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TB Tuberculosis is a chronic granulomatous disease and a major health problem in developing countries. About 1/3rd of the world’s population is infected with Mycobact. tuberculosis. The increase in TB associated with HIV infection Emergence of ‘multidrug resistant’ (MDR) TB which now accounts for 15% of previously treated, and 3% of new TB cases worldwide, is threatening the whole future of current antitubercular chemotherapy. Anti-TB drugs First line drugs: 1. Isoniazid 2. Rifampicin 3. Pyrazinamide 4. Ethambutol 5. Streptomycin First line: These drugs have high antitubercular efficacy; are used routinely. Second line drugs: Para-aminosalicylic acid (PAS) Kanamycin Amikacin Ethionamide Prothionamide Fluoroquinolones (Ofloxacin , Levofloxacin, Moxifloxacin, Ciprofloxacin) Second line: These drugs have either low antitubercular efficacy or higher toxicity or both; are used as reserve drugs. Alternative grouping of antitubercular drugs Group I (high efficiency): Isoniazid, Rifampicin. Group II (average efficiency): Streptomycin, Kanamycin, Viomycin, Cycloserine, Ethambutol, Ethionamide, Protionamid, Pyrazinamide. Group III (low efficiency): PAS, thioacetazone. The highest activity against Mycobac. tuberculosis are isoniazid and rifampicin, so the strategy of modern chemotherapy for patients with new diagnosed tuberculosis are based on combinations of these drugs. The combination of isoniazid and rifampicin with other anti-TB drugs 1st line (pyrazinamide, streptomycin and ethambutol) can achieve cure most patients. 2nd line drugs(reserve), are used only for the treatment of multidrug resistant tuberculosis. Anti-TB drugs Isoniazid One of the most effective anti-TB drugs (1st line). Bactericidal effect on mycobacteria in the process of reproduction, bacteriostatic - in the resting stage. The most frequent ADR: neurotoxicity(paresthesias, numbness, mental disturbances, convulsions), hepatotoxicity Prophylactic use of pyridoxine Rifampicin st One of the most active anti-TB drugs (1 line). Bactericidal activity. The most frequent HP: hepatotoxicity. Can colour urine, sputum and saliva in red. Rifabutin nd Anti-TB drugs (2 line). The structure and properties similar to rifampicin. Differences: - more active against atypical mycobacteri; bioavailability does not depend on food intake; - can cause uveitis; - interacts with fewer drugs; - not applied to children up to 14 years Pyrazinamide anti-TB drugs (1st line), with an average efficiency. Weak bactericidal effect. Produce "sterilizing" effect. Low toxicity. The most frequent ADR: gastrointestinal ADRs Anti-TB drugs Ethambutol Anti-TB drugs (1st line), with an average efficiency. Bacteriostatic action. Low toxicity. Act only on fast multiplying bacilli. The most frequent ADR: gastro-intestinal and visual disturbances (visual control) PAS Anti-TB drugs (2nd line) with low efficiency. Bacteriostatic action. Average toxicity. Poorly tolerated due to frequent ADR – GIT Does not add the efficacy for more active drugs Only delays development of resistance Anti-TB drugs Streptomycin Because of need for i.m. injections and lower margin of safety (ototoxicity and nephrotoxicity) Streptomycin is used only as an alternative to or in addition to other 1st line anti- TB drugs. Use is restricted to a maximum of 2 months. It is thus also labelled as a ‘supplemental’ 1st line drug. Syphilis Syphilis A sexually transmitted infection caused by Treponema pallidum. The primary stage classically presents with a single chancre (a firm, painless, non-itchy skin ulceration) In secondary syphilis a diffuse rash which frequently involves the palms of the hands and soles of the feet occurs. There may also be sores in the mouth or vagina. In latent syphilis there are little to no symptoms which can last for years. In tertiary syphilis there are gummas (soft non-cancerous growths), neurological, or heart symptoms. It may also be transmitted from mother to baby during pregnancy or at birth, resulting in congenital syphilis. Syphilis has been known as "the great imitator" as it may cause symptoms similar to many other diseases. Treatment The first-choice treatment for syphilis remains a single dose of intramuscular benzathine penicillin G. Doxycycline and tetracycline are alternative choices for those allergic to penicillin; due to the risk of birth defects these are not recommended for pregnant women. Ceftriaxone, a third-generation cephalosporin antibiotic, may be as effective as penicillin-based treatment if a person is allergic. Anthelmintic Drugs Anthelmintics are drugs that either kill (vermicide) or expel (vermifuge) infesting helminths. Helminthiasis is prevalent globally (1/3rd of world’s population carriers them), but is more common in developing countries with poorer personal and environmental hygiene. Helminthiases Helminthiasis also known as worm infection, is any macroparasitic disease of humans in which a part of the body is infected with parasitic worms, known as helminths. Helminths are classified into: Tapeworms (Cestoda- Taenia solium,T. saginata, Diphyllobothrium) Flukes (Trematoda- Clonorchis sinensis and Fasciola hepatica) Roundworms-(Nematodes- ascarids (Ascaris), filarias, hookworms, pinworms (Enterobius) and whipworms (Trichuris trichiura)) Helminthiasis is rarely fatal, but is a major cause of chronic illness, malnutrition, and anemia as secondary effects. Anthelmintics or antihelminthics 1) Broad-spectrum benzimidazoles are the first line treatment of gastrointestinal parasites: Mebendazole -effective against roundworms Albendazole- effective against roundworms and tapeworms. 2) Pyrantel, Levamisole, Ivermectin are effective against adult and migrating larval stages of roundworms. 3) Praziquantel is the drug of choice for flatworms. 4) Artemisinins are proving to be candidates as drugs of choice for trematodiasis/Flukes Mebendazole It has produced nearly 100% cure rate/reduction in egg count in roundworms. The immobilizing and lethal action on worms Mechanism of action It binds to microtubular proteins of the parasite and inhibits its polymerization → It blocks glucose and other nutrients uptake in the parasite → the gradual immobilization and eventual death Adverse effects (well tolerated): Diarrhoea, nausea and abdominal pain Allergic reactions Albendazole It is effective first-line of treatment against: Flatworms Flukes/trematodes Tapeworm/cestodes Nematodes Other uses As an antiprotozoal agent, it may be used against giardiasis and microsporidiosis. Praziquantel is the drug of choice for flatworms infections Mechanism of action act by causing leakage of intracellular calcium from the membranes →contracture and paralysis. Selectivity of action on tapeworms and flukes. Adverse effects It tastes bitter: can produce nausea and abdominal pain. Headache, dizziness and sedation. Allergic reactions Pyrantel It was introduced in 1969 for pinworm infestation in children Efficacy against Ascaris, Enterobius and Ancylostoma is high and comparable to that of mebendazole. Mechanism of action Pyrantel causes activation of N-cholinergic receptors in the worms → persistent depolarization → slowly developing contracture and spastic paralysis. Cholinergic receptors in mammalian skeletal muscle have very low affinity for pyrantel. Adverse effects occasional g.i. symptoms, headache and dizziness Levamisole Active against many nematodes, but use is restricted to ascariasis and ancylostomiasis as a second line drug. Mechanism of action The ganglia in worms are stimulated causing tonic paralysis and expulsion of live worms. Levamisole is an immunomodulator as well: restores depressed T cell function. Adverse effects One or two doses used in helminthiasis are well tolerated. Nausea, abdominal pain, fatigue, drowsiness. Ivermectin Ivermectin is the drug of choice for single dose treatment of onchocerciasis and strongyloidosis. Ivermectin is also highly effective in cutaneous larva igrans and ascariasis Ivermectin is the only drug effective orally in scabies and pediculosis Mechanism of action It acts through a special type of glutamate gated Cl¯ channel found only in invertebrates. Such channels are not involved in the motor control of flukes and tapeworms which are unaffected by ivermectin →Nematodes develop tonic paralysis Side effects Pruritus, giddiness, nausea, abdominal pain, constipation, lethargy and transient ECG changes Antiprotozoal Drugs Protozoan infections are parasitic diseases caused by organisms formerly classified in the Kingdom Protozoa. Examples include Entamoeba histolytica, Plasmodium, Giardia lamblia, Trypanosoma, etc. ANTIAMOEBIC DRUGS CLASSIFICATION 1. Tissue amoebicides (a) For both intestinal and extraintestinal amoebiasis: Nitroimidazoles: Metronidazole, Tinidazole, Ornidazole Alkaloids: Emetine, Dehydroemetine (b) For extraintestinal amoebiasis only: Chloroquine 2. Luminal amoebicides (a) Amide : Diloxanide furoate, Nitazoxanide (b) 8-Hydroxyquinolines: Iodoquinol (c) Antibiotics: Tetracyclines, Paromomycin NITROIMIDAZOLES It has broad-spectrum cidal activity against anaerobic protozoa (Giardia lamblia, Trichomonas vaginalis, Entamoeba histolytica)+ Clostridium perfringens, Cl. difficile, Helicobacter pylori, Campylobacter, peptococci, spirochetes and anaerobic Streptococci are sensitive. Uses: Amoebiasis (first line drug for all forms of amoebic infection) Giardiasis Trichomonas vaginitis (It is the drug of choice) Anaerobic bacterial infections (They occur mostly after colorectal or pelvic surgery,appendicectomy, etc) Pseudomembranous enterocolitis (due to Cl.difficile) Helicobacter pylori gastritis/peptic ulcer Guinea worm infestation (the drug of choice) NITROIMIDAZOLES Adverse effects Side effects are frequent and unpleasant, but mostly nonserious. Anorexia, nausea, metallic taste and abdominal cramps, diarrhea Allergic reactions Prolonged administration may cause peripheral neuropathy and seizures Emetine, Dehydroemetine Alkaloids from Cephaelis ipecacuanha. Directly acting amoebicides—kills trophozoites but has no effect on cysts. It is highly efficacious in amoebic liver abscess also. Emetine cannot be given orally because it will be vomited out(due to CTZ stimulation and gastric irritation),. It is administered by s.c. or i.m. injection ADR: High systemic toxicity (nausea, vomiting, abdominal cramps, diarrhoea, weakness, stiffness of muscles, myositis, hypotension, ECG changes and myocarditis). Use now rarely used only in patients not tolerating metronidazole. Chloroquine Highly concentrated in liver. Therefore, it is used in hepatic amoebiasis only. It is employed only when metronidazole fails to clear the infection or is not tolerated. Diloxanide furoate FURAMIDE It is a highly effective luminal amoebicide which directly kills trophozoites responsible for production of cysts. Poor tissue amoebicidal action. However, a single course produces high (80%) cure rate in mild intestinal amoebiasis and in asymptomatic cyst passers. ADR: Flatulence, occasional nausea, itching and rarely urticaria. It is a preferred drug for mild intestinal/asymptomatic amoebiasis, and is given after or along with any tissue amoebicide to eradicate cysts. Combined use with metronidazole/tinidazole is quite popular. Some chronic cases require repeat courses for eradication. Nitazoxanide Nitazoxanide is the most effective drug for Cryptosporidium parvum infection (upto 88% cure), which causes diarrhoea, especially in children and AIDS patients. It is also indicated in giardiasis, and in amoebic dysentery as luminal amoebicide. Side effects: Abdominal pain, vomiting and headache Iodoquinol Are active against Entamoeba, Giardia, Trichomonas In intestinal amoebiasis as alternative to diloxanide furoate. Side effects: Nausea, transient loose and green stools, pruritus, Iodism (furunculosis, inflammation of mucous membranes) due to chronic iodine overload. Goiter may develop. Individuals sensitive to iodine may experience acute reaction with chills, fever, angioedema and cutaneous haemorrhages. Prolonged/repeated use more than 14 days can cause neuritis and optic damage (blindness). ANTIBIOTICS Tetracyclines direct inhibitory action on Entamoeba with a more efficacious luminal amoebicide Paromomycin It is an aminoglycoside antibiotic is active against many protozoa like Emtamoeba, Giardia, Cryptosporidium, Trichomonas, Leishmania Orally administered paromomycin acts only in the gut lumen. It is neither absorbed nor degraded in the ntestines, and is eliminated unchanged in the faeces. In India and Africa, parenteral (i.m.) paromomycin is being used in resistant Kala-azar Side effects: nausea, vomiting, abdominal cramps, diarrhoea DRUGS FOR GIARDIASIS Giardia lamblia is a flagellate protozoon which infects children and adults by oro-faecal contamination and mostly lives in the intestine. It causes acute watery short duration diarrhoea with foul smellling stools, gas and abdominal cramps. Metronidazole (drug of choice) Nitazoxanide Paromomycin DRUGS FOR TRICHOMONIASIS Trichomonas vaginalis is protozoon which causes vulvovaginitis. It is a common sexually transmitted disease affecting ~ 10% sexually active women. Drugs used orally Metronidazole (drug of choice) Additional intravaginal drugs Iodoquinol Povidone-iodine DRUGS FOR LEISHMANIASIS Visceral leishmaniasis (kala-azar) Leishmania donovani Is fatal unless treated Dermal leishmaniasis (oriental sore) L. braziliensis and L. tropica Not a life-threatening condition Amphotericin B (AMB) Miltefosine Local application of drugs: Sodium stibogluconate (or Sodium stibogluconate Meglumine antimonate—in French speaking countries) Paromomycin Paromomycin (15%) ointment Leishmaniasis is transmitted by the bite of the female sandfly phlebotomus Amphotericin B (AMB) Antifungal antibiotic The older and less expensive - with deoxycholate (AMB- DOC), The newer and very expensive - incorporated in liposomes (L-AMB). Presently, AMB is the drug with highest cure rate in kala-azar: 99% clinical cure High toxicity and need for prolonged hospitalization, monitoring and repeated slow i.v. infusions limit its application. AMB is the drug of choice in pregnant women and breast feeding mothers. AMB is also useful in mucocutaneous leishmaniasis. Miltefosine First orally active drug for kala-azar. Now is the 1st line treatment of VL A 4 week course of miltefosine has achieved >95% cure rate in India and 90% in Ethiopia. ADR: Anorexia, vomiting and diarrhoea Skin allergy rise in hepatic transaminases Reversible kidney dysfunction Teratogenic (It is contraindicated in pregnant women). Sodium stibogluconate (SSG) Antimony compound It has been the standard 1st line drug for VL in most parts of the world achieving > 90% cure rate, but is no longer effective because of extensive resistance. Adverse effects Nausea, vomiting, metallic taste, cough, pain abdomen, pain and stiffness of injected muscle, sterile abscesses Pancreatitis, liver and kidney damage, myelosuppression Q-T prolongation Used alone or in combination with paromomycin, SSG is still a 1st line drug in East Africa, Central Asia and South America. However, response is relatively poor