McKenna's Pharmacology for Nursing, 2e

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P A R T 4  Drugs acting on the central and peripheral nervous systems

DRUGS FOR TREATING GENERALISED SEIZURES Drugs typically used to treat generalised seizures stabil­ ise the nerve membranes by blocking channels in the cell membrane or altering receptor sites. Because they work generally on the CNS, sedation and other CNS effects often result. Various drugs are used to treat gen­ eralised seizures, including hydantoins, barbiturates, barbiturate-like drugs, benzodiazepines and succini­ mides. These drugs affect the entire brain and reduce the chance of sudden electrical outburst. Associated adverse effects are often related to total brain stabilisa­ tion (Figure 23.2). Absence seizures, another type of generalised seizure, may require drugs that are different from those used to treat or prevent other types of generalised

seizures. The succinimides and drugs that modulate the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are most frequently used (see Table 23.2). H ydantoins The currently available hydantoin in Australia and New Zealand is phenytoin ( Dilantin ). Because hydantoins are generally less sedating than many other antiepileptics, phenytoin may be the drug of choice for people who are not willing to tolerate sedation and drowsiness. It does have significant adverse effects; thus, less toxic drugs, such as benzodiazepines, have replaced it in many situations. Therapeutic actions and indications Phenytoin stabilises nerve membranes throughout the CNS directly by influencing ionic channels in the cell membrane, thereby decreasing excitability and hyper­ excitability to stimulation. By decreasing conduction through nerve pathways, it reduces the tonic–clonic, muscular and emotional responses to stimulation. See Table 23.2 for usual indications. Pharmacokinetics Phenytoin is well absorbed from the GI tract, metabo­ lised in the liver and excreted in the urine. Therapeutic serum phenytoin levels range from 10 to 20 mcg/mL. In general the reported plasma half-life of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady state therapeutic levels are achieved at least 7 to 10 days (5 to 7 half-lives) after initiation of therapy with rec­ ommended doses of 300 mg/day. Conventionally, with drugs following linear kinetics the half-life is used to determine the dose rate, drug accumulation and the time to reach steady state. Phenytoin, however, demonstrates non-linear kinetics and therefore the half-life is affected by the degree of absorption, saturation of metabolic pathways, dose and the degree of metabolic enzyme induction. This results in considerable inter- and intra-in­ dividual variability in phenytoin pharmacokinetics. As phenytoin is highly protein bound, free phenytoin levels may be altered in people whose protein binding characteristics differ from normal. Protein binding may be lower in neonates and hyperbilirubinaemic infants; it may also be altered in people with hypoalbuminaemia, uraemia or acute trauma and in pregnancy. Phenytoin is available in oral (also available in paediatric formulation e.g. syrup) and parenteral forms.

Barbiturates depress conduction in brainstem and cortex Cortex

Limbic system

RAS

Zolpidem affects serotonin levels in RAS

Cerebellum

Mechanisms not understood: levetiracetam

Acetazolamide, zonisamide alter Na + and Ca + channels

Sodiumvalproate GABA effects, and decreases electrical activity Benzodiazepines GABA effects, to inhibit neuron firing Hydantoins stabilise nerve membranes Cell firing inhibited, leading to stabilisation

GABA

Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine and topiramate increase GABA activity and block Na + and Ca + channels to stop APs

FIGURE 23.2  Sites of action of drugs used to treat various types of epilepsy. AP, action potential; GABA, gamma-aminobutyric acid; RAS, reticular activating system.