32.tuberculosis and leprosy

ANTITUBERCULAR DRUGS

• Tuberculosis is a chronic granulomatous disease caused by Mycobacterium tuberculosis

• A major health problem in developing countries

Aims of treatment

• To kill the dividing bacilli & to destroy the persisters in order to prevent relapse and ensure complete cure

To prevent development of drug resistance. To decrease transmission to others.

Drugs are combined to:• Delay the development of resistance• Reduce toxicity• Shorten the course of treatmentDuration of therapy: Depends on 1.Site of disease, 2.Bacillary load, 3.Severity of disease, 4.History of treatment and resistance.

Classification

1. First line antitubercular drugs (standard drugs)• Isoniazid (H)• Rifampicin (R)• Pyrazinamide (Z)• Ethambutol (E)• Streptomycin (S)

2. Second line antitubercular drugs (Reserve drugs)

• Amikacin• Para - aminosalicylic acid• Kanamycin• Cycloserine• Ethionamide• Thiacetazone• Ciprofloxacin, moxifloxacin, gatifloxacin• Clarithromycin, azithromycin• Rifabutin, rifapentine

Newer agents

First line antitubercular drugs (standard drugs)

ISONIAZID (Isonicotinic acid hydrazide, INH)

• Mechanism: inhibits the biosynthesis of mycolic acids, which are essential constituents of the mycobacterial cell wall

Adverse Reactions:• Hepatitis - loss of appetite, nausea, vomiting,

jaundice, and right upper quadrant pain • Peripheral neuropathy (deficiency of

pyridoxine )• Fever, skin rashes , arthralgia, GI disturbances• Psychosis, optic neuritis and rarely

convulsions

RIFAMPIN• Mechanism:

inhibits bacterial DNA-dependent

RNA polymerase

inhibits RNA synthesis

Adverse effects• Hepatitis• Flu-like syndrome – fever, chills, headache,

muscle & joint pain• GI disturbances• Skin rashes, itching, & flushing• Orange-red discoloration of body fluid

secretions such as urine, tears, saliva, sweat, sputum etc - patient to be informed

ETHAMBUTOLMechanism:• Inhibits arabinosyl transferases that are

involved in mycobacterial cell wall synthesis Adverse effects:• Optic neuritis: red -green color blindness• Hyperuricaemia• Skin rashes & joint pain

PYRAZINAMIDEMechanism:•Like INH, pyrazinamide inhibits mycolic acid biosynthesis but by a different mechanism.Adverse effects :•Dose-dependent hepatotoxicity•Hyperuricaemia•Anorexia, nausea, vomiting, fever and skin rashes

Streptomycin• It was the first effective drug developed for the

treatment of tuberculosis. • Is an aminoglycoside antibiotic• Adverse effects: ototoxicity, nephrotoxicity

and neuromuscular blockade

SECOND-LINE DRUGS

In case of resistance to first-line agentsIn case of failure of clinical response to

conventional therapy In case of serious treatment limiting adverse

drug reactions

Treatment of Tuberculosis:• WHO recommends the use of multidrug

therapy (MDT) for all cases of tuberculosis. The objectives of MDT are:– To make the patient non-infectious as early as

possible by rapidly killing the dividing bacilli by using 3-4 bactericidal drugs.

– To prevent the development of drug resistant bacilli.

– To prevent relapse by killing the persisters or dormant bacilli.

– To reduce the total duration of effective therapy.

Short Course Chemotherapy (SCC)Intensive phase: • Tuberculocidal drugs used• The main objective is to render the patient

non-contagious.2HRZE:

INH RifampinPyrazinamideEthambutol

Continuation phase: • This phase helps to eliminate persisters and

prevents relapse4HR:

INH Rifampin

Antileprotic drugs

Classification:

Sulfone – Dapsone Phenazine derivative – Clofazimine Antitubercular drugs – Rifampicin EthionamideOther antibiotics – Ofloxacin Minocycline Clarithromycin

DapsoneUse : antileprotic agent

Adverse effects: Haemolytic anemia & methaemoglobinaemia – G6PD deficiency cases Sulfone syndrome – fever, dermatitis, pruritus,

anemia lymphadenopathy & hepatitis GI disturbances, headache, itching Peripheral neuropathy

2. Rifampicin – used in multidrug regimens – kills most

of the bacilli

3. Clofazimine:MOA – binds to mycobacterial DNA - inhibits its template function – anti-inflammatory effect

Use : antileprotic agent

Adverse effects: Accumulates in tissues : red-to-brown

discoloration of the skin Pigmentation of the conjunctiva & cornea GI disturbances

Treatment of LeprosyPaucibacillary :- Dapsone:100mg dailyRifampin:600mg once a month-Supervised.Duration:- 6 months.

Multibacillary Leprosy:-Dapsone:- 100mg dailyRifampin:- 600mg once a month supervisedClofazimine:- 300mg once a month supervised,50 mg

daily.Duration:- 24 Months.