1. Adam Whalley, PharmD PGY-1 Pharmacy Resident
Levocarnitine for the treatment of valproic-acid-induced hyperammonemic encephalopathy
Adam Whalley, PharmD
PGY-1 Pharmacy Resident

2. Objective
Describe the key components of valproic acid-induced hyperammonemic encephalopathy (VHE)
Define the role of levocarnitine in the treatment of VHE in an adult population

3. Background
Valproic acid (VPA) is an anticonvulsant which may be used in the treatment of bipolar disorder
50% of patients treated with valproic acid will develop elevated ammonia levels
Often asymptomatic requiring no intervention
Am J Health Syst Pharm. 2012;69:35-39

4. True or False
Only patient’s with hepatic dysfunction or supratherapeutic valproic acid levels are at risk for VHE.
False

5. Patient Case
DL is a 55 y/o female presenting with increased confusion, lethargy, and tremors
PMH: type 1 diabetes mellitus, hypertension, bipolar disorder
Medications:
Insulin NPH 50 units Subcutaneously BID
Lisinopril 20 mg PO once daily
VPA (Depakote®ER) 1500 mg PO QPM
Talk about differential with hypoglycemic seizures
Causes of encephalopathy – lyte abnormalities, overdose, acid-base disorders, sepsis, wenicke’s encephalopathy (thiamine def. d/t etoh)

6. Labs ALT: 30 IU/L AST: 21 IU/L Total Billirubin: 0.1 mg/dL
ALT: 30 IU/L
AST: 21 IU/L
Total Billirubin: 0.1 mg/dL
Serum VPA: 100 mcg/ml ( mcg/ml)
Negative toxicology screening
All other lab values within normal limits except
Ammonia: 145 µmol/L (11-32 µmol/L)
208

7. Signs and Symptoms of VHE
Acute onset of neurological symptoms
Confusion
Altered mental status
Seizures
Coma
Can occur in the absence of hepatic dysfunction
Can occur despite therapeutic VPA serum levels

8. Metabolism of VPA Hepatic Metabolism Cytosolic Omega-oxidation
Glucuronidation
Mitochondrial Beta-oxidation
Cytosolic Omega-oxidation
VPA broken down in liver via glucuronidation, beta-oxidation, and some cytosolic omega-
oxidation

9. Potential Mechanism of VHE
Decreased concentrations of alpha-ketoglutarate
Carnitine deficiency
Shift from beta-oxidation to omega oxidation creates excess propionic acid
Accumulation of toxic metabolite
Propionic acid prevents breakdown of ammonia
Elevated ammonia levels
At risk pts: use of other anticonvulsants, liver dysfunction, metabolic abnormalities (natural carnitine def.) protein rich diet, hypercatabolic states
1)Accumulation:
VPA broken down in liver via glucuronidation, beta-oxidation, and some cytosolic omega-
oxidation
long term use thought to shift more to omega-oxidation  more toxic
metabolites
2-propyl-2-pentenoic acid(possible encephalopathy)
1-propyl-4pentenoic acid (hepatotoxic)
propioic acid (Inhibits cabamyl phosphate synthetase-I (involved in ammonia elimination)build up of ammonia in blood  encephalopathy 2) renal theory – VPA causes more glutamine to cross mitochondrial membrane in kidneys leading to breakdown to glutamate and increased ammonia
1)Carinitine deficiency
decreased concentrations of alpha-ketoglutarate
Am J Health Syst Pharm. 2012;69:35-39

10. Role of levocarnitine Treatment of VHE associated with:
Acute overdose involving VPA
Chronic use of VPA
Recent changes in therapy with VPA
Prevention of VHE in high risk patients
Alternative agents:
Ammonia – case reports – decreased GI pH and ammonia to ammonium in the gut preventing reabsorption and increasing excretion
Naloxone – case reports – some show benefit in acute vpa tox but others show no benefit
Activated charcoal
Hemodialysis
Acute overdose – retrospective review of poison control shows safe for the treatment of VPA overdose with elevated ammonia. Dosages not reported. No statistical analysis.
Chronic use –
- Acutely ill with loss of consciousness and ammonia >300 IV preferred at doses of
100mg/kg
- less severe symptoms (confusion lethargy) ammonia ~100 or so consider PO (may not need to d/c VPA)
Recent changes – dose increases or initiation may cause VHE
Prevention – chronic use of levocarnitine in patient which require continued treatment with VPA
Am J Health Syst Pharm. 2012;69:35-39

11. Dosing levocarnitine
FDA approved for primary or secondary carnitine deficiency
Oral solution: 1,000 mg PO per day in divided doses
Oral Tablet: 990 mg PO 2-3 times per day
IV: 50 mg/kg/day in divided doses
Off-label use: acute VPA toxicity
100 mg/kg IV bolus followed by 50 mg/kg IV bolus every 8 hours
Active isomer of carnitine
Tmax 3-5 hours in healthy person
T1/ hours
Mostly urinary excretion
Transient N/V most common side effects
Rarely – htn, hypotension, tachyarhytmia, chest pain, HA, hypercalcemia, anemia, seizures
Possibel therapeutic range 35-60umol/L
Causes of encephalopathy – lyte abnormalities, overdose, acid-base disorders, sepsis, wenicke’s encephalopathy (thiamine def. d/t etoh)
Ammonia – case reports – decreased GI pH and ammonia to ammonium in the gut preventing reabsorption and increasing excretion
Naloxone – case reports – some show benefit in acute vpa tox but others show no benefit
Activated charcoal
Hemodialysis
Levocarnitine. In: Lexi-Drugs [database on the Internet]. Accessed 2016 Oct. 6

12. Formulations Only use prescription quality products
OTC dietary supplements of L-Carnitine are available but should not be used to treat VHE

13. Back to DL ALT: 30 IU/L AST: 21 IU/L Total Billirubin: 0.1 mg/dL
ALT: 30 IU/L
AST: 21 IU/L
Total Billirubin: 0.1 mg/dL
Serum VPA: 100 mcg/ml ( mcg/ml)
Negative toxicology screening
All other lab values within normal limits except
Ammonia: 145 µmol/L (11-32 µmol/L)
208

14. In a patient with chronic symptomatic hyperammonemia requiring continued use of VPA, the best choice of treatment is?
Activated charcoal
Levocarnitine 990 mg BID
Lactulose
L-Carnitine 500 mg TID

15. Summary
VHE can present in patients with no hepatic dysfunction and regardless of serum VPA concentrations
Levocarnitine corrects the VPA-associated carnitine deficiency leading to decreased ammonia levels
Levocarnitine can be used in acute and chronic hyperammonemia

16. Questions?