ANTIMYCOBACTERIAL DRUGS Prof. Dr. Ece Genç

LEARNING OUTCOMES Identify the characteristic pharmacodynamic and pharmacokinetic properties of izoniazid and rifampin List the typical adverse effects of antituberculosis and antileprosy drugs

ANTIMYCOBACTERIAL DRUGS First line of drugs:Alternative drugs: Isoniazid (INH)Amikacin RifampinCiprofloxacin EthambutolEthionamide Streptomycinp-Aminosalicylate Pyrazinamide

STRUCTURE OF MYCOBACTERIA CELL WALL >60% of the cell wall is lipid, 2- branched, 3-hydroxy fatty acids with chains mad e of C atoms. Difficult for drugs to penetrate. Efflux pumps in the cell membrane, another defence, ATP binding casette permeases comprise a full 2.5% of the genomeof MT.

NEVER USE A SINGLE DRUG THERAPY Isoniazid –rifampicin combination administered for 9 months will cure % of cases Addition of pyrazinamide for this combination for the first 2 months allows total duration to be reduced to 6 months Rifampin, ethambutol, pyrazinamide 6 mo

RIFAMPIN Rifampin is a semisynthetic derivative of rifamycin B→ streptomyces mediterranei Active in vitro against gram positive and gram negative cocci, some enteric bacteria, mycobacteria and clamydiae Resistant mutants are present at ~ 1 in 10 6 organisms B-esterases and cholinesterases remove the Rifabutin is equally effective as an antimycobacterial agent Preferred over rifampin in the treatment of tuberculosis or other mycobacterial infections in AIDS patients (cytochrome P450 substrates, protease inhibitors efavirenz)

MECHANISM Blocks beta unit of DNA dependent RNA polymerase of mycobacteria and other microorganisms Resistance develops rapidly, limits the wider use of the drug. It is acquired by a one step genetic mutation of the DNA-dependent RNA polymerase. One of every 10 7 to 10 8 tubercle bacilli, is resistant to the drug.

PK After oral administration rifamycins are absorbed to variable extents Food ↓ rifampin Cpmax by 1/3 Rifampin should be taken on an empty stomach Rifabutin absorption is not effected by food Drug is progressively deacetylated With repeated administration AUC ↓ Good penetration into many tissues, but not to CNS (P-glycoprotein) 30% xcreted in urine 60-65% in feces. Adjustment of dosage is not necessary in patients w impaired renal function.

Induces P450 enzymes such as CYP1A2, 2C9, 2C19, 3A4 and decreased half-life is observed HIV protease and non-nucleoside reverse transcriptase inhibitors, digitoxin, quinidine, ketoconazole, propranolol, verapamil, methadone, oral contraceptives, reduces plasma levels of phenytoin, warfarin, Thephilline, halothane, fluconazole, cyclosporin, corticosteroids, barbiturates and sulfonylureas.

UNDESIRABLE EFFECTS Generally well tolerated. Rash 0.8%, fever 0.5%, nausea and vomiting 1.5% Secretions (urine, sweat) turn orange-red. Hepatitis rarely is seen (especially in alcoholics or preexisting disease) if given < twice weekly flu like (rash, fever, nausea and vomiting) symptoms in 20% of patients. GI disturbances have occasionally required discontinuation of drug Strongly induces liver drug-metabolizing enzymes

ISONIAZID Isonicotinic acid hydrazide is a primary drug for tuberculosis. Is a prodrug activated by catalase- peroxidase (KatG) activity within susceptible cells Inhibits mycolic acid synthesis in wall of Mycobacterium tuberculosis.

PK PO. Readily absorbed-reduced w food-, widely distributed. N-acetylated, thus, slow acetylators have greater toxicity. Kidney excretion. 75% - 90% is excreted in the urine within 24h mostly as a metabolite Available as a pill elixir and for paranteral administration

METABOLIC STEPS IN INH Enoyl acyl carrier protein reductase ↓ synthesis of mycolic acid

INH CLEARANCE DUE TO NAT2 POLYMORPHISMS Fast acetylators are found in Inuit and Japanese Slow acetylators most Scandinavians, Jews, North African whites

RESISTANCE The most common mechanism is mutations in catalase-peroxidase that decrease the drug’s activity. Cross-resistance between isoniazid and other agents (except ethionamide) does not occur. Approximately one in 10 6 tubercule bacilli will be genetically resistant to isoniazid. Tuberculous cavities may contain as many as 10 7 to 10 9 microorganisms.

UNDESIRABLE EFFECTS Incidence of adverse effects estimated ~ 5.4%. Rash 2%, fever 1.2%, jaundine 0.6%, peripheral neuritis 0.2%. Peripheral neuropathies* (can be prevented by pretreating with pyridoxine – mg per day- in malnourished patients and those predisposed to neuropathy –elderly, pregnant, HIV infected, diabetics, alcoholics, uremics-), hepatitis, hepatotoxicity. Most commonly paresthesia of feet and hands.

UNDESIRABLE EFFECTS 2 Hypersensitivity to INH may result in fever, various skin eruptions, hepatitis, and rashes. Hematological reactions such as agranulocytosis, eosinophilia, thrombocytopenia, anemia can happen. INH may precipitate convulsions in patients w seizure disorders (if no history, incidence is rare).

UNDESIRABLE EFFECTS 3 Severe hepatic injury leading to death may occur. (Acetylhydrazine causes hepatic damage ) Rare >20 y of age. 0.3% 20-34y 1.2% 35-49y 2.3% >50y Patients receiving isoniazid should be carefully evaluated at monthly intervals for symptoms of hepatitis (anorexia, malaise, fatigue and jaundice Some prefer aspartate aminotransferase activity measurement at monthly intervals in high risk individuals Xs alcohol intake, history of liver disease). Elevation 5X normal is cause for drug discontinuation.

ETHAMBUTOL Inhibits mycolic acid synthesis in bacterial cell wall Effective against mycobacteria, no activity against any other genus

PK PO % of an orally administered dose is absorbed from the GI tract. Wide distribution. Reaches 50% concentration in CNS 80% of the ingested dose is excreted unchanged in the urine (in renal failure dose should be reduced) The rest is metabolized by alcohol dehydrogenase→aldehyde and aldehyde dehydrogenase→dicarboxylic acid

UNDESIRABLE EFFECTS Very few serious untoward reactions. Reversible optic neuritis. Initial red/green color blindness, then loss of central vision. Dose related and usually reversible. Patients must have ophthalmologic exam prior to treatment.

PYRAZINAMIDE It is converted to pyrazinoic acid,the active form (prodrug) pyrazinamidases Mechanism is unknown. Bactericidal Acting on intracellular organisms. Well absorbed orally,metabolized in liver excreted mainly through kidney

PK Well absorbed from the GI tract, widely distributed in body tissues including inmflamed meninges. Half life is 8-11 h. It is primarily xcreted by renal glomerular filtration. Hydrolyzed and hydroxylated before excretion.

Clinical uses Mycobacterial infections (TB) mainly in multidrug resistance cases. It is important in short –course (6 months) regimens with isoniazid and rifampicin. Prophylaxis of TB in combination with ciprofloxacin.

Adverse effects Hepatotoxic Hyperuricemia Nausea & vomiting Drug fever & skin rash

The multiplication of M. Tuberculosis is suppressed by ethionamide. It is a prodrog and activated by a mycobacterial redux system.

It is a secondary agent. To be used concurrently with other drugs only when therapy w primary agents is ineffective or contraindicated. Orally administered Anorexia, nausea, vomiting, gastric irritation, variety of neurologic symptoms. Pyridoxine relieves the neurologic symptoms.

DOSE REGIMENS

Mycobacterium tuberculosis readily develops resistance to single-drug therapy. Three or four drugs are used in the 'initial phase' for the first 2 months to rapidly reduce the bacterial population until bacterial sensitivities are known, when treatment is continued with two drugs for a further 6 months ('continuation phase') to achieve a cure. In some cases, more prolonged treatment may be necessary, especially for tuberculous meningitis or for resistant mycobacteria.

Ethambutol is not used for treatment of young children because of difficulty in monitoring for eye toxicity. Streptomycin is used in some countries in the initial phase of treatment. In countries that cannot afford rifampicin, thiacetazone is often used with isoniazid and initially streptomycin.

Compliance can be a major problem in the treatment of tuberculosis, and combination tablets are often used to maximise this. In developed countries, directly observed treatment (DOT) has been instituted to improve compliance. This can result in major improvements in eradication

WHAT IS DOTS Political commitment Microscopy services Drug supplies Surveillance and monitoring systems

DOTS Once patients with infectious TB (bacilli visible in sputum smear) have been identified using microscopy services health and community workers and trained volunteers observe and record patients swallowing the full course of the correct anti TB medicines. Treatment lasts 6-8 months.

DOTS DOTS produces cure rates of up to 95 percent even in the poorest countries. DOTS prevents new infections by curing infectious patients DOTS PREVENTS THE DEVELOPMENT OF MULTIDRUG RESISTANCE TB BY ENSURING THE FULL COURSE OF TREATMENT IS FOLLOWED. A six month of drugs for DOTS costs US 11 dollars per patients in some parts of the world. The world Bank has ranked the DOTS strategy as one of the most cost effective of all health interventions.

Streptomycin Life threating forms of TB ( meningitis, dissiminated disease). Resistant cases (Multidrug resistance tuberculosis at least to INH & rifampicin ). Amikacin can be used as alternative to streptomycin. Both active mainly against extracellular bacilli.

Ethionamide As isoniazid blocks synthesis of mycolic acid. Available only in oral form. Metabolized by the liver,excreted by kidney. It is poorly tolerated because of : -intense gastric irritation -neurologic symptoms -hepatotoxicity Used in TB & leprosy.

DRUGS USED IN LEPROSY DAPSONE Inhibits folate synthesis. Well absorbed orally,widely distributed N acetylated, N-oxidation via CYP2E1 Excreted into bile and reabsorbed in the intestine. Excreted in urine as acetylated. It is well tolerated.

DAPSON’S MODE OF ACTION

Clinical uses Tuberculoid leprosy. Lepromatous leprosy in combination with rifampin & clofazimine. To prevent & treat Pneumocystis pneumonia in AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii).

Adverse effects Haemolytic anaemia Methemoglobinemia Gastrointestinal intolerance Fever, pruritus, rashes.

Clofazimine It is a phenazine dye. Unknown mechanism of action,may be DNA binding. Antiinflammatory effect. Absorption from the gut is variable. Given orally, once daily. Excreted mainly in feces. Stored mainly in reticuloendothelial tissues and skin. Half-life 2 months. Delayed onset of action (6 weeks).