Second-line anti-TB drugs

1. Second-line anti-TB drugs

2. Classes of antituberculosis drugs

3. Second-line Anti-TB Drugs • Weaker than first-line. • Cause adverse reactions. • Difficult for patient to tolerate • Should be taken for long periods • Very expensive. • Cure rates are much lower than of patients susceptible to the first-line drugs.

5. Drugs used in Egypt Ethionamide, Prothionamide PAS Cycloserine Ofloxacin Kanamycin

8. Storage; at room temperature (15–25 °C) in air-tight containers.

11. Drug inter-actions • 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.

12. Adverse effects Frequent:neurological and psychiatric disturbances, including headaches, irritability, sleep disturbances, aggression, and tremors, guminflammation, 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.

15. 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.

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

20. 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.

21. 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 (1–3%); 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.

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

24. KANAMYCIN (Km)DRUG CLASS: AMINOGLYCOSIDE • Bactericidal, inhibit protein synthesis; • Aminoglycosides are not metabolized in the liver, they are excreted unchanged in the urine.

25. In extr-acellularfluid, 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.

26. Preparation and dose • Kanamycin sulfate, sterile powder for intramuscular injection in sealed vials. • The optimal dose is 15 mg/kg body weight, usually 750 mg to 1 g given daily or 5–6 days per week, by deep intramuscular injection. • Rotation of injection sites avoids local discomfort. When necessary. • 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.

27. Storage: • Powder stable at room temperature (15–25 °C), diluted solution should be used the same day.

28. Oral absorption There is no significant oral absorption.

29. Adverse effects • Frequent: - Pain at injection site, renal failure (usually reversible). • Occasional: • vestibular and auditory damage – usually irreversible; genetic predisposition possible (check family for aminoglycosideototoxicity), • nephrotoxicity (dose-related to cumulative and peak concentrations, increased risk with renal insufficiency, often irreversible), • peripheral neuropathy, • rash.

34. Preparation and dose • Tablets (200, 300 or 400 mg). • Vials (10 ml) or flexible containers (50 and 100 ml) with aqueous or 5% dextrose IV solutions equivalent to 200 and 400 mg. • Usual dose: 400 mg twice daily.

35. Storage At room temperature (15–25 °C), in airtight containers protected from light.

36. Oral absorption

37. Distribution & CSF penetration • About 25% is bound to plasma proteins. Ofloxacin 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.

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

39. Drug interactions • 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.

40. Pregnancy & intolerance of fluoroquinolones.

41. Pain, swelling or tearing of a tendon or muscle or joint pain. • Rashes, hives, bruising or blistering, trouble breathing. • Diarrhea • Yellow skin or eyes. • Anxiety, confusion or dizziness.

42. P-AMINOSALICYLIC ACID (PAS)DRUG CLASS: SALICYLIC ACID; ANTI-FOLATE • Bacteriostatic, disrupts folic acid metabolism. • Excreted via glomerular filtration and tubular secretion.

43. Preparation and dose • 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 10–12 g daily in 2 divided doses. • Children: 200–300 mg/kg daily in 2–4 divided doses.

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

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

46. Distribution & CSF penetration Distributed in peritoneal fluid, pleural fluid, synovial fluid. Not well distributed in CSF (10–15%) and bile.

47. Adverse effects • Frequent: gastrointestinal intolerance (anorexia and diarrhoea); hypo-thyroidism (increased risk with concomitant use of ethionamide). • Occasional: hepatitis (0.3–0.5%); allergic reactions; thyroid enlargement; malabsorption syndrome; increased prothrombin time; fever. • Carefuluse in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

48. Drug interactions • 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.

49. Contraindications • Allergy to aspirin; • severe renal disease; • hypersensitivity to the drug.

50. 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