antipsychotics

6.2.5 Antipsychotic and

New Oxford Textbook of Psychiatry

Antipsychotic drugs

Introduction

The discovery by Delay and Denicker in 1953 that chlorpromazine was effective in treating core psychotic symptoms, i.e. delusions, hallucinations, and disorganized thinking, was one of the most important ever made in psychiatry and among the most important in all of medicine. These drugs have been invaluable in providing clues to the aetiology of schizophrenia and other forms of mental illness with psychotic features and as tools in understanding fundamental neural processes, especially those involving dopamine, the key neurotransmitter involved in psychosis.

The classes of antipsychotic drugs

Antipsychotic drugs have been classified into typical and atypical groups.

Typical antipsychotic drugs are those which produce extrapyramidal side-effects at clinically effective doses in the majority of patients. Extrapyramidal side-effects include Parkinsonism (muscle rigidity, loss of associated movements), acute dystonic reactions, dyskinesias, akathisia (restlessness), and tardive dyskinesia. They are also called neuroleptics because of their inhibitory effect upon locomotion activity.

Atypical antipsychotic drugs are those with a significantly lower propensity to produce extrapyramidal side-effects at clinically effective doses. They are sometimes referred to as novel antipsychotic drugs, reflecting the later development of most of these compounds (with the exception of clozapine) or by their pharmacology, for example multireceptor antagonists or serotonin (5-hydroxytryptamine) 2A antagonists.

            Some also interact with

•         D1 dopaminergic

•         5HT2 serotonergic

•         Alpha adrenergic receptors

•         H₁ Histamine receptors

Classification Antipsychotic agents

Tricyclic Antipsychotics

Three ring structure in which two benzene rings are linked by a sulphur and nitrogen atom. Substitution of the side chain on the Nitrogen on position 10 is responsible for the change in potency of the member of this group.

   Phenothiazines

1. Aliphatic side chain:

Chlorpromazine and Triflupromazine relatively low in potency; moderate extrapyramidal actions.

2. Piperidine ring side chain

Thioridazine and Mesoridazine have lower incidence of extrapyramidal side effects high central muscarinic activity

3. Piperazine group side chain

Trifluperazine, and Fluphenazine are highly potent, low muscarinic activity with high incidence of extrapyramidal side effects.

           Thioxanthenes

            Aliphatic side chain e.g. Chlorprothixene

            Piperazine side chain e.g. Clopenthixol, flupenthixol, piflutixol and thiothexine.

Dibenzepines

Contain seven member central ring e.g. loxapine, Metiapine, zotapine and clothiapine.

Butyrophenones

Phenylbutylpiperidine e.g. Halopendol, Droperidol and Spiperone.

Butylpiperidine e.g. Fluspirillin, Penfluridol and Pimozide.

Heterocyclic Compounds

Indole group e.g. Molindone and Oxypartine.

Pentacyclic group e.g. Butaclamol,

Quatenary Benzamides e.g. Metaclopramide; Sulpiride, Eticlopride and Remoxipride

Atypical group

The prototypical atypical antipsychotic drug is clozapine, a dibenzodiazepine.

Others include olanzapine, which is a thienobenzodiazepine, quetiapine, which is a dibenzothiazepine, and risperidone, which is a benzisoxazol. Iloperidone and ziprasidone are some of the most recent antipsychotics. These drugs are all potent 5-HT_2A antagonists as well as multireceptor antagonists. Sertindole has a similar pharmacology but was withdrawn, at least temporarily, due to apparent adverse cardiovascular side-effects. Amisulpride and remoxipride are substituted benzamides. Both are selective D₂/D₃ antagonists. Remoxipride was withdrawn shortly after its introduction because of a high rate of aplastic anaemia. There is no evidence that amisulpride has a similar vulnerability.

Pharmacokinetics

The relationship between the plasma concentration and the clinical effect of antipsychotic drugs is highly variable, and the dosage has to be adjusted on a trial-and-error basis.

Body_ID: P045056

The plasma half-life of most antipsychotic drugs is 15-30 h, clearance depending entirely on hepatic transformation by a combination of oxidative and conjugative reactions.

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Most antipsychotic drugs can be given orally or in urgent situations by intramuscular injection. Slow-release (depot) preparations of many are available, in which the active drug is esterified with heptanoic or decanoic acid and dissolved in oil. Given as an intramuscular injection, the drug acts for 2-4 weeks, but initially may produce acute side effects. These preparations are widely used to minimise compliance problems.

CPZ and Thioridazine has a systemic bioavailability of 25%-35%, Haloperidol-65%

Most anti-psychotics are highly lipid soluble and protein bound (92-95%), they have clinical duration of action than would be expected for their plasma half-lives.

Metabolism

Most are completely metabolised some metabolites e.g 7-OH Chlorpromazine retain some activity.

Dopaminergic pathways

Mesolimbic-Mesocortical pathway which projects from cell bodies near the substantia nigra to the limbic system and neocortex.

Nigrostrial pathway- Neurons project from the substantia nigra to the caudate nucleus and putamen (coordinate movements).

Tubero-Infundibular system- connects arcuate nuclei and post pituitary (involves in the inhibition of prolactin secretion.

Medulary-periventricular pathway- consists of neurons in the motor nucleus of the vagus whose projections are not well defined. (May be involved in eating behaviour).

Incerto-hypothalamic pathway- forms connections from the medial zona incerto to the hypothalamus and the amygdala (regulate anticipatory motivational phase of copulatory behaviour in rats).

Body_ID: P045024 Body_ID: P045027 page 555 Body_ID: PB045002 Body_ID: HC045017 DOPAMINE RECEPTORS Body_ID: HC045018 Body_ID: None  There are five subtypes, which fall into two functional classes: the D1 type, comprising D1 and D5, and the D2 type, comprising D2, D3 and D4. Antipsychotic drugs owe their therapeutic effects mainly to blockade of D2 receptors. Antipsychotic effects require about 80% block of D2 receptors. The first-generation compounds show some preference for D2 over D1 receptors, whereas some of the newer agents (e.g. sulpiride, amisulpride, remoxipride) are highly selective for D2 receptors. More recently, D2 antagonists that dissociate rapidly from the receptor and D2 partial agonists have been introduced in an attempt to reduce extrapyramidal motor side effects. Body_ID: P045029 Body_ID: PB045003 It is the antagonism of D2 receptors in the mesolimbic pathway that is believed to relieve the positive symptoms of schizophrenia. Unfortunately, systemically administered antipsychotic drugs do not discriminate between D2 receptors in distinct brain regions and D2 receptors in other brain pathways will also be blocked. Thus, antipsychotic drugs produce unwanted motor effects (block of D2 receptors in the nigrostriatal pathway), enhance prolactin secretion (block of D2 receptors in the tuberoinfundibular pathway), reduce pleasure (block of D2 receptors in the reward component of the mesolimbic pathway) and perhaps even worsen the negative symptoms of schizophrenia (block of D2 receptors in the prefrontal cortex, although these are only expressed at a low density-D1 receptors being in greater abundance). While all antipsychotic drugs block D2 receptors and should therefore in theory induce all of these unwanted effects, some have additional pharmacological activity (e.g. mACh receptor antagonism and 5-HT2A receptor antagonism) that, to varying degrees, ameliorate unwanted effects . 5-HT2A antagonism may help to alleviate the negative and cognitive impairments of schizophrenia. Body_ID: P045030 Body_ID: P045031 5-HYDROXYTRYPTAMINE RECEPTORS Body_ID: HC045019 Body_ID: None The idea that 5-HT dysfunction could be involved in schizophrenia has drifted in and out of favour many times. It was originally based on the fact that LSD, a partial agonist at 5-HT2A receptors produces hallucinations. Nowadays, conventional wisdom is that 5-HT may not be directly involved in the pathogenesis of schizophrenia. Nevertheless, pharmacological manipulation of 5-HT receptor activity, combined with D2 receptor antagonism, has resulted in new drugs with improved therapeutic profiles. There are many types of 5-HT receptors with disparate functions in the body. It is the 5-HT2A receptor and, to a lesser extent, the 5-HT1A receptor that are important in the treatment of schizophrenia. Body_ID: P045032 5-HT2A receptors are Gi/Go-coupled receptors and their activation produces neuronal inhibition (through decreased neuronal excitability at the soma and decreased transmitter release at the nerve terminals). In this way, in the nigrostriatal pathway, 5-HT2A receptors control the release of dopamine. Drugs with 5-HT2A antagonist properties (e.g. olanzapine and risperidone) enhance dopamine release in the striatum by reducing the inhibitory effect of 5-HT. This will reduce extrapyramidal side effects. In contrast, in the mesolimbic pathway, the combined effects of D2 and 5-HT2A antagonism are thought to counteract the increased dopamine function that gives rise to positive symptoms of schizophrenia Body_ID: P045033 5-HT1A receptors are somatodendritic autoreceptors that inhibit 5-HT release. Antipsychotic drugs that are agonists or partial agonists at 5-HT1A receptors (e.g. quetiapine; ) may work by decreasing 5-HT release thus enhancing dopamine release in the striatum and prefrontal cortex. Body_ID: P045034 MUSCARINIC ACETYLCHOLINE RECEPTORS Body_ID: HC045020 Some phenothiazine antipsychotic drugs induce fewer extrapyramidal side effects than others, and this correlates with their affinity as muscarinic antagonists. Also, some newer, atypical drugs possess muscarinic antagonist properties (e.g. olanzepine). In the striatum, dopaminergic nerve terminals are thought to innervate cholinergic interneurons that express inhibitory D2 receptors. It is suggested that there is normally a balance between D2 receptor activation and muscarinic receptor activation. Blocking D2 receptors in the striatum with an antipsychotic agent will result in enhanced acetylcholine release on to muscarinic receptors, thus producing extrapyramidal side effects, which are counteracted if the D2 antagonist also has muscarinic antagonist activity. Maintaining the dopamine/acetylcholine balance was also the rationale for the use of benztropine to reduce extrapyramidal effects of antipsychotic drugs . Muscarinic antagonist activity does, however, induce side effects such as constipation, dry mouth and blurred vision. BEHAVIOURAL EFFECTS Body_ID: P045038 In humans, antipsychotic drugs produce a state of apathy and reduced initiative. The recipient displays few emotions, is slow to respond to external stimuli and tends to drowse off. The subject is, however, easily aroused and can respond to questions accurately, with no marked loss of intellectual function. Aggressive tendencies are strongly inhibited. Effects differ from those of sedative anxiolytic drugs, which also cause drowsiness and confusion but with euphoria rather than apathy. Body_ID: P045039 Many antipsychotic drugs are antiemetic, reflecting antagonism at dopamine, muscarinic, histamine and possibly 5-HT receptors. Body_ID: P045040 UNWANTED EFFECTS Body_ID: HC045022 EXTRAPYRAMIDAL MOTOR DISTURBANCES Body_ID: HC045023 Antipsychotic drugs produce two main kinds of motor disturbance in humans: acute dystonias and tardive dyskinesias, collectively termed extrapyramidal side effects. These all result directly or indirectly from D2 receptor blockade in the nigrostriatal pathway. Extrapyramidal side effects constitute one of the main disadvantages of first-generation antipsychotic drugs. The term atypical was originally applied to some of the newer compounds that show much less tendency to produce extrapyramidal side effects. Body_ID: P045041 Acute dystonias are involuntary movements (restlessness, muscle spasms, protruding tongue, fixed upward gaze, torticollis [involuntary spasm of neck muscles]), often accompanied by symptoms of Parkinson's disease. They occur commonly in the first few weeks, often declining with time, and are reversible on stopping drug treatment. The timing is consistent with block of the dopaminergic nigrostriatal pathway. Concomitant block of muscarinic receptors and 5-HT2A receptors mitigates the motor effects of dopamine receptor antagonists . Body_ID: P045042 Tardive dyskinesia  develops after months or years (hence 'tardive') in 20-40% of patients treated with first-generation antipsychotic drugs, and is one of the main problems of antipsychotic therapy. Its seriousness lies in the fact that it is a disabling and often irreversible condition, which often gets worse when antipsychotic therapy is stopped and is resistant to treatment. The syndrome consists of involuntary movements, often of the face and tongue, but also of the trunk and limbs, which can be severely disabling. Body_ID: P045043 ▾ There are several theories about the mechanism of tardive dyskinesia . One is that it is associated with a gradual increase in the number of D2 receptors in the striatum, which is less marked during treatment with the atypical than with the first generation of antipsychotic drugs. Another possibility is that chronic block of inhibitory dopamine receptors enhances catecholamine and/or glutamate release in the striatum, leading to excitotoxic neurodegeneration . Body_ID: P045045 ENDOCRINE EFFECTS Dopamine, released in the median eminence by neurons of the tuberohypophyseal pathway,acts physiologically via D2 receptors to inhibit prolactin secretion. Blocking D2 receptors by antipsychotic drugs can therefore increase the plasma prolactin concentration , resulting in breast swelling, pain and lactation, which can occur in men as well as in women. Body_ID: P045046 OTHER UNWANTED EFFECTS Body_ID: HC045025 Drowsiness and sedation, which tend to decrease with continued use, occur with many antipsychotic drugs. Antihistamine (H1) activity is a property of some phenothiazine antipsychotics (e.g. chlorpromazine) and contributes to their sedative and antiemetic properties, but not to their antipsychotic action. Body_ID: P045047 All antipsychotic drugs block a variety of receptors, particularly acetylcholine (muscarinic), histamine (H1), noradrenaline (α) and 5-HT. Body_ID: P045048 While block of muscarinic receptors produces a variety of peripheral effects, including blurring of vision and increased intraocular pressure, dry mouth and eyes, constipation and urinary retention , it may, however, also be beneficial in relation to extrapyramidal side effects . Body_ID: P045050 Blocking α-adrenoceptors causes orthostatic hypotension  but does not seem to be important for their antipsychotic action. Body_ID: P045051 Weight gain is a common and troublesome side effect. Increased risk of diabetes and cardiovascular disease occurs with several atypical antipsychotic drugs. These effects are probably related to their antagonist actions at H1, 5-HT and muscarinic receptors. Body_ID: P045052 Various idiosyncratic and hypersensitivity reactions can occur, the most important being the following: Jaundice, which occurs with older phenothiazines such as chlorpromazine. Leukopenia and agranulocytosis are rare but potentially fatal, and occur in the first few weeks of treatment. Urticarial skin reactions are common but usually mild. Excessive sensitivity to ultraviolet light may also occur. Antipsychotic malignant syndrome is a rare but serious complication similar to the malignant hyperthermia syndrome seen with certain anaesthetics . Muscle rigidity is accompanied by a rapid rise in body temperature and mental confusion. It is usually reversible, but death from renal or cardiovascular failure occurs in 10-20% of cases. Body_ID: P045053 Body_ID: PB045005 Body_ID: P0562 Body_ID: HC045026 Body_ID: P045055 Body_ID: P045058 CLINICAL USE AND CLINICAL EFFICACY Body_ID: HC045027 The major use of antipsychotic drugs is in the treatment of schizophrenia and acute behavioural emergencies, but they are also used to treat other conditions, such as deviant antisocial behaviour, motor tics and intractable hiccup. Their use to treat restlessness and agitation in the elderly is highly questionable. In addition, they are used as adjunct therapy in psychotic depression, bipolar disorder and mania. Some of the newer antipsychotic drugs (e.g. sulpiride) have been claimed to have specific antidepressant actions. Phenothiazines and related drugs are also useful as antiemetics Body_ID: P045059 Body_ID: P045060