Carbamazepine tolerance

Tolerability" should not be confused with the term "tolerance", which describes the diminution in effects of a drug on prolonged exposure. Tolerance may be due to increased clearance because of autoinduction of the enzymes that metabolise the drug, such as occurs with some antiepileptic drugs, for example, carbamazepine. Tolerance may also result from altered pharmacodynamics, which is common with drugs acting on the CNS. 

Pharmacologic treatment of RLS includes dopaminergic agents, benzodiazepines, opioids, or anticonvulsants. In mild cases of RLS, benzodiazepines may be first-line agents. Clonazepam, lorazepam, triazolam, and temazepam have been effective. Clonazepam 0.5 to 2 mg is most frequently studied. Opiates such as methadone 5 to 20 mg, codeine 30 to 120 mg, and oxycodone 2.5 mg are very effective, but the development of tolerance is a concern. Abuse potential with opiates is also a concern due to the chronic nature of the condition. Other agents that have been used include apomorphine, amantadine, tramadol, magnesium, oxycodone, propoxyphene, gabapentin, bromocriptine, clonidine, and carbamazepine. Tolerance may de-... 

A 9-year-old girl and two teenage boys, all of them taking the highest dosages of carbamazepine tolerable (without adverse effects), developed signs of toxicity after taking acetazolamide 250 to 750 mg daily. Their serum carbamazepine levels were found to have increased by about 25 to 50%. In one instance toxicity appeared within 48 hours. ... 

Studies suggest that as monotherapy for partial seizures, lamotrigine is as effective as carbamazepine and phenytoin lamotrigine may be better tolerated. Clinical data suggest that oxcarbazepine is as effective as phenytoin, valproic acid, and immediate-release carbamazepine, with perhaps fewer side effects. 

Carbamazepine is also most beneficial for patients with mixed episodes and rapid cycling. However, many patients find the side effects of carbamazepine more troublesome than those of valproate, and becanse carbamazepine has a penchant for nntoward drug-drug interactions, we reserve the use of carbamazepine for those patients who are unable to tolerate valproate, lithium, and the atypical antipsychotic... 

Anticonvulsants. Scattered case reports suggest that carbamazepine (Tegretol) and valproic acid (Depakote, Depakene) may be helpful in the treatment of panic disorder. This has yet to be verified in systematic studies. Furthermore, because these anticonvulsants are hindered by toxicity and side effect concerns (cf. Chapter 3), they should only be considered if other better studied and more tolerable treatment options have failed. 

Elderly no data specifically concerning the elderly is available for second generation AEDs adverse effects with first generation AEDs result from kinetic alterations carbamazepine is often poorly tolerated. 

Carbamazepine has become a major drug in the treatment of seizure disorders. It has high efficacy, is well tolerated by most patients, and exhibits fewer long-term side effects than other drugs. 

Like most of the agents that block sodium channels, side effects associated with carbamazepine administration involve the central nervous system (CNS). Drowsiness is the most common side effect, followed by nausea, headache, dizziness, incoordination, vertigo, and diplopia. These effects occur particularly when the drug is first taken, but tolerance often develops over a few weeks. There appears to be little risk of cognitive impairment with carbamazepine. 

Geriatric Considerations - Summary Well-tolerated in older adults. Adjust dose based on creatinine clearance. Autoinduction of metabolism does not occur as seen with carbamazepine, but drug interactions are still an issue. Many of the CNS effects occur early in treatment and are transitory. One-third of patients with hypersensitivity reactions to carbamazepine will experience cross-sensitivity to oxcarbazepine. 

Because bupropion is metabolized in the liver, medications that alter hepatic enzyme metabolism, such as carbamazepine or cimetidine, may effect blood concentrations. Bupropion should not be administered in combination with the MAOIs because of risk of hypertensive crisis. Levo-dopa use in conjunction with bupropion has been associated with confusion, hallucinations, and dyskinesia. Although generally well tolerated, there are case reports documenting that the... 

Carbamazepine has been shown to be better tolerated as long-term monotherapy than DVP in children with epilepsy or febrile convulsions (Herranz et ah, 1988). Nevertheless, a comparison of the adverse effect profile in the Kowatch sample (Kowatch et ah, 2000) shows that nausea (46%), rash (8%), and dizziness (8%) were more prevalent in youngsters taking CBZ, compared to children on DVP, who experienced overall less nausea (20%), rash (0%), and dizziness (0%). 

For patients who cannot tolerate carbamazepine, valproic acid may be a useful alternative, as it has demonstrated success in reducing avoidant and hyperarousal symptoms in adults (Fesler, 1991). There have been no published controlled trials of anticonvulsants... 

Mechanism of tolerance. The molecular events involved in the development of tolerance to carbamazepine have not been clearly identified. However, in a preclinical animal model using amygdala-kindled seizures, S. R. B. Weiss and colleagues (1995) in our laboratory have found that the variety of seizure-induced adaptive changes that usually emerge following seizures fail to do so with development of tolerance to the anticonvulsant effects of carbamazepine. The loss of these adaptive changes, such as increases in... 

The use of combination therapy with carbamazepine and valproate (Keck et al. 1992b Ketter et al. 1992) may also be helpful in avoiding or delaying the development of episodic breakthroughs progressing toward tolerance. We have observed that many animals show cyclic response to the anticonvulsants while they are progressing toward the development of complete loss of efficacy via tolerance [Post and Weiss 1996). If doses of... 

In an attempt to switch the patient to the less expensive L-type CCB verapamil for discharge, she was introduced slowly to the transition on a blind basis and was also unable to maintain her previous degree of clinical improvement with carbamazepine and nimodipine (Figure 6-5C). Maximally tolerated daily doses were 320 mg of verapamil and 600 mg of carbamazepine. In light of this recrudescence of clinical symptomatology, the patient was introduced to the transition on a blind basis back to nimodipine, and substantial recapturing of her clinical responsivity was again observed. After a slowly tapered transition to the less expensive dihydropyridine CCB... 

Support is scant for the efficacy of anticonvulsant agents in the treatment of OCD (Jenike 1990 Joffe and Swinson 1987). If there is a role for carbamazepine in OCD, it may be in patients with clinical or electroen-cephalographic evidence of a seizure disorder (Jenike and Brotman 1984 Khanna 1988). The anti-OC efficacy of combined SRI-carbamazepine treatment has not been adequately studied. Sodium valproate was found ineffective in two cases of OCD (McElroy and Pope 1988 McElroy et al. 1987). However, one author has suggested that sodium valproate may be a useful pretreatment for patients with OCD who might otherwise tolerate SRIs poorly (Deltito 1994). The anticonvulsant clonazepam is discussed earlier in this chapter. 

Clark M, Massenburg GS, Weiss SRB, et al Analysis of the hippocampal GABA, receptor system in kindled rats by autoradiographic and in situ hybridization techniques contingent tolerance to carbamazepine. Brain Res Mol Brain Res 26 309-319, 1994... 

Elphick M, Lyons F, Cowen PJ Low tolerability of carbamazepine in psychiatric patients may restrict its clinical usefulness. J Psychopharmacol 2 1-4, 1988... 

Rosen JB, Weiss SRB, Post RM Contingent tolerance to carbamazepine alterations in TRH mRNA and TRH receptor binding in limbic structures. Brain Res 651 252-260, 1994... 

Weiss SRB, Post RM, Sohn E, et al Cross tolerance between carbamazepine and valproate on amygdala-kindled seizures. Epilepsy Res 16 37-44, 1993 Weiss SRB, Clark M, Rosen JB, et al Contingent tolerance to the anticonvulsant effects of carbamazepine relationship to loss of endogenous adaptive mechanisms. Brain Res Brain Res Rev 20 305-325, 1995 Weissman MM Panic disorder impact on the quality of life. J Clin Psychiatry 52 [suppl) 6-8, 1991... 

The antiepileptic agent carbamazepine (Tegretol1 1) has been discussed for many years as an alternative to lithium because it also has an antimanic effect and prophylactic activity against depression, with possibly better tolerability. However, carbamazepine has not yet been proven to be superior to lithium,... 

The rate of absorption of carbamazepine varies widely among patients, although almost complete absorption apparently occurs in all. Peak levels are usually achieved 6-8 hours after administration. Slowing absorption by giving the drug after meals helps the patient tolerate larger total daily doses. 

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