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carbamazepine

carbamazepine

overview

  • related to tricyclics, used as anticonvulsant since 1965 in UK and since 1974 in the US and marketed as Tegretol.
  • also used as a mood stabiliser in bipolar disorders, and for trigeminal neuralgia and other types of neuropathic pain
  • Good for partial seizures & in the convulsive seizures of generalised epilepsy
    • resembles anticonvulsant spectrum of phenytoin;
    • debatable less impairment to cognitive function compared with phenytoin;
  • Similar actions as phenytoin - same effect on Na channels, but also:
    • better at blocking pentylenetetrazol-induced seizures
    • therapeutic responses in manic-depress. including those not responding to lithium carbonate;
    • decreases ADH secretion ⇒ diuresis;
    • anticonvulsant action antagonised by clonidine, noradrenaline depletion;
    • antagonises adenosine receptors ⇒ related to antidepressant effects?;
  • T1/2 = 30-40hrs at onset of Rx but reduces to 15-20hrs with continued intake, because it induces its own metabolism
  • therapeutic serum level (25-50umol/L, 6-12mg/L) is a useful initial guide to the potential adequacy of Rx with the drug. However, this range applies only if no other anticonvulsant is being taken which enhances the conversion of carbamazepine to its epoxide metabolite which is a potent anticonvulsant & sedative not accounted for in carbamazepine assays - ie. phenytoin, phenobarbitone - in this case, therapuetic range is reduced by half.

adverse effects

  • commonly causes drowsiness, headaches and migraines, motor coordination impairment
  • need to gradually introduce over several weeks to avoid XS sedation.
  • toxicity maximally occurs 1-3hrs after each dose (eg. diplopia, gait ataxia, drowsiness);
  • typically greatly decrease a person's alcohol tolerance
  • reversible auditory effect whereby patients perceive sounds about a semitone lower than previously - not great for musicians!
  • may aggravate juvenile myoclonic epilepsy
  • linked to serious adverse cognitive anomalies, including EEG slowing and cell apoptosis.
  • macular hypersensitivity reactions:
    • in northern Europeans, HLA-A*3101 allele which has a prevalence of 2-5%, increases risk of hypersensitivity reactions from 3.8% in non-carriers to 26% in carriers, while 42% of the 12 patients with SJS-TEN carried this allele 1)
    • in Han Chinese, HLA-A*3101 carriers are at risk of mild hypersensitivity reactions but not SJS-TENS, but apparently this allele is associated with SJS-TENS in Japanese patients??2).
  • toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome
    • these conditions have a mortality of ~5%
    • carbamazepine directly binds to HLA-B molecules on antigen presenting T cells and contribute to cell death mediated by cytotoxic T cells
    • in south-east Asia:
      • these are associated with the HLA-B*1502 allele in Han Chinese populations who have a 200-10,000 fold risk of developing SJS-TEN if given carbamazepine than noncarriers of that gene, but no significant increase in carbamazepine-induced macular hypersensitivity reactions.
      • patients of Han Chinese descent should be considered for genotyping prior to commencing Rx otherwise population risk of SJS-TEN is ~0.23%.3).
    • it seems to be associated with the HLA-A*3101 allele in Japanese and Northern Europeans but not in Hans Chinese4).
    • HLA-B58 seems to be associated in Europeans.
  • aplastic anaemia (rare)
  • thrombocytopenia (rarely severe)
  • may exacerbate preexisting cases of hypothyroidism
  • Oxcarbazepine, a derivative of carbamazepine, reportedly has fewer and less serious side effects

drug interactions

  • carbamazepine has multiple drug interactions of clinical significance - see literature
  • should not be used within 2 weeks of taking MAO inhibitors
  • lower levels of carbamazepine are seen when administrated with:
    • phenobarbital, phenytoin (Dilantin), or primidone (Mysoline)
  • as a CYP450 inducer, it may increase clearance of many drugs, decreasing their blood levels including:
    • warfarin (Coumadin), phenytoin (Dilantin), theophylline, and valproic acid
  • carbamazepine also increases the metabolism of the hormones in combined oral contraceptive pill (OCP) and can reduce their effectiveness, potentially leading to unexpected pregnancies
  • drugs that decrease the metabolism of carbamazepine or otherwise increase its levels include:
    • erythromycin, cimetidine (Tagamet), propoxyphene (Darvon), and calcium channel blockers
  • Valproic acid and valnoctamide both inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide into inactive metabolites.By inhibiting mEH, valproic acid and valnoctamide cause a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.
  • Grapefruit juice raises the bioavailability of carbamazepine by inhibiting CYP3A4 enzymes in the gut wall and in the liver.

Mx of overdose:

  • consider elective intubation prior to transport if >50mg/kg ingested as this will cause coma
1)
NEJM 364:12 March 24 2011, p 1134-1143
2) , 3) , 4)
NEJM 364:12 March 24 2011 p1126-1133
carbamazepine.txt · Last modified: 2011/04/05 18:38 (external edit)