ANTITUBERCULOSIS DRUGS
Outline

The Therapeutic Problem

Therapeutic Goals

• Prevention or prophylaxis
• Cure of clinical disease
• Prolonged therapy
• Combined therapy
• Compliance
• Development of drug resistance
• Cures, ideally, 95-100%

The Disease

• Mycobacterium tuberculosis
  • Cell wall -- high lipid (60% dry weight) content
  • Mycolic acid a major component
  • Slow growth
  • Survive within phagocytes
  • resistance to chemical disinfectants
• Atypical Mycobacteria

Members

• Isoniazid, (INH) [Dow-Isoniazid, Nydrazid]
• Rifampin [Rifadin, Rimactane]
• Rafabutin [Mycobutin] AMADE93, 1:33
• pyrazinamide (PZA)
• Capreomycin Sulfate [Capastat Sulfate]
• Cycloserine [Seromycin]
• Ethambutol Hydrochloride [Myambutol]
• Ethionamide [Trecator-SC]
• Streptomycin Sulfate

ISONIAZID [INH, NYDRAZID]

General comments

• Prophylaxis as single agent
• Cure -- ALWAYS in combination
  • Slows development of resistance

Chemistry / structure

• Resembles the B-vitamin, nicotinic acid
• Need supplementation with the vitamin during Rx

Antibacterial activity

• Bacteriostatic at most concentrations

Resistance

• Increasing
• Easy to create by culture techniques

Mechanism of action

• Inhibits mycolic acid synthesis

Pharmacokinetics

• IM and PO
• Well absorbed
• Widely distributed
  • intracellular
  • CSF
  • Necrotic material
• Elimination mainly acetylation
  • Bimodal distribution in human population
  • Fast and slow acetylators
  • Elimination half-life:
    • Fast = 70 min
    • Slow = 180 min
  • Fast/Slow = 50:50 Western countries (whites and blacks)
  • Fast/Slow = 90/10 Eskimos and Japanese
  • Slow dominant most Scandinavians, Jews, and North African Caucasians.

Adverse Effects

• Most notable -- peripheral neuritis
  • Supplement with pyridoxine
• Others - see reference

RIFAMPIN (Rifadin^R, Rimactane^R)

Source/Structure

• Macrocyclic antibiotic
• Streptomyces mediterranei

Antibacterial Spectrum

• M. tuberculosis
• cidal
• Broad spectrum of bacteria
• Many Gram(-)
• Many chlamydiae

Resistance

• Develops quickly
• Not use drug alone for TB or other bacteria

Mechanism of Action

• Binds to DNA-dependent RNA polymerase
• Inhibits initiation -- not elongation

Pharmacokinetics

• PO -- Well absorbed
• Broadly distributed -- even CSF
• Orange-red color stains tissues / secrections / urine
• Half-life of rifampin is 1.5 to 5 h and is increased by hepatic dysfunction.
• Autoinduction of metabolism
  • Half-life shortens 40% first 14 days of Rx
  • Hepatic microsomal induction

Adverse reactions

• Relatively safe
• Jaundice
  • rare if liver normal
  • Increases if chronic liver disease, old age, alcoholism
• Drug interaction
  • Hepatic microsomal induction
  • Shortens half-life of many drugs, eg.,
    • prednisone, digitoxin, quinidine, ketoconazole, propranolol, metoprolol, clofibrate, and sulfonylureas, oral contraceptives, and oral anticoagulants. It has precipitated methadone withdrawal.
• Redman syndrome
  • Marked overdosage
  • Severe liver damange
  • bright red urine, tears, saliva
  • skin resembles broiled lobster
• Other effects -- see reference

Recent applications

• Never used alone -- resistance development
• Tuberculosis
• Leprosy
• Fungi/yeasts -- additive or synergistic with amphotericin B
• Various bacterial infections, e.g., with a beta-lactam or vancomycin for staphylococcal endocarditis.

RIFABUTIN (Mycobutin^R)

• New -- resembles rifampicin
• Indication: prevention of disseminated MAC disease in advanced AIDS

REFERENCES

See Antileprosy drugs handout