Morning Report: 10/1/2013

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