Antipsychotics pharmacodynamics

Medications that have been used as treatment for anxiety and depression in the postwithdrawal state include antidepressants, benzodia2epines and other anxiolytics, antipsychotics, and lithium. In general, the indications for use of these medications in alcoholic patients are similar to those for use in nonalcoholic patients with psychiatric illness. However, following careful differential diagnosis, the choice of medications should take into account the increased potential for adverse effects when the medications are prescribed to alcoholic patients. For example, adverse effects can result from pharmacodynamic interactions with medical disorders commonly present in alcoholic patients, as well as from pharmacokinetic interactions with medications prescribed to treat these disorders (Sullivan and O Connor 2004). 

With respect to other ethnic groups, African Americans may have a differential sensitivity to weight gain on clozapine (de Leon etal, 2007). They may also require lower doses than Caucasians (Kelly et al, 2006) and inter-individual as well as ethnic responsiveness maybe partly explained by differences in dopamine receptor polymorphisms (Hwang et al, 2005). It is conceivable that side effects may also be differentially expressed based on pharmacodynamic differences resulting from polymorphisms in other receptor types (histaminergic, muscarinic, etc.). This area remains largely unexplored with respect to ethnic differences in antipsychotic side effects. 

It is widely held that differences exist in the usage and dosage of antipsychotics among ethnic minority groups. A number of factors are felt to account for these differences and include sociocultural variables (racial bias, cultural divide between patient and physician, language), as well as biological variables (pharmacogenetic, pharmacokinetic, and pharmacodynamic). 

Jeste DV, Lacro JP, Palmer B et al. (1999) Incidence of tardive dyskinesia in early stages of low-dose treatment with typical antipsychotics in older patients. Am I Psychiatry 156(2) 309-311 Klotz U (1998) Effect of age on pharmacokinetics and pharmacodynamics in man. Int I Clin Pharmacol Ther 36(11) 581-585... 

There are some clinically important pharmacodynamic drug-drug interactions to be mentioned. Antipsychotics will potentiate the central depressant effects of sedatives and of alcohol. They will also increase the risk of respiratory-depressant effects of opiates. Inducers of drug metabolic enzymes like for example rifampicin and several antiepileptics, may increase the elimination rate of antipsychotic agents and thus decrease their efficacy. 

Because of their multiple effects, antipsychotic drugs produce more important pharmacodynamic than phar-... 

Numerous drug-drug interactions have been reported with the antipsychotic agents. These may be mediated through pharmacodynamic effects. For example, antipsychotics that block aj-adrenergic receptors may potentiate the antihypertensive effects of prazosin, labetalol, and some other antihypertensive agents. Conversely, antipsychotics associated with a2-adrenergic receptor blockade may interfere with the antihypertensive effects of clonidine and methyldopa (Richelson, 1999). 

In pharmacodynamic interactions, the pharmacological effect of a drug is changed by the action of a second drug at a common receptor or bioactive site. For example, low-potency antipsychotics and tertiary amine TCAs have anticholinergic, antihistaminic, a-adrenergic antagonist, and quinidine-Kke effects. Therefore, concurrent administration of chlorpromazine and imipramine results in additive sedation, constipation, postural hypotension, and depression of cardiac conduction. 

Two different aspects have to be considered in the answer economic and scientific. An economic interest to have a variety of products in the market exists on the part of those pharmaceutical companies that have developed and marketed or are developing antipsychotics. Consequently, their advertising places the emphasis on the special features and advantages of individual medications, even though the differences between many products are not always very relevant clinically. Nevertheless, the differences that actually exist between products with regard to their pharmacokinetic and pharmacodynamic properties are of scientific interest, especially those related to the effects of atypical versus typical antipsychotics ... 

Pharmacodynamics, antipsychotics also differ in their pharmacodynamics, i.e. their pharmacological and clinical profiles of action. A rough distinction is made between highly sedative, hypnotic antipsychotics (e.g. clopenthixol, levomepromazine) and other products with weaker initial sedative action (e.g. fluphenazine and haloperidol). Sedative antipsychotics are prescribed for states of major unrest, often combined with insomnia, whereas the less sedative antipsychotics are preferred for patients suffering from delusions and hallucinations but in whom heavy sedation during daytime is undesirable. 

In a report of 122 elderly patients on risperidone, hypotension was noted in 28.7% and symptomatic orthostatic hypotension was noted in 9.8%. Significant decreases in blood pressure occurred with risperidone treatment (p = 0.0001) and were common in patients with cardiovascular disease and those taking an SSRI or valproate (p = 0.03) (502). Hence, like other antipsychotics, risperidone should be prescribed cautiously for elderly patients and those with preexisting cardiac disease. Its hypotensive versus its orthostatic hypotensive effects may be an age-related pharmacodynamic response. Blood pressure, including orthostatic blood pressure, should be monitored routinely until the risperidone dosage is stabilized. Furthermore, when risperidone therapy is initiated in the elderly, dosage should be titrated from 0.25 to 0.5 mg two times a day with increments of 0.25 to 0.5 mg weekly (92). 

Common pharmacodynamic interactions involve the additive anticholinergic or antidopaminergic effects of antipsychotics. Thus, concomitantly administered antiparkinsonian agents (e.g., benztropine) may increase the chances of toxicity (e.g., delirium) while dopamimetic agents (e.g., levodopa) may counteract the antipsychotic or neurotoxic effects of these agents. 

Table 5-27 and Table 5-28 summarize the clinically relevant pharmacokinetic and pharmacodynamic properties of other novel antipsychotics ( 326). Drug interactions with these agents were not systematically evaluated because controlled clinical trials usually prohibit concurrent medications. There are also many special circumstances (e.g., patients with comorbid medical diseases, substance abuse, epilepsy, or atypical indications such as agitation associated with mental retardation or dementia) that are not usually addressed in clinical research trials. Thus, much remains to be learned about significant drug interactions in these patient groups. To our knowledge, however, no consistent, serious, clinically relevant interactions have been reported. 

Antipsychotics produce more important pharmacodynamic than pharmacokinetic interactions because of their multiple effects. Additive effects may occur when these drugs are combined with others that have sedative effects, a-adrenoceptor-blocking action, anticholinergic effects, and—for thioridazine and ziprasidone—quinidine-like action. 

Drug interactions with lithium have been reviewed (569-573) another review focused on interactions in the elderly (573). A review of drug interactions with lithium considered both pharmacokinetic interactions [for example diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs)] and pharmacodynamic interactions (for example antipsychotic drugs, SSRIs) and summarized the most important ones in tabular form (569). 

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