Treatment of Epilepsy Flashcards

Question

PK Quirks of Valproate

Answer 1

Dosage form: IV, tab (chrono form too), syrup Highly albumin-bound - saturable protein binding within therapeutic range - Higher free fraction of valproate with low alb Displacement by endogenous compounds Total [valproate] increases in nonlinear function with dosage increase - Unbound [valproate] increases in linear function

Answer 2

Dosage form: Tablets (Immediate release & CR) Highly protein bound CYP3A4 Metabolism > 99% Autoinduction - Do not start with desired maintenance dose, gradually increase over initial first few weeks Clearance increases & t1/2 shortens - [Carbamazepine} will decline & stabilise in accord with the new clearance & t1/2

Answer 3

- Start low, go slow - Avoid large dosing challenges - Restricting therapy to one drug only Adjusting adm schedule: - Largest dose at bedtime - Split into smaller doses - Reduce total daily dose (if possible) - SR formulation

Answer 4

CNS: Somnolence, fatigue, dizziness, visual disturbances GI: N/V (Carbamazepine, valproate) Psychiatric: Behavioural disturbances (Levetiracetam) Cognition: Usually speech fluency (Topiramate) - Adverse SEs usually > prominent at higher ASM concentrations

Answer 5

- Blood dyscrasia (aplastic anaemia, agranulocytosis) - Hepatotoxicity (Phenytoin & valproate, carbamazepine) - Pancreatitis (Sodium valproate) - Lupus-like reaction - Exfoliative dermatitis - TEN/SJS - Most likely to occur in 1st few months of therapy

Answer 6

Note: Tends to be drug-specific & not directly related to plasma concentrations of ASMs [Connective Tissue] 1) Gingival Hyperplasia (~50% Phenytoin pts) - Gum enlargement 2) Hirsutism (Phenytoin) - Children & young adults 3) Alopecia (Sodium valproate) [Neurological] 1) Encephalopathy (Prolonged phenytoin @ high doses, phenobarbitone) 2) Peripheral neuropathy (Prolonged phenytoin, may also occur with carbamazepine & phenobarbitone) - May respond with folate supplementation [GI] 1) Increased weight gain (sodium valproate) 2) Anorexia & weight loss (topiramate) [Endocrine] 1) Osteomalacia (Phenytoin, carbamazepine, phenobarbitone & valproate also) - Increased clearance of Vit D leading to secondary hyperparathyroidism, increased bone turnover & reduced bone density [Hemotological] 1) Blood dyscrasias 2) Megaloblastic anaemia [Neonatal cognitive defects] - Phenytoin, Phenobarbitone, Topiramate - Valproate (cognition) [Suicidal ideation] - No change, just monitor

Answer 7

1) Pharmacogenetic testing (HLA-B*1502 testing for Carbamazepine) - Han Chi & other Asian ethnic groups - HLA-B*1502 + : Avoid CBZ/PT 2) Follow dosing guidance (Lamotrigine) - Risk of serious cutaneous rxns with high starting doses, rapid dose escalations, concomitant valproate (CYP inhibitor) 3) Identify potential cross-sensitivity reactions (ASMs with aromatic rings) - ASMs with aromatic rings: Phenytoin, Carbamazepine, Phenobarbital, Lamotrigine, Oxcarbazepine - -> Can form arene-oxide intermediate that can b.c immunogenic through interactions with proteins/cellular macromolecules - -> If allergic: Prefer to switch - -> If mild rash & benefit > risk: May want to stick to it & monitor

Answer 8

- Plasma [ASM] correlate much better with clinical effects - ASM treatment prophylactic - -> Seizures occur @ irregular intervals - -> Difficult to ascertain whether prescribed dose can produce long-term control - Not easy to recognise signs of toxicity - ASMs subjected to PK variability - -> Diff in dosage requirements across pts - No lab parameters to monitor clinical efficacy/toxicity for ASM

Answer 9

1) To establish an individual's therapeutic range - Helps in subsequent changes 2) To assess lack of efficacy 3) To assess loss of efficacy (breakthrough seizures) 4) To assess potential toxicity

Answer 10

- Receive counselling on impt of early discussion on family planning - Potential risk to foetus - Use of OC

Answer 11

May be discontinued after a min of 2yrs w/o a seizure - Decision to stop med involves balance between risks of continuation & implications of relapse - Discussions with pts & their carers/family members

Answer 12

Conditions resulting either from: i) Failure of mechanisms resp for seizure termination ii) Initiation of mechanisms leading to... - Abnormally prolonged seizures that can have long-term consequences

Answer 13

0-5min Stabilization phase: Stabilise patient & time seizure 5-20min Initial therapy: *Benzodiazepine 1st line* i) IM Midazolam/ IV Lorazepam/ IV Diazepam or not ii) IV phenobarbital/ Rectal Lorazepam/ INS Midazolam 20-40min 2nd therapy: (To be given as single dose) i) IV fosphenytoin/ IV Valproic acid/ IV Levetiracetam or not ii) IV phenobarbital 40-60min 3rd therapy: Repeat 2nd line therapy or Anaesthetic doses of midazolam/ thiopental/ pentobarbital/ propofol (with continuous EEG monitoring)