McKenna's Pharmacology for Nursing, 2e

360

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

Pharmacokinetics Diazepam is available in oral, rectal and parenteral forms. Diazepam has a biphasic elimination curve, the terminal half-life being 1–2 days. It is extensively protein-bound. Diazepam is metabolised in the liver and the following active metabolites are produced: desmethyldiazepam, methyloxazepam, oxazepam and temazepam. The metabolites are then eliminated by the kidneys in either their free or conjugated form. The half-life of diazepam is prolonged in individuals with kidney or liver disease. Diazepam and its active metab­ olites show significant accumulation during multiple dosage regimens. Steady state plasma concentrations are attained in 5 days to 2 weeks, as some of its metabolites take several days to weeks to be eliminated. Clonazepam, on the other hand, is quickly and almost completely absorbed after oral administration. Peak plasma concentrations are reached in most cases within 1–4 hours after an oral dose. The absorption half-life is around 25 minutes. Bioavailability is 90% after oral administration. The mean elimination half-life is 30–40 hours. The elimination half-life and clearance values in neonates are of the same order of magnitude as those reported for adults. Clonazepam is now available in liquid form, making it a good choice for people who have difficulty swallow­ ing capsules or tablets. These agents are well absorbed from the GI tract, metabolised in the liver and excreted in the urine. They have a long half-life of 18–50 hours. Contraindications and cautions Contraindications for benzodiazepines are the same as those discussed for phenytoin. Adverse effects The most common adverse effects associated with benzodiazepines relate to CNS depression and its effects on body function: depression, confusion, drowsiness, lethargy, fatigue, constipation, dry mouth, anorexia, cardiac arrhythmias and changes in blood pressure, urinary retention and loss of libido. Benzodiaze­ pines may be associated with physical dependence and withdrawal syndrome. In infants and young children clonazepam may cause increased production of saliva and bronchial secretions. Therefore special attention must be paid to maintaining patency of the airways. The dosage of clonazepam must be carefully adjusted to individual requirements in people: with pre-existing disease of the respiratory system (e.g. chronic obstruc­ tive pulmonary disease); with pre-existing disease of the liver; undergoing treatment with other centrally acting medications or anticonvulsant (antiepileptic) agents (see Clinincally important drug–drug interactions). Like all medicines of this type, clonazepam may, depending

on dosage, administration and individual susceptibil­ ity, modify the person’s reactions (e.g. driving ability, behaviour in traffic). Clinically important drug–drug interactions Because the risk of CNS depression is increased when benzodiazepines are taken with alcohol, people should be advised not to drink alcohol while they are taking these agents. Always consult a drug reference before any drug is added or withdrawn from a therapeutic regimen that involves any of these agents. Prototype summary: Diazepam Indications: Management of anxiety disorders; acute alcohol withdrawal; muscle relaxant; treatment of tetanus; adjunct in status epilepticus and severe recurrent convulsive seizures; preoperative relief of anxiety and tension; management of epilepsy in people who require intermittent use to control bouts of increased seizure activity. Actions: Acts in the limbic system and reticular formation; potentiates the effects of GABA; has little effect on cortical function. Pharmacokinetics: Route Onset Peak Duration Oral 30–60 mins 1–2 hours 3 hours IM 15–30 mins 30–45 mins 3 hours IV 1–5 mins 30 mins 15–60 mins Rectal Rapid 1.5 hours 3 hours T 1/2 : 20 to 80 hours; metabolised in the liver, excreted in the urine. Adverse effects: Drowsiness, sedation, depression, lethargy, apathy, fatigue, disorientation, bradycardia, tachycardia, paradoxical excitatory reactions, constipation, diarrhoea, incontinence, urinary retention, drug dependence with withdrawal syndrome. S uccinimides The currently available succinimide is ethosuximide ( Zarontin ). Ethosuximide is most frequently used to treat absence seizures, a form of generalised seizure. Therapeutic actions and indications Although the exact mechanism of action is not under­ stood, ethosuximide suppresses the abnormal electrical activity in the brain that is associated with absence seizures. The action may be related to activity in inhib­ itory neural pathways in the brain (see Figure 23.2).