Thanks to Dr. Martinez for today’s Morning Report!
CASE:
26 y/o M recently immigrated from Haiti p/w AMS after episode of whole body shaking. Per mom, he is not responsive. He was well until this morning with no complaints except for a cough x months. He was given an antibiotic for his chronic cough. She thinks he has been on this antibiotic for 6 weeks. He missed yesterdays dose. On exam pt has respiratory depression, is not responding to painful stimuli, has non-reactive pupils and is tachycardic.
Isoniazid Toxicity
PHARMACOLOGY:
-Selective for mycobacterium
-Inhibits mycolic acid synthesis
-Interferes with cell wall synthesisàbactericidal
PRESENTATION:
-AMS
-Seizures/Status epilepticus
-Peripheral neuropathy
-Hepatotoxicity
CELLULAR TOXICITY:
Produces toxicity via deficiencies in pyridoxine (B6) and GABA
B6 deficiency:
1) INH metabolites attach and inactivate pyridoxine
2) INH inhibits Pyridoxine Phosphokinase
- Enzyme necessary to activate Pyridoxine to Pyridoxal -5-Phosphate
- This is a cofactor in many pyridoxine dependent reactions
- Active B6 used in macronutrient metabolism (amino acid, glucose and lipid metabolism), neurotransmitter synthesis (GABA, serotonin, dopamine, epinephrine, norepinephrine), Histamine synthesis, Hgb synthesis and gene expression
- Mechanism for peripheral neuropathy
GABA Deficiency:
1) An inhibitory neurotransmitter that modifies or suppresses excitatory neurons
2) GABA is produced in a pyridoxine-dependent decarboxylation reaction
3) B6 deficiency leads to a reduction in GABA production
4) INH inhibits glutamate dehydrogenase (catalyzes glutamate à GABA)
5) GABA deficiency may manifest as seizures (acute overdose)
CLINICAL:
Hepatoxicity:
-INH metabolized in the liver, eliminated by kidney
-Metabolites such as acetylhydrazine causes direct hepatocellular toxicity (first 8 wks)
Seizures:
-Usually with high doses (>20 mg/kg, in some 2g)
-30 minutes up to 2 hours post exposure
-Tachycardia, tachypnea, and elevated temp may occur as a result of seizure activity
-May be non-convulsive
-Can lead to anoxia, aspiration, anoxic encephalopathy and dementia
Peripheral Neuropathy:
-As above, improved with B6 supplements.
MANAGEMENT:
-ABC’s
-Intubate if severely altered, not responsive, status (short acting blockade to not mask seizures)
-Pyridoxine
-Binds to INH, repletes pyridoxal 5′ phosphate
-Facilitates the production of GABA
-Works within minutes
-1 g intravenously for every gram of INH ingested
-5 g IV to an adult with unknown dose
-70 mg/kg (max 5 g) to a child
-Given at a rate of 0.5 g/min
-May be repeated with refractory seizures
-Indicated in known ingestion, new onset seizures on INH, Seizure of unknown etiology refractory to Benzo’s
-GABA Agonist
– Benzo’s act on the GABA receptor and enhance neuroinhibition.
-Ativan 2 mg IV Q5min
-In children, Ativan 0.05 to 0.1 mg/kg IV, up to 2 mg per dose
-Phenobarbital may be used as adjunct in refractory seizures
-Phenobarb is 20 mg/kg by slow IV
-Shorter acting barbiturates can cause hypotension
-If intubated Propofol (potentiates GABA receptor activity + NA channel blocker)
-Phenytoin and Fosphenytoin: not indicated in INH seizures
LABS:
-MUDPILES???
-Nearly all the metabolic derangements associated with severe INH toxicity are the result of status epilepticus or refractory seizure activity –> Lactic Acidosis
-Stop the Seizures
-Vent support to correct acidemia (metabolism of the excess lactate regenerates bicarbonate)
DISPOSITION:
-Patients with unintentional exposures who remain asymptomatic with normal vital signs for six hours –> discharge.
-P/W seizures should be admitted to ICU. Pt with prolonged coma need further Pyridoxine and ICU setting
WHO NEEDS SUPPLEMENTS:
CDC recommends for diabetes, HIV, renal failure, alcoholism, pregnancy or breastfeeding
Jay Khadpe MD
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