Clinical Pharmacology and Therapeutics

112 SCHIZOPHRENIA AND BEHAVIOURAL EMERGENCIES
DRUGS USED IN TREATMENT
CONVENTIONAL ANTIPSYCHOTIC DRUGS
The principal action of the conventional antipsychotic drugs
(see Table 19.1), such as chlorpromazine (a phenothiazine) and
haloperidol (a butyrophenone), is an antagonism of D 2 receptors
in the forebrain. The effect on D 1 receptors is variable.
Blockade of the D 2 receptors induces extrapyramidal effects.
Repeated adminstration causes an increase in D 2 -receptor sensitivity
due to an increase in abundance of these receptors. This
appears to underlie the tardive dyskinesias that are caused by
prolonged use of the conventional antipsychotic drugs.
The choice of drug is largely determined by the demands of
the clinical situation, in particular the degree of sedation
needed and the patient’s susceptibility to extrapyramidal toxicity
and hypotension.
Uses
These include the following:
1. schizophrenia – antipsychotic drugs are more effective
against first-rank (positive) symptoms (hallucinations,
thought disorder, delusions, feelings of external control)
than against negative symptoms (apathy and
withdrawal);
2. other excited psychotic states, including mania and
delirium;
3. anti-emetic and anti-hiccough;
4. premedication and in neuroleptanalgesia;
5. terminal illness, including potentiating desired actions of
opioids while reducing nausea and vomiting;
6. severe agitation and panic;
7. aggressive and violent behaviour;
8. movement and mental disorders in Huntington’s disease.
Adverse effects
1. The most common adverse effects are dose-dependent
extensions of pharmacological actions:
• extrapyramidal symptoms (related to tight binding to,
and receptor occupancy of, D 2 receptors) – parkinsonism
Table 19.1: Conventional antipsychotic drugs
Sedation Extrapyramidal Hypotension
symptoms
Phenothiazines
Chlorpromazine
Fluphenazine a
Butyrophenones
Haloperidol
Thioxanthines
Fluphenthixol a
a Depot preparation available.
All increase serum prolactin levels
Note: Pimozide causes a prolonged QT and cardiac arrhythmias.
including tremor, acute dystonias, e.g. torticollis,
fixed upward gaze, tongue protrusion; akathisia
(uncontrollable restlessness with feelings of anxiety
and agitation) and tardive dyskinesia. Tardive
dyskinesia consists of persistent, repetitive, dystonic
athetoid or choreiform movements of voluntary
muscles. Usually the face and mouth are involved,
causing repetitive sucking, chewing and lip smacking.
The tongue may be injured. The movements are
usually mild, but can be severe and incapacitating.
This effect follows months or years of antipsychotic
treatment;
• anticholinergic – dry mouth, nasal stuffiness,
constipation, urinary retention, blurred vision;
• postural hypotension due to α-adrenergic blockade.
Gradual build up of the dose improves tolerability;
• sedation (which may be desirable in agitated patients),
drowsiness and confusion. Tolerance usually develops
after several weeks on a maintenance dose. Emotional
flattening is common, but it may be difficult to
distinguish this feature from schizophrenia.
Depression may develop, particularly following
treatment of hypomania, and is again difficult to
distinguish confidently from the natural history of the
disease. Acute confusion is uncommon.
2. Jaundice occurs in 2–4% of patients taking
chlorpromazine, usually during the second to fourth
weeks of treatment. It is due to intrahepatic cholestasis
and is a hypersensitivity phenomenon associated with
eosinophilia. Substitution of another phenothiazine may
not reactivate the jaundice.
3. Ocular disorders during chronic administration include
corneal and lens opacities and pigmentary retinopathy.
This may be associated with cutaneous light sensitivity.
4. About 5% of patients develop urticarial, maculopapular
or petechial rashes. These disappear on withdrawal of
the drug and may not recur if the drug is reinstated.
Contact dermatitis and light sensitivity are common
complications. Abnormal melanin pigmentation may
develop in the skin.
5. Hyperprolactinaemia.
6. Blood dyscrasias are uncommon, but may be lethal,
particularly leukopenia and thrombocytopenia. These
usually develop in the early days or weeks of treatment.
The incidence of agranulocytosis is approximately 1 in
10 000 patients receiving chlorpromazine.
7. Cardiac dysrhythmia, including torsades de pointes
(see Chapter 32) and arrest.
8. Malignant neuroleptic syndrome is rare but potentially
fatal. Its clinical features are rigidity, hyperpyrexia,
stupor or coma, and autonomic disorder. It responds to
treatment with dantrolene (a ryanodine receptor
antagonist that blocks intracellular Ca 2 mobilization).
9. Seizures, particularly in alcoholics. Pre-existing epilepsy
may be aggravated.
10. Impaired temperature control, with hypothermia in cold
weather and hyperthermia in hot weather.