more frequent in slow acetylators because slow acetylators achieve higher drug plasma levels. Isoniazid promotes renal excretion of pyridoxine, resulting in relative deficiency and neuropathy.

c.       CNS toxicity may range from excitability and seizures to psychosis.

d.      Others include gastrointestinal intolerance, anemia, rash, tinnitus, and urinary retention.

Rifampin

Antibacterial Activity

In addition to M. tuberculosis, rifampin is active against Staphylococcus aureus, Neisseria meningitidis, Haemophilus influenzae, Chlamydiae, and certain viruses.

Mechanism of Action: Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria and other microorganisms by forming a stable drug-enzyme complex, leading to suppression of initiation of chain formation in RNA synthesis. More specifically, the β-subunit of this complex enzyme is site of action of drug. High concentrations of rifamycin antibiotics can inhibit RNA synthesis in mammalian mitochondria, viral DNA-dependent RNA polymerases, and reverse transcriptases. Rifampin is bactericidal for both intracellular and extracellular microorganisms

Pharmacokinetics

Well absorbed orally, and peak serum concentration is seen within 2 to 4 hours. Drug absorption is impaired if given concurrently with aminosalicylic acid or is taken immediately after a meal. It is widely distributed throughout body, and therapeutic levels are achieved in all body fluids, including cerebrospinal fluid. Rifampin is capable of inducing its own metabolism, so its half-life reduced to 2 hours within a week of continued therapy. The deacetylated form of rifampin is active and undergoes biliary excretion and enterohepatic recirculation and excreted in urine.

Resistance

Rifampin resistance results from a point mutation or deletion in rpoB, the gene for β-subunit of RNA polymerase, thereby preventing the binding of RNA polymerase.

Adverse Reactions

Rifampin imparts a harmless orange color to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained).

Occasional adverse effects include rashes, thrombocytopenia, and nephritis. It may cause cholestatic jaundice and occasionally hepatitis. Rifampin commonly causes light-chain proteinuria. If administered less often than twice weekly, rifampin causes a flu-like syndrome characterized by fever, chills, myalgias, anemia, and thrombocytopenia and sometimes is associated with acute tubular necrosis.

Drug interactions:Rifampin strongly induces most cytochrome P450 isoforms, which increases elimination of other drugs including methadone, anticoagulants, cyclosporine, anticonvulsants, protease inhibitors, nonnucleoside reverse transcriptase inhibitors, contraceptives. Administration of rifampin results in significantly lower serum levels of these drugs.

Clinical Uses

a.       Rifampin is first-line antitubercular drug used in treatment of all forms of pulmonary and extrapulmonary tuberculosis.

b.      It is an alternative to isoniazid in treatment of latent tuberculosis infection.

c.       It may be combined with an antileprosy agent for treatment of leprosy and to protect those in close contact with patients having H. influenza type b and N. meningitidis infection;

d.      It also used in methicillin-resistant staphylococcal infections, such as osteomyelitis and prosthetic valve endocarditis.

Pyrazinamide

Pyrazinamide is a synthetic analogue of nicotinamide. Its exact mechanism of action is not known, although its target appears to be mycobacterial fatty acid synthetase involved in mycolic acid biosynthesis. Thus, pyrazinamide is highly effective on intracellular mycobacteria. The mycobacterial enzyme pyrazinamidase converts pyrazinamide to pyrazinoic acid, the active form of drug. A mutation in gene (pncA) that encodes pyrazinamidase is responsible for drug resistance; resistance can be delayed through use of drug combination therapy.

Pharmacokinetics

Well absorbed from GI tract and widely distributed throughout body. It penetrates tissues, macrophages, and tuberculous cavities and has excellent activity on intracellular organisms; its plasma half-life is 9 to 10 hours in patients with normal renal function. The drug and its metabolites are excreted primarily by renal glomerular filtration.

Clinical Uses

Pyrazinamide is an essential component of multidrug short-term therapy of tuberculosis. In combination with isoniazid and rifampin, it is active against intracellular organisms that may cause relapse.

Adverse Reactions

Hepatotoxicity is major concern. It also can inhibit excretion of urates, resulting in hyperuricemia. All patients taking pyrazinamide develop hyperuricemia and possibly acute gouty arthritis. Other adverse effects include nausea, vomiting, anorexia, drug fever, and malaise. Pyrazinamide is not recommended for use during pregnancy.

Ethambutol

Ethambutol is a water-soluble, heat-stable compound that acts by inhibition of arabinosyl transferase enzymes that are involved in cell wall biosynthesis. Nearly all strains of M. tuberculosis and M. kansasii and most strains of Mycobacterium avium-intracellulare are sensitive to ethambutol.

Drug resistance relates to point mutations in the gene (EmbB) that encodes the arabinosyl transferases that are involved in mycobacterial cell wall synthesis.

Pharmacokinetics

Well absorbed (70–80%) from gut, peak serum concentrations are seen within 2 to 4 hours; half-life is 3 to 4 hours. Widely distributed in all body fluids, including cerebrospinal fluid, even in absence of inflammation. Unchanged drug is excreted in urine within 24 hours of ingestion. Up to 15% is excreted in urine as an aldehyde and a dicarboxylic acid metabolite.

Clinical Uses

Ethambutol has replaced aminosalicylic acid as first-line antitubercular drug. It is included as fourth drug, along with isoniazid, pyrazinamide, and rifampin, in patients infected with MDR strains. It is used in combination in treatment of M. aviumintracellulare infection in AIDS patients.

Side effect is retrobulbar neuritis impairing visual acuity and redgreen color discrimination; and is dose related and reverses slowly if drug is discontinued. Mild GI intolerance, allergic reaction, fever, dizziness, and mental confusion are also possible. Hyperuricemia is associated with ethambutol use due to a decreased renal excretion of urates; gouty arthritis may result.

RECOMMENDATION FOR TREATMENT OF LATENT TUBERCULOSIS INFECTION

Recently revised recommendations for treatment of latent tuberculosis infection (LTBI) include new therapeutic regimens as follows:

Isoniazid for 9 months daily or twice weekly is preferred for all adults.

Or

Isoniazid for 6 months daily or twice weekly is acceptable for HIV-negative patients and is cost effective.

Or

Rifampin and pyrazinamide daily for 2 months is appropriate for isoniazid-resistant tuberculosis.

Or

Rifampin daily for 4 months may be given to individualswho cannot tolerate pyrazinamide.

RECOMMENDATIONS FOR TREATMENT OF ACTIVE TUBERCULOSIS

The commonly used regimen for drug-susceptible tuberculosis consists of isoniazid, rifampin, and pyrazinamide daily for 2 months, followed by isoniazid and rifampindaily or two to three times a week for 4 months. If isoniazid resistance is suspected, ethambutol or streptomycin should be added to the regimen until susceptibility of mycobacterium is determined. This regimen will provide at least two drugs to which the M. tuberculosis isolate is susceptible in more than 95% of patients.

Alternative regimens include isoniazid, rifampin, pyrazinamide, and either streptomycin or ethambutolfor 2 weeks followed biweekly with the same regimen for 6 weeks, and subsequently with biweekly administration of isoniazid and rifampin for 16 weeks.

In HIV infected patients the treatment should be prolonged 9 to 12 months or sometimes even longer if response is slow. Treatment of tuberculosis is more challenging in HIV-infected population taking highly active antiretroviral therapy because of drug interactions.

Anti-neoplastic drugs.

Classification

1.      Alkylating agents

i.                    Nitrogenmustards Ex: mechlorethamine, melphalen, cyclophosphamide, uracil mustard and chlorambucil

ii.                  Ethylenimines Ex: thriethylene thiophosphoramide

iii.                Alkyl sulfonates Ex: busulfan

2.      Antimetabolites

i.                    Folic acid antagonists-methotrexate

ii.                  Purin antagonist – 6 mercaptopurine, azatiopurine

iii.                Pyrimidine antagonists-fluorouracil, cytosine, arabinoside, flurodeoxyuridine

3.      Radioactive isotopes=radioiodine, radiogold, radiophosphorus

4.      Cytotoxic antibiotics-actinomycin-D, mitomycin-D, rubidomycin, doxorubicin, bleomycin, and mithramycin,

5.      Antimitotic plant products-vincristine, vinblastine, vindesion, taxol, etoposide, camptotheptin analogues

6.      Hormones and hormone antagonists-estrogen, progestins, corticosteroids, tamoxifen, flutamide, cyproterone, GnRH analogues and somastatin analogues-octreotide.

7.      Monoclonal antibodies and tyrosine kinase inhibitors-trastuzumab, rituximab, and imatinib

8.      Biological response modifiers-interferons, BCG, levamisole

9.      Misc-hydroxyurea, procarbasine, mitotane,, l-asparginase, cisplatin, tretinoin.

Mechanism of Action of alkylating agents

Alkylating agents exert their cytotoxic effects via transfer of their alkyl groups to various cellular constituents. Alkylations of DNA within the nucleus represent major interactions that lead to cell death. These drugs react chemically with sulfhydryl, amino, hydroxyl, carboxyl, and phosphate groups of other cellular nucleophiles.

It also involves intramolecular cyclization to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent

The major site of alkylation within DNA is the N7 position of guanine; however, other bases are also alkylated to lesser degrees, including N1 and N3 of adenine, N3 of cytosine, and O6 of guanine, as well as phosphate atoms and proteins associated with DNA. These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most alkylating agents are bifunctional, with two reactive groups.

Alkylation of guanine can result in miscoding through abnormal base pairing with thymine or in depurination by excision of guanine residues. The latter effect leads to DNA strand breakage through scission of the sugar-phosphate backbone of DNA. Cross-linking of DNA appears to be of major importance to cytotoxic action of alkylating agents, and replicating cells are most susceptible to these drugs.

Schematic diagram of Mechanism of Action ofalkylating agentsis shown below

TOXICITIES OF ALKYLATING AGENTS

Bone Marrow Toxicity-Acute myelosuppression, Busulfan suppresses all blood elements, particularly stem cells, and may produce a prolonged and cumulative myelosuppression lasting months or even years. Both cellular and humoral immunity are suppressed by alkylating agents, which have been used to treat various autoimmune diseases. Immunosuppression is reversible at doses used in most anticancer protocols.

Mucosal Toxicity-Alkylating agents are highly toxic to dividing mucosal cells, leading to oral mucosal ulceration and intestinal denudation. The mucosal effects are significant in high-dose chemotherapy protocols associated with bone marrow reconstitution, as they predispose to bacterial sepsis arising from the gastrointestinal tract.

Neurotoxicity-CNS toxicity manifest in form of nausea and vomiting, after I.V. administration of nitrogen mustard or BCNU. Ifosfamide is most neurotoxic of this class of agents, producing altered mental status, coma, generalized seizures, and cerebellar ataxia.

Other Organ Toxicities-While mucosal and bone marrow toxicities occur predictably and acutely with conventional doses of these drugs, other organ toxicities may occur after prolonged or high-dose use; these effects can appear after months or years, and may be irreversible and even lethal. All alkylating agents have caused pulmonary fibrosis. Finally, all alkylating agents have toxic effects on the male and female reproductive systems, causing an often permanent amenorrhea, particularly in perimenopausal women, and irreversible azoospermia in men.

Leukemogenesis-Acute nonlymphocytic leukemia, in patients treated on regimens containing alkylating drugs. It is often preceded by a period of neutropenia or anemia, and bone marrow morphology consistent with myelodysplasia.

Hair Follicle Toxicity-Anticancer drugs damage hair follicles and produce partial or complete alopecia. Patients should be warned of this reaction, if paclitaxel, cyclophosphamide, doxorubicin, vincristine, methotrexate, or dactinomycin is used. Hair usually regrows normally after completion of chemotherapy.

Therapeutic Uses.

Mechlorethamine HCl used primarily in combination chemotherapy regimen MOPP (mechlorethamine, vincristine [ONCOVIN], procarbazine, and prednisone) in patients with Hodgkin's disease. It is also used topically for treatment of cutaneous T-cell lymphoma as a solution that is rapidly mixed and applied to affected areas of skin.

Cyclophosphamide is administered orally or intravenously. It is employed in treatment of breast cancer and lymphomas. The clinical spectrum of activity is very broad. It is an essential component of many effective drug combinations for non-Hodgkin's lymphomas, ovarian cancers, and solid tumors in children. Because of its potent immunosuppressive properties, it is used to prevent organ rejection after transplantation.

Ifosfamide is approved for use in combination for germ cell testicular cancer and used to treat pediatric and adult sarcomas.

Melphalan for multiple myeloma is used, in combination with other agents. Melphalan also may be used in myeloablative regimens followed by bone marrow or peripheral blood stem cell reconstitution.

Chlorambucil In treating chronic lymphocytic leukemia (CLL), it is a standard agent for patients with chronic lymphocytic leukemia and primary (Waldenstrom's) macroglobulinemia, and may be used for follicular lymphoma.

Tetracyclines

Tetracycline is a semisynthetic derivative of chlortetracycline. Demeclocycline is the product of a mutant strain of Strep. aureofaciens, and methacycline, doxycycline, and minocycline all are semisynthetic derivatives. The tetracyclines are close congeners of polycyclic naphthacenecarboxamide

Ex:Demeclocycline, doxycycline, minocycline, tetracycline

Mechanism of Action-The primary mode of action is inhibition of protein synthesis.Tetracyclines bind to 30S ribosome and thereby prevent binding of aminoacyl transfer RNA (tRNA) to A site (acceptor site) on 50S ribosomal unit. The tetracyclines affect both eukaryotic and prokaryotic cells but are selectively toxic for bacteria, because they readily penetrate microbial membranes and accumulate in cytoplasm through an energy dependent tetracycline transport system that is absent from mammalian cells.

Schematic diagram of Mechanism of Actionof Tetracycline is shown below

Resistance is related largely to changes in cell permeability and resultant decreased accumulation of drug due to increased efflux from the cell by an energy dependent mechanism.

Antimicrobial Activity

Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. They are active against many gram-positive and gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and L forms; and against some protozoa, eg, amebas. The antibacterial activities of most Tetracyclines are similar except that Tetracycline-resistant strains may be susceptible to doxycycline, minocycline, and tigecycline, all of which are poor substrates for the efflux pump that mediates resistance. Differences in clinical efficacy for susceptible organisms are minor and attributable largely to features of absorption, distribution, and excretion of individual drugs.

Therapeutic Uses

a.       Rickettsial infections: Tetracyclines are effective and life-saving in rickettsial infections, including Rocky Mountain spotted fever, recrudescent epidemic typhus (Brill's disease), murine typhus, scrub typhus, rickettsialpox, and Q fever.

b.      Mycoplasma Infections:Mycoplasma pneumoniae is sensitive to tetracyclines. Treatment of pneumonia with tetracycline shortens duration of fever, cough, malaise, fatigue, pulmonary rales, and radiological abnormalities in lungs.

c.       Chlamydia-Lymphogranuloma Venereum, Pneumonia, bronchitis, or sinusitis caused by Chlamydia pneumoniae responds to tetracycline therapy.

d.      Nonspecific Urethritis is due to Chlamydia trachomatis. Doxycycline, is effective

e.       Sexually Transmitted Diseases: Because of resistance, doxycycline no longer is recommended for gonococcal infections. Doxycycline or azithromycin is effective for gonococcal urethritis

f.       Anthrax: Doxycycline is indicated for prevention or treatment of anthrax.

g.      Bacillary Infections-Tetracyclines in combination with rifampin or streptomycin are effective for acute and chronic infections caused by Brucella melitensis, Brucellasuis, and Brucella abortus.

h.      Other Bacillary Infections: Therapy with tetracyclines is often ineffective in infections caused by Shigella, Salmonella, or other EnterobacteriaceaeCoccal Infections. Because of resistance, tetracyclines fell into disuse for infections caused by staphylococci, streptococci, or meningococci. However, community strains of methicillin-resistant S. aureus often are susceptible to tetracycline, doxycycline, or minocycline, which appear to be effective for uncomplicated skin and soft-tissue infections.

i.        It is useful in acute treatment and for prophylaxis of leptospirosis (Leptospira spp.). Borrelia spp., including B. recurrentis (relapsing fever) and B. burgdorferi (Lyme disease), respond to therapy with a tetracycline. The tetracyclines used to treat susceptible atypical mycobacterial pathogens, including M. marinum.

j.        It is used to treat acne. They may act by inhibiting propionibacteria, which reside in sebaceous follicles and metabolize lipids into irritating free fatty acids. The relatively low doses of tetracycline used for acne.

Toxic Effects

a.       Gastrointestinal: All tetracyclines can produce gastrointestinal irritation, after oral administration. Epigastric burning and distress, abdominal discomfort, nausea, vomiting, and diarrhea may occur. Tolerability can be improved by administering drug with food, but tetracyclines should not be taken with dairy products or antacids.

b.      Photosensitivity: Demeclocycline, doxycycline, and other tetracyclines to lesser extent may produce mild-to-severe photosensitivity reactions in the skin of treated individuals exposed to sunlight. Onycholysis and pigmentation of nails may develop with or without accompanying photosensitivity.

c.       Hepatic Toxicity: Oxytetracycline and tetracycline are least hepatotoxic of these agents. Pregnant women are susceptible to tetracycline-induced hepatic damage.

d.      Renal Toxicity: Tetracyclines may aggravate azotemia in patients with renal disease because of their catabolic effects.

e.       Fanconi syndrome, characterized by nausea, vomiting, polyuria, polydipsia, proteinuria, acidosis, glycosuria, and aminoaciduria, has been observed in patients ingesting outdated and degraded tetracycline.

f.       Effects on Teeth: Children receiving long- or short-term therapy with a tetracycline may develop permanent brown discoloration of teeth. The larger the drug dose relative to body weight, the more intense enamel discoloration. The deposition of drug in teeth and bones probably is due to its chelating property and formation of a tetracycline-calcium orthophosphate complex.

g.      Treatment of pregnant patients with tetracyclines may produce discoloration of teeth in their children.

Amino glycosides

The aminoglycoside group includes gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, and neomycin. These are used primarily to treat infections caused by aerobic gram-negative bacteria; streptomycin is important agent for treatment of tuberculosis. The aminoglycosides are bactericidal inhibitors of protein synthesis. Mutations affecting proteins in bacterial ribosome, the target for these drugs, can confer marked resistance to their action. These agents contain amino sugars linked to an aminocyclitol ring by glycosidic bonds.

Mechanism of Action-Amino glycosides are irreversible inhibitors of protein synthesis. The initial event is passive diffusion via porin channels across outer membrane. Drug is then actively transported across cell membrane into cytoplasm by an oxygen-dependent process.

Inside the cell, Amino glycosides bind to specific 30S-subunit ribosomal proteins. Protein synthesis is inhibited by Amino glycosides in at least three ways: (1) interference with initiation complex of peptide formation; (2) misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide, resulting in a nonfunctional or toxic protein; and (3) breakup of polysomes into nonfunctional monosomes. These activities occur simultaneously, and overall effect is irreversible and lethal for cell.

Schematic diagram of Mechanism of Action of Amino glycosides is shown below

UNTOWARD EFFECTS OF THE AMINOGLYCOSIDE

a. Ototoxicity-Vestibular and auditory dysfunction can follow administration of any of aminoglycosides. Accumulation of these drugs in perilymph and endolymph of inner ear. Accumulation occurs predominantly when concentrations in plasma are high. Diffusion back into bloodstream is slow. Ototoxicity has been linked to mutations in a mitochondrial ribosomal RNA gene, indicating that a genetic predisposition exists for this side effect. Ototoxicity is largely irreversible and results from progressive destruction of vestibular or cochlear sensory cells, which are highly sensitive to damage by aminoglycosides. It is recommended that patients receiving high doses and/or prolonged courses of aminoglycosides be monitored carefully for ototoxicity; deafness may occur.

b.                  Nephrotoxicity-Patients who receive aminoglycoside will develop mild renal impairment that is reversible because proximal tubular cells have capacity to regenerate. The toxicity results from accumulation and retention of aminoglycoside in proximal tubular cells. The initial manifestation of damage at this site is excretion of enzymes of renal tubular brush border. After several days, there is defect in renal concentrating ability, mild proteinuria, and appearance of hyaline and granular casts. The glomerular filtration rate is reduced after several additional days. Hypokalemia, hypocalcemia, and hypophosphatemia are seen infrequently.

c.                   Neuromuscular Blockade-An unusual toxic reaction of acute neuromuscular blockade and apnea has been attributed to aminoglycosides. Patients with myasthenia gravis are susceptible to neuromuscular blockade by aminoglycosides. Aminoglycosides may inhibit prejunctional release of acetylcholine and reducing postsynaptic sensitivity to the transmitter, but Ca²⁺ can overcome this effect, and i.v. administration of calcium salt is preferred treatment for this toxicity. Inhibitors of acetylcholinesterase (e.g., edrophonium and neostigmine) is been used.

d.                  On Nervous System-The administration of streptomycin may produce dysfunction of optic nerve, including scotomas, presenting as enlargement of blind spot. Among the less common toxic reactions to streptomycin is peripheral neuritis.

e.                   Others effects aminoglycosides have little allergenic potential; anaphylaxis and rash are unusual. Rare hypersensitivity reactions including skin rashes, eosinophilia, fever, blood dyscrasias, angioedema, exfoliative dermatitis, stomatitis, and anaphylactic shock is reported. Parenterally administered aminoglycosides are not associated with pseudomembranous colitis, probably because they do not disrupt normal anaerobic flora.

CLINICAL USES

a.       Serious Gram-Negative Bacillary Infections-Gentamicin is used to treat serious infections due to gram negative aerobic bacilli, such as Escherichia coli and Klebsiella pneumoniae, and Proteus, Serratia, Acinetobacter, Staphylococcus aureus, Citrobacter, and Enterobacter spp. The combination of gentamicin and clindamycin is useful in patients with intraabdominal infection or abscess secondary to penetrating trauma, diverticulitis, cholangitis, appendicitis, peritonitis, or postsurgical wound infection.  Streptomycin is drug of choice for patients with pneumonia due to Yersinia pestis (plague) or Francisella tularensis (tularemia).

b.      Eradication of Facultative Gut Flora-Orally administered neomycin is used to suppress facultative flora of gut in patients with hepatic encephalopathy

c.       Cystic Fibrosis: P. aeruginosa is found in bronchial secretions of patients with cystic fibrosis.

d.      Endocarditis-A combination of gentamicin and ampicillin is recommended as prophylaxis of endocarditis prior to surgery or instrumentation of the gastrointestinal or genitourinary tracts for patients at high risk for endocarditis.

e.       Meningitis-The degree of penetration of aminoglycosides into cerebrospinal fluid is proportional to degree of inflammation of meninges. However, aminoglycosides are best combined with beta-lactams or other antibiotics in treatment of meningitis.

f.       Tuberculosis:-In response to increasing prevalence of mycobacterial resistance to standard antibiotic chemotherapy, use of aminoglycosides is increasing in patients at high risk for having resistant infections. Streptomycin is useful in initial therapy of severe or disseminated tuberculosis.

g.      Ophthalmological Infection-Because of high concentrations of gentamicin achieved in conjunctival sac, it is effective against all typical bacterial pathogens that cause conjunctivitis. High-dose formulations of gentamicin are necessary for treating bacterial ophthalmic keratitis.

h.      Gonococcal Urethritis-Spectinomycin is used to treat uncomplicated gonococcal urethritis in patients who are allergic to beta-lactam.

Antimalarial drugs

Classification

1.      Cinchona alkaloids-quinine, quinidine

2.      Quinoline derivatives

a.       4-aminoquinolones-chloroquine, amodiaquine, hydroxyquinoline, pyronaridine,

b.      8-aminoquinolones-primaquine, tafleoquine, bulaquine,

c.       Quinolone methanol-mefloquine, halofantrine, lumefantrine

3.      Antifolates

a.       Biguanides-proguanil

b.      Diamiopyrimides-pyrimethamine

c.       Sulfonamides-trimethoprim

4.      Artemisinin compounds-artesunate, artether, artemether, sulfadoxine

5.      Antimicrobials-doxycycline, clindamycin, atovaquone

Chloroquine

Antimalarial Action-Chloroquine is highly effective blood schizonticide. It is also moderately effective against gametocytes of P vivax, P ovale, and P malariae, but not against those of P falciparum. Chloroquine is not active against liver stage parasites.

Mechanism of Action-Chloroquine probably acts by concentrating in parasite food vacuoles, preventing polymerization of hemoglobin breakdown product, heme, into hemozoin, and thus eliciting parasite toxicity due to buildup of free heme.

Schematic diagram of Mechanism of Action of Chloroquine is shown below

Resistancechloroquine is now very common among strains of P falciparum and uncommon but increasing for P vivax. In P falciparum, mutations in a putative transporter, PfCRT, have been correlated with resistance. Chloroquine resistance can be reversed by certain agents, including verapamil, desipramine, and chlorpheniramine, but the clinical value of resistance-reversing drugs is not established.

Pharmacokinetics-Absorption from gastrointestinal tract is rapid and complete. The drug is distributed widely and is bound to body tissues, with liver containing 500 times the blood concentration. Desethylchloroquine is major metabolite formed following hepatic metabolism, and both parent compound and its metabolites are slowly eliminated by renal excretion. The half-life of drug is 6 to 7 days.

Clinical Uses

a.       Chloroquine is drug of choice in treatment of nonfalciparum and sensitive falciparum malaria. It rapidly terminates fever (in 24–48 hours) and clears parasitemia (in 48–72 hours) caused by sensitive parasites. It is also still used to treat falciparum malaria in many areas with widespread resistance, owing to its safety and the fact that immune individuals respond to treatment even when infecting parasites are partially resistant to chloroquine.

b.      Chloroquine does not eliminate dormant liver forms of P vivax and P ovale, hence, primaquine must be added for radical cure of these species.

c.       Chemoprophylaxis-Chloroquine is preferred chemoprophylactic agent in malarious regions without resistant falciparum malaria. Eradication of P vivax and P ovale requires a course of primaquine to clear hepatic stages.

d.      Amebic Liver Abscess-Chloroquine reaches high liver concentrations and may be used for amebic abscesses that fail initial therapy with metronidazole.

Adverse Effects

a.       Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon. Dosing after meals may reduce adverse effects.

b.      Rare reactions include hemolysis in glucose-6-phosphate dehydrogenase deficient persons, impaired hearing, and confusion, psychosis, seizures, agranulocytosis, and exfoliative dermatitis, alopecia, bleaching of hair, hypotension, and electrocardiographic changes.

c.       Long-term administration of high doses of chloroquine for rheumatologic diseases results in irreversible ototoxicity, retinopathy, myopathy, and peripheral neuropathy.

d.      Large i.m. injections or rapid i.v. infusions of chloroquine hydrochloride can result in severe hypotension and respiratory and cardiac arrest.

Contraindications-Chloroquine is contraindicated in patients with psoriasis or porphyria, in whom it may precipitate acute attacks of these diseases. It should not be used in those with retinal or visual field abnormalities or myopathy.

Mechanism of action of Tamoxifen- it is synthetic antiestrogen used in treatment of breast cancer. Normally, estrogens act by binding to cytoplasmic protein receptor, and resulting hormone–receptor complex is then translocated into nucleus, where it induces synthesis of ribosomal RNA and messenger RNA at specific sites on DNA of target cell. Tamoxifen also avidly binds to estrogen receptors and competes with endogenous estrogens for these critical sites. The drug–receptor complex has little or no estrogen agonist activity.Tamoxifen directly inhibits growth of human breast cancer cells that contain estrogen receptors but has little effect on cells without such receptors.

PROTEIN SYNTHESIS INHIBITORS

a.       Tetracycline-Ex:Demeclycycline, doxycycline, minocycline, tetracycline

b.      Aminoglycoides: gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, and neomycin.

c.       Macrolides Ex: azithromycin, clarithromycin, erythromycin, telithromycin

d.      Misc: chloramphenicol, clindamycin, dalfopristin, linezolid

MACROLIDE ANTIBIOTICS

Mechanism of Action- Macrolides binds to 50S ribosomal subunit of bacteria but not to 80S mammalian ribosome; this accounts for its selective toxicity. Binding to ribosome occurs at site near peptidyltransferase, with resultant inhibition of translocation, peptide bond formation, and release of oligopeptidyl tRNA. However, unlike chloramphenicol, macrolides do not inhibit protein synthesis by intact mitochondria, and this suggests that the mitochondrial membrane is not permeable to erythromycin.

LINCOSAMIDES

Mechanism of Action-The lincosamide family of antibiotics includes lincomycin (Lincocin) and clindamycin (Cleocin), both of which inhibit protein synthesis. They bind to 50S ribosomal subunit at a binding site close to or overlapping the binding sites for chloramphenicol and erythromycin. They block peptide bond formation by interference at either the A or P site on ribosome.

Methotrexate

Mechanism of action –it competitively inhibits binding of folic acid to enzyme dihydrofolate reductase.This enzyme catalyzes formation of tetrahydrofolate, as follows:

dihydrofolate reductase

Folic acid                                               tetrahydrofolate

(FH2)                                                      (FH4)

Tetrahydrofolate is in turn converted to N5, N10- methylenetetrahydrofolate, which is an essential cofactor for synthesis of thymidylate, purines, methionine, and glycine. The mechanism by which methotrexate brings about cell death appears to be inhibition of DNA synthesis through a blockage of biosynthesis of thymidylate and purines. Cells in S-phase are most sensitive to cytotoxic effects. RNA and protein synthesis may be inhibited and also may delay progression through cell cycle, from G1 to S.

Schematic diagram of Mechanism of Action of Methotrexateis shown below

Therapeutic Uses:

a.       Methotrexate is part of curative combination chemotherapy for acute lymphoblastic leukemias, Burkitt’s lymphoma, and trophoblastic choriocarcinoma.

b.      It is useful in adjuvant therapy of breast carcinoma; in palliation of metastatic breast, head, neck, cervical, and lung carcinomas; and in mycosis fungoides.

c.       High-dose methotrexate administration with leucovorin rescue has produced remissions in 30% of patients with metastatic osteogenic sarcoma.

d.      Methotrexate can be safely administered intrathecally for treatment of meningeal metastases.

e.       Its routine use as prophylactic intrathecal chemotherapy in acute lymphoblastic leukemia has greatly reduced incidence of recurrences in CNS and has contributed to cure rate in this disease.

f.       Daily oral doses of methotrexate are used for severe cases of nonneoplastic skin disease, and

g.      It has been used as an immunosuppressive agent in severe rheumatoid arthritis.

Adverse effects:

a.       Myelosuppression is major dose-limiting toxicity associated with methotrexate therapy.

b.       Gastrointestinal toxicity may appear in form of ulcerative mucositis and diarrhea.

c.       At high doses it causes Nausea, alopecia, dermatitis and renal toxicity due to precipitation of drug in renal tubules, and should not be used in patients with renal impairment.

d.      Intrathecal administration may produce neurological toxicity ranging from mild arachnoiditis to severe and progressive myelopathy or encephalopathy.

e.       Chronic low dose therapy, as used for psoriasis, may result in cirrhosis of liver.

f.       It produces an acute, potentially lethal lung toxicity that is thought to be allergic or hypersensitivity pneumonitis.

g.      Methotrexate is a potent teratogen and abortifacient

Mercaptopurine (6-Mercaptopurine)-It is analogue of hypoxanthine and is first agents shown to be active against acute leukemias. It is now used as part of maintenance therapy in acute lymphoblastic leukemia.

Mercaptopurine must be activated to a nucleotide by enzyme HGPRTase. This metabolite is capable of inhibiting synthesis of normal purines adenine and guanine at initial aminotransferase step and inhibiting conversion of nosinic acid to nucleotides adenylate and guanylate at several steps. Some mercaptopurine is also incorporated into DNA in form of thioguanine. The mechanism to antitumor action is not clear.

Therapeutic Uses:It is used in maintenance therapy of acute lymphoblastic leukemia. It also displays activity against acute and chronic myelogenous leukemias.

Adverse effects:myelosuppression, nausea, vomiting, and hepatic toxicity.

Anticancer drugs.

Adverse effect of anticancer drugs

i.        Bone Marrow Toxicity-Inhibition of granulocytopenia, thrombocytopenia, and eythropoiesis. Immunosuppression is reversible at doses used in most anticancer protocols.

ii.      Oral cavity: the oral mucosa is particularly susceptible to cytotoxic drugs because of high epithelial cell turnoever.

iii.    Mucosal Toxicity-Inhibition of epithelial renewal leading to diarrhea. The mucosal effects are particularly significant in high-dose chemotherapy protocols associated with bone marrow reconstitution, as they predispose to bacterial sepsis arising from the gastrointestinal tract.

iv.    Neurotoxicity-CNS toxicity manifest in the form of nausea and vomiting.

v.      Lymphoreticular tissue-lymphocytopenia and inhibitonof lymphocyte function results in suppressionof cell mediated as well as humoral immunity.

vi.    Hair Follicle Toxicity Most anticancer drugs damage hair follicles and produce partial or complete alopecia. Hair usually regrows normally after completion of chemotherapy.

vii.  Foetus: All cytotoxic drugs given to pregnant women damage the developing foetus i.e. abortion, foetal death, teratogenesis.

viii.                        Hyperuricaemia-This is secondary to massive cell destruction. Gout and urate stones in urinary tract develop.

Therapeutic Uses.

a.       Mechlorethamine HCl used primarily in combination chemotherapy regimen MOPP (mechlorethamine, vincristine [ONCOVIN], procarbazine, and prednisone) in patients with Hodgkin's disease. It is also used topically for treatment of cutaneous T-cell lymphoma as a solution that is rapidly mixed and applied to affected areas of skin.

b.      Cyclophosphamide is administered orally or intravenously. It is employed in treatment of breast cancer and lymphomas. The clinical spectrum of activity is very broad. It is an essential component of many effective drug combinations for non-Hodgkin's lymphomas, ovarian cancers, and solid tumors in children. Because of its potent immunosuppressive properties, it is used to prevent organ rejection after transplantation.

c.       Ifosfamide is approved for use in combination for germ cell testicular cancer and used to treat pediatric and adult sarcomas.

d.      Melphalan for multiple myeloma is used, in combination with other agents. Melphalan also may be used in myeloablative regimens followed by bone marrow or peripheral blood stem cell reconstitution.

e.       Chlorambucil In treating chronic lymphocytic leukemia (CLL), it is a standard agent for patients with chronic lymphocytic leukemia and primary (Waldenstrom's) macroglobulinemia, and may be used for follicular lymphoma.

f.       Mercaptopurine is used in maintenance therapy of acute lymphoblastic leukemia. It also displays activity against acute and chronic myelogenous leukemias.

g.      Thioguanine is used primarily as part of a combined induction of chemotherapy in acute myelogenous leukemia

h.      Etoposide is useful against testicular and ovarian germ cell cancers, lymphomas, small cell lung cancers, and acute myelogenous and lymphoblastic leukemia.

i.        Paclitaxel is most active of all anticancer drugs, with significant efficacy against carcinomas of breast, ovary, lung, head, and neck. It is combined with cisplatin in therapy of ovarian and lung carcinomas and with doxorubicin in treating breast cancer.

Beta lactum antibiotics

Classification of beta lactum antibiotics

a.       PENICILLINS: Ex-Amoxicillin, Ampicillin, Carbenicillin, Cloxacillin, Dicloxacillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Ticarcillin,

b.      CEPHALOSPORINS: Ex-Cefaclor, Cefadroxil, Cefamandole, Cefazolin, Cefdinir, Cefepime, Cefixime, Cefmetazole, Cefonicid, Cefoperazone, Cefotaxime, Cefotetan, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cephalexin, Cephapirin,  and Cephradine

c.       CARBAPENEMS, CARBACEPHEMS, AND MONOBACTAMS: Ex-Aztreonam, Imipenem-cilastatin, Loracarbef, Meropenem

MECHANISM OF ACTION-The final reaction in bacterial cell wall synthesis is a cross-linking of adjacent peptidoglycan strands by a transpeptidation reaction. In this reaction, bacterial transpeptidases cleave terminal D-alanine from a pentapeptide on one peptidoglycan strand and then cross-link it with pentapeptide of another peptidoglycan strand. The cross-linked peptidoglycan (murein) strands give structural integrity to cell walls and permit bacteria to survive environments that do not match organism’s internal osmotic pressure.

The beta-lactam antibiotics structurally resemble terminal D-alanyl-D-alanine (D-Ala-D-Ala) in pentapeptides on peptidoglycan. Bacterial transpeptidases covalently bind beta-lactam antibiotics at enzyme active site, and resultant acyl enzyme molecule is stable and inactive. The intact beta-lactam ring is required for antibiotic action. The beta- lactam ring modifies active serine site on transpeptidases and blocks further enzyme function.

In addition to transpeptidases, other penicillin-binding proteins (PBPs) function as transglycosylases and carboxypeptidases. All PBPs are involved with assembly, maintenance, or regulation of peptidoglycan cell wall synthesis. When beta-lactam antibiotics inactivate PBPs, the consequence to bacterium is structurally weakened cell wall, aberrant morphological form, cell lysis, and death.

Anthelmentics 

Anthelmintics are the agents which are used to expel worms from the body.

Classification

1.      For nematodes-diethyl carbamzine, ivermectin, mebendazole, pyrantel pamoate, thiabendazole

2.      For trematodies-praziquantel

3.      For cestodes-albendazole, niclosamide

Mebendazole is a synthetic benzimidazole that has a wide spectrum of anthelmintic activity and a low incidence of adverse effects.

MECHANISM OF ACTION

Unlike thiabendazole, mebendazole (Vermox) does not inhibit fumarate reductase. While mebendazole binds to both mammalian and nematode tubulin, it exhibits a differential affinity for the latter, possibly explaining the selective action of drug. The selective binding to nematode tubulin may inhibit glucose absorption, leading to glycogen consumption and ATP depletion.

Anthelmintic Actions

Mebendazole probably acts by inhibiting microtubule synthesis; the parent drug appears to be active form. Efficacy of drug varies with gastrointestinal transit time, with intensity of infection, and perhaps with strain of parasite. The drug kills hookworm, ascaris, and trichuris eggs.

Pharmacokinetics: Less than 10% of orally administered mebendazole is absorbed. The absorbed drug is protein-bound (> 90%), rapidly converted to inactive metabolites (primarily during its first pass in the liver), and has half-life of 2–6 hours. It is excreted mostly in urine; Absorption is increased if drug is ingested with a fatty meal.

Clinical Uses: Used in ascariasis, trichuriasis, and hookworm and pinworm infection. It can be taken before or after meals; the tablets should be chewed before swallowing.

Adverse Reactions: Mild nausea, vomiting, diarrhea, and abdominal pain. Rare side effects are hypersensitivity reactions (rash, urticaria), agranulocytosis, alopecia, and elevation of liver enzymes.

Contraindications: Mebendazole is teratogenic in animals and therefore contraindicated in pregnancy. It should be used with caution in children under 2 years of age because of limited experience and rare reports of Convulsions. Plasma levels may be decreased by concomitant use of carbamazepine or phenytoin and increased by cimetidine. Mebendazole should be used with caution in those with cirrhosis.

Albendazole

MECHANISM OF ACTION-Albendazole appears to cause cytoplasmic microtubular degeneration, which in turn impairs vital cellular processes and leads to parasite death.There is some evidence that drug also inhibits helminth-specific ATP generation by fumarate reductase.

Pharmacokinetics: Given orally and is poorly absorbed because of its poor water solubility. Oral bioavailability is increased as much as five times when drug is given with a fatty meal instead of on empty stomach. Concurrent treatment with corticosteroids increases plasma concentrations of albendazole. Rapidly metabolized in liver to an active sulfoxide metabolite.The half life is 8 to 12 hours.

Therapeutic uses:

a.       It has broad spectrum of activity against intestinal nematodes and cestodes, as well as liver flukes Opisthorchis sinensis, Opisthorchis viverrini, and Clonorchis sinensis.

b.      It also used successfully against Giardia lamblia. Albendazole is an effective treatment of hydatid cyst disease (echinococcosis).

c.       It also is effective in treating cerebral and spinal neurocysticercosis. Albendazole is recommended for treatment of gnathostomiasis.

Niclosamide (Niclocide) was widely used to treat infestations of cestodes.

Mechanism of Action-it inhibits production of energy derived from anaerobic metabolism. It has ATPase stimulating properties. Inhibition of anaerobic incorporation of inorganic phosphate into ATP is detrimental to parasite. Niclosamide can uncouple oxidative phosphorylation in mammalian mitochondria, but this action requires dosages higher than those used in treating worm infections. The drug affects scolex and proximal segments of cestodes, resulting in detachment of scolex from intestinal wall and eventual evacuation of cestodes from intestine by normal peristaltic action of host’s bowel. As niclosamide is not absorbed from intestinal tract, high concentrations can be achieved in intestinal lumen.The drug is not ovicidal.

Clinical Use

a.       Used in treatment of tapeworm infections caused by Taenia saginata, Taenia solium, Diphyllobothrium latum, Fasciolopsis buski, and Hymenolepis nana.

b.      It is an effective alternative to praziquantel for treating infections caused by T. saginata (beef tapeworm), T. solium (pork tapeworm), and D. latum (fish tapeworm) and is active against most other tapeworm infections.

Adverse Effects: No serious side effects are associated with its use, although some patients report abdominal discomfort and loose stools.

Praziquante (Biltricide)

The neuromuscular effects appear to increase parasite motility leading to spastic paralysis. The drug increases calcium permeability through parasite-specific ion channels, so that tegmental and muscle cells of parasite accumulate calcium.This action is followed by vacuolization and exposure of hitherto masked tegmental antigens, lipid anchored protein, and actin. Insertion of drug into fluke’s lipid bilayer causes conformational changes, rendering fluke susceptible to antibody- and complement-mediated assault.

Clinical uses:

a.       Used in treatment of schistosomiasis, possessing activity against male and female adults and immature stages.

b.      Unlike other agents, it is active against all three major species (S. haematobium, S. mansoni, and S. japonicum).

c.       it has activity against other flukes, such as C. sinensis, Paragonimus westermani, O. viverrini, and the tapeworms (D. latum, H. nana, T. saginata, and T. solium

Adverse reactions include gastrointestinal intolerance with nausea, vomiting, and abdominal discomfort.

Cotrimazole

The introduction of trimethoprim in combination with sulfamethoxazole is known as cotrimoxazole.

Antibacterial Spectrum- The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole. Most gram-negative and gram-positive microorganisms are sensitive to trimethoprim, but resistance can develop when drug is used alone. Pseudomonas aeruginosa, Bacteroides fragilis, and enterococci usually are resistant.

Efficacy of Trimethoprim-Sulfamethoxazole in Combination-Chlamydia diphtheriae and N. meningitidis are susceptible to trimethoprim-sulfamethoxazole. From 50% to 95% of strains of Staphylococcus aureus, Staphylococcus epidermidis, S. pyogenes, the viridans group of streptococci, E. coli, Proteus mirabilis, Proteus morganii, Proteus rettgeri, Enterobacter spp., Salmonella, Shigella, Pseudomonas pseudomallei, Serratia, and Alcaligenes spp. are inhibited. Also sensitive are Klebsiella spp., Brucella abortus, Pasteurella haemolytica, Yersinia pseudotuberculosis, Yersinia enterocolitica, and Nocardia asteroides. However, a maximal degree of synergism occurs when microorganisms are sensitive to both components.

Mechanism of Action- The antimicrobial activity of combination of trimethoprim and sulfamethoxazole results from its actions on two steps of enzymatic pathway for synthesis of tetrahydrofolic acid. Sulfonamide inhibits incorporation of PABA into folic acid, and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate.

Bacterial Resistance to trimethoprim-sulfamethoxazole is a rapidly increasing problem, although resistance is lower than it is to either of the agents alone. Resistance is due to acquisition of plasmid that codes for an altered dihydrofolate reductase. The development of resistance is a problem for treatment of many different bacterial infections. Emergence of trimethoprim-sulfamethoxazole-resistant S. aureus and Enterobacteriaceae is problem in AIDS patients receiving the drug for prophylaxis of Pneumocystis jiroveci.

Absorption, Distribution, and Excretion.

a.       Trimethoprim is well absorbed from GI tract, and peak blood levels are achieved in about 2 hours. Tissue levels exceed those of plasma, and urine concentration of trimethoprim may be 100 times that of plasma. Trimethoprim readily enters CSF, if inflammation is present. The half-life of Trimethoprim is 11 hours.

b.      Sulfamethoxazole (t_1/2 is 10 hours) is frequently coadministered with trimethoprim in a fixed dose ratio of 1:5 (trimethoprim to sulfamethoxazole). Peak drug levels in plasma are achieved in 1 to 4 hours following oral administration and 1 to 1.5 hours after IV infusion.

c.       TMP-SMX plasma ratio is 1:20, which is ratio most effective for producing a synergistic effect against most susceptible pathogens.

d.      Both trimethoprim and sulfamethoxazole bind to plasma protein (45 and 66% respectively) and both are metabolized in liver.

e.       Both parent drugs and their metabolites are excreted by kidney within 24 hours; both drugs cross the placenta and are found in breast milk.

Therapeutic Uses

a.       Urinary Tract Infections- Treatment of uncomplicated lower urinary tract infections with trimethoprim-sulfamethoxazole is highly effective for sensitive bacteria. It shown to produce a better therapeutic effect than does either of its components given separately against Enterobacteriaceae.

b.      Trimethoprim-sulfamethoxazole is often effective for treatment of bacterial prostatitis.

c.       Bacterial Respiratory Tract Infections- Trimethoprim-sulfamethoxazole is effective for acute exacerbations of chronic bronchitis. Administration of sulfamethoxazole-trimethoprim twice a day is effective in decreasing fever, purulence and volume of sputum, and sputum bacterial count.

d.      Gastrointestinal Infections- The combination is an alternative to fluoroquinolone for treatment of shigellosis because many strains are resistant to ampicillin; however, resistance to trimethoprim-sulfamethoxazole is increasingly common.

e.       Trimethoprim-sulfamethoxazole appears to be effective in management of carriers of sensitive strains of Salmonella typhi and other Salmonella spp.

f.       Infection by Pneumocystis jiroveci. High-dose therapy is effective for this severe infection in AIDS patients. Lower-dose oral therapy has been used successfully in AIDS patients with less severe pneumonia. Prophylaxis is effective in preventing pneumonia caused by this organism in patients with AIDS.

g.      Prophylaxis in Neutropenic Patients- used for prophylaxis of infection by P. carinii. Significant protection against sepsis caused by gram-negative bacteria was noted when given to severely neutropenic patients.

h.      Miscellaneous Infections-Nocardia infections have been treated successfully with the combination.

i.        Trimethoprim-sulfamethoxazole is used successfully in treatment of Whipple's disease, infection by Stenotrophomonas maltophilia, and infection by the intestinal parasites Cyclospora and Isospora.

j.        Trimethoprim-sulfamethoxazole also has been used to treat methicillin-resistant strains of S. aureus.

Untoward Effects

a.       There is no evidence that trimethoprim-sulfamethoxazole, when given in recommended doses, induces folate deficiency in normal persons.

b.      Trimethoprim-sulfamethoxazole may cause or precipitate megaloblastosis, leukopenia, or thrombocytopenia.

c.       Exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Lyell's syndrome) are rare, occurring primarily in elders.

d.      Nausea and vomiting constitute the bulk of GI reactions; diarrhea is rare. Glossitis and stomatitis are common.

e.       CNS reactions consist of headache, depression, and hallucinations, manifestations known to be produced by sulfonamides.

f.       Permanent impairment of renal function may follow the use of trimethoprim-sulfamethoxazole in patients with renal disease.

Chloramphenicol- mechanism of action and therapeutic uses

Mechanism of Action-It is a nitrobenzene derivative that affects protein synthesis by binding to 50S ribosomal subunit and preventing peptide bond formation. It prevents attachment of amino acid end of aminoacyl-tRNA to A site, hence, association of peptidyltransferase with amino acid substrate.

Schematic diagram of Mechanism of Action of Chloramphenicol is shown below

Resistance due to changes in ribosome binding site results in a decreased affinity for drug, decreased permeability, and plasmids that code for enzymes that degrade the antibiotic. The drug-induced inhibition of mitochondrial protein synthesis is probably responsible for associated toxicity.

Clinical Uses

a.       Because of potential toxicity, bacterial resistance, and availability of many other effective alternatives, it is rarely used.

b.      It is used for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever.

c.       It is an alternative to a beta-lactam antibiotic for treatment of meningococcal meningitis in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci.

d.      It is used topically in treatment of eye infections because of its broad spectrum and its penetration of ocular tissues and aqueous humor. It is ineffective for chlamydial infections.

Antiamoebics

Antiamoebics are the agents which are used in treatment of protozoal infections

Classification

1.      Tissue amoebicide

a.       For both intestine and extraintestinal amoebiasis

i.                    Nitroimidazoles-metronidazole, tinidazole, senidazole, ornidazole, satranidazole

ii.                  Alkaloids-emetine, dihydroemetine

2.      Luminal amoebicide

a.       Amide:diloxanide furoate, nitazoxamide

b.      8-hydroxyquinolones-iodochlorohydroxyquin, clioquinol, iodoquinol

c.       Antibiotics-tetracyclines

Metronidazole (Flagyl, Metrogel)

It exerts activity against most anaerobic bacteria and several protozoa.The drugs freely penetrate protozoal and bacterial cells but not mammalian cells. Metronidazole can function as an electron sink, and because it does so, its 5-nitro group is reduced. The enzyme, pyruvate-ferredoxin oxidoreductase, found only in anaerobic organisms, reduces metronidazole and thereby activates the drug. Reduced metronidazole disrupts replication and transcription and inhibits DNA repair.

Antimicrobial Spectrum-Metronidazole inhibits E. histolytica, G. lamblia, T. vaginalis, Blastocystis hominis, B. coli, and the helminth Dracunculus medinensis. It is also bactericidal for obligate anaerobic gram-positive and gram-negative bacteria except Actinomyces spp. It is not active against aerobes or facultative anaerobes.

Tinidazole, a 5-nitroimidazole closely related to metronidazole, is effective against vaginal trichomoniasis resistant to metronidazole.

Absorption, Metabolism, and Excretion

Absorption is good from intestinal tract. Food delays but does not reduce absorption. Distributed in body fluids and has half-life of 8 hours. High levels are found in plasma and CSF. Less than 20% binds to plasma proteins. Metabolized by oxidation and glucuronide formation in liver and excreted by kidneys, small amounts found in saliva and breast milk.

Clinical Uses of Metronidazole

a.      It is most effective agent available for treatment of individuals with all forms of amebiasis, with perhaps the exception of the person who is asymptomatic but continues to excrete cysts.

b.      It is active against intestinal and extraintestinal cysts and trophozoites.

c.       It has been found to be effective in treating D. medinensis (Guinea worm) infections and Helicobacter pylori.

d.      It is also used in treatment of giardiasis infections

Adverse Effects:Nausea, vomiting, cramps, diarrhea, and a metallic taste.The urine is often dark or redbrown. Less frequently, unsteadiness, vertigo, ataxia, paresthesias, peripheral neuropathy, encephalopathy, and neutropenia are reported.

Drug interactions:Since metronidazole is a weak inhibitor of alcohol dehydrogenase, alcohol ingestion should be avoided during treatment. A psychotic reaction also may be produced. Metronidazole interferes with metabolism of warfarin and may potentiate its anticoagulant activity. Phenobarbital and corticosteroids lower metronidazole plasma levels by increasing its metabolism, whereas cimetidine raises levels by impairing metronidazole metabolism.The drug is not recommended for use during pregnancy.

Iodoquinolis a halogenated 8-hydroxyquinoline derivative whose precise mechanism of action is not known but is thought to involve an inactivation of essential parasite enzymes.

Iodoquinol kills the trophozoite forms of E. histolytica, B. coli, B. hominis, and Dientamoeba fragilis.

Absorption, Metabolism, and Excretion: well absorbed from GIT and excreted in urine as glucuronide and sulfate conjugates. Most of an orally administered dose is excreted in feces. It has plasma half-life of about 12 hours.

Iodoquinol is drug of choice in treatment of asymptomatic amebiasis and D. fragilis infections. It is also used in combination with other drugs in treatment of other forms of amebiasis and as an alternative to tetracycline in treatment of balantidiasis.

Adverse reactions are related to the iodine content of drug; the toxicity is often expressed as skin reactions, thyroid enlargement, and interference with thyroid function studies. Headache and diarrhea also occur. Chronic use of clioquinol, a closely related agent, has been linked to myelitis like illness and to optic atrophy with permanent loss of vision.

Diloxanide Furoateis an amebicide that is effective against trophozoites in intestinal tract. The drug is administered only orally and rapidly absorbed from gastrointestinal tract following hydrolysis of ester group. Diloxanide is excreted in urine, as glucuronide.

Side effects: flatulence, abdominal distention, anorexia, nausea, vomiting, diarrhea, pruritus, and urticaria occur

Drugs used for Giardiasis

Giardiasis is caused by the protozoan Giardia lamblia and is characterized by gastrointestinal symptoms ranging from an acute self-limiting watery diarrhea to a chronic condition associated with episodic diarrhea and occasional instances of malabsorption. The parasite is similar to E. histolytica.

Ex: metronidazole, Nitazoxanide, tinidazole, ornidazole, secnidazole, quiniodochlor, furazolidine

Metronidazole Refer Q. No.7 (5 marks)

NITAZOXANIDE

Antimicrobial Effects: Nitazoxanide and its active metabolite, tizoxanide (desacetyl-nitazoxanide), inhibit growth of sporozoites and oocytes of C. parvum and inhibit growth of trophozoites of G. intestinalis, E. histolytica, and T. vaginalis in vitro. Activity against other protozoans, including Blastocystis hominis, Isospora belli, and Cyclospora cayetanensis is seen. It also shows activity against intestinal helminths: Hymenolepsis nana, Trichuris trichura, Ascaris lumbricoides, Enterobius vermicularis, Ancylostoma duodenale, Strongyloides stercoralis, and the liver fluke Fasciola hepatica. It is effective against some anaerobic or microaerophilic bacteria, including Clostridium spp. and H. pylori, is reported.

Mechanism of Action: Exact mechanisms remain unclear; it appears to interfere with PFOR enzyme-dependent electron-transfer reaction. This reaction is essential in anaerobic metabolism. Nitazoxanide does not appear to produce DNA mutations.

Absorption, Fate, and Excretion On oral administration, it is hydrolyzed rapidly to its active metabolite tizoxanide, which undergoes conjugation primarily to tizoxanide glucuronide. Bioavailability after oral dose is excellent, and maximum plasma concentrations of metabolites are detected within 1 to 4 hours of administration of parent compound. Tizoxanide is greater than 99.9% bound to plasma proteins and is excreted in urine, bile, and feces.

Therapeutic Uses of Nitazoxanide

a.       Treatment of G. intestinalis infection in children under the age of 12 and for treatment of diarrhea in children under 12 caused by cryptosporidia

b.      It has been used as a single agent to treat mixed infections with intestinal parasites.

c.       Effective parasite clearance after nitazoxanide treatment was shown for G. intestinalis, E. histolytica/E. dispar, B. hominis, C. parvum, C. cayetanensis, I. belli, H. nana, T. trichura, A. lumbricoides, and E. vermicularis.

d.      It has some efficacy against Fasciola hepatica infections, and used to treat infections with G. intestinalis that is resistant to metronidazole and albendazole.

Side Effects: Abdominal pain, diarrhea, vomiting, and headache have been reported. A greenish tint to urine is seen in most individuals taking nitazoxanide.

Antiviral drugs with examples

Classification

1.      Antiherpes virus-idoxuridine, acyclovir, valocyclovir, famcicyclovir, ganciclovir, foscarnet,

2.      Antiretrovirus

a.       Nucleoside reverse transcriptase inhibitors-zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir

b.      Non-Nucleoside reverse transcriptase inhibitors-Nevirapin,e Efavirenz, delavirdine,

c.       Protease inhibitors-ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, lopinavir

d.      Fusion inhibitor-enfuvirtide

3.      Anti-influenza virus-amantadine, rimantadine

4.      For Hepatic viral infections-Adefovir, Entecavir, interferon, lamivudine

Peptide drugs

Bacitracin and polymyxins are polypeptide antibiotics. Vancomycin, a glycopeptide, although not without side effects, is widely used.Teicoplanin is a new glycopeptides antibiotic that may be beneficial against certain infections caused by gram-positive organisms.

BACITRACIN-is a mixture of polypeptide antibiotics produced by Bacillus subtilis.

Mechanism of Action-It prevents cell wall synthesis by binding to a lipid pyrophosphate carrier that transports cell wall precursors to growing cell wall. Bacitracin inhibits dephosphorylation of this lipid carrier, a step essential to carrier molecule’s ability to accept cell wall constituents for transport.

Antimicrobial Spectrum-it inhibits gram-positive cocci, including Staphylococcus aureus, streptococci, a few gram-negative organisms, and one anaerobe, Clostridium difficile.

Absorption, Distribution, and Excretion

Bacitracin is primarily a topical antibiotic. Previously, it was administered intramuscularly, but the toxicity associated with its parenteral administration has precluded systemic use. It is not absorbed from gastrointestinal tract following oral administration.

Clinical Uses

a.       Bacitracin is highly active against staphylococci, Streptococcus pyogenes, and C. difficile. It has high degree of activity against the group.

b.      Bacitracin is well tolerated topically and orally and is frequently used in combination with other agents (Tetracyclines, Chloramphenicol, Macrolides, and Lincosamides) in form of creams, ointments, and aerosol preparations. Hydrocortisone has been added to combination for its anti-inflammatory effects.

c.       Bacitracin preparations are effective in treatment of impetigo and other superficial skin infections.

GLYCOPEPTIDES: VANCOMYCIN AND TEICOPLANIN

Mechanism of Action-Glycopeptides is inhibitors of cell wall synthesis. They bind to terminal carboxyl group on Dalanyl- D-alanine terminus of N-acetylglucosamine- N-acetylmuramic acid peptide and prevent polymerization of linear peptidoglycan by peptidoglycan synthase.They are bactericidal in vitro.

Antimicrobial Spectrum

The glycopeptides are narrow-spectrum agents that are active against gram-positive organisms. Like vancomycin, teicoplanin is bacteriostatic against staphylococci, streptococci, and enterococci. Gram-positive rods, such as Bacillus anthracis, Corynebacterium diphtheriae, Clostridium tetani, and Clostridium perfringens, are also sensitive to the glycopeptides. The glycopeptides are not effective against gram-negative rods, mycobacteria, or fungi.

Absorption, Distribution, and Excretion

Vancomycin is poorly absorbed from GIT, resulting in high concentrations in feces.  Peak serum levels are achieved 2 hours after IV administration, and about 55% is bound to serum protein and serum half-life is 5 to 11 hours. The dose of must be carefully adjusted to avoid toxicity or ineffective treatment, especially in patients undergoing hemodialysis. Renal excretion is predominant, with 80 to 90% of an administered dose eliminated in 24 hours. Only small amounts appear in stool and bile after i. v. administration.

Teicoplanin, like vancomycin, is not absorbed from intestinal tract. Peak plasma levels are achieved about 2 hours after intramuscular administration. The drug distributes widely in tissues; plasma protein binding is about 90%.The half-life approximates 50 hours, which is longer than vancomycin, and may make it useful for outpatient administration. Like vancomycin, teicoplanin is excreted by kidneys.

Clinical Uses

a.       Vancomycin and teicoplanin has excellent activity against staphylococci and streptococci, but because of wide availability of equally effective and less toxic drugs, they are second-line drugs in treatment of most infections. As antistaphylococcal agents they are less effective than beta-lactam cephalosporin antibiotics.

b.      Vancomycin is also an effective alternative therapy for treatment of staphylococcal enterocolitis and endocarditis.

c.       Staphylococcal vascular shunt infections in persons undergoing renal dialysis have been successfully treated with vancomycin.

d.      Vancomycin in oral form can also be used in patients in whom C. difficile colitis is not responding to metronidazole.

e.       Teicoplanin used to treat a wide range of gram-positive infections, including endocarditis and peritonitis. It is not as effective as beta-lactams, but its actions are similar to those of vancomycin against staphylococcal infections.

Adverse Effects

Ototoxicity, which may result in tinnitus, hightone hearing loss, and deafness in extreme instances. More commonly, the intravenous infusion of vancomycin can result in chills, fever, and a maculopapular skin rash often involving head and upper thorax (red man syndrome). Red man syndrome is associated with increased levels of serum histamine.Vancomycin is rarely nephrotoxic when used alone. Teicoplanin rarely causes red man syndrome or nephrotoxicity.

polymyxins-These are group of antibiotics produced by Bacillus polymyxa. Polymyxin B (Aerosporin) and colistin (polymyxin E, Coly-Mycin) are used in treatment of bacterial diseases.

Mechanism of Action- These are polypeptide antibiotics that contain both hydrophilic and lipophilic regions. These antibiotics accumulate in cell membrane and probably interact with membrane phospholipids. Most likely the fatty acid portion of antibiotic penetrates hydrophobic portion of membrane phospholipid and polypeptide ring binds to exposed phosphate groups of membrane. Such an interaction would distort membrane, impair its selective permeability, produce leakage of metabolites, and inhibit cellular processes.

Antimicrobial Spectrum- polymyxins are active against facultative gram-negative bacteria, P. aeruginosa.

Absorption, Distribution, and Excretion

Not well absorbed from gastrointestinal tract. An intramuscular injection results in high drug concentrations in liver and kidneys, but antibiotic does not enter cerebrospinal fluid even in presence of inflammation. Slowly excreted by glomerular filtration; it is due to binding in tissues. Elimination is decreased in patients with renal disease, and drug accumulation can lead to toxicity.

Clinical Uses

In combination with neomycin, polymyxin B can be used as bladder irrigant to reduce risk of catheter associated infections, although this use remains controversial. It also can be used as topical therapy in external otitis caused by P. aeruginosa.

Adverse Effects

a.       Nephrotoxicity is caused by Colistin and polymyxin B when used parenterally, and any preexisting renal insufficiency will potentiate nephrotoxicity caused by these antibiotics.

b.      Neurotoxicity is a rare adverse reaction that can be recognized by perioral paresthesia, numbness, weakness, ataxia, and blurred vision.

c.       These drugs may precipitate respiratory arrest both in patients given muscle relaxants during anesthesia and in persons with myasthenia gravis.

Urinary antiseptics

Urinary antiseptics are drugs that exert their antimicrobial effect in the urine and are devoid of virtually any significant systemic effect. Prolonged use for prophylaxis and/or suppression is common in recurrent or chronic UTIs where other antimicrobials can be used only for short durations because they do not sustain sterility.

Nitrofurantoin

Mechanism of Action: Enzymes capable of reducing nitrofurantoin appear to be crucial for its activation. Highly reactive intermediates are formed, and these seem to be responsible for the observed capacity of the drug to damage DNA. Bacteria reduce nitrofurantoin more rapidly than do mammalian cells, and this is thought to account for the selective antimicrobial activity of the compound.

Pharmacodynamics:

Nitrofurantoin is bacteriostatic and bactericidal for many gram-positive and gram-negative bacteria. Bacteria that are susceptible to drug rarely become resistant during therapy. Nitrofurantoin is active against many strains of E. coli and enterococci. However, most species of Proteus and Pseudomonas and many species of Enterobacter and Klebsiella are resistant. Clinical drug resistance emerges slowly. There is no cross-resistance between nitrofurantoin and other antimicrobial agents.

Pharmacokinetics:

Well absorbed after ingestion. Metabolized and excreted so rapidly that no systemic antibacterial action is achieved. Excreted in urine by glomerular filtration and tubular secretion. With average daily doses, concentrations of 200 g/mL are reached in urine. In renal failure, urine levels are insufficient for antibacterial action, but high blood levels may cause toxicity.

Clinical Use

a.       Used in treatment and/or prophylaxis of microbial infections, primarily in lower UTIs caused by susceptible bacteria; it is not used as a bacterial suppressant.

b.      It is often used prophylactically post intercourse in women with chronic UTIs. Although serum drug concentrations are low, concentrations are found in urine that is well above the minimum inhibitory concentration for susceptible bacteria.

c.       The bacteriostatic or bactericidal activity of nitrofurantoin is concentration dependent and ensures bactericidal activity.

d.      Nitrofurazone, a topical antibiotic, used in treatment of burns or skin grafts in which bacterial contamination may cause tissue rejection.

Nitrofurantoin is contraindicated in patients with severe renal insufficiency. Oral nitrofurantoin can be given for months for the suppression of chronic urinary tract infection. It is desirable to keep urinary pH below 5.5, which greatly enhances drug activity.

Adverse effects: Anorexia, nausea, and vomiting. Neuropathies and hemolytic anemia occur in glucose-6-phosphate dehydrogenase deficiency. Nitrofurantoin antagonizes the action of nalidixic acid. Rashes, pulmonary infiltration, and other hypersensitivity reactions have been reported.

Methenamine (hexamethylenetetramine) is a urinary tract antiseptic and prodrug that owes its activity to its capacity to generate formaldehyde.

Mechanism of Action-it is an aromatic acid that is hydrolyzed at acid pH (<6) to liberate ammonia and active alkylating agent formaldehyde, which denatures protein and is bactericidal. Methenamine is usually administered as a salt of either mandelic or hippuric acid. Not only do these acids acidify the urine, which is necessary to generate formaldehyde, but also, resulting low urine pH is by itself bacteriostatic for some organisms.

Antimicrobial Activity Nearly all bacteria are sensitive to free formaldehyde at concentrations of about 20 mg/ml. Urea-splitting microorganisms (e.g., Proteus spp.) tend to raise the pH of the urine and thus inhibit the release of formaldehyde. Microorganisms do not develop resistance to formaldehyde.

Clinical uses:

a.       It is used for long-term prophylactic or suppressive therapy of recurring UTIs.

b.      It is not a primary drug for therapy of acute infections.

c.       It should be used to maintain sterile urine after antimicrobial agents is employed to eradicate infection.

Adverse reactions

a.       Gastric distress (nausea and vomiting), bladder irritation (e.g., dysuria, polyuria, hematuria, and urgency) may occur.

b.      The mandelic salt can crystallize in urine if there is inadequate urine flow and should not be given to patients with renal failure.

c.       Patients with preexisting hepatic insufficiency may develop acute hepatic failure due to the small quantities of ammonia formed during methenamine hydrolysis.

d.      The coadministration of methenamine with certain sulfonamides (sulfamethizole or sulfathiazole) can form a urine precipitate resulting in drug antagonism.

Kanamycin

The use of kanamycin has declined markedly because its spectrum of activity is limited compared with other aminoglycosides, and it is among the most toxic.

Mechanism of Action- Same as Amino glycosides Refer Q. No.5 (10 marks)

Antimicrobial Activity & Resistance

It is active against gram-positive and gram-negative bacteria and some mycobacteria. Pseudomonas and streptococci are generally resistant. Mechanisms of antibacterial action and resistance are same as with other aminoglycosides. The widespread use of these drugs in bowel preparation for elective surgery has resulted in selection of resistant organisms and some outbreaks of enterocolitis in hospitals. Cross-resistance between kanamycin and neomycin is complete.

Therapeutic Uses

Kanamycin has been employed to treat tuberculosis in combination with other effective drugs. It has no therapeutic advantage over streptomycin or amikacin and probably is more toxic; either should be used instead, depending on susceptibility of isolate.

Kanamycin can be administered orally as adjunctive therapy in cases of hepatic encephalopathy.

Untoward Effects

a.      Ototoxic and nephrotoxic. Like neomycin, its oral administration can cause malabsorption and superinfection.

b.      Hypersensitivity reactions, primarily skin rashes, occur in 6% to 8% of patients when neomycin is applied topically.

c.       Individuals sensitive to this agent may develop cross-reactions when exposed to other aminoglycosides.

d.      Individuals treated with the drug by mouth sometimes develop a spruelike syndrome with diarrhea, steatorrhea, and azotorrhea. Overgrowth of yeasts in intestine also may occur; this is not associated with diarrhea or other symptoms.

Polyene antibiotics

Ex: Amphotericin B, Nystatin, hamycin, and Natamycin

Amphotericin B

Antifungal Activity: it has clinical activity against Candida spp., Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Sporothrix schenckii, Coccidioides immitis, Paracoccidioides braziliensis, Aspergillus spp., Penicillium marneffei, and agents of mucormycosis.

Amphotericin B has limited activity against protozoa Leishmania braziliensis and Naegleria fowleri. The drug has no antibacterial activity.

Mechanism of Action: The antifungal activity depends principally on its binding to sterol moiety, primarily ergosterol that is present in membrane of sensitive fungi. By virtue of their interaction with these sterols, polyenes appear to form pores or channels that increase permeability of membrane, allowing leakage of a variety of small molecules.

Schematic diagram of Mechanism of Action of Amphotericin Bis shown below

Fungal Resistance: Some isolates of Candida lusitaniae have appeared to be relatively resistant. Aspergillus terreus may be more resistant to amphotericin B than other Aspergillus species.

Pharmacokinetics

Poorly absorbed from GIT. Oral amphotericin B is effective only on fungi within lumen of the tract and cannot be used for treatment of systemic disease. More than 90% bound by serum proteins. Mostly metabolized and excreted slowly in urine. The serum t_1/2 is approximately 15 days. Widely distributed in most tissues, but only 2–3% of blood level is reached in cerebrospinal fluid.

Adverse Effects

The toxicity of amphotericin B can be divided into two broad categories: immediate reactions, related to the infusion of the drug, and those occurring more slowly.

a.       Infusion-Related Toxicity-These reactions are nearly universal and consist of fever, chills, muscle spasms, vomiting, headache, and hypotension. Premedication with antipyretics, antihistamines, meperidine, or corticosteroids can be helpful.

b.      Slower Toxicity-Renal damage is most significant toxic reaction. The degree of azotemia is variable and stabilizes during therapy, but can be serious enough to necessitate dialysis. Abnormalities of liver function tests are seen, due to reduced erythropoietin production by damaged renal tubular cells. After intrathecal therapy with amphotericin, seizures and a chemical arachnoiditis may develop, often with serious neurologic sequelae

Clinical Use

a.       Owing to its broad spectrum of activity and fungicidal action, it remains drug of choice for nearly all life-threatening mycotic infections. 

b.      It is also used as empirical therapy for selected patients in whom the risks of leaving a systemic fungal infection untreated are high.  Intrathecal therapy for fungal meningitis is poorly tolerated.

c.       Mycotic corneal ulcers and keratitis can be cured with topical drops as well as by direct subconjunctival injection.

d.      Fungal arthritis has been treated with adjunctive local injection directly into joint.

e.       Candiduria responds to bladder irrigation with amphotericin B.

Nystatin

It is a polyene antifungal drug with a ring structure similar to that of amphotericin B and a mechanism of action identical to that of amphotericin B. Too toxic for systemic use; nystatin is limited to topical treatment of superficial infections caused by C. albicans. Infections commonly treated by this drug include oral candidiasis (thrush), mild esophageal candidiasis, and vaginitis.

Antimetabolites

i.                    Folic acid antagonists-methotrexate

ii.                  Purin antagonist – 6 mercaptopurine, azatiopurine

iii.                Pyrimidine antagonists-fluorouracil, cytosine, arabinoside, flurodeoxyuridine

Methotrexate

Mechanism of action- Refer Q. No.11 (10 marks)

Pharmacological actions:-

1.            Cytotoxic actions:- it has predominant action on bone marrow. It inhibits erythorpoiesis, myelopoiesis and aplasia of bone. This causes marked peripheral granulocytopenia, reitculocytopenia and moderate lymphophenia. It also causes ulceration of intestinal mucosa leading to sever hemorrhage, desquamating enteritis. It can cross placental barrier and interfere with embryogenesis leading to fetal abnormalities and death.

2.            Immunosuppressive action: it is potent immunosuppressant and acts by preventing cloan expansion of both B & T lymphocytes.

3.            Anti-inflamatory action: used in small does it reduces lymphtocytes proliferation, rheumatoid factor production, leukocyte-endothelia interation, leukocyte-leukocuyte interationand intereferes with rease of inflammaotr cytokines.

Absorption, Metabolism, and Excretion

Well absorbed orally and 50% bound to plasma proteins. The plasma decay that follows an i. v. injection is triphasic, with a distribution phase, an initial elimination phase, and a prolonged elimination phase. The last phase is thought to reflect slow release of methotrexate from tissues. Drug is excreted from glomerular filtration and active renal tubular secretion. The formation of polyglutamic acid conjugates of methotrexate is seen in tumor cells and in liver and may be a important determinant of cytotoxicity. Methotrexate polyglutamates, retained in cell are potent inhibitors of dihydrofolate reductase.

Drug Interactions

Salicylates, probenecid, and sulfonamides inhibit the renal tubular secretion of methotrexate and may displace it from plasma proteins. Asparaginase inhibits protein synthesis and may protect cells from methotrexate cytotoxicity by delaying progression from G1 to S-phase. Methotrexate may either enhance or inhibit action of fluorouracil, depending on administration.

Drug Resistance

Resistance to methotrexate has been attributed to (1) decreased drug transport, (2) decreased formation of cytotoxic MTX polyglutamates, (3) synthesis of increased levels of DHFR through gene amplification, and (4) altered DHFR with reduced affinity for methotrexate.

Therapeutic Uses:

a.       Methotrexate is part of curative combination chemotherapy for acute lymphoblastic leukemias, Burkitt’s lymphoma, and trophoblastic choriocarcinoma.

b.      It is useful in adjuvant therapy of breast carcinoma; in palliation of metastatic breast, head, neck, cervical, and lung carcinomas; and in mycosis fungoides.

c.       High-dose methotrexate administration with leucovorin rescue has produced remissions in 30% of patients with metastatic osteogenic sarcoma.

d.      Methotrexate can be safely administered intrathecally for treatment of meningeal metastases.

e.       Its routine use as prophylactic intrathecal chemotherapy in acute lymphoblastic leukemia has greatly reduced incidence of recurrences in CNS and has contributed to cure rate in this disease.

f.       Daily oral doses of methotrexate are used for severe cases of nonneoplastic skin disease, and

g.      It has been used as an immunosuppressive agent in severe rheumatoid arthritis.

Adverse effects:

a.       Myelosuppression is major dose-limiting toxicity associated with methotrexate therapy.

b.       Gastrointestinal toxicity may appear in form of ulcerative mucositis and diarrhea.

c.       At high doses it causes Nausea, alopecia, dermatitis and renal toxicity due to precipitation of drug in renal tubules, and should not be used in patients with renal impairment.

d.      Intrathecal administration may produce neurological toxicity ranging from mild arachnoiditis to severe and progressive myelopathy or encephalopathy.

e.       Chronic low dose therapy, as used for psoriasis, may result in cirrhosis of liver.

f.       It produces an acute, potentially lethal lung toxicity that is thought to be allergic or hypersensitivity pneumonitis.

g.      Methotrexate is a potent teratogen and abortifacient

Mercaptopurine (6-Mercaptopurine)-It is analogue of hypoxanthine and is first agents shown to be active against acute leukemias. It is now used as part of maintenance therapy in acute lymphoblastic leukemia.

Mercaptopurine must be activated to a nucleotide by enzyme HGPRTase. This metabolite is capable of inhibiting synthesis of normal purines adenine and guanine at initial aminotransferase step and inhibiting conversion of nosinic acid to nucleotides adenylate and guanylate at several steps. Some mercaptopurine is also incorporated into DNA in form of thioguanine. The significance of these mechanisms to antitumor action of mercaptopurine is not clear.

Resistance to mercaptopurine may be a result of decreased drug activation by HGPRTase or increased inactivation by alkaline phosphatase.

On I.V. administration, plasma half-life is 21 minutes in children and 47 minutes in adults. After oral administration, peak plasma levels are attained within 2 hours. The drug is 20% bound to plasma proteins and does not enter CSF. Xanthine oxidase is enzyme involved in metabolic inactivation of mercaptopurine.

Therapeutic Uses:

It is used in maintenance therapy of acute lymphoblastic leukemia. It also displays activity against acute and chronic myelogenous leukemias.

Adverse effects: myelosuppression, nausea, vomiting, and hepatic toxicity.

Alkylating agents

i.                    Nitrogenmustards Ex: mechlorethamin,e melphalen, cyclophosphamide, uracil mustard and chlorambucil

ii.                  Ethylenimines Ex: thriethylene thiophosphoramide

iii.                Alkyl sulfonates Ex: busulfan

Mechanism of Action of alkylating agents Refer Q. No.3 (10 marks)

Pharmacological Actions

Cytotoxic Actions: Alkylating agents are those that disturb DNA synthesis and cell division. The capacity of these drugs to interfere with DNA integrity and function and to induce cell death in rapidly proliferating tissues provides the basis for their therapeutic and toxic properties. Whereas certain alkylating agents may have damaging effects on tissues with normally low mitotic indicesfor example, liver, kidney, and mature lymphocytes. Acute effects are manifest primarily against rapidly proliferating tissues.  Lethality of DNA alkylation depends on the recognition of adduct, the creation of DNA strand breaks by repair enzymes, and an intact apoptotic response. The actual mechanism of cell death related to DNA alkylation is not yet well characterized.

            In nondividing cells, DNA damage activates a checkpoint that depends on presence of normal p53 gene. Cells thus blocked in G₁/S interface either repair DNA alkylation or undergo apoptosis. Malignant cells with mutant or absent p53 fail to suspend cell-cycle progression, do not undergo apoptosis, and exhibit resistance to these drugs.

Mechanisms of Resistance to Alkylating Agents Resistance develops rapidly when used as single agent. Specific biochemical changes implicated in development of resistance include:

a.        Decreased permeation of actively transported drugs (mechlorethamine and melphalan);

b.      Increased intracellular concentrations of nucleophilic substances, principally thiols such as glutathione, which can conjugate with and detoxify electrophilic intermediates;

c.       Increased activity of DNA repair pathways, which may differ for various alkylating agents. Thus, increased activity of complex nucleotide excision repair (NER) pathway seems to correlate with resistance to most chloroethyl and platinum.

d.      Increased rates of metabolism of activated forms of cyclophosphamide and ifosfamide to their inactive keto and carboxy metabolites by aldehyde dehydrogenase.

TOXICITIES OF ALKYLATING AGENTS

Bone Marrow Toxicity-Acute myelosuppression, Busulfan suppresses all blood elements, particularly stem cells, and may produce a prolonged and cumulative myelosuppression lasting months or even years. Both cellular and humoral immunity are suppressed by alkylating agents, which have been used to treat various autoimmune diseases. Immunosuppression is reversible at doses used in most anticancer protocols.

Mucosal Toxicity-Alkylating agents are highly toxic to dividing mucosal cells, leading to oral mucosal ulceration and intestinal denudation. The mucosal effects are significant in high-dose chemotherapy protocols associated with bone marrow reconstitution, as they predispose to bacterial sepsis arising from the gastrointestinal tract.

Neurotoxicity-CNS toxicity manifest in form of nausea and vomiting, after I.V. administration of nitrogen mustard or BCNU. Ifosfamide is most neurotoxic of this class of agents, producing altered mental status, coma, generalized seizures, and cerebellar ataxia.

Other Organ Toxicities-While mucosal and bone marrow toxicities occur predictably and acutely with conventional doses of these drugs, other organ toxicities may occur after prolonged or high-dose use; these effects can appear after months or years, and may be irreversible and even lethal. All alkylating agents have caused pulmonary fibrosis. Finally, all alkylating agents have toxic effects on the male and female reproductive systems, causing an often permanent amenorrhea, particularly in perimenopausal women, and irreversible azoospermia in men.

Leukemogenesis-Acute nonlymphocytic leukemia, in patients treated on regimens containing alkylating drugs. It is often preceded by a period of neutropenia or anemia, and bone marrow morphology consistent with myelodysplasia.

Hair Follicle Toxicity-Anticancer drugs damage hair follicles and produce partial or complete alopecia. Patients should be warned of this reaction, if paclitaxel, cyclophosphamide, doxorubicin, vincristine, methotrexate, or dactinomycin is used. Hair usually regrows normally after completion of chemotherapy.

Therapeutic Uses.

Mechlorethamine HCl used primarily in combination chemotherapy regimen MOPP (mechlorethamine, vincristine [ONCOVIN], procarbazine, and prednisone) in patients with Hodgkin's disease. It is also used topically for treatment of cutaneous T-cell lymphoma as a solution that is rapidly mixed and applied to affected areas of skin.

Cyclophosphamide is administered orally or intravenously. It is employed in treatment of breast cancer and lymphomas. The clinical spectrum of activity is very broad. It is an essential component of many effective drug combinations for non-Hodgkin's lymphomas, ovarian cancers, and solid tumors in children. Because of its potent immunosuppressive properties, it is used to prevent organ rejection after transplantation.

Ifosfamide is approved for use in combination for germ cell testicular cancer and used to treat pediatric and adult sarcomas.

Melphalan for multiple myeloma is used, in combination with other agents. Melphalan also may be used in myeloablative regimens followed by bone marrow or peripheral blood stem cell reconstitution.

Chlorambucil In treating chronic lymphocytic leukemia (CLL), it is a standard agent for patients with chronic lymphocytic leukemia and primary (Waldenstrom's) macroglobulinemia, and may be used for follicular lymphoma.

Therapeutic uses and adverse effects of streptomycin

a.       Bacterial Endocarditis-Streptomycin and penicillin in combination are synergistically bactericidal in vitro and in animal models of infection against strains of enterococci, group D streptococci, and the various oral streptococci of the viridans group. A combination of penicillin G and streptomycin may be indicated for treatment of streptococcal endocarditis.

b.      Tularemia-Streptomycin (or gentamicin) is drug of choice

c.       Plague- Streptomycin is effective agent for the treatment of all forms of plague.

d.      Tuberculosis-streptomycin always should be used in combination with at least one or two other drugs to which the causative strain is susceptible.

Adverse Reactions

a.       Fever, skin rashes, and other allergic manifestations. This occurs most frequently with prolonged contact with the drug either in patients who receive a prolonged course of treatment (eg, for tuberculosis) or in medical personnel who handle the drug.

b.      Ototoxicity and nephrotoxicity are the major concerns during administration of streptomycin and other aminoglycosides.

c.       Most serious toxic effect with streptomycin is disturbance of vestibular function—vertigo and loss of balance. The frequency and severity of this disturbance are in proportion to the age of the patient, the blood levels of the drug, and the duration of administration. Vestibular dysfunction may follow a few weeks of unusually high blood levels or months of relatively low blood levels. Vestibular toxicity tends to be irreversible.

d.      Streptomycin given during pregnancy can cause deafness in the newborn and therefore is relatively contraindicated.

Antifungal antibiotics

Classification

a.       Drugs for subcutaneous and systemic mycoses-amphoterecin B, caspfungin, fluconazole, flucystosine, itraconazole, ketoconazole, vorcmazole

b.      Drugs for cutaneous mycoses Ex-butaconazole, clotrimazole, griseofulvin, nystatin, miconazole, terbinafine

Griseofulvin

Antifungal activity: it acts by inhibition of hyphal cell wall synthesis, effects on nucleic acid synthesis, and inhibition of mitosis. Griseofulvin interferes with microtubules of mitotic spindle and with cytoplasmic microtubules. The destruction of cytoplasmic microtubules may result in impaired processing of newly synthesized cell wall constituents at the growing tips of hyphae. Griseofulvin is active only against growing cells.

Griseofulvin is most effective in treating tinea infections of the scalp and glabrous (nonhairy) skin. Dermatophyte infections of the nails respond only to prolonged administration of griseofulvin. Fingernails may respond to 6 months of therapy, whereas toenails are quite recalcitrant to treatment and may require 8–18 months of therapy; relapse almost invariably occurs.

Adverse effects: Headache,nausea, vomiting, diarrhea, photosensitivity, peripheral neuritis, and occasionally mental confusion. Griseofulvin is derived from a penicillium mold, and cross-sensitivity with penicillin may occur.

It is contraindicated in patients with porphyria or hepatic failure or those who have hypersensitivity reactions to it in the past. Its safety in pregnant patients has not been established. Leukopenia and proteinuria have occasionally been reported. Coumarin anticoagulant activity may be altered by griseofulvin, and anticoagulant dosage may require adjustment.

Cephalosporins

CEPHALOSPORINS: Ex-Cefaclor, Cefadroxil, Cefamandole, Cefazolin, Cefdinir, Cefepime, Cefixime, Cefmetazole, Cefonicid, Cefoperazone, Cefotaxime, Cefotetan, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cephalexin, Cephapirin,  and Cephradine

Mechanism of Action: Cephalosporins and cephamycins inhibit bacterial cell wall synthesis in a manner similar to that of penicillin.

The final reaction in bacterial cell wall synthesis is a cross-linking of adjacent peptidoglycan strands by a transpeptidation reaction. In this reaction, bacterial transpeptidases cleave terminal D-alanine from a pentapeptide on one peptidoglycan strand and then cross-link it with pentapeptide of another peptidoglycan strand. The cross-linked peptidoglycan (murein) strands give structural integrity to cell walls and permit bacteria to survive environments that do not match organism’s internal osmotic pressure.

The beta-lactam antibiotics structurally resemble terminal D-alanyl-D-alanine (D-Ala-D-Ala) in pentapeptides on peptidoglycan. Bacterial transpeptidases covalently bind beta-lactam antibiotics at enzyme active site, and resultant acyl enzyme molecule is stable and inactive. The intact beta-lactam ring is required for antibiotic action. The beta- lactam ring modifies active serine site on transpeptidases and blocks further enzyme function. In addition to transpeptidases, other penicillin-binding proteins (PBPs) function as transglycosylases and carboxypeptidases. All PBPs are involved with assembly, maintenance, or regulation of peptidoglycan cell wall synthesis. When beta-lactam antibiotics inactivate PBPs, the consequence to bacterium is structurally weakened cell wall, aberrant morphological form, cell lysis, and death.Penicillins and cephalosporins kill bacterial cells only when they are actively growing and synthesizing cell wall.

Therapeutic Uses

a.       The first-generation cephalosporins are excellent agents for skin and soft tissue infections owing to S. aureus and S. pyogenes. A single dose of cefazolin just before surgery is preferred prophylaxis for procedures in which skin flora are likely pathogens.

b.      The oral second-generation cephalosporins can be used to treat respiratory tract infections, for treatment of penicillin-resistant S. pneumoniae pneumonia and otitis media. In situations such as intra-abdominal infections, pelvic inflammatory disease, and diabetic foot infection, cefoxitin and cefotetan both are effective.

c.       The third-generation cephalosporins, is drug of choice for serious infections caused by Klebsiella, Enterobacter, Proteus, Providencia, Serratia, and Haemophilus spp. Cefotaxime or ceftriaxone are used for initial treatment of gonorrhea and meningitis in nonimmunocompromised adults and children because of their antimicrobial activity, good penetration into CSF. They are drugs of choice for treatment of meningitis caused by H. influenzae, sensitive S. pneumoniae, N. meningitidis, and gram-negative enteric bacteria. The antimicrobial spectrum of cefotaxime and ceftriaxone is excellent for treatment of community-acquired pneumonia, i.e., caused by pneumococci, H. influenzae, or S. aureus.

d.      The fourth-generation cephalosporins are indicated for empirical treatment of nosocomial infections where antibiotic resistance owing to extended-spectrum b-lactamases. For example, cefepime has superior activity against nosocomial isolates of Enterobacter, Citrobacter, and Serratia spp.

Chloramphenicol- mechanism of action and adverse effects.

Mechanism of Action

Resistance due to changes in ribosome binding site results in a decreased affinity for drug, decreased permeability, and plasmids that code for enzymes that degrade the antibiotic. The drug-induced inhibition of mitochondrial protein synthesis is probably responsible for associated toxicity.

Adverse Reactions

a.       Gastrointestinal Disturbances-Adults occasionally develop nausea, vomiting, and diarrhea. This is rare in children. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora.

b.      Bone Marrow Disturbances-Chloramphenicol causes a dose-related reversible suppression of red cell production. Aplastic anemia, a rare consequence of chloramphenicol administration by any route, is an idiosyncratic reaction unrelated to dose, although it occurs more frequently with prolonged use. It tends to be irreversible and can be fatal.

c.       Toxicity for Newborn Infants-Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse. To avoid this toxic effect, chloramphenicol should be used with caution in infants and the dosage limited to 50 mg/kg/d or less.

d.      Interaction with Other DrugsChloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides.

Macrolids uses

Antibiotics in this group include erythromycin, clarithromycin, azithromycin, and oleandomycin.

Macrolids are used in treatment of Mycoplasma pneumoniae infections, eradication of Corynebacterium diphtheriae from pharyngeal carriers, the early preparoxysmal stage of pertussis, chlamydial infections, and recently, treatment of Legionnaires’ disease, Campylobacter enteritis, and chlamydial conjunctivitis, and prevention of secondary pneumonia in neonates.

Erythromycin is effective in treatment and prevention of S. pyogenes and other streptococcal infections, but not those caused by the more resistant fecal streptococci. It is a second-line drug for treatment of gonorrhea and syphilis. Although erythromycin is popular for treatment of middle ear and sinus infections, including H. influenzae, possible erythromycin-resistant S. pneumonia is a concern.

Antiviral

Three basic approaches are used to control viral diseases:

a.       Vaccination is used successfully to prevent measles, rubella, mumps, poliomyelitis, yellow fever, smallpox, chickenpox, and hepatitis B.

b.      The chemotherapy of viral infections may involve interference with any or all of the steps in the viral replication cycle and

c.       Stimulation of host resistance is least used of antiviral intervention strategies.

Classification

1.      Antiherpes virus-idoxuridine, acyclovir, valocyclovir, famcicyclovir, ganciclovir, foscarnet,

2.      Antiretrovirus

a.       Nucleoside reverse transcriptase inhibitors-zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir

b.      Non-Nucleoside reverse transcriptase inhibitors-Nevirapin,e Efavirenz, delavirdine,

c.       Protease inhibitors-ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, lopinavir

d.      Fusion inhibitor-enfuvirtide

3.      Anti-influenza virus-amantadine, rimantadine

4.      For Hepatic viral infections-Adefovir, Entecavir, interferon, lamivudine

Acyclovir

Acyclovir is an acyclic guanosine derivative with clinical activity against HSV-1, HSV-2, and VZV. In vitro activity against Epstein-Barr virus, cytomegalovirus, and human herpesvirus-6 is present but comparatively weaker.

Mechanism of Action: Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by the virus-specified thymidine kinase and then to the di- and triphosphate compounds by the host's cellular enzymes. Because it requires viral kinase for initial phosphorylation, is selectively activated and accumulates only in infected cells.

Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: competitive inhibition with deoxy GTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex; and chain termination following incorporation into the viral DNA.

Clinical Uses

a.       Oral acyclovir has multiple uses i.e., in primary genital herpes, shortens duration of symptoms, the time of viral shedding, and the time to resolution of lesions; in recurrent genital herpes.

b.      Long-term chronic suppression of genital herpes with oral acyclovir decreases the frequency both of symptomatic recurrences and of asymptomatic viral shedding in patients with frequent recurrences, thus decreasing sexual transmission.

c.       Oral acyclovir decreases the total number of lesions and duration of varicella and cutaneous zoster. However, because VZV is less susceptible to acyclovir than HSV, higher doses are required.

Roxithromycin

It is semi-synthetic long acting acid-stable macrolide whose antimicrobial spectrum resembles that of erythromycin. It is more potent against Branh-Catarahalis, Gard. Vaginalis, and Legionella, but, less potent against B.pertussis. Good enteral absorption and tissue penetration, plasma t_1/2 is 12 hrs. It is an alternative to erythromycin for respiratory, ENT, skin, and soft tissue and geital tract infections with similar efficacy.

Clavulanic acid

Clavulanic acid is produced by Streptomyces clavuligerus. These substances resemble beta-lactam molecules, but they have very weak antibacterial action. They are potent inhibitors of many but not all bacterial β-lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes.

β-Lactamase inhibitors are most active against Ambler class A β-lactamases such as those produced by staphylococci, H influenzae, N gonorrhoeae, salmonella, shigella, E coli, and K pneumoniae. They are not good inhibitors of class C b-lactamases, which typically are chromosomally encoded and inducible, produced by enterobacter, citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal b-lactamases of bacteroides and branhamella.

Ampicillin

This drug is the prototype of the group.

Pharmacological Properties Ampicillin is stable in acid and is well absorbed after oral administration. Intake of food prior to ingestion of ampicillin diminishes absorption. Half-life is 80 minutes. Severe renal impairment markedly prolongs the persistence of ampicillin in the plasma. Peritoneal dialysis is ineffective in removing the drug from the blood, but hemodialysis removes 40% of body store in 7 hours. Adjustment of the dose is required in renal dysfunction. Ampicillin appears in the bile, undergoes enterohepatic circulation, and is excreted in feces.

Therapeutic Indications

a.      Upper Respiratory Infections. Ampicillin is active against S. pyogenes and many strains of S. pneumoniae and H. influenzae, which are major upper respiratory bacterial pathogens.

b.      Urinary Tract Infections caused by Enterobacteriaceae, and E. coli is the most common species; ampicillin often is an effective agent, although resistance is increasingly common. Enterococcal urinary tract infections are treated effectively with ampicillin alone.

c.       Meningitis. Acute bacterial meningitis in children is due to S. pneumoniae or N. meningitidis. Since 20% to 30% of strains of S. pneumoniae now may be resistant to this antibiotic, ampicillin is not indicated for single-agent treatment of meningitis.

d.      Salmonella Infections Disease associated with bacteremia, disease with metastatic foci, and the enteric fever syndrome respond favorably to antibiotics.

Norfloxacin

It is derivative of fluoroquinolones, they are active against a variety of gram-positive and gram-negative bacteria. Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.

Clinical Uses

a.       Fluoroquinolones are effective in urinary tract infections even when caused by multidrug-resistant bacteria, eg, pseudomonas.

b.      It is also effective for bacterial diarrhea caused by shigella, salmonella, toxigenic E coli, and campylobacter.

c.       Fluoroquinolones (except norfloxacin) have been used in infections of soft tissues, bones, and joints and in intra-abdominal and respiratory tract infections, including those caused by multidrug-resistant organisms such as pseudomonas and enterobacter.

Adverse Effects

a.       Nausea, vomiting, and diarrhea.

b.      Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests develop.

c.       Photosensitivity has been reported.

d.      Fluoroquinolones may damage growing cartilage and cause an arthropathy. Thus, these drugs are not routinely recommended for patients under 18 years of age.

e.       Tendinitis, a rare complication that has been reported in adults, is potentially more serious because of the risk of tendon rupture. They should be avoided during pregnancy in the absence of specific data documenting their safety.

Betalactamase inhibitors

Betalactamase inhibitors - These substances resemble β-lactam molecules, but themselves have very weak antibacterial action. They are potent inhibitors of many but not all bacterial lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes.β-Lactamase inhibitors are most active against Ambler class A lactamases such as those produced by staphylococci, H influenzae, N gonorrhoeae, salmonella, shigella, E coli, and K pneumoniae. They are not good inhibitors of class C b-lactamases, which typically are chromosomally encoded and inducible, produced by enterobacter, citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal lactamases of legionella, bacteroides, and branhamella.

Ex: Clavulanic Acid, Sulbactam, & Tazobactam

The three inhibitors differ slightly with respect to pharmacology, stability, potency, and activity, but these differences are of little therapeutic significance. β-Lactamase inhibitors are available only in fixed combinations with specific penicillins.

An inhibitor will extend the spectrum of penicillin provided that the inactivity of the penicillin is due to destruction by lactamase and that the inhibitor is active against the lactamase that is produced.

The indications for penicillin- beta-lactamase inhibitor combinations are empirical therapy for infections caused by pathogens in both immunocompromised and immunocompetent patients and treatment of mixed aerobic and anaerobic infections, such as intraabdominal infections.

Broad spectrum antibiotics

Chloramphenicol-used for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever. It is an alternative to beta-lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci.

Chloramphenicol is used topically in treatment of eye infections because of its broad spectrum and its penetration of ocular tissues and the aqueous humor. It is ineffective for chlamydial infections.

Tetracycline is a semisynthetic derivative of chlortetracycline. It displays broad-spectrum activity and are effective against both gram-positive and gram-negative bacteria, including Rickettsia, Coxiella, Mycoplasma, and Chlamydia spp.. Tetracycline resistance has increased among pneumococci and gonococci, which limits their use in the treatment of infections caused by these organisms

Amikacin

The spectrum of antimicrobial activity of amikacin is broadest of group. Because of its resistance to many of aminoglycoside-inactivating enzymes, it has special role in hospitals where gentamicin- and tobramycin-resistant microorganisms are prevalent. Amikacin is similar to kanamycin.

Therapeutic Usesof Amikacin

a.       It is preferred agent for initial treatment of serious nosocomial gram-negative bacillary infections in hospitals where resistance to gentamicin and tobramycin has become a significant problem.

b.      It is active against majority of aerobic gram-negative bacilli in community and the hospital. This includes most strains of Serratia, Proteus, and P. aeruginosa.

c.       It is active against nearly all strains of Klebsiella, Enterobacter, and E. coli that are resistant to gentamicin and tobramycin.

Untoward Effects: As with other aminoglycosides, amikacin causes ototoxicity and nephrotoxicity. Auditory deficits are produced most commonly.

Adverse effects of Penicillins

a.      The penicillins are remarkably nontoxic.

b.      Serious adverse effects are due to hypersensitivity. All penicillins are cross-sensitizing and cross-reacting.

c.       The antigenic determinants are degradation products of penicillins, particularly penicilloic acid and products of alkaline hydrolysis bound to host protein. The incidence of allergic reactions in small children is negligible.

d.      Allergic reactions include anaphylactic shock; serum sickness-type reactions (now rare—urticaria, fever, joint swelling, angioneurotic edema, intense pruritus, and respiratory embarrassment occurring 7–12 days after exposure); and a variety of skin rashes.

e.       Oral lesions, fever, interstitial nephritis, eosinophilia, hemolytic anemia and other hematologic disturbances, and vasculitis may also occur.

f.       Most patients allergic to penicillins can be treated with alternative drugs. If necessary, desensitization can be accomplished with gradually increasing doses of penicillin.

g.      In patients with renal failure, penicillin in high doses can cause seizures. Large doses given orally may lead to gastrointestinal upset, particularly nausea, vomiting, and diarrhea.

h.      Secondary infections such as vaginal candidiasis may occur.

Pyrimethamine

Antimalarial Action-Pyrimethamine act slowly against erythrocytic forms of susceptible strains of all four human malaria species.

Mechanism of Action-it selectively inhibits plasmodial dihydrofolate reductase, a key enzyme in pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in folate pathway, dihydropteroate synthase; combinations of inhibitors of these two enzymes provide synergistic activity.

Resistanceto folate antagonists and sulfonamides is common for P falciparum and less common for P vivax. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase.

Pharmacokinetics: Slowly but adequately absorbed from GIT. Reaches peak plasma levels 2–6 hours after an oral dose, is bound to plasma proteins, and has elimination half-life of t 3.5 days. Metabolized and excreted mainly by kidneys.

Clinical Uses

a.       Chemoprophylaxis with single folate antagonists is no longer recommended because of frequent resistance, but a number of agents are used in combination regimens.

b.      Pyrimethamine, in combination with sulfadiazine, is first-line therapy in treatment of toxoplasmosis, including acute infection, congenital infection, and disease in immunocompromised patients and high-dose therapy is required followed by chronic suppressive therapy.

c.       Treatment of Chloroquine-Resistant Falciparum Malari

d.      Presumptive Treatment of Falciparum Malari

e.       Pneumocystosis

Adverse Effects:Gastrointestinal symptoms, skin rashes, and itching are rare, mouth ulcers and alopecia.

Antiretrovirus drugs

Classification:

a.       Nucleoside reverse transcriptase inhibitors-zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir

b.      Non-Nucleoside reverse transcriptase inhibitors-Nevirapin,e Efavirenz, delavirdine,

c.       Protease inhibitors-ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, lopinavir

d.      Fusion inhibitor-enfuvirtide

Zidovudine

Zidovudine decreases rate of clinical disease progression and prolongs survival in HIV-infected individuals. Efficacy is demonstrated intreatment of HIV-associated dementia and thrombocytopenia. In pregnancy, a regimen of oral beginning between 14 and 34 weeks of gestation (100 mg five times a day), intravenous during labor (2 mg/kg over 1 hour, then 1 mg/kg/h by continuous infusion), and zidovudine syrup to neonate from birth through 6 weeks of age (2 mg/kg every 6 hours) has been shown to reduce rate of vertical (mother-to newborn) transmission of HIV.

Pharmacokinetics

Well absorbed from gut and distributed to most body tissues and fluids, including cerebrospinal fluid, drug levels are 60–65% in serum. Plasma protein binding is 35%, half-life averages 1 hour, and intracellular half-life of phosphorylated compound is 3.3 hours. Eliminated by renal excretion following glucuronidation in liver.

Adverse effect:

a.       Myelosuppression, resulting in anemia or neutropenia.

b.      Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy.

c.       Thrombocytopenia, hyperpigmentation of the nails, and myopathy.

d.      Very high doses can cause anxiety, confusion, and tremulousness.

Minocycline

Antibacterial Spectrum:The tetracyclines display broad-spectrum activity and are effective against both gram-positive and gram-negative bacteria, including Rickettsia, Coxiella, Mycoplasma, and Chlamydia spp.. Minocycline is more active and oxytetracycline and tetracycline are less active than other members of this group.

Absorption, Distribution, Metabolism, and Excretion

Absorbed from stomach and upper GIT. Absorption is improved with food. Distributed throughout body tissues and fluids in concentrations that reflects lipid solubility of each individual agent. Minocycline are lipid soluble Peak serum levels are reached approximately 2 hours, excreted primarily in feces

Clinical Uses

Minocycline is an effective alternative to rifampin for eradication of meningococci, including sulfonamideresistant strains, from the nasopharynx. However, the high incidence of dose-related vestibular side effects renders it less acceptable.

Adverse Effects

a.       Nausea, vomiting, epigastric burning, stomatitis, and glossitis,

b.      Intravenous injection can cause phlebitis.

c.       If given over long periods, it can result in negative nitrogen balance, which may lead to elevated blood urea nitrogen.

d.      Hepatotoxicity occurs but severe during pregnancy,

e.       When combination of uremia and increasing jaundice can be fatal. 

f.       Photosensitivity, observed as abnormal sunburn reaction,

Dapsone

Antibacterial Activity: Dapsone is bacteriostatic, but not bactericidal, for M. leprae. M. leprae may become resistant to drug during therapy.

Mechanism of action of sulfones is same as sulfonamides: they are competitive inhibitors of dihydropteroate synthase and prevent normal bacterial utilization of para-amino-benzoic acid. Both possess same range of antibacterial activity and both are antagonized by para-aminobenzoic acid.

Therapeutic Uses- Dapsone, combined with other antileprosy agents like rifampin and clofazimine, is used in treatment of both multibacillary and paucibacillary M. leprae infections. Dapsone is also used in treatment and prevention of Pneumocystis carinii pneumonia in AIDS patients who are allergic to or intolerant of trimethoprim–sulfamethoxazole.

Untoward Effects: The sulfones can produce nonhemolytic anemia, methemoglobinemia, and sometimes acute hemolytic anemia in persons with a glucose-6-phosphate dehydrogenasedeficiency.Within a few weeks of therapy somepatients may develop acute skin lesions described assulfone syndrome or dapsone dermatitis. Some rare sideeffects include fever, pruritus, paresthesia, reversibleneuropathy, and hepatotoxicity.

8-aminoquinolones

Primaquine is drug of choice for eradication of dormant liver forms of P vivax and P ovale. Primaquine phosphate is a synthetic 8-aminoquinoline.

Antimalarial Action:Primaquine is active against hepatic stages of all human malaria parasites. It is the only available agent active against dormant hypnozoite stages of P vivax and P ovale.It is also gametocidal against the four human malaria species. It acts against erythrocytic stage parasites, but this activity is too weak to play an important role. The mechanism is unknown.

Clinical Uses

a.       Therapy (Radical Cure) of Acute Vivax and Ovale Malaria

b.      Terminal Prophylaxis of Vivax and Ovale Malaria

c.       Chemoprophylaxis of Malaria

d.      Gametocidal Action

e.       Pneumocystis jiroveci Infection

Adverse Effects

a.       Nausea, epigastric pain, abdominal cramps, and headache, and these symptoms are more common with higher dosages and when drug is taken on empty stomach.

b.      More serious but rare adverse effects include leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias.

c.       Standard doses may cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects.

Clofazimines

Clofazimine is a phenazine dye that can be used as an alternative to dapsone. Its mechanism of action is unknown but may involve DNA binding.

Clofazimine is given to treat sulfone-resistant leprosy or to patients who are intolerant to sulfones. It also exerts an antiinflammatory effect and prevents erythema nodosum leprosum, which can interrupt treatment with dapsone and is advantage of clofazimine over other antileprosy drugs. Ulcerative lesions caused by Mycobacterium ulcerans respond well to clofazimine. It also has some activity against M. tuberculosis and can be used as last resort therapy for treatment of MDR tuberculosis.

Absorption from the gut is variable, excreted in feces. Stored in reticuloendothelial tissues and skin, and itscrystals can be seen inside phagocytic eticuloendothelial cells. It is slowly released, so that serum half-life may be 2 months.

Untoward effect is skin discoloration ranging from red-brown to nearly black. Gastrointestinal intolerance occurs occasionally.

Ornidazole

Antiparasitic and Antimicrobial Effects: The activity is similar to metronidazole, Metronidazole and related nitroimidazoles are active in vitro against a wide variety of anaerobic protozoal parasites and anaerobic. The compound is directly trichomonacidal. The drug also has potent amebicidal activity against E. histolytica. Trophozoites of G. lamblia are affected by metronidazole at concentrations of 1 to 50 mg/ml in vitro.

It manifests antibacterial activity against all anaerobic cocci and both anaerobic gram-negative bacilli, including Bacteroides spp., and anaerobic spore-forming gram-positive bacilli. Nonsporulating gram-positive bacilli often are resistant, as are aerobic and facultatively anaerobic bacteria.

Adverse Effects: Nausea, headache, dry mouth, or a metallic taste in mouth occurs commonly. Infrequent adverse effects include vomiting, diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria, dark urine, vertigo, paresthesias, and neutropenia. Taking the drug with meals lessens GI irritation, pancreatitis and severe CNS toxicity.

Clinical Uses

a.       Drug of choice in treatment of all tissue infections with E histolytica.

b.      Treatment of choice for giardiasis.

c.       Treatment of choice for Trichomoniasis

Ketoconazole

Ketoconazole was the first oral azole introduced into clinical use. It is distinguished from triazoles by its greater propensity to inhibit mammalian cytochrome P450 enzymes; that is, it is less selective for fungal P450 than newer azoles.

Mechanism of Action: The antifungal activity of azole drugs results from reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. The specificity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes. Imidazoles exhibit a lesser degree of specificity than triazoles, accounting for their higher incidence of drug interactions and side effects.

Clinical Use

The spectrum of action is broad, ranging from many candida species, Cryptococcus neoformans, the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes, and, in the case of itraconazole and voriconazole, even aspergillus infections. They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as Pseudallescheria boydii.

Adverse Effectsis minor gastrointestinal upset azoles are relatively nontoxic. All azoles have been reported to cause abnormalities in liver enzymes and, rarely, clinical hepatitis.

Erythromycin 

Antimicrobial Activity: Erythromycin is effective against gram-positive organisms, especially pneumococci, streptococci, staphylococci, and corynebacteria. Mycoplasma, legionella, Chlamydia trachomatis, C psittaci, C pneumoniae, helicobacter, listeria, and certain mycobacteria (Mycobacterium kansasii, M scrofulaceum) are also susceptible.

Gram-negative organisms such as Neisseria sp, Bordetella pertussis, Bartonella henselae, and B quintana, some rickettsia sp, Treponema pallidum, and campylobacter sp are susceptible. Haemophilus influenzae is less susceptible.

Clinical Uses

a.       It is drug of choice in corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma); in respiratory, neonatal, ocular, or genital chlamydial infections; and

b.      In treatment of community-acquired pneumonia because its spectrum of activity includes pneumococcus, mycoplasma, and legionella.

c.       It is also useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci (assuming that the isolate is susceptible), streptococci, or pneumococci.

d.      It has been recommended as prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease.

Adverse Reactions

Gastrointestinal EffectsAnorexia, nausea, vomiting, and diarrhea.

Liver Toxicitycan produce acute cholestatic hepatitis

Methicillin

It is highly penicillinase resistant but not acid resistant-must be injected. It is an inducer of penicillinase production. MRSA has emerged in many area, these are insensitive to all penicilinase resistant penicillins and to beta lactams.

Adverse effects: haematuria, albuminuria, and reversible intestinal nephritis.

Suprainfection

All individuals who receive therapeutic doses of antibiotics undergo alterations in normal microbial population of intestinal, upper respiratory and genitourinary tracts; as a result, some develop superinfection, defined as appearance of bacteriological and clinical evidence of a new infection during chemotherapy. This phenomenon is common and potentially very dangerous because microorganisms responsible for new infection can be drug-resistant strains of Enterobacteriaceae, Pseudomonas, and Candida or other fungi.

Superinfection (supra infection) is due to removal of inhibitory influence of the normal flora, which produces antibacterial substances and also presumably compete for essential nutrients. The broader the antibacterial spectrum and longer the period of antibiotic treatment, the greater is alteration in normal microflora, and greater is possibility that a single, typically drug-resistant microorganism will become predominant, invade the host, and produce infection. The most specific and narrowest spectrum antimicrobial agent should be chosen to treat infections whenever feasible.

Nalidixic acid

Nalidixic acid, the first antibacterial quinolone. It is not fluorinated and is excreted too rapidly to be useful for systemic infections.

Mechanism of action is same as that of fluoroquinolones; they are active against a variety of gram-positive and gram-negative bacteria.jjjQuinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.

These agents were useful only for treatment of urinary tract infections and rarely used now, having been made obsolete by more efficacious fluorinated quinolones.