McKenna's Pharmacology for Nursing, 2e

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C H A P T E R 2 3 Antiseizure agents

barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists and GABA prodrugs. Lamotrigine and lacosamide may inhibit voltage- sensitive sodium and calcium channels, stabilise nerve cell membranes and modulate calcium-dependent presynaptic release of excitatory neurotransmitters. Levetiracetam is a newer drug, and its mechanism of action is not understood; its antiepileptic action does not seem to be associated with any known mechanisms of inhibitory or excitatory neurotransmission. (See also the Focus on safe medication administration for informa­ tion about potentially serious name confusion that has occurred with levetiracetam.) Oxcarbazepine’s exact mechanism of action is also unknown. It inhibits voltage-sensitive sodium channels, stabilising hyperexcited nerve cell membranes. It also increases potassium conductance and modulates calcium-dependent presynaptic release of excitatory neurotransmitters. Any or all of these effects may be responsible for the antiseizure effects of the drug. Pregabalin has a high binding affinity for voltage- gated calcium channels in the cerebrovascular system. It seems to modulate the calcium function in these neurons, leading to a decreased release of neurotransmitters into the synaptic cleft and a decrease in cell activity. Pre­ gabalin does not show affinity for receptor sites or alter responses associated with the action of several common drugs for treating seizures or pain. Pregabalin does not interact with either GABA-A or GABA-B receptors; it is not converted metabolically into GABA or a GABA agonist; it is not an inhibitor of GABA uptake or degra­ dation. Tiagabine (not available in New Zealand) binds to GABA reuptake receptors, causing an increase in GABA levels in the brain. Because GABA is an inhibi­ tory neurotransmitter, the result is a stabilising of nerve membranes and a decrease in excessive activity. Topiramate is another newer drug that blocks sodium channels in neurons with sustained depolaris­ ation and increases GABA activity, inhibiting nerve activity. Topiramate increases the frequency at which gamma-aminobutyrate (GABA) activates GABA-A receptors, and enhances the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter. This effect is not blocked by fluma­ zenil, a benzodiazepine antagonist, nor does topiramate increase the duration of the channel opening time, which differentiates topiramate from barbiturates that modulate GABA-A receptors. Pharmacokinetics These drugs are all given orally. Levetiracetam is also available for IV use. Carbamazepine is absorbed from the GI tract and metabolised in the liver by the cytochrome P450

system. It is excreted in the urine with a half-life of 25–65 hours. Gabapentin is well absorbed from the GI tract and widely distributed in the body. It is excreted unchanged in the urine with a half-life of 5–7 hours. Lamotrigine and lacosamide are rapidly absorbed from the GI tract, metabolised in the liver and primar­ ily excreted in the urine. The half-life of lamotrigine is approximately 25 hours. Levetiracetam is rapidly absorbed from the GI tract, reaching peak levels in 1 hour. It goes through very little metabolism, with most of the drug being excreted unchanged in the urine with a half-life of 6–8 hours. Oxcarbazepine is completely absorbed from the GI tract and extensively metabolised in the liver. It is excreted in the urine with a half-life of 2 and then 9 hours. Pregabalin is rapidly absorbed orally, reaching peak levels in 1.5 hours. It is not metabolised but is eliminated unchanged in the urine with a half-life of 6.3 hours. Tiagabine is rapidly absorbed from the GI tract, reaching peak levels in 45 minutes. It is metabolised in the liver by the cytochrome P450 system. It is excreted in the urine with a half-life of 4–7 hours. Topiramate is rapidly absorbed from the GI tract, reaching peak levels in 2 hours. It is widely distributed and is excreted unchanged in the urine. Contraindications and cautions Contraindications to the drugs used to control partial seizures include the following conditions: presence of any known allergy to the drug; bone marrow suppres­ sion, which could be exacerbated by the drug effects ; and severe hepatic dysfunction, which could be exacer- bated and could interfere with the metabolism of the drugs. Carbamazepine, gabapentin and oxcarbazine have been shown to be dangerous to a fetus and should not be used during pregnancy. Women of childbearing age should be advised to use contraception. These drugs enter breast milk and can cause serious adverse effects in the baby. If any of these drugs is needed during breast­ feeding, another method of feeding the baby should be used. There are no clear studies about the effects of lamotrigine, levetiracetam, pregabalin, tiagabine or topiramate use during pregnancy and breastfeeding. Therefore, these drugs should not be used during preg­ nancy or breastfeeding unless the benefits to the mother clearly outweigh potential adverse effects in the fetus or neonate. Men considering fathering a child should be advised that, in animal studies, males receiving pregab­ alin had decreased fertility and associated birth defects in offspring. Caution should also be used in the following situ­ ations: with renal or hepatic dysfunction, which could