Seizures can be exacerbated by concurrent medical conditions. Two common problems faced by neurologists are sleep apnea and renal disease.
Sleep disorders are common, treatable conditions that frequently coexist with epilepsy. Understanding the relationship between epilepsy and sleep disorders is important for optimizing management of the epilepsy patient in several ways:
- Epilepsy and its treatment may affect sleep organization and daytime alertness.
- Treatment of a coexisting sleep disorder may improve seizure control, daytime alertness, or both.
- Sleep disorders (e.g., sleepwalking, nocturnal panic disorder, sleep attacks due to excessive daytime sleepiness) may mimic epileptic seizures.
Patients with medically refractory epilepsy may have a higher prevalence of obstructive sleep apnea (OSA) than the general population and treating OSA may impact favorably on seizure control. Therefore, it is important to suspect and diagnose OSA in the patient with epilepsy.
Neurologists are often asked to consult on patients with renal disease and seizures. Among patients with known epilepsy, the most commonly encountered problem is management of antiepileptic drug therapy. To understand the effects of renal impairment and hemodialysis on steady-state AED plasma concentration, it is first necessary to understand the normal physiology of renal clearance of drugs.
Principles of renal clearance
Renal excretion of drugs and their metabolites is determined by three processes:
- glomerular filtration
- tubular secretion
- passive tubular resorption
Filtration is determined primarily by glomerular filtration (measured clinically as creatinine clearance) and plasma protein binding. Only non–protein bound (free) drug in the plasma can pass through the glomerular filter. This has important implications, which are discussed later.
Some drugs are actively transported from the plasma to the urine by two independent carrier systems. One carrier system transports organic acids such as acetazolamide and glucuronide drug metabolites. The other carrier system transports organic bases such as cimetidine. In practice, the only antiepileptic drug (AED) with significant tubular secretion is acetazolamide (80% excretion via acidic secretion system). A small portion (probably not clinically important) of gabapentin is excreted via the basic secretion system, as evidenced by inhibition of renal clearance of gabapentin by co-administration of cimetidine. Otherwise, renal tubular secretion is not an important mechanism for clearance of unchanged AEDs.
Lipid-soluble (nonionized) molecules pass through biological membranes by simple diffusion, while water-soluble (ionized) molecules do not. Resorption of water in renal tubules creates a concentration gradient that facilitates back-diffusion of lipid-soluble drugs from the glomerular filtrate into the plasma. Thus, water-soluble drugs (e.g., gabapentin, levetiracetam) are excreted in the urine. Lipid-soluble drugs (e.g., carbamazepine, phenytoin) are not excreted via the urine.
The renal elimination of ionizable drugs with pKa values within the range of urinary pH (5–8) can be increased or decreased by altering urine pH. Such alterations in pH will alter the proportions of drug that are ionized (water-soluble, excreted in urine) and nonionized (lipid-soluble, resorbed into plasma). For example, alkalinization of the urine will increase the rate of elimination of phenobarbital (weak acid, pKa = 7.3) in case of phenobarbital overdose.
In summary, the renal clearance of AEDs is determined by protein binding, glomerular filtration rate, and the drug's water solubility. Water-soluble (ionized) drugs are excreted via the urine and lipid-soluble drugs are not. Most drug metabolites (e.g., epoxides, glucuronides) are more water-soluble than the parent drug and are excreted in the urine.
Factors determining steady-state drug plasma concentration
The mean steady-state plasma concentration of a drug during chronic oral dosing is:
Where F= fraction of drug absorbed, D= dose, t= dosing interval, Clr= renal clearance, ClH= hepatic clearance and ClO= clearance via other routes.
For drugs having no renal tubular secretion (all AEDs except acetazolamide), renal clearance can be defined as:
Where GFR= glomerular filtration rate, Cur= concentration of drug in urine, Cp= concentration of drug in plasma, and Qur= urine flow rate.
The hepatic clearance of a drug by a hepatic enzyme system is:
Where QH= hematic blood flow rate, f= free (non=protein bound) fraction of drug on plasma, Vmax= the maximum velocity of the enzyme, and KM= the Michaelis-Menten constant of the enzyme.
Combining these three equations yields:
This equation is admittedly cumbersome and complex. It need not be memorized, but it does provide a useful checklist of all the factors that may influence drug plasma concentration. Most of the factors listed in the equation can be affected by renal impairment.
Effect of renal impairment on fraction of drug absorbed (F)
There are reports that renal disease may reduce oral absorption because of alteration of gastric pH, edema of the gastrointestinal tract due to irritant properties of waste products such as urea, and administration of antacids. However, bioavailability studies typically compare area under the plasma concentration versus time (AUC) of drug given for healthy persons and renally impaired patients. AUC is determined by fraction of drug absorbed, drug clearance, and drug protein binding. Since clearance and protein binding can be affected by renal impairment, simple measurements of AUC for determination of F may be invalidated because of alterations in one or both of these factors. Techniques that correct for changes in clearance and protein binding have produced variable results when applied to studies of F in patients with renal impairment.
Effect of renal impairment on drug protein binding
The plasma protein binding of acidic drugs (e.g., phenytoin, valproic acid) is markedly reduced in patients with severe renal impairment. The effects of lesser degrees of renal impairment have not been studied as extensively.
The proposed mechanisms for reduced protein binding in renal insufficiency include:
- decreased plasma albumin concentration
- accumulation of endogenous binding inhibitors
- competition for binding sites by metabolites of the administered parent drug
For drugs cleared principally by hepatic enzymes, the last complicated equation shown above can be simplified to:
Thus, the total (protein-bound and nonbound) mean steady-state plasma concentration decreases when the free fraction of drug increases in situations such as renal insufficiency.
The mean steady-state free or non-protein bound concentration of drug (CssF) can be expressed as:
Combining the two equations above yields:
Note this important relationship: For drugs metabolized by hepatic enzymes, changes in protein binding affect the total steady-state plasma concentration, but the free drug plasma concentration remains constant.
For example, with renal insufficiency, the total plasma concentration of a protein-bound drug cleared by the liver, such as phenytoin, decreases owing to an increase in the free fraction of the drug, but the free concentration of phenytoin remains unchanged. Seizure patients with renal insufficiency may receive toxic doses of phenytoin if the total plasma concentration is the basis for selecting the dosing rate.
Another example of the effects of changes in protein binding on free and total drug plasma concentration is the interaction of valproate with phenytoin. Both drugs have high protein binding. When valproate is added to phenytoin, the free fraction of phenytoin increases because it is displaced from protein binding sites by valproate. The total phenytoin plasma concentration decreases, but the free phenytoin plasma concentration remains constant. This can lead to toxic dosing of phenytoin if the dosing rate is based on its total plasma concentration.
Effect of renal impairment on drug metabolism
Renal impairment will decrease the excretion of drugs eliminated by renal clearance (see next section). Certain drugs (e.g., acetaminophen) are metabolized by the kidney, and this metabolism is reduced in renal failure. No antiepileptic drugs (AEDs) are in this group. There is animal and human evidence that the nonrenal clearance of certain drugs is decreased by 20% to 80% in the presence of renal insufficiency.
Metabolic enzyme systems that may be affected by renal impairment are:
The mechanism of these metabolic changes may be accumulation of inhibitors or toxins or collateral effects of the disease causing renal insufficiency.
Hydroxylation, demethylation and glucuronidation are results of metabolism of some AEDs. This raises the possibility of a decrease in nonrenal clearance of some AEDs in renal failure. This possibility has not been studied extensively.
Effect of renal impairment on drug excretion:
The total clearance of the drug is the sum of renal clearance (CLr) plus hepatic clearance (CLH) plus other routes of clearance (e.g. sweat).
Renal clearance can be defined as
Where CLF= clearance via filtration, RS= the rate of renal tubular secretion, RR= the rate of renal tubular resorption, and Cp= drug plasma concentration.
The effect of renal disease on drug clearance thus depends upon several factors:
- the relative contribution of renal clearance to total clearance
- drug filtration
- tubular secretion rate
- tubular resorption rate
- drug plasma concentration
For some drugs (e.g., gabapentin, levetiracetam), renal clearance accounts for most or all of total clearance. For other drugs (e.g., phenytoin, carbamazepine), renal clearance accounts for little of total clearance.
The rate of filtration of a drug (Rf) depends on GFR, drug plasma concentration, and free fraction of the drug in plasma
In renal impairment, the glomerular filtration rate (GFR) will decrease and the free fraction of drug in plasma may increase, as discussed above.
Renal tubular secretion does not occur with the commonly used AEDs.
Tubular resorption depends upon lipid solubility and the ability to cross biological membranes. Lipid-soluble drugs readily cross the renal tubule and are readily resorbed. For example, phenytoin is highly lipid-soluble, and almost no phenytoin is cleared by the kidney.
Thus, there can be no general statement about how renal impairment will affect total drug clearance, since the effect of renal impairment depends upon the combined effects of the factors listed above. The effects of renal impairment on specific AEDs are discussed separately.
Drug dosing rate adjustments:
Calculating an appropriate dosing rate for a patient with renal impairment requires the clinician to consider several factors involving the patient and the drug:
Changes in renal clearance are correlated with changes in creatinine clearance (ClCR) by a constant q, which is different for each drug.
Total drug clearance (CLT) is the sum of renal clearance (CLR) plus nonrenal clearance (CLN).
Steady-state mean drug plasma concentration (Css) is equal to dosing rate (D) divided by total clearance.
Rearranging this equation leads to
Thus, the simplest approach to adjusting dosing rate in renal insufficiency is to:
- empirically determine q for the drug
- measure creatinine clearance for the individual
- select a desired plasma concentration
- calculate dose from the above equations
Although simple, this approach fails to account for differences in age and weight and for changes in volume of distribution, bioavailability, and nonrenal clearance that may occur in renal insufficiency. Roland and Tozer have described a more complete method for dosage adjustment in renal failure, using:
- volume of distribution of the unbound drug in healthy subjects
- volume of distribution of unbound drug in renal insufficiency
- fraction of drug absorbed in healthy subjects
- fraction of drug absorbed in renal insufficiency
- ratio of the individual patient's creatinine clearance to normal creatinine clearance
- fraction of unchanged drug eliminated renally in healthy subjects
Other complex methods of adjusting dosing regimen in renal failure are reviewed by Matzke and Millikin.
All available methods for computing dosing regimens in renal insufficiency have errors. The actual plasma drug concentration obtained with the calculated dosing rate may vary considerably from the desired plasma concentration. The patient and the drug plasma concentration must be monitored and the dosing rate may need to be modified from the calculated rate.
Effects of hemodialysis:
Antiepileptic drugs (AEDs) are cleared from the circulation by hemodialysis, principally by diffusion from the blood into the dialysate through the filter membrane. The drug moves from the blood (high concentration) to the dialysate (low concentration) via a concentration gradient. (The principles applicable to hemodialysis also apply to peritoneal dialysis.)
Many factors determine the rate of clearance of a drug during hemodialysis:
- Water solubility. Water-soluble drugs readily cross dialysis membranes, whereas drugs that are not readily water-soluble do not. Many CNS drugs (e.g., carbamazepine, phenytoin, tricyclic antidepressants) are lipid-soluble compounds that are not readily water-soluble. (Lipid solubility permits passage across the blood-brain barrier.)
- Protein binding. Only non–protein-bound drugs can cross dialysis membranes. Drugs that are highly protein-bound (e.g., phenytoin, valproate) are difficult to remove from the systemic circulation by hemodialysis.
- Volume of distribution. Drugs that remain mainly in the blood are more readily removed than drugs that are distributed extensively into tissues.
- Molecular size. Drugs must pass through pores of a specified size during hemodialysis. Molecules larger than 500 atomic mass units usually do not pass through hemodialysis filters. AEDs have atomic masses less than 500, however, so molecular size is not an issue for dialysis of AEDs.
- Dialysis conditions. There are many types of dialysis filters. Filter characteristics, filter size, blood flow rate, and dialysis flow rate all affect the hemodialysis clearance of a drug.
There is no simple equation to predict the amount of an AED that will be lost during dialysis. Drugs that are water-soluble, not highly protein-bound, and that have a small volume of distribution are readily removed by hemodialysis. Drugs with high lipid solubility (i.e., low water solubility), high protein binding, and high volume of distribution will be difficult to remove by hemodialysis.
Correction for drug loss during hemodialysis
The plasma concentration of a drug that has been partially removed during dialysis can be restored to the desired level using the following equation to calculate a loading dose (LD) of the drug:
Where Cchange= desired change in plasma concentration and VD= volume of distribution
For example, to increase the plasma concentration of phenytoin by 5 mg/L (5mcg/mL), the clinician would multiply 5 mg/L by the phenytoin volume of distribution, 0.7L/kg, resulting in a loading dose of 3.5 mg/kg.
For gabapentin, levetiracetam, and topiramate, a standard replacement dose is recommended after hemodialysis.
Adapted from Browne TR. Renal disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;49-62. With permission from Elsevier (www.elsevier.com).