Mechanism of Action

RIPE — Rifampin, Isoniazid (INH), Pyrazinamide, Ethambutol — is the four-drug regimen for the intensive phase of active TB, given together because Mycobacterium tuberculosis mutates readily and monotherapy guarantees resistance. Each agent hits a different bacterial target: INH disrupts mycolic acid (cell wall) synthesis, rifampin inhibits RNA polymerase, pyrazinamide disrupts membrane metabolism in acidic intracellular environments, and ethambutol blocks arabinosyl transferase (cell wall). The four drugs run together for ~2 months (intensive phase), then therapy narrows to rifampin + INH for 4 more months (continuation phase) — at least 6 months total. Directly Observed Therapy (DOT) is standard of care because non-adherence is the primary driver of multidrug-resistant TB.

RIPE regimen — phases (≥6 months total)

Intensive phase (~2 months)all 4 drugs: Rifampin + Isoniazid + Pyrazinamide + Ethambutol
Pyrazinamide stopped at 2 monthstime-based decision; Ethambutol may be dropped earlier if susceptibility to INH + rifampin is confirmed (lab-based)
Continuation phase (~4 months)Rifampin + Isoniazid only

Common Medications

rifampinPrototype

orange-red body fluids; potent CYP450 inducer; hepatotoxic

isoniazid

INH; highest hepatotoxicity risk; depletes B6 → neuropathy

pyrazinamide

hyperuricemia / gout flares

ethambutol

optic neuritis — Ethambutol = Eyes

Indications

active pulmonary tuberculosis

RIPE 4-drug regimen, intensive then continuation phase

latent TB infection

treated differently — typically INH monotherapy 9 months, or shorter CDC regimens (3-mo INH+rifapentine, 4-mo rifampin)

Side Effects

orange-red body fluids Hallmark

rifampin — urine, tears, sweat; harmless and expected; stains contact lenses

peripheral neuropathy

isoniazid depletes pyridoxine (B6); prevent with B6 25–50 mg/day

hyperuricemia

pyrazinamide; gout-like joint pain — monitor uric acid

nausea

GI upset

Contraindications & Interactions

Contraindications

monotherapy for active TB

guarantees resistance — always 4 drugs in the intensive phase

active hepatic disease

relative — all three of R/I/P are hepatotoxic; weigh risk and monitor closely

Interactions

oral contraceptives

rifampin CYP450 induction reduces effectiveness — use backup contraception

warfarin

rifampin induction lowers warfarin levels

HIV antiretrovirals

rifampin induction reduces antiretroviral levels

alcohol

additive hepatotoxicity with INH/rifampin/pyrazinamide

Administration & Monitoring

baseline liver function panel

INH, rifampin, pyrazinamide all hepatotoxic; baseline + when symptoms arise (AST, ALT)

baseline visual acuity exam

ethambutol; baseline + monthly acuity and color discrimination

co-prescribe vitamin B6

pyridoxine 25–50 mg/day with isoniazid to prevent neuropathy

monitor uric acid

pyrazinamide hyperuricemia / gout

directly observed therapy

DOT — watch the client swallow every dose; standard of care

hold ethambutol for vision changesHold

new blurred vision — hold, notify provider, ophthalmology exam

track sputum cultures

negative conversion (not symptom relief) is the measure of cure; persistent positivity at 2 mo → susceptibility testing + DOT

Patient Teaching

take all drugs for the full course

at least 6 months; stopping early breeds drug-resistant TB

expect orange-red body fluids

rifampin; urine, tears, and sweat — harmless; will stain soft contact lenses

report yellowing of skin

jaundice — sign of hepatotoxicity

report dark urine

possible hepatotoxicity — distinct from rifampin's orange tint

report nausea or abdominal pain

hepatotoxicity warning sign

report vision changes immediately

ethambutol optic neuritis

take vitamin B6 daily

prophylactic with INH from the start, not after symptoms

avoid alcohol

additive liver injury

use backup contraception

rifampin reduces oral contraceptive effectiveness

Report Nowescalate immediately

hepatotoxicity HallmarkALT >3× ULN with symptoms

INH highest risk; also rifampin + pyrazinamide; jaundice, dark urine, nausea, RUQ pain — stop all hepatotoxic drugs, reintroduce one at a time

optic neuritis

ethambutol; decreased visual acuity + red-green color blindness; hold drug, notify provider, ophthalmology — reversible if caught early

severe peripheral neuropathy

isoniazid pyridoxine depletion; progressive numbness/tingling — may be permanent if untreated; ensure B6

Clinical Pearl

RIPE organ map: Rifampin → liver + fluids turn orange, Isoniazid → nerves (give B6), Pyrazinamide → joints (uric acid), Ethambutol → Eyes. RIPE together for two, then RI for four more — six months minimum, every dose observed. Stopping early doesn't just fail; it creates drug-resistant TB.