Pharmacology_Katzung

Pharmacology_Katzung. Tiagabine is a lipophilic, blood-brain barrier-permeant analog of nipecotic acid, a GABA uptake inhibitor that is not active systemically. The chemical structure of tiagabine consists of the active moiety—nipecotic acid—and a lipophilic anchor that allows the molecule to cross the blood-brain barrier. Tiagabine is highly selective for the GAT-1 GABA transporter isoform, the most abundant GABA transporter expressed in brain, and has little or no activity on the other sodiumand chloride-dependent GABA transporters, GAT-2, GAT-3, or BGT-1. The action of the GABA that is released by inhibitory neurons is normally terminated by reuptake into the neuron and surrounding glia by these transporters. Tiagabine inhibits the movement of GABA from the extracellular space—where the GABA can act on neuronal receptors—to the intracellular compartment, where it is inactive. This action of tiagabine causes prolongation of GABA-mediated inhibitory synaptic responses and potentiation of tonic inhibition;


Pharmacology_Katzung

Pharmacology_Katzung. receptors—to the intracellular compartment, where it is inactive. This action of tiagabine causes prolongation of GABA-mediated inhibitory synaptic responses and potentiation of tonic inhibition; the latter is caused by the action of GABA on extrasynaptic GABA receptors. Tiagabine is considered a “rationally designed” antiseizure drug because it was developed with the understanding that potentiation of GABA action in the brain is a possible antiseizure mechanism.


Pharmacology_Katzung

Pharmacology_Katzung. Tiagabine is indicated for the adjunctive treatment of focal seizures, with or without secondary generalization. In adults, the recommended initial dose is 4 mg/d with weekly increments of 4–8 mg/d to total doses of 16–56 mg/d. Initial dosages can be given twice a day, but a change to three times a day is recommended above 30–32 mg/d. Divided doses as often as four times daily are sometimes required. Adverse effects and apparent lack of efficacy limit the use of this drug. Minor adverse events are dose related and include nervousness, dizziness, tremor, difficulty concentrating, and depression. Excessive confusion, somnolence, or ataxia may require discontinuation. Psychosis occurs rarely. The drug can cause seizures in some patients, notably those taking the drug for other indications. Rash is an uncommon idiosyncratic adverse effect.


Pharmacology_Katzung

Pharmacology_Katzung. Tiagabine is 90–100% bioavailable, has linear kinetics, and is highly protein bound. The half-life is 5–8 hours and decreases in the presence of enzyme-inducing drugs. Food decreases the peak plasma concentration but not the area under the concentration curve (see Chapter 3). To avoid adverse effects, the drug should be taken with food. Hepatic impairment causes a slight decrease in clearance and may necessitate a lower dose. The drug is oxidized in the liver by CYP3A. Elimination is primarily in the feces (60–65%) and urine (25%). Retigabine (US Adopted Name: ezogabine), a potassium channel opener, is a third-line treatment for focal seizures. Because retigabine causes pigment discoloration of the retina and skin, its use is limited to those who have failed to respond to other agents. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Retigabine is an allosteric opener of KCNQ2-5 (Kv7.2-Kv7.5) voltage-gated potassium channels, which are localized, in part, in axons and nerve terminals. Opening KCNQ potassium channels in presynaptic terminals inhibits the release of various neurotransmitters, including glutamate, which may be responsible for the seizure protection.


Pharmacology_Katzung

Pharmacology_Katzung. Doses of retigabine range from 600 to 1200 mg/d, with 900 mg/d expected to be the most common. The drug is administered in three divided doses, and the dose must be titrated beginning at 300 mg/d. Most adverse effects are dose-related and include dizziness, somnolence, blurred vision, confusion, and dysarthria. Urinary symptoms, including retention, hesitation, and dysuria, believed to be due to effects of the drug on KCNQ potassium channels in detrusor smooth muscle, may occur. They are generally mild and usually do not require drug discontinuation. In 2013, reports began to appear of blue pigmentation, primarily on the skin and lips, but also on the palate, sclera, and conjunctiva. The skin dyspigmentation is due to the presence of coarse melanin granules within dermal cells and not to deposition of the drug within the tissue. The skin discoloration has not been associated with more serious adverse effects but may be of cosmetic significance. In addition, however, retinal pigment


Pharmacology_Katzung

Pharmacology_Katzung. deposition of the drug within the tissue. The skin discoloration has not been associated with more serious adverse effects but may be of cosmetic significance. In addition, however, retinal pigment abnormalities can occur independent of skin changes. Of particular concern are postmarketing reports of macular abnormalities characterized as vitelliform lesions, such as those seen in macular degeneration or dystrophy. Decreased visual acuity has been reported, but documentation is lacking. Nevertheless, because of the ophthalmologic adverse reactions, regulatory agencies have recommended use of retigabine only in cases where other antiseizure drugs are not adequate or not tolerated.


Pharmacology_Katzung

Pharmacology_Katzung. Absorption of retigabine is not affected by food, and kinetics are linear; drug interactions are minimal. The major metabolic pathways in humans are N-glucuronidation and N-acetylation. The drug neither inhibits nor induces the major CYP enzymes involved in drug metabolism. Correct diagnosis is critical to antiseizure drug selection. The agents described in the previous section are effective for the treatment of focal onset seizures, including focal-to-bilateral tonicclonic seizures (secondarily generalized tonic-clonic seizures), but some can worsen certain seizure types in generalized epilepsy syndromes. A variety of drugs were shown initially to be effective in the treatment of focal onset seizures and are primarily used to treat these types of seizures; in addition, these drugs have also found uses in the treatment of certain generalized onset seizure types. These drugs are described below.


Pharmacology_Katzung

Pharmacology_Katzung. Lamotrigine is considered a sodium channel-blocking antiseizure drug; it is effective for the treatment of focal seizures, as are other drugs in this category. In addition, clinical trials of lamotrigine have demonstrated effectiveness in the treatment of generalized tonicclonic seizures (in idiopathic generalized epilepsy) and in the treatment of generalized absence epilepsy. In the latter, lamotrigine is not as effective as ethosuximide or valproate. The drug is generally well tolerated; however, it can produce a potentially fatal rash (Stevens-Johnson syndrome). Although adverse effects are similar to those of other sodium channel-blocking antiseizure drugs, lamotrigine paradoxically may cause insomnia instead of sedation. Lamotrigine causes fewer adverse cognitive effects than carbamazepine or topiramate. It can also improve depression in patients with epilepsy and reduces the risk of relapse in bipolar disorder.


Pharmacology_Katzung

Pharmacology_Katzung. Lamotrigine was developed when investigators thought that the antifolate effects of certain antiseizure drugs such as phenytoin might contribute to their effectiveness. Several phenyltriazines were developed; although their antifolate properties were weak, some were active in seizure screening tests. The antifolate activity of lamotrigine is not believed to contribute to its therapeutic activity in epilepsy. Mechanism of Action The action of lamotrigine on voltage-gated sodium channels is similar to that of carbamazepine. The mechanism by which lamotrigine is effective against absence seizures is not known.


Pharmacology_Katzung

Pharmacology_Katzung. Although most controlled studies have evaluated lamotrigine as add-on therapy, the drug is effective as monotherapy for focal seizures, and lamotrigine is now widely prescribed for this indication because of its excellent tolerability. Despite being less effective than ethosuximide and valproate for absence epilepsy, lamotrigine may be prescribed because of its tolerability or in females of childbearing age because it has fewer fetal risks than valproate. Lamotrigine is also approved for primary generalized tonic-clonic seizures and generalized seizures of the Lennox-Gastaut syndrome. Adverse effects include dizziness, headache, diplopia, nausea, insomnia, somnolence, and skin rash. The rash is a typical hypersensitivity reaction. Although the risk of rash may be diminished by introducing the drug slowly, pediatric patients are at greater risk. Serious rash occurs in approximately 0.3–0.8% of children age 2–17 years, whereas in adults, the rate is 0.08–0.3%.


Pharmacology_Katzung

Pharmacology_Katzung. Lamotrigine is almost completely absorbed and has a volume of distribution of 1–1.4 L/kg. Protein binding is only about 55%. The drug has linear kinetics and is metabolized primarily by glucuronidation in the liver to the inactive 2-N-glucuronide, which is excreted in the urine. Lamotrigine has a half-life of approximately 24 hours in normal volunteers; this decreases to 13–15 hours in patients taking enzyme-inducing drugs. Lamotrigine is effective in the treatment of focal seizures in adults at dosages typically between 100 and 300 mg/d. The initial dose is 25 mg/d, increasing to 50 mg/d after 2 weeks; thereafter, titration can proceed by 50 mg/d every 1–2 weeks to a usual maintenance dose of 225–375 mg/d (in two divided doses). Therapeutic serum levels have not been established, but toxicity is infrequent with levels < 10 mcg/mL. The combination of lamotrigine and valproate is believed to be particularly efficacious. However, valproate causes a two-fold increase in the half-life of


Pharmacology_Katzung

Pharmacology_Katzung. is infrequent with levels < 10 mcg/mL. The combination of lamotrigine and valproate is believed to be particularly efficacious. However, valproate causes a two-fold increase in the half-life of lamotrigine and can increase blood levels correspondingly, leading to a risk of skin rash if valproate is added to a stable regimen of lamotrigine. In patients receiving valproate, the initial dose of lamotrigine must be reduced to 12.5–25 mg every other day, with increases of 25–50 mg/d every 2 weeks as needed to a usual maintenance dose of 100–200 mg/d.


Pharmacology_Katzung

Pharmacology_Katzung. Levetiracetam is a broad-spectrum antiseizure agent and one of the most commonly prescribed drugs for epilepsy, primarily because of its perceived favorable adverse effect profile, broad therapeutic window, favorable pharmacokinetic properties, and lack of drug-drug interactions. Mechanism of Action Levetiracetam is an analog of piracetam, which is purported to be a cognition enhancer. In animal testing, levetiracetam is not active in the MES or PTZ tests, but it does have activity against seizures in the 6-Hz and kindling models. Levetiracetam binds selectively to SV2A, a ubiquitous synaptic vesicle integral membrane protein, which may function as a positive effector of synaptic vesicle exocytosis. The drug accesses the luminal side of recycling synaptic vesicles by vesicular endocytosis. Binding to SV2A in the vesicle reduces the release of the excitatory neurotransmitter glutamate during trains of high-frequency activity.


Pharmacology_Katzung

Pharmacology_Katzung. Levetiracetam is effective in the treatment of focal seizures in adults and children, primary generalized tonic-clonic seizures, and the myoclonic seizures of juvenile myoclonic epilepsy. Adult dosing can begin with 500 or 1000 mg/d. The dosage can be increased every 2–4 weeks by 1000 mg to a maximum dosage of 3000 mg/d. The drug is dosed twice daily. Adverse effects include somnolence, asthenia, ataxia, infection (colds), and dizziness. Less common but more serious are behavioral and mood changes, such as irritability, aggression, agitation, anger, anxiety, apathy, depression, and emotional lability. Oral formulations include extended-release tablets; an intravenous preparation is also available.


Pharmacology_Katzung

Pharmacology_Katzung. Oral absorption of levetiracetam is rapid and nearly complete, with peak plasma concentrations in 1.3 hours. Food slows the rate of absorption but does not affect the amount absorbed. Kinetics are linear. Protein binding is less than 10%. The plasma half-life is 6–8 hours, but may be longer in the elderly. Two-thirds of the drug is excreted unchanged in the urine and the remainder as the inactive deaminated metabolite 2-pyrrolidone-N-butyric acid. The metabolism of levetiracetam occurs in the blood. There is no metabolism in the liver, and drug interactions are minimal.


Pharmacology_Katzung

Pharmacology_Katzung. Brivaracetam, the 4-n-propyl analog of levetiracetam, is a high-affinity SV2A ligand recently approved for the treatment of focal (partial) onset seizures. Whether it will prove to have the broad-spectrum activity of levetiracetam remains to be demonstrated; given the similarity of the mechanisms of action, however, a broad spectrum is expected. Brivaracetam is active in animal models of generalized epilepsies. It improved or abolished the photoparoxysmal response (abnormal occurrence of cortical spikes or spike and wave discharges on EEG in response to intermittent light stimulation) in patients with generalized epilepsies. In addition, the drug reduced the frequency of generalized seizures in a small number of patients with generalized seizures included in a clinical trial. Brivaracetam exhibits linear pharmacokinetics over a wide dose range (10–600 mg, single oral dose). It is rapidly and completely absorbed after oral administration; has an elimination half-life of 7–8 hours,


Pharmacology_Katzung

Pharmacology_Katzung. exhibits linear pharmacokinetics over a wide dose range (10–600 mg, single oral dose). It is rapidly and completely absorbed after oral administration; has an elimination half-life of 7–8 hours, which allows twice-daily dosing; and has low plasma protein binding (<20%).


Pharmacology_Katzung

Pharmacology_Katzung. Coadministration of brivaracetam with carbamazepine may increase exposure to carbamazepine epoxide, the active metabolite of carbamazepine, possibly leading to adverse effects; carbamazepine dose reduction should be considered. Similarly, coadministration of brivaracetam with phenytoin may increase phenytoin levels. Coadministration of other antiseizure drugs is unlikely to affect brivaracetam exposure. Brivaracetam provides no added therapeutic benefit when administered in conjunction with levetiracetam; both drugs act on SV2A. Perampanel is an orally active AMPA receptor antagonist approved for the treatment of focal seizures and primary generalized tonicclonic seizures in idiopathic generalized epilepsies. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Perampanel is a potent noncompetitive antagonist of the AMPA receptor, a subtype of the ionotropic glutamate receptor that is the main mediator of synaptic excitation in the central nervous system (Figure 24–1). AMPA receptors are critical to local generation of seizure activity in epileptic foci and are also responsible for the neuron-to-neuron spread of excitation. Partial blockade of AMPA receptors by therapeutic concentrations of perampanel reduces the likelihood of seizure occurrence. In generalized convulsive seizures, whether occurring as a secondarily generalized convulsion following a focal seizure or as a primary generalized seizure, excitatory cortical neurons engage subcortical centers, including the thalamus, that relay the excitation throughout both hemispheres. This spread of excitation to distant sites is mediated by AMPA receptors at the excitatory synapses that long axons make on their distant targets. Perampanel is therefore well suited to inhibit this spread of


Pharmacology_Katzung

Pharmacology_Katzung. of excitation to distant sites is mediated by AMPA receptors at the excitatory synapses that long axons make on their distant targets. Perampanel is therefore well suited to inhibit this spread of excitation, which may account for its activity in preventing secondary and primary generalized convulsive seizures. Perampanel binds to an allosteric site on the extracellular side of the channel, acting as a wedge to prevent channel opening.


Pharmacology_Katzung

Pharmacology_Katzung. A typical maintenance dose of perampanel for patients 12 years of age and older is 4, 6, or 8 mg/d. Higher doses may be needed in patients who are receiving CYP3A4-inducing antiseizure drugs. Perampanel use is often associated with behavioral adverse reactions including aggression, hostility, irritability, and anger. The frequency of these adverse effects increases in a dose-dependent fashion, and they occur more often in younger patients and in those with learning disabilities or dementia. Alcohol use may exacerbate the level of anger. Other common adverse effects are dizziness, somnolence, and headache. Falls are more common at higher doses.


Pharmacology_Katzung

Pharmacology_Katzung. Perampanel has a long half-life, typically ranging from 70 to 110 hours, which permits once-daily dosing. Because of the long half-life, steady state is not achieved for 2–3 weeks; the prescriber should make dosage changes no more frequently than at 2-week (or longer) intervals. The kinetics are linear in the dose range of 2–12 mg/d. The half-life is prolonged in moderate hepatic failure. Absorption is rapid and the drug is fully bioavailable. Although food slows the rate of absorption, the extent is not affected. Perampanel is 95% bound to plasma proteins. The drug is extensively metabolized via initial oxidation by CYP3A4 and subsequent glucuronidation.


Pharmacology_Katzung

Pharmacology_Katzung. The most significant drug interactions with perampanel are with potent CYP3A4 inducer antiseizure drugs such as carbamazepine, oxcarbazepine, and phenytoin. Concomitant use with such agents increases the clearance of perampanel by 50–70%, which may require the use of higher perampanel doses. Of somewhat lesser concern is the potential for strong CYP3A4 inhibitors to increase the levels of perampanel. Perampanel may decrease the effectiveness of levonorgestrel-containing hormonal contraceptives.


Pharmacology_Katzung

Pharmacology_Katzung. In 1903, chemists in Germany discovered that lipophilic derivatives of barbituric acid induced sleep in dogs. Phenobarbital was introduced into the clinical market in 1912 as a sleeping aid; it was serendipitously found to be useful in the treatment of epilepsy. In comparison with anesthetic barbiturates such as pentobarbital, phenobarbital is preferred in the chronic treatment of epilepsy because it is less sedative at antiseizure doses. Intravenous pentobarbital, however, is frequently used to induce general anesthesia in the treatment of drug-refractory status epilepticus. Phenobarbital is the oldest of the currently available antiseizure drugs; however, the drug is no longer a first choice in the developed world because of its sedative properties and many drug interactions. It is still useful for neonatal seizures.


Pharmacology_Katzung

Pharmacology_Katzung. Four barbituric acid derivatives were once used for epilepsy: phenobarbital, mephobarbital, metharbital, and primidone. Only phenobarbital and primidone remain in common use. Mechanism of Action (see also Chapter 22) Barbiturates such as phenobarbital act as positive allosteric modulators of GABAA receptors at low concentrations (see Figure 22–6); at higher concentrations, the drugs directly activate GABAA receptors. In contrast to benzodiazepines, which augment the frequency of GABAA receptor chloride channel opening, barbiturates increase the mean open duration of the channel without altering either channel conductance or opening frequency. Phenobarbital also exerts other actions on synaptic function and intrinsic neuronal excitability mechanisms; some of these could be relevant to its clinical antiseizure activity, including block of AMPA receptors or voltage-activated calcium channels.


Pharmacology_Katzung

Pharmacology_Katzung. Phenobarbital is useful in the treatment of focal seizures and generalized tonic-clonic seizures. Evidence-based comparisons of phenobarbital with phenytoin and carbamazepine have shown no difference in seizure control, but phenobarbital was more likely to be discontinued due to adverse effects. Phenobarbital may be useful in the treatment of myoclonic seizures, such as in juvenile myoclonic epilepsy, but it is not a drug of first choice. Phenobarbital may worsen absence seizures and infantile spasms. Long-term administration of phenobarbital leads to physical dependence such that seizure threshold is reduced upon withdrawal. The drug must be discontinued gradually over several weeks to avoid the occurrence of severe seizures or status epilepticus. Pharmacokinetics, Therapeutic Levels, & Dosage


Pharmacology_Katzung

Pharmacology_Katzung. Pharmacokinetics, Therapeutic Levels, & Dosage For pharmacokinetics, drug interactions, and toxicity of phenobarbital, see Chapter 22. The dose of phenobarbital is individualized based on clinical response. Dosing information from clinical trials is limited. Doses in the range of 60–200 mg, divided two or three times daily, are typically used. The minimally effective dose may be 60 mg/d, and the median effective dose range may be 100–150 mg/d. The accepted serum concentration reference range is 15 to 40 mcg/mL, although many patients tolerate chronic levels above 40 mcg/mL. Mean steady-state plasma phenobarbital levels with 60 and 100 mg/d dosing are 14 and 21 mcg/mL, respectively.


Pharmacology_Katzung

Pharmacology_Katzung. Primidone (2-desoxyphenobarbital) is a derivative of phenobarbital. In the early 1950s, the drug was found to have anti-seizure activity in animal models; subsequent evidence showed it to be clinically active in the treatment of epilepsy. It was widely used until the 1960s, but was then largely abandoned because of its high incidence of adverse effects. It is effective for the treatment of essential tremor and is still used for this indication. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Primidone is metabolized to phenobarbital and phenylethylmalonamide (PEMA). All three compounds are active antiseizure agents. Although phenobarbital is roughly equally active in the MES and PTZ animal tests, primidone has greater activity in the MES test than the PTZ test, indicating that it acts more like the sodium channel-blocking antiseizure drugs than phenobarbital. Also, in animal models, primidone causes relatively less acute motor impairment than phenobarbital. With chronic treatment, phenobarbital is thought to mediate most of the antiseizure activity of primidone. Attempts to determine the relative contributions of the parent drug and its two metabolites have been conducted in newborn infants, in whom drug-metabolizing enzyme systems are very immature and in whom primidone is only slowly metabolized. In these patients, primidone is effective in controlling seizures, confirming that it has intrinsic antiseizure activity. This conclusion was reinforced by studies in older


Pharmacology_Katzung

Pharmacology_Katzung. only slowly metabolized. In these patients, primidone is effective in controlling seizures, confirming that it has intrinsic antiseizure activity. This conclusion was reinforced by studies in older patients initiating treatment with primidone, in which seizure control was obtained before phenobarbital concentrations reached the therapeutic range.


Pharmacology_Katzung

Pharmacology_Katzung. Primidone is effective against focal seizures and generalized tonicclonic seizures, but its overall effectiveness is less than drugs such as carbamazepine and phenytoin because of a high incidence of acute toxicity on initial administration and because of chronic sedative effects at effective doses. Primidone is also used in some movement disorders (see Chapter 28).


Pharmacology_Katzung

Pharmacology_Katzung. Primidone is completely absorbed, usually reaching peak concentrations about 3 hours after oral administration. Primidone is only 30% bound to plasma proteins. The volume of distribution is 0.6 L/kg. As shown in the text figure, primidone is metabolized by oxidation to phenobarbital, which accumulates slowly, and by scission of the heterocyclic ring to form PEMA. Both primidone and phenobarbital also undergo subsequent conjugation and excretion. Primidone has a larger clearance than most other anti-seizure drugs (2 L/kg/d), corresponding to a half-life of 6–8 hours. PEMA clearance is approximately half that of primidone, but phenobarbital has a very low clearance (see Table 3–1). The appearance of phenobarbital corresponds to the disappearance of primidone. During chronic therapy, the phenobarbital levels derived from primidone are usually two to three times higher than the primidone levels.


Pharmacology_Katzung

Pharmacology_Katzung. Primidone is most efficacious when plasma levels are in the range of 8–12 mcg/mL. Concomitant levels of its metabolite, phenobarbital, at steady state, usually vary from 15 to 30 mcg/mL. Dosages of 10–20 mg/kg/d are necessary to obtain these levels. Primidone should be started at a low daily dose, which is then gradually escalated over several days to a few weeks to avoid prominent sedation and gastrointestinal complaints. When adjusting doses of the drug, the parent drug reaches steady state rapidly (30–40 hours), but the active metabolites phenobarbital and PEMA reach steady state much more slowly, at approximately 20 days and 3–4 days, respectively.


Pharmacology_Katzung

Pharmacology_Katzung. The dose-related adverse effects of primidone are similar to those of its metabolite, phenobarbital, except that many patients experience severe adverse effects on initial dosing including drowsiness, dizziness, ataxia, nausea, and vomiting. Tolerance to these adverse effects develops in hours to days and can be minimized by slow titration. Felbamate is a dicarbamate that is used in the treatment of focal seizures and in the Lennox-Gastaut syndrome. It is structurally related to the sedative-hypnotic meprobamate. Felbamate is generally well tolerated; some patients report improved alertness. However, because the drug can cause both aplastic anemia and severe hepatitis, felbamate is used only for patients with refractory seizures who respond poorly to other medications. Despite the seriousness of the adverse effects, thousands of patients worldwide use this medication.


Pharmacology_Katzung

Pharmacology_Katzung. Felbamate appears to have multiple mechanisms of action. It produces a use-dependent block of N-methyl-d-aspartate (NMDA) receptors, with selectivity for those containing the GluN2B (NR2B) subunit; the drug also produces a barbiturate-like potentiation of GABAA receptor responses. Oral felbamate is well absorbed (> 90%). Of the absorbed dose, 30–50% is excreted unchanged in the urine. The remainder is metabolized by CYP3A4 and CYP2E1 in the liver. The mean terminal half-life of 20 hours in monotherapy decreases to 13–14 hours in the presence of phenytoin or carbamazepine. The typical starting dose of felbamate is 400 mg three times a day. The dose may be escalated slowly to a maximum dose of 3600 mg/d, although some patients have received doses as high as 6000 mg/d. Effective plasma levels range from 30 to 100 mcg/mL. In addition to its usefulness in focal seizures, felbamate ameliorates atonic seizures as well as other seizure types in the Lennox-Gastaut syndrome. Felbamate decreases


Pharmacology_Katzung

Pharmacology_Katzung. range from 30 to 100 mcg/mL. In addition to its usefulness in focal seizures, felbamate ameliorates atonic seizures as well as other seizure types in the Lennox-Gastaut syndrome. Felbamate decreases the clearance of phenytoin and valproic acid and increases their blood levels; dose reductions of these drugs may be necessary when felbamate is initiated. Felbamate reduces levels of carbamazepine but increases levels of the metabolite carbamazepine epoxide, which may be associated with adverse effects including dizziness, diplopia, or headache.


Pharmacology_Katzung

Pharmacology_Katzung. A limited number of antiseizure drugs are first-line agents in the treatment of patients who exhibit multiple generalized onset seizure types. Valproate is especially effective and is considered the first-choice treatment for such patients. However, it has various troublesome side effects and is a known human teratogen; its use is avoided in women of childbearing potential. Other drugs that may have broad activity in generalized epilepsies are topiramate and zonisamide. Valproate is a first-line broad-spectrum antiseizure drug that is thought to offer protection against many seizure types. In addition, it is used as a mood stabilizer in bipolar disorder and as prophylactic treatment for migraine. Valproate was found to have antiseizure properties when used as a solvent in the search for other drugs effective against seizures.


Pharmacology_Katzung

Pharmacology_Katzung. Valproic acid is a short-chain branched fatty acid that is liquid at room temperature; it is formulated as an oral syrup solution or in gelatin capsules. More commonly, however, the drug is used in a coordination complex—referred to as divalproex sodium—composed of equal parts of valproic acid and the salt sodium valproate. An extended-release divalproex formulation in a hydrophilic polymer matrix allows once-a-day oral administration. Valproic acid has a pKa value of 4.56 and is therefore fully ionized at body pH; for that reason, the active form of the drug is the valproate ion, regardless of whether valproic acid or the salt of the acid is administered. Valproic acid is one of a series of fatty carboxylic acids that have antiseizure activity; this activity appears to be greatest for carbon chain lengths of five to eight atoms. The amides and esters of valproic acid are also active antiseizure agents. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action The mechanism or mechanisms whereby valproate exerts its therapeutic actions are not known. Valproate has broad-spectrum efficacy in animal models, conferring seizure protection in diverse chemoconvulsant seizure models, the MES test, and the kindling models. The time course of valproate’s antiseizure activity is poorly correlated with blood or tissue levels of the parent drug, an observation that has led to speculation regarding the active species.


Pharmacology_Katzung

Pharmacology_Katzung. Valproate is one of the most versatile and effective antiseizure drugs. It is widely used for myoclonic (such as in juvenile myoclonic epilepsy), atonic (as in Lennox-Gastaut syndrome), and generalized onset tonic-clonic seizures. Valproate is also effective in the treatment of generalized absence seizures and is often preferred to ethosuximide when the patient has concomitant generalized tonic-clonic seizures. Valproate is also effective in focal seizures, but it may not be as effective as carbamazepine or phenytoin. Intravenous formulations can be used to treat status epilepticus.


Pharmacology_Katzung

Pharmacology_Katzung. Valproate is well absorbed after an oral dose, with bioavailability greater than 80%. Peak blood levels are observed within 2 hours. Food may delay absorption, and the drug may have improved tolerability if it is administered after meals. Valproate is highly bound to plasma proteins, but protein binding becomes saturated as the concentration increases at the upper end of the therapeutic range, resulting in an increase in the plasma free fraction of valproate from 10% at plasma concentrations up to 75 mcg/mL to 30% at levels greater that 150 mcg/mL. Such increases lead to an apparent increase in the clearance of total valproate at high doses. The half-life varies from 9 to 18 hours; extended-release formulations are therefore preferred. Because valproate is highly protein bound, it is largely confined to blood plasma; the drug has a low volume of distribution of approximately 0.15 L/kg. Approximately 20% of the drug is excreted as a direct conjugate.


Pharmacology_Katzung

Pharmacology_Katzung. An initial daily dose of 15 mg/kg is recommended with slow titration to the therapeutic dose. Dosages of 25–30 mg/kg/d may be adequate in some patients, but others may require 60 mg/kg/d or even more. Therapeutic levels of valproate range from 50 to 100 mcg/mL, but concentrations up to 150 mcg/mL are generally tolerated and may be required.


Pharmacology_Katzung

Pharmacology_Katzung. Valproate inhibits the metabolism of several drugs, including phenobarbital and ethosuximide, leading to higher steady-state concentrations of these agents. Levels of phenobarbital may rise steeply, causing stupor or coma. Valproate displaces phenytoin from plasma proteins, causing an increase in the free fraction of phenytoin, and total phenytoin concentrations in the therapeutic range may be associated with toxicity. Although valproate does not increase levels of carbamazepine itself, levels of carbamazepine epoxide may be increased. Valproate can dramatically decrease the clearance of lamotrigine, resulting in a twoto three-fold prolongation of lamotrigine’s half-life.


Pharmacology_Katzung

Pharmacology_Katzung. The most common dose-related adverse effects of valproate are nausea, vomiting, and other gastrointestinal complaints such as abdominal pain and heartburn. The drug should be started gradually to avoid these symptoms. A fine tremor is frequently seen at higher levels. Other reversible adverse effects occurring in some patients include weight gain, increased appetite, and hair loss.


Pharmacology_Katzung

Pharmacology_Katzung. Valproate rarely causes idiosyncratic hepatic toxicity that may be severe and has been fatal. The risk is greatest for patients under 2 years of age and for those taking multiple medications. Initial aspartate aminotransferase values may not be elevated in susceptible patients, although these levels do eventually become abnormal. Most fatalities have occurred within 4 months after initiation of therapy. The other observed idiosyncratic adverse effect with valproate is thrombocytopenia, although documented cases of abnormal bleeding are lacking. Valproate can interfere with conversion of ammonia to urea. It can cause lethargy associated with increased blood ammonia concentrations. Fatal hyperammonemic encephalopathy has occurred in patients with genetic defects in urea metabolism; the drug is contraindicated in these patients.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment with valproate during the first trimester of pregnancy is associated with a 1–2% risk of neural tube defects including spina bifida. In addition, an increased incidence of cardiovascular, orofacial, and digital abnormalities has been noted. Finally, cognitive impairment in offspring has been reported. These observations must be strongly considered in the choice of drugs in women of child-bearing potential. Topiramate is a broad-spectrum antiseizure drug whose chemical structure is that of a sulfamate-substituted monosaccharide derived from d-fructose. It is used in the treatment of focal seizures, primary generalized seizures, and seizures in the Lennox-Gastaut syndrome. Topiramate is also commonly used for migraine headache prophylaxis. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Topiramate likely acts through several cellular targets, which may account for its broad-spectrum activity in epilepsy and migraine. Possible sites of action relevant to its clinical activities are (1) voltage-gated sodium channels; (2) GABAA receptor subtypes; and (3) AMPA or kainate receptors. The drug is a weak inhibitor of carbonic anhydrase isoenzymes II and IV, but this is not thought to account for its antiseizure effects. In rare cases, the inhibition of carbonic anhydrase may cause metabolic acidosis of clinical importance.


Pharmacology_Katzung

Pharmacology_Katzung. Topiramate is effective in the treatment of focal seizures in adults and children and in primary generalized tonic-clonic seizures. The drug is approved for the Lennox-Gastaut syndrome and may be effective in juvenile myoclonic epilepsy, infantile spasms, Dravet’s syndrome (severe myoclonic epilepsy in infancy), and even childhood absence seizures. The initial dose in newly diagnosed patients is typically 100 mg/d, but maintenance doses usually range from 200 to 400 mg/d. Most clinicians begin at a low dose (25–50 mg/d) and increase slowly to prevent adverse effects. Cognitive side effects commonly occur with topiramate and are a frequent reason for discontinuation. Affected patients experience impaired expressive language function (dysnomia and diminished verbal fluency), impaired verbal memory, and a general slowing of cognitive processing. These effects are unlike other antiseizure drugs and often occur without sedation or mood change. The incidence of cognitive side effects


Pharmacology_Katzung

Pharmacology_Katzung. verbal memory, and a general slowing of cognitive processing. These effects are unlike other antiseizure drugs and often occur without sedation or mood change. The incidence of cognitive side effects increases in a dose-dependent fashion, reaching 26% at a dose of 400 mg/d; however, some patients are completely unaffected even at higher dosages. Another troublesome adverse effect that commonly occurs with topiramate is paresthesias, typically occurring during initiation of therapy or at high doses; the symptoms may resolve with continuing treatment. Other dose-related adverse effects that occur frequently in the first 4 weeks of topiramate therapy are somnolence, fatigue, dizziness, nervousness, and confusion. Acute myopia and angle-closure glaucoma may require prompt drug withdrawal. Urolithiasis occurs in 0.5–1.5% of patients on long-term therapy and is more common in men. In some patients, carbonic anhydrase inhibition is associated with reduced serum bicarbonate that is usually


Pharmacology_Katzung

Pharmacology_Katzung. occurs in 0.5–1.5% of patients on long-term therapy and is more common in men. In some patients, carbonic anhydrase inhibition is associated with reduced serum bicarbonate that is usually asymptomatic but may result in nonspecific symptoms such as fatigue, anorexia, or nausea and vomiting. The potential for chronic untreated hyperchloremic non-anion gap metabolic acidosis for bone health is unknown. Decreased sweating (oligohydrosis) and an elevation in body temperature may occur during exposure to hot weather, mostly in children. Long-term topiramate therapy is often associated with significant weight loss, primarily due to a reduction in body fat mass. In clinical trials, 85% of adults receiving topiramate lost weight, which on average amounted to 5% of mean baseline body weight. Greater weight loss occurs in those with higher pretreatment weight. Weight loss is gradual and typically peaks at 12–18 months after initiation of therapy. Beneficial changes in lipid profile, glycemic


Pharmacology_Katzung

Pharmacology_Katzung. weight loss occurs in those with higher pretreatment weight. Weight loss is gradual and typically peaks at 12–18 months after initiation of therapy. Beneficial changes in lipid profile, glycemic control, and blood pressure may accompany the weight loss. Data in humans suggest a link between topiramate use in the first trimester of pregnancy and oral cleft formation in newborns (relative risk 16to 21-fold).


Pharmacology_Katzung

Pharmacology_Katzung. Topiramate is rapidly absorbed (about 2 hours) and is 80% bioavailable. There is minimal food effect on absorption, minimal (15%) plasma protein binding, and only moderate (20–50%) metabolism; no active metabolites are formed. The drug is primarily excreted in the urine (50–80% is unchanged). The monotherapy half-life is 20–30 hours, but drops to 12–15 hours when administered with concomitant enzyme-inducing drugs. Immediate-release formulations are usually administered in two daily doses. Extended-release formulations are available that have been approved for once-daily administration. Although increased levels are seen with renal failure and hepatic impairment, there is no age or gender effect, no autoinduction, and no inhibition of metabolism, and kinetics are linear. Drug interactions do occur and can be complex, but the major effect is on topiramate levels rather than on the levels of other antiseizure drugs. Birth control pills may be less effective in the presence of


Pharmacology_Katzung

Pharmacology_Katzung. do occur and can be complex, but the major effect is on topiramate levels rather than on the levels of other antiseizure drugs. Birth control pills may be less effective in the presence of topiramate, and alternative modes of contraception are recommended in women taking more than 200 mg/d; however, oral contraceptives with a higher content of ethinyl estradiol (50 mcg) may be satisfactory.


Pharmacology_Katzung

Pharmacology_Katzung. Zonisamide is a broad-spectrum antiseizure drug that is effective for focal and generalized tonic-clonic seizures in adults and children and may also be effective in some myoclonic epilepsies and in infantile spasms. There are reports of improvement in generalized onset tonic-clonic seizures and atypical absence seizures.


Pharmacology_Katzung

Pharmacology_Katzung. There is little information on the mechanism of action of zonisamide. Although it does block voltage-gated sodium channels, other actions may also contribute to its antiseizure activity. Zonisamide has high bioavailability, modest protein binding (>50–60%), and a half-life of 1–3 days, so it can be administered once daily. The drug is extensively metabolized by acetylation to form N-acetyl-zonisamide, which is excreted in the urine unchanged, and by CYP3A4 to form 2-sulfamoylacetylphenol, which is excreted as the glucuronide. Maintenance doses are 200–400 mg/d in adults (maximum 600 mg/d) and 4–8 mg/kg/d in children (maximum 12 mg/kg/d). Adverse effects include drowsiness, cognitive impairment, renal stones, and potentially serious skin rashes. Zonisamide has no clinically significant effects on the pharmacokinetics of other antiseizure drugs. However, antiseizure drugs such as carbamazepine, phenytoin, and phenobarbital that induce CYP3A4 increase the clearance of zonisamide,


Pharmacology_Katzung

Pharmacology_Katzung. effects on the pharmacokinetics of other antiseizure drugs. However, antiseizure drugs such as carbamazepine, phenytoin, and phenobarbital that induce CYP3A4 increase the clearance of zonisamide, shortening its half-life; concomitant use with CYP3A4-inducing agents may therefore require an increase in zonisamide dose. Zonisamide, like topiramate, contains sulphur: zonisamide is a sulfonamide, whereas topiramate contains the same sulfonamide structure but is strictly a sulfamate. They have similar pharmacologic actions, including carbonic anhydrase inhibition like acetazolamide, which is also a sulfonamide. Both zonisamide and topiramate are associated with weight loss. They also both (rarely) cause kidney stones and oligohydrosis. Whether these actions are related to the common sulfonamide structure is not known.


Pharmacology_Katzung

Pharmacology_Katzung. Ethosuximide and valproate are effective and well-tolerated treatments for generalized absence seizures in childhood absence epilepsy; lamotrigine is possibly effective. Ethosuximide is considered in this section along with trimethadione, which is of historical interest. Ethosuximide is a first-line drug for the treatment of generalized absence seizures. It can be used as monotherapy unless generalized tonic-clonic seizures are also present, in which case valproate is preferred or ethosuximide can be combined with another drug effective against generalized tonic-clonic seizures. Ethosuximide was introduced in 1958 as the third of three marketed succinimides; the other two, phensuximide and methsuximide, are rarely used. Ethosuximide and methsuximide have asymmetric carbons (asterisks in below figure) and are used as racemates. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Ethosuximide is thought to act by inhibition of low-voltageactivated T-type calcium channels in thalamocortical neurons that underlie the 3-Hz spike-wave discharges of generalized absence seizures. Other ion channels affected include voltage-gated sodium channels, calcium-activated potassium channels, and inward rectifier potassium channels; these actions may contribute to the efficacy of ethosuximide in absence epilepsy.


Pharmacology_Katzung

Pharmacology_Katzung. Studies in the mid-1970s provided evidence that monotherapy with ethosuximide is effective in the treatment of childhood generalized absence seizures. There is also evidence that it is effective in the treatment of atypical absence and epileptic negative myoclonus, a rare seizure type characterized by interruption of ongoing electromyographic activity contralateral to a lateralized spike-and-wave discharge. If ethosuximide in monotherapy does not lead to seizure control, the drug can be used in combination with valproate or other agents such as benzodiazepines.


Pharmacology_Katzung

Pharmacology_Katzung. Absorption is complete following administration of the oral dosage forms. Peak levels are observed 3–7 hours after oral administration of the capsules. Ethosuximide is not protein bound. During longterm administration, approximately 20% of the dose is excreted unchanged by the kidney. The remaining drug is metabolized in the liver, principally by CYP3A hydroxylation, to inactive metabolites. Ethosuximide has a very low total body clearance (0.25 L/kg/d). This corresponds to a half-life of approximately 40 hours, although values from 18 to 72 hours have been reported.


Pharmacology_Katzung

Pharmacology_Katzung. In children, a common starting dose is 10–15 mg/kg/d, with titration according to clinical response to a maintenance dose of 15–40 mg/kg/d. In older children and adults, the initial dose is 250 or 500 mg/d, increasing in 250-mg increments to clinical response to a maximum of 1500 mg/d. While dosing is based on titration to maximal seizure control with acceptable tolerability, the accepted therapeutic serum concentration range is 40–100 mcg/mL (although plasma levels up to 150 mcg/mL may be necessary and tolerated in some patients). There is a linear relationship between ethosuximide dose and steady-state plasma levels. While the long half-life could allow once-daily dosing, ethosuximide is generally administered in two or even three divided doses to minimize adverse gastrointestinal effects.


Pharmacology_Katzung

Pharmacology_Katzung. Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations owing to inhibition of ethosuximide metabolism. No other important drug interactions have been reported. The most common dose-related adverse effect of ethosuximide is gastric distress, including pain, nausea, and vomiting. When an adverse effect does occur, temporary dosage reductions may allow adaptation. Other dose-related adverse effects are transient lethargy or fatigue and, much less commonly, headache, dizziness, hiccup, and euphoria. Behavioral changes are usually in the direction of improvement. Non-dose-related or idiosyncratic adverse effects of ethosuximide are extremely uncommon.


Pharmacology_Katzung

Pharmacology_Katzung. Trimethadione is an oxazolidinedione antiseizure drug introduced in 1945. It is no longer marketed in the USA but is available elsewhere. Trimethadione is effective in the treatment of generalized absence seizures and was the drug of choice for this seizure type until the introduction of ethosuximide. Trimethadione has numerous dose-related and idiosyncratic side effects, including hemeralopia (day blindness). Because of the high propensity for side effects, trimethadione and the related oxazolidinediones paramethadione and dimethadione, the major metabolite of trimethadione, are now rarely used. Valproate is the drug of first choice for the treatment of myoclonic seizures. Other drugs effective in the treatment of this seizure type are levetiracetam, zonisamide, topiramate, and lamotrigine.


Pharmacology_Katzung

Pharmacology_Katzung. Valproate is the drug of first choice for the treatment of myoclonic seizures. Other drugs effective in the treatment of this seizure type are levetiracetam, zonisamide, topiramate, and lamotrigine. Valproate in combination with lamotrigine and a benzodiazepine is the most widely used treatment for atonic seizures. Topiramate, felbamate, and lamotrigine are used in the treatment of Lennox-Gastaut syndrome; clinical trials have shown improvement in atonic seizures. The sodium channel-blocking antiseizure drugs phenobarbital and vigabatrin should be used with caution because they may worsen atonic seizures. Clobazam and rufinamide, discussed in this section, are also used in the treatment of seizures associated Lennox-Gastaut syndrome and have been demonstrated in clinical trials to reduce the frequency of atonic seizures.


Pharmacology_Katzung

Pharmacology_Katzung. Clobazam is widely used for the treatment of focal seizures in many countries, although it is not approved for that indication in the United States, where its only approved use is for treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older. Clobazam is a 1,5-benzodiazepine and structurally different from other marketed benzodiazepines, which are 1,4-benzodiazepines. Like the 1,4-benzodiazepines, however, clobazam is a positive allosteric modulator of GABAA receptors and has similar pharmacologic activities and adverse effects. In addition, while tolerance occurs to clobazam in animal models within days to weeks of chronic administration, retrospective studies assessing the extent of tolerance in the clinical setting have suggested that tolerance is not a prominent issue in clinical treatment. Side effects that occur in a dose-dependent fashion include somnolence and sedation, dysarthria, drooling, and behavioral changes, including aggression.


Pharmacology_Katzung

Pharmacology_Katzung. not a prominent issue in clinical treatment. Side effects that occur in a dose-dependent fashion include somnolence and sedation, dysarthria, drooling, and behavioral changes, including aggression. Withdrawal symptoms may occur with abrupt discontinuation. Clobazam has a half-life of 18 hours and is effective at dosages of 0.5–1 mg/kg/d. Clobazam is metabolized in the liver by CYP and non-CYP transformations, with up to 14 metabolites; however, the major metabolite is desmethylclobazam (norclobazam). With long-term administration of clobazam, levels of norclobazam, which has a longer half-life than clobazam, are 8to 20-times higher than those of the parent.


Pharmacology_Katzung

Pharmacology_Katzung. Norclobazam has antiseizure activity, although it is weaker than clobazam. Nevertheless, because norclobazam levels are so much higher at steady state, seizure protection during chronic therapy is likely mainly due to norclobazam. Clobazam is a moderate inhibitor of CYP2D6 and has been shown to significantly increase the levels of drugs metabolized by this isoenzyme such as phenytoin and carbamazepine. Reduced dosing may be required when these antiseizure drugs are used in combination with clobazam. Rufinamide is a triazole derivative identified by screening in animal seizure models. It is effective for atonic seizures in Lennox-Gastaut syndrome, but there is also some evidence of efficacy in the treatment of focal seizures. In the USA and Europe, rufinamide is only approved for treatment of seizures associated with the Lennox-Gastaut syndrome. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action In mice and rats, rufinamide is protective in the MES test and, at higher doses, in the PTZ test. Its only known action that is relevant to seizure protection is as a blocker of voltage-gated sodium channels. In the Lennox-Gastaut syndrome, rufinamide is effective against all seizure types but especially against atonic seizures. Some clinical data suggest it may be effective against focal seizures. Treatment in children is typically started at 10 mg/kg/d in two equally divided doses and gradually increased to 45 mg/kg/d to a maximum of 3200 mg/d. Adults can begin with 400–800 mg/d in two equally divided doses up to a maximum of 3200 mg/d as tolerated. The drug should be given with food. The most common adverse events are somnolence and vomiting.


Pharmacology_Katzung

Pharmacology_Katzung. Rufinamide is well absorbed, and plasma concentrations peak between 4 and 6 hours. The half-life is 6–10 hours, and minimal plasma protein binding is observed. Although cytochrome P450 enzymes are not involved, the drug is extensively metabolized to inactive products. Most of the drug is excreted in the urine; an acid metabolite accounts for about two-thirds of the dose. Most drug-drug interactions are minor except that valproate may decrease the clearance of rufinamide; dosing with valproate, particularly in children, may need to be decreased, typically by 50%.


Pharmacology_Katzung

Pharmacology_Katzung. Dravet’s syndrome (severe myoclonic epilepsy of infancy) is a rare genetic epileptic encephalopathy characterized by diverse generalized and focal seizure types, including myoclonic seizures, tonic-clonic seizures, absence seizures, atonic seizures, and one-sided hemiconvulsive and focal seizures. Mutations of the SCN1A gene encoding Nav1.1 voltage-dependent sodium channels cause 79% of diagnosed cases of Dravet’s syndrome. Although drugs such as clobazam, valproate, and topiramate are used, none of these is very effective. Stiripentol is not approved in the USA but is widely used in Europe. In patients with SCN1A gene mutations, sodium channel-blocking antiseizure drugs are contraindicated because they worsen seizures.


Pharmacology_Katzung

Pharmacology_Katzung. STIRIPENTOL Stiripentol is an aromatic allylic alcohol that has activity in the treatment of Dravet’s syndrome. Clinical studies indicate that it reduces the frequency of prolonged seizures in children with this condition. Stiripentol is often used in conjunction with HHOONH2NH2 clobazam or valproate; whether it has activity by itself has not been studied in clinical trials. The drug has various actions on GABA-mediated neurotransmission including acting as a positive allosteric modulator of GABAA receptors. It is a potent inhibitor of CYP3A4, CYP1A2, and CYP2C19 and dramatically increases the levels of clobazam and its active metabolite norclobazam; it also inhibits valproate metabolism. These drug-drug interactions have been proposed as the basis for the clinical effectiveness of stiripentol, and elevations in concomitant drugs likely contribute to some extent to efficacy. However, stiripentol has activity in various animal seizure models, indicating that it has antiseizure activity


Pharmacology_Katzung

Pharmacology_Katzung. and elevations in concomitant drugs likely contribute to some extent to efficacy. However, stiripentol has activity in various animal seizure models, indicating that it has antiseizure activity in its own right. Dosing is complex, typically beginning with a reduction in concomitant medications. Stiripentol is then started at 10 mg/kg/d and is increased gradually as tolerated. The most frequent adverse effects are sedation/drowsiness, reduced appetite, slowing of mental function, ataxia, diplopia, nausea, and abdominal pain. Stiripentol exhibits nonlinear pharmacokinetics, decreasing in clearance as the dose increases.


Pharmacology_Katzung

Pharmacology_Katzung. Infantile spasms are treated with adrenocorticotropic hormone (ACTH) by intramuscular injection or oral corticosteroids such as prednisone or hydrocortisone. Vigabatrin is also often used and is particularly effective in cases associated with tuberous sclerosis. Other antiseizure medications that may be helpful are valproate, topiramate, zonisamide, or a benzodiazepine such as clonazepam or nitrazepam. ACTH and corticosteroids are associated with substantial morbidity, and vigabatrin, as discussed below, has a risk of permanent loss of vision. The goal of treatment is cessation of seizures, and this generally requires ACTH, corticosteroids, or vigabatrin and is not generally achieved with the safer antiseizure agents. The mechanism of action of ACTH and corticosteroids in the treatment of infantile spasms is unknown.


Pharmacology_Katzung

Pharmacology_Katzung. Vigabatrin is an analog of GABA, designed as an inhibitor of GABA transaminase (GABA-T), the enzyme responsible for the metabolism of synaptically released GABA. Vigabatrin is effective in the treatment of focal seizures (but not generalized seizures) and in the treatment of infantile spasms. Because it may cause irreversible visual loss, it is usually reserved for patients with seizures refractory to other treatments. Mechanism of Action Vigabatrin is a specific, irreversible inhibitor of GABA-T, producing a sustained increase in the extracellular concentrations of GABA in the brain. This paradoxically leads to inhibition of synaptic GABAA receptor responses, but also prolongs the activation of extrasynaptic GABAA receptors that mediate tonic inhibition. Vigabatrin is effective in a wide range of animal seizure models. Vigabatrin is marketed as a racemate; the S(+) enantiomer is active and the R(−) enantiomer appears to be inactive.


Pharmacology_Katzung

Pharmacology_Katzung. Vigabatrin is useful in the treatment of infantile spasms, especially when associated with tuberous sclerosis. The drug is also effective against focal seizures. The half-life is approximately 6–8 hours, but the pharmacodynamic activity of the drug is more prolonged and not well correlated with the plasma half-life because recovery from the drug requires synthesis of replacement GABA-T enzyme. In infants, the dosage is 50–150 mg/kg/d. In adults, vigabatrin is started at an oral dosage of 500 mg twice daily; a total of 2–3 g/d may be required for full effectiveness. The most important adverse effect of vigabatrin is irreversible retinal dysfunction. Patients may develop permanent bilateral concentric visual field constriction that is often asymptomatic but can be disabling. Minimal evidence also suggests that vigabatrin also can damage the central retina. The onset of vision loss can occur within weeks of starting treatment or after months or years. Other adverse effects are


Pharmacology_Katzung

Pharmacology_Katzung. evidence also suggests that vigabatrin also can damage the central retina. The onset of vision loss can occur within weeks of starting treatment or after months or years. Other adverse effects are somnolence, headache, dizziness, and weight gain. Less common but more troublesome adverse effects are agitation, confusion, and psychosis; preexisting mental illness is a relative contraindication.


Pharmacology_Katzung

Pharmacology_Katzung. Seven benzodiazepines play roles in the treatment of seizures and epilepsy (see also Chapter 22). All produce their functional effects by positive allosteric modulation of GABAA receptors; however, subtle structural differences among the benzodiazepines result in differences in their pharmacokinetic properties. Certain benzodiazepines are the first-line acute treatment for seizures, either in status epilepticus or acute repetitive seizures (seizure clusters). However, two prominent aspects of benzodiazepines limit their usefulness in the chronic therapy of epilepsy. The first is their pronounced sedative effects; however, in children, there may be a paradoxical hyperactivity, as is the case with other sedative agents such as barbiturates. The second problem is tolerance, in which seizures may respond initially but recur within a few months. As a result of these limitations, benzodiazepines are infrequently used in the chronic treatment of epilepsy.


Pharmacology_Katzung

Pharmacology_Katzung. Diazepam given intravenously is a first-line treatment for status epilepticus. It is also used in a rectal gel formulation for the treatment of acute repetitive seizures (seizure clusters). The drug is occasionally given orally on a long-term basis, although it is not considered very effective in this application, because of the development of tolerance. Lorazepam is more commonly used in the treatment of status epilepticus because it has a more prolonged duration of action after bolus intravenous injection. There is evidence that intramuscular midazolam, which is water soluble, is preferred in the out-ofhospital treatment of status epilepticus because the delay required to achieve intravenous access may be avoided. Clonazepam is a long-acting benzodiazepine that on a milligram basis is one of the most potent antiseizure agents known. It has documented efficacy in the treatment of absence, atonic, and myoclonic seizures. As is the case for all benzodiazepines, sedation is prominent,


Pharmacology_Katzung

Pharmacology_Katzung. one of the most potent antiseizure agents known. It has documented efficacy in the treatment of absence, atonic, and myoclonic seizures. As is the case for all benzodiazepines, sedation is prominent, especially on initiation of therapy; starting doses should be small. Maximal tolerated doses are usually in the range of 0.1–0.2 mg/kg/d, but many weeks of gradually increasing daily doses may be needed to achieve these dosages in some patients. Nitrazepam is not marketed in the USA but is used in many other countries, especially for infantile spasms and myoclonic seizures. Clorazepate dipotassium is approved in the USA for the treatment of focal seizures. Drowsiness and lethargy are common adverse effects, but as long as the drug is increased gradually, dosages as high as 90 mg/d can be given. Clobazam is described earlier in this chapter under atonic seizures.


Pharmacology_Katzung

Pharmacology_Katzung. Carbonic anhydrases are enzymes that catalyze the interconversion between CO2 and bicarbonate (see Chapter 15). Inhibitors of carbonic anhydrases, particularly the cytosolic forms CA II and CA VII, exhibit antiseizure activity. Bicarbonate efflux through GABAA receptors can exert a depolarizing (excitatory) influence that is especially relevant during intense GABAA receptor activation, as occurs during seizures, when there is diminution of the hyperpolarizing chloride gradient. Carbonic anhydrase inhibition prevents the replenishment of intracellular bicarbonate and depresses the depolarizing action of bicarbonate.


Pharmacology_Katzung

Pharmacology_Katzung. The prototypical carbonic anhydrase inhibitor is the sulfonamide acetazolamide (see Chapter 15), which has broad-spectrum antiseizure activity in animal models. In addition, acetazolamide is believed to have clinical antiseizure activity, at least transiently, against most types of seizures including focal and generalized tonic-clonic seizures and especially generalized absence seizures. However, acetazolamide is rarely used for chronic therapy because tolerance develops rapidly, with return of seizures usually within a few weeks. The drug is often used in the intermittent treatment of menstrual seizure exacerbations in women. The usual dosage is approximately 10 mg/kg/d to a maximum of 1000 mg/d.


Pharmacology_Katzung

Pharmacology_Katzung. Another sulfonamide carbonic anhydrase inhibitor, sulthiame, became established in the treatment of focal seizures in the 1950s and has also been reported to be effective in benign focal epilepsy with centrotemporal spikes (BECTS) and infantile spasms, but results of controlled trials are not available. Its use has declined in routine practice, other than in a few countries in Europe and in Israel. It is not available in the USA. As noted previously, topiramate and zonisamide are sulfur-containing molecules with weak carbonic anhydrase activity. There is little evidence that this activity is a major factor in their therapeutic effects.


Pharmacology_Katzung

Pharmacology_Katzung. The pharmacokinetic behavior of most antiseizure drugs varies markedly from patient to patient so that dosing must be individualized. Therapeutic drug concentration monitoring is often used as an aid to dosing. Established references ranges are available for most of the older antiseizure drugs (Table 24–3). Such ranges are generally not available for newer drugs, although there may be information on blood levels associated with efficacy. In all cases, the ranges should be interpreted flexibly given individual variability in response. Drug levels can be helpful (1) to guide dose adjustments when there is a change in drug formulation, (2) when breakthrough seizures occur, (3) when an interacting medication is added to or removed from a patient’s regimen, (4) during pregnancy, (5) to establish an individual therapeutic concentration range when a patient is in remission, (6) to determine whether adverse effects are related to drug levels, and (7) to assess adherence.


Pharmacology_Katzung

Pharmacology_Katzung. Status epilepticus is clinically defined as abnormally prolonged or repetitive seizures. Status epilepticus presents in several forms: (1) convulsive status epilepticus consisting of repeated generalized for some antiseizure drugs. 1These data are provided only as a general guideline. Many patients will respond better at different levels, and some patients may have drug-related adverse events within the listed reference ranges.2Monohydroxy metabolites (combination of eslicarbazepine and R-licarbazepine).3Not well established. 4Not well established; values given were associated with positive response.


Pharmacology_Katzung

Pharmacology_Katzung. tonic-clonic seizures with persistent postictal depression of neurologic function between seizures; (2) nonconvulsive status epilepticus, a persistent change in behavior or mental processes with continuous epileptiform EEG but without major motor signs; and (3) focal status epilepticus, with or without altered awareness. Convulsive status epilepticus is a life-threatening emergency that requires immediate treatment. Traditionally, convulsive status epilepticus was defined as more than 30 minutes of either (1) continuous seizure activity or (2) two or more sequential seizures without full recovery of consciousness between seizures.


Pharmacology_Katzung

Pharmacology_Katzung. Because persistent seizure activity is believed to cause permanent neuronal injury and because the majority of seizures terminate in 2 to 3 minutes, it is now generally accepted that treatment should be begun when the seizure duration reaches 5 minutes for generalized tonic-clonic seizures and 10 minutes for focal seizures with or without impairment of consciousness. It is noteworthy that convulsive status epilepticus may evolve to nonconvulsive status epilepticus.


Pharmacology_Katzung

Pharmacology_Katzung. The initial treatment of choice is a benzodiazepine, either intravenous lorazepam or diazepam, although there is evidence that intramuscular midazolam may be equally effective. Lorazepam is less lipophilic than diazepam (logP values of 2.4 and 2.8, respectively) and does not undergo as rapid redistribution from brain to peripheral tissues as does diazepam. Clinically effective diazepam concentrations in the brain following an intravenous bolus fall rapidly as the drug exits the central compartment into peripheral fat. Lorazepam has less extensive peripheral tissue uptake, allowing clinically effective concentrations to remain in the central compartment for much longer. Although lorazepam is now used more frequently than diazepam because of the perceived pharmacokinetic advantage, recent appraisals of the clinical data have not found evidence to favor lorazepam. In the prehospital setting, rectal diazepam, intranasal midazolam, or buccal midazolam are acceptable alternative first


Pharmacology_Katzung

Pharmacology_Katzung. appraisals of the clinical data have not found evidence to favor lorazepam. In the prehospital setting, rectal diazepam, intranasal midazolam, or buccal midazolam are acceptable alternative first treatments if the preferred options are not available. If seizures continue, a second therapy is administered. Intravenous fosphenytoin or phenytoin is most common in the USA, although there is no evidence that these choices are superior to intravenous valproate or levetiracetam. Phenobarbital is also an acceptable second therapy, but it has a long half-life causing persistent side effects including severe sedation, respiratory depression, and hypotension. Lacosamide is available in an intravenous formulation, but there is little published experience to assess its efficacy. If the second therapy fails to stop the seizures, an additional second-line agent is often tried. Refractory status epilepticus occurs when seizures continue or recur at least 30 minutes after treatment with first and


Pharmacology_Katzung

Pharmacology_Katzung. fails to stop the seizures, an additional second-line agent is often tried. Refractory status epilepticus occurs when seizures continue or recur at least 30 minutes after treatment with first and second therapy agents. Refractory status epilepticus is treated with anesthetic doses of pentobarbital, propofol, midazolam, or thiopental. Case reports indicate that ketamine may be effective. If status epilepticus continues or recurs 24 hours or more after the onset of anesthesia, the condition is considered super-refractory. Often, super-refractory status epilepticus is recognized when anesthetics are withdrawn and seizures recur. There are no established therapies for super-refractory status epilepticus other than to reinstitute general anesthesia.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment of focal status epilepticus is similar to therapy for convulsive status epilepticus, although in some cases simply instituting oral antiseizure drug therapy is sufficient. Focal status epilepticus must be distinguished from absence status epilepticus, which is a prolonged, generalized absence seizure that usually lasts for hours or even days. Absence status epilepticus can often be effectively treated with a benzodiazepine followed by intravenous valproate or oral or nasogastric ethosuximide. Absence status epilepticus can occur when an inappropriate antiseizure drug, such as tiagabine or carbamazepine, is used in a patient with idiopathic generalized epilepsy.


Pharmacology_Katzung

Pharmacology_Katzung. Acute repetitive seizures, also referred to as seizure clusters, are groups of seizures that occur more frequently than the patient’s habitual frequency. The clusters can occur rapidly over several minutes, or they may occur over a longer time period of 1 or 2 days. In acute repetitive seizures, there is complete recovery between seizures so that patients do not meet the definition of status epilepticus. However, the condition is concerning nevertheless because, in the absence of treatment, prolonged seizures or status epilepticus can occur. Acute repetitive seizures can be treated in the emergency department with intravenous benzodiazepines or other antiseizure drugs. In the USA, diazepam rectal gel is the only approved treatment for out-of-hospital treatment of acute repetitive seizures. Outside the USA, rectal paraldehyde is sometimes used. Administering rectal medications can be difficult, time consuming, and an embarrassing experience for the patient and caregivers; such products


Pharmacology_Katzung

Pharmacology_Katzung. Outside the USA, rectal paraldehyde is sometimes used. Administering rectal medications can be difficult, time consuming, and an embarrassing experience for the patient and caregivers; such products are generally limited to use in children because of the social stigma and the mechanical difficulties of positioning adults. Buccal (oromucosal) midazolam, in which the treatment solution is administered to the buccal mucosa using an oral syringe, is commonly used in Europe and elsewhere in the world. Intranasal midazolam, diazepam, and lorazepam have also been shown to be efficacious; these drugs are not approved for this route of administration in the USA, but some clinicians use intranasal midazolam or oral benzodiazepines on an off-label basis.


Pharmacology_Katzung

Pharmacology_Katzung. Most women with epilepsy who become pregnant require continued antiseizure drug therapy for seizure control. No antiseizure drug is known to be completely safe for the developing fetus.


Pharmacology_Katzung

Pharmacology_Katzung. Valproate is a known human teratogen. First-trimester exposure is associated with an approximately three-fold increased risk of major congenital malformations, most commonly spina bifida (absolute risk, 6–9%). Phenobarbital use during pregnancy is also associated with an elevated risk of major congenital malformation, most often cardiac defects. First-trimester in utero exposure to topiramate is associated with an approximately 10-fold increase in oral clefts risk (absolute risk, 1.4%). If possible, valproate, phenobarbital, and topiramate should be avoided in women of childbearing potential, and if the drugs cannot be eliminated, they should be used at the lowest dose possible because the risk, at least for valproate, has been shown to be dose-dependent. Other antiseizure drugs may present a lower risk of major congenital malformations (or the risk is poorly understood), but the risk for most drugs, including carbamazepine, phenytoin, and levetiracetam is not zero. In addition to


Pharmacology_Katzung

Pharmacology_Katzung. a lower risk of major congenital malformations (or the risk is poorly understood), but the risk for most drugs, including carbamazepine, phenytoin, and levetiracetam is not zero. In addition to congenital malformations, there is evidence that first-trimester exposure is associated with cognitive impairment. In particular, fetal exposure to valproate is associated with a dose-dependent reduction in cognitive abilities across a range of domains including IQ. Fetal exposure to lamotrigine or levetiracetam may be safer with regard to cognition than other antiseizure drugs, and these two agents also have the lowest risks of major congenital malformations. Polytherapy may increase the risk of neurodevelopmental deficits, particularly when one of the drugs is valproate. In addition, there is evidence that valproate exposure may be associated with an increased risk of autism spectrum disorder.


Pharmacology_Katzung

Pharmacology_Katzung. Some antiepileptic drugs such as primidone, levetiracetam, gabapentin, lamotrigine, and topiramate penetrate into breast milk in relatively high concentrations. For example, in one study, plasma concentrations of lamotrigine in breastfeeding infants were 18.3% of maternal plasma concentrations. Other antiseizure drugs that are highly protein bound, such as valproate, phenobarbital, phenytoin, and carbamazepine, do not penetrate into breast milk substantially. Case series have not reported adverse effects on the newborn of antiseizure drug exposure via breast milk, although there are some reports of sedation with the barbiturates and benzodiazepines. As a general rule, breastfeeding should not be discouraged given the lack of evidence of harm and the known positive benefits.


Pharmacology_Katzung

Pharmacology_Katzung. An analysis of suicidal behavior during clinical trials of antiseizure drugs was carried out by the US Food and Drug Administration in 2008. The presence of either suicidal behavior or suicidal ideation was 0.37% in patients taking active drugs and 0.24% in patients taking placebo. This led to an alert of an increased risk of suicide in people taking antiseizure drugs. Following the report, several studies have addressed the issue in various ways but have not provided convincing data that, as a class, antiseizure drugs induce suicide-related behaviors. Some data suggest a possible association of lamotrigine, levetiracetam, and topiramate with suicidality, but further research is needed. Patients treated with antiseizure drugs and their families should be informed of the risk of suicidality.


Pharmacology_Katzung

Pharmacology_Katzung. Antiseizure drugs may not need to be taken indefinitely. Children who are seizure free for periods longer than 2–4 years while on antiseizure medications will remain so when medications are withdrawn in 70% of cases. The risk of recurrence depends on the seizure syndrome. Resolution of seizures is common for generalized absence epilepsy but not for juvenile myoclonic epilepsy. Other risk factors for recurrence are an abnormal EEG, the presence of neurologic deficits, or when seizure control had been difficult to achieve. There is little information on antiseizure drug withdrawal in seizure-free adults. Withdrawal is believed to be more likely to be successful in patients with generalized epilepsies who exhibit a single seizure type, whereas longer duration of epilepsy, an abnormal neurologic examination, an abnormal EEG, and certain epilepsy syndromes, including juvenile myoclonic epilepsy, are associated with increased risk of recurrence. Drugs are generally withdrawn slowly over a


Pharmacology_Katzung

Pharmacology_Katzung. examination, an abnormal EEG, and certain epilepsy syndromes, including juvenile myoclonic epilepsy, are associated with increased risk of recurrence. Drugs are generally withdrawn slowly over a 1to 3-month period or longer. Abrupt cessation may be associated with return of seizures and even a risk of status epilepticus. Some drugs are more easily withdrawn than others. Physical dependence occurs with barbiturates and benzodiazepines, and there is a well-recognized risk of rebound seizures with abrupt withdrawal.


Pharmacology_Katzung

Pharmacology_Katzung. Several potential new antiseizure drugs are in late clinical development; these are Staccato (thermal aerosol inhaled) alprazolam, for acute repetitive seizures; intranasal midazolam, for acute repetitive seizures; allopregnanolone, for status epilepticus; ganaxolone, for status epilepticus and rare epilepsy syndromes; cannabidiol, for epileptic encephalopathies and focal seizures; cannabidivarin, for focal seizures; cenobamate (YKP3089), for focal seizures; fenfluramine, for Dravet’s syndrome; and stiripentol, for Dravet’s syndrome. Other drugs are in earlier stages of development; current information can be found on the Epilepsy Foundation website at http://www.epilepsy.com/etp/pipeline_new_therapies. • Oxcarbazepine:


Pharmacology_Katzung

Pharmacology_Katzung. Similar to carbamazepine; 100% bioavailability; 1-2 h t1/2 but active metabolites with t1/2 of 8-12 h; fewer interactions reported acetate: Similar to oxcarbazepine but shown to be effective when given once daily and may be more rapidly converted to the active metabolite • ValproateUnknown Nearly complete (>90%) absorption •peaklevelsformulationdependent•highly(90%)boundtoplasmaproteins•extensivelymetabolizedinliver•t1/2 5–16 h Generalized tonic-clonic seizures, partial seizures, absence seizures, myoclonic seizures, other generalized seizure; migraine prophylaxis Toxicity: Nausea, tremor, weight gain, hair loss,teratogenic,hepatotoxic•Interactions: Phenobarbital, phenytoin, carbamazepine, lamotrigine, felbamate, rifampin, ethosuximide, primidone • LevetiracetamSV2A ligand Nearly complete (~95%) absorption •peaklevelsin1–2h•notboundtoplasmaproteins•minimalmetabolismin blood to inactive metabolite; ~66% excreted unchanged in urine •t1/2 6–11 h Focal seizures, generalized tonic-clonic


Pharmacology_Katzung

Pharmacology_Katzung. (~95%) absorption •peaklevelsin1–2h•notboundtoplasmaproteins•minimalmetabolismin blood to inactive metabolite; ~66% excreted unchanged in urine •t1/2 6–11 h Focal seizures, generalized tonic-clonic seizures, myoclonic seizures Toxicity: Nervousness, dizziness, depression, seizures•Interactions: Rare Brivaracetam: Similar to levetiracetam but interaction with carbamazepine • Lorazepam: Similar to diazepam absorption • peak concentrations in 1–1.5 h • IV for status epilepticus • highly (95–98%) bound to plasma proteins • extensively metabolized to several active metabolites • t1/2 of active metabolite N-desmethyldiazepam up to 100 h


Pharmacology_Katzung

Pharmacology_Katzung. Bioavailability >80% • peak concentrations in 1–4 h • highly (86%) bound to plasma proteins • extensively metabolized in liver; no active metabolites • t1/2 12–56 h Status epilepticus, seizure clusters; sedation, anxiety, muscle relaxation (muscle spasms, spasticity), acute alcohol withdrawal Absence seizures, myoclonic seizures, infantile spasms Toxicity: Sedation • Interactions: Additive with sedative-hypnotics Toxicity: Similar to diazepam • Interactions: Additive with sedative-hypnotics • Clobazam: Indications include absence seizures, myoclonic seizures, infantile spasms


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS Carbamazepine forms Carbamazepine Generic, Tegretol Carbamazepine injection Carnexiv Clobazam Onfi Clonazepam Generic, Klonopin Clorazepate dipotassium Generic, Tranxene Diazepam forms Diazepam Generic, Valium, others Diazepam rectal gel Diastat Acudial Eslicarbazepine acetate Aptiom, Stedesa Ethosuximide Generic, Zarontin Ethotoin Peganone Felbamate Generic, Felbatol Fosphenytoin Generic, Cerebyx Gabapentin Generic, Neurontin, Gralise Gabapentin enacarbil Horizant Lacosamide forms Lacosamide Vimpat Lacosamide injection Vimpat injection Lamotrigine forms Lamotrigine Generic, Lamictal Lamotrigine extended release Generic, Lamictal XR Levetiracetam Generic, Keppra, Spritam Lorazepam Generic, Ativan Mephenytoin Mesantoin (discontinued in United States) Methsuximide Celontin Oxcarbazepine Generic, Trileptal, Oxtellar XR Pentobarbital sodium Generic, Nembutal Sodium Perampanel Fycompa Phenobarbital Generic, Luminal Sodium, others


Pharmacology_Katzung

Pharmacology_Katzung. in United States) Methsuximide Celontin Oxcarbazepine Generic, Trileptal, Oxtellar XR Pentobarbital sodium Generic, Nembutal Sodium Perampanel Fycompa Phenobarbital Generic, Luminal Sodium, others Phenytoin Phenytoin, Dilantin, others Pregabalin Lyrica Primidone Generic, Mysoline Retigabine (ezogabine) Potiga, Trobalt Rufinamide Banzel Stiripentol Diacomit Tiagabine Generic, Gabitril Topiramate forms Topiramate Generic, Topamax Topiramate extended release Trokendi XR, Qudexy XR Trimethadione Tridione Valproate/valproic acid forms Valproic acid Generic, Depakene Divalproex sodium delayed release Generic, Depakote Divalproex sodium extended release Depakote ER Valproate sodium injection Generic, Depacon Vigabatrin Sabril Zonisamide Generic, Zonegran PREPARATIONS AVAILABLE


Pharmacology_Katzung

Pharmacology_Katzung. Ettinger AB, Argoff CE: Use of antiepileptic drugs for non-epileptic conditions: Psychiatric disorders and chronic pain. Neurotherapeutics 2007;4:75. French JA et al: Development of new treatment approaches for epilepsy: Unmet needs and opportunities. Epilepsia 2013;54(Suppl 4):3. Glauser TA et al: Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 2010;362:790. Glauser TA et al: Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr 2016;16:48. Grover EH, Nazzal Y, Hirsch LJ: Treatment of convulsive status epilepticus. Curr Treat Options Neurol 2016;18:11. Haut SR: Seizure clusters: Characteristics and treatment. Curr Opin Neurol 2015;28:143.


Pharmacology_Katzung

Pharmacology_Katzung. Haut SR: Seizure clusters: Characteristics and treatment. Curr Opin Neurol 2015;28:143. Kaminski RM et al: SV2A is a broad-spectrum anticonvulsant target: Functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology 2008;54:715. Löscher W et al: Synaptic vesicle glycoprotein 2A ligands in the treatment of epilepsy and beyond. CNS Drugs 2016;30:1055. Meldrum BS, Rogawski MA: Molecular targets for antiepileptic drug development. Neurotherapeutics 2007;4:18. Patsalos P: Antiepileptic Drug Interactions. A Clinical Guide. Springer International Publishing, 2016. Patsalos PN: Drug interactions with the newer antiepileptic drugs (AEDs)—Part 1: Pharmacokinetic and pharmacodynamic interactions between AEDs. Clin Pharmacokinet 2013;52:927.


Pharmacology_Katzung

Pharmacology_Katzung. Patsalos PN: Drug interactions with the newer antiepileptic drugs (AEDs)—Part 1: Pharmacokinetic and pharmacodynamic interactions between AEDs. Clin Pharmacokinet 2013;52:927. Porter RJ et al: AED mechanisms and principles of drug treatment. In: Stefan H, Theodore W (editors): Handbook of Clinical Neurology, 3rd series, Epilepsies Part 2: Treatment. Elsevier, 2012. Porter RJ et al: Clinical development of drugs for epilepsy: A review of approaches in the United States and Europe. Epilepsy Res 2010;89:163. Rogawski MA et al: Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res 2015;110:189. Rogawski MA, Hanada T: Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand 2013;127 (Suppl 197):19. Rogawski MA, Löscher W, Rho JM: Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med 2016;6:a022780.


Pharmacology_Katzung

Pharmacology_Katzung. Rogawski MA, Löscher W, Rho JM: Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med 2016;6:a022780. Steinhof BJ et al: Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: A pooled analysis of three phase III studies. Epilepsia 2013;54:1481. Vélez-Ruiz NJ, Pennell PB: Issues for women with epilepsy. Neurol Clin 2016;34:411. Wilcox KS et al: Issues related to development of new anti-seizure treatments. Epilepsia 2013;54(Suppl 4):24. Xie X et al: Electrophysiological and pharmacological properties of the human brain type IIA Na+ channel expressed in a stable mammalian cell line. Pflugers Arch 2001;441:425. Xie X, Hagan RM: Cellular and molecular actions of lamotrigine: Possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998;38:119.


Pharmacology_Katzung

Pharmacology_Katzung. Xie X, Hagan RM: Cellular and molecular actions of lamotrigine: Possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998;38:119. Lamotrigine was gradually added to the regimen to a dosage of 200 mg bid. Since then, the patient has been seizure-free for almost 2 years but now comes to the office for a medi-cation review. Gradual discontinuation of levetiracetam is planned if the patient continues to do well for another year, although risk of recurrent seizures is always present when medications are withdrawn. Helge Eilers, MD, & Spencer Yost, MD


Pharmacology_Katzung

Pharmacology_Katzung. Helge Eilers, MD, & Spencer Yost, MD An elderly man with type 2 diabetes mellitus and ischemic pain in the lower extremity is scheduled for femoral-to-popliteal artery bypass surgery. He has a history of hyper-tension and coronary artery disease with symptoms of stable angina. He can walk only half a block before pain in his legs forces him to stop. He has a 50-pack-year smoking history but stopped 2 years ago. Medications include atenolol, atorvastatin, and hydrochlorothiazide. The nurse in the preoperative holding area obtains the following vital signs: temperature 36.8°C (98.2°F), blood pressure 168/100 mm Hg, heart rate 78 bpm, oxygen saturation by pulse oximeter 96% while breathing room air, and pain 5/10 in the right lower leg after walking into the hospital. What anesthetic agents will you choose for his anesthetic plan? Why? Does the choice of anesthetic make a difference?


Pharmacology_Katzung

Pharmacology_Katzung. For centuries, humans relied on natural medicines and physical methods to control surgical pain. Historical texts describe the sedative effects of cannabis, henbane, mandrake, and opium poppy. Physical methods such as cold, nerve compression, carotid artery occlusion, and cerebral concussion were also employed, with variable effect. Although surgery was performed under ether anesthesia as early as 1842, the first public demonstration of surgical general anesthesia in 1846 is generally accepted as the start of the modern era of anesthesia. For the first time, physicians had a reliable means to keep their patients from experiencing pain during surgical procedures.


Pharmacology_Katzung

Pharmacology_Katzung. The neurophysiologic state produced by general anesthetics is characterized by five primary effects: unconsciousness, amnesia, analgesia, inhibition of autonomic reflexes, and skeletal muscle relaxation. None of the currently available anesthetic agents when used alone can achieve all five of these desired effects well. An ideal anesthetic drug should also induce rapid, smooth loss of consciousness, be rapidly reversible upon discontinuation, and possess a wide margin of safety.


Pharmacology_Katzung

Pharmacology_Katzung. The modern practice of anesthesiology relies on the use of combinations of intravenous and inhaled drugs (balanced anesthesia techniques) to take advantage of the favorable properties of each agent while minimizing their adverse effects. The choice of anesthetic technique is determined by the type of diagnostic, therapeutic, or surgical intervention that the patient needs. For minor superficial surgery or invasive diagnostic procedures, oral or parenteral sedatives can be combined with local anesthetics in a technique termed monitored anesthesia care (MAC) (see Box: Sedation & Monitored Anesthesia Care, and Chapter 26). These techniques provide profound analgesia, with retention of the patient’s ability to maintain a patent airway and to respond to verbal commands. For more invasive surgical procedures, anesthesia may begin with a preoperative benzodiazepine, be induced with an intravenous agent (eg, thiopental or propofol), and be maintained with a combination of inhaled (eg,


Pharmacology_Katzung

Pharmacology_Katzung. surgical procedures, anesthesia may begin with a preoperative benzodiazepine, be induced with an intravenous agent (eg, thiopental or propofol), and be maintained with a combination of inhaled (eg, volatile agents, nitrous oxide) and/or intravenous drugs (eg, propofol, opioid analgesics).


Pharmacology_Katzung

Pharmacology_Katzung. General anesthetics have been in clinical use for more than 170 years, but their mechanism of action remains unknown. Initial research focused on identifying a single biologic site of action for these drugs. In recent years, this “unitary theory” of anesthetic action has been supplanted by a more complex picture of molecular targets located at multiple levels of the central nervous system (CNS). Ongoing research has focused on molecular, cellular, and network effects to identify the mechanism of general anesthesia.


Pharmacology_Katzung

Pharmacology_Katzung. Anesthetics affect neurons at various cellular locations, but the primary focus has been on the synapse. A presynaptic action may alter the release of neurotransmitters, whereas a postsynaptic effect may change the frequency or amplitude of impulses exiting the synapse. The cumulative effect of these actions may produce strengthened inhibition or diminished excitation within key areas of the CNS. Studies on isolated spinal cord tissue have demonstrated that excitatory transmission is impaired more strongly by anesthetics than inhibitory effects are potentiated.


Pharmacology_Katzung

Pharmacology_Katzung. The principal molecular targets of anesthetic action that have been studied are neuronal ion channels that mediate impulse conduction in the CNS. Chloride channels (γ-aminobutyric acid-A [GABAA] and glycine receptors) and potassium channels (K2P, possibly KV, and KATP channels) remain the primary inhibitory ion channels considered legitimate candidates of anesthetic action. Excitatory ion channel targets include those activated by acetylcholine (nicotinic and muscarinic receptors), by glutamate (amino3-hydroxy-5-methyl-4-isoxazol-propionic acid [AMPA], kainate, and N-methyl-d-aspartate [NMDA] receptors), or by serotonin (5-HT2 and 5-HT3 receptors). Figure 25–1 depicts the relation of these inhibitory and excitatory targets of anesthetics within the context of the nerve terminal.


Pharmacology_Katzung

Pharmacology_Katzung. Recently, researchers using powerful new investigational tools such as extended array electroencephalograms and functional magnetic resonance imaging have focused on neural networks within the brain that are altered by general anesthetics (see Box: What Does Anesthesia Represent & Where Does It Work? for more details).


Pharmacology_Katzung

Pharmacology_Katzung. A clear distinction should be made between volatile and gaseous anesthetics, both of which are administered by inhalation. Volatile anesthetics (halothane, enflurane, isoflurane, desflurane, sevoflurane) have low vapor pressures and thus high boiling points so that they are liquids at room temperature (20°C) and sea-level ambient pressure, whereas gaseous anesthetics (nitrous oxide, xenon) have high vapor pressures and low boiling points so that they are in gas form at room temperature. The characteristics of volatile anesthetics make it necessary that they be administered using precision vaporizers. Figure 25–2 shows the chemical structures of important, clinically used, inhaled anesthetics.


Pharmacology_Katzung

Pharmacology_Katzung. Inhaled anesthetics, both volatile and gaseous, are taken up through gas exchange in the alveoli of the lung. Uptake from the alveoli into the blood and distribution and partitioning into the effect compartments within the body are important determinants of the kinetics of these agents. As stated previously, an ideal anesthetic should have a rapid onset (induction) and offset (emergence). To achieve this, the effect site concentration within the CNS (brain and spinal cord) will need to change rapidly. Several factors determine how quickly the CNS concentration changes.


Pharmacology_Katzung

Pharmacology_Katzung. Many diagnostic and minor therapeutic surgical procedures can be performed without general anesthesia using sedation-based anesthetic techniques. In this setting, regional or local anesthesia supplemented with midazolam or propofol and opioid analgesics (or ketamine) may be a more appropriate and safer approach than general anesthesia for superficial surgical procedures. This anesthetic technique is known as monitored anesthesia care, abbreviated as MAC, and should not be confused with the minimal alveolar concentration for the comparison of potencies of inhaled anesthetics (see text and Box: What Does Anesthesia Represent & Where Does It Work?). The technique typically involves premedica-tion with intravenous midazolam to produce anxiolysis, amnesia, and mild sedation, followed by a titrated, variable-rate propofol infusion (to provide moderate to deep levels of sedation). A potent opioid analgesic or ketamine may be added to blunt pain associ-ated with the injection of local


Pharmacology_Katzung

Pharmacology_Katzung. a titrated, variable-rate propofol infusion (to provide moderate to deep levels of sedation). A potent opioid analgesic or ketamine may be added to blunt pain associ-ated with the injection of local anesthesia and the procedure itself. Another approach, used primarily by nonanesthesiologists, is called conscious sedation. This technique produces alleviation of anxiety and pain with less alteration to the level of conscious-ness by using smaller doses of sedative medications. In this state, the patient retains the ability to maintain a patent airway and is responsive to verbal commands. A wide variety of intravenous anesthetic drugs can be used in conscious sedation (eg, diaz-epam, midazolam, propofol). Use of benzodiazepines and opioid analgesics (eg, fentanyl) in conscious sedation protocols has the advantage of being reversible by the specific receptor antagonist drugs (flumazenil and naloxone, respectively). MAC or conscious sedation can be used to supplement regional anesthesia


Pharmacology_Katzung

Pharmacology_Katzung. has the advantage of being reversible by the specific receptor antagonist drugs (flumazenil and naloxone, respectively). MAC or conscious sedation can be used to supplement regional anesthesia techniques such as peripheral nerve blocks or neuraxial anesthesia. A specialized form of sedation is occasionally required in the intensive care unit (ICU), when patients are under severe stress and require mechanical ventilation for prolonged periods. In this situation, sedative-hypnotic drugs and low doses of intra-venous anesthetics may be combined. Recently, dexmedetomi-dine has become a popular choice for this indication. Deep sedation is similar to a light state of general anesthe-sia characterized by decreased consciousness from which the patient is not easily aroused. The transition from deep sedation to general anesthesia is fluid and can be difficult to define. Because deep sedation is accompanied by loss of verbal respon-siveness, protective airway reflexes, and the ability to


Pharmacology_Katzung

Pharmacology_Katzung. deep sedation to general anesthesia is fluid and can be difficult to define. Because deep sedation is accompanied by loss of verbal respon-siveness, protective airway reflexes, and the ability to maintain a patent airway, this state may be indistinguishable from general anesthesia. A practitioner with expertise in airway management (anesthesiologist or nurse anesthetist) must be present. Intravenous agents used in deep sedation protocols mainly include the sedative-hypnotics propofol and midazolam, some-times in combination with potent opioid analgesics or ketamine, depending on the level of pain associated with the surgery or procedure.