Neuroleptic drugs adverse effects

Neuroleptic-like malignant syndrome is a serious but very rare adverse effect of some drugs, of e.g., neuroleptics, some anaesthetics and apparently tolca-pone. Symptoms include hyperthermia, muscle deterioration, even dissolution. 

Clozapine and olanzapine are atypical antipsychotic drugs used in the treatment of schizophrenia. Their strnctnres are depicted in Scheme 2.36. The use of clozapine and olanzapine, which are more effective than standard neuroleptic drugs in the treatment of refractory schizophrenia, is, however, limited becanse of their adverse effects. These adverse effects are ascribed to the formation of the corresponding cation-radicals in living organisms under oxidation by bone marrow cells. These cation-radicals eliminate protons from the NH fragments and generate their nitrenium cations. The nitreninm cations are covalently bonnd to the life-important proteins. This results in the toxic effects of clozapine and olanzapine (Sikora et al. 2007). 

Adverse effects of the TCAs on the brain include confusion, impaired memory and cognition and occasionally delirium some of these effects have been reported to occur in up to 30% of patients over the age of 50. These effects may occasionally be confused with a recurrence of the s)nnptoms of depression and are probably due to the central antimuscarinic activity of these drugs. Tremor also occurs frequently, particularly in the elderly, and may be controlled by the concurrent administration of propranolol. Neuroleptics are normally not recommended to be used in combination with TCAs as they are liable to accentuate the side effects of the latter drugs. The risk of seizures, and the switch from depression to mania in bipolar patients, has also been reported following TCA administration. 

Despite the widespread use of neuroleptics in maintenance treatment of bipolar disorder, there have not been any systematic studies of their suitability for this role. Through clinical experience it has been widely accepted that neuroleptics are useful adjunctive treatments to lithium and related drugs. Treatment refractory patients frequently respond to atypical antipsychotics such as clozapine or risperidone. Such adverse effects as EPS, cognitive dysfunction and weight gain frequently limit the long-term use of classical neuroleptics. For this reason, the atypical neuroleptics such as olanzapine and risperidone should now be considered as alternatives for maintenance treatment. 

In anesthesia drugs from several groups are used as premedication. Pre-anesthetic medication can decrease the anesthetic doses which otherwise would be required to induce anesthesia and so decrease the risk for adverse effects. Pre-anesthetic medication will increase the rate of induction of anesthesia and can reduce pre-operative pain and anxiety. Drugs include benzodiazepines for sedation and their muscle relaxant properties, opiates for pain relieve and anticholinergics or histamine Hi receptor antagonists against nausea and vomiting. Neuroleptics are also used as premedication for their antiemetic effects. 

A rare, but potentially fatal idiosyncratic adverse effect is neuroleptic malignant syndrome. This can occur with any antipsychotic drug. The symptoms are rigidity, hyperthermia, autonomic lability, and reduced level of consciousness. Massively elevated levels of creatinine kinase are usually found. Prior to 1984, the mortality rate was around 25% but improved early recognition has considerably reduced this. Management is cessation of antipsychotics, appropriate conservative measures and dantrolene if necessary for muscle rigidity. 

A further reminder of the structural resemblance of amoxapine to the neuroleptic drugs has been provided by an adverse effect reported with both amoxapine and its close congener, loxapine (87). 

The effects of neuroleptic drugs on menstrual status and the relation between menstrual status and neuroleptic drug efficacy and adverse effects have been explored (744). In contrast to prior reports (SEDA-18, 50), there was not a high prevalence of menstrual irregularities or amenorrhea in 27 premenopausal women with chronic schizophrenia treated with typical neuroleptic drugs. 

In 48 patients with schizophrenia taking clozapine, olanzapine, risperidone, or typical neuroleptic drugs, and 31 untreated healthy control subjects newer neuroleptic drugs, such as clozapine and olanzapine, compared with typical agents, were associated with adverse effects on blood glucose regulation (774). 

Weight gain related to the use of atypical neuroleptic drugs in children and adolescents, in whom this adverse effect is of particular concern, has been reviewed (804). The published data suggest that clozapine and olanzapine... 

Two women with neuroleptic-drug induced hyperprolactinemia, menstrual dysfunction, and galactorrhea had improvement in these adverse effects during treatment with olanzapine (855). 

Sertindole. This is structurally unique among the atypical neuroleptics in that it is an indole derivative with a high affinity for 5-HT2A, D2-like (Dj, D3, D4) and also alpha-1 receptors. The antagonistic action on the 5-HT2 receptors probably accounts for its beneficial effects on negative symptoms. Sertindole was suspended from marketing a few years ago because of the rare occurrence of cardiac conduction defects. As the causal relationship of this adverse effect to the drug was never firmly established it is likely to be relaunched in the near future. 

In CONCLUSION, the use of the "classical" neuroleptics, as exemplified by the phenothiazines, thioxanthines, butyrophenones and diphenylbutyl-piperidines, has been a landmark in the pharmacotherapy of schizophrenia and psychotic disorders. The efficacy of such drugs in the alleviation of the symptoms of schizophrenia is universally accepted. However, it is also evident that they have a spectrum of adverse effects that frequently renders their long-term use problematic. Side effects such as akathisia, Parkinsonism, tardive dyskinesia and the all too frequent changes in peripheral autonomic activity are largely predictable from the structure of the molecules and the basic animal pharmacology data. Such adverse effects, and the difficulties encountered when attempting to reduce their frequency and severity by concurrent medication, has stimulated the development of "atypical" neuroleptics such as clozapine and risperidone which, hopefully, will combine efficacy with a reduction in side effects. 

Mania can occur in any age group. Acute manic episodes in the elderly may best be managed with high potency neuroleptics. The use of lithium is not contraindicated in the elderly provided renal clearance is reasonably normal. The dose administered should be carefully monitored, as the half-life of the drug is increased in the elderly to 36-48 hours in comparison to about 24 hours in the young adult. The serum lithium concentration in the elderly should be maintained at about 0.5 mEq/litre. It is essential to ensure that the elderly patient is not on a salt-restricted diet before starting lithium therapy. The side effects and toxicity of lithium have been discussed in detail elsewhere (see p. 198 et seq.), and, apart from an increase in the frequency of confusional states in the elderly patient, the same adverse effects can be expected as in the younger patient. 

Multiple sites in the CNS are affected by LSD. The drug shows serotonin (5-HT) agonist activity at presynaptic receptors in the midbrain, binding to both 5-HT and 5-HT2 receptors. Activation of the sympathetic nervous system occurs, which causes pupillary dilation, increased blood pressure, piloerection, and increased body temperature. Taken orally, low doses of LSD can induce hallucinations with brilliant colors, and mood alteration occurs. Tolerance and physical dependence have occurred, but true dependence is rare. Adverse effects include hyperreflexia, nausea, and muscular weakness. Sometimes high doses produce long-lasting psychotic changes in susceptible individuals. Haloperidol (see p. 127) and other neuroleptics can block the hallucinatory action of LSD and quickly abort the syndrome. 

Adverse effects commonly observed in individuals treated with neuroleptic drugs. 

Adverse effects of the neuroleptic drugs occur in practically all patients and are significant in about 80% (Figure 13.5). Although antipsychotic drugs have an array of adverse effects, their therapeutic index is high. 

Adverse effects Large doses of meperidine cause tremors, muscle twitches, and rarely, convulsions. The drug differs from opioids in that in large doses it dilates the pupil and causes hyperactive reflexes. Severe hypotension can occur when the drug is administered postoperatively. When used with major neuroleptics, depression is greatly enhanced. Administration to patients taking monoamine oxidase inhibitors (see p. 123) can provoke severe reactions such as convulsions and hyperthermia. Meperidine can cause dependence, and can substitute for morphine or heroin in use by addicts. Cross-tolerance with the other opioids occurs. 

More than a dozen drugs, almost all of them in use for many years, can be classified as neuroleptics. The phenothiazine derivatives were originally the most commonly used class of neuroleptic drugs. Chlorproma-zine is the prototype, developed in France and introduced into North America in 1953 by Heinz Lehmann. Its brand name in Canada and England is Largactil, and in the United tates, Thorazine. The antidepressant amoxapine (Asendin) is metabolized into a neuroleptic and has similar effects and, more important, adverse effects, such as tardive dyskinesia. All the classic neuroleptics block dopamine, but all of them also affect other neurotransmitter systems. 

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