A Textbook of Clinical Pharmacology and Therapeutics

The Boston Collaborative Survey indicated that adverse
reactions are most common in patients receiving high doses,
and that they usually occur soon after starting treatment.
The most common serious reactions were fits, coma, severe
hypotension, leukopenia, thrombocytopenia and cardiac
arrest.

Contraindications and cautions

These include the following:

• coma due to cerebral depressants, bone marrow
  depression, phaeochromocytoma, epilepsy, chronic
  respiratory disease, hepatic impairment or Parkinson’s
  disease;


• caution is needed in the elderly, especially in hot or cold
  weather;


• pregnancy, lactation;


• alcoholism.

Pharmacokinetics

The pharmacokinetics of conventional antipsychotic drugs
have been little studied. They have multiple metabolites and
their large apparent volumes of distribution (Vd) (e.g. for
chlorpromazineVd22 L/kg) result in low plasma concen-
trations, presenting technical difficulties in estimation. Most is
known about chlorpromazine, see Box 19.4.

Drug interactions

These include the following:

• alcohol and other CNS depressants – enhanced sedation;


• hypotensive drugs and anaesthetics – enhanced
  hypotension;


• increased risk of cardiac arrhythmias with drugs that
  prolong the QT interval (e.g. amiodarone,sotalol);


• tricyclic antidepressants – increased antimuscarinic
  actions;


• metoclopramide– increased extrapyramidal effects and
  akathisia;


• antagonism of anti-Parkinsonian dopamine agonists (e.g.
  L-dopa) (these are in any case contraindicated in
  schizophrenia).

ATYPICAL ANTIPSYCHOTIC DRUGS

The term ‘atyptical antipsychotic’ is used very imprecisely.

‘Newer’ or ‘second-generation’ antipsychotics are synonymous

in some texts. In comparison to the conventional antipsychotics

where potency is closely related to D 2 receptor blockade, atyp-

ical antipsychotics bind less tightly to D 2 receptors and have

additional pharmacological activity which varies with the drug.

Efficacy against negative symptoms, as well as less extrapyra-

midal side effects, are characteristic. These may be the result of

the transient (‘hit and run’) binding to D 2 receptors.

Clozapineis the original ‘atypical’ antipsychotic and is

described below. Its use is limited to resistant patients due to

the risk of agranulocytosis. A variety of other atypical anti-

psychotic drugs are available. Features of clozapineare:

• D 4 5HT 2 blockade;


• D 1 D 2 blockade;


• α-adrenoceptor blockade;


• effective in resistant patients;


• effective against negative and positive symptoms;


• virtually free from extrapyramidal effects;


• agranulocytosis (3%) – use is restricted to patients licensed
  with a monitoring service: blood count (weekly for first
  18 weeks, then every two weeks till one year, then every
  four weeks);


• severe postural hypotension – initiate therapy under
  supervision;


• sedation, dizziness, hypersalivation;


• weight gain, glucose intolerance, possible intestinal
  obstruction;


• myocarditis and cardiomyopathy;


• pulmonary embolism;


• seizures.

Many newer alternatives, but none with the unique properties

of clozapine, e.g. risperidone, olanzapine, aripiprazole,

amisulpride,quetiapineandzotepine, have been introduced.

Their pharmacology, efficacy and adverse effects vary.

Although more expensive, in June 2002 NICE recommended

Box 19.4: Pharmacokinetics (chlorpromazine)

• Dose regimes are largely empirical.


• There is variable absorption.


• There are 70 metabolites, some of which are
  active.


• Enterohepatic circulation is involved.


• There is enormous variability in plasma concentrations
  andt1/2.


• There is a vast volume of distribution.


• Brain:plasma concentration is 5:1.


• Reduced doses should be prescribed in the elderly
  (for both pharmacokinetic and pharmacodynamic
  differences).

Case history

A 50-year-old woman whose schizophrenia is treated

with oral haloperidol is admitted to the Accident and

Emergency Department with a high fever, fluctuating level

of consciousness, muscular rigidity, pallor, tachycardia,

labile blood pressure and urinary incontinence.

Question 1

What is the likely diagnosis?

Question 2

How should this patient be managed?

Answer 1

Neuroleptic malignant syndrome.

Answer 2

1. Stop the haloperidol.


2. Initiate supportive therapy.


3. Bromocriptine (value uncertain).


4. Dantrolene (value uncertain).

SCHIZOPHRENIA 113