Effects On Sleep

Antipsychotic drugs have inconsistent effects on sleep patterns but tend to normalize sleep disturbances characteristic of many psychoses and mania. The capacity to prolong and enhance the effect of opioid and hypnotic drugs appears to parallel the sedative, rather than the neuroleptic, potency of a particular agent; thus, potent, less-sedating antipsychotics do not enhance sleep.

EFFECTS ON SPECIFIC AREAS OF THE NERVOUS SYSTEM The antipsychotic drugs affect all levels of the CNS. Theories on the actions of antipsychotic agents are based on their ability to antagonize the actions of DA as a neurotransmitter in the basal ganglia and limbic portions of the forebrain. Although supported by a large body of data, these theories reflect a degree of circularity in the consideration of antipsychotic drug candidates for development after identifying their antidopaminergic activity.

Cerebral Cortex Since psychosis involves disordered thought processes, cortical effects of antipsychotic drugs are of particular interest. Antipsychotic drugs interact with dopaminergic projections to the prefrontal and deep-temporal (limbic) regions of the cerebral cortex, with relative sparing of these areas from adaptive changes in DA metabolism that would suggest tolerance to the actions of neuroleptics.

Seizure Threshold

Many neuroleptic drugs can lower the seizure threshold and induce discharges in the electroencephalogram (EEG) that are associated with epileptic seizure disorders. Clozapine, olanzapine, and aliphatic phenothiazines with low potency (e.g., chlorpromazine) seem particularly able to do this, while the more potent piperazine phenothiazines and thioxanthenes (notably fluphenazine and thiothixene), risperidone, and quetiapine are much less likely to have this effect. The butyrophenones and molindone variably and unpredictably rarely cause seizures. Clozapine has a clearly dose-related risk of inducing seizures in nonepileptic patients. Antipsy-chotic agents, especially clozapine, olanzapine, and low-potency phenothiazines and thioxan-thenes, should be used with extreme caution, if at all, in untreated epileptic patients and in patients undergoing withdrawal from CNS depressants such as alcohol, barbiturates, or benzo-diazepines. Most antipsychotic drugs, especially the piperazines, and the newer atypical agents aripiprazole, quetiapine, risperidone, and ziprasidone, can be used safely in epileptic patients if moderate doses are attained gradually and if concomitant anticonvulsant drug therapy is maintained (see Chapter 19).

Basal Ganglia Because the extrapyramidal effects of many antipsychotic drugs are prominent, a great deal of interest has centered on their actions in the basal ganglia, notably the caudate nucleus, putamen, globus pallidus, and allied nuclei, which play a crucial role in the control of posture and the extrapyramidal aspects of movement. The critical pathogenic role of DA deficiency in this region in Parkinson's disease, the potent activity of neuroleptics as DA receptor antagonists, and the striking resemblance between clinical manifestations of Parkinson's disease and some of the neurological effects of neuroleptic drugs have all focused attention on the role of deficient dopaminergic activity in some of the neuroleptic-induced extrapyramidal effects.

Antagonism of DA-mediated synaptic neurotransmission is an important action of many antipsychotics; this prompted the proposal that many adverse extrapyramidal neurological and neuroen-docrinological effects of the neuroleptics are mediated by antidopaminergic effects in the basal ganglia and hypothalamic systems, whereas the antipsychotic effects of neuroleptics are mediated by modification of dopaminergic neurotransmission in the limbic and mesocortical systems. Thus, neuroleptic drugs (but not their inactive congeners) initially increase the rate of production of DA metabolites, the rate of conversion of the precursor amino acid l-tyrosine to l-dihydroxypheny-lalanine (l-DOPA) and its metabolites, and initially increase the rate of firing of DA-containing cells in the midbrain. These effects presumably represent adaptive responses of neuronal systems aimed at reducing the impact of impaired synaptic transmission at dopaminergic terminals in the forebrain.

Evidence supporting this interpretation includes the observation that small doses of neurolep-tics block behavioral or neuroendocrine effects of systemically administered or intracerebrally injected dopaminergic agonists. Many antipsychotic drugs also block the effects of agonists on DA-sensitive adenylyl cyclase associated with Dj/D5-receptors in forebrain tissue (Figure 18—1). Atypical antipsychotic drugs such as clozapine and quetiapine are characterized by low affinity or weak actions in such tests. Initially, the standard antipsychotics increase firing and metabolic activity in dopaminergic neurons. These responses eventually are replaced by diminished presynaptic activity ("depolarization inactivation") with reduced firing and production of DA, particularly in the extrapyramidal basal ganglia. The timing of these adaptive changes following the administration of neuroleptics correlates well with the gradual evolution of parkinsonian bradyki-nesia over several days.

Estimated clinical potencies of most antipsychotic drugs correlate well with their relative potencies in vitro to inhibit binding of radioligands to D2 receptors. Almost all clinically effective antipsychotic agents (with the notable exception of clozapine and quetiapine) have high or moderate affinity for D2 receptors. Although some antipsychotics (especially thioxanthenes, phenothiazines, and clozapine) bind with relatively high affinity to D1 receptors, they also block D2 receptors and D2-like receptors, including the D3 and D4 subtypes. Butyrophenones and con-

Presynaptic dopamine neuron

Postsynaptic receptive neuron

FIGURE 18-1 Sites of action of neuroleptics and Itihium. In varicosities ("terminals") along dopamine (DA) neurons projecting from midbrain to forebrain, tyrosine is oxidized to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, then decarboxylated to DA by aromatic l-amino acid decarboxylase (AAD) and stored in vesicles. Following exocytotic release (inhibited by Li+) by depolarization in the presence of Ca2+, DA interacts with postsynaptic receptors (R) of Dj and D2 types (and structurally similar but less prevalent Dj-like and D2-like receptors), as well as with presynaptic D2 and D3 autoreceptors. Inactivation of transsynaptic communication occurs primarily by active transport ("reuptake" via DAT) of DA into presynaptic terminals (inhibited by many stimulants), with secondary deamination by mitochondrial monoamine oxidase (MAO). Postsynaptic Dj receptors, through Gs, activate adenylyl cyclase (AC) to increase cyclic AMP (cAMP), whereas D2 receptors inhibit AC through Gr D2 receptors also activate receptor-operated K+ channels, suppress voltage-gated Ca2+ currents, and stimulate phospholipase C (PLC), perhaps via the bg subunits liberated from activated Gi (see Chapter 1), activating the IP3-Ca2+ pathway, thereby modulating a variety of Ca2+-dependent activities including protein kinases. Lithium inhibits the phosphatase that liberates inositol (I) from inositol phosphate (IP). Both Li+ and valproate can modify the abundance or function of G proteins and effectors, as well as protein kinases and several cell and nuclear regulatory factors. D2-like autoreceptors suppress synthesis of DA by diminishing phosphorylation of rate-limiting TH, and by limiting DA release (possibly through modulation of Ca2+ or K+ currents). In contrast, presynaptic A2 adenosine receptors (A^) activate AC and, via the cyclic AMP-PKApathway, TH activity. Nearly all antipsychotic agents block D2 receptors and autoreceptors; some also block Dj receptors. Initially in antipsychotic treatment, DA neurons activate and release more DA, but following repeated treatment, they enter a state of physiological depolarization inactivation, with diminished production and release of DA, in addition to continued receptor blockade. ER, endoplasmic reticulum.

geners (e.g., haloperidol, pimozide, N-methylspiperone) and experimental benzamide neuroleptics are relatively selective antagonists of D2 and D3 receptors, with either high (nemonapride) or low (eticlopride, raclopride, remoxipride) D4 affinity.

Many other antipsychotic agents are active a1 adrenergic antagonists. This action may contribute to sedative and hypotensive side effects or may underlie useful psychotropic effects. Many antipsychotic agents (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasi-done) also have affinity for forebrain 5-HT2a receptors (see Chapter 11). This mixture of moderate affinities for several CNS receptor types (including muscarinic and H1 receptors) may contribute to the distinct pharmacological profiles of the atypical antipsychotic agent clozapine and other newer atypical antipsychotics.

Limbic System Dopaminergic projections from the midbrain terminate on septal nuclei, the olfactory tubercle and basal forebrain, the amygdala, and other structures within the temporal and prefrontal cerebral lobes and the hippocampus. The DA hypothesis has focused considerable attention on the mesolimbic and mesocortical systems as possible sites where antipsychotic effects are mediated. Speculations about the pathophysiology of idiopathic psychoses such as schizophrenia have long centered on dopaminergic functions in the limbic system.

Certain important effects of antipsychotic drugs are similar in extrapyramidal and limbic regions; however, the extrapyramidal and antipsychotic actions of these drugs differ in several ways: while some acute extrapyramidal effects of neuroleptics tend to diminish or disappear with time or with concurrent administration of anticholinergic drugs, antipsychotic effects do not. Moreover, dopaminergic subsystems in the forebrain differ functionally and in their physiological responses to drugs: anticholinergic agents block the increased turnover of DA in the basal ganglia induced by neuroleptic agents, but not in dopaminergic terminals of limbic areas; tolerance to the enhanced DA metabolism by antipsychotics is much less prominent in cortical and limbic areas than in extrapyramidal areas.

Newer Dopaminergic Receptors in Basal Ganglia and Limbic System

The discovery that D3 and D4 receptors are preferentially expressed in limbic areas has led to efforts to identify selective inhibitors for these receptors that might have antipsychotic efficacy and low risk of extrapyramidal effects. Clozapine has modest selectivity for D4 receptors over other DA receptor types. D4 receptors, preferentially localized in cortical and limbic brain regions in relatively low abundance, are upregulated after repeated administration of most typical and atypical antipsychotic drugs. These receptors may contribute to clinical antipsychotic actions, but agents that are D4 selective or mixed D4/5-HT2A antagonists have not proved effective in the treatment of psychotic patients.

D3 receptors are unlikely to play a pivotal role in antipsychotic drug actions, perhaps because their avid affinity for endogenous DA prevents their interaction with antipsychotics. The subtle and atypical functional activities of cerebral D3 receptors suggest that D3 agonists rather than antagonists may have useful psychotropic effects, particularly in antagonizing stimulant-reward and dependence behaviors.

Hypothalamus and Endocrine Systems Endocrine changes occur because of effects of antipsychotic drugs on the hypothalamus or pituitary, including their antidopaminergic actions. Most older antipsychotics and risperidone increase prolactin secretion, probably due to a blockade of the pituitary actions of the tuberoinfundibular dopaminergic neurons. These neurons project from the arcuate nucleus of the hypothalamus to the median eminence, where they deliver DA to the anterior pituitary via the hypophyseoportal blood vessels. D2 receptors on lactotropes in the anterior pituitary mediate the tonic prolactin-inhibiting action of DA (see Chapter 55).

Correlations between the potencies of antipsychotic drugs in stimulating prolactin secretion and causing behavioral effects are excellent for many types of agents. Aripiprazole, clozapine, olanzapine, quetiapine, and ziprasidone are exceptional in having minimal or transient effects on prolactin, while olanzapine produces only minor, transient increases in prolactin levels. Risperidone has an unusually potent prolactin-elevating effect, even at doses with little extrapyramidal impact. Effects of neuroleptics on prolactin secretion generally occur at lower doses than do their antipsy-chotic effects. This may reflect their action outside the blood-brain barrier in the adenohypophysis, or differences in the regulation of pituitary and cerebral D2 receptors. Little tolerance develops to the effect of antipsychotic drugs on prolactin secretion, correlating with a relative lack of up- or down-regulation of pituitary D2 receptors and their relative sensitivity to DA partial agonists. The hyperprolactinemic effect of antipsychotics is rapidly reversible when the drugs are discontinued. This activity is presumed to be responsible for the galactorrhea that may be associated with their use. Perhaps due to the effects of hyperprolactinemia, some antipsychotic drugs reduce the secretion of gonadotropins and sex steroids, which can cause amenorrhea in women and sexual dysfunction or infertility in men.

Other autonomic effects of antipsychotic drugs are probably mediated by the hypothalamus, such as an impairment of the body's ability to regulate temperature. Clozapine can induce moderate elevations of body temperature that can be confusing clinically; central effects on temperature regulation and cardiovascular and respiratory function probably contribute to the features of neu-roleptic malignant syndrome (see Table 18-1).

Brainstem

Clinical doses of antipsychotic agents usually have little effect on respiration. However, vasomotor reflexes mediated by either the hypothalamus or the brainstem are depressed by some antipsychotics, which may lead to hypotension. This risk is associated particularly with older low-potency

Neurological Side Effects of Neuroleptic Drugs

Reaction

Features

Time of Maximal Risk

Proposed Mechanism

Treatment

Acute dystonia

Spasm of muscles of tongue, face,

1-5 days

Unknown

Antiparkinsonian agents are diagnostic

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