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C H A P T E R 2 1 Antidepressant agents

Caution should be used with TCAs in people with pre-existing cardiovascular (CV) disorders because of the cardiac stimulatory effects of the drug and with any con- dition that would be exacerbated by the anticholinergic effects , such as angle-closure glaucoma, urinary reten­ tion, prostate hypertrophy, or GI or genitourinary (GU) surgery. Care should also be taken with people with mental health problems, who may exhibit a worsening of psychoses or paranoia , and with manic–depressive people, who may shift to a manic stage. There is a black box warning on all of the TCAs bringing attention to a risk of suicidality, especially in children and adoles­ cents; caution should be used, and the amount of drug dispensed at any given time should be limited with poten­ tially suicidal people. In addition, caution is necessary in people with a history of seizures because the seizure threshold may be decreased secondary to stimulation of the receptor sites and in elderly people. The presence of hepatic or renal disease, which could interfere with metabolism and excretion of these drugs and lead to toxic levels , also necessitates caution and the need for a lower dose of the drug. Adverse effects The adverse effects of TCAs are associated with the effects of the drugs on the central nervous system (CNS) and on the peripheral nervous system. Sedation, sleep dis­ turbances, fatigue, hallucinations, disorientation, visual disturbances, difficulty in concentrating, weakness, ataxia and tremors may occur. Limited quantities of Antidepressant discontinuation syndrome may occur within 5 days of stopping treatment with antidepressant drugs; symptoms are usually mild and self-limiting (lasting for 1–2 weeks), but in some cases may be severe. Tricyclic antidepressants MAO inhibitors and antidepressants with a shorter half-life, such as paroxetine and venlafaxine, are associated with a higher risk of discontinuation symptoms. The risk of discontinuation symptoms is also increased if the antidepressant is stopped suddenly after regular administration for 8 weeks or more. Symptoms can also occur after a reduction in dose or omission of a dose. The dose should preferably be reduced gradually over about 4 weeks (fluoxetine is an exception to this rule due to its long half-life), or longer if discontinuation symptoms emerge (up to 6 months in people who have been on long-term maintenance treatment). Many people will continue to have symptoms despite a slow withdrawal. Antimuscarinic agents may assist with tricyclic antidepressant withdrawal. Source: New Zealand Formulary, www.nzf.org.nz/nzf_2225. html#nzf_2230 ■■ BOX 21.2  Antidepressant discontinuation syndrome

tricyclic antidepressants should be prescribed at any one time because their cardiovascular and epileptogenic effects are dangerous in overdosage. In particular, over­ dosage with dosulepin (dothiepin) and amitriptyline is associated with a relatively high rate of fatality. Use of TCAs may lead to GI anticholinergic effects, such as dry mouth, constipation, nausea, vomiting, anorexia, increased salivation, cramps and diarrhoea. Resultant GU effects may include urinary retention and hesitancy, loss of libido and changes in sexual func­ tioning. CV effects such as orthostatic hypotension, hypertension, arrhythmias, myocardial infarction, angina, palpitations and stroke may also pose problems. Miscellaneous reported effects include alopecia, weight gain or loss, flushing, chills and nasal congestion. These adverse effects may be intolerable to some people, who then stop taking the particular TCA. Abrupt cessation of all TCAs causes a withdrawal syndrome characterised by nausea, headache, vertigo, malaise and nightmares (see Box 21.2). Prototype summary: Imipramine Indications: Relief of symptoms of depression; enuresis in children older than 6 years; off-label consideration—control of chronic pain. Actions: Inhibits presynaptic reuptake of noradrenaline and serotonin; anticholinergic at CNS and peripheral receptors; sedating. Pharmacokinetics: Route Onset Peak Oral Varies 2–4 hours T 1/2 : 8 to 16 hours, metabolised in the liver, excreted in the urine. Adverse effects: sedation, anticholinergic effects, confusion, anxiety, orthostatic hypotension, dry mouth, constipation, urinary retention, rash, bone marrow depression. Clinically important drug–drug interactions If TCAs are given with cimetidine, fluoxetine or raniti­ dine, an increase in TCA levels results, with an increase in both therapeutic and adverse effects, especially anticholinergic conditions. People should be monitored closely, and appropriate dose reductions should be made. Other drug combinations may also pose problems. The combination of TCAs and oral anticoagulants leads to higher serum levels of the anticoagulants and increased risk of bleeding. Blood tests should be done frequently, and appropriate dose adjustments in the oral anticoagulant should be made.