A Textbook of 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 recep-
tors 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 sen-
sitivity 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 tox-
icity 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;


2. 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
   
   
   
   

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.


8. Impaired temperature control, with hypothermia in cold
   weather and hyperthermia in hot weather.

Table 19.1:Conventional antipsychotic drugs

Sedation Extrapyramidal Hypotension

symptoms

Phenothiazines

Chlorpromazine   

Fluphenazinea   

Butyrophenones

Haloperidol   

Thioxanthines

Fluphenthixola  

aDepot preparation available.
All increase serum prolactin levels
Note: Pimozide causes a prolonged QT and cardiac arrhythmias.