T.B powerpoint

Chemotherapy Of Mycobacterial Infections

Dr.Mohamed daood PhD student in Pharmacology

TUBERCULOSIS: caused by mycobacterium avium

Problems in Chemotherapy.


-grow more slowly than other bacteria -develop resistance rapidly -intracellular pathogens

Chemotherapy of T.B.

"First-line" drugs isoniazid rifamycins ethambutol pyrazinamide

second-line

Aminoglycosides ethionamide aminosalicylic acid cycloserine capreomycin fluoroquinolones macrolides

PRODRUG

mycobacterial catalase - peroxidase(KatG)

active metabolite

MYCOLIC ACIDS

Isoniazid

Mechanism of Action

Antibacterial Activity:

-bacteriostatic & -bactericidal

Bacterial Resistance:

Pharmacokinetics

-Absorption -Distribution -Metabolism: fast slow -excretion

Adverse Reactions:

immunological -Fever -skin rashes -Drug-induced systemic lupus erythematosus

B. direct toxicity:

-Isoniazid -induced hepatitis -Peripheral neuropathy

RNA SYNTHESIS
Rifampin
Rifampin
RNA polymerase

Rifamycins: Rifampin, rifabutin and rifapentine

Mechanism of action

Antimicrobial spectrum

Rifampin is bactericidal for both intracellular and extracellular mycobacteria, including M. tuberculosis, and atypical mycobacteria, such as M. kansasii. It is effective against many gram-positive and gram-negative organisms .

Resistance

Pharmacokinetics

-Absorption -Distribution -Metabolism enterohepatic cycling

hepatic mixed-function oxidases, (autoinduction).

Adverse effects:


-nausea, vomiting, and rash. -increased incidence of severe hepatic dysfunction when rifampin is administered alone or concomitantly with isoniazid. -a flu-like syndrome is associated with fever, chills, and myalgias


-Drug interactions: Because rifampin can induce a number of cytochrome P450 enzymes, it can decrease the half-lives of other drugs that are coadministered and metabolized by this system. This may lead to higher dosage requirements for these agents.

Pyrazinamidase

Pyrazinamide
pyrazinoic acid,


Pyrazinamide

Mechanism of action:

Antimicrobial spectrum:

bactericidal to only actively dividing organisms.

Resistance

Pharmacokinetics

-Absorption -Distribution -Metabolism -excretion



Adverse effects:

Urate retention can also occur and may precipitate a gouty attack .

Ethambutol
Ethambutol
Arabinosyl -T
Arabinogalactan molecules

Ethambutol

Mechanism of action Ethambutol inhibits arabinosyl transferase

Antimicrobial spectrum

bacteriostatic and specific for most strains of M. tuberculosis and M. kansasii.

Resistance

Resistance is not problem if the drug is employed with other antitubercular agents.

Pharmacokinetics

Absorbed on oral administration, ethambutol is well distributed throughout the body. Penetration into the central nervous system (CNS) is therapeutically adequate in tuberculous meningitis. Both parent drug and metabolites are excreted by glomerular filtration and tubular secretion.

Adverse effects

-optic neuritis

-urate excretion is decreased by the drug; thus, gout may be exacerbated

Alternate second-line drugs

-Streptomycin: -Capreomycin:

Cycloserine

Mechanism of action antagonize the steps in bacterial cell wall synthesis involving D-alanine.

Antimicrobial spectrum

- tuberculostatic agent

Pharmacokinetics

-orally effective, -It distributes well throughout body fluids, including the CSF. Cycloserine is metabolized, and both parent and metabolite are excreted in urine. Accumulation occurs with renal insufficiency.

Adverse effects

involve CNS disturbances, and epileptic seizure activity may be exacerbated. Peripheral neuropathies are also a problem, but they respond to pyridoxine.

Leprosy; caused by Mycobacterium leprae.

Chemotherapy

The triple-drug regimen of dapsone, clofazimine, and rifampin for 6 to 24 months.

Dapsone



Mechanism of Action. Dapsone is structurally related to the sulfonamides and similarly inhibits folate synthesis.

Antibacterial Activity

is bacteriostatic for Mycobacterium leprae, but resistant strains are encountered.

Pharmacokinetics

The drug is well absorbed from the gastrointestinal tract and is distributed throughout the body, with high levels concentrated in the skin. The parent drug enters the enterohepatic circulation and undergoes hepatic acetylation. Both parent drug and metabolites are eliminated through the urine.

Adverse reactions

-hemolysis -methemoglobinemia. - peripheral neuropathy

Clofazimine

Mechanism of Action -binds to DNA and prevents it from serving as a template for future DNA replication. -Its redox properties may lead to the generation of cytotoxic oxygen radicals that are also toxic to the bacteria.

Antibacterial Activity

Clofazimine is bactericidal to M. leprae

Pharmacokinetics

Following oral absorption, the drug accumulates in tissues, allowing intermittent therapy, but it does not enter the CNS.

Adverse Reactions

-red-brown discoloration of the skin. -enteritis

Rifampin