Page 531 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 29 Antipsychotic Agents & Lithium 517

very strongly correlated with clinical antipsychotic and extrapy-
10 –5
Sulpiride ramidal potency (Figure 29–3, bottom). In vivo imaging studies
D 1 Clebopride Molindone of D -receptor occupancy indicate that for antipsychotic efficacy,
K (mol/L) on 3 H-SCH 23390 binding 10 –7 Spiperone Haloperidol Clozapine is not required for some second-generation antipsychotic drugs
2
the typical antipsychotic drugs must be given in sufficient doses
to achieve at least 60% occupancy of striatal D receptors. This
2
–6
10
such as clozapine and olanzapine, which are effective at lower
Chlorpromazine
occupancy levels of 30–50%, most likely because of their concur-
rent high occupancy of 5-HT receptors. The first-generation
2A
antipsychotic drugs produce EPS when the occupancy of striatal
D receptors reaches 80% or higher.
Thioridazine
2
Positron emission tomography (PET) studies with aripiprazole
Trifluperazine
Fluphenazine
2
–8
10
cause EPS because it is a partial D -receptor agonist. Aripiprazole
2
Flupenthixol show very high occupancy of D receptors, but this drug does not
also gains therapeutic efficacy through its 5-HT antagonism and
2A
possibly 5-HT partial agonism.
1A
10 –7 These findings have been incorporated into the dopamine
Promazine hypothesis of schizophrenia. However, additional factors compli-
IC 50 (mol/L) on 3 H-haloperidol binding 10 –9 Trifluperidol Pimozide Haloperidol Thioridazine not known whether schizophrenia or the antipsychotic drugs alter
Chlorpromazine
D
cate interpretation of dopamine receptor data. For example, dopa-
Trazodone
2
Clozapine
mine receptors exist in both high- and low-affinity forms, and it is
Molindone
–8
10
Moperone
Prochlorperazine
the proportions of receptors in these two forms.
Trifluperazine
It has not been convincingly demonstrated that antagonism of
Thiothixene
any dopamine receptor other than the D receptor plays a role in
2
Fluphenazine
Droperidol
the action of antipsychotic drugs. Selective and relatively specific
D -, D -, and D -receptor antagonists have been tested repeat-
4
1
3
edly with no evidence of antipsychotic action. Most of the newer
Benperidol
atypical antipsychotic agents and some of the traditional ones have
10
–10
Spiroperidol
a higher affinity for the 5-HT receptor than for the D recep-
2
2A
tor (Table 29–1), suggesting an important role for the serotonin
0.1 1 10 100 1000 5-HT system in the etiology of schizophrenia and the action of
Range and average clinical dose for these drugs.
controlling schizophrenia (mg/d)
FIGURE 29–3 Correlations between the therapeutic potency C. Differences among Antipsychotic Drugs
of antipsychotic drugs and their affinity for binding to dopamine Although all effective antipsychotic drugs block D receptors, the
2
D 1 (top) or D 2 receptors (bottom). Potency is indicated on the degree of this blockade in relation to other actions on receptors
horizontal axes; it decreases to the right. Binding affinity for D 1 varies considerably among drugs. Vast numbers of ligand-receptor
receptors was measured by displacing the selective D 1 ligand SCH binding experiments have been performed in an effort to discover
23390; affinity for D 2 receptors was similarly measured by displacing a single receptor action that would best predict antipsychotic
the selective D 2 ligand haloperidol. Binding affinity decreases efficacy. A summary of the relative receptor-binding affinities of
upward. (Reprinted, with permission, of Wiley-Liss, Inc., a subsidiary of John Wiley several key agents in such comparisons illustrates the difficulty in
& Sons, Inc., from Seeman P: Dopamine receptors and the dopamine hypothesis of
schizophrenia. Synapse 1987;1:133.) drawing simple conclusions from such experiments:
Chlorpromazine: α = 5-HT > D > D 1
2A
2
1
Haloperidol: D > α > D > 5-HT > D > H 1
4
1
2
1
2A
The D receptor is coded on chromosome 11, decreases cAMP (by Clozapine: D = α > 5-HT > D = D 1
2
2A
4
1
2
G -coupled inhibition of adenylyl cyclase), and inhibits calcium Olanzapine: 5-HT > H > D > D > α > D
i
2
1
4
1
2A
1
channels but opens potassium channels. It is found both pre- and Aripiprazole: D = 5-HT > D > α = H >> D
postsynaptically on neurons in the caudate-putamen, nucleus 2 2A 4 1 1 1
2
accumbens, and olfactory tubercle. A second member of this fam- Quetiapine: H > α > M > D > 5-HT 2A
1
1,3
1
ily, the D receptor, also coded by a gene on chromosome 11, is Thus, most of the second-generation and some first-generation
3
thought to also decrease cAMP and is located in the frontal cortex, antipsychotic agents are at least as potent in inhibiting 5-HT
2
medulla, and midbrain. D receptors also decrease cAMP and are receptors as they are in inhibiting D 2 receptors. Aripiprazole and
4
concentrated in the cortex. brexpiprazole appear to be partial agonists of D receptors. Vary-
2
The first-generation antipsychotic agents block D receptors ing degrees of antagonism of α adrenoceptors are also seen with
2
2
stereoselectively for the most part, and their binding affinity is risperidone, clozapine, olanzapine, quetiapine, and aripiprazole.