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Valproic Acid
VPA
By
Dr MOHAMMUD IBRAHEEM
OUR POINTS
1. PHARMACOKINETICS
2. INDICATIONS
3. MECHANISM OF ACTION
4. ADMINISTRATION
5. SE
6. DRUG-DRUG INTERACTIONS
7. CONTRAINDICATIONS
8. TOXICITY
Discovery
VPA was initially synthesized in 1882 as a derivative of
valeric acid (branched, short-chain, and naturally
occurring fatty acid present in plants and animals).
The anticonvulsant properties of VPA were discovered by
in 1962.
In 1966, the first human trial of VPA to treat epilepsy.
They fined that VPA decreases the occurrence and
intensity of seizures without causing significant AE.
The FDA approved VPA in 1978 to treat absence
seizures and in 1983 for treating complex partial
seizures.
PHARMACOKINETICS
Absorption
VPA is absorbed from the GIT. its bioavailability is 81%-
89%, depending on the drug formulation, gastric
emptying and food intake;
The delayed-release and EX formulations reduces the
peak plasma concentration and increase the drug's
duration of action.
The peak plasma concentration occurs within 1-4 h after
administration of IR formulations and within 4-17h after
administration of ER formulations.
The absorption is enhanced by food, especially meals
rich in fat. This elevate the bioavailability by 35% and
extend the time required to reach peak concentration by
4h
Distribution
VPA exhibits a strong affinity for plasma proteins, with a
binding rate of 90%. The binding rate of VPA is
concentration dependent and decreases as the plasma
concentration increases.
The distribution volume is low (0.1-0.4 L/kg).
VPA cross the BBB. Its concentration within the CSF is
10%-20% of its plasma concentration.
VPA cross the placental barrier causing teratogenic
effects. The fetal concentration of VPA is 70%-100% of
the maternal concentration.
VPA is excreted into breast milk, reaching concentrations
similar to those in the plasma
Metabolism
VPA is extensively metabolized in the liver through
A. Oxidation,
B. Beta-oxidation,
C. Conjugation with carnitine or glycine.
D. Glucuronidation, primarily metabolizing pathway, is
mediated by UDP-glucuronosyltransferase (UGT),
leading to the formation of valproate glucuronide,
the major inactive metabolite of VPA.
Other metabolites of VPA include 2-propyl-4-pentenoic
acid, 2-propyl-2-pentenoic acid, 3-keto-VPA, 3-
hydroxy-VPA, and valproyl-CoA.
Elimination
The primary route of elimination is through the
kidneys, involving the excretion of its
metabolites. About 30% to 50% of the
administered dose of VPA is excreted
unchanged in the urine, whereas the rest is
excreted as metabolites.
The elimination rate of VPA is subject to
dosage dependency and saturation effects,
signifying that it adheres to zero-order kinetics
at higher doses and shifts to first-order
kinetics at lower doses.
INDICATIONS
FDA-Approved Indications
1. A monotherapy and adjunctive therapy to
address complex partial seizures in adult and
pediatric patients aged 10 and older.
2. A standalone and adjunctive therapy to treat
both simple and complex absence seizures
in adults and pediatric patients.
3. An adjunctive therapy for patients with
multiple seizure types, encompassing
absence seizures.
Off-Label Uses
1. Manic episodes associated with bipolar
disorder
2. Migraine prophylaxis
3. Emergency treatment of status epilepticus
4. Diabetic peripheral neuropathy
5. Postherpetic neuralgia
6. Impulsivity, agitation, and aggression
VPA in SE
Infusion of valproate at either 1.5 or 3
mg/kg/min, The maximum dose per infusion
permitted was 15-30 mg/kg.
A recent systematic review compared the
relative efficacy of five AEDs (valproate,
lacosamide, levetiracetam, phenobarbital,
phenytoin) in treatment of benzodiazepine-
resistant convulsive SE showed that the
efficacy of valproate was higher than that of
other AEDs .
VPA in SE
Studies of the safety of IV valproate
administration in patients with SE showed a
low incidence of AE overall (<10 %) mainly
dizziness, thrombocytopenia, and mild
hypotension), which was independent of
infusion rates. There were no unexpected
side effects.
MECHANISM OF ACTION
Mechanism of Action
VPA has diverse mechanisms of action that
are not yet fully comprehended. they include:
Inhibition of voltage-gated sodium channels:
VPA obstructs the entry of sodium ions into
neurons, leading to decreased neuron
excitability and firing rate. This prevents
generating and propagating abnormal
electrical impulses responsible for triggering
seizures.
Mechanism of Action
Inhibition of gamma-aminobutyric acid (GABA)
transaminases and uccinate semialdehyde
dehydrogenase :
VPA inhibits GABA transaminase enzymeand
uccinate semialdehyde dehydrogenase, which are
responsible for the degradation of GABA.
In cases of neuropathic pain, VPA has been
demonstrated to impede neurogenic inflammation
through GABA-A receptor-mediated inhibition
Mechanism of Action
Enhancement of GABA synthesis:
VPA stimulates the synthesis of GABA by
increasing the expression and activity of
glutamic acid decarboxylase (GAD), the
enzyme responsible for converting
glutamate into GABA.
Mechanism of Action
Inhibition of HDACs:
VPA inhibits HDAC enzymes, notably HDAC1, which are
involved in the regulation of gene expression by
modifying the acetylation status of histones (proteins that
wrap around DNA). This process leads to changes in
chromatin structure, influencing the transcription of many
genes, including those linked to neuronal plasticity,
synaptic transmission, neurogenesis, neuroprotection,
and inflammation. This phenomenon could potentially
elucidate a portion of the enduring effects of VPA on
mood, cognition, neurodevelopment, apoptosis, and its
potential antitumor properties.
Mechanism of Action
Modulation of calcium channels:
VPA modulates the activity of calcium
channels, (T-type, L-type, and N-type). These
channels are essential in neuronal signaling,
neurotransmitter release, gene expression,
and cellular survival. The exact effects of VPA
on calcium channels are complex and depend
on, channel subtype, location, state, and co-
expression with other proteins.
Mechanism of Action
VPA inhibits T-type calcium channel , which
have been implicated in absence seizures
and thalamocortical oscillations.
VPA enhances L-type calcium channel ,
which are involved in neuronal plasticity and
neuroprotection.
VPA affect N-type calcium channel
associated with neuropathic pain and
migraine.
ADMINISTRATION
Administration
VPA is administered orally through tablets,
syrup, capsules, or IV .
The tablet comes in 2 variations, which include
a delayed-release formulation with strengths of
125 mg, 250 mg, and 500 mg and an extended-
release formulation with strengths of 250 mg
and 500 mg.
The capsule form of the medication is available
in 125 mg strength. The injectable formulation is
offered at a concentration of 100 mg/mL.
Adult Dosage
Complex partial seizures: The starting dose is
10-15 mg/kg/d, with an increase of 5-10 mg/kg/d
every 7 days. The maximum dosage is 60
mg/kg/d, and if doses exceed 250 mg daily, It is
administered in divided doses.
Simple or complex absence seizures: The
starting dose is 15 mg/kg/d, with an increase of
5-10 mg/kg/d every 7 days. The maximum
dosage is 60 mg/kg/d, if doses exceed 250 mg
daily, it is administered in divided dose.
Adult Dosage
Mania: the initial dosage is 25 mg/kg once daily, with
increase of up to 60 mg/kg/d. dose is 250-500 mg taken
3 times a day. In the case of the ER formulation,.
Migraines: 250-500 mg, taken twice daily for 1 week.
The ER formulation can be initiated at 500 mg,
administered once daily for 1 week. The dosage can be
escalated to a maximum of 1000 mg daily if necessary.
The therapeutic range for total valproate in epilepsy is
50 to 100 mcg/mL, and in mania, it is 50 to 125
mcg/mL. To achieve the maximum concentration within
the body, VPA takes around 14 days.
Specific Patient Population
 renal impairment: Dosage adjustments are not
required.
 hepatic impairment: VPA is contraindicated in patients
with hepatic impairment and or mitochondrial
disorders caused by mutations in the polymerase-
gamma (POLG) gene, as Alpers-Huttenlocher
syndrome. The use in patients with other types of
hepatic impairment requires close monitoring of LFTs.
In patients with Child-Pugh class A or B, the dose
should be decreased by 50%. For those with Child-
Pugh class C, the dose should be reduced by 75%.
The plasma concentration of VPA should be
maintained within the therapeutic range of 50 to 100
mcg/mL.
Specific Patient Population
 Pregnancy considerations: VPA traverse the placental
barrier and lead to teratogenic effects. VPA increases
the risk of major congenital malformations
1. Neural tube defects (NTDs) as spina bifida and
anencephaly. The risk of NTDs is about 10 times
higher than the general population,
2. Other malformations include craniofacial,
cardiovascular, hypospadias, and limb defects.
3. VPA affect fetal neurodevelopment and cause
cognitive impairment, behavioral problems, and
autism spectrum disorders.
Specific Patient Population
Breastfeeding considerations: VPA is excreted into
breast milk. The SE in breastfed infants include
1) Sedation, Irritability,
2) Poor feeding, Weight loss,
3) Thrombocytopenia,
4) Liver dysfunction.
The risk of SE is higher in infants younger than 2
months, especially those who are premature,
possess low birth weight, or have underlying
medical conditions.
Specific Patient Population
Pediatric patients:
VPA in pediatric requires close monitoring of clinical and
laboratory parameters. The dosage should be
personalized, considering age, weight, seizure type,
concurrent medications, and plasma concentration.
The initial dose for pediatric ranges from 10-15 mg/kg/d,
divided into 2 or 3 doses. The dosage can be increased
by 5-10 mg/kg/week until seizure control is achieved or
SE occur. The usual maintenance dose is 20 to 60
mg/kg/d. There is a risk of fatal hepatotoxicity especially
in children younger than 2.
Specific Patient Population
Geriatric patients: Older patients might experience
heightened vulnerability to the SE due to age-
related changes in pharmacokinetics and
increased susceptibility to hepatotoxicity. In this
population, it is advisable to commence with lower
initial doses and implement more gradual titration
schedules. Regularly monitoring liver function,
renal function, and potential drug interactions is
paramount in ensuring VPA's safe and effective
use in older patients.
SE
Common Adverse Effects of VPA
The common AE include gastrointestinal, neurological,
and hematological symptoms. The AE include
1. Headache, somnolence, dizziness, tremor, tinnitus,
blurred vision, nystagmus,
2. Abdominal pain, nausea and vomiting, diarrhea,
constipation,
3. Thrombocytopenia, petechiae and ecchymosis,
4. Asthenia, emotional lability, insomnia, depression,
rash, nervousness,
5. Weight changes, alopecia, appetite changes,
photosensitivity, myalgia, and dyspnea
6. Alanine transaminase (ALT) and aspartate
aminotransferase (AST) elevation,.
Severe Adverse Effects of VPA
1. Hepatotoxicity,
2. Hallucinations, Suicidality, psychosis,
3. Toxic epidermal necrolysis, Stevens-Johnson
syndrome, anaphylaxis,
4. Hyponatremia, SIADH, pancreatitis,
thrombocytopenia, pancytopenia,
hyperammonemia, myelosuppression, hypothermia,
aplastic anemia, bleeding, erythema multiforme,
5. Polycystic ovarian syndrome, cerebral
pseudoatrophy, encephalopathy, and coma.
these AE are infrequent, they can potentially be life-
threatening.
DRUG-DRUG INTERACTIONS
Drug-Drug Interactions
VPA interacts with an array of drugs;
Some can be beneficial and enhance the
therapeutic effect or reduce its AE.
Certain interactions can be detrimental,
potentially diminishing the therapeutic
efficacy or increasing AE.
Some interactions are bidirectional,
impacting both VPA and the concurrently
administered medication.
Enzyme-inducing drug interactions
VPA is a weak inhibitor of various cytochrome
P450 (CYP) enzymes, including CYP2C9 and
CYP2C19. Coadministration of drugs that
induce these enzymes, such as
carbamazepine, phenytoin, and rifampin, can
increase the metabolism of VPA. This may
result in decreased plasma concentration levels
and potentially compromise the efficacy of the
medication.
Enzyme-inhibiting drug
interactions
VPA is primarily metabolized via the
glucuronidation pathway, mediated by UGT
enzymes. Drugs that inhibit UGT enzymes,
such as aspirin, felbamate, and some
nonsteroidal anti-inflammatory drugs
(NSAIDs) lead to increased plasma
concentrations of VPA.
Protein-binding interactions
Valproic acid, phenytoin and tiagabine are
highly bound to plasma proteins.
When VPA is administered concurrently with
other highly protein-bound medications, as
salicylates and sulfonamides, the potential
exists for competition over albumin-binding
sites. This could potentially elevate the free
fraction of VPA and increase the risk of adverse
effects of the drug.
Interactions with antiepileptic
drugs
Carbamazepine, phenytoin, phenobarbital and
primidone stimulate the metabolism and reduce the
serum concentration of valproic acid; the plasma
concentration of valproic acid can be reduced on
average by 50–75%.
Caution is required when an enzyme-inducing agent
is discontinued, because the serum concentration of
concurrently administered AEDs may increase to
potentially toxic levels.
levetiracetam, gabapentin, pregabalin and vigabatrin
are not affected to any important extent by
comedication with other AEDs
Interactions with antiepileptic
drugs
The inhibition of the metabolism of lamotrigine and
phenobarbital by VPA. Inhibition of lamotrigine
metabolism at dosages of valproate around 500 mg day
and results in twofold increase in serum lamotrigine
level. patients comedicated with valproate lamotrigine
should be initiated at reduced dosages (in adults, 25 mg
on alternate days) and titrated slowly. Although, there is
no risk of rash when valproate is added on in a patient
already stabilized on lamotrigine, neurotoxic effects may
occur if the dosage of the latter is not reduced by about
50% as soon as the dosage of valproate reaches.
CONTRAINDICATIONS
Contraindications
VPA is contraindicated in patients with
1. significant hepatic impairment,
2. hypersensitivity to components of the drug
or its class,
3. urea cycle disorders,
4. mitochondrial disorders,
5. suspected disorders in patients younger
than 2
6. during pregnancy.
Caution is necessary
1. Individuals younger than 2,
2. Pediatric and geriatric populations,
3. Renal impairment,
4. Organic brain disorders, head injury, MR
5. Congenital metabolic disorders, hereditary
mitochondrial disorders, decreased
gastrointestinal transit time,
6. Hepatic disease,
7. Active or historical depression,
8. Undergoing multiple anticonvulsant
treatments,
9. Myelosuppression, bleeding.
Box warnings
Severe hepatic failure incidents have been
reported within the first 6 months of
treatment. Patients younger than 2 are at
elevated risk. Anticonvulsant polytherapy is
associated with an elevated risk of fatality.
In older patients, hepatotoxicity may present
with symptoms of weakness, lethargy,
anorexia, facial edema, vomiting, and loss of
seizure control.
Box warnings
Administering VPA to patients with
mitochondrial disease, specifically POLG-
related mitochondrial disorders, has been
shown to amplify the risk of hepatotoxicity and
mortality. VPA should only be used in patients
older than 2 with suspected mitochondrial
disorders who have not responded to
alternative anticonvulsant therapies. Close
monitoring of LFTs and screening for POLG
mutations are recommended in such cases.
Box warnings
VPA use can cause life-threatening
pancreatitis. Cases of hemorrhagic pancreatitis
with rapid progression to fatality have been
reported across all age groups, irrespective of
the treatment duration. If patients exhibit
symptoms suggestive of pancreatitis, such as
nausea, vomiting, abdominal pain, or anorexia,
it is recommended to discontinue the
medication and initiate alternative treatment
options based on clinical indication.
Box warnings
VPA can cause severe congenital malformations,
including NTDs, which result in lower IQ scores.,
elevated risk of autism spectrum disorders in
children.
The administration of VPA to pregnant for migraine
is contraindicated. According to APA guidelines,
women with bipolar disorder who opt to continue
VPA treatment during pregnancy should undergo
additional screening as their healthcare providers
recommend.
Monitoring
LFTs is monitored at baseline and then at regular
intervals, particularly within the first 6 months of
treatment. CBC with differential, coagulation tests, and
ammonia.
Screening to detect signs of depression, alterations in
behavior, and suicidality.
Serum drug levels; 50 to 100 mcg/mL for epilepsy and 50
to 125 mcg/mL for mania. The toxic levels are indicated
as >175 mcg/mL before the morning dose of VPA. When
hypoalbuminemia is present, assessing valproate's free
levels is essential, as the total concentration
measurements may be inaccurate.
TOXICITY
toxicity
Signs and Symptoms of Overdose
1. CNS depression manifest as drowsiness, confusion, ataxia,
nystagmus, diplopia, dysarthria, tremor, or coma.
2. Metabolic acidosis present with tachypnea, hypotension,
arrhythmias, or shock.
3. Hypernatremia manifest as thirst, dry mucous membranes,
agitation, seizures, or coma.
4. Hyperammonemia manifest as lethargy, vomiting, ataxia, or
encephalopathy.
5. Hepatotoxicity can be evident through elevated liver enzymes.
6. Pancreatitis,
7. Hypoglycemia
8. Multiorgan failure
toxicity
Management of Overdose
a) Discontinuation of VPA
b) Supportive care: monitoring vital signs,
maintaining airway patency, administering
respiratory support when needed, and
addressing fluid and electrolyte imbalances.
c) Enhanced elimination: In cases of severe
toxicity or significantly elevated VPA levels,
hemodialysis or hemoperfusion may be
considered.
THANK YOU

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Valproic Acid. (VPA). Antiseizure medication

  • 2. OUR POINTS 1. PHARMACOKINETICS 2. INDICATIONS 3. MECHANISM OF ACTION 4. ADMINISTRATION 5. SE 6. DRUG-DRUG INTERACTIONS 7. CONTRAINDICATIONS 8. TOXICITY
  • 3. Discovery VPA was initially synthesized in 1882 as a derivative of valeric acid (branched, short-chain, and naturally occurring fatty acid present in plants and animals). The anticonvulsant properties of VPA were discovered by in 1962. In 1966, the first human trial of VPA to treat epilepsy. They fined that VPA decreases the occurrence and intensity of seizures without causing significant AE. The FDA approved VPA in 1978 to treat absence seizures and in 1983 for treating complex partial seizures.
  • 5. Absorption VPA is absorbed from the GIT. its bioavailability is 81%- 89%, depending on the drug formulation, gastric emptying and food intake; The delayed-release and EX formulations reduces the peak plasma concentration and increase the drug's duration of action. The peak plasma concentration occurs within 1-4 h after administration of IR formulations and within 4-17h after administration of ER formulations. The absorption is enhanced by food, especially meals rich in fat. This elevate the bioavailability by 35% and extend the time required to reach peak concentration by 4h
  • 6. Distribution VPA exhibits a strong affinity for plasma proteins, with a binding rate of 90%. The binding rate of VPA is concentration dependent and decreases as the plasma concentration increases. The distribution volume is low (0.1-0.4 L/kg). VPA cross the BBB. Its concentration within the CSF is 10%-20% of its plasma concentration. VPA cross the placental barrier causing teratogenic effects. The fetal concentration of VPA is 70%-100% of the maternal concentration. VPA is excreted into breast milk, reaching concentrations similar to those in the plasma
  • 7. Metabolism VPA is extensively metabolized in the liver through A. Oxidation, B. Beta-oxidation, C. Conjugation with carnitine or glycine. D. Glucuronidation, primarily metabolizing pathway, is mediated by UDP-glucuronosyltransferase (UGT), leading to the formation of valproate glucuronide, the major inactive metabolite of VPA. Other metabolites of VPA include 2-propyl-4-pentenoic acid, 2-propyl-2-pentenoic acid, 3-keto-VPA, 3- hydroxy-VPA, and valproyl-CoA.
  • 8. Elimination The primary route of elimination is through the kidneys, involving the excretion of its metabolites. About 30% to 50% of the administered dose of VPA is excreted unchanged in the urine, whereas the rest is excreted as metabolites. The elimination rate of VPA is subject to dosage dependency and saturation effects, signifying that it adheres to zero-order kinetics at higher doses and shifts to first-order kinetics at lower doses.
  • 10. FDA-Approved Indications 1. A monotherapy and adjunctive therapy to address complex partial seizures in adult and pediatric patients aged 10 and older. 2. A standalone and adjunctive therapy to treat both simple and complex absence seizures in adults and pediatric patients. 3. An adjunctive therapy for patients with multiple seizure types, encompassing absence seizures.
  • 11. Off-Label Uses 1. Manic episodes associated with bipolar disorder 2. Migraine prophylaxis 3. Emergency treatment of status epilepticus 4. Diabetic peripheral neuropathy 5. Postherpetic neuralgia 6. Impulsivity, agitation, and aggression
  • 12. VPA in SE Infusion of valproate at either 1.5 or 3 mg/kg/min, The maximum dose per infusion permitted was 15-30 mg/kg. A recent systematic review compared the relative efficacy of five AEDs (valproate, lacosamide, levetiracetam, phenobarbital, phenytoin) in treatment of benzodiazepine- resistant convulsive SE showed that the efficacy of valproate was higher than that of other AEDs .
  • 13. VPA in SE Studies of the safety of IV valproate administration in patients with SE showed a low incidence of AE overall (<10 %) mainly dizziness, thrombocytopenia, and mild hypotension), which was independent of infusion rates. There were no unexpected side effects.
  • 15. Mechanism of Action VPA has diverse mechanisms of action that are not yet fully comprehended. they include: Inhibition of voltage-gated sodium channels: VPA obstructs the entry of sodium ions into neurons, leading to decreased neuron excitability and firing rate. This prevents generating and propagating abnormal electrical impulses responsible for triggering seizures.
  • 16. Mechanism of Action Inhibition of gamma-aminobutyric acid (GABA) transaminases and uccinate semialdehyde dehydrogenase : VPA inhibits GABA transaminase enzymeand uccinate semialdehyde dehydrogenase, which are responsible for the degradation of GABA. In cases of neuropathic pain, VPA has been demonstrated to impede neurogenic inflammation through GABA-A receptor-mediated inhibition
  • 17. Mechanism of Action Enhancement of GABA synthesis: VPA stimulates the synthesis of GABA by increasing the expression and activity of glutamic acid decarboxylase (GAD), the enzyme responsible for converting glutamate into GABA.
  • 18. Mechanism of Action Inhibition of HDACs: VPA inhibits HDAC enzymes, notably HDAC1, which are involved in the regulation of gene expression by modifying the acetylation status of histones (proteins that wrap around DNA). This process leads to changes in chromatin structure, influencing the transcription of many genes, including those linked to neuronal plasticity, synaptic transmission, neurogenesis, neuroprotection, and inflammation. This phenomenon could potentially elucidate a portion of the enduring effects of VPA on mood, cognition, neurodevelopment, apoptosis, and its potential antitumor properties.
  • 19. Mechanism of Action Modulation of calcium channels: VPA modulates the activity of calcium channels, (T-type, L-type, and N-type). These channels are essential in neuronal signaling, neurotransmitter release, gene expression, and cellular survival. The exact effects of VPA on calcium channels are complex and depend on, channel subtype, location, state, and co- expression with other proteins.
  • 20. Mechanism of Action VPA inhibits T-type calcium channel , which have been implicated in absence seizures and thalamocortical oscillations. VPA enhances L-type calcium channel , which are involved in neuronal plasticity and neuroprotection. VPA affect N-type calcium channel associated with neuropathic pain and migraine.
  • 22. Administration VPA is administered orally through tablets, syrup, capsules, or IV . The tablet comes in 2 variations, which include a delayed-release formulation with strengths of 125 mg, 250 mg, and 500 mg and an extended- release formulation with strengths of 250 mg and 500 mg. The capsule form of the medication is available in 125 mg strength. The injectable formulation is offered at a concentration of 100 mg/mL.
  • 23. Adult Dosage Complex partial seizures: The starting dose is 10-15 mg/kg/d, with an increase of 5-10 mg/kg/d every 7 days. The maximum dosage is 60 mg/kg/d, and if doses exceed 250 mg daily, It is administered in divided doses. Simple or complex absence seizures: The starting dose is 15 mg/kg/d, with an increase of 5-10 mg/kg/d every 7 days. The maximum dosage is 60 mg/kg/d, if doses exceed 250 mg daily, it is administered in divided dose.
  • 24. Adult Dosage Mania: the initial dosage is 25 mg/kg once daily, with increase of up to 60 mg/kg/d. dose is 250-500 mg taken 3 times a day. In the case of the ER formulation,. Migraines: 250-500 mg, taken twice daily for 1 week. The ER formulation can be initiated at 500 mg, administered once daily for 1 week. The dosage can be escalated to a maximum of 1000 mg daily if necessary. The therapeutic range for total valproate in epilepsy is 50 to 100 mcg/mL, and in mania, it is 50 to 125 mcg/mL. To achieve the maximum concentration within the body, VPA takes around 14 days.
  • 25. Specific Patient Population  renal impairment: Dosage adjustments are not required.  hepatic impairment: VPA is contraindicated in patients with hepatic impairment and or mitochondrial disorders caused by mutations in the polymerase- gamma (POLG) gene, as Alpers-Huttenlocher syndrome. The use in patients with other types of hepatic impairment requires close monitoring of LFTs. In patients with Child-Pugh class A or B, the dose should be decreased by 50%. For those with Child- Pugh class C, the dose should be reduced by 75%. The plasma concentration of VPA should be maintained within the therapeutic range of 50 to 100 mcg/mL.
  • 26. Specific Patient Population  Pregnancy considerations: VPA traverse the placental barrier and lead to teratogenic effects. VPA increases the risk of major congenital malformations 1. Neural tube defects (NTDs) as spina bifida and anencephaly. The risk of NTDs is about 10 times higher than the general population, 2. Other malformations include craniofacial, cardiovascular, hypospadias, and limb defects. 3. VPA affect fetal neurodevelopment and cause cognitive impairment, behavioral problems, and autism spectrum disorders.
  • 27. Specific Patient Population Breastfeeding considerations: VPA is excreted into breast milk. The SE in breastfed infants include 1) Sedation, Irritability, 2) Poor feeding, Weight loss, 3) Thrombocytopenia, 4) Liver dysfunction. The risk of SE is higher in infants younger than 2 months, especially those who are premature, possess low birth weight, or have underlying medical conditions.
  • 28. Specific Patient Population Pediatric patients: VPA in pediatric requires close monitoring of clinical and laboratory parameters. The dosage should be personalized, considering age, weight, seizure type, concurrent medications, and plasma concentration. The initial dose for pediatric ranges from 10-15 mg/kg/d, divided into 2 or 3 doses. The dosage can be increased by 5-10 mg/kg/week until seizure control is achieved or SE occur. The usual maintenance dose is 20 to 60 mg/kg/d. There is a risk of fatal hepatotoxicity especially in children younger than 2.
  • 29. Specific Patient Population Geriatric patients: Older patients might experience heightened vulnerability to the SE due to age- related changes in pharmacokinetics and increased susceptibility to hepatotoxicity. In this population, it is advisable to commence with lower initial doses and implement more gradual titration schedules. Regularly monitoring liver function, renal function, and potential drug interactions is paramount in ensuring VPA's safe and effective use in older patients.
  • 30. SE
  • 31. Common Adverse Effects of VPA The common AE include gastrointestinal, neurological, and hematological symptoms. The AE include 1. Headache, somnolence, dizziness, tremor, tinnitus, blurred vision, nystagmus, 2. Abdominal pain, nausea and vomiting, diarrhea, constipation, 3. Thrombocytopenia, petechiae and ecchymosis, 4. Asthenia, emotional lability, insomnia, depression, rash, nervousness, 5. Weight changes, alopecia, appetite changes, photosensitivity, myalgia, and dyspnea 6. Alanine transaminase (ALT) and aspartate aminotransferase (AST) elevation,.
  • 32. Severe Adverse Effects of VPA 1. Hepatotoxicity, 2. Hallucinations, Suicidality, psychosis, 3. Toxic epidermal necrolysis, Stevens-Johnson syndrome, anaphylaxis, 4. Hyponatremia, SIADH, pancreatitis, thrombocytopenia, pancytopenia, hyperammonemia, myelosuppression, hypothermia, aplastic anemia, bleeding, erythema multiforme, 5. Polycystic ovarian syndrome, cerebral pseudoatrophy, encephalopathy, and coma. these AE are infrequent, they can potentially be life- threatening.
  • 34. Drug-Drug Interactions VPA interacts with an array of drugs; Some can be beneficial and enhance the therapeutic effect or reduce its AE. Certain interactions can be detrimental, potentially diminishing the therapeutic efficacy or increasing AE. Some interactions are bidirectional, impacting both VPA and the concurrently administered medication.
  • 35. Enzyme-inducing drug interactions VPA is a weak inhibitor of various cytochrome P450 (CYP) enzymes, including CYP2C9 and CYP2C19. Coadministration of drugs that induce these enzymes, such as carbamazepine, phenytoin, and rifampin, can increase the metabolism of VPA. This may result in decreased plasma concentration levels and potentially compromise the efficacy of the medication.
  • 36. Enzyme-inhibiting drug interactions VPA is primarily metabolized via the glucuronidation pathway, mediated by UGT enzymes. Drugs that inhibit UGT enzymes, such as aspirin, felbamate, and some nonsteroidal anti-inflammatory drugs (NSAIDs) lead to increased plasma concentrations of VPA.
  • 37. Protein-binding interactions Valproic acid, phenytoin and tiagabine are highly bound to plasma proteins. When VPA is administered concurrently with other highly protein-bound medications, as salicylates and sulfonamides, the potential exists for competition over albumin-binding sites. This could potentially elevate the free fraction of VPA and increase the risk of adverse effects of the drug.
  • 38. Interactions with antiepileptic drugs Carbamazepine, phenytoin, phenobarbital and primidone stimulate the metabolism and reduce the serum concentration of valproic acid; the plasma concentration of valproic acid can be reduced on average by 50–75%. Caution is required when an enzyme-inducing agent is discontinued, because the serum concentration of concurrently administered AEDs may increase to potentially toxic levels. levetiracetam, gabapentin, pregabalin and vigabatrin are not affected to any important extent by comedication with other AEDs
  • 39. Interactions with antiepileptic drugs The inhibition of the metabolism of lamotrigine and phenobarbital by VPA. Inhibition of lamotrigine metabolism at dosages of valproate around 500 mg day and results in twofold increase in serum lamotrigine level. patients comedicated with valproate lamotrigine should be initiated at reduced dosages (in adults, 25 mg on alternate days) and titrated slowly. Although, there is no risk of rash when valproate is added on in a patient already stabilized on lamotrigine, neurotoxic effects may occur if the dosage of the latter is not reduced by about 50% as soon as the dosage of valproate reaches.
  • 41. Contraindications VPA is contraindicated in patients with 1. significant hepatic impairment, 2. hypersensitivity to components of the drug or its class, 3. urea cycle disorders, 4. mitochondrial disorders, 5. suspected disorders in patients younger than 2 6. during pregnancy.
  • 42. Caution is necessary 1. Individuals younger than 2, 2. Pediatric and geriatric populations, 3. Renal impairment, 4. Organic brain disorders, head injury, MR 5. Congenital metabolic disorders, hereditary mitochondrial disorders, decreased gastrointestinal transit time, 6. Hepatic disease, 7. Active or historical depression, 8. Undergoing multiple anticonvulsant treatments, 9. Myelosuppression, bleeding.
  • 43. Box warnings Severe hepatic failure incidents have been reported within the first 6 months of treatment. Patients younger than 2 are at elevated risk. Anticonvulsant polytherapy is associated with an elevated risk of fatality. In older patients, hepatotoxicity may present with symptoms of weakness, lethargy, anorexia, facial edema, vomiting, and loss of seizure control.
  • 44. Box warnings Administering VPA to patients with mitochondrial disease, specifically POLG- related mitochondrial disorders, has been shown to amplify the risk of hepatotoxicity and mortality. VPA should only be used in patients older than 2 with suspected mitochondrial disorders who have not responded to alternative anticonvulsant therapies. Close monitoring of LFTs and screening for POLG mutations are recommended in such cases.
  • 45. Box warnings VPA use can cause life-threatening pancreatitis. Cases of hemorrhagic pancreatitis with rapid progression to fatality have been reported across all age groups, irrespective of the treatment duration. If patients exhibit symptoms suggestive of pancreatitis, such as nausea, vomiting, abdominal pain, or anorexia, it is recommended to discontinue the medication and initiate alternative treatment options based on clinical indication.
  • 46. Box warnings VPA can cause severe congenital malformations, including NTDs, which result in lower IQ scores., elevated risk of autism spectrum disorders in children. The administration of VPA to pregnant for migraine is contraindicated. According to APA guidelines, women with bipolar disorder who opt to continue VPA treatment during pregnancy should undergo additional screening as their healthcare providers recommend.
  • 47. Monitoring LFTs is monitored at baseline and then at regular intervals, particularly within the first 6 months of treatment. CBC with differential, coagulation tests, and ammonia. Screening to detect signs of depression, alterations in behavior, and suicidality. Serum drug levels; 50 to 100 mcg/mL for epilepsy and 50 to 125 mcg/mL for mania. The toxic levels are indicated as >175 mcg/mL before the morning dose of VPA. When hypoalbuminemia is present, assessing valproate's free levels is essential, as the total concentration measurements may be inaccurate.
  • 49. toxicity Signs and Symptoms of Overdose 1. CNS depression manifest as drowsiness, confusion, ataxia, nystagmus, diplopia, dysarthria, tremor, or coma. 2. Metabolic acidosis present with tachypnea, hypotension, arrhythmias, or shock. 3. Hypernatremia manifest as thirst, dry mucous membranes, agitation, seizures, or coma. 4. Hyperammonemia manifest as lethargy, vomiting, ataxia, or encephalopathy. 5. Hepatotoxicity can be evident through elevated liver enzymes. 6. Pancreatitis, 7. Hypoglycemia 8. Multiorgan failure
  • 50. toxicity Management of Overdose a) Discontinuation of VPA b) Supportive care: monitoring vital signs, maintaining airway patency, administering respiratory support when needed, and addressing fluid and electrolyte imbalances. c) Enhanced elimination: In cases of severe toxicity or significantly elevated VPA levels, hemodialysis or hemoperfusion may be considered.