Dr A.P Kansal Professor and Head Cum DMS Dept. of Chest and Tuberculosis Govt. Medical College, Patiala.

Dr A.P Kansal Professor and Head Cum DMS Dept. of Chest and Tuberculosis Govt. Medical College, Patiala

Tuberculosis: It is an infection caused by Mycobacterium tuberculosis. They are acid fast bacilli. The chemotherapy of Mycobacterial infections is complicated because of: Limited information about mechanism of action of antimycobacterial drugs. They are notorious to develop resistance. The intracellular location of mycobacteria. The chronic nature of the disease. Patients compliance Anti-TB drugs are given as combination regimens for different durations.

Classes of antituberculosis drugs DRUGS (ABBREVIATION)GROUPING Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z) Group 1 First-line oral antituberculosis agents Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vi) Group 2 Injectable antituberculosis agents Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin (Lfx); Moxifloxacin (Mfx);a Gatifloxacin (Gfx)a Group 3 Fluoroquinolones Ethionamide (Eto); Protionamide (Pto); Cycloserine (Cs); Terizidone (Trd)a; P- aminosalicylic acid (PAS); Thioacetazone (Th)b Group 4 Oral bacteriostatic second-line antituberculosis agents Clofazimine (Cfz); Amoxicillin/Clavulanate (Amx/ Clv); Clarithromycin (Clr); Linezolid (Lzd) Group 5 Antituberculosis agents with unclear efficacy (not recommended by WHO for routine use in MDR-TB patients)

Anti-tuberculosis drugs can be divided into two major categories: base on their efficacies and toxicities -First-line drugs: good efficacy, cheap, less toxicity and being well tolerated to patients Isoniazid (INH), rifampicin, pyrazinamide, ethambutol, streptomycin. -Second-line drugs: usually used as alternatives to the first-line drug when drug resistance occurs or when a particular therapy is required. Para-aminosalicylic acid, kanamycin, amikacin, capreomycin, ciprofloxacin, ethionamide.

It is the most active drug for the treatment of tuberculosis After orally administered, well absorbed, widely distributed in body, including cerebrospinal fluid. INH can also penetrate into macrophages. Most INH is metabolized in the liver.

Probably related to the inhibition of synthesis of mycolic acids, which are important and characteristic components of mycobacterial cell wall. As a result of the activity, tubercle bacilli lose their features of acid-resistance, water-resistance and proliferating ability, leading to death.

It is bactericidal for actively growing tubercle bacilli. But, for resting tubercle bacilli, it is bacteriostatic. Isoniazid is able to penetrate into phagocytic cells and thus is active against both extracellular and intracellular organisms. This drug is not effective against atypical mycobacteria.

Isoniazid is the most widely used agent in the treatment and prophylaxis of tuberculosis. Isoniazid is usually given orally in dose of 5 mg/kg/d--- max.300 mg/d --- single dose in adults, in combination with other Anti T.B drugs

Allergic Reaction: fever, skin rash Hepatotoxicity : Up to 20% of patients taking INH develop elevated serum amino transferase levels. Severe hepatic injury occurs more frequently in patients over the age of 35, especially in those who drink alcohol daily. Isoniazid is discontinued if symptoms of hepatitis develop or if the aminotransferase activity increases to more than five times normal or s. bilirubin rises more than three times..

Peripheral and CNS toxicity occur. This toxicity probably results from an increased excretion of pyridoxine induced by isoniazid, which produces a pyridoxine deficiency. Peripheral neuritis, urinary retention, insomnia, and psychotic episodes can occur. Concurrent pyridoxine administration with INH prevents most of these complications.

Synthetic derivates of rifamycin B produced by Sterptomyces mediterranei oral administration, well absorbed, widely distributed in body, including sputum and tubercular cavities; adequate CSF concentrations are achieved only in the presence of meningeal inflammation. most of the drug is excreted as a deacylated metabolite in faeces and in the urine, half-life is about 4 hours.

Broad-spectrum It is active against Gram positive cocci (including drug resistant S.aureus), some bacteria, mycobacteria It is bactericidal for mycobacteria. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.

RFP binds strongly to the -subunit of DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Drug-resistance to Rifampicin, due to target mutations in RNA polymerase, occurs readily. No cross-resistance to other classes of antimicrobial drugs.

Against Mycobacterial infections It often uses in combination with other agents (Tuberculosis, rifampin) in order to prevent emergence of drug-resistant mycobacteria in a dose of 10mg/kg/day. Leprosy Other infections like Rifampin can be used in a variety of gram-positive coccal infections, especially the serious cases that cannot be effectively treated with other drugs. It is also used as prophylaxis for meningitis caused by highly penicillin-resistant strains of pneumococci.

1) Hepatitis 2)Haemolytic Syn: Purpura,Haemolysis,Shock &Renal failure 3)Exfoliative Dermatitis in H.I.V +ve 4)Oliguria and Haemolytic anemia 5)Flu like Syndrome If administered less than twice weekly, chills, myalgia,anemia, thrombocytopenia, sometimes acute tubular necrosis can occur.

Urine, sweat, tears, and contact lenses may take on an red colour because of rifampicin administration, this effect is harmless. Light-chain proteinuria and impaired antibody response may occur. Rifampin induces hepatic microsomal enzymes and therefore, affects the half-life of a number of drugs. 1. OCPill contraceptive failure,Estrogen to be / nonhormonal methods to accept 2. Oral anticoagulant 3. Oral hypoglycaemic drugs 4. Corticosteroid drugs 5. Antiarrythmic drugs -Digitoxin,Quinidine 6. Antiretroviral drugs PI &NNRTI except EFAVIRENZ 7. Antifungal Drugs Ketoconazole

Inhibits many strains of M. tuberculosis, bacteriostatic Well absorbed from the gut and widely distributed in all body tissues and fluids. As with all antituberculotic drugs, resistance to ethambutol emerges rapidly when the drug is used alone. Dose:- 15-25 mg/kg/day orally once daily. The most common serious adverse effect is dose related optic neuritis, causing loss of visual acuity and red- green color-blindness, but are reversible.

Pyrazinamide is a pyrazine analogue of nicotinamide. At neutral pH, it is inactive, but at pH 5.5 it inhibits tubercle bacilli and some other mycobacteria. Quickly absorbed after orally administered Widely distributed in body tissues,including inflamed meninges. Excreted mainly by glomerular filtration

It is used in combination with INH and RFP in multiagent short-term therapy in a dose of 25 mg /Kg/day to exert its activity against residual intracellular organisms that may cause relapse. Tubercle bacilli develop resistance to pyrazinamide fairly readily, but no cross resistance with other antimycobacterial drug. Liver damage is the most serious and common adverse reactions. Therefore, liver function studies should be performed before and during therapy. Hyperuricemia, Non- gouty poly arthralgia, Drug Fever. GIT upsets, nausea, vomiting. Should be avoided in pregnancy

Streptomycin is the first antimicrobial drug which was used to treat tuberculosis. It is effective against most tubercle bacilli, but its activity is weaker than that of INH and RFP. Streptomycin penetrates into cells poorly, and drug resistance is produced easily. Limitation of its use i)dose related toxicity ii)devlopment of resistant org. iii)pt compliance is poor due to i.m injections

Against Mycobacterium TB Infections: Used when an injectable drug is required in severe, life threatening form of infection: Disseminated Tuberculosis Tuberculous Meningitis Infections resistant to other drugs. Dose: 1 g / (15mg/kg/day) I/M or I/V daily. 20-40mg/kg/day for children-not to exceed 1-1.5 G/d. Given in combination with other drugs to delay / prevent emergence of resistance.

OTOTOXICITY - drugs get conc. in labrynthine fluid leading to both vestibular & cochlear damage NEPHROTOXICITY Neuromuscular paralysis. Sterile abscess at the inj. site Contra Indication: Not to be given in pregnancy Avoid use with other ototoxic drug eg;High ceiling diuretics,Minocycline,Cisplatin Avoid use of other nephrotoxic drug eg;Amphotericin B, Vancomycin,Cyclosporin,Cisplatin Pts with renal disease. Cautious use with muscle relaxant.

Weaker than first-line. Cause more adverse effects. Difficult for patient to tolerate Should be taken for long periods Very expensive. Cure rates are much lower.

Second line anti-TB drugs include:ThiacetazoneEthionamide, prothionamidePASCycloserineFluoroquinolonesAminoglycsidesPossible reinforcing drugs (Third line drugs)ClofazimineAmoxicilline-clavulanic acidClarithromycinRifabutine

CYCLOSERINE (Cs ) G CLASS: ANALOG OF D-ALANINE Bacteriostatic, 60-70 % excreted unchanged in urine via glomerular filtration; small amount excreted in faeces;small amount metabolized.No cross resistance with other anti-TB drugs

Capsules (250 mg). 1015 mg/kg daily (max. 1000 mg), Usually 500750 mg per day given in two divided doses. Forms and dosage:

Oral absorption Oral absorption: Modestly decreased by food (best to take on an empty stomach).

Widely distributed in tissues and body fluids with very good CSF penetration (80100% of serum concentration attained in the CSF, higher level with inflamed meninges) Distribution and CSF penetration:

Drug interactions Ethionamide: additive nervous system side- effects. Isoniazid: additive nervous system side-effects. Phenytoin: may increase phenytoin levels. Toxic effect if combined with alcohol, increases risk of seizures. Vitamin B6 decreases CNS effect.

Frequent: neurological and psychiatric disturbances, including headaches, irritability, sleep disturbances, aggression, and tremors, gum inflammation, pale skin, depression, confusion, dizziness, restlessness, anxiety, nightmares, severe headache, drowsiness. Occasional: Visual changes; skin rash; numbness, tingling or burning in hands and feet; jaundice; eye pain. Rare: seizures, suicidal thoughts.

Hypersensitivity to cycloserine.Epilepsy.Depression, severe anxiety or psychosis.Severe renal insufficiency.Excessive concurrent use of alcohol. Contra-indications:

Alerting symptoms: Seizures Shakiness or trouble talking Depression or thoughts of intentional self-harm Anxiety, confusion or loss of memory Personality changes, such as aggressive behaviour Rash Headache

ETHIONAMIDE (Eto), PROTIONAMIDE (Pto) DRUG CLASS: CARBOTHIONAMIDES GROUP, DERIVATIVES OF ISONICOTINIC ACID Bacteriostatic. complete cross-resistance between ethionamide and protionamide. Partial cross resistance with thiacetazone. Extensively metabolized, probably, in the liver. Less than 1% of the dosage excreted in urine unchanged.

Preparation and dosage: Tablets containing 125 mg or 250 mg of active drug. The maximum optimum daily dose is 1520 mg/kg/day (max. 1 g/day), usually 500750 mg.

Oral absorption: 100% absorbed but sometimes erratic absorption caused by gastrointestinal disturbances associated with the medication.

Distribution and CSF penetration: Rapidly and widely distributed into body tissues and fluids with significant concentrations also are present in CSF.

Adverse effects: Frequent: severe gastrointestinal intolerance (nausea, vomiting, diarrhoea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia and weight loss). Adverse gastrointestinal effects appear to be dose- related, with approximately 50% of patients unable to tolerate 1 g as a single dose. Gastrointestinal effects may be minimized by decreasing dosage, by changing the time of drug administration, or by the concurrent administration of an antiemetic agent.

Adverse effects, cont. Occasional : allergic reactions; psychotic disturbances (including depression), drowsiness, dizziness, restlessness, headache, and postural hypotension. Neurotoxicity (administration of pyridoxine has been recommended to prevent or relieve neurotoxic effects); Transient increases in serum bilirubin; reversible hepatitis (2%) with jaundice (13%); Gynaecomastia; menstrual irregularity, arthralgias, leukopenia, Hypothyroidism especially when combined with PAS. Rare: reports of peripheral neuritis, optic neuritis, diplopia, blurred vision, and a pellagra-like syndrome, reactions including rash, photosensitivity, thrombocytopenia and purpura.

Drug inter-actions: Cycloserine: potential increase incidence of neurotoxicity. Ethionamide temporarily raises serum concentrations of isoniazid. Thionamides may potentiate the adverse effects of other antituberculosis drugs administered concomitantly. In particular, convulsions have been reported when ethionamide is administered with cycloserine. Excessive ethanol ingestion should be avoided because of possible psychotic reaction. PAS: possible increase in liver toxicity, monitor liver enzymes;Hypothyroidism in case of combined administration.

Hypersensitivity to cycloserine. Epilepsy. Depression, severe anxiety or psychosis. Severe renal insufficiency. Excessive concurrent use of alcohol.

Bactericidal, inhibit protein synthesis; Aminoglycosides are not metabolized in the liver, they are excreted unchanged in the urine. Other drugs in this class are amikacin and capreomycin.

Distribution & CSF penetration: In extracellular fluid, abscesses, ascitic fluid, pericardial fluid, pleural fluid, synovial fluid, lymphatic fluid and peritoneal fluid. Not well distributed into bile, aqueous humour, bronchial secretions, sputum and CSF. Penetrates inflamed meninges only.

1. Kanamycin sulfate, sterile powder for intramuscular injection in sealed vials. 2. The optimal dose is 15 mg/kg body weight, usually 750 mg to 1 g given daily or 56 days per week, by deep intramuscular injection. 3. Rotation of injection sites avoids local discomfort. When necessary. 4. It is possible to give the drug at the same total dose 2 or 3 times weekly during the continuation phase, under close monitoring for adverse effects.

There is no significant oral absorption.

Frequent: - Pain at injection site, renal failure (usually reversible). Occasional: - Vestibular and auditory damage usually irreversible; genetic predisposition possible (check family for aminoglycoside ototoxicity), - Nephrotoxicity (dose-related to cumulative and peak concentrations, increased risk with renal insufficiency, often irreversible), - Peripheral neuropathy, - Rash.

Drug interactions: Co-administration of aminoglycosides with loop diuretics may have an additive or synergistic ototoxicity. possible enhanced action of non-depolarizing muscle relaxant resulting in possible respiratory depression. Nephrotoxic agents (amphotericin B, foscarnet, cidofovir): additive nephrotoxicity. Penicillins: in vitro inactivation (possible). Do not mix together before administration.

Contraindications Pregnancy (congenital deafness seen with streptomycin and kanamycin use in pregnancy). Hypersensitivity to aminoglycosides. Caution with renal, hepatic, vestibular or auditory impairment.

Alerting symptoms Problems with hearing; dizziness Rash Decreased urination Swelling, pain or redness at injection site Muscle twitching or weakness

Levofloxacin DRUG CLASS: FLUOROQUINOLONES Bactericidal: acts by inhibiting reproduction of bacterial DNA. There is no cross-resistance with other anti-tuberculosis agents, Levofloxacin is excreted largely as unchanged drug in the urine.

Tablets (500 and 750 mg). Also available as i/v, oral solution and drops Usual dose: 750 mg once daily.

9098% oral absorption Oral absorption

About 25% is bound to plasma proteins. levofloxacin is widely distributed in body fluids, including the CSF, and tissue penetration is good. It crosses the placenta and is distributed into breast milk. It also appears in the bile.

Generally well tolerated. Occasional : gastrointestinal intolerance; CNS-headache, malaise, insomnia, restlessness, and dizziness. Rare: allergic reactions; diarrhea; photosensitivity; increased LFTs; tendon rupture; peripheral neuropathy.

Fluoroquinolones inhibit hepatic drug metabolism and may interfere with the clearance of drugs such as theophylline and caffeine that are metabolized by the liver. Cations such as aluminium, magnesium or iron reduce the absorption of Ofloxacin and related drugs when given concomitantly. Changes in the pharmacokinetics of fluoroquinolones have been reported when given with histamine H2 antagonists, possibly due to changes in gastric pH, but do not seem to be of much clinical significance.

Contraindications Pregnancy & intolerance of fluoroquinolones.

Alerting symptoms 1. Pain, swelling or tearing of a tendon or muscle or joint pain. 2. Rashes, bruising or blistering, 3. Diarrhea 4. Yellow skin or eyes. 5. Anxiety, confusion or dizziness.

Bacteriostatic, disrupts folic acid metabolism. Excreted via glomerular filtration and tubular secretion.

Tablets, sugar-coated, containing sodium salt: sodium p-aminosalicylate, 0.5 g of PAS. Granules of PAS with an acid-resistant outer coating, rapidly dissolved in neutral media, 4 g per packet. 150 mg/kg or 1012 g daily in 2 divided doses. Children: 200300 mg/kg daily in 24 divided doses.

Packets should be kept in the refrigerator or freezer. Other formulations may not require refrigeration.

Incomplete absorption (usually 60 65%), sometimes requires increased doses to achieve therapeutic levels.

Distributed in peritoneal fluid, pleural fluid, synovial fluid. Not well distributed in CSF (1015%) and bile.

Frequent: gastrointestinal intolerance (anorexia and diarrhoea); hypo-thyroidism (increased risk with concomitant use of ethionamide). Occasional: hepatitis (0.30.5%); allergic reactions; thyroid enlargement; malabsorption syndrome; increased prothrombin time; fever. Careful use in patients with glucose-6- phosphate dehydrogenase (G6PD) deficiency.

Digoxin: possible decrease in digoxin absorption; monitor digoxin level may need to be increased. Ethionamide: possible increase in liver toxicity, monitor liver enzymes; hypothyroidism in case of combined administration. Isoniazid: decreased acetylation of isoniazid resulting in increased isoniazid level. Dose may need to be decreased.

Allergy to aspirin; severe renal disease; hypersensitivity to the drug.

Alerting symptoms Skin rash, severe itching, or hives Severe abdominal pain, nausea or vomiting Unusual tiredness or loss of appetite Black stools as a result of intestinal bleeding

Dr A.P Kansal Professor and Head Cum DMS Dept. of Chest and Tuberculosis Govt. Medical College, Patiala.

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