Anti-TB Drugs

What are the symptoms when suspecting TB?

• Cough >2 Weeks

• Chest and Back Pains > 1 month

• Fever > 1 month

• Hemoptysis or Streaking of Blood in Sputum

• Progressive Weight Loss

What are the first line agents in tuberculosis?

R.I.P.E.

• Rifampin

• Isoniazid

• Pyrazinamide

• Ethambutol

Rifamycins mechanism?

Inhibits RNA Polymerase

Binds to b-subunit of DNA-dependent RNA polymerase and inhibits RNA synthesis → Cannot make structural proteins for the mycobacterium

Which drug inhibits RNA polymerase to prevent formation of RNA needed to make bacterial protein?

Rifamycins

Rifampin

Rifambutin

A/E of Rifampin (RIF)?

• Red/Orange Color Urine (NORMAL AND HARMLESS)

Isoniazid (INH) mechanism?

• Once it enters mycobacteria, its activated by KAT-G (mycobacterial catalase-peroxidase) into ACTIVE METABOLITE

• Active metabolite then binds with a NAD-dependent covalent complex of

  • Acyl Carrier Protein (AcpM)

  • KasA (beta-ketoacyl carrier protein)

• This complex then inhibits ENOYL REDUCTASE which synthesizes mycolic acids

• INHIBITED MYCOLIC ACID SYNTHESIS

  Lose mycolic acids of bacterial cell wall

Which drug is taken into bacterial cell, acted upon catalase peroxidase into active INH (metabolite) which binds NAD which inhibits Enoyl Reductase (enzyme important for mycolic acid synthesis)?

Isoniazid

A/E of Isoniazid?

• Drug-Induced SLE

• Anion Gap Metabolic Acidosis

  Ketoacidosis

  Lactic Acidosis

Relative B6 deficiency which can lead to:

• Peripheral Neuropathy

• Anemia

• Risk of Seizures

• Hepatitis (MAJOR TOXIC EFFECT)

Pyrazinamide (PZA) mechanism?

• Pyrazinamide is converted to PYRAZINOIC ACID (active metabolite) by Mycobacterial Pyrazinamidase

• Pyrazinoic Acid disrupts mycobacterial cell membrane metabolism and transport function

• INHIBITED CELL MEMBRANE COMPONENT SYNTHESIS

Also reduced mycolic acid synthesis

A/E of Pyrazinamide (PZA)?

• Hepatotoxicity

• Hyperuricemia (less uric acid excretion)

  More exaggerated gout!!

Which anti-TB drug is referred to as the “sterilizing agent” which prevents TB relapse?

Pyrazinamide

In conjunction with Rifampin and Ethambutol

Ethambutol (EMB) mechanism?

Inhibits Arabinosoyl transferase

• Prevents synthesis of arabino-galactan via ARABINOSE + GALACTOSE

• Inhibited CELL WALL SYNTHESIS (Arabino-galactan)

Which drug inhibits arabinosyl transferase preventing formation of arabino-galactan (component of cell wall)?

Ethambutol

Ethambutol primarily affects which layer of the bacterial cell wall?

Arabino-galactan layer of the cell wall

A/E of Ethambutol (EMB)?

• Optic or Retrobulbar Neuritis (visual disturbance → reduced acuity) COMMON A/E

  Red-green blindness

Dapsone mechanism?

Inhibits Folate Synthesis

Inhibits enzymes that convert Par-aminobenzoic acid into Dihydrofolate → and Tetrahydrofolate

These NUCLEOTIDES are usually incorporated to make mycobacteria DNA and RNA

Which drug inhibits PABA from being converted to DHF and THF involved in nucleotide synthesis?

Dapsone

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Folate Synthesis Inhibition

A/E of Dapsone?

• Methemoglobinemia (oxidizes hemoglobin into ferric form and cannot bind O2)

• HEMOLYSIS (if patient has G6PD-Deficiency)

Contraindication to Dapsone?

G6PD-Deficiency

LEADS TO HEMOLYSIS

Streptomycin mechanism?

Inhibits 30s ribosomal subunit = INHIBITS PROTEIN SYNTHESIS

Inhibits it to prevent action with RNA to make protein

Which anti-TB drug inhibits the 30s ribosomal subunit preventing bacterial protein synthesis?

Streptomycin

What drugs are used in Latent TB?

• Rifampin (RIF) 4 months

• Isoniazid (INH) 6-9 months

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(+) Tuberculin Skin Test

(-) Symptoms

What drug regimen can be used in active TB?

R.I.P.E. regimen for 2 months (8 weeks) INTENSIVE PHASE

• Rifampin

• Isoniazid

• Pyrazinamide

• Ethambutol

Next administer a R.I. regimen for 4 months (18 weeks) CONTINUATION PHASE

Rifampin

Isoniazid

Give B6 supplement due to B6 deficiency associated with prolonged isoniazid use

What drugs are used to treat Leprosy?

• Dapsone

• Rifampicin

• Clofazimin - if you suspect multibacillary leprosy

Indication on when to use clofazimin?

Multibacillary leprosy (tuberculoid form of leprosy)

What are the agents used as prophylaxis to prevent dissemination of MAC in AIDS patients?

• Azithromycin

• Clarithromycin

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Indication: Patients with <50/ml CD4 cell count

What agents can be used in Nontuberculous Mycobacteria (Atypical Mycobacteria)

• Macrolides

• Sulfonamides

• Tetracyclines

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M. Kansaii: Give 3 Drug Combo → Rifampin, Ethambutol and Isoniazid (partially susceptible)

MAC: Macrolides (Azithromycin and Clarithromycin), Rifampin and Ethambutol

You have a patient positive for TB and you find out he is also positive for HIV. You have him initially under Rifampin regimen.

What can you do to adjust this?

Switch out to RIFAMBUTIN

Less CYP metabolism and NRTI