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

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

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

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

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)

Labs ALT: 30 IU/L AST: 21 IU/L Total Billirubin: 0.1 mg/dL 98 18 4.4 30 0.8 ALT: 30 IU/L AST: 21 IU/L Total Billirubin: 0.1 mg/dL Serum VPA: 100 mcg/ml (50-125 mcg/ml) Negative toxicology screening All other lab values within normal limits except Ammonia: 145 µmol/L (11-32 µmol/L) 208

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

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

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

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

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 T1/2 2-15 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

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

Back to DL ALT: 30 IU/L AST: 21 IU/L Total Billirubin: 0.1 mg/dL 98 18 4.4 30 0.8 ALT: 30 IU/L AST: 21 IU/L Total Billirubin: 0.1 mg/dL Serum VPA: 100 mcg/ml (50-125 mcg/ml) Negative toxicology screening All other lab values within normal limits except Ammonia: 145 µmol/L (11-32 µmol/L) 208

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

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

Questions?