Details of Isoniazid:

Can it penetrate Granulomas?

Can it penetrate Caseating Granulomas?

Can it penetrate Macrophages?

MOA?

SOA?

PK?

Metabolization?

Adverse Reactions?

- Penetrates Granulomas

- Penetrates Caseating Granulomas

- Penetrates Macrophages

MOA: Inhibition of Mycolic Acid Synthesis through inhibition of Acyl Carrier protein and Ketoacyl carrier protein synthetase; also inhibits Vitamin B6 reactions

SOA:  Given in combo, enters all fluids and cells, even CNS.  Penetrates the macrophages, granulomas, effective vs. microbes.

PK: Readily absorbed from GI, aluminum decreases absorption, inhibits P450 2E, increased toxicity with warfarin, carbemezapam, phenytoin (anticoags)

- Undergoes Phase II first; metabolized by Acetylation, excreted prim. by the kidneys.

- Adverse Rxns include Hepatotoxicity (jaundice, necrosis, hepatitis), skin rash, GI, and CNS problems.

- Resistance includes mutation of KatG (high), KasA, and acyl carrier protein reductase mutation (low)

Details of Rifampin:

Can it penetrate Granulomas?

Can it penetrate Caseating Granulomas?

Can it penetrate Macrophages?

MOA?

SOA?

PK?

Metabolization?

Adverse Reactions?

- Penetrates well in to macrophages/granulomas

- Binds to beta subunit of bacterial RNA polymerase responsible for Tx.  Stops change initiation (initiation of new scripts).  No effect on scripts already being transcribed.  No effect on elongation.

- Bacteriocidal against wide range of gram negative and gram positive organisms. 

- Well absorbed from GI, food decreases absorption, penetrates all fluids and tissues, even CNS so it could treat meningitis

- Secreted in to bile

- Metabolized as a result of acetylation (inactive) or deacetylation (active)

- Side effects include GI problems, flu-like symptoms, hepatitis, ORANGE tears and stuff.  Increased metabolism of other drugs because of induction of P450 (1A2, 2C9, 2C19, 2D6, 3A4)

- Resistance is an altered RNA polyermase, the rpoB gene for beta subunit.  Decreases binding 

Details of Ethambutol:

Can it penetrate Granulomas?

Can it penetrate Caseating Granulomas?

Can it penetrate Macrophages?

MOA?

SOA?

PK?

Metabolization?

Adverse Reactions?

- D-isomer 200x more active than L-isomer, change/replacement of N will destroy activity, same with alcohol groups.

- Does not penetrate well in to macrophages

- Inhibition of mycolic acid synthesis through inhibiting arabinsyl transferase (embAB).

- If mycobacterium are not rapidly dividing you won't see effect; static effect if they are rapidly dividing.

- Orally effective, widely distributed throughout body, Aluminum decreases absorption, Renal excretion is 50% parent drug, Biliary is 20% parent drug.

- Side effects include loss of vision and red/green color blindness, proportional to length of therapy, increase in uric acid in blood may cause gout attack.

Details of Pyrazinamide:

Can it penetrate Granulomas?

Can it penetrate Caseating Granulomas?

Can it penetrate Macrophages?

MOA?

SOA?

PK?

Metabolization?

Adverse Reactions?

- Active form is Pyrazinoic acid, inactive is 5-OH-Pyrazinoic acid.

- Effective inside granulomas, macrophages, and against intracellular mycobacteria.

- More effective under acidic conditions

- Inhibition of fatty acid synthase I, which decreases synthesis of mycolic acids.

- Adverse effects include GI effects, Hepatotoxicity (check serum enzyme levels), increased uric acid in blood.

- 2nd line drugs if antimycobacterials don't work are Streptomycin and Fluoroquinolones. 

- Resistance is mutation of pyrazinamidase and a decreased of uptake of pyrazinamide in mycobacterial cells.

Granulomas are RIPE for the picking.

R - Rifampin

I - Isoniazid

P - Pyrazinamide

E - Ethambutol