Tuberculous Medication Toxicology

The number of people infected with TB is surprisingly high. Therefore, many people are exposed to anti-tubuerculosis medications, and a thorough understanding of toxicity is paramount to the Toxicologist’s practice.

Answer 4 correctly identifies the mechanism of action (MOA) of INH. Answer 1 describes the MOA of penicillins on gram positive bacteria. Answer 2 describes the MOA of fluoroquinolones. Answer 3 describes the mechanism of toxicity in humans, and the reason why we supplement with B6 when treating with INH. Answer 5 describe the MOA of aminoglycosides, macrolides, tetracyclines, chloramphenicol, neomycin, and linezolid.

Hydrazine is the correct answer. Diacetyl hyrazine and isonicitonic acid are non toxic. The Nicotinoyl radical is only formed within the mycobacterial cell.

It is likely the structural similarity between pyridoxine and INH that leads to the inhibition of pyridoxine phosphokinase. By inhibiting this enzyme, there is decreased GABA synthesis as well as increased build up glutamate, which is an excitotory neurotransmitter that can also contribute to seizure activity. All of the other answers are incorrect.

Of the above answers, only INH is associated with drug induced Lupus.

At 20 mg/kg the probability of seizure increases. After 35-40 mg/kg, seizures are probable. Therefore, the correct answer is 20 mg/kg.

The correct answer is that INH is most closely associated with peripheral neuropathy, which can include “stocking and glove” type sensory deficit and progress toward ataxia. Although not completely elucidated, the etiology is most likely due to pyridoxine deficiency. Case reports of patients presenting with a Wernicke’s Encephalopathy presentation have also been reported. Macular degeneration is not associated with INH administration. Hemorrhagic cystitis is classically associated with cyclophosphamide, ifosfamide, and ketamine. Prosopagnosia, or agnosia to facial recognition, would most likely be attributable to a primary neurologic region within the fusiform gyrus (although other lesions could contribute).

The correct dose is 5 g to reverse Isoniazid induced status epilepticus. In the US this entails giving fifty 100mg vials. If this many vials are not available, a viable alternative involves placing an NG tube to administer the PO formulation of pyridoxine.

The patient is a candidate for GI decontamination; furthermore, empiric pyridoxine administration may reduce the possibility of developing seizure. Administering activated charcoal alone would not be sufficient management of this patient. Gastric lavage would be indicated if the patient needed to be intubated, which is not the case here. Whole bowel irrigation would not be the best choice because it may not delay absorption and an antidote is available. Administering 5 g pyridoxine alone is not correct because some sort of GI decontamination should be performed as well.

Rifampin has been shown to induce CYP3A4 and P-Glycoprotein. None of the other answers are correct.

Of all of the options above, ethambutol is most closely associated with optic neuritis. The theoretical mechanism of toxicity involves chelation of Zinc of Copper. Thus, all patients who are prescribed Ethambutol should receive ophthalmologic testing prior to induction.

Patients taking pyrazinamide have been shown to have elevated serum uric acid concentrations. All of the other answers are incorrect.

Cycloserine is a partial agonist at both glycine and NMDA receptors, pontentially explaining the near 50% incidence of neuropsychiatric effects. It is contraindicated in patients with histories of seizure or depression. All of the other answers are incorrect.

Up to 5% of patients develop hepatitis while on this medication. Furthermore, it is structurally analogous to methimizole, so thyroid functions should be routinely monitored. No other answer choice includes this couple.

FDA surveillance data have shown an association with prolonged QTc; however, the association with significant cardiac dysrhythmias is not clear at this point in time. None of the other answers have been associated with this anti-tuberculoid xenobiotic.