Carbamazepine has been used as AEDs since , and is most effective against partial seizures. Two basic mechanisms of action have been proposed: 1 enhancement of sodium channel inactivation by reducing high-frequency repetitive firing of action potentials, 2 and action on synaptic transmission.
Carbamazepine - Clinical Pharmacology
The aim of this study was to provide a review of carbamazepine pharmacokinetics and its management guidelines in Iranian epileptic population. Carbamazepine is highly bound to plasma proteins.
The rate or extent of absorption was not be affected by food. It is completely metabolized and the main metabolite is carbamazepine-epoxide CBZ-E. Carbamazepine induces its own metabolism, leading to increased clearance, shortened serum half-life, and progressive decrease in serum levels.
Increases in daily dosage are necessary to maintain plasma concentration. Severe liver dysfunction may cause disordered pharmacokinetics. In cardiac failure, congestion of major vital organs, including kidneys, may result in abnormally slow absorption and metabolism. Carbamazepine shows variability due to its narrow therapeutic window.
What is carbamazepine?
Therefore clinical management in a3n Iranian epileptic population should focus on results derived from therapeutic drug monitoring in order to reduce inter and intra- individual variability in plasma drug concentrations.
Carbamazepine C 15 H 12 N 2 O is a tricyclic compound that is most efficient against partial seizure with or without secondary generalization. The introduction of carbamazepine into the area of epilepsy specified a new phase to control epileptic attacks. Carbamazepine was discovered by chemist Walter Schindler in Switzerland It was first marketed as a drug to treat trigeminal in and has been used as an anticonvulsant and antiepileptic in the UK since , and has been approved in the US since [ 1 , 2 , 3 ] Epilepsy is a widespread continual neurological turmoil illustrated by seizures.
Carbamazepine is an anticonvulsant and mood-stabilizing drug used mainly in the management of epilepsy, bipolar disorder trigeminal neuralgia , attention-deficit hyperactivity disorder ADHD , schizophrenia, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, disorder, borderline, and post-traumatic stress disorder such as postcerbervascular accident thalamic pain.
Carbamazepine might exacerbate juvenile myoclonic epilepsy, so it is important to uncover any history of jerking, particularly in the morning, prior to starting the drug.
It may also worsen other types of generalized seizure disorders, particularly absence seizure. In highly strung cells such as neurons sodium channels are accountable for the mounting part of exploit potentials. Sodium channels are vital covering proteins, which figure ion channels, caring out sodium during a cells plasma covering.
In addition to diminution associated with high-occurrence rhythmic release of action potentials, carbamazepine also increases the inhibitory neurotransmitter GABA gamma amino butyric acid and decreases excitatory neurotransmitter glutamate Glue.
It depresses synaptic function and potentiation is reduced only in supratherapeutic levels. Carbamazepine obstructs catecholamine uptake at high concentrations. As it is chemically connected to the tricyclic antidepressants, it inhibits biogenic amine reuptake. Binding of carbamazepine to two subtypes of adenosine receptors, A 1 and A 2 would allow broad binding to occur at remedial meditations.
A quick review of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012
Therefore carbamazepine acts throughout action at the A 1 -receptor subtype as potent inhibitory manipulate adenosine on neuronal action and neurotransmitter discharge. Carbamazepine acts as an antagonist at these receptors and would be expected to increase neuronal excitability.
Extended period related to prescription of drug results in an augmented amount of A 1 required location that could be linked with diminished sensitivity to systemically ordered drug. As clinical management of this drug needs an individualized scheduled program, the aim of this study was to provide a review of the pharmacokinetics of carbamazepine and its management guidelines in an Iranian epileptic population.
Table 1 shows pharmacokinetic data. Carbamazepine is a highly lipid soluble which slowly dissolves in gastrointestinal fluid.
There are no bioavailability data for neonates or infants, but physical chemical characteristics suggest deprived and inconsistent absorption in these groups. In children receiving continuation treatment, the suspension is absorbed more quickly than are tablet formulations, resulting in a considerably earlier time to attain greatest serum concentration T max , C max. The faster rate of absorption occasionally produces transient concentration-dependent central nervous system side-effects.
Smaller doses given more frequently will usually correct this problem. Additional increases in maintenance doses may give rise to additional induction.
Many deteriorating children require three or four daily doses to keep therapeutic plasma concentrations. Convulsion may be prohibited at comparatively inferior levels, and harmful effects may emerge at concentrations within the proposed remedial range, perhaps as a consequence of the high metabolite-to-parent drug concentration ratio in children.
Concentration of CBZ-E and clearance of carbamazepine in children are higher than in adults for the respective parent-drug concentrations and these levels correlate to some degree with associated drugs, age, and sex.
The elimination half-life is approximately 15 h. Dose adjustment is not needed in either renal disease or dialysis. Close monitoring of serum levels of carbamazepine and the 10, 11 epoxide should be maintained, however, especially with long-term administration in patients with liver dysfunction.
Carbamazepine is mainly eliminated by the cytochrome P system and has an active metabolite.
Its major metabolite, carbamazepine epoxide is an active anticonvulsant and is thought to have the same mechanism of action. Carbamazepine undergoes autoinduction in which clearance increases over time following exposure to the drug e.
Carbamazepine mechanism of action pdf
The half-life of carbamazepine ranges from 10 to 20 h but diminishes with autoinduction to 4 to 12 h. This increase in ratio could be due to either an enhanced carbamazepine clearance or an inhibition of CBZ-E clearance.
Hyponatremia is not occasionally connected with carbamazepine use in the elderly and is linked to variation in antidiuretic hormone regulation. Less common side-effects may include cardiac arrhythmias, blurry or double vision, temporary loss of blood cells or platelets and in rare cases can cause aplastic anemia.
With standard consume small reductions in white cell count and serum sodium is ordinary. In rare cases, the loss of platelets may become life-threatening. In this case frequent blood tests during the first few months of use could be followed by three to four tests per year for established patients. Additionally, carbamazepine may possibly exacerbate preexisting cases of hypothyroidism, so yearly thyroid function tests are advisable for persons taking the drug.
The mechanism of carbamazepine teratogenicity is unknown. The highest rates of malformations among infants exposed to AEDs were in those exposed to carbamazepine, phenobarbital, and valproate simultaneously in utero and it was hypothesized that the increased metabolites were responsible. Cytochrome P enzymes are important for the metabolism of several drugs such as numerous AEDs.
Therefore, enzyme-inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. Upon commencement of carbamazepine treatment, concentrations are predictable and follow individual pharmacokinetic parameters established for the specific patient.
When the dosage of drug increasing, the CYP 3 A 4 activity increasing. Subsequently clearance of drug speeding up and half-life become shortening which is called autoinduction.
Autoinduction will continue with subsequent increases in dose but will usually reach a plateau within days of a maintenance dose. Increases in dose at a rate of mg every weeks may be required to achieve a stable seizure threshold. Stable carbamazepine concentrations occur usually within weeks after commencement of treatment.
In combination of carbamazepine with valproic acid microsomal epoxide hydrolase; mEH the enzyme in charge for the analysis of carbamazepine,11 epoxide into inert metabolites , could be restrain by valproic acid.
By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion. The combination of valproate and carbamazepine results in increased concentrations of carbamazepine epoxide. Lower levels of carbamazepine are seen when administrated with phenobarbital, phenytoin or half-life primidone. Drugs that are more rapidly metabolized with carbamazepine include warfarin, lamotrigin, phenytoin, theophylline, and half-life valproic acid.
Drugs that decrease the metabolism of carbamazepine or increase its levels include erythromycin, cimetidine, propoxyphene, and calcium channel blockers. Carbamazepine also increases the metabolism of the hormones in birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.
As a drug that induces cytochrome P enzymes, it accelerates elimination of many benzodiazepines and decreases their action. Grapefruit juice increases the bioavailability of carbamazepine by inhibiting CYP 3 A 4 enzymes in the gut wall and in the liver. Substantial inter-patient inconsistency occurs with admiration to the enzymatic activity of the CYP isoenzymes.
In spite of the recognized strategies for carbamazepine prescription and subsequently its management in epileptic patients, the question of monotherapy or polypharmacy, needs further investigation. Finally, carbamazepine should be prescribed in a rational basis based on therapeutic drug monitoring in Iranian epileptic population. We would like to gratefully acknowledge the Research Deputy of Isfahan University of Medical Sciences for its financial support to this research.
Conflict of Interest: None declared. National Center for Biotechnology Information , U. J Res Med Sci. Author information Article notes Copyright and License information Disclaimer. Address for correspondence: Dr. E-mail: ri. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3. This article has been cited by other articles in PMC.
Abstract Background: Carbamazepine has been used as AEDs since , and is most effective against partial seizures. Results: Carbamazepine is highly bound to plasma proteins.
Conclusion: Carbamazepine shows variability due to its narrow therapeutic window. Keywords: Carbamazepine, epilepsy, epoxide, pharmacokinetics, review.
Pharmacology - ANTIEPILEPTIC DRUGS (MADE EASY)
RESULTS research and review articles relevant to the topic carbamazepine pharmacokinetics directly or indirectly have been found and the following features related to the kinetics of the drug in patients with epilepsy have been drawn out. Open in a separate window.
Beyond derivatives of iminodibenzyls. Helv Chim Acta. Okuma T, Kishimoto A. A history of investigation on the mood stabilizing effect of carbamazepine in Japan. Psychiatry Clin Neurosci.
Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I. J Pharm Sci. Kramer MA, Cash S.