Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 21B) docx

19 PSYCHOTROPI C DRUG S

The reality is more complex since the receptor

binding profile of clozapine and the newer atypical

antipsychotic agents suggests that D2-receptor

blockade is not essential for antipsychotic effect.

The atypical drugs act on numerous receptors and

modulate several interacting transmitter systems.

Clozapine is a highly effective antipsychotic. It has

little affinity for the D2-receptor compared with

classical drugs but binds more avidly to other

dopamine subtypes (e.g. D1, D3 and D4). It blocks

muscarinic acetylcholine receptors, as do certain

classical agents (e.g. thioridazine), a property which

may reduce the experience of extrapyramidal effects.

Clozapine binds more readily as an antagonist at

a2-adrenoceptors than the classical drugs and also

blocks histamine and serotonin receptors (5HT2 and

others).

The newer atypical psychotropics vary widely

in their receptor binding profiles. Olanzapine and

quetiapine bear resemblance to the profile of cloza￾pine in that their therapeutic effects appear to derive

from action on different receptors and transmitter

systems. All atypicals (except amisulpride) exhibit

greater antagonism of 5HT2-receptors than D2-

receptors compared with the classical agents.

Atypical drugs that do antagonise dopamine D2-

receptors appear to have affinity for those in the

Fig. 19.3 Sagittal brain section illustrating dopaminergic pathways.

I. Mesolimbic pathway (overactive in psychotic illness according to

the dopamine hypothesis of schizophrenia).VTA= ventrotegmental

area. 2. Nigrostriatal pathway (involved in motor control,

underactive in Parkinson's Disease and associated with

extrapyramidal motor symptoms). 3. Tuberoinfundibular pathway

(inhibits prolactin release from the hypothalamus).

mesolimbic system (producing antipsychotic effect)

rather than the nigrostriatal system (associated with

unwanted motor effects). In contrast to classical

antipsychotics, risperidone shares with clozapine

an ability antagonise a2-adrenoceptors, a property

which may have utility in the treatment of schizo￾phrenia and is seen as an area of interest for

developing new drugs.

PHARMACOKINETICS

Like antidepressants, antipsychotics are well

absorbed and distributed after oral administration.

In situations where very rapid relief of symptoms

or disturbed behaviour is required, faster uptake

into plasma can be achieved through the intramus￾cular route. Again in common with antidepressants,

antipsychotics are mainly metabolised by cyto￾chrome P450 isoenzymes in the liver, e.g. CYP 2D6

(zuclopenthixol, risperidone [Table 19.2a]), CYP 3A4

(sertindole [Table 19.2b]), CYP 1A2 (olanzapine,

clozapine). Metabolism of some compounds is parti￾cularly complex (e.g. chlorpromazine, haloperidol),

involving more than one main pathway, utilising

several P450 enzymes or resulting in the production

of many inactive metabolites. Antipsychotic plasma

levels can be increased or decreased by co￾prescription of drugs which are inhibitors, inducers

or substrates of the same isozyme. Amisulpride is

an exception to the general rule as it is eliminated

by the kidneys without hepatic metabolism.

Examples of plasma half-lives for antipsychotics

include quetiapine 7 h, clozapine 12 h, haloperidol

18 h and olazapine 33 h. Depot intramuscular injec￾tions are available from which drug is released over

2-4 weeks.

EFFICACY

Symptoms in schizophrenia are defined as positive

and negative (Table 19.4). Whilst a classical anti￾psychotic drug should provide adequate treatment

of positive symptoms including hallucinations and

delusions in at least 60% of cases, patients are often

left with unresolved negative symptoms such as

apathy, flattening of affect and alogia. Evidence

suggests that clozapine and the newer atypicals

have a significant advantage over classical drugs

against negative symptoms. Clozapine has a

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