Carbamazepine

Question 1

Therapeutic range of carbamazepine

Answer 1

4-12 mg/L

preferred 4-8 mg/L to avoid CNS side effects

Question 2

Toxicities

Answer 2

11-15 mg/L: somnolence, nystagmus, ataxia

15-25 mg/L: combativeness, hallucination, chorea

> 25 mg/L: seizures and coma

Question 3

Which organs are affected by side effects of carbamazepine?

Answer 3

Blood: dyscrasias: aplastic anemia, anemia, thrombocytopenia, leukopenia, agranulocytosis, pancytopenia

liver: hepatoxic monitor liver, LFT before use

GI: N/V, anorexia, anticholinergic: xerostomia

heart: bradycardia in the elderly, pt over 50 should have an ECG before use

Question 4

Dermatologic side effects

Answer 4

-antiepileptic drug (AED) hypersensitivity syndrome (skin) -> contraindicated with other aromatic anticonvulsants causing this reaction

-CBZ-induced SJS syndrome and toxic epidermal necrolysis (TENS): risk is 10x higher in asians

Question 5

CBZ-induced SIADH

Answer 5

-Syndrome of inappropriate antidiuretic hormone

-signs: thirst, N/V, depression, confusion, lethargy, seizures

(-pt with acute depression or seizures should check their sodium levels)

Question 6

What is the metabolite of CBZ?

Answer 6

-Carbamezaine 10,11 epoxide (CBZE)
-antiepileptic but also neurotoxic
-50% protein bound

Question 7

What is the ratio between CBZ and CBZE

Answer 7

-in patients not receiving any other CYP450 inducing drugs: CBZE to CBZ = 0.1 - 0.25

-in patients receiving CYP450 inducers:
CBZE to CBZ = 0.25 - 0.5

numbers are higher in those with CYP inducers -> bc more CBZE is produced (nominator)

-pt with CBZ toxicity may have normal CBZ levels -> CHECK CBZE levels

eg: CBZE: 3 mg/L and CBZ: 10 mg/L; 3/10 = 0.3
CBZ is therapeutic but CBZE is not

Question 8

What is the bioavailability of carbamazepine?

Answer 8

F = 0.8

Extended-release tablet: 0.71

(Vd = 1.4 L/kg - intermediate water-solubility )

eg: Gentamicin is very water-soluble and not very well distributed: Vd = 0.3L/kg
Propofol: >10L/kg -> very well distributed, fat-soluble

Question 9

How much of CBZ is protein-bound?

Answer 9

-70-80%

-caution: when administered with a highly protein-bound drug it may kick off CBZ from albumin and the free serum concentration increases -> TOXICITY

Question 10

What is the half-life of CBZ

Answer 10

-long: 25-30h

Question 11

What is a unique pharmacokinetic characteristic of CBZ?

Answer 11

-Auto-induced metabolism

-half-life goes from 25-30h to 6-8h

-only in a naive patient (patients on other CYP inducer will not have auto-induced metabolism

-the metabolism increases with time -> increase the dose over a month

-start slow and low

Question 12

How is CBZ metabolized

Answer 12

by CYP3A4 -> CBZ to CBZE (Carbamezapine 10,11 epoxide)

-CYP450 inhibitor will increase CBZ concentration
-CYP3A4 inducer will decrease CBZ concentration

Question 13

What is the clearance of CBZ?

Answer 13

Monotherapy: 0.064 L/kg/hr
(polytherapy: 0.1 L/kg/hr) with other drugs: like phenytoin, phenobarbital (CYP inducers)

Question 14

CYP3A4 inhibitors

Answer 14

-Macrolides: erythromycin, clarithromycin, troleandomycin
-Antiarrythmics: Amiodarone, Dronedarone
-Non-DHP-CCB: Diltiazem, Verapamil
-Azoles: Flucanozole, Ketocanozole, Itracanozole, Voriconazole

-Grape juice

Question 15

CYP3A4 inducers

Answer 15

Universal (3A4, 1A2, 2C9, 2C19)
-Carbamezepine
-Phenytoin
-Phenobarbital
-Primidone
-Rifampin/Rifabutin
-St. John’s wort

Specific inducers (3A4)
-Dexamethasone (corticosteroid)
-Nerivapine (NNRTI for HIV)

Question 16

What causes diurnal fluctiations?

Answer 16

-these are fluctuations in CBZ metabolism throughout theday in patients with TID dosing (40%)

-changes in CBZ protein-binding, changes in metabolism, decreased CBZ absorption (due to CBZ’s anticholinergic effects)

-Michaelis Menten absorption -> CNS toxicity
-give at bedtime

-monitor multiple levels: troughs might be higher at night then in the morning