What are the indications of carbamazepine?
Epilepsy Neuralgias Bipolar disorder and psychotic disorder
What is the MOA of carbamazepine?
Prevents repetitive firing of actions potentials in depolarized neurons by limiting sodium influx through sodium channels
Discuss the bioavailability of carbamazepine.
Imediate release = 85-90% Extendeded release = 90%
What is the time to peak of carbamazepine?
Immediate release = 3-8 hours Extended release = 3-12 hours
Discuss the distribution of carbamazepine
Lipophilic (needs to pass through the BBB) Vd = 0.8 - 1.9 L/kg 40-90% protein bound Bound to albumin and alpha-1 acid glycoprotein
Discuss the metabolism of carbamazepine
Active metabolite = carbamazepine epoxide Auto-induction (induces enzymes that are responsible for its own metabolism)
How does auto-induction affect half-life?
shortens half-life over time changes from 25-65 hours to ~12-17 hours after repeated doses over 3-5 weeks
How does old age or liver disease affect elimination of carbamazepine as metabolites in urine?
Clearance is decrased
How does renal disease/dialysis affect elimination of carbamazepine as metabolites in urine?
Clearance is not changed
What is normal dosing and schedule of carbamazepine?
Start at 100 to 200 mg/day PO Ususal dose is 200 mg PO BID Increase every 3-14 days Maximum dose is 1600 mg/day
What is the therapeutic level of carbamazepine?
4-12 mcg/L
What are the monitoring recommendations for carbamazepine?
Trough levels recommended Give time for auto-inductions to stabilize before adjusting based on a level
What are the AE of carbamazepine?
diplopia headache dizziness N/V sedation lethargy leukopenia (without immunodeficiency --> shifts WBC to a tissue compartment) rash aplastic anemia toxic hepatitis antidiuretic effects
What are the drug interactions with carbamazepine?
CYP450 inducers of 1A2, 2B6, 2C8, 2C9, 2C19, 3A4, and p-glycoprotein Decreases the concentration of : estrogen contraceptives, dabigatran, fosphenytoin voriconizole, divalproex
32 yo female on Carbamazepine 400 mg po BID for seizure disorder. She started this dose 1 week ago.
Maintain current dose and recheck trough level in 2 weeks since autoinduction may not have started.
What are the indications for Valproic acid?
Epilepsy Bipolar disorder Migraines
What is the MOA for valproic acid?
Increases GABA function Limits sustained, repetitive firing of sodium channels Glutamate alterations
Discuss ADME of valproic acid
A : >90% bioavailability, half-life 9-16 hoursD : Vd = 11 L/1.73m2 M: UDPGT-catalyzed glucuronidation, beta-oxidation, minor CYP450 metabolism (2A6, 2C9, 2C19, 2B6E : metabolites unchanged in urine
Discuss dosing of valproic acid
Initial dose = 15mg/kg PO (ususally 500mg) 1-3 x/day IV loading dose = 15 mg/kg IV over 20 g/min Can increase by 5-10 mg/kg weekly Recommend to dose up to 60mg/kg/day
What is the therapeutic range of valproic acid?
50-150 mcg/ml
What is the monitoring parameters for valproic acid?
Draw trough levels 2-4 days after initiation, change in dose, addition of interacting medications
What are the AE of valproic acid?
Dose related : tremor, weight gain, hair loss or thinning, menstrual irregularitiesN/V, dyspepsia w/ immediate release formulations Idiosyncratic:hepatotoxicity, thromboycytopenia, pancreatitis, polycystic ovary disease
What are the drug-drug interactions with valproic acid?
phenytoin carbamazepine ethosuximide
**will decrease serum concentrations of valproic acid**
What are the indications for phenobarbital/primidone?
epilepsy commonly 2nd or 3rd line agent for refractory seizures
What is the MOA for phenobarbital?
Enhances the effects of GABA which prolongs opening at the chloride channel at GABAA receptor, resulting in neuronal hyperpolarization
What is primidone metabolized to?
phenobarbital
What is the ADME of phenobarbital/primidone?
A : F=100%, peak= 0.5-4 hours, half-life = 36-125 hoursD : Vdphenobarb =0.6-0.7 L/kg, Vdprimidone =0.43-1.1 L/kg; bimodal (first to highly perfused organs, then to all body tissues); protein binding = phenobarb 55%, primidone 80%M : glucurondiation, p-hydroxylation via CYP2C9 & 2C19E : hepatic metabolism, excreted unchanged in urine 20-45%, decreased in hepatic & renal impairment
What is the dosing of phenobarbital?
Loading dose : 15-20 mg/kg ONCEMaintenance dose : Adults = 1.5-2 mg/kg/day; Peds = 3-6 mg/kg/dayFrequency : given 2-3 x/dayTitration should be slow due to long half-life, long periods between dose increase Kinetics are linear therefore dose & concentration should increase/decrease proportionately
What is the dosing for primidone?
Start with 100-125mg at bedtime x 3 days Increase by 100-125 mg/day every 3 days until at goal With increasing dose spread to a frequency of 3-4 times/day Maintenance dose : 10-25 mg/kg/day
What is the therapeutic range for phenobarbital?
15-40 mcg/ml
Whis is the therapeutic range for primidone?
5-12 mcg/ml Get both primidone and phenobarbital levels Trough level recommended 2-3 weeks after initiation or change in dose
What are the AE of phenobarbital/primidone?
GI upset, ataxia, HA, confusion, folate deficiency, vitamin D deficiency, osteomalacia, megaloblastic anemia, porphyria, and skin rash Adults : sedation, lethargy, cognitive impairmentChildren & elderly : hyperactivity & agitation; can suppress cognitive development in childrenPhenobarb concentration >60 mcg/mL = stupor & coma
What are the drug interactions of phenobarbital/primidone?
it is an enzyme inducer of the CYP 450 system, NADPH-cytochrome reductase UDPGT, and enzymes involved in glucoronic acid synthesis
What drugs are decreased by phenobarbital?
contraceptives lamotrigine oxcarbazepine phenytoin zonisamide
What drugs increase phenobarbital concentrations?
divalproex and felbamate
What supplement(s) should a patient take while on phenobarbital due to a specific deficiency that can occur?
calcium/vitamin D supplements due to to vitamin D deficiency
What indiciation is ethosuximide used?
drug of choice for absence seizures
What is the MOA for ethosuximide?
reduces T-type calcium currents in thalamic neurons
Discuss ADME of ethosuximide
A : F=100%; peak 3-7 hours; half-life 60 hoursD : NOT lipophilic; Vd= 0.7 L/kg; No protein binding; distributes to CSF and throughout body (except for fat)M : No 1st pass metabolism, hydrolyzed by 3A4 mainly, further metabolite is conjugatedE : metabolites eliminated in urine; unchanged in urine (10-20%), clearance reduced in renal and liver disease
What is the dosing for ethosuximide?
Maintenance : start at 15-30 mg/kg/day POUsually 750-1500 mg/day divided PO BID Adjustments should be made slowly due to long half-life
What is the therapeutic range for ethosuximide?
40-100 mcg/L
What is the monitoring for ethosuximide?
Trough levels recommended
What are the AE of ethosuximide?
hiccups, N/V, abdomincal pain, anorexia, headache, dizziness, drowsiness, unsteadiness, rash, and transient leukopenia
T/F: Ethosuximide does not induce or inhibit metabolism of other drugsTrue False
TRUE
Which anti-epileptics have long half-lives that mandate slow titration?
phenytoin phenobarbital ethosuximide
Which anti-epileptics are NTI medications?
phenytoin carbamazepine ethosuximide
