Old generation AED drugs Flashcards
Phenobarbita
The first of old-generation antiepileptic drugs (AEDs) that are currently marketed was phenobarbital, which came into clinical use in 1912. Its initial use was as a sedative and sleep aid. Its efficacy against seizures was discovered later (Table 16.1).
Phenobarbital exerts its action by binding to the GABA-A receptor and enhancing chloride currents by prolonging the opening of the chlo-ride channel. It may also have other actions including blocking high-voltage-activated cal- cium channels and AMPA subtype glutamate receptors.
Phenobarbital is available as oral preparations as well as parenteral solution. Its oral availability is greater than 90%. Its protein binding is about 45%. Its volume of distribution is approximately 0.6 L/kg. Phenobarbital is mostly metabolized in the liver but 20–25% is eliminated unchanged in the urine. The half-life in adults is 80–100 h. The half-life is longer in newborns and shorter in young children.
Phenobarbital is a potent inducer of P4 50 enzymes. It does accelerate the meta- bolism and reduces the levels of anti-epileptic drugs processed by this enzyme system. For example, phenobarbital reduces serum concen- trations of valproate, ethosuximide, lamotrigine and others. It reduces the serum concentration of carbamazepine but may increase the carba- mazepine epoxide to carbamazepine ratio. It reduces the efficacy of warfarin, steroids, and the oral contraceptive.
Phenobarbital has a variable effect on pheny- toin concentration; while it may induce pheny- toin metabolism, it may also compete with phenytoin for metabolic enzymes CYP 2C9 and 2C19. Phenobarbital serum concentration may be increased by the inhibitors valproate and felbamate.
The main adverse effects of phenobarbital are sedation, mood changes (particularly depres- sion), hyperactivity and irritability in children, and decreased memory and concentration. It also has long-term adverse effects. Long-term use of phenobarbital is associated with decreased bone density and some connective tissue disorders, particularly Dupuytren’s contractures, plantar fibromatosis, and frozen shoulder. Phenobarbital is associated with increased risk of cardiac mal- formations in the exposed fetus and reduced cognitive abilities in the exposed male offspring. It is assigned to pregnancy category D.
Phenobarbital is effective against partial onset (focal) seizures, generalized tonic–clonic sei- zures, and other generalized onset seizures except for absence. The recommended thera- peutic concentration is 50 and 2 14 mg/L. Phenobarbital is not a drug of first choice in developed countries, because of its adverse effects, namely sedation, and because of its enzyme-inducing properties. However, it is inexpensive and widely available, and may be the only affordable antiepileptic drug in much of the developing world.
Primidone is converted to phenobarbital and phenylethylmalonamide (PEMA), which is also an active metabolite. Unlike phenobarbital, primidone does not have a direct effect on GABA receptors. Primidone and phenobarbital may act synergistically to reduce sustained high-frequency repetitive firing, at clinically rel- evant concentrations. This is an effect on the sodium channel that neither drug has when used alone. As mentioned earlier, phenobarbital acts at the GABA-A receptor to prolong the opening of the chloride channel. The mechanism of action of PEMA is unknown, and its anti-seizure activity is modest. Primidone is available only as an oral preparation. It is poorly soluble, precluding an IV preparation.
Primidone oral bioavailability is fairly complete. Its volume of distribution is *0.7 L/kg. Its protein binding is low, less than 10% for primi- done and for PEMA.
Primidone is metabolized in the liver. PEMA is the first detected metabolite. When used in monotherapy, about 25% of oral primidone is converted to phenobarbital. After one dose, approximately 64% of primidone is excreted nchanged in the urine. In the presence of enzyme induction, only about 40% is excreted unchanged. In monotherapy, primidone half-life is 10–15 h; it is shorter (6.5–8.3 h) in the pres- ence of enzyme inducers.
In the presence of inducers, particularly phenytoin, the ratio of primidone-to- phenobarbital is reduced due to the acceleration of primidone-to-phenobarbital conversion.
Primidone and phenobarbital are potent enzyme inducers, decreasing the efficacy of drugs metabolized by the p450 enzymes system. Since phenobarbital will be present when primidone is used, all phenobarbital interactions are also pre-sent by necessity.
Primidone has acute toxic reactions that are different from phenobarbital. It can produce transient drowsiness, dizziness, ataxia, nausea, and vomiting that can be debilitating. These reactions are present even before phenobarbital has appeared as a metabolite. Therefore, a slow titration of primidone is necessary. Tolerance to these acute adverse experiences develops rapidly within hours to days. Otherwise, primidone has similar adverse experiences to phenobarbital, including adverse experiences from long-term use.
Primidone is effective against the same seizure types as phenobarbital. The recommended primidone therapeutic plasma concentration is 5– 12 mg/L. A phenobarbital level should also be monitored. Since about 25% of oral primidone is converted to phenobarbital, the dose of primi- done required for a certain level is about 4–5 times the dose of phenobarbital required for that same level. Primidone was found to have equal efficacy but lower tolerability in comparison with phenobarbital, phenytoin, and carbamazepine.
Phenytoin
- Phenytoin has been used since 1938 when Houston and Merritt discovered its efficacy in the maximum electroshock animal model. Phenytoin acts by binding to active state of the sodium channel and reducing high-frequency firing (as might occur during a seizure), while allowing normal action potentials to occur.
Phenytoin is available as oral preparations and parenteral solution. There is also a phenytoin prodrug for parenteral administration, fosphenytoin.
Phenytoin absorption is variable. The rate and extent of absorption may also differ among formulations and is affected by a variety of factors including age and food. While oral bioavailability can be greater than 90% in adults, it is decreased in neonates and is also decreased in the presence of nasogastric feedings, calcium, and antacids. There is limited absorption in the stomach. Absorption is primarily in the duodenum where the higher pH increases the phenytoin solubility. The time to maximal concentration is shorter with immediate release preparations and longer with extended-release formulations. The volume of distribution is approximately 0.75 L/Kg. Protein binding is approximately 90%.
The major pathway of elimination of pheny- toin is hydroxylation, mediated mainly by the cytochrome p450 enzymes CYP 2C9 and to a lesser extent CYP 2C19. Phenytoin follows nonlinear kinetics. Small changes in CYP 2C9 activity may have clinically significant effects. Some CYP 2C9 alleles are associated with reduced clearance of phenytoin. The importance of CYP 2C19 increases with higher levels. Some inhibitors such as ticlopidine and isoniazid may ead to phenytoin accumulation. Similarly, some alleles are associated with decreased activity leading to accumulation.
The phenytoin half-life is dependent on the serum concentration. The initial half-life is approximately 22 h (with the range of 8–60 h). The half-life increases as the serum concentration increases within and above the recommended therapeutic range (10–20 mg/L).
The mechanism of the nonlinear elimination kinetics is that enzymes responsible for most of phenytoin elimination are partially saturated with concentrations within the recommended range (with individual variation as to the concentration at which this phenomenon first appears). These enzymes are not able to increase their activity in proportion to phenytoin concentration, as the concentration increases in the recommended therapeutic range. Therefore, steady-state phenytoin level increases disproportionately as the maintenance dose is increased within and above the recommended therapeutic range.
Below are two examples of the consequences of phenytoin nonlinear kinetics.
Example 1: A daily dose of 300 mg per day results in a concentration of 9 mg/L, with some residual seizures. Increasing the dose to 400 mg per day, a 30% increase in dose would have been expected to increase the steady-state concentra- tion by 30%, to 12 mg/L, if phenytoin were to follow linear elimination kinetics. However, with its nonlinear kinetics, the concentration increases disproportionately, by more than 300%, to 31 mg/L, with associated toxicity. Therefore, when increasing phenytoin dose within the therapeutic range, small increments should be used (e.g., 30–60 mg).
Example 2: A patient presents with phenytoin toxicity and a serum concentration of 40 mg/L. The half-life was previously estimated at 24 h when the serum concentration was 13 mg/L. However, after phenytoin was stopped, it took 3 days for the serum concentration to drop below 20 mg/L. The reason for this is that the half-life was markedly prolonged in the presence of toxicity.
Phenytoin is affected by drugs that decrease absorption (e.g., nasogastric tube feedings) drugs that compete for protein binding (such as val- proate) and by enzyme inducers or inhibitors. Drugs that cause phenytoin accumulation include amiodarone, azoles, fluoxetine/fluvoxamine, and isoniazid.
Phenytoin is a potent enzyme inducer that reduces the efficacy of other drugs metabo- lized by the p450 enzyme system, including a number of other antiepileptic drugs.
Phenytoin protein binding plays an important role in some phenytoin interactions. The protein-free phenytoin level is responsible for its therapeutic effect and for its toxicity. The free fraction increases in the presence of low-protein state, renal failure, hepatic failure, old age, or with co-administration of valproate. Therapeutic decisions are usually made based on the total phenytoin level, assuming that 10% is free. However, a free level should be obtained in clinical situations where an increase in the free fraction is expected.
As an example of the potential consequences of altered protein binding of phenytoin, a patient with epilepsy and renal impairment may be having uncontrolled seizures with a total phenytoin concentration of 15 mg/L. The deci- sion has to be made whether the dose should be increased to improve seizure control or should be decreased because of toxicity causing a para- doxical increase in seizure frequency. The protein-free concentration turns out to be 4.5 mg/L, equivalent to a total phenytoin con- centration of 45 mg/L under the condition of normal protein binding. In this case, holding phenytoin was the correct approach.
While renal and hepatic failures are frequently associated with the decreased albumin concentration, the reduction in protein binding may also occur as a result of small molecules that compete for protein binding.
Valproate competes with phenytoin for pro- tein binding. In monotherapy, each of phenytoin and valproate are approximately 90% protein-bound, and the free phenytoin level is about 10% of the total level. With concomitant use, each 1 mg/L of valproate increases the free fraction of phenytoin by approximately 0.1–0.2%. At a valproate level of 100 mg/L, the free phenytoin fraction may increase to 20–30% A phenytoin level of 15 mg/L may actually be toxic with a free level of 3–4.5 mg/L, equivalent to a total level of 30–45 mg/L in the presence of normal protein binding.
When a low-protein state is present as the only factor affecting protein binding, the total phenytoin level can be corrected using the fol- lowing formula: Cn = Co/[(0.02 albu- min) + 0.1], where Cn is the normal total level and Co is the observed total level.
Phenytoin concentration-dependent adverse effects include nystagmus, ataxia, incoordination, diplopia, dysarthria, and drowsiness. In addition, exacerbation of seizures may occur with con- centrations above 30 mg/L. Some individuals may experience prominent adverse effects within the recommended therapeutic range, including cognitive adverse effects.
Idiosyncratic reactions may be related to the formation of an arene oxide, the active metabo- lite that forms due to inadequate epoxide hydrolase activity. Allergic rash occurs in up to 8.5% of patients. Serious severe rash such as Stevens–Johnson syndrome or toxic epidermal necrolysis are much less common. A hypersensi- tivity syndrome may occur rarely, with rash, fever, lymphadenopathy, eosinophilia, elevated liver enzymes, and renal failure.
Phenytoin also has long-term adverse effects including gingival hyperplasia, hirsutism, acne, cerebellar atrophy (which may also occur after acute intoxication), reduced bone density, reduced folate levels, anemia, and macrocytosis. Phenytoin also has potential teratogenicity and is classified with pregnancy category D.
The IV preparation is associated with local reactions such as pain and burning at the infusion site, phlebitis, cellulitis, or necrosis from extravasation, and the purple glove syndrome with discoloration then petechial rash. Cardio- vascular adverse experiences include hypoten- sion, conduction abnormality, and arrhythmia. They are related in part to the vehicle, propylene glycol. They can be avoided with the slowing of the infusion rate, which should not exceed 50 mg/m.
Phenytoin is effective against partial onset (focal seizures) and generalized tonic–clonic eizures. Efficacy against tonic and atonic sei- zures is less well established. Phenytoin is not effective against generalized myoclonic or gen- eralized absence seizures and may even exacer- bate these seizures.
Phenytoin can be loaded orally (18 mg/kg divided into 3 doses given 2–3 h apart). IV loading dose for status epilepticus is 18– 20 mg/kg. Phenytoin should be evaluated in normal saline, not dextrose 5% in water. It should be administered into a large vein with a maximum rate not exceeding 50 mg/min.
Intramuscular injection is not recommended due to slow and erratic absorption as well as crystallization at the injection site causing pain and a sterile abscess.
Fosphenytoin
Fosphenytoin is a water-soluble phenytoin pro- drug. It can be given intravenously or intramus- cularly. It is rapidly and completely converted to phenytoin by the cleavage of the phosphate group by nonspecific phosphatases. Its conver- sion half-life is 8–18 min, and the conversion is completed in a little more than 1 h. It is highly bound to serum albumin (95–99%). It displaces phenytoin from protein-binding sites after IV administration, increasing unbound phenytoin concentrations as a function of fosphenytoin concentration. It is indicated for a replacement of oral fosphenytoin or for intravenous or intra- muscular loading. It is marketed in phenytoin equivalents, so the loading dose is the same as phenytoin. The maximum rate of intravenous infusion is much higher, at 150 mg/min, in view of the absence of propylene glycol. A therapeutic phenytoin level is usually reached within 10 min after IV loading and within 30 min after intra- muscular administration.
Fosphenytoin has a lower incidence of local reactions. However, intravenous administration in the awake individual is commonly associated with paresthesias and itching, most often in the groin and perianal region, as well as the trunk and the back of the head. This adverse experi- ence is related to infusion rate and subside apidly after the end of infusion. It is not seen with intramuscular administration.
Carbamazepine
Carbamazepine is a related structure to tricyclic antidepressants. Its mechanism of action is reducing high-frequency neuronal firing through the blocking of the sodium channel in a voltage and use dependent fashion.
It has good bioavailability of 80–90%, and it is lipophilic but poorly water-soluble, making parenteral formulation difficult. Its protein binding is about 75%, usually not of clinical importance.
Carbamazepine is cleared almost entirely via hepatic metabolism. The most important metabolic product is carbamazepine-10,11-epoxide, produced via oxidation through CYP 3A4 and CYP 2C8. It is an active metabolite which is also responsible for some adverse effects.
Carba- mazepine induces its own metabolism. This process, known as autoinduction, causes increased clearance, shortened half-life, and lower serum concentration of carbamazepine over time. The process typically takes 2– 4 weeks. As a result, carbamazepine cannot be started at the target maintenance dose. It has to be titrated gradually.
Carbamazepine is a potent inducer of p450 enzyme system (particularly CYP 3A4, CYP 2C9, CYP 2C19, and CYP 1A2), increasing the clearance of agents metabolized by these enzymes. The list of drugs affected includes hormonal contraceptives, warfarin, and several antiepileptic drugs, including valproate and lamotrigine.
Carbamazepine is affected by agents that induce or inhibit CYP 3A4. The list includes erythromycin and other macrolide antibiotics (except azithromycin), fluoxetine, propoxyphene, and grapefruit juice among others. The level of carbamazepine epoxide is increased by the con- comitant use of valproate, felbamate, oxcar- bazepine, and zonisamide.
The most common adverse experiences with carbamazepine are nausea, GI discomfort, headache, dizziness, incoordination, unsteadi- ness, vertigo, sedation, tiredness, blurred vision, diplopia, nystagmus, and tremor. Benign leukopenia is common, occurring in 10–20% of instances. It is most often transient and may be persistent though not progressive. This is to be distinguished from the more serious but very rare aplastic anemia. Carbamazepine can cause hyponatremia. Cognitive impairment has been reported on neuropsychological testing. Long-term use is associated with weight gain and decreased bone density. Carbamazepine has been found to increase sex hormone binding globulin and decrease testosterone concentration.
Idiosyncratic adverse experiences include rash, rare Stevens–Johnson syndrome and toxic epidermal necrolysis, as well as very rare hypersensitivity syndrome with fever, rash, end organ involvement. Lupus-like syndrome is rare, as are hepatotoxicity and aplastic anemia (esti- mated at 1 in 200,000). There is a strong asso- ciation between the HLA-B1502 allele and carbamazepine-induced Stevens–Johnson syn- drome in Asian populations and individuals of Asian descent. The FDA has issued an alert and updated product labeling recommending genetic testing of HLA-B polymorphisms to predict carbamazepine-induced serious skin reactions in individuals of Asian descent.
Carbamazepine has been assigned pregnancy category D due to increased risk of spina bifida when used in polytherapy.
Carbamazepine is effective against partial onset (focal) seizures and against generalized tonic–clonic seizures. However, it may exacer- bate absence and myoclonic seizures as well as atonic seizures. The recommended therapeutic range is 4–12 mg/L.
The efficacy and tolerability of carba- mazepine, phenobarbital, phenytoin, and primi- done were compared in a large, multicenter, double-blind, cooperative veterans administra- tion trial [9]. Six hundred and twenty-two adults with partial and secondarily generalized tonic– clonic seizures were randomly assigned to one of the four drugs and were followed for two years or until the drug failed due to uncontrolled seizures or unacceptable side effects. The overall treat- ment success was highest with carbamazepine and phenytoin, intermediate with phenobarbital and lowest with primidone. The drugs had overall equal efficacy, and the difference in treatment success was related to tolerability. Primidone caused more intolerable acute toxic effects, mainly nausea, vomiting, dizziness, sedation, decreased libido, and impotence. When specific seizure types were analyzed, control of secondarily generalized tonic–clonic seizures did not differ significantly with the 4 drugs, but carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital. As a result, carbamazepine became the drug against which new antiepileptic drugs were compared.
Oxcarbazepine
Even though oxcarbazepine was first introduced in the USA in 2000, it is listed with the old-generation drugs since it was introduced in some European countries as early as 1963. Oxcarbazepine is structurally related to carba- mazepine, but different from carbamazepine in its metabolism and in the induction of metabolic pathways. Oxcarbazepine has a similar mecha- nism of action to carbamazepine, inhibiting high-frequency repetitive neuronal firing by blocking voltage-gated sodium channels. It also modulates high-voltage-activated calcium channels.
Oxcarbazepine absorption is almost complete with a bioavailability of about 99%. It is very rapidly metabolized to a monohydroxy deriva- tive, an active metabolite responsible for oxcar- bazepine activity. Oxcarbazepine protein binding is about 60% while the monohydroxy derivative protein binding is about 40%. The oxcarbazepine half-life is 1–3.7 h. The monohydroxy derivative is further metabolized and has a half-life of 8– 10 h. Oxcarbazepine does not induce its own metabolism.
The monohydroxy derivative level decreases in the presence of enzyme-inducing drugs. One major advantage of oxcarbazepine over carba- mazepine is that it is not affected by CYP 3A4 inhibitors such as erythromycin, fluoxetine, pro- poxyphene, and grapefruit juice. Oxcarbazepine does not induce the metabolism of other antiepileptic drugs or warfarin. It weakly induces CYP 3A4 which is responsible for estrogen metabolism, thus reducing the efficacy of the birth control pill at high doses. Oxcarbazepine also weakly inhibits CYP 2C19, thus raising phenytoin level when used at high doses.
The most common adverse effects of oxcar- bazepine are somnolence, headache, dizziness, blurred vision, diplopia, fatigue, nausea, vomit- ing, and ataxia. Rash has been reported in 2–4% of individuals. Oxcarbazepine can cause hyponatremia, which is more likely in older individuals and those taking a diuretic. Oxcar- bazepine does not has the effect on sex hormone binding-globulin and testosterone that carba- mazepine has. Oxcarbazepine was assigned pregnancy cate- gory C.
Oxcarbazepine is effective against partial onset (focal) seizures. The recommended therapeutic range is 15–35 mg/L. Oxcarbazepine is a narrow spectrum drug that should be avoided in indi- viduals with generalized epilepsy. Oxcarbazepine may exacerbate absence and myoclonic seizures.
Multiple comparative monotherapy trials for new onset partial epilepsy have demonstrated that oxcarbazepine is equal in efficacy to phenytoin and carbamazepine but with superior tolerability [1, 3, 5, 6, 11–13]. Conversion to oxcarbazepine from carbamazepine can be made overnight using a 1.5-to-1 ratio when the carba- mazepine dose is 800 mg or less. At higher carbamazepine doses, a slower conversion and a lower ratio are advisable. Conversion from car- bamazepine to oxcarbazepine will be accompa- nied by enzyme de-induction and possible elevation of some medication levels. In addition, sodium level may decrease after conversion from carbamazepine.
Valproate/Divalproex
Valproate discovery was serendipitous as it was used as a solvent for antiepileptic drugs in test- ing. Valproate is a short chain, branched fatty acid. It has multiple mechanisms of action, including the blocking of sodium channels, gabapentin potentiation, and blocking of T cal- cium channels.
The main form of valproate used clinically is divalproex sodium, a complex composed of equal parts of valproate and sodium valproate. Preparations include immediate release valproate capsules, tablets, and syrup; delayed-release enteric coated tablets of dival- proex sodium; divalproex sodium enteric coated sprinkles; extended-release divalproex sodium; and parenteral sodium valproate. The delayed-release enteric coated tablets are rapidly absorbed after the coating is dissolved, or the extended-release divalproex sodium is absorbed slowly.
Oral bioavailability is almost complete for most of valproate preparations, but 90% for the extended-release preparation. The time to maximal concentration is very dependent on the preparation. It is 2 h for the syrup and up to 17 h for the extended-release divalproex. The volume of distribution is 0.13–0.19 L/kg in adults. Pro- tein binding is about 90%. The free fraction increases with increasing total concentration and can reach 30% 150 mg/L.
Valproate is extensively metabolized by p450 enzymes, including CYP 2A6, CYP 2B6, CYP 2C9, and CYP 2C19. The half-life in adults is 13–16 h without induction and about 9 h with enzyme-inducing drugs.
Valproate metabolism is induced by pheny- toin, carbamazepine, and phenobarbital. Val- proate levels will increase after the withdrawal of these enzyme-inducing drugs. Valproate levels increase with coadministration of felbamate and clobazam.
Valproate can inhibit the metabolism of phenobarbital, lamotrigine, rufinamide, and carbamazepine epoxide, causing increased serum concentrations. Valproate competes with pheny- toin for protein binding (look under phenytoin for potential consequences of this interaction).
Valproate adverse effects include gastric irri- tation with nausea, vomiting, GI distress, and anorexia. These adverse effects are most likely with the enteric coated preparation and the extended-release formulations. Other adverse effects include tremor, weight gain, hair loss, peripheral edema, thrombocytopenia, and drowsiness/lethargy/confusion. A reversible dementia and brain atrophy have been described in some individuals, particularly in seniors. Encephalopathy may occur when valproate is used in polytherapy. Hyperammonemia may be seen in some individuals. Carnitine deficiency has been reported and associated with tiredness.
Idiosyncratic adverse experiences include fatal hepatotoxicity and pancreatitis. The risk factors for severe hepatotoxicity are polytherapy and young age. Hepatotoxicity is most likely to occur below age 3, with a risk of 1 in 600. Above age 40, the risk is less than 1 in 100,000. Mon- itoring of liver enzymes is recommended in young children.
Valproate is teratogenic and was assigned pregnancy category D. Valproate teratogenicity is dose-dependent. The risk of major congenital malformations can be higher than 30% at doses greater than 1100 mg per day [15]. At doses below 1000 mg per day, the malformation rate was about 3.2%. In addition in utero exposure to valproate has been associated with reduced ver- bal IQ and autism [2, 10]. This developmental toxicity is also dose-dependent.
Valproate has a wide spectrum of efficacy against partial onset (focal) and all generalized onset seizures, including absence and myoclonic seizures. It is also FDA-indicated for migraine prophylaxis and bipolar disorder. The recom- mended therapeutic range is 40–100 mg/L. An important class III comparative study showed that valproate was more effective than lamotrig- ine and better tolerated than topiramate for the treatment of generalized epilepsy [7]. However, in another cooperative Veterans Administration Study, valproate was less effective than carba- mazepine for complex partial seizures, even though the two drugs were equally effective for secondarily generalized tonic–clonic seizures [8]. In addition, carbamazepine was better tolerated
Ethosuximide mechanism of action is blockade of the T-type calcium currents in the thalamus.
It has an excellent oral bioavailability (greater than 90%), and volume of distribution is 0.65 L/kg. Protein binding is very low, less than 10%. Ethosuximide is extensively metabolized in the liver with oxidative biotransformation to inactive metabolites, mainly by CYP 3A4 has a long half-life of 30–60 h (shorter in children). Ethosuximide has no effect on hepatic p450 enzymes and is unlikely to affect other drugs. However, it is susceptible to interactions from inducers and inhibitors of p450 enzyme system. Its clearance is increased with enzyme inducers and may decrease with valproate and isoniazid.
Most ethosuximide adverse effects are dose-related and helped by dividing the dose and administration with meals. Among these, GI side effects include nausea, abdominal discomfort, anorexia, vomiting, and diarrhea; CNS adverse effects include drowsiness, insomnia, nervous- ness, dizziness, hiccups, fatigue, ataxia, and behavior changes such as aggression, irritability, and hyperactivity; hematologic side effects include granulocytopenia. Headaches, psychosis, depression, and hallucinations (visual or audi- tory) are not clearly dose-related.
Idiosyncratic adverse experiences include rash, Stevens–Johnson syndrome, SLE, rare aplastic anemia, thrombocytopenia, or agranulo- cytosis, and rare autoimmune thyroiditis.
Ethosuximide has been assigned a pregnancy category D due to increased risk of birth defects.
Ethosuximide has a narrow spectrum of activity with efficacy limited to generalized absence seizures. It is not effective against any other seizure type. A large, multicenter, double-blind, randomized, controlled trial to compare the efficacy, tolerability, and neuropsy- chological effects of ethosuximide, valproic acid, and lamotrigine favored ethosuximide [4]. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar and higher than the rate for lamotrigine. However, attentional dysfunction was more common with valproic acid than with ethosuximide. As a result, ethosuximide became the drug of choice for pure generalized absence seizures. The recommended therapeutic range is 40–100 mg/L. It is recommended that a complete blood count be checked before and after 2– 3 months of treatment.
Benzodiazepines
Benzodiazepines as a family act mainly on the GABA-A receptor, increasing the frequency of GABA-mediated chloride channel openings. Benzodiazepines have a wide spectrum of effi- cacy. Among the benzodiazepines most com- monly used for epilepsy, diazepam and lorazepam are primarily used for acute seizure emergencies, particularly status epilepticus and acute repetitive seizures, while clonazepam, clorazepate, and clobazam are used mainly for chronic epilepsy management.
Most benzodiazepines have good oral bioavailability (larger than 80%). One exception is midazolam (not discussed in this chapter), which is metabolized in intestinal epithelium, resulting in a bioavailability of about 40% [14]. All benzodiazepines rapidly cross the blood– brain barrier, with diffusion rate and onset of action determined by lipid solubility. Benzodi- azepines have large volumes of distribution and are characterized by 2-compartment distribution model; after initial rapid distribution in the blood, benzodiazepines diffuse into a second compart- ment. For example, diazepam redistributes to adipose tissue after intravenous administration. While the true half-life is 36 h, the redistribution half-life is less than 1 h. Benzodiazepines are also highly protein-bound.
While benzodiazepines are generally similar in absorption and distribution, they vary consid- erably in their metabolism and elimination rate [14]. Diazepam, clorazepate, and clobazam are converted to active metabolites while lorazepam and clonazepam are converted to inactive metabolites (Table 16.2).
Benzodiazepines have both pharmacokinetic and pharmacodynamic interactions. Pharma- cokinetic interactions are dependent on the specific metabolic pathway. Inhibition of the major pathway may cause accumulation, while inhibition of a minor pathway has limited effect. On the other hand, induction of either a major or minor pathway will reduce the benzodiazepine concentration. The clinical effect of induction and inhibition also depends on the presence of active metabolites and metabolic pathways (Table 16.3).
Benzodiazepines have similar adverse expe- riences, particularly drowsiness, to which toler- ance may develop. With higher doses, nystagmus, incoordination, ataxia, and dysarthria may occur. Behavioral disturbances may occur, more commonly in children (aggression, hyper- activity, paranoia). Most benzodiazepines are assigned pregnancy category D. Tolerance may develop to the therapeutic effect of benzodi- azepines, so that after a few weeks or months of treatment, efficacy is lost, or any higher dose is required to maintain efficacy. Withdrawal sei- zures may occur with abrupt discontinuation.
Below is specific information on individual benzodiazepines.
Clonazepam has minimal interactions, except that its clearance is increased by inducers. Clonazepam is used for long-term treatment as well as acute seizure management. Only an oral form is available in the USA, while an intra- venous formulation is available abroad. It has an official FDA indication for myoclonic seizures. However, it has a wide spectrum of efficacy against partial and generalized seizure types.
Diazepam is metabolized to desmethyl- diazepam (DMD). Like other benzodiazepines, it is highly protein-bound. Valproate may increase free diazepam levels due to displacement from protein binding. Diazepam is available in oral tablet and liquid form, rectal gel, and parenteral solution. It is also being investigated for nasal administration. It is used for acute repetitive seizures and for status epilepticus. When used for status epilepticus through intravenous route, an additional agent needs to be administered to maintain seizure control beyond the first 15– 30 min, because of diazepam’s short duration of action due to redistribution. Diazepam is not usually adequate for chronic use except that a diazepam course can be used in some syndromes such as Landau–Kleffner syndrome and electrical status epilepticus during sleep (ESES).
Lorazepam is metabolized in the liver through glucuronidation and excreted by the kidneys. It does not have active metabolites. Its clearance is reduced by valproate and other inhibitors. It is available in oral and parenteral forms. It is not appropriate for chronic use. Its main use is for status epilepticus. It has a longer duration of action than diazepam despite its shorter half-life, as a result of less lipid solubility and less redis- tribution to adipose tissue. Lorazepam can also be used orally to stop mild seizure clusters/acute repetitive seizures.
Clorazepate is a prodrug, as it is rapidly decarboxylated in the stomach to form the active desmethyldiazepam (DMD). It is FDA-approved for management of anxiety disorders and as adjunctive therapy in the management of partial seizures. It is available in oral form only, in immediate and extended-release preparations.
Clobazam was only approved in the USA in 2009, but is listed with the old-generation antiepileptic drugs because it has been used in Europe since 1975. It is the only ,5–benzodiazepine (referring to position of nitrogen atoms in the heterocyclic ring), while other benzodiazepines are 1,4–benzodiazepines. It is metabolized in the liver to the active N– desmethylclobazam. It is less sedating than 1,4-benzodiazepines. It is available in tablets and syrup. It is FDA-indicated for seizures associated with the Lennox–Gastaut syndrome, but it has a wide spectrum of efficacy as with other benzodiazepines.
Benzodiazepine metabolism
Enzymes involved in benzodiazepine metabolism
Pharmokinetics of old-generation AEDs
