SODIUM VALPROATE - A REVIEWSODIUM VALPROATE - A REVIEW

Dr. Dr. B. PRAKASHB. PRAKASH. MD. DM. FAGE.,. MD. DM. FAGE.,

Associate Professor – Neurology (PSG IMS & R)Associate Professor – Neurology (PSG IMS & R)89 – A, East Lokamanya Street, RS Puram, Coimbatore.89 – A, East Lokamanya Street, RS Puram, Coimbatore.

prakashneuro@yahoo.co.in, 978 948 1179 / 936 32 00 393 prakashneuro@yahoo.co.in, 978 948 1179 / 936 32 00 393

EPILEPSY MANAGEMENT MEETEPILEPSY MANAGEMENT MEETBy COIMBATORE NEURO CLUB By COIMBATORE NEURO CLUB And SANOFI AVENTIS And SANOFI AVENTIS

HOTEL ALANKAR GRANDEHOTEL ALANKAR GRANDERam Nagar, CoimbatoreRam Nagar, Coimbatore99thth April, 2011. 7:30 pm April, 2011. 7:30 pm

SVP - INTRODUCTIONSVP - INTRODUCTION

SVP is first line AED with broadest spectrum of activitySVP is first line AED with broadest spectrum of activity

Excellent Efficacy : >35 yrs of clinical experience (1963)Excellent Efficacy : >35 yrs of clinical experience (1963)

Its efficacy as monotherapy is equivalent to that of Its efficacy as monotherapy is equivalent to that of

CBZ, DPH, PB in both Generalized & Partial EpilepsiesCBZ, DPH, PB in both Generalized & Partial Epilepsies

It is also used in other conditionsIt is also used in other conditions

The GI adv. effects are overcome with EC tabletsThe GI adv. effects are overcome with EC tablets

SVP- ABSORPTIONSVP- ABSORPTIONBioavailabilityBioavailability

Oral VA = Rectal VA Syp = Intravenous VAOral VA = Rectal VA Syp = Intravenous VAAbsorptionAbsorption

Syrup and uncoated tablet Syrup and uncoated tablet Rapidly absorbed.Rapidly absorbed. Peak level 2hrsPeak level 2hrs

Enteric coated tabletEnteric coated tablet Absorbed slowlyAbsorbed slowly Only after reaching duodenumOnly after reaching duodenum

Delay in the absorptionDelay in the absorption Delayed Gastric emptying timeDelayed Gastric emptying time Co-administration with foodCo-administration with food

SVP - PharmacokineticsSVP - PharmacokineticsBioavailability : 80 -100%Bioavailability : 80 -100%

Reaches brain: 95% in first pass effectReaches brain: 95% in first pass effect

Metabolism : Glucuronidation, Metabolism : Glucuronidation, ββ Oxidation Oxidation

Catalyzed by CYP 450 when co-administeredCatalyzed by CYP 450 when co-administered

Protein binding is reduced in Protein binding is reduced in Elderly, Chronic Hepatic Disease, Renal Impairment, Other Drugs (Aspirin)Elderly, Chronic Hepatic Disease, Renal Impairment, Other Drugs (Aspirin)

SVP- Mechanism of ActionSVP- Mechanism of Action

Inhibition of GABA degradationInhibition of GABA degradationIncrease in GABA synthesisIncrease in GABA synthesisInhibition of NMDA receptorsInhibition of NMDA receptorsBlockade of Na+ channelsBlockade of Na+ channels

main in focal seizmain in focal seiz

Acts against spike wave dischargesActs against spike wave dischargesReduces ictal activity in cortexReduces ictal activity in cortex

SVP- ELIMINATIONSVP- ELIMINATIONT ½ : 14 hours ; (With enzyme inducers - 9 hours)T ½ : 14 hours ; (With enzyme inducers - 9 hours)Elimination is only by metabolism Elimination is only by metabolism Metabolites: Metabolites:

VA Glucuronide (40% of VA) VA Glucuronide (40% of VA) Urinary excretion Urinary excretion3 oxo VA (33% of VA) 3 oxo VA (33% of VA) Urinary excretion Urinary excretion2 ene VA2 ene VA

Delayed but significant accumulation in brainDelayed but significant accumulation in brain Cleared slowly / No embryo / Hepato toxicityCleared slowly / No embryo / Hepato toxicity Better AED than VABetter AED than VA

VA VA 4 ene VA (By 4 ene VA (By Cyt P 450) Cyt P 450) Hepatotoxicity Hepatotoxicity DPH / PB / CBZ induces P450 DPH / PB / CBZ induces P450 Hepatotoxicity Hepatotoxicity

SODIUM VALPROATE - DOSAGESODIUM VALPROATE - DOSAGE( 2 - 3 Times Daily )( 2 - 3 Times Daily )

ADULTADULTInitial Initial : 400 - 500 mg/d: 400 - 500 mg/dMaintenance Maintenance : 500 - 2500 mg/d: 500 - 2500 mg/d

CHILDRENCHILDRENInitial Initial : 15 mg/kg/d, : 15 mg/kg/d,

Maintenance Maintenance : 20 - 40 mg/kg/d (< 20 kg wt) : 20 - 40 mg/kg/d (< 20 kg wt) : 20 - 30 mg/kg/d (>20 kg wt): 20 - 30 mg/kg/d (>20 kg wt)

SVP – DOSE ADJUSTMENTSVP – DOSE ADJUSTMENT

CONDITIONS ↓/↑ REASON

CHILDREN ↑ Rapid metabolizer

NEONATES ↓ Slow metabolizer / ↑ Unbound fraction

OLD AGE ↓ ↓ Protein binding / Reduced clearance

PREGNANCY No change ↓ Total level / ↑ Unbound fraction

CIRRHOSIS ↓ ↓ Protein binding / ↓ Unbound clearance

RENAL DISEASE Slightly ↓ No impact on pharmacokinetics/ ↓ Protein binding

SVP – IV Infusion SVP – IV Infusion (1996)(1996)

BolusBolus15 to 20 mg/kg over 5 to 10 minutes (at 1.5 - 3mg/kg/min)15 to 20 mg/kg over 5 to 10 minutes (at 1.5 - 3mg/kg/min)For 60 Kg Adult: 100 mg /min for 10 min (1000 mg bolus)For 60 Kg Adult: 100 mg /min for 10 min (1000 mg bolus)

Constant infusionConstant infusionAdult : 0.5 mg/kg/hr (1mg/kg/hr in pts on enzyme inducers)Adult : 0.5 mg/kg/hr (1mg/kg/hr in pts on enzyme inducers)Children: 1 mg/kg/hr (1.5mg/kg/hr in pts on Enzyme inducers)Children: 1 mg/kg/hr (1.5mg/kg/hr in pts on Enzyme inducers)

Tolerable loading dose in rare circumstancesTolerable loading dose in rare circumstances6 mg/kg/min up to 45mg/kg6 mg/kg/min up to 45mg/kgFor 60 Kg Adult: 360 mg / min over 7 min (2700 mg bolus)For 60 Kg Adult: 360 mg / min over 7 min (2700 mg bolus)

SAFETY OF RAPID IV SVP INFUSIONSAFETY OF RAPID IV SVP INFUSION

Rapid admn of undiluted SVP is safeRapid admn of undiluted SVP is safe

No adverse effects in CVS, CNS,GI during rapid infusionNo adverse effects in CVS, CNS,GI during rapid infusion

Main adverse effect : Pain/burning at infusion site Main adverse effect : Pain/burning at infusion site Epilepsia 48.3:478-483,2007 Epilepsia 48.3:478-483,2007

SVP – IV Dose and efficacy in SESVP – IV Dose and efficacy in SE

TYPE OF SE VPA DOSE (mg/kg)(range) Success rate

Partial onset TCSEGeneralized TCSE

32.8 (20-50)29.4 (20-40)

89%90%

Absence SEInfantile spasm

27.5 ( 20-30)41.9 (30-60)

80%75%

Neonatal SECP SE

35.4 (20-50)39.9 (30-50)

80%67%

IDEAL TIME FOR IDEAL TIME FOR TROUGH LEVEL ASSESMENT ? TROUGH LEVEL ASSESMENT ? (8am – 8pm)(8am – 8pm)

a)a) Fasting, at 6 amFasting, at 6 am

b)b) Just before morning dose, at 8 amJust before morning dose, at 8 am

c)c) 2 hrs after morning dose, at 10 am2 hrs after morning dose, at 10 am

d)d) 4 hrs after morning dose, at 12 noon4 hrs after morning dose, at 12 noon

e)e) Trough levels could not be assessedTrough levels could not be assessed This graph is not for this answer

SVP - SERUM LEVEL MONITORINGSVP - SERUM LEVEL MONITORING

Indications :Indications :Combination therapy with enzyme inducersCombination therapy with enzyme inducers

Reference range :Reference range :50 - 100 mg/L ( 350-700 µmol/L)50 - 100 mg/L ( 350-700 µmol/L)

Limitations :Limitations :Short half lifeShort half lifeHigh fluctuationsHigh fluctuationsPoor correlation of Sr level and cl. effect at a particular timePoor correlation of Sr level and cl. effect at a particular time

MULTIPLE MEASUREMENT & CAUTIOUS CORRELATIONMULTIPLE MEASUREMENT & CAUTIOUS CORRELATION

SVP- DRUG INTERACTION MECHANISMSSVP- DRUG INTERACTION MECHANISMS

Metabolism of SVP is sensitive to enzyme inductionMetabolism of SVP is sensitive to enzyme induction

SVP inhibits the metabolism of other drugsSVP inhibits the metabolism of other drugs

SVP has high affinity to Serum Proteins SVP has high affinity to Serum Proteins displaces displaces other drugs from proteinsother drugs from proteins

SVP- DRUG INTERACTIONSSVP- DRUG INTERACTIONS

SVP SVP Increases the serum levels of Increases the serum levels ofPhenobarbitone Phenobarbitone : 70%: 70%Lamotrigine Lamotrigine : > 2.5 times of T ½ : > 2.5 times of T ½

( In patients on SVP - Introduce LTG gradually )( In patients on SVP - Introduce LTG gradually )( While W/D of SVP - Increase the dose of LTG rapidly )( While W/D of SVP - Increase the dose of LTG rapidly )

CBZ Metabolite increasedCBZ Metabolite increasedDPH levels DPH levels ↑ due to displacement from protein binding site↑ due to displacement from protein binding siteOthers: Others:

Rufinamide, Lorazepam, Felbamate, Rufinamide, Lorazepam, Felbamate, TCAs, Zidovudine, Nimodipine TCAs, Zidovudine, Nimodipine

SVP- DRUG INTERACTIONSSVP- DRUG INTERACTIONS

BENEFITSBENEFITS

In cases of failure of Mono TherapyIn cases of failure of Mono Therapy

SVP + LTG : Good seizure controlSVP + LTG : Good seizure control

SVP + ETX : Good control of absence seizures SVP + ETX : Good control of absence seizures

SVP- DRUG INTERACTIONSSVP- DRUG INTERACTIONS

Drugs Drugs ↑Serum SVP (May ↑Serum SVP (May SVP Toxicity) SVP Toxicity)

Felbamate (Enzyme Inhibitor)Felbamate (Enzyme Inhibitor)

Stiripentol / Stiripentol / ClobazamClobazam

Fluoxetine / Fluoxetine / INH / Aspirin INH / Aspirin

SVP- DRUG INTERACTIONS SVP- DRUG INTERACTIONS

DRUGS DRUGS ↓ Serum SVP ↓ Serum SVP DPH / PB / CBZ / PrimidoneDPH / PB / CBZ / Primidone By enzyme induction By enzyme induction

CBZ + DPH (Combined)CBZ + DPH (Combined) ↓ SVP by 50% ↓ SVP by 50% (Reduction is more in children)(Reduction is more in children)

Lamotrigine Lamotrigine ↓ SVP by 25% ↓ SVP by 25%

Estrogen (OCP)Estrogen (OCP) ↓ SVP ↓ SVP

Others Others ↓ SVP ↓ SVP(Meropenem, Imepenam, Rifampicin, Ritonavir) (Meropenem, Imepenam, Rifampicin, Ritonavir)

SVP- INDICATIONSSVP- INDICATIONS

Gen seizuresGen seizuresGTCSGTCSAbsence SeizuresAbsence SeizuresMyoclonic SeizuresMyoclonic Seizures

Partial seizuresPartial seizures SPS SPS CPSCPS LGSLGS WSWS Neonatal seizure Neonatal seizure Febrile seizuresFebrile seizures

SVP - EFFICACYSVP - EFFICACY

Primary Generalized SeizuresPrimary Generalized SeizuresAbsence seizuresAbsence seizuresGeneralized Tonic Clonic SeizuresGeneralized Tonic Clonic SeizuresMyoclonic SeizuresMyoclonic Seizures

True Broad spectrum AEDTrue Broad spectrum AEDGood efficacy against most SeizuresGood efficacy against most SeizuresDifficult to classify epilepsiesDifficult to classify epilepsies

VALPROATELAMOTRIGINE

SVP in Generalized Tonic Clonic SeizSVP in Generalized Tonic Clonic Seiz

Highly effective as monotherapyHighly effective as monotherapy

Total control as add on if not controlled with 1Total control as add on if not controlled with 1stst drug drugEpilepsia: 1991; 4: 33-38Epilepsia: 1991; 4: 33-38

The control of Generalized Seizure is 73% in SVPThe control of Generalized Seizure is 73% in SVPOnly 47% in DPHOnly 47% in DPH

In children the response rate is still highIn children the response rate is still high

SVP IN ABSENCE SEIZURESSVP IN ABSENCE SEIZURES

Efficacy of SVP in absence seiz – well reportedEfficacy of SVP in absence seiz – well reported

SVP vs ETX : SVP vs ETX : EqualEqual in 2 studies in 2 studies

Dev. Med. Child. Neu. 1982;24;830-836Dev. Med. Child. Neu. 1982;24;830-836

Neurology 1982;32;157-163Neurology 1982;32;157-163

SVP achieves seizure control SVP achieves seizure control fasterfaster than LTG than LTG

Epilepsia : 2004; 45: 1049 -1053Epilepsia : 2004; 45: 1049 -1053

Simple absences Simple absences totally controlled with SVP totally controlled with SVP monotherapymonotherapy

Atypical / Complex absences need combination Atypical / Complex absences need combination

SVP + LTG / SVP + ETXSVP + LTG / SVP + ETX

SVP IN MYOCLONIC SVP IN MYOCLONIC EPILEPSYEPILEPSY

Drug of Choice in Myoclonic epilepsyDrug of Choice in Myoclonic epilepsy

EEG sensitivity to Photic Stimulation is suppressed by SVPEEG sensitivity to Photic Stimulation is suppressed by SVP

The response is excellent in Juvenile Myoclonic EpilepsyThe response is excellent in Juvenile Myoclonic Epilepsy

Good response in Benign Myoclonic epilepsy of infancyGood response in Benign Myoclonic epilepsy of infancy

Post anoxic intention Myoclonus Post anoxic intention Myoclonus Some success Some success

Progressive Myoclonus Epilepsy : SVP + Clonazepam usedProgressive Myoclonus Epilepsy : SVP + Clonazepam used

Studies of SVP in Partial SeizuresStudies of SVP in Partial Seizures

1984 - Seizure control is better than 1984 - Seizure control is better than CBZCBZ

1985 - Seizure control is 1985 - Seizure control is equalequal among DPH,CBZ & SVP among DPH,CBZ & SVP

1988 - 1988 - SVPSVP is better in Long term efficacy and safety is better in Long term efficacy and safety

1992 - Higher score for 1992 - Higher score for CBZ in 12 months, not after 24 monthsCBZ in 12 months, not after 24 months

SVP IN EPILEPSY SYNDROMESSVP IN EPILEPSY SYNDROMES

Lennox - Gastaut Syndrome :Lennox - Gastaut Syndrome :50-80% improvement in 1/350-80% improvement in 1/3rdrd of patients after SVP use of patients after SVP use

West Syndrome (Infantile Spasms):West Syndrome (Infantile Spasms):8/19 does not require ACTH if SVP is used8/19 does not require ACTH if SVP is used

Dose: Dose: 20-6020-60 mg/Kg/d mg/Kg/d

Response is good with ACTH but Side effects are moreResponse is good with ACTH but Side effects are more

Overall efficacy of SVP is goodOverall efficacy of SVP is good

Long term efficacy of SVP vs. LTGLong term efficacy of SVP vs. LTGin IGE in children and adolescents in IGE in children and adolescents

Retention rate (Not discontinued):Retention rate (Not discontinued):After 12 months : SVP-89%, LTG 69%After 12 months : SVP-89%, LTG 69%After 24 months : SVP-83%, LTG-57%After 24 months : SVP-83%, LTG-57%

Reason for discontinuation :Reason for discontinuation :SVP- Hairloss, Diarrhoea, Abdominal discomfort, Weight gainSVP- Hairloss, Diarrhoea, Abdominal discomfort, Weight gainLTG- Lack of efficacyLTG- Lack of efficacy

SVP in STATUS EPILEPTICUSSVP in STATUS EPILEPTICUS

Low incidence of Respiratory & Cardiac depressionLow incidence of Respiratory & Cardiac depression

S/E : S/E : Hepatic dysfn, Pancreatitis, ↑Ammonia, ↑BT Hepatic dysfn, Pancreatitis, ↑Ammonia, ↑BT

SVP should be avoided in mitochondrial diseasesSVP should be avoided in mitochondrial diseases

SVP use in HeadacheSVP use in Headache

Prophylaxis against chronic migraineProphylaxis against chronic migraine

More useful in migraine than CTTHMore useful in migraine than CTTH

Highly effectiveHighly effective

Good tolerabilityGood tolerability

Excellent safety profileExcellent safety profile

Long term efficacyLong term efficacy

SVP – Other Clinical UsesSVP – Other Clinical Uses

Painful NeuropathyPainful Neuropathy

Trigeminal NeuralgiaTrigeminal Neuralgia

Bipolar DisordersBipolar Disorders

Acute Manic EpisodesAcute Manic Episodes

Certain neoplasmsCertain neoplasms

MND (SMA / ALS)MND (SMA / ALS)

SVP – Current Place in TherapySVP – Current Place in Therapy

Broad spectrum AEDBroad spectrum AED

First line therapy in IGEFirst line therapy in IGE

Not yet in the 1Not yet in the 1stst line in Partial Seizures line in Partial Seizures

DOC in Myoclonic epilepsyDOC in Myoclonic epilepsy

Use with cautionUse with caution Neonates and females with child bearing ageNeonates and females with child bearing age

SVP - Preferred situationsSVP - Preferred situations

Newly diagnosed epilepsyNewly diagnosed epilepsy

Multiple seizure typesMultiple seizure types

Epilepsies with Myoclonic componentEpilepsies with Myoclonic component

Photosensitive epilepsiesPhotosensitive epilepsies

Cognitive impairmentCognitive impairment

Special syndromes ( Dravet’s, West Syndrome)Special syndromes ( Dravet’s, West Syndrome)

BZD refractory Status epilepticusBZD refractory Status epilepticus

Elderly with cardiac conduction defectsElderly with cardiac conduction defects

SVP - HepatotoxicitySVP - HepatotoxicityFATAL HEPATOTOXICITY FATAL HEPATOTOXICITY Most feared S/EMost feared S/ESpecial risk in Inborn errors of metabolismSpecial risk in Inborn errors of metabolism

Urea cycle defects, Organic aciduriaUrea cycle defects, Organic aciduriaOther risk factorsOther risk factors

Young age Young age Polytherapy (1 in 20,000) vs Monotherapy (1 in 2,00,000)Polytherapy (1 in 20,000) vs Monotherapy (1 in 2,00,000)

Liver function monitoring is of little value Liver function monitoring is of little value Benign ↑in enzyme is common Benign ↑in enzyme is common Progressive ↑in enzyme is not seen before fatal hepatotoxicityProgressive ↑in enzyme is not seen before fatal hepatotoxicity

Clinical recognition of hepatic failure is important Clinical recognition of hepatic failure is important Nausea, jaundice, vomiting, edema, anorexia, Loss of seizure controlNausea, jaundice, vomiting, edema, anorexia, Loss of seizure control

SVP - Adverse effects : HepatopathySVP - Adverse effects : Hepatopathy

Type 1Type 1

Dose dependent elevation of Dose dependent elevation of liver enzymesliver enzymes

Normalize after Normalize after discontinuationdiscontinuation

Treated with carnitidine Treated with carnitidine supplementationsupplementation

Type 2Type 2Idiosyncratic, lethal but rareIdiosyncratic, lethal but rareSeveral mechanismsSeveral mechanisms

Inhibition of Inhibition of ββ Oxidation Oxidation Inhibition Of oxidative Inhibition Of oxidative

phosphorylation,phosphorylation, Inhibition of gluconeogenesisInhibition of gluconeogenesis Inhibition of urea synthesisInhibition of urea synthesis Steatogenic effectSteatogenic effect ↓ ↓ in intracellular carnitinein intracellular carnitine ↓ ↓ in intracellular coA (common in intracellular coA (common

path)path)Probably due to SVP Probably due to SVP

Metabolite: 4-ene -VPAMetabolite: 4-ene -VPA

SVP – Hepato toxicity ManagementSVP – Hepato toxicity Management

Regular Hepatic Failure measuresRegular Hepatic Failure measures

IV Cartinine has a protective roleIV Cartinine has a protective role

L - Cartinine supplementation should be given to L - Cartinine supplementation should be given to Cartinine deficiencyCartinine deficiency Symptomatic hyperammonemiaSymptomatic hyperammonemia Infants and children on VAInfants and children on VA Patients on ketogenic dietPatients on ketogenic diet Patients on haemodialysisPatients on haemodialysis Premature infants with parentral nutritionPremature infants with parentral nutrition

SVP- Adv eff: PANCREATITISSVP- Adv eff: PANCREATITISFirst described by Bataladen in 1979First described by Bataladen in 1979

Serious complicationSerious complicationIdiosyncratic reactionIdiosyncratic reactionDirect toxic effect of free radicals on Pancreatic cell membraneDirect toxic effect of free radicals on Pancreatic cell membrane

Vomiting/ abdominal pain Vomiting/ abdominal pain Suspect SuspectAmylase / Lipase Amylase / Lipase useful tools useful tools

20% ↑ is seen in patients on VA without pancreatitis20% ↑ is seen in patients on VA without pancreatitis

13% of Pancreatitis is drug induced 13% of Pancreatitis is drug induced

SVP - Neurologic Adv EffectsSVP - Neurologic Adv Effects

TremorTremorMost CommonMost Common

Like essential tremorLike essential tremor

Dose related Dose related

Occurs in 10%Occurs in 10%

Treated by ↓ing the doseTreated by ↓ing the dose

PropranololPropranolol

SVP - Neurologic Adv EffectsSVP - Neurologic Adv Effects

Unique / specific AE :Unique / specific AE :

Acute mental changes Acute mental changes Stupor/Coma Stupor/Coma

Gen. Delta waves in EEGGen. Delta waves in EEG

↑ ↑ Ammonia, ↓ Cartinine (Associated but not causative)Ammonia, ↓ Cartinine (Associated but not causative)

Reversible in 3 days of discontinuationReversible in 3 days of discontinuation

Occurs during adding 2Occurs during adding 2ndnd drug drug

SVP - ENCEPHALOPATHYSVP - ENCEPHALOPATHYFour forms:Four forms:1.1. Direct toxic effect of VPA with high serum VPA + normal NH3Direct toxic effect of VPA with high serum VPA + normal NH32.2. Encephalopathy with impaired liver function + ↑NH3Encephalopathy with impaired liver function + ↑NH33.3. Encephalopathy with Hepatopathy + Normal NH3Encephalopathy with Hepatopathy + Normal NH34.4. Hyper ammonemic EncephalopathyHyper ammonemic Encephalopathy(Liv Fail with hyper amm / without amm) (No Liv fail with amm / without amm)(Liv Fail with hyper amm / without amm) (No Liv fail with amm / without amm)

Mechanisms:Mechanisms: VPAVPA ↓Glutamate synthesis ↓Glutamate synthesis ↑NH3 ↑NH3 Direct Neuronal toxicity (↑Glutamate/ NH3 conc. in astrocytes)Direct Neuronal toxicity (↑Glutamate/ NH3 conc. in astrocytes)

ENCEPHALOPATHYENCEPHALOPATHY Extremely rare complicationExtremely rare complication Mostly in patients with inborn metabolism errorsMostly in patients with inborn metabolism errors More in SVP + TOP combinationMore in SVP + TOP combination

SVP - HyperammonemiaSVP - HyperammonemiaSVP / SVP+ Enzyme inducer SVP / SVP+ Enzyme inducer ↑NH ↑NH33 is common is common

Routine monitoring Routine monitoring notnot required required

Cartinine levels are low in SVP / PolypharmacyCartinine levels are low in SVP / Polypharmacy

Symptomatic ↑NHSymptomatic ↑NH33 occurs in urea cycle disorders occurs in urea cycle disorders which leads which leads to mental changes, encephalopathy, reye like syndrometo mental changes, encephalopathy, reye like syndrome

L-Cartinine L-Cartinine may ↓may ↓NHNH33 ( not clinically beneficial) ( not clinically beneficial)

SVP - Endocrine Adv. EffectsSVP - Endocrine Adv. Effects

Menstrual irregularitiesMenstrual irregularities

HyperandrogenismHyperandrogenism

Hyper insulinismHyper insulinism

Pubertal arrestPubertal arrest

SVP - Teratogenic Adv. EffectsSVP - Teratogenic Adv. Effects

Incidence of Neural tube defects : 1-2%Incidence of Neural tube defects : 1-2%

↑↑es with higher dosagees with higher dosage

Folate supplementation should be given (Role-?)Folate supplementation should be given (Role-?)

Developmental delay, Learning disabilityDevelopmental delay, Learning disability

SVP- Adverse effectsSVP- Adverse effects

Polycystic ovaries:Polycystic ovaries:

First reported by Isojardi in 1993First reported by Isojardi in 1993

Amenorrhea/ Oligomenorrhea/ Prolonged menstrual cycleAmenorrhea/ Oligomenorrhea/ Prolonged menstrual cycle

SVP SVP ↑Androgen synthesis in ovary↑Androgen synthesis in ovary

Testosterone Testosterone Estradiol (by Aromatase [Inhibited by SVP]) Estradiol (by Aromatase [Inhibited by SVP])

SVP- reduces efficacy of Oral contraceptivesSVP- reduces efficacy of Oral contraceptives

SVP- Miscellaneous Adverse EffectsSVP- Miscellaneous Adverse Effects

Thinning of hairThinning of hair

Hair loss Hair loss (long term/Biotin Def)(long term/Biotin Def)

Alopecia may occur (28%)Alopecia may occur (28%)

Nocturnal enuresisNocturnal enuresis

Facial / limb edemaFacial / limb edema

HyponatremiaHyponatremia

Skin rashes / SLESkin rashes / SLE

May May ↓Bone mineral density↓Bone mineral density

AsterixisAsterixis

LethargyLethargy

SedationSedation

ConfusionConfusion

DrowsinessDrowsiness

Reversible ParkinsonismReversible Parkinsonism

Reversible DementiaReversible Dementia

Pseudoatrophy of the BrainPseudoatrophy of the Brain

SVP- Hematologic Adv. EffectsSVP- Hematologic Adv. EffectsRareRare

Thrombocytopenia , Impaired platelet function, Fibrinogen Thrombocytopenia , Impaired platelet function, Fibrinogen depletion, Coagulation factor deficiencies may occur ( Dose depletion, Coagulation factor deficiencies may occur ( Dose Dependent )Dependent )

Stop SVP - 1 month before any major surgeryStop SVP - 1 month before any major surgery

Neutropenia / bone marrow suppression may also occurNeutropenia / bone marrow suppression may also occur

SVP- Adv eff: SVP- Adv eff: Weight gain Weight gain

Occurs in 20%Occurs in 20%

Mainly in adolescents, not in childrenMainly in adolescents, not in children

Cause : ↓Cause : ↓ββ-oxidation of fatty acids -oxidation of fatty acids

Associated with Associated with Increased IIncreased Insulin concentrationnsulin concentration

Interference of hepatic insulin metabolismInterference of hepatic insulin metabolism

High SVPHigh SVP level level

HypertriglyceridemiaHypertriglyceridemia

Lower HDL levelLower HDL level

SVP - GI Side EffectsSVP - GI Side Effects

GIGI Side effects: Side effects:Nausea, vomiting, anorexia, GI distressNausea, vomiting, anorexia, GI distress

less if enteric coated tab is usedless if enteric coated tab is used

SVP Over dosageSVP Over dosage

Over dosage leads to Over dosage leads to Somnolence, Heart block, Coma, Death Somnolence, Heart block, Coma, Death

ManagementManagementSVP and metabolites are DialysableSVP and metabolites are DialysableNaloxone reverses the CNS depressant effectsNaloxone reverses the CNS depressant effects

CONCLUSIONCONCLUSION

SVP is the first line AED in most cases of Epilepsy.SVP is the first line AED in most cases of Epilepsy.

The serious SE are less commonThe serious SE are less common

The common SE are tolerableThe common SE are tolerable

If used with caution, SVP is the dependable AEDIf used with caution, SVP is the dependable AED

Avoid SVP in : Hepatic impairment / Child bearing age womenAvoid SVP in : Hepatic impairment / Child bearing age women

DOC in : Absences / Myoclonic / GTCS DOC in : Absences / Myoclonic / GTCS

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