General Principles of Pharmacology for Epilepsy Patients and Their Caregivers
I recently attended a workshop for parents of children with epilepsy designed to gather opinions about the launch of an educational website. During the workshop, the following question was raised to this small group, “What information do you need from health-care providers to better understand the medical management of your child’s epilepsy?” The most honest and profound response I heard was, “I just want the nitty gritty.”
As a pharmacist who comprehends the nitty gritty of drugs and as a mother of a child with a treatment-resistant epilepsy, I’ve determined that the concepts of “nitty gritty” and “understanding the medical management of epilepsy” are, unfortunately, somewhat mutually contradictory, because the subject is complicated. I hope to provide some idea of the pharmacologic considerations undertaken in the medical management of epilepsy in this article. Additionally, the reader will gain a better understanding of why certain instructions are given relative to medication administration and storage and how drug formulations are optimized for the prevention or treatment of seizures.
Pharmacology focuses on how medicines work to treat disease. This article provides a basic overview of pharmacology important to the medical management of epilepsy. Practical advice includes what to do if you or your child has thrown up an antiepileptic medication shortly after ingestion, safely administering antiepileptic drugs with food products, using the rectal route of administration to treat fever or seizures, and managing generic substitution of antiepileptic drugs.
How can a drug I swallow work in my brain?
Pharmacokinetics deals with the absorption, distribution, metabolism, and elimination of drugs in the body. These processes determine how much of a drug gets to where it needs to work and the intensity of the drug’s effect relative to time. The human body is composed of cells; each specialized to perform a function. We all have, for example, brain cells, heart cells, bone cells, etc. For a drug to interact with a cell, it first must connect with a receptor on the cell’s surface, which is like a customized doorway for particular chemicals. Receptors are proteins that bind to very specific drugs or chemicals. Every cell has countless surface receptors.
The process of a drug interacting with a receptor can be thought of as a key interacting with a lock and is known as pharmacodynamics. A key (drug) is designed to fit a unique lock (receptor). Receptors are located throughout the body and often have naturally occurring “keys,” which are chemicals that fit the “lock” (receptor) in order to allow for a specific biologic response to occur. When a drug is used as the “key” to the receptor instead of a naturally occurring chemical, the end result is either a therapeutic response (the drug works), a therapeutic failure (the drug doesn’t work), or toxicity (side effect).
The ideal for seizure management is no seizures, no side effects. Currently, about 30 percent of patients with epilepsy do not get acceptable seizure relief after a trial of two or more medications. Additionally, we must accept a certain level of toxicity for acceptable seizure control in many cases. As we understand more about the causes of epilepsy and individual response to drugs through genetic research, our hope is to come closer to the ideal of seizure management and ultimately a cure for epilepsy.
The general principles of pharmacokinetics, including absorption, distribution, metabolism, and elimination, are illustrated in Figure 1.
Key Concepts in Understanding How Drugs Work in the Body
Absorption describes the rate and extent to which a drug leaves the site of administration, for example, how quickly a pill gets out of the stomach and into the blood.
Distribution refers to how widely the drug spreads through the body. Distribution of a drug that has been absorbed or injected into the bloodstream occurs when the drug is distributed to cells and spaces in the body. How the drug is distributed is dependent on physical and chemical properties of the drug. During the first few minutes after absorption, the drug goes to organs that get a lot of blood flow including the heart, liver, kidney, and brain.
Several factors affect the extent to which a drug gets to the brain, including how well it dissolves in fat, its chemical properties, and how well it crosses a protective barrier to the brain called the blood-brain barrier. If for example, a drug is very soluble in fat tissue, then people with a lot of fat tissue may trap the drug in their fat. This sometimes makes it hard to achieve therapeutic blood levels of phenytoin (Dilantin). Another important factor in distribution is protein binding. The blood contains albumin (and other proteins) that stick to many drugs. If a drug is 90 percent bound to blood albumin, then only 10 percent of the dose is available to get into brain to stop seizures.
Metabolism is the clearance of drug from the body. Most, but not all, drugs are broken down in the liver. They are then eliminated (excreted) in the urine or stool. Liver or kidney problems can interfere with metabolism and elimination and cause drugs to accumulate, resulting in toxicity.
Metabolism of drugs occurs mostly by enzymes, which are proteins that break down the drug into active or inactive products known as metabolites. Most of these enzymes are found in the liver, but may also be found in the kidneys, lungs, gastrointestinal tract, and skin. Other chemical processes may be involved in the metabolism of drugs. Genetic (inherited or passed from parents) variability of drug metabolism, exposure to environmental toxins, concomitant drug administration and/or disease state(s), impaired liver function, and age may be responsible for decreased efficacy, prolonged therapeutic effect, and increased toxicity of drugs.
Many antiepileptic drugs are metabolized by similar liver enzymes and may interact with each other, altering the concentration of drug in the blood and available to the receptor. It is important to let each treating physician know all drugs and supplements being taken. Changing one drug or supplement that interacts with another drug can change the effects of the interacting drug by altering blood levels.
While in the bottle, drugs also break down naturally over time and under certain environmental conditions. The drug manufacturer will make recommendations on expiration date and storage based on studies necessary to get the drug approved by the FDA. These recommendations should be followed so that the correct potency and purity of the drug is guaranteed. Storage recommendations may include: protect from light, refrigerate, do not freeze, or protect from heat. Drugs should not be taken beyond the manufacturer’s expiration date.
Elimination or excretion of drugs from the body occurs mainly through the kidneys. Drugs can be eliminated from the body unchanged or metabolized into active or inactive drug. Drugs can also be excreted in the feces, through the lungs, the skin, and through the breast. Impaired kidney function can cause a buildup of drug and active metabolites and will increase toxicity and prolong the duration of drug action.
The net result of the absorption, distribution, metabolism, and elimination process is how much drug is available to work as intended, or how much drug is “bioavailable.”
How Drugs Are Administered Has an Effect on Absorption
Sites of administration of a drug include oral, buccal (through the cheek), sublingual (under the tongue), subcutaneous (through the skin), rectal, intra-muscular, nasal, pulmonary (through the lungs), and intravenous (through the vein). How a drug is administered is the major determinant of how quickly the drug works. Drugs are most commonly administered orally. Oral administration provides the safest, most convenient, and most economic means of drug delivery. Drugs that are given by mouth are absorbed from the stomach and pass through the liver, which is a major site of drug processing, before reaching the blood to circulate to the receptor. On average, it takes 1.5 hours for maximal drug concentration to be reached after swallowing a pill, more on a full stomach. The prescribing doctor considers factors that may modify absorption of the oral antiepileptic drugs, which are listed in Table 1.
Pharmacist Advice: If a patient vomits within fifteen minutes of taking prescribed antiepileptic therapy, the entire dose of drug(s) should be re-administered. If the vomiting occurs between fifteen and forty-five minutes of administration, one-half dose of the drug(s) should be re-administered if possible, depending on formulation of drug (some pills cannot be halved). After forty-five minutes, it is not necessary to re-administer drug in most cases. Discuss this advice with the prescriber and formulate an individual plan for emergencies.
Oral administration of drugs prevents seizures, but does not provide rapid relief from a prolonged seizure (> 10 minutes) or status epilepticus (>30 minutes)—also known as seizure emergencies. The treatment of a prolonged seizure should be through administration of medication via the rectal, sublingual, buccal, nasal, or intra-muscular route in the home or outpatient setting. The sublingual, nasal, buccal, and intra-muscular routes of delivery bypass liver metabolism and allow a quicker concentration of drug into the bloodstream compared to oral digestion.
These routes of drug administration are not officially recommended by the drug manufacturers or the Food and Drug Administration (FDA), because they have not been proven safe and effective in formal clinical trials. However, these routes often do work and are used in urgent situations.
Approximately 50 percent of the drug that is absorbed by the rectum will bypass the liver, allowing faster concentration compared with oral digestion but slower onset and concentration relative to the other alternative routes. Intravenous administration of a drug is required when one wants to quickly reach the desired concentration of a drug in blood, but it can only be done by trained health-care professionals, usually in the ambulance or hospital setting. Drugs injected directly into the blood stream bypass the liver and go directly to the receptor, minimizing time required for desired effect. Intravenous administration of antiepileptic drugs by health-care personnel is warranted when other routes of administration fail to stop a seizure.
Table 1: Factors that may modify oral antiepileptic drugs
- Liver problems or disease or interaction with other drugs processed (metabolized) by liver
- Concentration of drug in water (solubility)—best concentration occurs with most water-soluble drug form
- pH and binding to protein in blood
- Blood flow to site of absorption
- Size of surface area (example–inhaling drug or applying to large skin area)
- Strength of drug
- Physical/chemical characteristics of the drug
- How long the drug stays in the blood
- Special coatings or formulation of drug (sustained-release formulas, etc.)
Pharmacist Advice: Remember the rectal route of administration when treating fever in a child that suffers from febrile seizures. Rectal administration of acetaminophen or paracetamol is useful when a child is post-ictal and when quicker onset of fever reduction is desired. Acetaminophen or paracetamol suppositories are available over the counter in most pharmacies. One antiepileptic medicine, Diastat, is designed to be given by rectal administration to stop seizures.
The doctor, nurse, or pharmacist gives instructions on how to take medication for the optimal effect. These instructions are based on studies, required by regulatory agencies (i.e., the FDA in the United States or the EMEA in Europe), that identify how the drug is absorbed and which circumstances provide maximum efficacy with minimal side effects.
How does the doctor know how much drug to prescribe or how to change doses?
Optimizing dosage regimens while minimizing toxicity is by trial and error. Clinical studies required for a drug’s approval determine optimal dosing regimens and provide general guidelines on the use of the drug. Some antiepileptic drugs are dosed based on strategic target blood levels that require periodic blood monitoring; whereas, other drugs are dosed based on achievable drug effect within the defined recommended manufacturer‘s dose. Therapeutic efficacy of antiepileptic drugs in most clinical trials is defined as a greater reduction in seizures compared to placebo when the study drug is added to the existing antiepileptic drug therapy. The clinical studies also yield recommendations on which seizure types will respond to the medication.
Clinicians have the discretion to prescribe more than the recommended dose or target blood level when seizures are not responding to manufacturer recommended doses. In most cases, higher doses lead to increased toxicity. In order to evaluate the risk-benefit of a certain dose of the drug, it is necessary for the patient or caregiver to give feedback to the prescriber about how well the drug is working and the side effects experienced. Doctors may also prescribe a drug “off-label,” meaning for a condition outside of FDA approved indications, when there is significant clinical data to support the use of a drug for other diseases or conditions. In special circumstances with treatment-resistant epilepsy, doctors may obtain permission to prescribe drugs that are undergoing clinical studies and which as yet are not FDA or EMEA approved. Some unapproved drugs can be imported into the United States through compassionate use provisions. For example, Frisium (clobazam), which is approved in Europe and Canada but not the United States, can be purchased legally by an American provided that the doctor stipulates that the drug is a “medical necessity” for the patient.
Generally, changes in the dose of a drug are made by no more than a 50 percent increase or decrease and no more frequently than three to four times the number of hours it takes for one-half of drug concentration in the blood to be eliminated (known as half-life). This concept of half-life also determines how often a drug needs to be given each day. Logically, a drug with a longer half-life is given less frequently during the day, and changes in doses of this drug will be over longer intervals compared to a drug that is dosed more frequently and has a shorter half-life. Failure to take antiepileptic drugs in the time intervals prescribed subjects the patient to low drug levels and a greater probability of breakthrough seizures.
Quick withdrawal of antiepileptic drugs can be dangerous because it can also precipitate seizures. When changes in antiepileptic drug therapy are made due to lack of efficacy or side effects, the doctor will carefully withdraw a medication while introducing another. Each patient’s antiepileptic drug regiment should be optimized to minimize seizures and side effects; however, sometimes the toxicity associated with the drug is accepted for seizure control. My Epilepsy Diary, found at http://www.epilepsy.com/seizurediary, is a great way to keep up with seizures, medications, and side effects in an effort to optimize the medical management of epilepsy.
I read that epilepsy drugs can interact with other drugs and even food. How important is this?
Drug interactions are very important, because many people take more than one drug. Drug A might cause either an increase or decrease in the effectiveness or side effects of Drug B. Many different types of drug interactions are possible. Let’s take an example of a person who has been taking lamotrigine (Lamictal) for many years. Because of ongoing seizures, the doctor prescribes divalproex (Depakote). Depakote inhibits the liver’s ability to metabolize and clear Lamictal. Therefore, within days of adding Depakote, the blood level of Lamictal may double from the drug interaction, even without changing the Lamictal dosage.
An epilepsy drug can also interact with a non-epilepsy drug, such as with the blood thinner Coumadin. Doctors who prescribe many types of epilepsy medicines are trained to know and attend to drug interactions, and prepare patients for their effects. Pharmacists are also great resources for information about drug interactions and educating the patient. Multidrug interactions can become very complicated, but several computer programs obtainable online (for example, www.drugs.com/drug_interactions.html) can flag the most important interactions. And don’t forget—stopping a drug may also produce an interaction and therefore should never be done without direction and agreement from your doctor.
It is important for the prescribing doctor to know all medications being taken by the patient including vitamins, herbal, homeopathic, or other supplements as well as other disease states since these variables can affect how antiepileptic drugs work.
Pay attention to the directions and labels on the medication relative to timing of drug administration and food intake. Again, these instructions are based on studies that have shown optimal bioavailability. Dairy products, which create an alkaline (high pH) environment in the stomach, provide a good example of how certain foods can affect drug absorption. This alkaline environment is not optimal for the absorption of some drugs, so avoiding dairy products around the time of medication administration is necessary for best efficacy.
When administering a liquid medication form you may notice a “Shake well” label on the bottle. Shaking the bottle ensures the concentration of drug is accurate in the liquid form. “Do not chew” is another common instruction for certain antiepileptic drugs that have been formulated to be released more slowly in a coated or encapsulated form. If your drug is a long-acting form, then breaking the pill usually eliminates the slow-release feature. Finally, pay attention to the oral formulation of a drug. Pills, caplets or tablets that are not “scored” (i.e., produced with a line in the middle or in equal divisions of the product), are usually not meant to be divided. Dividing a drug that is not manufactured to be divided may change how long the drug is active in the body and induce a seizure. Check with a pharmacist if you are not sure whether a drug can be safely cut in half.
Pharmacist Advice: Spreading the contents of a powder, opened capsule, or crushed pill on food for administration to a child should be done with caution. Most antiepileptic drugs that can be opened or crushed may be administered this way safely; however, the food-drug mixture should be consumed immediately to avoid chemical reaction between drug and food. Also, pay attention to warning labels about co-administration with food and/or dairy products.
Should I use generic epilepsy drugs?
A generic drug is considered to be “therapeutically equivalent” to the brand name drug if it contains an identical amount of the active ingredient in the same dosage form and meets the equivalent standards set forth by the FDA for strength, quality, purity, and identity. “Therapeutic equivalence” implies that substitution of a generic drug for the brand name drug will yield the same clinic efficacy and side effects. The FDA reports the mean (average) difference in blood concentration (bioequivalence) measures in several hundred studies is between 3.5 percent and 4.3 percent. Keep in mind that this difference may be compounded if the generic product is supplied by multiple manufacturers to a pharmacy and the patient receives a different manufacturer’s generic product at the time of refill. Often you may pick up a refill at the pharmacy and notice the pill is a different color or shape or has different markings than the original prescription on previous refill. This is because multiple generic manufacturers supply the drug to pharmacies.
Generic drugs do not undergo therapeutic equivalence testing; the presumption of therapeutic equivalence is based on generic drugs achieving blood levels similar to those with the brand name drug. Professional and patient epilepsy support organizations worldwide are concerned with generic formulation substitutions and have issued statements opposing the substitution of brand-name antiepileptic drugs with generic products without a physician’s prior approval. Until studies are conducted to better clarify the risks of generic formulation substitution in patients with epilepsy, health-care providers and people with epilepsy should understand the potential risks and benefits of generic substitution and proceed cautiously. It is advisable to exercise extra caution with patients at highest risk of seizure complications, including pregnant patients, patients with recurrent status epilepticus, or patients who are driving because they have been seizure free for a long time.
Medicaid or national insurance plans, private insurance providers, or pharmacies may automatically substitute generic products as they become available. If the prescribing doctor and patient or caregiver decides it is not in the patient’s best interest to use a generic antiepileptic drug, the first step is for the prescriber to write on the prescription or sign on appropriate signature line “Dispense as written.” If the insurance carrier denies coverage for the drug due to a “therapeutic equivalence” policy for prescription drugs, an appeal may be necessary, including a letter of medical necessity from one’s doctor regarding the need of the brand drug. Contact the insurance plan administrator for procedures regarding appeal for brand drug only. But be aware that the insurance company may require a higher co-pay for branded drugs.
If you have changed from a brand to a generic drug or from one generic to another generic, be sure to clarify with your pharmacist that the drug is an appropriate substitution. If you take both the old and the new drug, you may get a dangerous double-dose!
Pharmacist Advice: If the prescriber and patient or caregiver decide that the branded product is not affordable or that substitution is inevitable, it is prudent to request that the pharmacy utilize the same generic company for each refill of the product to avoid further variation in bioavailability.
As we move closer to understanding the “nitty gritty” of epilepsy management, we can better understand the pharmacokinetic principles that guide clinicians in epilepsy medication management. Although readers may forget the technical terms, hopefully, they will remember the practical advice from this article about managing a patient that has vomited antiepileptic medication shortly after ingestion, safely administering antiepileptic drug on food products, utilizing the rectal route of administration to treat fever, and managing generic substitution of antiepileptic drugs. The next Epilepsy Pharmacist article will feature a break-down of antiepileptic drugs, their uses, and side effects.
Harriet Davies is a pharmacist and the mother of four-year-old Lilly, who suffers from Dravet syndrome, a genetic and catastrophic epilepsy syndrome. She is a tireless epilepsy advocate and works with many advocacy groups aside from the Intractable Childhood Epilepsy Alliance (ICE), which she founded. She serves on the Professional Advisory Board of the Charlie Foundation and as a medical consultant for pharmaceutical companies who wish to bring products for rare diseases to the United States. Michelle lives with Lilly, her husband Tim, and older daughter, Logan, in Lewisville, North Carolina.
Sources, Notes and Citations
1. FIP Statement of Policy, Medicines Information for Patients. International Pharmaceutical Federation, The Hague, The Netherlands 2008. http://www.fip.org/www/?page=statements
2. Benet, L.Z., D. L. Kroetz et al. “Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination.” In: Hardman, J.G., L.E. Limbird et al., eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics; 9th Ed. McGraw-Hill, 1996: 3-27.
3. 17th Expert Committee on the Selection and Use of Essential Medicines, Geneva March 2009. http://www.who.int/selection_medicines/committees/expert/17/en/index.html
4. Liow. K., G.I. Barkley et al. “The American Academy of Neurology. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy.” Neur 68 (2007): 1249-1250.
5. Privitera, M.D., “Generic Antiepileptic Drugs: Current Controversies and Future Directions.” Epilepsy Currents 8(5) (2008): 113-117.
6. Position statement on the substitution of different formulations of antiepileptic drugs for the treatment of epilepsy. www.aesnet.org.
7. www.usp.org The USP Pictogram Library enables you to use standardized images to convey medication instructions, precautions, and/or warnings to patients and consumers. Pictograms are particularly helpful in passing on important information to patients with a lower level reading ability and patients who use English as a second language. Pictograms are available free-of-charge to professionals and patient information providers to reinforce printed or oral instructions.