Phenothiazine adverse effects

These antihistamines infreguently cause typical phenothiazine adverse effects. See the Antipsychotic Agents monograph for a complete discussion. 

Neuroleptic activity profiles. The marked differences in action spectra of the phenothiazines, their derivatives and analogues, which may partially resemble those of butyrophenones, are important in determining therapeutic uses of neuroleptics. Relevant parameters include antipsychotic efficacy (symbolized by the arrow) the extent of sedation and the ability to induce ex-trapyramidal adverse effects. The latter depends on relative differences in antagonism towards dopamine and acetylcholine, respectively (p. 188). Thus, the butyrophenones carry an increased risk of adverse motor reactions because Lullmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and oonditlons of lloense. 

Altered homeostasis in older persons can lead to important and common adverse drug effects the less robust homeostatic milieu may be stressed by drugs, causing adverse effects. Examples include orthostatic hypotension due to antihypertensives and other agents that cause a-adrenergic blockade (e.g. terazosin, doxazosin, tricyclic antidepressants and phenothiazines) in those with barorecep-tor dysfunction. Diuretics can cause hyponatraemia or hypokalaemia in older patients, whereas ACE inhibitors and NSAIDs can cause hyperkalaemia. 

The term behavioral toxicity has been used in the child psychiatry literature to describe the following adverse effects of antipsychotics, particularly low-potency phenothiazines (e.g., chlorpromazine, thioridazine) ... 

When levodopa is given without a peripheral decarboxylase inhibitor, anorexia and nausea and vomiting occur in about 80% of patients. These adverse effects can be minimized by taking the drug in divided doses, with or immediately after meals, and by increasing the total daily dose very slowly antacids taken 30-60 minutes before levodopa may also be beneficial. The vomiting has been attributed to stimulation of the chemoreceptor trigger zone located in the brain stem but outside the blood-brain barrier. Fortunately, tolerance to this emetic effect develops in many patients. Antiemetics such as phenothiazines should be avoided because they reduce the antiparkinsonism effects of levodopa and may exacerbate the disease. 

Reserpine depletes cerebral dopamine by preventing intraneuronal storage (see Chapter 6) it is introduced in low doses (eg, 0.25 mg daily), and the daily dose is then built up gradually (eg, by 0.25 mg every week) until benefit occurs or adverse effects become troublesome. A daily dose of 2-5 mg is often effective in suppressing abnormal movements, but adverse effects may include hypotension, depression, sedation, diarrhea, and nasal congestion. Tetrabenazine (12.5-50 mg orally three times daily) resembles reserpine in depleting cerebral dopamine and has less troublesome adverse effects it is now available in the USA. Treatment with postsynaptic dopamine receptor blockers such as phenothiazines and... 

If these measures fail, clonidine, fluphenazine, clonazepam, or carbamazepine should be tried. The pharmacologic properties of these drugs are discussed elsewhere in this book. Clonidine reduces motor or vocal tics in about 50% of children so treated. It may act by reducing activity in noradrenergic neurons in the locus coeruleus. It is introduced at a dose of 2-3 mcg/kg/d, increasing after 2 weeks to 4 mcg/kg/d and then, if required, to 5 mcg/kg/d. It may cause an initial transient fall in blood pressure. The most common adverse effect is sedation other adverse effects include reduced or excessive salivation and diarrhea. Phenothiazines such as fluphenazine sometimes help the tics, as do dopamine... 

Haloperidol Blockade of D2 receptors >> 5HT2A receptors Some a blockade, but minimal M receptor blockade and much less sedation than the phenothiazines Schizophrenia (alleviates positive symptoms), bipolar disorder (manic phase), Huntington s chorea, Tourette s syndrome Oral and parenteral forms with metabolism-dependent elimination Toxicity Extrapyramidal dysfunction is major adverse effect... 

Dicyclomine (Bentyl) [Anrimuscarinic, GI Anrispasmodic/ Anticholinergic] Uses Functional IBS Action Smooth-muscle relaxant Dose Adults. 20 mg PO qid T to 160 mg/d max or 20 mg EM q6h, 80 mg/d - qid then T to 160 mg/d, max 2 wk Feds. Infants >6 mo 5mg/dose tid-qid Children 10 mg/dose tid-qid Caution [B, -] Contra Infants <6 mo, NAG, MyG, severe UC, BOO Disp Caps, tabs, syrup, inj SE Anticholinergic SEs may limit dose Interactions T Anticholinergic effects W/ anticholinergics, antihistamines, amantadine, MAOIs, TCAs, phenothiazides T effects OF atenolol, digoxin X effects H7 antacids X effects OF haloperidol, ketoconazole, levodopa, phenothiazines EMS Avoid procainamide usage, may T adverse effects may T effects of digoxin, monitor... 

Phenothiazine medications for alcohol withdrawal have potentially serious adverse effects (eg, increasing seizures) that probably outweigh their benefits. Antihistamines have been used but with little justification. 

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. 

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. 

Erythrocyte/plasma lithium concentration ratios were lower in patients taking phenothiazines or haloperidol than in those taking lithium alone (620,621), and the former group had a higher incidence of neurological and renal adverse effects (621). 

High doses of piperazine can enhance the adverse effects of chlorpromazine and other phenothiazines (667). 

NOTE chlorpromazine is the primary phenothiazine known to cause these adverse effects.)... 

All phenothiazines may show antimuscarinic adverse effects. This can include mydriasis and cycloplegia with subsequent decreased... 

Antipsychotics. Phenothiazines, butyrophenones and thioxanthenes are best avoided unless the indications are compelling amounts in milk are small but animal studies suggest adverse effects on the developing nervous system. In particular. 

Cross-reactions between phenothiazine tranquillizers and first-generation antihistamines are possible, as well as reactions between antihistamines and ethylenediamine present in some creams and ointments. As local sensitization is quite common, topical use of antihistamines is not recommended. Despite these disadvantages they are stiU available in many countries as over-the-counter products. Topical antihistamines in sufficient doses can also cause systemic adverse effects. 

Procyclidine is an anticholinergic drug (1). The usual oral dose, which lies between 20 and 30 mg/day, is likely to produce only mild anticholinergic adverse effects, but involuntary movements, with chewing and sucking, have been described in some patients (SEDA-1, 120). Even small doses have produced toxic confusional states when procyclidine was combined with phenothiazines for schizophrenia. Procyclidine is more hkely to produce sedation than stimulation. 

Toxicity. Serious medication-related adverse effects associated with actual or potential damage to tissues, organs, or the entire body system. Toxicity may be directly related to critically elevated blood levels of a drug and may be acute (as in tricyclic antidepressant overdose) or chronic (as in prolonged, moderately elevated lithium level). A drug may also produce "toxic effects" at therapeutic doses (such as phenothiazine s potential for inducing bone marrow damage, which in turn causes decreased production of white blood cells). 

Phenothiazines may decrease the seizure threshold in small animal patients and are contraindicated in dogs and cats with seizure disorders. Although in the horse, seizure disorders are rare (see Ch. 9) and the influence of these drugs on the seizure threshold is unknown, the phenothiazines should be avoided in horses with a history of seizures. Phenothiazines are also contraindicated in animals recently exposed to organophosphate insecticides because of the potential to enhance the toxicity to these drugs (Fernandez et al 1975). In addition, the concomitant administration of phenothiazines and procaine or procaine benzylpenicillin is not advised because of the potential to enhance the adverse effects of procaine (Chapman et al 1992). 

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