I currently work as a researcher at one of the top UK neurological hospitals. My past education includes a joint BA degree in Maths and Education, an MA in Psychology and an MSc in Cognitive and Clinical Neuroscience. All of my degrees where earned at esteemed institutions. At the moment, I am doing my PhD in an Ivory League university in the UK. In the past I have worked in the education and social psychology fields, where I gained a lot of experience in these areas. All of my degrees to date have been awarded with first class or distinction and I am very accustomed to writing scientific papers, as I have written a plethora of publications regarding child development, psychology, sociology, health policy, health economics, and pharmaceutical trials. Below you can see an example of one of my essays that earned distinction.

Sample

The pharmacokinetic mechanisms of antiepileptic drugs

Epilepsy is one of the most common serious neurological conditions, affecting approximately 1% of the world population at any one time (about 50 million people worldwide). Although approximately 70% of patients with newly diagnosed epilepsy are rendered seizure-free by currently available antiepileptic drugs (AEDs), overall, seizures remain inadequately controlled in 30% of patients. The difficulty in achieving total control of seizures is largely related to the adverse effects that can result from pharmacokinetic interactions in polytherapy regimens. It has been estimated that in 6% of patients experiencing AED intoxication, a drug interaction was the cause. The purpose of this paper is to discuss and evaluate the importance of the pharmacokinetic interactions of antiepileptic drugs.

Pharmacokinetic interactions, in which one drug interferes with the disposition of another, alter the concentration of the drug at the site of action. Pharmacokinetic interactions can occur during any stage of drug disposition (i.e.) during absorption, distribution, metabolism or elimination), and they are associated with drug-concentration changes in the peripheral plasma compartment. They may also take place, in the case of centrally acting agents such as AEDs, in the central brain compartment (e.g.) cerebrospinal fluid or the extracellular fluid site of drug action). Below, the various pharmacokinetic principles shall be examined, with examples of how the various, currently available, AEDs interact. Through these examples, the significance of knowing the pharmacokinetics of the various AEDs will become evident.

Pharmacokinetic effects during drug absorption

Absorption is the entry of drug molecules into the systemic circulation via the mucous membranes of the gut or lungs, via the skin, or from the site of an injection. Drug interactions with AEDs are rare during absorption, although antacids have been shown to reduce the absorption of some AEDs (e.g.) phenytoin, Phenobarbital carbamazepine, and gabapentin) by decreasing the acidity of the stomach and also by formation of insoluble complexes that cannot be absorbed.

Pharmacokinetic effects on drug distribution

Interactions affecting drug distribution may involve competition between two drugs for binding sites on plasma proteins. In quantitative terms, these interactions can be important only for drugs that are over 90% bound to plasma proteins and, among AEDs, only phenytoin, valproic acid, diazepam, and tiagabine belong to this category.

The most commonly occurring plasma-protein displacement interaction involving AEDs is the displacement of phenytoin by valproic acid. The most important implication of this interaction is that in the presence of valproic acid the “therapeutic” range of total plasma phenytoin concentrations is shifted towards lower values.

Pharmacokinetic effects on drug metabolism

By far the most important pharmacokinetic interactions with AEDs are those related to induction or inhibition of drug metabolism.

Enzyme induction, which is caused mainly by carbamazepine, phenytoin, and barbiturates, is increased synthesis of drug-metabolising isoenzymes in the liver and in other tissues. If the affected drug has an active metabolite, induction can result in increased metabolite concentration and possibly an increase in drug toxicity. The time course of induction is generally gradual and dose-dependent.

Enzyme inhibition is the phenomenon by which a drug or its metabolite blocks the activity of one or more drug-metabolising enzymes, which results in a decrease in the rate of metabolism of the affected drug. This, in turn, will lead to high plasma concentrations of the drug and, possibly, clinical toxicity.

Pharmacokinetic effects on drug elimination

Elimination is the removal of drug molecules from the body by excretion, usually by the kidneys or by biotransformation, mainly in the liver. Drugs that undergo extensive renal elimination in unchanged form may be susceptible to interactions affecting the excretion process, particularly when it involves active transport mechanisms or when the ionised state of the drug is highly sensitive to changes in urine pH. Agents that cause alkalisation of urine increase the elimination of phenobarbital by reducing the reabsorption of this acidic drug from renal tubuli.

Based on the above examples of pharmacokinetic interactions, it is evident why, in recent years, the importance of pharmacokinetics in antiepileptic drug therapeutics has been increasingly recognised, and the characterisation of the clinical pharmacokinetic profile of a new antiepileptic drug has become an integral and early component of drug development. Consequently, pharmacokinetic considerations are especially relevant with antiepileptic drugs for several reasons:

Firstly, patients with epilepsy generally require chronic therapy, and, therefore, a dosing strategy that enhances compliance is essential. Good knowledge of the pharmacokinetic mechanisms of the various AEDs will significantly aid the decision of which dosing strategy is the most efficient. Also, many patients will be prescribed two or more antiepileptic drugs, oftentimes at the highest possible doses.

Additionally, all patients with chronic epilepsy can be expected to develop during their lifetime concomitant nonepilepsy-related diseases that require additional drug therapy, increasing the potential for drug interactions and toxicity. Thus, it is desirable that the drugs do not cause interactions that can precipitate toxicity.

As AED interactions can have substantial effects on clinical outcome, a therapeutic algorithm for management options in response to such interactions has been proposed. A few simple rules can help to limit adverse consequences of AED interactions: multiple drug therapy should be used only when it is clearly indicated. Most patients with epilepsy can be best managed with an individualised dose of a single AED. Most interactions are metabolically based and can be predicted from knowledge of the isoenzymes involved in the metabolism of the most commonly used drugs and the effects of these drugs on the same isoenzymes. Physicians should be aware of the most important interactions, underlying mechanisms, and any corrective action required (e.g.) changes to dose). Combination of AEDs with similar adverse effect profiles (e.g.) benzodiazepines and barbiturates) should be avoided and combinations for which there is clinical evidence of favourable interactions should be preferentially selected. The clinical response to new drugs introduced or discontinued from the patient’s regimen should be carefully monitored. Unexpected responses to a change in the regimen could result from interaction between AEDs and the dose should be adjusted when appropriate.

Furthermore, if a pharmacokinetic interaction is anticipated, the plasma concentration of the affected drug should be monitored. Physicians should be aware that under certain circumstances (e.g.) in the presence of drug displacement proteins), routine total drug concentration measurements can be misleading and patient management may benefit from monitoring of free drug concentrations. In some cases, dose adjustments may have to be implemented at the time the interacting drug is added or removed.

Additionally, the probability of a pharmacokinetic drug interaction occurring is largely dependent on patient-related factors. Age and systemic condition of the patient can influence pharmacokinetic parameters. Therefore in this case, also, the physician must know which AEDs to use and which dosing strategy to follow, in the case of special risk groups where the pharmacokinetics are altered (e.g.) elderly patients, neonates, pregnant women).

Regarding the elderly, elimination of many drugs is slower, mainly because of reduced hepatic and renal blood flow, which lengthens drug half-life above published values based on young adults. In addition, albumin levels fall with age and this increases the free fraction of drugs that are highly protein bound, thus increasing risk of toxicity, especially for highly protein-bound drugs. Further, older people are often more sensitive to drug effects at a given free level. In the elderly, AEDs should usually be started at a lower dose and increased at a slower rate than in younger patients.

In children, drug metabolism and disposition can differ significantly from that in adults. Beyond the neonatal period, when protein binding and drug metabolic rates are low, children usually have faster drug elimination rates and reduced serum half-lives relative to adults. Some children require almost twice the adult mg/kg dosage, particularly if combination therapy with enzyme-inducers is employed. Furthermore, because of shorter paediatric half-lives, most AEDs require at least three times daily administration in children 1-10 years of age.

It is also noteworthy that in cases of pregnancy, the volume of distribution and the rate of drug metabolism are increased whereas protein binding is decreased. For most AEDs, the optimal dose increases as pregnancy progresses.

Finally, knowledge of pharmacokinetic mechanisms has led to awareness of which pharmacokinetic characteristics an AED should have in order to be ideal, something which will consequently lead to improved AED design. Such characteristics include rapid absorption after oral ingestion, good bioavailability with rapid achievement of steady-state concentrations, linear kinetics, minimal or no protein-binding, a half-life offering once- or twice-daily dosing, absence of drug–drug interactions, and no metabolism.

Concluding, it is evident that an awareness of antiepileptic drug pharmacokinetics aids in the choice of an appropriate drug and permits the design of an optimal dosage schedule for each patient. By anticipating possible drug interactions, or alterations in metabolism, the physician may often avert adverse effects and breakthrough seizures.

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