Anti Tuberculosis

Laboratorium Farmakologi dan Terapeutik Jurusan Kedokteran FKIK UNSOED

Classification of Drugs
3 Groups depending upon the degree of effectiveness and potential side effects First Line: (Primary agents)
are the most effective and have lowest toxicity.

Isoniazid, Rifampin

Second Line:
Less effective and more toxic effects include (in no particular order): p-amino salicylic

acid, Streptomycin, Ethambutol

Third Line
are least effective and most toxic. Amikacin,

Kanamycin, Capreomycin, Viomycin, Kanamycin, Cycloserine

Primary agents Isoniazid Rifampin Pyrazinamide 300 mg/d 600 mg/d 25 mg/kg/d

Ethambutol
Streptomycin Secondary agents

1525 mg/kg/d
15 mg/kg/d

Amikacin
Aminosalicylic acid Capreomycin Ciprofloxacin Clofazimine Cycloserine Ethionamide Levofloxacin Rifabutin

15 mg/kg/d
812 g/d 15 mg/kg/d 1500 mg/d, divided 200 mg/d 5001000 mg/d, divided 500750 mg/d 500 mg/d 300 mg/d2

Rifapentine

600 mg once or twice weekly

Recommended Duration of Therapy for Tuberculosis.

Regimen (in Approximate Order of Preference)

Isoniazid, rifampin, pyrazinamide Isoniazid, rifampin Rifampin, ethambutol, pyrazinamide Rifampin, ethambutol Isoniazid, ethambutol

Duration in Months
6 9 6 12 18

All others

24

Isoniazid
Considered the drug of choice for the chemotherapy of TB.

is bacteriostatic for resting bacilli, bactericidal for growing bacilli.

Mechanism of action
Unknown, but the hypothesis include effects on lipids, nucleic acid and biosynthesis. Primary action seems to inhibit the biosynthesis of mycolic acids which are part of cell wall structure.

Resistance
Organism eventually develops resistance. The mechanism of resistance is related to the failure of the drug to penetrate or be taken up by the micro-organism (by active transport system),
Remember treatment is up to 2 years.

Pharmacokinetics
Absorption: INH rapidly absorbed either oral or parenteral route. Distribution:

Diffuses readily into all bodily fluids does not bind to plasma proteins In the CSF the [conc] is about 20% of [plasma], t1/2 =1-3 hrs.

Excretion
75-95% of a dose excreted in the urine in 24 hr. - Mostly as a metabolite. - The main excretory product- acetylisoniazid. This is a result of enzymatic acetylation Very important in terms of metabolism, Isoniazid is under genetic control, There are 2 groups of people. Fast and slow acetylators

Excretion cont.
Those that have slow acetyl transferase activity are slow acetylators, may produce more of the toxic intermediate. ==> Autosomal Dominant Ethnicity- Eskimos,Native American Indians, and Asians are fast aceytlators,

Adverse Effects
Induced Hepatitis (2% of Population) due to the buildup of toxic metabolic products of acetylisoniazid --> acetylhydrazine. This is more frequent in slow acetylators. Hepatic reactions to Isoniazid are also age dependent

Patients with renal failure, the normal dose can be given, because it is secreted in the inactive form. Patients with hepatic insufficiency - give a reduced dose of the drug. Glucose 6- Phosphate deficiency. People with a deficiency of Glucose-6-phosphate cannot adequately process the drug.

Drug Interaction
Competition between Isoniazid and Phenytoin (anticonvulsant). They both compete for drug metabolism enzymes. Phenytoin interferes with metabolism of isoniazid by reduction in excretion or enhancement of effect of isoniazid

Rifampin
Mechanism of Action Rifampin inhibits DNA dependent RNA polymerase of the bacilli.

Resistance:
Due to alteration of the target (DNA dependent RNA polymerase) of the drug, prevents further initiation but not elongation. The micro-organism can change the structure of the enzyme so that the drug no longer has an effect.

Pharmacokinetics
Absorption
peak levels reached 2-4 hrs. after oral dose rapidly eliminated in the bile and reabsorbed (enterohepatic circulation) It can be delayed with use of aminosalicylic acid. during this time there is a progressive deacylation of the drug; the metabolites maintain full effect Half life is 6 hours.

Distribution: Throughout the total body water Present in effective concentrations in many organs and body fluids including CSF, With Rifampin you must warn patients: The drug has an orange red color in body excretions, This color will be imparted to all body fluids.

Adverse Effects:
Does not cause many side effects in any great frequency. G.I. reactions: Anorexia, Nausea ,Vomiting Mild abdominal pain, Hepatic Reactions in children, pregnant women and alcoholics, can result in minor elevations in serum transaminase as some jaundice

Allergic Reactions Fever Skin Eruptions Rash Pruritis Rifampin does induce microsomal drug metabolizing enzymes. This will decrease the half-life of some other drugs. (ie. phenytoin, digitoxin)

WARNING!
Rifampin and Isoniazid are the most effective drugs for the treatment of TB, The drug enjoys high patient compliance and acceptability. But these 2 drugs should never be given alone!

They are always used in combination because resistance occurs to one drug alone very rapidly.
Prophylaxis is with one drug usually isoniazid.

2nd Line Drugs: Not as effective and have more toxicity

Streptomycin The first drug used clinically for treatment of TB 1947-1952; was the only drug available at that time. is an aminoglycoside antibiotic acts by protein synthesis inhibitor and decreases the fidelity mRNA and garbles the message, leads to nonsense proteins. Streptomycin only binds to the 30s subunit.

Adverse Effects: affects C. Nerve 8: auditory and vestibular functions. - this drug is now 2nd 'line because of its toxicity. Nephrotoxicity, ototxicity,tinnitus, vertigo Can cause fetal harm when administered to a pregnant woman

para- Aminosalicylic Acid

a structural analog of PABA (p-aminobenzoic acid) is bacteriostatic inhibits de novo folate synthesis half life = 1 hour after 4 g. dose you can give this drug up to 12 grams per day. 80% of the drug is excreted in the urine and 50% of that is as an acetylated metabolite which is insoluble. You must make sure the patient's urine is normal or alkaline.

Adverse effects
GI irritation due to the amount of drug given (high doses) nausea, vomiting, bleeding, occurs in 30-40% of the patients. be careful with those who have peptic ulcers Hypersensitivity reactions Rash, Fever some hepatotoxicity All will disappear when the drug is stopped This drug has poor patient acceptability and compliance:

Third Line Drugs - least effective and most toxic

Third line drugs are used when resistance is developed to 1st and 2nd line drugs; these drugs are also used in combination.

Aminoglycosides Capreomycin - Viomycin - Kanamycin

Adverse effects
These drugs are: Nephrotoxic - will cause Proteinuria, Hematuria,
Nitrogen metabolism, and Electrolyte disturbances However effect is reversible when drug is stopped.

Ototoxic will result in deafness and

some loss of vestibular function, leads to cranial nerve 8 damage. The nerve damage is permanent. Capreomycin has replaced viomycin because of less toxic effects, but all three drugs have the same effects.

Cycloserine
can cause CNS disturbances Therapeutic States Cycloserine should be used when retreatment is necessary or when the microorganism is resistant to the other drugs. It must be given in combination with other anti-tuberculosis drugs.

Mechanism of Action: An analog of D-alanine synthetase, will block bacterial cell wall synthesis.

Pharmacokinetics: Rapidly absorbed Peak [plasma] occurs in 3-4 hours Distributed throughout all body fluids, including CSF About 50% is excreted in unchanged form in the urine during the first 12 hours. Only about 35% of the drug metabolized This drug can accumulate to toxic conc in patients with renal insufficiency

Toxicity: Most common in the CNS: Headache, Tremor, Vertigo, Confusion, Nervousness, Psychotic states with suicidal tendencies , Paranoid reactions, Catatonic and depressed reactions

Chemoprophylaxis of TB
Used only in high risk groups

Household members and other close contacts of a patient with active TB. A positive skin test in persons less than 35 years. A positive skin test reactive in the immunosuppressed, persons with leukemia, and Hodgkin's Disease, HIV + patients with a positive TB test,

The drug of choice for chemoprophylaxis is isoniazid. Prophylaxis uses only one drug. In patients who are HIV+ and TB+ and have the disease; they are treated for a minimum of 9 months, The first 2 months using isoniazid and rifampin and for the next 7 months or longer, use only 2 or 3 of the 2nd/3rd line drugs and Isoniazid/Rifampin.

Treatment
Isoniazid, Ethambutol, & Rifampin are given for 2 months. Isoniazid & Rifampin are given for 4 months. If you suspect resistance to isoniazid use Isoniazid, Ethambutol, Rifampin & Parazinamide. Incidence of drug resistance is 2-5% in the U.S. Prolonged bed rest is not necessary or helpful in obtaining a speedy recovery. The patient must be seen at regular and frequent intervals to follow the course of the disease and treatment. Look for toxic effects