Transcript 7 Valproic Induced Carnitine Deficiency

Valproic Induced
Carnitine Deficiency
China & Epilepsy
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Epilepsy is a brain disorder characterized by an enduring predisposition to generate
epileptic seizures and by the neurobiological, cognitive, psychological, and social
consequences of this condition.
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There are about 9 million people with epilepsy in China, around 6 million of who
experience continuing seizures every year).
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There are estimated to be 400,000.00 new cases every year, of which about 60 % –
70% are in rural areas*.
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The overall prevalence of epilepsy is 2.89‰**.
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The prevalence of males and females is 3.83‰ and 3.45‰, respectively**.
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The location-specific prevalence in urban and rural areas is 2.34‰ and 3.17‰,
respectively**.
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A higher prevalence of epilepsy is found in the subgroup analysis by male, rural, age
group of 10-19 and generalized seizures**.
*2003 data **2013 data
China Top Selling Anti-Epileptic Drugs
Background
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Valproic acid is a broad-spectrum antiepileptic medication that is also used for a
number of nonseizure conditions including bipolar disorder, panic disorder, and
peripheral neuropathy
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The antiepileptic mechanism of action is thought to potentiate the brain’s gammaaminobutyric acid system, directly act on neuronal membranes, or reduce excitatory
transmission by excitatory neurotransmitters.
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Valproic acid is readily absorbed from the gastrointestinal tract, with an oral
bioavailability of 80–90%, and generally reaches peak concentrations within 4 hours.
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While generally considered a safe medication, valproic acid is associated with a
number of adverse effects with therapeutic use.
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Approximately half of patients treated with valproic acid develop asymptomatic
hyperammonemia and carnitine deficiency.
Mechanism of VHE
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Valproic acid is a branched-chain carboxylic acid that has a chemical structure similar
to that of short-chain fatty acids.
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It undergoes extensive hepatic metabolism through glucuronidation, mitochondrial
beta-oxidation, and, to a lesser extent, cytosolic omega-oxidation.
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Depletion of carnitine stores during long-term or high-dosage valproic acid therapy
results in a shift from mitochondrial beta-oxidation to increased omega-oxidation.
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This increases the production of toxic metabolites from omega-oxidation, including 2propyl-2-pentenoic acid (a possible cause of cerebral edema), 2-propyl-4-pentenoic
acid (a possible cause of hepatotoxicity), and propionic acid.
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The propionic acid metabolite inhibits mitochondrial carbamyl phosphate synthetase I,
an enzyme involved in ammonia elimination.
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This decrease in ammonia elimination results in greater levels of ammonia in the
blood, which can cause encephalopathy.
VPA & the Carnitine Shuttle
Lheureux 2009
Liver Metabolism of VPA
Lheureux 2009
Effects of decreased β-oxidation and increased ωoxidation of fatty acids and VPA on the urea cycle.
NAGA, N-acetyl glutamic acid; CoA, coenzyme A;
CPS, carbamyl phosphate synthetase; OTC,
ornithine transcarbamylase; 4-en-VPA, 2-propyl-4pentanoic acid.
Lheureux 2009
Valproic acid adverse effects
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Valproic acid adverse reactions include:
– skin reactions (eg, Stevens-Johnson syndrome),
– hematologic effects (myelosuppression),
– hepatotoxicity,
– reproductive effects (eg, increased rates of neural tube defects),
– metabolic effects (eg, hyperammonemia and carnitine deficiency).
Valproic acid overdose
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Valproic acid overdose causes:
– central nervous system (CNS) depression that can progress to coma;
– cerebral edema;
– metabolic derangements such as hyperammonemia with carnitine deficiency;
– cardiovascular instability (hypotension);
– pancreatitis;
– hepatic failure.
Valproic-acid-induced hyperammonemic
encephalopathy
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Valproic-acid-induced hyperammonemic
characterized by an acute onset of:
– impaired consciousness,
– focal neurologic symptoms, and
– increased seizure frequency.
encephalopathy
(VHE)
is
generally
VHE risk factors
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There are multiple risk factors for the development of VHE.
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Patients who are treated with multiple anticonvulsants (such as valproic acid
combined with phenobarbital, phenytoin, or carbamazepine) have an increased risk of
VHE.
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While liver dysfunction can be a VHE risk factor, VHE also occurs in patients with
normal liver function test results.
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Metabolic abnormalities (e.g., carnitine deficiency), congenital defects in the urea
enzymatic cycle, a protein-rich diet, and hypercatabolic states may also increase
ammonia production.
Correlation between Valproic Acid (VPA) levels and
acylcarnitine-free Carnitine Ratio in subjects taking VPA for
at least 6 months
Pearzon R = 0,553 p = ,002 (2-tailed analysis)
Moreno 2005
Symptomatic Hyperammonemia Due to
Valproic Acid Therapy in a Psychiatric Setting
Carr 2007
Results: Effect of oral - iv L-carnitine
Treatment
Duration (in days) of the hepatotoxic episode prior stopping VPA
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“Hepatic” survival was more effective after L-carnitine treatment
L-carnitine benefit was more evident when VPA was stopped promptly (< 5 days)
Bohan TP et al. Neurology 2001; 56: 1405-1409
Results: Effect of oral vs iv L-carnitine
Treatment
Duration (in days) of the hepatotoxic episode prior stopping VPA
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Hepatic survival was more evident after intravenous L-carnitine treatment
Bohan TP et al. Neurology 2001; 56: 1405-1409
Results: Effect of Oral L-carnitine
Treatment
Prolonged oral L-carnitine
supplementation is associated
with a reduction in blood
ammonia
Böhles H et al. Acta Pediatr 1996; 85: 446-449
VHE treatment
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Treatment of VHE includes discontinuing valproic acid therapy and correcting other
potential causes of encephalopathy, such as:
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electrolyte disorders,
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drug overdoses,
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acid-base disorders,
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sepsis,
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Wernicke’s encephalopathy
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L-Carnitine IV 50-100 mg/Kg
• followed by L-Carnitine oral supplementation for carnitine deficiency prevention.