SODIUM VALPROATE - A REVIEW Dr.  B. PRAKASH . MD. DM. FAGE., Associate Professor – Neurology (PSG IMS & R) 89 – A, East Lo...
SVP - INTRODUCTION <ul><li>SVP is first line AED with broadest spectrum of activity </li></ul><ul><li>Excellent Efficacy :...
SVP- ABSORPTION <ul><li>Bioavailability </li></ul><ul><ul><li>Oral VA = Rectal VA Syp  = Intravenous VA </li></ul></ul><ul...
SVP - Pharmacokinetics <ul><li>Bioavailability : 80 -100% </li></ul><ul><li>Reaches brain:  95% in first pass effect </li>...
SVP- Mechanism of Action <ul><li>Inhibition of GABA degradation </li></ul><ul><li>Increase in GABA synthesis </li></ul><ul...
SVP- ELIMINATION <ul><li>T ½ : 14 hours ;  (With enzyme inducers - 9 hours) </li></ul><ul><li>Elimination is only by metab...
SODIUM VALPROATE - DOSAGE ( 2 - 3 Times Daily ) <ul><li>ADULT </li></ul><ul><li>Initial  : 400 - 500  mg/d </li></ul><ul><...
SVP – DOSE ADJUSTMENT CONDITIONS ↓ /↑ REASON CHILDREN ↑ Rapid metabolizer NEONATES ↓ Slow metabolizer / ↑ Unbound fraction...
SVP – IV Infusion  (1996) <ul><li>Bolus </li></ul><ul><li>15 to 20 mg/kg over 5 to 10 minutes (at 1.5 - 3mg/kg/min) </li><...
SAFETY OF RAPID IV SVP INFUSION <ul><li>Rapid admn of undiluted SVP is safe </li></ul><ul><li>No adverse effects in CVS, C...
SVP – IV  Dose and efficacy in SE TYPE OF SE VPA DOSE (mg/kg)(range) Success rate Partial onset TCSE Generalized TCSE 32.8...
IDEAL TIME FOR  TROUGH LEVEL ASSESMENT ?  (8am – 8pm) <ul><li>Fasting, at 6 am </li></ul><ul><li>Just before morning dose,...
SVP - SERUM LEVEL MONITORING <ul><li>Indications : </li></ul><ul><li>Combination therapy with enzyme inducers </li></ul><u...
SVP- DRUG INTERACTION MECHANISMS <ul><li>Metabolism of SVP is sensitive to enzyme induction </li></ul><ul><li>SVP inhibits...
SVP- DRUG INTERACTIONS <ul><li>SVP    Increases the serum levels of </li></ul><ul><li>Phenobarbitone  : 70% </li></ul><ul...
SVP- DRUG INTERACTIONS <ul><li>BENEFITS </li></ul><ul><li>In cases of failure of Mono Therapy </li></ul><ul><ul><li>SVP + ...
SVP- DRUG INTERACTIONS <ul><li>Drugs     ↑Serum SVP  (May    SVP Toxicity) </li></ul><ul><li>Felbamate  (Enzyme Inhibito...
SVP- DRUG INTERACTIONS  <ul><li>DRUGS     ↓ Serum SVP  </li></ul><ul><li>DPH / PB / CBZ / Primidone   By enzyme inductio...
SVP- INDICATIONS <ul><li>Gen seizures </li></ul><ul><ul><li>GTCS </li></ul></ul><ul><ul><li>Absence Seizures </li></ul></u...
SVP - EFFICACY <ul><li>Primary Generalized Seizures </li></ul><ul><ul><li>Absence seizures </li></ul></ul><ul><ul><li>Gene...
VALPROATE LAMOTRIGINE
SVP in Generalized Tonic Clonic Seiz <ul><li>Highly effective as monotherapy </li></ul><ul><li>Total control as add on if ...
SVP IN ABSENCE SEIZURES <ul><li>Efficacy of SVP in absence seiz – well reported </li></ul><ul><li>SVP vs ETX :  Equal  in ...
SVP IN MYOCLONIC EPILEPSY <ul><li>Drug of Choice in Myoclonic epilepsy </li></ul><ul><li>EEG sensitivity to Photic Stimula...
Studies of SVP in Partial Seizures <ul><li>1984 - Seizure control is better than  CBZ </li></ul><ul><li>1985 - Seizure con...
SVP IN EPILEPSY SYNDROMES <ul><li>Lennox - Gastaut Syndrome : </li></ul><ul><li>50-80% improvement in 1/3 rd  of patients ...
Long term efficacy of SVP vs. LTG in IGE in children and adolescents  <ul><li>Retention rate (Not discontinued): </li></ul...
SVP in STATUS EPILEPTICUS <ul><li>Low incidence of Respiratory & Cardiac depression </li></ul><ul><li>S/E :  </li></ul><ul...
SVP use in Headache <ul><li>Prophylaxis against chronic migraine </li></ul><ul><li>More useful in  migraine than CTTH </li...
SVP – Other Clinical Uses <ul><li>Painful Neuropathy </li></ul><ul><li>Trigeminal Neuralgia </li></ul><ul><li>Bipolar Diso...
SVP – Current Place in Therapy <ul><li>Broad spectrum AED </li></ul><ul><li>First line therapy in IGE </li></ul><ul><li>No...
SVP - Preferred situations <ul><li>Newly diagnosed epilepsy </li></ul><ul><li>Multiple seizure types </li></ul><ul><li>Epi...
SVP - Hepatotoxicity <ul><li>FATAL HEPATOTOXICITY  </li></ul><ul><li>Most feared S/E </li></ul><ul><li>Special risk in Inb...
SVP - Adverse effects : Hepatopathy <ul><li>Type 1 </li></ul><ul><li>Dose dependent elevation of liver enzymes </li></ul><...
SVP  –  Hepato toxicity Management <ul><li>Regular Hepatic Failure measures </li></ul><ul><li>IV Cartinine has a protectiv...
SVP- Adv eff: PANCREATITIS <ul><li>First described by Bataladen in 1979 </li></ul><ul><li>Serious complication </li></ul><...
SVP - Neurologic Adv Effects <ul><li>Tremor </li></ul><ul><li>Most Common </li></ul><ul><li>Like essential tremor </li></u...
SVP - Neurologic Adv Effects <ul><li>Unique / specific AE : </li></ul><ul><li>Acute mental changes     Stupor/Coma </li><...
SVP - ENCEPHALOPATHY <ul><li>Four forms: </li></ul><ul><li>Direct toxic effect of VPA with high serum VPA + normal NH3 </l...
SVP - Hyperammonemia <ul><li>SVP / SVP+ Enzyme inducer     ↑NH 3  is common </li></ul><ul><li>Routine monitoring  not  re...
SVP - Endocrine Adv. Effects <ul><li>Menstrual irregularities </li></ul><ul><li>Hyperandrogenism </li></ul><ul><li>Hyper i...
SVP - Teratogenic Adv. Effects <ul><li>Incidence of Neural tube defects  : 1-2% </li></ul><ul><li>↑ es  with higher dosage...
SVP- Adverse effects <ul><li>Polycystic ovaries: </li></ul><ul><li>First reported by Isojardi in 1993 </li></ul><ul><li>Am...
SVP- Miscellaneous Adverse Effects <ul><li>Thinning of hair </li></ul><ul><li>Hair loss  (long term/Biotin Def) </li></ul>...
SVP- Hematologic Adv. Effects <ul><li>Rare </li></ul><ul><li>Thrombocytopenia , Impaired platelet function, Fibrinogen dep...
SVP- Adv eff:  Weight gain  <ul><li>Occurs in 20% </li></ul><ul><li>Mainly in adolescents, not in children </li></ul><ul><...
SVP - GI Side Effects <ul><li>GI  Side effects: </li></ul><ul><li>Nausea, vomiting, anorexia, GI distress </li></ul><ul><u...
SVP Over dosage <ul><li>Over dosage leads to  </li></ul><ul><ul><li>Somnolence, Heart block, Coma, Death  </li></ul></ul><...
CONCLUSION <ul><li>SVP is the first line AED in most cases of Epilepsy. </li></ul><ul><li>The serious SE are less common <...
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Sodium valproate a review

  1. 1. SODIUM VALPROATE - A REVIEW Dr. B. PRAKASH . MD. DM. FAGE., Associate Professor – Neurology (PSG IMS & R) 89 – A, East Lokamanya Street, RS Puram, Coimbatore. prakashneuro@yahoo.co.in, 978 948 1179 / 936 32 00 393 EPILEPSY MANAGEMENT MEET By COIMBATORE NEURO CLUB And SANOFI AVENTIS HOTEL ALANKAR GRANDE Ram Nagar, Coimbatore 9 th April, 2011. 7:30 pm
  2. 2. SVP - INTRODUCTION <ul><li>SVP is first line AED with broadest spectrum of activity </li></ul><ul><li>Excellent Efficacy : >35 yrs of clinical experience (1963) </li></ul><ul><li>Its efficacy as monotherapy is equivalent to that of CBZ, DPH, PB in both Generalized & Partial Epilepsies </li></ul><ul><li>It is also used in other conditions </li></ul><ul><li>The GI adv. effects are overcome with EC tablets </li></ul>
  3. 3. SVP- ABSORPTION <ul><li>Bioavailability </li></ul><ul><ul><li>Oral VA = Rectal VA Syp = Intravenous VA </li></ul></ul><ul><li>Absorption </li></ul><ul><ul><li>Syrup and uncoated tablet </li></ul></ul><ul><ul><ul><li>Rapidly absorbed. </li></ul></ul></ul><ul><ul><ul><li>Peak level 2hrs </li></ul></ul></ul><ul><ul><li>Enteric coated tablet </li></ul></ul><ul><ul><ul><li>Absorbed slowly </li></ul></ul></ul><ul><ul><ul><li>Only after reaching duodenum </li></ul></ul></ul><ul><ul><li>Delay in the absorption </li></ul></ul><ul><ul><ul><li>Delayed Gastric emptying time </li></ul></ul></ul><ul><ul><ul><li>Co-administration with food </li></ul></ul></ul>
  4. 4. SVP - Pharmacokinetics <ul><li>Bioavailability : 80 -100% </li></ul><ul><li>Reaches brain: 95% in first pass effect </li></ul><ul><li>Metabolism : Glucuronidation, β Oxidation </li></ul><ul><li>Catalyzed by CYP 450 when co-administered </li></ul><ul><li>Protein binding is reduced in </li></ul><ul><ul><li>Elderly, Chronic Hepatic Disease, Renal Impairment, Other Drugs (Aspirin) </li></ul></ul>
  5. 5. SVP- Mechanism of Action <ul><li>Inhibition of GABA degradation </li></ul><ul><li>Increase in GABA synthesis </li></ul><ul><li>Inhibition of NMDA receptors </li></ul><ul><li>Blockade of Na+ channels </li></ul><ul><ul><li>main in focal seiz </li></ul></ul><ul><li>Acts against spike wave discharges </li></ul><ul><li>Reduces ictal activity in cortex </li></ul>
  6. 6. SVP- ELIMINATION <ul><li>T ½ : 14 hours ; (With enzyme inducers - 9 hours) </li></ul><ul><li>Elimination is only by metabolism </li></ul><ul><li>Metabolites: </li></ul><ul><ul><li>VA Glucuronide (40% of VA)  Urinary excretion </li></ul></ul><ul><ul><li>3 oxo VA (33% of VA)  Urinary excretion </li></ul></ul><ul><ul><li>2 ene VA </li></ul></ul><ul><ul><ul><li>Delayed but significant accumulation in brain </li></ul></ul></ul><ul><ul><ul><li>Cleared slowly / No embryo / Hepato toxicity </li></ul></ul></ul><ul><ul><ul><li>Better AED than VA </li></ul></ul></ul><ul><li>VA  4 ene VA (By Cyt P 450)  Hepatotoxicity </li></ul><ul><li>DPH / PB / CBZ induces P450  Hepatotoxicity </li></ul>
  7. 7. SODIUM VALPROATE - DOSAGE ( 2 - 3 Times Daily ) <ul><li>ADULT </li></ul><ul><li>Initial : 400 - 500 mg/d </li></ul><ul><li>Maintenance : 500 - 2500 mg/d </li></ul><ul><li>CHILDREN </li></ul><ul><li>Initial : 15 mg/kg/d, </li></ul><ul><li>Maintenance : 20 - 40 mg/kg/d (< 20 kg wt) </li></ul><ul><li>: 20 - 30 mg/kg/d (>20 kg wt) </li></ul>
  8. 8. SVP – 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
  9. 9. SVP – IV Infusion (1996) <ul><li>Bolus </li></ul><ul><li>15 to 20 mg/kg over 5 to 10 minutes (at 1.5 - 3mg/kg/min) </li></ul><ul><li>For 60 Kg Adult: 100 mg /min for 10 min (1000 mg bolus) </li></ul><ul><li>Constant infusion </li></ul><ul><li>Adult : 0.5 mg/kg/hr (1mg/kg/hr in pts on enzyme inducers) </li></ul><ul><li>Children: 1 mg/kg/hr (1.5mg/kg/hr in pts on Enzyme inducers) </li></ul><ul><li>Tolerable loading dose in rare circumstances </li></ul><ul><li>6 mg/kg/min up to 45mg/kg </li></ul><ul><li>For 60 Kg Adult: 360 mg / min over 7 min (2700 mg bolus) </li></ul>
  10. 10. SAFETY OF RAPID IV SVP INFUSION <ul><li>Rapid admn of undiluted SVP is safe </li></ul><ul><li>No adverse effects in CVS, CNS,GI during rapid infusion </li></ul><ul><li>Main adverse effect : Pain/burning at infusion site </li></ul><ul><li>Epilepsia 48.3:478-483,2007 </li></ul>
  11. 11. SVP – IV Dose and efficacy in SE TYPE OF SE VPA DOSE (mg/kg)(range) Success rate Partial onset TCSE Generalized TCSE 32.8 (20-50) 29.4 (20-40) 89% 90% Absence SE Infantile spasm 27.5 ( 20-30) 41.9 (30-60) 80% 75% Neonatal SE CP SE 35.4 (20-50) 39.9 (30-50) 80% 67%
  12. 12. IDEAL TIME FOR TROUGH LEVEL ASSESMENT ? (8am – 8pm) <ul><li>Fasting, at 6 am </li></ul><ul><li>Just before morning dose, at 8 am </li></ul><ul><li>2 hrs after morning dose, at 10 am </li></ul><ul><li>4 hrs after morning dose, at 12 noon </li></ul><ul><li>Trough levels could not be assessed </li></ul>This graph is not for this answer
  13. 13. SVP - SERUM LEVEL MONITORING <ul><li>Indications : </li></ul><ul><li>Combination therapy with enzyme inducers </li></ul><ul><li>Reference range : </li></ul><ul><li>50 - 100 mg/L ( 350-700 µmol/L) </li></ul><ul><li>Limitations : </li></ul><ul><li>Short half life </li></ul><ul><li>High fluctuations </li></ul><ul><li>Poor correlation of Sr level and cl. effect at a particular time </li></ul><ul><li>MULTIPLE MEASUREMENT & CAUTIOUS CORRELATION </li></ul>
  14. 14. SVP- DRUG INTERACTION MECHANISMS <ul><li>Metabolism of SVP is sensitive to enzyme induction </li></ul><ul><li>SVP inhibits the metabolism of other drugs </li></ul><ul><li>SVP has high affinity to Serum Proteins  displaces other drugs from proteins </li></ul>
  15. 15. SVP- DRUG INTERACTIONS <ul><li>SVP  Increases the serum levels of </li></ul><ul><li>Phenobarbitone : 70% </li></ul><ul><li>Lamotrigine : > 2.5 times of T ½ </li></ul><ul><ul><ul><li>( In patients on SVP - Introduce LTG gradually ) </li></ul></ul></ul><ul><ul><ul><li>( While W/D of SVP - Increase the dose of LTG rapidly ) </li></ul></ul></ul><ul><li>CBZ Metabolite increased </li></ul><ul><li>DPH levels ↑ due to displacement from protein binding site </li></ul><ul><li>Others: </li></ul><ul><ul><li>Rufinamide, Lorazepam, Felbamate, </li></ul></ul><ul><ul><li>TCAs, Zidovudine, Nimodipine </li></ul></ul>
  16. 16. SVP- DRUG INTERACTIONS <ul><li>BENEFITS </li></ul><ul><li>In cases of failure of Mono Therapy </li></ul><ul><ul><li>SVP + LTG : Good seizure control </li></ul></ul><ul><ul><li>SVP + ETX : Good control of absence seizures </li></ul></ul>
  17. 17. SVP- DRUG INTERACTIONS <ul><li>Drugs  ↑Serum SVP (May  SVP Toxicity) </li></ul><ul><li>Felbamate (Enzyme Inhibitor) </li></ul><ul><li>Stiripentol / Clobazam </li></ul><ul><li>Fluoxetine / INH / Aspirin </li></ul>
  18. 18. SVP- DRUG INTERACTIONS <ul><li>DRUGS  ↓ Serum SVP </li></ul><ul><li>DPH / PB / CBZ / Primidone  By enzyme induction </li></ul><ul><li>CBZ + DPH (Combined)  ↓ SVP by 50% </li></ul><ul><ul><li>(Reduction is more in children) </li></ul></ul><ul><li>Lamotrigine  ↓ SVP by 25% </li></ul><ul><li>Estrogen (OCP)  ↓ SVP </li></ul><ul><li>Others  ↓ SVP </li></ul><ul><ul><li>(Meropenem, Imepenam, Rifampicin, Ritonavir) </li></ul></ul>
  19. 19. SVP- INDICATIONS <ul><li>Gen seizures </li></ul><ul><ul><li>GTCS </li></ul></ul><ul><ul><li>Absence Seizures </li></ul></ul><ul><ul><li>Myoclonic Seizures </li></ul></ul><ul><li>Partial seizures </li></ul><ul><ul><li>SPS </li></ul></ul><ul><ul><li>CPS </li></ul></ul><ul><ul><li>LGS </li></ul></ul><ul><ul><li>WS </li></ul></ul><ul><ul><li>Neonatal seizure </li></ul></ul><ul><ul><li>Febrile seizures </li></ul></ul>
  20. 20. SVP - EFFICACY <ul><li>Primary Generalized Seizures </li></ul><ul><ul><li>Absence seizures </li></ul></ul><ul><ul><li>Generalized Tonic Clonic Seizures </li></ul></ul><ul><ul><li>Myoclonic Seizures </li></ul></ul><ul><li>True Broad spectrum AED </li></ul><ul><li>Good efficacy against most Seizures </li></ul><ul><li>Difficult to classify epilepsies </li></ul>
  21. 21. VALPROATE LAMOTRIGINE
  22. 22. SVP in Generalized Tonic Clonic Seiz <ul><li>Highly effective as monotherapy </li></ul><ul><li>Total control as add on if not controlled with 1 st drug </li></ul><ul><ul><ul><li>Epilepsia: 1991; 4: 33-38 </li></ul></ul></ul><ul><li>The control of Generalized Seizure is 73% in SVP </li></ul><ul><ul><li>Only 47% in DPH </li></ul></ul><ul><li>In children the response rate is still high </li></ul>
  23. 23. SVP IN ABSENCE SEIZURES <ul><li>Efficacy of SVP in absence seiz – well reported </li></ul><ul><li>SVP vs ETX : Equal in 2 studies </li></ul><ul><ul><ul><li>Dev. Med. Child. Neu. 1982;24;830-836 </li></ul></ul></ul><ul><ul><ul><li>Neurology 1982;32;157-163 </li></ul></ul></ul><ul><li>SVP achieves seizure control faster than LTG </li></ul><ul><ul><ul><li>Epilepsia : 2004; 45: 1049 -1053 </li></ul></ul></ul><ul><li>Simple absences  totally controlled with SVP monotherapy </li></ul><ul><li>Atypical / Complex absences need combination </li></ul><ul><ul><li>SVP + LTG / SVP + ETX </li></ul></ul>
  24. 24. SVP IN MYOCLONIC EPILEPSY <ul><li>Drug of Choice in Myoclonic epilepsy </li></ul><ul><li>EEG sensitivity to Photic Stimulation is suppressed by SVP </li></ul><ul><li>The response is excellent in Juvenile Myoclonic Epilepsy </li></ul><ul><li>Good response in Benign Myoclonic epilepsy of infancy </li></ul><ul><li>Post anoxic intention Myoclonus  Some success </li></ul><ul><li>Progressive Myoclonus Epilepsy : SVP + Clonazepam used </li></ul>
  25. 25. Studies of SVP in Partial Seizures <ul><li>1984 - Seizure control is better than CBZ </li></ul><ul><li>1985 - Seizure control is equal among DPH,CBZ & SVP </li></ul><ul><li>1988 - SVP is better in Long term efficacy and safety </li></ul><ul><li>1992 - Higher score for CBZ in 12 months, not after 24 months </li></ul>
  26. 26. SVP IN EPILEPSY SYNDROMES <ul><li>Lennox - Gastaut Syndrome : </li></ul><ul><li>50-80% improvement in 1/3 rd of patients after SVP use </li></ul><ul><li>West Syndrome (Infantile Spasms): </li></ul><ul><li>8/19 does not require ACTH if SVP is used </li></ul><ul><li>Dose: 20-60 mg/Kg/d </li></ul><ul><li>Response is good with ACTH but Side effects are more </li></ul><ul><li>Overall efficacy of SVP is good </li></ul>
  27. 27. Long term efficacy of SVP vs. LTG in IGE in children and adolescents <ul><li>Retention rate (Not discontinued): </li></ul><ul><li>After 12 months : SVP-89%, LTG 69% </li></ul><ul><li>After 24 months : SVP-83%, LTG-57% </li></ul><ul><li>Reason for discontinuation : </li></ul><ul><li>SVP- Hairloss, Diarrhoea, Abdominal discomfort, Weight gain </li></ul><ul><li>LTG- Lack of efficacy </li></ul>
  28. 28. SVP in STATUS EPILEPTICUS <ul><li>Low incidence of Respiratory & Cardiac depression </li></ul><ul><li>S/E : </li></ul><ul><ul><li>Hepatic dysfn, Pancreatitis, ↑Ammonia, ↑BT </li></ul></ul><ul><li>SVP should be avoided in mitochondrial diseases </li></ul>
  29. 29. SVP use in Headache <ul><li>Prophylaxis against chronic migraine </li></ul><ul><li>More useful in migraine than CTTH </li></ul><ul><li>Highly effective </li></ul><ul><li>Good tolerability </li></ul><ul><li>Excellent safety profile </li></ul><ul><li>Long term efficacy </li></ul>
  30. 30. SVP – Other Clinical Uses <ul><li>Painful Neuropathy </li></ul><ul><li>Trigeminal Neuralgia </li></ul><ul><li>Bipolar Disorders </li></ul><ul><li>Acute Manic Episodes </li></ul><ul><li>Certain neoplasms </li></ul><ul><li>MND (SMA / ALS) </li></ul>
  31. 31. SVP – Current Place in Therapy <ul><li>Broad spectrum AED </li></ul><ul><li>First line therapy in IGE </li></ul><ul><li>Not yet in the 1 st line in Partial Seizures </li></ul><ul><li>DOC in Myoclonic epilepsy </li></ul><ul><li>Use with caution </li></ul><ul><ul><ul><li>Neonates and females with child bearing age </li></ul></ul></ul>
  32. 32. SVP - Preferred situations <ul><li>Newly diagnosed epilepsy </li></ul><ul><li>Multiple seizure types </li></ul><ul><li>Epilepsies with Myoclonic component </li></ul><ul><li>Photosensitive epilepsies </li></ul><ul><li>Cognitive impairment </li></ul><ul><li>Special syndromes ( Dravet’s, West Syndrome) </li></ul><ul><li>BZD refractory Status epilepticus </li></ul><ul><li>Elderly with cardiac conduction defects </li></ul>
  33. 33. SVP - Hepatotoxicity <ul><li>FATAL HEPATOTOXICITY </li></ul><ul><li>Most feared S/E </li></ul><ul><li>Special risk in Inborn errors of metabolism </li></ul><ul><ul><ul><li>Urea cycle defects, Organic aciduria </li></ul></ul></ul><ul><li>Other risk factors </li></ul><ul><ul><ul><li>Young age </li></ul></ul></ul><ul><ul><ul><li>Polytherapy (1 in 20,000) vs Monotherapy (1 in 2,00,000) </li></ul></ul></ul><ul><li>Liver function monitoring is of little value </li></ul><ul><ul><ul><li>Benign ↑in enzyme is common </li></ul></ul></ul><ul><ul><ul><li>Progressive ↑in enzyme is not seen before fatal hepatotoxicity </li></ul></ul></ul><ul><li>Clinical recognition of hepatic failure is important </li></ul><ul><ul><ul><li>Nausea, jaundice, vomiting, edema, anorexia, Loss of seizure control </li></ul></ul></ul>
  34. 34. SVP - Adverse effects : Hepatopathy <ul><li>Type 1 </li></ul><ul><li>Dose dependent elevation of liver enzymes </li></ul><ul><li>Normalize after discontinuation </li></ul><ul><li>Treated with carnitidine supplementation </li></ul><ul><li>Type 2 </li></ul><ul><li>Idiosyncratic, lethal but rare </li></ul><ul><li>Several mechanisms </li></ul><ul><ul><li>Inhibition of β Oxidation </li></ul></ul><ul><ul><li>Inhibition Of oxidative phosphorylation, </li></ul></ul><ul><ul><li>Inhibition of gluconeogenesis </li></ul></ul><ul><ul><li>Inhibition of urea synthesis </li></ul></ul><ul><ul><li>Steatogenic effect </li></ul></ul><ul><ul><li>↓ in intracellular carnitine </li></ul></ul><ul><ul><li>↓ in intracellular coA (common path) </li></ul></ul><ul><li>Probably due to SVP Metabolite: 4-ene -VPA </li></ul>
  35. 35. SVP – Hepato toxicity Management <ul><li>Regular Hepatic Failure measures </li></ul><ul><li>IV Cartinine has a protective role </li></ul><ul><li>L - Cartinine supplementation should be given to </li></ul><ul><ul><li>Cartinine deficiency </li></ul></ul><ul><ul><li>Symptomatic hyperammonemia </li></ul></ul><ul><ul><li>Infants and children on VA </li></ul></ul><ul><ul><li>Patients on ketogenic diet </li></ul></ul><ul><ul><li>Patients on haemodialysis </li></ul></ul><ul><ul><li>Premature infants with parentral nutrition </li></ul></ul>
  36. 36. SVP- Adv eff: PANCREATITIS <ul><li>First described by Bataladen in 1979 </li></ul><ul><li>Serious complication </li></ul><ul><li>Idiosyncratic reaction </li></ul><ul><li>Direct toxic effect of free radicals on Pancreatic cell membrane </li></ul><ul><li>Vomiting/ abdominal pain  Suspect </li></ul><ul><li> Amylase / Lipase  useful tools </li></ul><ul><ul><ul><li>20% ↑ is seen in patients on VA without pancreatitis </li></ul></ul></ul><ul><li>13% of Pancreatitis is drug induced </li></ul>
  37. 37. SVP - Neurologic Adv Effects <ul><li>Tremor </li></ul><ul><li>Most Common </li></ul><ul><li>Like essential tremor </li></ul><ul><li>Dose related </li></ul><ul><li>Occurs in 10% </li></ul><ul><li>Treated by ↓ing the dose </li></ul><ul><li>Propranolol </li></ul>
  38. 38. SVP - Neurologic Adv Effects <ul><li>Unique / specific AE : </li></ul><ul><li>Acute mental changes  Stupor/Coma </li></ul><ul><li>Gen. Delta waves in EEG </li></ul><ul><li>↑ Ammonia, ↓ Cartinine (Associated but not causative) </li></ul><ul><li>Reversible in 3 days of discontinuation </li></ul><ul><li>Occurs during adding 2 nd drug </li></ul>
  39. 39. SVP - ENCEPHALOPATHY <ul><li>Four forms: </li></ul><ul><li>Direct toxic effect of VPA with high serum VPA + normal NH3 </li></ul><ul><li>Encephalopathy with impaired liver function + ↑NH3 </li></ul><ul><li>Encephalopathy with Hepatopathy + Normal NH3 </li></ul><ul><li>Hyper ammonemic Encephalopathy </li></ul><ul><li>(Liv Fail with hyper amm / without amm) (No Liv fail with amm / without amm) </li></ul><ul><li>Mechanisms: </li></ul><ul><li>VPA  ↓Glutamate synthesis  ↑NH3 </li></ul><ul><li>Direct Neuronal toxicity (↑Glutamate/ NH3 conc. in astrocytes) </li></ul><ul><li>ENCEPHALOPATHY </li></ul><ul><li>Extremely rare complication </li></ul><ul><li>Mostly in patients with inborn metabolism errors </li></ul><ul><li>More in SVP + TOP combination </li></ul>
  40. 40. SVP - Hyperammonemia <ul><li>SVP / SVP+ Enzyme inducer  ↑NH 3 is common </li></ul><ul><li>Routine monitoring not required </li></ul><ul><li>Cartinine levels are low in SVP / Polypharmacy </li></ul><ul><li>Symptomatic ↑NH 3 occurs in urea cycle disorders which leads to mental changes, encephalopathy, reye like syndrome </li></ul><ul><li>L-Cartinine may ↓ NH 3 ( not clinically beneficial) </li></ul>
  41. 41. SVP - Endocrine Adv. Effects <ul><li>Menstrual irregularities </li></ul><ul><li>Hyperandrogenism </li></ul><ul><li>Hyper insulinism </li></ul><ul><li>Pubertal arrest </li></ul>
  42. 42. SVP - Teratogenic Adv. Effects <ul><li>Incidence of Neural tube defects : 1-2% </li></ul><ul><li>↑ es with higher dosage </li></ul><ul><li>Folate supplementation should be given (Role-?) </li></ul><ul><li>Developmental delay, Learning disability </li></ul>
  43. 43. SVP- Adverse effects <ul><li>Polycystic ovaries: </li></ul><ul><li>First reported by Isojardi in 1993 </li></ul><ul><li>Amenorrhea/ Oligomenorrhea/ Prolonged menstrual cycle </li></ul><ul><li>SVP  ↑Androgen synthesis in ovary </li></ul><ul><li>Testosterone  Estradiol (by Aromatase [Inhibited by SVP]) </li></ul><ul><li>SVP- reduces efficacy of Oral contraceptives </li></ul>
  44. 44. SVP- Miscellaneous Adverse Effects <ul><li>Thinning of hair </li></ul><ul><li>Hair loss (long term/Biotin Def) </li></ul><ul><li>Alopecia may occur (28%) </li></ul><ul><li>Nocturnal enuresis </li></ul><ul><li>Facial / limb edema </li></ul><ul><li>Hyponatremia </li></ul><ul><li>Skin rashes / SLE </li></ul><ul><li>May ↓Bone mineral density </li></ul><ul><li>Asterixis </li></ul><ul><li>Lethargy </li></ul><ul><li>Sedation </li></ul><ul><li>Confusion </li></ul><ul><li>Drowsiness </li></ul><ul><li>Reversible Parkinsonism </li></ul><ul><li>Reversible Dementia </li></ul><ul><li>Pseudoatrophy of the Brain </li></ul>
  45. 45. SVP- Hematologic Adv. Effects <ul><li>Rare </li></ul><ul><li>Thrombocytopenia , Impaired platelet function, Fibrinogen depletion, Coagulation factor deficiencies may occur ( Dose Dependent ) </li></ul><ul><li>Stop SVP - 1 month before any major surgery </li></ul><ul><li>Neutropenia / bone marrow suppression may also occur </li></ul>
  46. 46. SVP- Adv eff: Weight gain <ul><li>Occurs in 20% </li></ul><ul><li>Mainly in adolescents, not in children </li></ul><ul><li>Cause : ↓ β -oxidation of fatty acids </li></ul><ul><li>Associated with </li></ul><ul><ul><li>Increased I nsulin concentration </li></ul></ul><ul><ul><ul><li>Interference of hepatic insulin metabolism </li></ul></ul></ul><ul><ul><li>High SVP level </li></ul></ul><ul><ul><li>Hypertriglyceridemia </li></ul></ul><ul><ul><li>Lower HDL level </li></ul></ul>
  47. 47. SVP - GI Side Effects <ul><li>GI Side effects: </li></ul><ul><li>Nausea, vomiting, anorexia, GI distress </li></ul><ul><ul><ul><li>less if enteric coated tab is used </li></ul></ul></ul>
  48. 48. SVP Over dosage <ul><li>Over dosage leads to </li></ul><ul><ul><li>Somnolence, Heart block, Coma, Death </li></ul></ul><ul><li>Management </li></ul><ul><ul><li>SVP and metabolites are Dialysable </li></ul></ul><ul><ul><li>Naloxone reverses the CNS depressant effects </li></ul></ul>
  49. 49. CONCLUSION <ul><li>SVP is the first line AED in most cases of Epilepsy. </li></ul><ul><li>The serious SE are less common </li></ul><ul><li>The common SE are tolerable </li></ul><ul><li>If used with caution, SVP is the dependable AED </li></ul><ul><li>Avoid SVP in : Hepatic impairment / Child bearing age women </li></ul><ul><li>DOC in : Absences / Myoclonic / GTCS </li></ul>
  50. 50. THANK YOU
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