The Magnificent Four

3.1 – “The Ma Magnificent gnificent Four” • RIPE therapy for tuberculosis (ripe tubers) given in 2 phase treatment: 4 drugs for 2 months, followed by 2 drugs usually for 4 months ($4 for 2, now $2 for 4), usually INH & rifampin. • Hepatotoxicity associated with all RIPE drugs. • Rifampin (the rifle sharpshooter) o Activity against mycobacteria & certain G- bugs. o Potent CYP450 inducer = “revs it up” (extremely active carriage) o MOA: binds bacterial DNA-dependent RNApol (shot RNA track switch, switching train from double stranded DNA track to single stranded RNA track) ▪ Resistance develops by mutations in RNA polymerase. Develop rapidly with isolated rifampin therapy. o Prophylactic monotherapy for close contacts for N. meningitidis, H. influenzae (carriage driver in close contact with rifleman; N.M. and logo on train for N. meningitidis; H. influenzae biplane) o Adverse effects ▪ Hepatitis is uncommon, but more common in patients with predisposing factors (including coadministration of other RIPE drugs & other hepatotoxic agents) (cow with liver spots) ▪ Orange-red discoloration of body fluids (literally everything – vomit, bile, urine, snot, CSF) (orange fluid spewing from carriage). Benign. • Isoniazid (isolated ranger): o most agents used alone will lead to rapid evolution of resistance. Not so INH. Sued in isolation for latent TB infections, preventing reactivation (ranger protecting sleeping - i.e. latent – cowboy next to cacti lacking upper lobe lesions – i.e. not reactivation TB). o Inhibits synthesis of mycolic acids, disrupting bacterial cell wall (fuchsia mycolic acid cacti beyond wall, ponchoed bandit being shot off wall) o Delivered as a prodrug activated by mycobacterial KatG catalase-peroxidase (bobcat with G-shaped tail is activating ranger). Resistance to INH develops by downregulating KatG (second bandit shooting bobcat). o Adverse effects sin ▪ Injury to nerves & hepatocytes ▪ Dose related peripheral neuropathy, ataxia, paresthesias (socking and glove). ▪ Metabolized by liver N-acetyltransferase. Slow acetylators have increased risk of adverse effects, higher drug serum concentrations, and increased half-life – increases risk for neuropathy (slow acetyl gunslinger). Caused by a pyridoxine (B6) deficiency d/t INH encouraged excretion. • Can prevent by coadministration of B6 (dice in ungloved hand) ▪ Acute OD can cause CNS toxicity including seizures (action lines on falling bandit) ▪ Hepatotoxicity (cow with liver spots): hepatocytes dysfunction so common will see asymptomatic ↑LFTs in many patients (LFT flag). However, serious hepatotoxicity can be fatal if not ceased. ▪ Drug-induced lupus (lone wolf for lone ranger) ▪ MUD PILES – can cause anion-gap metabolic acidosis (mud pile) ▪ Inhibits CYP450 (broken chrome bumper on inhibited carriage; INH inhibits) • Pyrazinamide (Pyromaniac) o Used only for TB o Nicotinamide analogue. May be bacteriostatic or bactericidal, depending on the concentration and susceptibility of the organism, although exact mechanism is unknown. It is active in vitro at an acidic pH of 5.6 or less, similar to that found in early, active tubercular inflammatory lesions o Adverse effects ▪ Hyperuricemia & needle-shaped uric acid crystal formation → gout (knitting needles). Not sufficient to discontinue therapy. ▪ Hepatotoxic, up to liver necrosis(cow with liver spots) • ethambutol (Ethel the horse whisperer) o Inhibits arabinosyl transferase → carbohydrate polymerization at cell wall (Ethel inhibiting an Arabian that is knocking over polymerized fencing) o Bacteriostatic (slowing horse, not killing him) o Adverse effects ▪ Optic neuritis – red green colorblind, loss of visual acuity (horse blinders) ▪ Hepatotoxic (cow with liver spots)