Antiepileptic Drugs
Although 10% of people will report at least one seizure in their lifetime, it is estimated that 1% to 2% of the population worldwide meets the diagnostic criteria for epilepsy (Table 13-1).1 Epilepsy is a collective term used to designate a group of chronic central nervous system (CNS) disorders characterized by the onset of sudden disturbances of sensory, motor, autonomic, or psychic origin. These disturbances are usually transient with the exception of status epilepticus and are almost always associated with abnormal discharges on the electroencephalogram. Only 30% of patients with seizures have an identifiable neurologic or systemic disorder.
The goal of pharmacologic treatment of epilepsy is to control seizures with minimal medication-related adverse effects. Approximately 70% of patients with epilepsy will become seizure-free using a single antiepileptic drug. For the remaining 30% of patients, further treatment options may include transitioning to another drug; combining the primary drug with an additional drug; or upon failure of medical therapy, progression to invasive procedures such as vagal nerve stimulator insertion or neurosurgical resection.2 The antiepileptic drug selected to treat epilepsy is highly individualized and tailored to the individual patient, explaining the high interpatient variability in drug regimens. Criteria that must be considered in choosing an antiepileptic drug include efficacy for the characteristic seizures experienced by the patient, tolerability, safety, ease of use and frequency of administration, and pharmacokinetics (Table 13-2).2 Over the last two decades, there has been a dramatic increase in drug choices, which offer markedly fewer side effects with often comparable efficacy to older drugs.3 However, dose-related side effects can limit the use of any of the antiepileptic drugs (Table 13-3). Although side effects are normally associated with higher plasma levels of the drug, the specific concentration at which a patient develops toxicity varies considerably (Table 13-4).4
Pharmacokinetics
All antiepileptic drugs are administered once daily or more frequently. Sustained-release preparations are becoming increasingly available and preferred by patients. Absorption of these drugs from the gastrointestinal tract occurs slowly over a period of hours and may be incomplete, especially for gabapentin. Protein binding varies greatly (0% for gabapentin to 90% or greater for phenytoin). Hepatic and renal disease may necessitate dose adjustment. Medications that rely on renal excretion include gabapentin, pregabalin, levetiracetam, vigabatrin, and zonisamide and should be dosed according to renal function. The remaining drugs should be dosed according to the patient’s degree of liver dysfunction.
Antiepileptic drug clearance and elimination half-time range from hours (carbamazepine, valproate, primidone, gabapentin) to days (phenytoin, lamotrigine, phenobarbital, zonisamide) (see Table 13-4). Because of their ability to induce or inhibit drug metabolism, all antiepileptic drugs, except gabapentin, levetiracetam, and vigabatrin, may be associated with pharmacokinetic drug interactions in which plasma drug concentrations and resulting pharmacologic effects of concomitantly administered drugs may be altered. Such drug interactions should be anticipated in all patients receiving antiepileptic drugs and subsequently receiving drugs for other purposes.
Drug Interactions Related to Protein Binding
Medications that compete for protein-binding sites of highly bound antiepileptic drugs (phenytoin, valproate, carbamazepine) can displace the bound drug and lead to increases in the plasma concentration of pharmacologically active antiepileptic drug. Commonly used medications that are highly protein bound include phenylbutazone, thyroxine, and salicylates. Albumin is the principal binding protein for antiepileptic drugs. Hypoalbuminemia, as may accompany renal or hepatic disease or malnutrition, can result in increased plasma concentrations of unbound antiepileptic drug, resulting in toxicity despite therapeutic plasma concentrations. In pregnancy, hypoalbuminemia is due to a progressive increase in central volume which offsets the effect of hypoalbuminemia.
Drug Interactions Related to Accelerated Metabolism
Enzyme-inducing antiepileptic drugs that accelerate metabolism (carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, topiramate, and primidone) may accelerate the metabolism of estrogen and progesterone and thus render oral contraceptives ineffective at usual doses. Patients being treated with antiepileptic drugs have increased dose requirements for thiopental, propofol, midazolam, opioids, and nondepolarizing neuromuscular blocking drug. Possible explanations for altered dose requirements for drugs administered during anesthesia include increased hepatic P450 enzyme activity as a result of enzyme-inducing effects of antiepileptic drugs, alterations in the number and/or responsiveness of receptors, and interactions with endogenous neurotransmitters.
Principles of Dosing
The initial dose is that which is high enough to expect clinical effect but low enough to avoid significant side effects (see Table 13-3). Gradual dose titration is recommended in all but emergency situations. The clinical response guides dose adjustment over time as there is significant variability in clinical response over a wide range of dosages. A common cause of medication ineffectiveness is failure to achieve a sufficiently high plasma concentration. Noncompliance is a particular concern in specific patient populations including adolescents and the elderly.1,2,4
To maintain plasma drug concentrations in a therapeutic range, equal doses of the antiepileptic drug are often administered at intervals equivalent to less than one elimination half-time of the drug (see Table 13-4). Dosing at one-half the drug’s elimination half-time ensures that a single missed dose will not result in the plasma concentration decreasing below a therapeutic level.
Plasma Concentrations and Laboratory Testing
Phenytoin is the only agent for which monitoring is routinely recommended due to its nonlinear saturation dose kinetics. Routine laboratory monitoring of plasma concentrations for all other agents is not recommended.2 For this reason, titration to clinical efficacy is recommended for guiding the dosages of antiepileptic drugs. Some patients may respond at low plasma concentrations, and some patients will not respond until high plasma concentrations are obtained. If a patient does not respond to a particular drug as expected, investigating the plasma drug concentration may aid in determining compliance and identifying potential pharmacokinetic interactions.2,4
Mechanism of Seizure Activity
Seizure activity in most patients with epilepsy has a localized or focal origin. The reason for the high frequency and synchronous firing in a seizure focus is usually unknown. Possible explanations include local biochemical changes, ischemia, loss of cellular inhibitory systems, infections, and head trauma.
Neurons in a chronic seizure focus exhibit a type of denervation hypersensitivity with regard to excitatory stimuli. The spread of seizure activity to neighboring normal cells is presumably restrained by normal inhibitory mechanisms. Factors such as changes in blood glucose concentrations, PaO2, PaCO2, pH, electrolyte balance, endocrine function, stress, and fatigue may facilitate the spread of a seizure focus into areas of the normal brain. If the spread is sufficiently extensive, the entire brain is activated and a tonic-clonic seizure with unconsciousness ensues. Conversely, if the spread is localized, the seizure produces signs and symptoms characteristic of the anatomic focus. Once initiated, a seizure is most likely maintained by reentry of excitatory impulses in a closed feedback pathway that may not even include the original seizure focus.
Mechanism of Drug Action
The mechanism of action of antiepileptic drugs is incompletely understood. It is commonly presumed that antiepileptic drugs control seizures by decreasing neuronal excitability or enhancing inhibition of neurotransmission. This is achieved by altering intrinsic membrane ion currents (sodium, potassium, and calcium conductance) or by affecting activity of inhibitory neurotransmitters. Ion currents affected by antiepileptic drugs are primarily those involving the voltage-gated sodium and calcium ion channels. Drugs that delay reactivation of sodium channels (phenytoin, carbamazepine, primidone, valproate, and lamotrigine) during high frequency neuronal firing produce an inhibitory effect on creation of action potentials until neuronal discharge is blocked. Some drugs (phenytoin, carbamazepine, valproate, lamotrigine, and zonisamide) act at both sodium and calcium ion channels. Other drugs (ethosuximide and phenobarbital) act selectively at calcium ion channels. Ethosuximide selectively blocks the T-type calcium ion current, which is thought to act as a pacemaker for thalamic neurons and may be important in absence seizures. Drugs (phenobarbital and benzodiazepines) that alter synaptic function act primarily by enhancing γ-aminobutyric acid (GABA)–mediated neuronal inhibition. Benzodiazepines increase the frequency of GABA-mediated ion channel openings, whereas barbiturates increase the duration of ion channel openings. Tiagabine delays the reuptake of GABA from synaptic clefts, effectively enhancing GABA-mediated neuronal inhibition after synaptic release of the neurotransmitter.
Major Antiepileptic Drugs
The principal antiepileptic drugs used to treat patients with epilepsy are carbamazepine, ethosuximide, pregabalin, gabapentin, clobazam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproate, and zonisamide (see Table 13-2). Since 2005, the number of agents has more than doubled, thereby offering broader therapeutic effectiveness with fewer drug interactions, broader spectrums of activity, and unique mechanisms of action (see Table 13-2) (Fig. 13-1).5
Benzodiazepines such as diazepam, lorazepam, and midazolam are used for short-term treatment of acute seizures or status epilepticus and are usually administered parenterally. Clonazepam can be used to treat epilepsy but most patients develop tolerance to its antiepileptic effects and sedation is a common side effect. Felbamate is reserved for use in selected patients with uncontrolled seizures due to its side effect profile. Clobazam, a benzodiazepine derivative, is a more recent addition to this class and is unique among other members of the class in that it does not induce significant levels of sedation and can be used for long-term therapy because tolerance is relatively uncommon.6
Drugs used in the treatment of partial seizures are carbamazepine, lamotrigine, oxcarbazepine, topiramate, zonisamide and phenytoin, which are highly effective and associated with an acceptable side effect profile (see Table 13-2). Valproate, lamotrigine, and topiramate are the antiepileptic drugs useful for treatment of patients with generalized seizures. Ethosuximide, lamotrigine, or valproate is effective in treatment of patients with generalized nonconvulsive seizures, especially absence seizures.
Adverse Side Effects
Antiepileptic drugs may potentially produce numerous and varied adverse side effects. Newer agents have a significantly more favorable side effect profile. Some adverse side effects are dose-related (sedation, lethargy, neurotoxicity), whereas others are idiosyncratic (hypersensitivity, hepatotoxicity, aplastic anemia) (see Table 13-3).
Maternal Epilepsy
As previously mentioned, pregnancy can result from enzyme inducing antiepileptic drugs that render oral contraceptive pills less effective. Seizures during pregnancy can result in significant morbidity and mortality to both mother and fetus, making seizure control during this period imperative.2 Monotherapy with the lowest dose possible is the guiding principle. Fetal organogenesis is largely complete by 8 weeks. Significant teratogenicity may occur during this period if pregnancy is not detected early enough to permit discontinuation of potentially teratogenic medications. Drug regimens in women of childbearing age should therefore be given special attention. In particular, parturients who take valproate and carbamazepine have more than double the risk of giving birth to a fetus with congenital malformations including neural tube defects such as spina bifida. Patients on lamotrigine have rates of congenital malformation comparable to the general population. Clobazam may be added as needed especially during labor. Conclusive data regarding other antiepileptic drugs during pregnancy is lacking, in part due to the ethical and regulatory difficulty of conducting randomized trials during pregnancy.1
Carbamazepine
Carbamazepine is an iminostilbenes derivative that is effective for suppression of nonconvulsive and convulsive partial seizures. In addition, this drug is useful in the management of patients with trigeminal neuralgia and glossopharyngeal neuralgia. Structurally, carbamazepine is related to the tricyclic antidepressant imipramine. Like phenytoin, carbamazepine alters ionic conductance and thus has a membrane-stabilizing effect.
Pharmacokinetics
This drug is available only as an oral preparation (see Table 13-4). Oral absorption is rapid, with peak plasma concentrations occurring 2 to 6 hours after ingestion. Plasma protein binding is 70% to 80%. The plasma elimination half-time is 8 to 24 hours. The principal metabolite of carbamazepine is an epoxide derivative that has antiseizure effects that may also be responsible for many of the dose-limiting side effects of this drug. Because this drug induces its own metabolism, many patients require a dosage increase in 2 to 4 weeks after initiation of therapy. The usual therapeutic plasma concentration of carbamazepine is 6 to 12 µg/mL.
Side Effects
The toxicity of carbamazepine is similar to that produced by phenytoin (see Table 13-3). Sedation, vertigo, diplopia, nausea, and vomiting are the most frequent side effects of this drug. Chronic diarrhea develops in some patients, whereas others experience the syndrome of inappropriate antidiuretic hormone secretion. Aplastic anemia, thrombocytopenia, hepatocellular and cholestatic jaundice, oliguria, hypertension, and cardiac dysrhythmias are rare but potentially life-threatening complications. Chronic suppression of white blood cell counts can occur. For these reasons, it may be prudent to monitor bone marrow, cardiac, hepatic, and renal function in patients being treated with carbamazepine. At high plasma concentrations, carbamazepine has an arginine vasopressin hormone-like action that may result in hyponatremia. Skin rash, often with other manifestations of drug allergy, occurs in approximately 10% of chronically treated patients.
In addition to inducing its own metabolism, carbamazepine can accelerate the hepatic oxidation and conjugation of other lipid-soluble drugs. The most common interaction is with oral contraceptive pills, and most women require an increase in the daily dose of estrogen. Carbamazepine also accelerates the metabolism of valproic acid, ethosuximide, corticosteroids, anticoagulants, and antipsychotic drugs. Drugs that inhibit the metabolism of carbamazepine sufficiently to cause toxic effects include cimetidine, propoxyphene, diltiazem, verapamil, isoniazid, and erythromycin.
Ethosuximide
Ethosuximide is the drug of choice for suppression of absence (petit mal) epilepsy in patients who do not also have tonic-clonic seizures. This drug acts by decreasing voltage-dependent calcium conductance in thalamic neurons. This is consistent with the speculated importance of the thalamocortical system in the etiology of absence seizures.
Pharmacokinetics
This drug is available only as an oral preparation (see Table 13-4). Peak plasma concentrations occur in 1 to 7 hours after oral administration. Ethosuximide is not significantly bound to albumin. Approximately 25% of the drug is excreted unchanged in urine, and the remainder is metabolized to inactive metabolites by hepatic microsomal enzymes. The elimination half-time is 20 to 60 hours. The usual maintenance dose of ethosuximide is 20 to 30 mg/kg. A plasma concentration of 40 to 100 µg/mL is required for satisfactory suppression of absence epilepsy.
Side Effects
Toxicity of ethosuximide is low, manifesting most often as gastrointestinal intolerance (nausea, vomiting) and CNS effects (lethargy, dizziness, ataxia, photophobia). There have been rare reports of bone marrow suppression.
Felbamate
Because of its potential to produce life-threatening side effects, felbamate is not used as a first-line drug for treatment of seizures but rather is reserved for patients with intractable epilepsy. Felbamate is used principally for poorly controlled partial and secondarily generalized seizures. It also decreases the frequency of seizures associated with the Lennox-Gastaut syndrome and myotonic and atonic forms of epilepsy.7 The mechanism of action of felbamate is unknown but may involve action at voltage-gated sodium channels, NMDA and non-NMDA glutamate receptors, voltage-gated calcium currents, and GABA receptor modulation.6
Pharmacokinetics
Oral absorption is prompt and the elimination half-time is prolonged (see Table 13-4). Felbamate undergoes minimal metabolism with most of the drug being excreted unchanged by the kidneys.
Side Effects
Serious side effects include aplastic anemia and hepatotoxicity (see Table 13-3). Monitoring of treated patients with complete blood counts and liver function tests is indicated. Because felbamate is metabolized by hepatic cytochrome P450 enzymes, its metabolism is affected by concurrent administration of other drugs that are also metabolized by this system. In particular, concomitant administration of carbamazepine or phenytoin may decrease plasma concentrations of felbamate. Likewise, since felbamate is a potent inhibitor of P450 enzymes, it can slow the metabolism of phenytoin, phenobarbital, and valproic acid. In this regard, if a patient is receiving phenytoin, carbamazepine, or valproic acid and receives felbamate, the dose of these drugs should be decreased by 20% to 30% to prevent toxic effects.
Gabapentin
The pharmacokinetic considerations for gabapentin are discussed in detail in Chapter 8. Gabapentin is an analog of GABA that increases synaptic GABA considerations. Gabapentin induces dose-related sedation and it has efficacy in the treatment of anxiety, panic, and major depression.8 Despite its multiple other uses, gabapentin has limited efficacy in the treatment of epilepsy.
Lamotrigine
Lamotrigine is a chemically novel anticonvulsant drug of the phenyltriazine class that most likely acts by stabilizing voltage-sensitive sodium ion channels, thus preventing release of aspartate and glutamate. This drug has a broad spectrum of activity and is effective when used alone or in combination in adults who have partial seizures or generalized seizures and in children with Lennox-Gastaut syndrome. When administered orally, lamotrigine is well absorbed and its plasma elimination half-time is about 25 hours (see Table 13-4). Drugs that induce hepatic microsomal enzymes (phenobarbital, phenytoin, and carbamazepine) decrease the elimination half-time of lamotrigine by about 50%, necessitating a higher dose. Conversely, valproic acid slows the metabolism of lamotrigine and extends its elimination half-time to about 60 hours. The most common side effects of lamotrigine are headache, nausea, vomiting, dizziness, diplopia, and ataxia (see Table 13-3). Tremor can be troublesome at higher doses. In approximately 5% of adults, a rash develops, which subsequently disappears in some patients, despite continued therapy. In a few patients, however, the rash is more serious, and fever, arthralgias, and eosinophilia occur. In rare cases, Stevens-Johnson syndrome has been reported.
Levetiracetam
Levetiracetam is effective in the management of partial-onset seizures in adults. Its mechanism of action is not fully known; however, it binds to certain presynaptic calcium channels, acting to reduce synaptic neurotransmitter release.9 Side effects are considered minor and include sedation, asthenia, anxiety, and headache. The pharmacokinetic profile of levetiracetam is favorable, with the absence of hepatic metabolism and minimal protein binding. No significant drug interactions have been described with coadministration of other antiepileptic drugs.
Oxcarbazepine
Oxcarbazepine is a keto analogue of carbamazepine that provides equivalent seizure control but with fewer adverse side effects. After administration, oxcarbazepine acts as a prodrug that is converted to an active metabolite, 10-hydroxycarbazepine. Oxcarbazepine and its active metabolite do not induce hepatic microsomal enzymes nor does it displace other drugs from plasma protein-binding sites. As such, they are safer drugs to be used in combination therapy. Oxcarbazepine causes dose-dependent hyponatremia in up to half of patients, mandating monitoring of serum sodium levels at those receiving higher doses of this agent.
Phenobarbital
Phenobarbital is a long-acting barbiturate that is effective against all seizure types except nonconvulsive primary generalized seizures. Cognitive and behavioral side effects limit this drug’s usefulness in the treatment of epilepsy. Because of these side effects, phenobarbital is considered a second-line drug in the treatment of epilepsy.
Phenobarbital appears to exert its antiepileptic properties partly through potentiation of the postsynaptic actions of the inhibitory neurotransmitter GABA and inhibition of the excitatory postsynaptic actions of glutamate. These drug-induced effects prolong the duration of chloride channel opening and thus limit the spread of seizure activity and increase the seizure threshold.
Pharmacokinetics
Oral absorption of phenobarbital is slow but nearly complete, with peak concentrations occurring 12 to 18 hours after a single dose (see Table 13-4). Plasma protein binding is 48% to 54%. Approximately 25% of phenobarbital is eliminated by pH-dependent renal excretion, with the remainder inactivated by hepatic microsomal enzymes. The principal metabolite is an inactive parahydroxyphenyl derivative that is excreted in urine as a sulfate conjugate. The elimination half-time of phenobarbital is prolonged.
The usual daily oral dose of phenobarbital is 60 mg in adults or 4 mg/kg in children. Plasma phenobarbital concentrations of 10 to 40 µg/mL are usually necessary for control of seizures. The value of measuring plasma phenobarbital concentrations is limited because the concentration associated with optimal control is highly variable among patients. In addition, the development of tolerance to the drug’s CNS effects makes the toxic threshold imprecise.
Side Effects
Sedation in adults and children and irritability and hyperactivity in children are the most troublesome side effects when this drug is used to treat epilepsy (see Table 13-3). Tolerance to the sedative effects of phenobarbital may develop with chronic therapy. Depression develops in many adults taking phenobarbital, and confusion may occur in elderly patients. Cognitive effects include slowing of task processing. Scarlatiniform or morbilliform rash occurs in up to 2% of patients. Megaloblastic anemia that responds to folic acid administration and osteomalacia that responds to vitamin D therapy may occur during chronic phenobarbital therapy as well as during treatment with phenytoin. Nystagmus and ataxia are likely if the plasma phenobarbital concentration is >40 µg/mL. Abnormal collagen deposition manifesting as Dupuytren contracture may occur. Congenital malformations may occur when phenobarbital is administered chronically during pregnancy. Coagulation defects and hemorrhage in the neonate must be considered in the setting of fetal exposure. Interactions between phenobarbital and other drugs usually involve induction of hepatic microsomal enzymes. In this regard, phenobarbital is the classic example of a hepatic microsomal enzyme inducer that can accelerate the metabolism of many lipid-soluble drugs.
Phenytoin
Phenytoin is the prototype of the hydantoins and is effective for the treatment of partial and generalized seizures. Available in oral and intravenous (IV) preparations, phenytoin may be administered acutely to achieve effective plasma concentrations within 20 minutes. This drug has a high therapeutic index, and its administration is not accompanied by excessive sedation.
Mechanism of Action
Phenytoin regulates neuronal excitability and thus the spread of seizure activity from a seizure focus by regulating sodium and possibly calcium ion transport across neuronal membranes. This stabilizing effect on cell membranes is relatively selective for the cerebral cortex, although the effect also extends to peripheral nerves. In addition to the effect on ion fluxes, phenytoin acts on second messengers such as calmodulin and the cyclic nucleotides.
Pharmacokinetics
Phenytoin is a weak acid (pK 8.3) that is maintained in aqueous solutions as a sodium salt (see Table 13-4). The drug precipitates in solutions with a pH of <7.8. Its poor water solubility may result in slow and sometimes variable absorption from the gastrointestinal tract (30% to 97%). The initial daily adult oral dosage is 3 to 4 mg/kg. Doses of >500 mg daily are rarely tolerated. The long duration of action of phenytoin allows a single daily dosage, but gastric intolerance may necessitate divided dosage. After intramuscular (IM) injection, the drug precipitates at the injection site and is slowly absorbed. For this reason, IM administration is not recommended. The rate of IV administration of phenytoin should not exceed 50 mg per minute in adults and 1 to 3 mg/kg per minute (or 50 mg per minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias.
Plasma Concentrations
Control of seizures is usually obtained when plasma concentrations of phenytoin are 10 to 20 µg/mL. In the control of digitalis-induced cardiac dysrhythmias, phenytoin, 0.5 to 1.0 mg/kg IV, is administered every 15 to 30 minutes until a satisfactory response is achieved or a maximum dose of 15 mg/kg is administered. A plasma phenytoin concentration of 8 to 16 µg/mL is usually sufficient to suppress cardiac dysrhythmias. Adverse side effects of phenytoin such as nystagmus and ataxia are likely when the plasma concentration of drug is >20 µg/mL. Nevertheless, the diagnosis of phenytoin toxicity should be made on the basis of clinical symptoms.
Protein Binding
Phenytoin is bound approximately 90% to plasma albumin. A greater fraction of phenytoin remains unbound in neonates, in patients with hypoalbuminemia, and in uremic patients.
Metabolism
Metabolism of phenytoin to inactive metabolites is by hepatic microsomal enzymes that are susceptible to stimulation or inhibition by other drugs. An estimated 98% of phenytoin is metabolized to the inactive derivative parahydroxyphenyl, which appears in urine as a glucuronide. Approximately 2% of phenytoin is recovered unchanged in urine.
When the plasma concentration of phenytoin is <10 µg/mL, metabolism follows first-order kinetics, and the elimination half-time averages 24 hours. At plasma concentrations of >10 µg/mL, the enzymes necessary for metabolism of phenytoin become saturated, and the elimination half-time becomes dose-dependent (zero-order kinetics). At this stage, relatively small increases in dose may result in dramatic increases in the plasma concentration of phenytoin. Zero-order kinetics in phenytoin metabolism resembles the metabolism of alcohol.
Side Effects
The side effects of phenytoin include CNS toxicity that manifests clinically as nystagmus, ataxia, diplopia, vertigo (cerebellar-vestibular dysfunction) and is likely when the plasma phenytoin concentration is >20 µg/mL. Peripheral neuropathy has been observed in up to 30% of chronically treated patients. Gingival hyperplasia occurs in approximately 20% of chronically treated patients and is probably the most common manifestation of phenytoin toxicity in children and adolescents. This complication is minimized by improved oral hygiene and does not necessarily require discontinuation of phenytoin therapy. Other reversible cosmetic side effects include acne, hirsutism, and facial coarsening. Administration of phenytoin during pregnancy may result in the fetal hydantoin syndrome, which manifests as wide-set eyes, broad mandible, and finger deformities.
Allergic reactions include morbilliform rash in 2% to 5% of patients. Hyperglycemia and glycosuria may reflect phenytoin-induced inhibition of insulin secretion. Megaloblastic anemia is rare and has been attributed to altered folic acid absorption but probably also involves altered folic acid metabolism. Phenytoin-induced hepatotoxicity, although rare, may occur in genetically susceptible persons who lack the enzyme phenytoin epoxide. This enzyme is necessary to convert an electrophilic intermediate formed after the oxidative metabolism of phenytoin to an inert and nontoxic product. Gastrointestinal irritation is due to alkalinity of the drug; this may be minimized by taking phenytoin after meals.
Phenytoin can induce the oxidative metabolism of many lipid-soluble drugs, including carbamazepine, valproic acid, ethosuximide, anticoagulants, and corticosteroids. Because its metabolism is saturable, inhibitory interactions are particularly likely to have neurotoxic effects. Interactions involving protein-binding displacement are not likely to be clinically significant.
Patients receiving phenytoin chronically have higher dose requirements for nondepolarizing neuromuscular blocking drugs such as vecuronium compared with untreated patients. Phenytoin induces hepatic enzymes and it is likely that metabolism and elimination of nondepolarizing neuromuscular blocking drugs is increased. Phenytoin may also produce mild blocking effects at the neuromuscular junction leading to upregulation of acetylcholine receptors.
Primidone
Primidone is metabolized to phenobarbital and another active metabolite, phenylethylmalonamide. The efficacy of this drug resembles that of phenobarbital, but it is less well tolerated. There is little to recommend this drug over phenobarbital for patients in whom treatment with a barbiturate is contemplated. Possible side effects include Dupuytren contracture, shortening of the QT segment, and coagulation defects. For this reason it is seldom prescribed.
Tiagabine
Tiagabine is a nipecotic acid moiety that is a potent inhibitor of GABA reuptake. This drug is utilized as adjunctive therapy for complex partial seizures. Possible side effects include dizziness, asthenia, aphasia, and tremor. Mental depression may accompany administration of tiagabine perhaps reflecting this drug’s ability to increase GABA concentrations. Drug interactions are unlikely despite the high protein binding of tiagabine reflecting the small amount of drug needed to achieve clinical efficacy. Tiagabine has no effect on hepatic enzymes.
Topiramate
Topiramate is a broad-spectrum antiepileptic drug that is indicated as monotherapy or adjunctive therapy in children and adults for the control of partial, generalized tonic-clonic, and absence seizures. Efficacy in treatment of other neurologic and psychiatric disorders has been reported including bulimia, migraine headache, and essential tremor. Topiramate inhibits voltage-gated sodium ion channels, high-voltage activated calcium ion channels, and glutamate-mediated neurotransmission at specific receptor subtypes. It enhances chloride ion flux in GABAA receptors, and inhibition of. In addition, topiramate is a weak inhibitor of carbonic anhydrase. Minor side effects may include sedation, dizziness, and ataxia. Nephrolithiasis occurs in about 1.5% of treated patients perhaps reflecting this drug’s action on carbonic anhydrase. Enzyme-inducing drugs decrease plasma concentrations of topiramate, but topiramate does not affect hepatic P450 enzymes and undergoes minimal protein binding.
Valproic Acid
Valproic acid is a branched-chain carboxylic acid that is effective in the treatment of all primary generalized epilepsies and all convulsive epilepsies. It is somewhat less effective for the suppression of nonconvulsive partial seizures. This drug acts by limiting sustained repetitive neuronal firing through voltage-dependent sodium channels.
Pharmacokinetics
Valproic acid is available as a syrup and in an enteric-coated formulation, which is preferred because it decreases gastrointestinal side effects. After oral administration, absorption is prompt, with peak plasma concentrations of valproic acid occurring in 1 to 4 hours. Binding to plasma proteins is >80%. More than 70% of the drug can be recovered as inactive glucuronide conjugates. The elimination half-time is 7 to 17 hours. The usual daily dose of valproic acid is 1 to 3 g to achieve a therapeutic plasma concentration of 50 to 100 µg/mL. Nevertheless, the daily variation in plasma concentrations of valproic acid is great, and routine monitoring may not be helpful unless it is correlated with the patient’s clinical condition.
Side Effects
Gastrointestinal side effects include anorexia, nausea, and vomiting. Weight gain is common in patients treated chronically with valproic acid. At higher doses, a fine distal tremor may develop. Thrombocytopenia is seen frequently at higher doses. The most serious side effect of valproic acid is hepatotoxicity occurring in about 0.2% of children younger than 2 years of age being treated chronically with this drug. The incidence of this potentially fatal hepatic necrosis decreases dramatically after 2 years of age. Approximately 20% of treated patients have hyperammonemia without hepatic damage. Sedation and ataxia are infrequent side effects of valproic acid.
Because valproic acid is partly eliminated as a ketone-containing metabolite, the urine ketone test may show false-positive results. Valproic acid can displace phenytoin and diazepam from protein-binding sites, resulting in increased pharmacologic effects produced by the displaced drug.
Valproic acid is an enzyme inhibitor. As a result of this enzyme inhibition, the metabolism of phenytoin is slowed by valproic acid. Valproic acid causes the plasma concentration of phenobarbital to increase almost 50%, presumably due to inhibition of hepatic microsomal enzymes. However, valproic acid does not interfere with the action of oral contraceptives.
Vigabatrin
Vigabatrin is used to treat refractory complex partial seizures. It may also be used as monotherapy to treat infantile spasms. Tablet and powder preparations are available and are bioequivalent. Its mechanism of action is imperfectly understood but is thought to involve irreversible inhibition of the GABA transaminase enzyme, thereby increasing the amount of GABA in the CNS. It is not protein bound and undergoes no significant metabolism. It is excreted unchanged in the urine. Dosage must therefore be adjusted if renal impairment is present. Significant side effects include permanent visual loss, anemia, somnolence, and fatigue.10
Zonisamide
Zonisamide is a broad-spectrum antiepileptic drug utilized as adjunctive therapy for management of partial and secondarily generalized seizures. Modulation of voltage-dependent calcium ion channels seems to be an important mechanism for this drugs ability to control seizures. In addition, zonisamide enhances GABA-mediated neuronal inhibition. Adverse side effects include sedation, dizziness, ataxia, anorexia, and behavioral disorders in children and manic responses in adults. Nephrolithiasis may occur in 3% of treated patients. Pharmacokinetic drug interactions are unlikely as zonisamide does not displace other drugs from protein-binding sites and effects on metabolism of other drugs are minimal.
Benzodiazepines
Benzodiazepines display anxiolytic, sedative, muscle-relaxant, and anticonvulsant effects (see Chapter 5). Benzodiazepine receptors in the brain are a subset of GABAA receptors. The binding of benzodiazepines to these receptors potentiates GABA-mediated neuronal inhibition, which increases chloride permeability and thereby leads to cellular hyperpolarization and inhibition of neuronal firing. In low doses, benzodiazepines suppress polysynaptic activity in the spinal cord and decrease neuronal activity in the mesencephalic reticular system.
Clonazepam
Clonazepam is generally added to other drug therapy and is used as a first-line drug only for myoclonic seizures.
Pharmacokinetics
Absorption of clonazepam after oral administration is rapid, with peak plasma concentrations occurring within 2 to 4 hours (see Table 13-4). IV administration of clonazepam results in rapid CNS effects. Approximately 50% of the drug is bound to plasma proteins. Clonazepam is extensively metabolized to inactive products, with <2% of an injected dose appearing unchanged in urine. The elimination half-time of this long-acting drug is 30 to 40 hours. The oral maintenance dose is unlikely to exceed 0.25 mg/kg. Therapeutic plasma concentrations of clonazepam are 0.02 to 0.08 µg/mL.
Side Effects
Sedation is present in approximately 50% of patients but tends to subside with chronic administration (see Table 13-3). Skeletal muscle incoordination and ataxia occur in approximately 30% of patients. Personality changes occur in approximately 25% of patients, manifesting as behavioral disturbances, including hyperactivity, irritability, and difficulty in concentration, especially in children. Elderly patients treated with clonazepam may experience depression. Increased salivary and bronchial secretions may be particularly prominent in children. Generalized seizure activity may be precipitated if the drug is discontinued abruptly.
Diazepam
Diazepam is a mainstay for the treatment of status epilepticus and local anesthetic–induced seizures. The typical approach is administration of 0.1 mg/kg IV every 10 to 15 minutes until seizure activity has been suppressed or a maximum dose of 30 mg has been administered (see Chapter 5). Diazepam has a long elimination half-time of 27 to 48 hours. Metabolism of diazepam results in active metabolites.
Lorazepam
Lorazepam has a shorter elimination half-time (8 to 25 hours) than diazepam but a longer duration of antiepileptic action because it is not rapidly redistributed. Lorazepam is metabolized in the liver and has no active metabolites. Lorazepam, which is available in parenteral and oral formulations, is used to treat status epilepticus and as intermittent therapy for seizure clusters.
Clobazam
Clobazam is used for complex partial, tonic-clonic, and myoclonic seizures primarily as a second-line agent. It is metabolized in the liver and has an active metabolite and is excreted by the kidneys. The elimination half-life is 16 to 18 hours. Its potential for sedation, lethargy, and loss of therapeutic effect is significantly lower than other benzodiazepines. Like other drugs of this class, significant withdrawal may occur if discontinuation is not gradual.11
Status Epilepticus
Status epilepticus is a medical emergency where the patient experiences prolonged or rapidly recurring convulsions for 5 minutes or more. The motor manifestations of convulsive status epilepticus may be symmetrical with tonic and then clonic activity. Rapid seizure control is associated with improved clinical outcome.12
Treatment
Treatment begins with ensuring a patent upper airway and administration of oxygen. Maintenance of ventilation may require tracheal intubation. IV access is obtained in anticipation of administering antiepileptic drugs. If hypoglycemia cannot be excluded, the patient is treated empirically with IV glucose (50 mL of 50% glucose for adults). Drug therapy of status epilepticus is typically with a benzodiazepine such as diazepam, lorazepam, or midazolam. In the absence of IV access, a rectal gel form of diazepam is available. Ventilatory depression necessitating support of ventilation may accompany administration of benzodiazepines. If benzodiazepines are not successful in extinguishing the seizure, other choices include fosphenytoin; phenytoin; phenobarbital; valproic acid; and continuous infusions of valproic acid, levetiracetam, and propofol. Hypotension and prolongation of the QT interval on the electrocardiogram may accompany administration of fosphenytoin necessitating a slowing in the rate of IV infusion.12
Drugs Used for Treatment of Parkinson’s Disease
Parkinson’s disease affects 1% of the population, predominantly in those older than 60 years of age although onset can occur significantly earlier. It is a chronically progressive neurodegenerative disease that results from the loss of dopaminergic neurons in the substantia nigra pars compacta region of the basal ganglia. The presence of Lewy bodies is also a consistent feature.13 Dopamine is thought to act principally as an inhibitory neurotransmitter and acetylcholine as an excitatory neurotransmitter within the extrapyramidal system, and a proper balance is necessary for normal function. Approximately 80% of the dopamine in the brain is concentrated in the basal ganglia, mostly in the caudate nucleus and putamen. In patients with Parkinson’s disease, the basal ganglia content of dopamine may be as low as 10% of normal. As a result, an excess of excitatory cholinergic activity manifesting as progressive tremor, skeletal muscle rigidity, bradykinesia, and disturbances of posture results.
The objective in treating Parkinson’s disease is to treat debilitating symptoms. Currently, all approved medications offer only palliative relief, as they do not affect progression of the disease. Often, combinations of drugs with effects on the dopaminergic and cholinergic components of the extrapyramidal nervous system are used. Treatment regimens are selected based on the age of the patient as well as severity of symptoms. Pharmacologic treatment commences when motor symptoms become bothersome to the patient. Treatment strategies can be divided into those addressing motor symptoms; those addressing other adverse effects of the disease including nausea, depression, autonomic disturbances and cognitive impairment; and those addressing medication-related side effects.13 Failure of pharmacologic therapy is an indication for deep brain stimulation, with the primary targets being the globus pallidus internus or subthalamic nucleus.14
Levodopa
Because dopamine does not readily cross the blood–brain barrier, the major approaches to therapy have involved the administration of its precursor, levodopa, or drugs that mimic the action of dopamine. Levodopa is the cornerstone of symptomatic therapy of Parkinson’s disease and its efficacy is unsurpassed even by newer drugs. Levodopa crosses the blood–brain barrier and is converted to dopamine by aromatic-L-amino-acid decarboxylase (dopa decarboxylase enzyme), acting to replenish dopamine stores in the basal ganglia. Levodopa is usually administered with a peripheral decarboxylase inhibitor (carbidopa or benserazide) to maximize entrance of this precursor into the brain before it is converted to dopamine. Furthermore, side effects associated with increased peripheral concentrations of dopamine are less when it is combined with a decarboxylase inhibitor. Absorption of levodopa from the gastrointestinal tract is efficient, but the brief elimination half-time (1 to 3 hours) requires frequent dosing intervals to maintain a therapeutic concentration. An IV formulation of levodopa is not available.
The beneficial therapeutic response to levodopa typically diminishes after 5 to 10 years of treatment, presumably reflecting progression of the disease process and continuing loss of nigrostriatal neurons with a capacity to store dopamine. Abrupt discontinuation of levodopa therapy may result in a precipitous return of symptoms of Parkinson’s disease and has been associated with a neuroleptic malignant-like syndrome. For this reason, levodopa should be continued throughout the perioperative period.
Metabolism
Approximately 95% of orally administered levodopa is rapidly decarboxylated to dopamine during the initial passage through the liver. The resulting dopamine cannot easily cross the blood–brain barrier to exert beneficial effects, whereas increased plasma concentrations of dopamine often lead to undesirable side effects. In this regard, inhibition of the peripheral activity of the decarboxylase enzyme greatly increases the fraction of administered levodopa that remains intact to cross the blood–brain barrier.
At least 30 metabolites of levodopa have been identified. Most of these metabolites are converted to dopamine, small amounts of which are subsequently metabolized to norepinephrine and epinephrine. Metabolism of dopamine yields 3,4-dihydroxyphenylacetic acid (homovanillic acid). Dietary methionine is necessary as a source of methyl donors to permit continued activity of catechol-O-methyltransferase (COMT), which is necessary for the metabolism of the excess amounts of dopamine that result from high doses of levodopa. Most metabolites of dopamine are excreted by the kidneys.
Side Effects
The most common side effects that occur during the first weeks of therapy with levodopa and dopamine agonists are nausea and hypotension. These side effects are associated with peak plasma concentrations of dopamine and may be minimized by taking medications after light meals or snacks. The most common problems that occur during long-term therapy are dyskinesias, fluctuations in mobility, increasing confusion, and psychosis. These problems become progressively more frequent after the first 3 years of therapy.
Gastrointestinal Dysfunction
Nausea and vomiting occur in about 80% of patients during the early period of treatment with levodopa. These responses reflect dopamine-induced stimulation of the chemoreceptor trigger zone which is not protected by the blood–brain barrier.15 Nausea can be effectively treated with domperidone, which does not easily cross the blood–brain barrier and is therefore unlikely to exacerbate symptoms of Parkinson’s disease. Domperidone inhibits dopamine-2 receptors in the chemoreceptor trigger zone of the medulla oblongata.16 Trimethobenzamide can also be used and has a direct action on the chemoreceptor trigger zone and is devoid of dopaminergic action.17 Dopamine-receptor antagonist antiemetics such as prochlorperazine, metoclopramide, promethazine must be avoided because they significantly worsen symptoms of Parkinson’s disease. Gastrointestinal side effects tend to disappear with continuing therapy as tolerance develops.13
Cardiovascular Changes
Cardiovascular changes associated with levodopa most likely reflect α- and β-adrenergic responses evoked by increased plasma concentrations of dopamine and its metabolism to norepinephrine and epinephrine. Transient flushing of the skin is common during levodopa therapy.
Orthostatic Hypotension
Approximately 30% of patients develop orthostatic hypotension early in therapy. This can be due to autonomic dysfunction from the disease or as a result of levodopa treatment. It can be a significant problem in some patients and warrants continuous evaluation as it can result in syncopal episodes. Initial treatment consists of increased fluid and sodium intake, elevation of the head of the patient’s bed, and compression stockings. If symptoms are persistent, administration of fludrocortisone, domperidone, or midodrine may be useful. Orthostatic hypotension becomes less prominent with continued therapy.13,15
Cardiac Dysrhythmias
Cardiac dysrhythmias, including sinus tachycardia, atrial and ventricular premature contractions, atrial fibrillation, and ventricular tachycardia, although rare, have been associated with levodopa therapy. Presumably, the potential β-adrenergic effects of dopamine and its metabolites on the heart contribute to cardiac dysrhythmias, although a cause-and-effect relationship has not been documented. Patients with preexisting disturbances of cardiac conduction or coronary artery disease are most likely to develop cardiac dysrhythmias in association with levodopa therapy. Propranolol is an effective treatment when cardiac dysrhythmias occur in these patients.15
Abnormal Involuntary Movements
Abnormal involuntary movements in the form of faciolingual tics; grimacing; and rocking movements of the arms, legs, or trunk are the most common side effects of chronic levodopa therapy, developing in about 50% of patients within 1 to 4 months after initiation of therapy. Rarely, exaggerated respiratory movements can produce an irregular gasping pattern, presumably reflecting dyskinesias of the diaphragm and intercostal muscles. Tolerance does not develop to abnormal involuntary movements.
Fluctuations in mobility are characterized by increasing bradykinesia at the end of an interval between doses. High-protein meals are avoided as a large influx of dietary amino acids can interfere with the transport of levodopa to the brain and result in sudden loss of mobility.
Psychiatric Disturbances
Confusion, visual hallucinations, and paranoia may reflect the natural disease process as well as its treatment. Elderly patients are particularly vulnerable to psychotic reactions, especially if treatment includes combinations of levodopa and anticholinergic drugs and the patient has a prior psychiatric history. Psychiatric disturbances usually begin as nocturnal phenomena, emphasizing the possible value of decreasing or discontinuing the last evening dose of levodopa. Neuroleptic drugs are not recommended for the treatment of psychiatric disturbances because these drugs may cause a protracted exacerbation of symptoms of Parkinson’s disease. Quetiapine is a commonly prescribed medication as is clozapine. The routine laboratory monitoring with clozapine due to the risk of agranulocytosis often makes quetiapine a more attractive option.13 Patients who develop drug-induced psychosis with no features of dementia may respond to electroconvulsive therapy.
Impulsive and compulsive behavior may also result from dopaminergic therapy. A history of obsessive compulsive disorder, addiction, or impulsive personality traits increases the likelihood. The development of these behaviors should be monitored regularly. Treatment is aimed at symptomatic relief primarily with dopamine agonists and less commonly with zonisamide, amantadine, topiramate, and valproate.13,18
Endocrine Changes
Dopamine inhibits the secretion of prolactin, presumably by stimulating the release of a prolactin inhibitory factor. The release of growth hormone that occurs in response to the administration of levodopa to normal patients is minimal or absent when levodopa is administered to patients with Parkinson’s disease. Indeed, signs of acromegaly or diabetes mellitus do not occur in patients treated with levodopa. Large doses of levodopa may cause hypokalemia associated with increased plasma levels of aldosterone.
Laboratory Measurements
Urinary metabolites of levodopa cause false-positive tests for ketoacidosis. These metabolites also color the urine red and then black on exposure to air. Mild, transient increases in the blood urea nitrogen concentration may occur and can usually be controlled by increasing fluid intake. Increased liver transaminase concentrations occasionally occur. Positive Coombs’ tests have been attributed to levodopa.
Drug Interactions
Drug interactions may occur in patients being treated with levodopa, resulting in increased or decreased therapeutic effects. Chronic treatment of animals with levodopa does not consistently change anesthetic requirements.
Antipsychotic Drugs
Antipsychotic drugs such as butyrophenones and phenothiazines can antagonize the effects of dopamine. For this reason, these drugs should not be administered to patients with known or suspected Parkinson’s disease. Indeed, administration of droperidol to patients being treated with levodopa has produced severe skeletal muscle rigidity and even pulmonary edema, presumably reflecting sudden antagonism of dopamine. Droperidol has even produced a Parkinson’s disease–like syndrome in otherwise healthy patients. Metoclopramide may also interfere with dopamine activity.
Monoamine Oxidase Inhibitors
Nonspecific monoamine oxidase inhibitors interfere with the inactivation of catecholamines, including dopamine, and are used in the treatment of atypical depression and Parkinson’s disease. As a result, these drugs can exaggerate the peripheral nervous system and CNS effects of levodopa. Hypertension and hyperthermia are side effects associated with the concurrent administration of these drugs.
Anticholinergic Drugs
Anticholinergic drugs act synergistically with levodopa to improve certain symptoms of Parkinson’s disease, especially tremor. Large doses of anticholinergics, however, can slow gastric emptying such that absorption of levodopa from the gastrointestinal tract is decreased.
Pyridoxine
Pyridoxine or vitamin B6, in doses as low as 5 mg as present in multivitamin preparations, can abolish the therapeutic efficacy of levodopa by enhancing the activity of pyridoxine-dependent dopa decarboxylase and thus increasing the metabolism of levodopa in the circulation before it can enter the CNS.
Peripheral Decarboxylase Inhibitors
Levodopa is usually administered with a peripheral carboxylase inhibitor such as carbidopa or benserazide. As a result, more levodopa escapes metabolism to dopamine in the peripheral circulation and is available to enter the CNS. Furthermore, side effects related to high systemic concentrations of dopamine are decreased when levodopa is administered with a peripheral decarboxylase inhibitor. Nausea, vomiting, and cardiac dysrhythmias are diminished or absent. The incidence of abnormal involuntary movements and psychiatric disturbances is not altered by the combination of levodopa with a decarboxylase inhibitor.
Several combinations of levodopa and a peripheral carboxylase inhibitor are available as a levodopa augmentation strategy. Sinemet is composed of levodopa and carbidopa in a 10:1 or 4:1 ratio. Madopar is composed of levodopa and benserazide in a 4:1 ratio. Controlled-release preparations of levodopa and carbidopa provide a more constant therapeutic effect, but the onset of action is slower and the bioavailability is decreased compared with the standard combinations. Both carbidopa and benserazide are noncompetitive inhibitors of decarboxylase so there is no value in administering progressively higher doses of these enzyme inhibitors. Carbidopa and benserazide do not cross the blood–brain barrier and lack pharmacologic activity when administered alone.
Catechol-O-methyltransferase Inhibitors
COMT is partially responsible for the peripheral breakdown of levodopa. Accordingly, another levodopa augmentation strategy consists of blocking the COMT enzyme activity in the gastrointestinal tract with tolcapone or entacapone. Administration of either of these drugs slows the elimination of carbidopa-levodopa thus increasing the plasma concentrations by 10% to 15%. In patients treated with tolcapone, the daily dose of carbidopa-levodopa may need to be decreased by 10% to 30% to avoid dyskinesias or other hyperdopaminergic side effects.
Side Effects
Both tolcapone and entacapone worsen levodopa-induced dyskinesias and cause nausea and diarrhea. Tolcapone may cause hepatotoxicity in rare patients emphasizing the need to monitor liver function tests in treated patients. Rhabdomyolysis has been associated with tolcapone therapy. Entacapone can cause the patient’s urine to appear orange. Both drugs can cause piloerection.
Synthetic Dopamine Agonists
Synthetic dopamine agonists require neither transformation nor facilitated transport across the blood–brain barrier. Available drugs include bromocriptine and pergolide (tetracyclic ergot alkaloids) and pramipexole, ropinirole, and rotigotine (nonergot alkaloids). After oral administration, the elimination half-time of bromocriptine and pergolide are longer than for levodopa. Absorption of bromocriptine from the gastrointestinal tract is rapid but incomplete. Extensive hepatic first-pass metabolism occurs and >90% of the metabolites are excreted in the bile, whereas <10% of the drug is excreted unchanged or as inactive metabolites in urine. Bromocriptine, 0.5 to 1.0 mg orally, is equivalent to levodopa, 100 mg in combination with either 25 mg of carbidopa or 25 mg of benserazide. The effectiveness of bromocriptine in the treatment of acromegaly reflects the paradoxical inhibitory effect of dopamine agonists on secretion of growth hormone. Bromocriptine also suppresses the excess prolactin secretion that is often associated with growth hormone secretion. A notable benefit of rotigotine is its antidepressant effects.
Side Effects
Visual and auditory hallucinations, hypotension, and dyskinesia occur more frequently in patients treated with bromocriptine than in those treated with levodopa. Synthetic dopamine agonists occasionally cause pleuropulmonary fibrosis, sometimes with pleural effusions. Depending on the severity of this side effect, the dose of agonist drug should be decreased or the drug discontinued. Another uncommon complication of dopamine agonist therapy is the development of erythromelalgia (red, edematous, tender extremities). If this complication occurs, it is usually necessary to discontinue the dopamine agonist. Asymptomatic increases of serum transaminase and alkaline phosphatase concentrations may occur. Vertigo and nausea are occasionally associated with bromocriptine therapy.
Nonergot alkaloids are supposed to cause less nausea and orthostatic hypotension than the ergot derivatives but this difference appears to be clinically insignificant. Nonergot alkaloids offer no advantage over ergot derivatives with respect to CNS side effects including confusion, hallucinations, and daytime sleep attacks that have been associated with motor vehicle accidents.
Anticholinergic Drugs
Anticholinergic drugs such as trihexyphenidyl and benztropine have modest effects on the clinical manifestations of Parkinson’s disease. These drugs blunt the effects of the excitatory neurotransmitter acetylcholine, thus correcting the balance between dopamine and acetylcholine that is disturbed in the direction of cholinergic dominance. Anticholinergic drugs may help control the tremor and decrease the excess salivation associated with Parkinson’s disease but seldom are useful for skeletal muscle rigidity and bradykinesia. Although the peripheral and CNS actions of these synthetic anticholinergic drugs are less prominent than those of atropine, side effects, including memory disturbances (especially in elderly patients), hallucinations, confusion, sedation, mydriasis, cycloplegia, adynamic ileus, and urinary retention, may still occur. The mydriatic effect could precipitate glaucoma in a susceptible patient. As more effective drugs have become available, the use of anticholinergic drugs to treat patients with Parkinson’s disease has diminished.
Amantadine
Amantadine is an antiviral drug used for prophylaxis against infection with influenza A. This drug was discovered by chance to also produce symptomatic improvement in patients with Parkinson’s disease. The mode of action of amantadine is not known, although it has been speculated that it facilitates the release of dopamine from dopaminergic terminals that remain in the nigrostriatum of patients with this disease. In addition, amantadine may delay uptake of dopamine back into nerve endings, exert anticholinergic effects, is a weak glutamate antagonist, and exhibits noncompetitive antagonist effects at N-methyl-D-aspartate (NMDA) receptors. Unlike anticholinergic drugs, amantadine may result in some improvement in skeletal muscle rigidity and bradykinesia. Amantadine is well absorbed after oral administration, and the elimination half-time is approximately 12 hours. More than 90% of the drug is excreted unchanged by the kidneys, necessitating dosage adjustments in patients with renal dysfunction. The side effects are similar to those produced by anticholinergic drugs but, in addition, chronic administration of amantadine tends to induce ankle edema and livedo reticularis of the legs with or without cardiac failure. In older patients, amantadine may aggravate confusion and psychosis.
Monoamine Oxidase Type B Enzyme Inhibitors
This category comprises two drugs, selegiline and rasagiline. Selegiline is a highly selective and irreversible inhibitor of monoamine oxidase type B enzyme (MAO-B) that has a weak antiparkinsonian effect when used alone and a moderate effect when used as an adjunct to carbidopa-levodopa. MAO-B enzyme activity is one of the principal catabolic pathways for dopamine in the CNS. Blocking MAO-B enzyme activity increases the intrasynaptic half-time of dopamine leading to improved motor fluctuations and tremor. In contrast to nonspecific monoamine oxidase inhibitors, selegiline does not result in life-threatening potentiation of the effects of catecholamines when administered concurrently with a centrally active amine. This reflects the fact that metabolism of norepinephrine in peripheral nerve endings is not altered by selegiline, which minimizes the likelihood of adverse responses during anesthesia in response to sympathomimetics. Insomnia is a significant side effect of selegiline. Other side effects of selegiline include confusion, hallucinations, mental depression, and paranoid ideation. Rasagiline has created enthusiasm as a potentially neuroprotective agent but this activity requires further evaluation.19 It has action at both the MAO-A and MAO-B enzyme, but its affinity is up to 16 times greater for MAO-B. It is recommended both as monotherapy and adjunctive therapy.20 Although a theoretical risk does exist for the precipitation of serotonin syndrome, this was not observed during clinical trials. Similarly, avoidance of tyramine is ideally recommended although no adverse reactions have been noted.21
Nonpharmacologic Treatment
Deep brain stimulation was approved to treat Parkinson’s disease by the U.S. Food and Drug Administration (FDA) in 2002. Although not curative, it effectively controls symptoms resistant to medications or allows reduced reliance on drugs whose side effects have proven problematic. The mechanism of action of deep brain stimulation is unknown.14 Other potential therapies under investigation include stem cell transplantation as well as transplantation of fetal mesencephalic tissue.
CENTRAL NERVOUS SYSTEM STIMULANTS
Analeptics are drugs that stimulate the CNS. These drugs were previously used in the treatment of generalized CNS depression accompanying deliberate drug overdoses, but this practice has been abandoned because these drugs lack specific antagonist properties and their margin of safety is narrow. The excitability of the CNS reflects a balance between excitatory and inhibitory influences that is normally maintained within relatively narrow limits. Analeptics can increase excitability either by blocking inhibition or by enhancing excitation.
Doxapram
Doxapram is an analeptic which acts centrally and at peripheral chemoreceptors to augment breathing efforts. The stimulus to ventilation produced by administration of doxapram, 1 mg/kg IV is similar to that produced by a PaO2 of 38 mm Hg acting on the carotid bodies. An increase in tidal volume, more than an increase in breathing frequency, is responsible for the doxapram-induced increase in minute ventilation. Oxygen consumption is increased concomitantly with the increase in minute ventilation.
Doxapram has a large margin of safety as reflected by a 20- to 40-fold difference in the dose that stimulates ventilation and the dose that produces seizures. Nevertheless, continuous infusion of doxapram, as is required to produce a sustained effect on ventilation, often results in evidence of subconvulsive CNS stimulation (hypertension, tachycardia, cardiac dysrhythmias, vomiting, and increased body temperature). These changes are consistent with increased sympathetic nervous system outflow. Continuous infusion is also required because the duration of action of a single IV dose is relatively short at 5 to 10 minutes. It is metabolized extensively, and less than 5% is excreted unchanged in the urine.
Clinical Uses
Doxapram administered as a continuous infusion (2 to 3 mg per minute) has been used as a temporary measure to maintain ventilation during administration of supplemental oxygen to patients with chronic obstructive airway disease who otherwise depend on a hypoxic drive to maintain adequate minute ventilation. Its role in the postoperative period has been used in preventing the ventilatory depression produced by opioids without altering analgesia. It has also been shown to be useful in treating postoperative shivering. Its use with apneic neonates in intensive care units can often delay or prevent intubation and ventilation, thus reducing ventilator associated morbidity and mortality.
Methylphenidate
Methylphenidate is a mild CNS stimulant structurally related to amphetamine. Absorption after oral administration is rapid, and its low protein binding and high lipid solubility results in rapid uptake into the brain. Methylphenidate is useful in the treatment of attention deficit hyperactivity disorder in children and adults.22 Hypertension, tachycardia, priapism, seizures, and serious cardiovascular events such as sudden cardiac death, stroke, and myocardial infarction have been described in patients treated with methylphenidate. Methylphenidate may also be effective in the treatment of narcolepsy, either alone or in combination with tricyclic antidepressants.23
Methylxanthines
Methylxanthines are represented by caffeine, theophylline, and theobromine. Solubility of methylxanthines is low and is enhanced by formation of complexes as represented by the combination of theophylline with ethylenediamine to form aminophylline. Methylxanthines have in common the ability to (a) stimulate the CNS, (b) produce diuresis, (c) increase myocardial contractility, and (d) relax smooth muscle, especially those in the airways.
Mechanism of Action
The best characterized cellular action of methylxanthines is antagonism of receptor-mediated actions of adenosine thus facilitating the release of catecholamines. Theophylline is more active than caffeine or theobromine as an antagonist at these receptors. At high concentrations, theophylline inhibits phosphodiesterase enzymes that are responsible for breakdown of cyclic adenosine monophosphate. Methylxanthines are completely absorbed after oral administration and eliminated primarily by metabolism in the liver. Unlike adults, premature infants metabolize theophylline in part to caffeine. Furthermore, the clearance of methylxanthines is greatly prolonged in the neonate compared with that in the adult.
Clinical Uses
Methylxanthines are used as analeptics to treat primary apnea of prematurity by stimulating medullary respiratory centers by increasing the sensitivity of these centers to carbon dioxide. The slowed metabolism of methylxanthines in neonates compared to adults is a consideration when using theophylline to stimulate ventilation in neonates. Smooth muscle relaxation and bronchodilation produced by theophylline may reflect a combination of effects including catecholamine release, phosphodiesterase inhibition, and inhibition of inflammation. The administration of theophylline during maintenance of anesthesia appears to have no added bronchodilator effect over that of the volatile anesthetic alone. Selective β2-adrenergic agonists delivered by inhalation have largely replaced theophylline preparations in the treatment of bronchospasm associated with asthma.
Toxicity
A single oral dose of theophylline, 5 mg/kg, will produce a peak plasma concentration of 10 µg/mL in adults within 1 to 2 hours following ingestion. Increased levels of unbound drug may result in signs of toxicity despite therapeutic plasma concentrations of drug (10 to 20 µg/mL). Theophylline plasma concentrations, only slightly greater than the recommended therapeutic range, can produce evidence of CNS stimulation (nervousness, tremors), and at higher concentrations or with rapid IV administration, seizures are a possibility. Vomiting most likely reflecting CNS stimulation is common when plasma concentrations exceed 15 µg/mL. Tachycardia and cardiac dysrhythmias may appear most likely due to drug-induced release of catecholamines from the adrenal medulla.
Drug Interactions
Drugs may enhance (carbamazepine, rifampin) or inhibit (cimetidine, erythromycin) the hepatic metabolism of theophylline. Larger doses of benzodiazepines may be required in the presence of theophylline as benzodiazepines increase the CNS concentrations of adenosine, a potent CNS depressant, whereas theophylline is an adenosine receptor antagonist. Ketamine may decrease the seizure threshold for theophylline. Theophylline can partially antagonize the effects of nondepolarizing neuromuscular blocking drugs presumably by inhibition of phosphodiesterase.
Caffeine
Caffeine is a methylxanthine-derived phosphodiesterase inhibitor that is present in a variety of beverages and nonprescription medications. A prominent effect of caffeine is CNS stimulation. In addition, this substance acts as a cerebral vasoconstrictor and may cause secretion of acidic gastric fluid.
Pharmacologic uses of caffeine include administration to neonates experiencing apnea of prematurity.24 Treatment of postdural puncture headache has historically been treated with doses ranging from 75 to 300 mg oral caffeine. Despite the limited evidence for this treatment, it continues to be a popular treatment modality.25–27 Caffeine may be included in common cold remedies in an attempt to offset the sedating effects of certain antihistamines.28
Almitrine
Almitrine acts on the carotid body chemoreceptors to increase minute ventilation. It has been demonstrated to increase PaO2 and decrease PaCO2 in patients with chronic respiratory failure associated with obstructive pulmonary disease. Its mechanism of action has not been elucidated.29 It is used as a measure to improve or prevent hypoxia during one-lung ventilation techniques, especially with IV anesthesia techniques.30,31 IV administration of almitrine improves PaO2 in patients with acute lung injury but may also induce lactic acidosis and hepatic dysfunction.32 Side effects of prolonged oral almitrine therapy include dyspnea and peripheral neuropathy which significantly limits its use.33
Modafinil
Modafinil is a wakefulness-promoting drug approved for patients with excessive daytime sleepiness associated with narcolepsy, obstructive sleep apnea, and shiftwork sleep disorder.34,35 In addition, it may result in euphoria, as well as alteration in mood, affect, and thinking. Its mechanism of action is unknown. Its absorption is rapid and peak plasma concentrations are reached after 4 hours. It undergoes hepatic metabolism and its inactive metabolites are excreted by the kidneys. A feeling of fatigue and sedation following recovery from general anesthesia may be countered by administration of modafinil.35
CENTRALLY ACTING MUSCLE RELAXANTS
The primary indication for centrally acting muscle relaxants is spasticity, which may accompany pathologic conditions such as stroke, cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis, and injuries to the CNS. They act directly on the CNS or on skeletal muscles to relieve spasticity. Spasticity of skeletal muscles occurs when there is an abnormal increase in resistance to passive movement of a skeletal muscle group because of hyperactive proprioceptive or stretch reflexes.
Baclofen
Baclofen is the chlorophenol derivative of GABA that acts as an agonist at GABAB receptors in the dorsal horn of the spinal cord and is often administered for treatment of spastic hypertonia of cerebral and spinal cord origin. Baclofen relieves spasticity by activating G protein–linked presynaptic GABAB receptors that hyperpolarize muscle spindle afferent neurons, thereby decreasing the number and amplitude of excitatory postsynaptic potentials along the dendrites of motor neurons. This drug has no effect on the neuromuscular junction. Baclofen is particularly effective in the treatment of flexor spasms and skeletal muscle rigidity associated with spinal cord injury or multiple sclerosis. Intrathecal administration of baclofen may be an effective treatment of spinal spasticity that has not responded to oral administration of the drug.
Baclofen is rapidly and almost completely absorbed from the gastrointestinal tract. The elimination half-time is 3 to 6 hours, with approximately 80% of the drug excreted unchanged in urine, emphasizing the need to modify the dose in patients with renal dysfunction. Therapeutic plasma concentrations are 80 to 400 mg/mL.
Use of baclofen is limited by its side effects, which include sedation, skeletal muscle weakness, and confusion. Sudden discontinuation of chronic baclofen therapy may result in severe withdrawal reactions including evidence of multiple organ system failure, tachycardia, and both auditory and visual hallucinations. A case of cardiac arrest due to baclofen withdrawal has been reported. Vocal cord spasm has been described following abrupt discontinuation of an intrathecal baclofen infusion. Coma, depression of ventilation, and seizures may accompany an overdose of baclofen. The threshold for initiation of seizures may be lowered in patients with epilepsy. Mild hypotension may occur in awake patients being treated with oral baclofen, whereas bradycardia, hypotension, and delayed awakening have been observed when general anesthesia is induced in these patients. Hemodynamic instability and delayed awakening following general anesthesia have been described in a patient receiving an accidental intrathecal overdose of baclofen. A decrease in sympathetic nervous system outflow from the CNS mediated by a GABA-baclofen–sensitive system might contribute to this hemodynamic response. Rarely, increases in liver transaminases and blood glucose levels have occurred.
Benzodiazepines
Benzodiazepines are widely used as centrally acting skeletal muscle relaxants. Diazepam is the most widely prescribed of this class, followed by clonazepam. These drugs are particularly beneficial for spinal spasticity and have little effect on cerebral spasticity. Sedation may limit the efficacy of these drugs as muscle relaxants but may be useful for relief of spasms that limit sleep.36
Botulinum Toxin
Botulinum toxin causes irreversible inhibition of presynaptic acetylcholine release. Injections are made into spastic muscles, thereby causing weakening of muscle tone. Botulinum toxin is used in cases of central or peripheral spasticity, particularly when limited muscle groups are affected. It has been used for spasticity and to prevent contractures in cerebral palsy, multiple sclerosis, and after stroke. Focally, it can be used for blepharospasm, hemifacial spasm, and torticollis.37
Cyclobenzaprine
Cyclobenzaprine is related structurally and pharmacologically to the tricyclic antidepressants. Its anticholinergic effects are similar to those of tricyclic antidepressants and can include dry mouth, tachycardia, blurred vision, and sedation. The agent is commonly used in the short-term (1 to 2 weeks) management of lumbar sprain-strain injuries associated with painful muscle spasm. The mechanism of skeletal muscle relaxant effects produced by cyclobenzaprine is unknown. It must not be administered in the presence of monoamine oxidase inhibitors. In view of the potential adverse side effects of some tricyclic antidepressant drugs on the heart, the use of cyclobenzaprine may be questionable in patients with cardiac dysrhythmias or altered conduction of cardiac impulses.
Tizanidine
Tizanidine is a short acting α2-adrenergic agonist whose structure is similar to clonidine. It reaches peak plasma levels at 2 hours after administration, and its clinical effect lasts only 6 hours, which necessitates repeated dosing if needed. Its absorption is highly variable depending on whether the patient has recently eaten or is fasted. Dosage adjustments must be made in patients with renal and hepatic dysfunction. Significant side effects include hypotension and care must be taken with patients who take antihypertensive agents. Significant sedation can also result, and there is an additive effect with other sedatives such as benzodiazepines. Discontinuation of therapy should be gradual as not to precipitate rebound hypertension, tachycardia, and/or hypertonia.
Dantrolene
Dantrolene exerts antispasmodic effects by inducing relaxation directly on muscle by decreasing calcium release from the sarcoplasmic reticulum. Its absorption from the gastrointestinal tract is slow and incomplete, and its half-life is 9 hours. The starting dose is usually 25 mg twice daily, and dosage can be increased up to 200 mg per day. Laboratory investigation for liver dysfunction should be undertaken prior to starting therapy as there is potential for hepatotoxicity especially in those patients with preexisting hepatic compromise.
References
1. Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011;10:446–456.
2. Elger CE, Schmidt D. Modern management of epilepsy: a practical approach. Epilepsy Behav. 2008;12:501–539.
3. Sirven JI, Noe K, Hoerth M, et al. Antiepileptic drugs 2012: recent advances and trends. Mayo Clin Proc. 2012;87(9):879–889.
4. Schmidt D. Drug treatment of epilepsy: options and limitations. Epilepsy Behav. 2009;15:56–65.
5. LaRoche SM, Helmers SL. The new antiepileptic drugs: clinical applications. JAMA. 2004;291(5):615–620.
6. Zupanc ML, Roell Werner R, Schwabe MS, et al. Efficacy of felbamate in the treatment of intractable pediatric epilepsy. Pediatr Neurol. 2010:42(6):396–403.
7. Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med. 1996;334:1583–1590.
8. Cavanna AE, Ali F, Rickards HE, et al. Behavioral and cognitive effects of anti-epileptic drugs. Discov Med. 2010;9:138–144.
9. Vogl C, Mochida S, Wolff C, et al. The synaptic vesicle glycoprotein 2A ligand levetiracetam inhibits presynaptic Ca2+ channels through an intracellular pathway. Mol Pharmacol. 2012;82:199–208.
10. Wild JM, Fone DL, Aljarudi S, et al. Modelling the risk of visual field loss arising from long-term exposure to the antiepileptic drug vigabatrin: a cross-sectional approach. CNS Drugs. 2013;27(10):841–849.
11. Klehm J, Sigride TS, Fernandez IS, et al. Clobazam: effect on frequency of seizures and safety profile in different subgroups of children with epilepsy. Pediatr Neurol. 2014:51(1):60–66.
12. Classen J, Silbergleit R, Weingart S, et al. Emergency neurological life support: status epilepticus. Neurocrit Care. 2012;17:S73–S78.
13. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311(16):1670–1683.
14. Follet K, Weaver F, Stern M, et al. Pallidal versus subthalmic deep-brain stimulation for Parkinson’s disease. N Eng J Med. 2010;362: 2077–2091.
15. Calne DB. Treatment of Parkinson’s disease. N Engl J Med. 1993; 329:1021–1027.
16. Braun M, Cawello W, Boekens, et al. Influence of domperidone on pharmacokinetics, safety, and tolerability of the dopamine agonist rotigotine. Br J Clin Pharmacol. 2009;67(2):209–215.
17. Gunzler SA. Apomorphine in the treatment of Parkinson disease and other movement disorders. Expert Opin Pharmacother. 2009;10(6):1027–1038.
18. Piray P, Zeighamy Y, Bahrami F, et al. Impulse control disorders in Parkinson’s disease are associated with dysfunction in stimulus valuation but not action valuation. J Neurosci. 2014;34(23): 7814–7824.
19. Teo KC, Ho SL. Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease. Transl Neurodegener. 2013;2(1):2–19.
20. Lew MF. Rasagiline treatment effects on parkinsonian tremor. Int J Neurosci. 2013;123(12):859–865.
21. Chen JJ, Swope DM, Dashtipour K. Comprehensive review of rasagiline, a second generation monoamine oxidase inhibitor, for the treatment of Parkinson’s disease. Clin Ther. 2007;29(9):1825–1849.
22. Wolraich ML, Doffing MA. Pharmacokinetic considerations in the treatment of attention-deficit hyperactivity disorder with methylphenidate. CNS Drugs. 2004;18(4):243–250.
23. Godfrey J. Safety of therapeutic methylphenidate in adults: a systematic review of the evidence. J Psychopharmacol. 2009;23(2): 194–205.
24. Schoen K, Yu T, Stockman C, et al. Use of methylxanthine therapies for the treatment and prevention of apnea of prematurity. Pediatr Drugs. 2014;16(2):169–177.
25. Baysinger CL, Pope JE, Lockhart EM, et al. The management of accidental dural puncture and postdural puncture puncture headache: a North American survey. J Clin Anesth. 2011;23(5):349–360.
26. Camman WR, Murray RS, Mushlin PS, et al. Effects of oral caffeine on postdural puncture headache. A double-blind, placebo-controlled trial. Anesth Analg. 1990;70:181–184.
27. Esmaoglu A, Akpinar H, Ugur F. Oral multidose caffeine-paracetamol combination is not effective for the prophylaxis of postdural puncture headache. J Clin Anesth. 2005;17:58–61.
28. Mitchell JL. Use of cough and cold preparations during breastfeeding. J Hum Lact. 1999;15(4):347–349.
29. Chen L, Miller FL, Malmkvist G, et al. Low-dose almitrine bismesylate enhances hypoxic pulmonary vasoconstriction in closed-chest dogs. Anesth Analg. 1990;71:475–483.
30. Bermejo S, Gallart L, Silva-Costa-Gomes T, et al. Almitrine fails to improve oxygenation during one-lung ventilation with sevoflurane anesthesia [ahead of print September 6, 2013]. J Cardiothorac Vasc Anesth. pii: S1053-0770(13)00163-8.
31. Dalibon N, Moutafis M, Liu N, et al. Treatment of hypoxemia during one-lung ventilation using intravenous almitrine. Anesth Analg. 2004;98:590–594.
32. B’chir A, Mebazaa A, Lossser M-R, et al. Intravenous almitrine bismesylate reversibly induces lactic acidosis and hepatic dysfunction in patients with acute lung injury. Anesthesiology. 1998;89: 823–830.
33. Howard P. Hypoxia, almitrine, and peripheral neuropathy. Thorax. 1999;44(4):247–250.
34. Launois SH, Tamisier R, Pepin JL. On treatment but still sleepy: cause and management of residual sleepiness in obstructive sleep apnea. Curr Opin Pulm Med. 2013;19(6):601–608.
35. Kumar R. Approved and investigational uses of modafinil: an evidence based review. Drugs. 2008;68(13):1803–1839.
36. Lapeyre E, Kuks JB, Meijler WJ. Spasticity: revisiting the role and the individual value of several pharmacological treatments. Neurorehabilitation. 2010;27(2):193–200.
37. Münchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ. 2000;320:161–165.