Antipsychotics specific agents

Tertiary-amine muscarinic receptor antagonists gain access to the central nervous system and are therefore the anticholinergic drugs used to treat parkinsonism and the extrapyramidal side effects of antipsychotic drugs. Specific agents used primarily for these conditions include benztropine mesylate (Cogentin) and trihexyphenidyl hydrochloride (Artane, others). 

The steady-state concentrations of antipsychotic drugs after multiple dosing have been measured to establish a relationship between plasma concentrations and clinical efficacy or to monitor adverse effects (360-363). The majority of drugs in the class seem to exhibit linear pharmacokinetics, despite the wide interindividual variations in pharmacokinetic properties observed for specific agents. Linear pharmacokinetics allows the dosage to be readily adjusted if the steady-state plasma concentration is in the sub-therapeutic or toxic range. 

There are few controlled studies in children and adolescents with bipolar disorder, thus little is known about the long-term efficacy and safety of specific agents or for combination therapies in this population. The only published guidehnes for children and adolescents are the Practice Parameters for the Assessment and Treatment of Children and Adolescents with Bipolar Disorder by the American Academy of Child and Adolescent Psychiatry, and a proposed treatment algorithm for pediatric bipolar disorder. A more complete review of using mood stabilizers and antipsychotics in children and adolescents can be found elsewhere. ... 

Pi peridinobenzimidazole also serves as starting material for the antipsychotic agent halopemide (69). In the absence of a specific reference, one may speculate that the first step involves alkylation with bromochloro-ethane to give halide The chlorine may then be converted to the primary amine by any of several methods such as reaction with phthalimide anion followed by hydrazinolysis. Acylation with j -fluorobenzoyl chloride then gives the desired product. 

No specific antiaggressive agent exists for children. Flowever, antipsychotics, anticonvulsants, mood stabilizers, antidepressants, sedative-anxiolytics, and beta-blockers are all used to target aggression. Unfortunately, few controlled studies exist that assess these agents. 

Antipsychotics. Clear guidelines for measuring therapeutic serum concentrations of antipsychotics have not yet been established. There may, however, be specific situations in which they may be of value (e.g., monitoring of haloperidol [HPDL] levels might be useful in patients on concurrent carbamazepine therapy because the latter agent can substantially reduce serum HPDL concentrations). These issues are discussed in greater detail in the Pharmacokinetics/Plasma Level section in Chapter 5. 

Avoidance of active concomitant medication is the next important requirement. Such medication constitutes a major artifact because it can markedly weaken the drug—placebo difference. Thus, compared treatments may appear equally efficacious due to the concomitant medication and not any inherent efficacy of the experimental agent. Some studies have used multiple agents, in different doses, with some known to be specifically effective for the disorder under investigation. For example, in some studies, comparing carbamazepine or valproate with placebo or lithium, patients have also received adjunctive antipsychotics, making firm conclusions difficult (see the section Alternative Treatment Strategies in Chapter 10). 

All clinically effective antipsychotics block DA receptor activity. Further, stimulation of this neurotransmitter can induce psychotic symptoms de novo or exacerbate an existing psychotic disorder. Atypical agents have differential impacts on other systems (e.g., 5-HT) in comparison with the earlier neuroleptic agents. They also selectively target specific DA tracts that may mediate the pathological condition, while sparing those tracts that mediate the unwanted adverse effects (e.g., EPS, TD). 

Typical doses of clonazepam have been in the range of 2 to 16 mg/day given on a once or twice per day schedule due to its longer half-life. A major advantage of this anticonvulsant is its relative lack of adverse effects and freedom from laboratory monitoring in comparison with CBZ and VPA. Clonazepam may be more useful when combined with lithium or CBZ rather than as a specific antimanic agent, perhaps supplanting the need for antipsychotics. In this sense, it can be viewed as a behavioral suppressor, rather than a true mood stabilizer (121). 

Although the usefulness of the atypical antipsychotics is best documented for the positive symptoms of schizophrenia, numerous studies are documenting the utility of these agents for the treatment of positive symptoms associated with several other disorders (discussed in Chapter 10 see Fig. 10—2). Atypical antipsychotics have become first-line acute and maintenance treatments for positive symptoms of psychosis, not only in schizophrenia but also in the acute manic and mixed manic-depressed phases of bipolar disorder in depressive psychosis and schizoaffective disorder in psychosis associated with behavioral disturbances in cognitive disorders such as Alzheimer s disease, Parkinson s disease, and other organic psychoses and in psychotic disorders in children and adolescents (Fig. 11—52, first-line treatments). In fact, current treatment standards have evolved in many countries so that atypical antipsychotics have largely replaced conventional antipsychotics for the treatment of positive psychotic symptoms except in a few specific clinical situations. 

Consequently, antipsychotic drugs all share a basic mechanism of action that involves dopamine receptor blockade. It is apparent, however, that they are not all equal in their ability to affect specific sub-types of dopamine receptors, and that their effectiveness and side effects are related to their affinity and preference for certain receptors. As indicated earlier, other neurotransmitters may also be involved in the pathogenesis of psychosis, and differences in specific antipsychotic medications may be related to their ability to directly or indirectly affect these other transmitters as well as block dopamine influence. Future studies will continue to clarify how current antipsychotics exert their beneficial effects and how new agents can be developed to be more selective in their effects on dopamine and other neurotransmitter pathways. 

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