Anti mycobacterial drugs pharmacology, Katzung ppt

1. PRESENTED BY: MUHAMMAD AMMAZ NAVEED
DPT 3RD YEAR
ROLL NO. 06
ANTIMYCOBACTERIAL DRUGS
Assignment: Pharmacology

2. INTRODUCTION
Mycobacteria:
• Mycobacteria are rod-shaped, aerobic bacteria that do not form spores.
• These are called “acid-fast” bacilli
• Their cell walls contain mycolic acid, which gives the genus its name.
Antimycobacterial Drugs:
Antimycobacterial drug is a type of drug used in chemotherapy to treat
mycobacterial infections.
Types:
Types include:
• Tuberculosis Treatment
• Leprosy treatment
• Non-tuberculous mycobacterail infection

3. RISK FACTORS
The chemotherapy of infections caused by Mycobacterium tuberculosis, M
leprae and M avium-intracellulare is complicated by numerous factors including:
1. Limited information about the mechanism of antimycobacterial drug action.
2. The development of resistance.
3. The slow growth & intracellular location of mycobacteria.
4. Chronic nature of mycobacterial disease, which require protracted drug
treatment and is associated with drug toxicity.
5. Patient compliance issues.

4. CLASSIFICATION

5. DRUS FOR TUBERCULOSIS
• TB treatment includes four first-line drugs.
• Second-line drugs are typically less effective, more toxic and less extensively
studied.
• These are used for patients who cannot tolerate first-line drugs or who are
infected with resistant TB.
• The first line agents used for the treatment of tuberculosis are:
1. Isoniazid (INH)
2. Rifampin
3. Ethambutol
4. Pyrazinamide

6. ISONIAZID
Isoniazid(INH) is a structural congener of pyridoxine.
Mechanism of action:
Its mechanism of action involves the inhibition of the synthesis of mycolic acids
which are essential components of mycobacterial cell wall.
• Resistance can emerge rapidly if the drug is used alone.
• High-level resistance is associated with mutation in katG gene that codes for
a catalase peroxidase involved in the bio activation of INH.
• Low level resistance occur via deletion in the inhA gene.
• INH is bactericidal in action.

7. ISONIAZID CONT.
Pharmakokinetics:
• Isoniazid is readily absorbed after oral administration.
• The drug diffuses into all body fluids, cells and caseous material and
penetrate to act on intracellular mycobacteria.
• The metabolism of INH is by acetylation and is under genetic control. Patient
maybe fast acetylator or slow acetylator.
• INH half-life in fast acetylator is 60-90 min.
• INH half-life in slow acetylator is 3-4 hours
• Fast acetylators may require higher dosage than slow acetylators for
equivalent therapeutic effects.

8. ISONIAZID CONT.
Adverse effects:
The adverse effects of Isoniazid are:
• Hepatitis: It can be fetal, increase with age and among those who drink
alcohol daily.
• Peripheral neuropathy: manifesting as parasthesia of hands and feet appear
to be due to a relative pyridoxine deficiency.
• Central nervous system adverse effects can occur including convulsions in
patients prone to seizures.
• Hypersensitivity reactions with Isoniazid as rashes and fever.

9. ISONIAZID CONT.
Clinical Uses:
• INH is the single most important drug used in
tuberculosis and is a component of most drug
combination regimens.
• INH is given in the treatment of latent infection
(prophylaxis), including skin test converters and for close
contacts of patients with active disease.

10. RIFAMPIN
Rifampin, a derivative of rifamycin, is bactericidal against M tuberculosis
Mechanism of action:
• The drug inhibits DNA-Dependant RNA polymerase in M tuberculosis and
many other microorganisms
• It is bactericidal for both intracellular and extracellular mycobacteria
• It is effective against many gram positive and gram negative organisms.
Other rifamycins:
• Rifabutin
• Rifapentine
• Rifaximin

11. RIFAMPIN CONT.
Pharmacokinetics:
• Absorbtion is adequate after oral administration.
• Distribution of rifampin occur to all body fluids and organs.
• The drug undergoes enterohepatic cycling and is partially metabolized in
liver.
• Both free drug and metabolites are eliminated mainly in the feces

12. RIFAMPIN CONT.
Adverse effects:
• Rifampin is generally well tolerated.
• The most common adverse reactions include nausea, vomiting and rash.
• Hepatitis and death due to liver failure are rare.
• There is modest increase in the incidence of hepatic dysfunction when
rifampin is coadministered with isoniazid
Drug interactions:
Because rifampin induces a number of phase I cytochrome P450 enzymes and
phase II enzymes, it can decrease the half-lives of coadministered drugs that are
metabolized by these enzymes.

13. RIFAMPIN CONT.
Clinical Uses:
• In the treatment of tuberculosis, Rifampin is almost
always used in combination with other drugs.
• Rifampin can be used as the sole drug in treatment of
latent tuberculosis in INH-intolerant patients.
• Rifampin maybe used with vancomycin for infections due
to resistant staphylococci or pneumococci.
• Other uses include meningococcal and staphylococcal
Carrier states.

14. ETHAMBUTOL
Ethambutol is bacteriostatic and specific for mycobacteria.
Mechanism of Action:
It inhibits arabinosyl transferase-an enzyme important for the synthesis of
mycobacterial cell wall.
• Ethambutol is used in combination with pyrazinamide, isoniazid and rifampin
pending culture and susceptibility data.
Pharmacokinetics:
• Ethambutol is well distributed throughout the body.
• Penetration into CNS is minimal and it is questionably adequate for
tuberculous meningitis
• Both the parent drug and metabolites are primarily excreted in urine.

15. ETHAMBUTOL CONT.
Adverse effects:
• The most important adverse effect is Optic neuritis, which results in
diminished visual acuity and loss of ability to discriminate between red and
green.
• The risk of optic neuritis increase with higher doses and in patients with renal
impairment.
• Uric acid excretion is decreased by ethambutol, and caution should be
exercised in patients with gout.

16. ETHAMBUTOL CONT.
Clinical Uses:
The main use of Ehambutol is in tuberculosis, and it is
always given in combination with other drugs.

17. PYRAZINAMIDE
Pyrazinamide is a synthetic, orally effective short course agent used in
combination with isoniazid, rifampin and ethambutol
• The precise mechanism of action of pyrazinamide is un clear.
• Pyrazinamide must be enzymatically hydrolyzed by pyrazinamydase to
pyrazinoic acid, which is the active form of the drug.
• Some resistant strains lack the pyrazinamidase enzyme.
• Pyrazinamide is active against tuberculosis bacilli in acidic lesions and in
macrophages.

18. PYRAZINAMIDE CONT.
Pharmacokinetics:
The drug distributes throughout the body,penetrating the CSF.
Adverse effects:
• Pyrazinamide may contribute liver toxicity.
• Uric acid retention is common but rarely precipitates a gouty attack.
This drug is usually discontinued after 2 month of a 6 month regimen.
Clinical Uses:
The combined use of Pyrazinamide with other antituberculous drugs is an
important factor in the success of short course treatment regimens.