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CLINICAL PHARMACOKINETICS OF ANTIPSYCHOTIC DRUGS

1. Introduction:

Antipsychotics (neuroleptics) form the corner stone in the treatment of schizophrenia and schizophrenia-like psychoses (eg. paranoid and manic conditions).

About 70% of patients with these psychoses will improve when given antipsychotics in an acute phase. The recurrence rate in patients not prescribed maintenance treatment is 3-4 times higher than in those given treatment, 20% of whom will relapse.

Also used extensively for sedation (questionable practice) and as antiemetics.

All antipsychotics in clinical use block post-synaptic D2-dopamine receptors in the mesolimbic area of the brain, which probably mediates the antipsychotic effect.

The effect on other receptors causes sedation and autonomic side effects (eg. postural hypotension, dry mouth, and constipation).

As with the antidepressants, large pharmacokinetic variability has been reported with the antipsychotics. This variability, coupled with the difficulties in measuring the response to therapy, makes the use of plasma level monitoring (TDM) a potentially attractive approach to the individualisation of dosage regimens.

 

2. Sub-groups of Antipsychotics:

Drug	Usual Daily Dosage (mg)
(a) Phenothiazines   Side Chain   Aliphatic Chlorpromazine (oral)  Piperidine Thioridazine (oral)  Piperazine Trifluoperazine (oral)  Fluphenazine HCI (oral)  Fluphenazine decanoate (im depot)	50-500   50-600  5-30 5-20 12.5-50 every 2 to 6 weeks
(b) Butyrophenones   Haloperidol (oral)  Haloperidol decanoate (im depot)	5-20  30-300 every 4 weeks
(c) Thioxanthenes   Thiothixene (oral)  Flupenthixol (oral)  Flupenthixol decanoate (im depot)	10-50  2-20  20-150 every 2 to 3 weeks
(d) Diphenylbutylpiperidones   Pimozide (oral)	2-15

There is no evidence that members of any particular group possess superior antipsychotic efficacy, but there are important differences in their adverse effects profiles (see later).

Summary of current treatment guidelines:

(a) Acute Schizophrenia:

- When parenteral medication is needed, use:-

Haloperidol 10 to 20mg, intravenously or intramuscularly, initially; can be repeated two hourly if needed, to 100mg daily¶.

- When oral medication is possible and sedation is required, use:-

Chlorpromazine 100 to 200mg, orally, three or four times a day

OR

Thioridazine 100 to 200mg, orally, three of four times a day.

- When oral medication is possible and sedation is not required, use:-

Haloperidol 20 to 60mg, orally, given twice daily to start and then at night only¶

OR

Trifluoperazine 20 to 60mg, orally, given twice daily to start and then at night only¶.

¶ The need to prevent and treat dystonic and extrapyramidal reactions is described under Adverse Effects. This is particularly important with intravenous or intramuscular Haloperidol.

 

(b) Chronic schizophrenia:

- Where compliance is good, use:-

Trifluoperazine 20 to 60mg, orally, at night¶

OR

Haloperidol 10 to 60mg, orally, at night¶.

- When compliance is poor, use:-

Fluphenazine decanoate 12.5mg, intramuscularly, given as a starting dose, then 25mg given a week later.

The usual maintenance dosage is 25 to 100mg, intramuscularly, every 2 to 4 weeks.

¶ The need to prevent and treat dystonic and extrapyramidal reactions is described under Adverse Effects. This is particularly important with intravenous or intramuscular Haloperidol.

 

3. Pharmacokinetic Overview:

In general, the antipsychotics share some basic physicochemical and pharmacokinetic properties. They are weak bases, poorly soluble in water but with a high lipid solubility. They exhibit the following:-

(i) Good GI absorption but reduced systemic bioavailability because of hepatic first-pass metabolism.

(ii) High hepatic clearance and a large apparent volume of distribution leading to an elimination half-life of about 24 hours for most of these drugs.

(iii) The renal elimination is negligible and it seems that these drugs usually do not possess active metabolites.

 

(a) Absorption:

- Absorption is rapid, with peak plasma levels 2-3 hours after oral doses.

- Extent of absorption is affected by a marked first-pass effect.

- Most compounds show a bioavailability of 40-60%.

- Considerable inter-patient variability, eg. Chlorpromazine 10-69%, Haloperidol 44-74%.

 

(b) Distribution:

- Extensive and variable binding to - acid glycoprotein in plasma.

- Extensive tissue uptake (high tissue binding due to lipid solubility) and resultant multicompartmental distribution behaviour.

- Large and variable apparent volume of distribution (approx. 10-40L/kg).

 

(c) Elimination:

- Mainly by metabolism - pathways differ between sub-groups.

Phenothiazines:

Are metabolised by ring sulphoxidation and ring hydroxylation, and the side chains may further be changed by oxidation and demethylation. Consequently, a large number of metabolites are formed that may be pharmacologically active and contribute to both antipsychotic and side effects.

Thioxanthenes:

Are essentially metabolised in the same manner as the phenothiazines, but are considered more resistant to hydroxylation.

Butyrophenones and Diphenylbutylpiperidones:

Are mainly metabolised by oxidative N-dealkylation that splits the molecule into two pharmacologically inactive portions. Other metabolic steps may include reduction of carbonyl groups and aromatic hydroxylation, which may result in the formation of active metabolites.

Elimination half-lives are approximately 20-30 hours (determined by Vd and hepatic Cl).

Therefore:-

(i) Once daily dosing is generally appropriate (especially once equilibration in the tissues and CNS has occurred).

(ii) Delay to achieve steady-state plasma levels and full therapeutic effect.

(iii) Prolonged effects after therapy has ceased.

Pharmacokinetic Parameters of Antipsychotics
Drug	Bioavailability (%)	Protein Binding (%)	Vd (L/kg)	Plasma t½ (Hours)	Metabolites Active	Therapeutic Plasma Concentrations (ng/mL)
Chlorpromazine	10-33	90-95	7-20	8-35	7-hydroxy	100-300
Thioridazine	25-33	99		9-30	Mesoridazine Sulphoridazine	200-800
Perphenazine	25		10-35	8-21	None known
Fluphenazine	50	90-95		14-24	None known	0.2-3.0
Thiothixene	50	90-95		34	None known	1.0-5.0¶ 10-30§
Haloperidol	40-70	92	10-35	12-36	Reduced Haloperidol	3.0-30
¶ Range observed measuring plasma concentrations 10-12 hours post-dose  § Range observed measuring plasma concentrations 2-4 hours post-dose Based on referenced 84, 102, 110, 241, 243, 248, 260, 261.

4. Factors Influencing Pharmacokinetics of Antipsychotics:

Genetically determined differences in drug metabolism:

- Age:

Possible reduction in metabolic clearance with advanced age: Maintenance dosage is generally less for elderly than for younger patients.

- Weight:

Apparent Vd and half-life increase in proportion to body weight.

- Sex:

No relevant differences in pharmacokinetics between males and females.

- Liver disease:

Reduced metabolic clearance in chronic liver disease.

- Drug interactions (few):

- Antacids may impair absorption: Space administration apart.

- Enhanced metabolism in the presence of inducing agents (eg. Phenytoin, Carbamazepine, Barbiturates).

- Cimetidine may inhibit the metabolism of antipsychotics.

- The effects of levodopa and guanethidine are reduced (pharmacodynamic).

- Autoinduction:

There is evidence that some antipsychotics (eg. Chlorpromazine and Thiothixene) may induce microsomal liver enzymes and cause plasma levels to fall, in spite of regular treatment with a fixed dosage.

5. Adverse Effects:

- CNS - sedation.

- Extrapyramidal movement disorders, eg. Parkinsonism, Akathisia.

- Tardive dyskinesia (occurs in 20-30% of all chronically treated patients).

- Usually commenced between 6-24 months from initiation of therapy.

- No convincing evidence that any agent is less likely to cause it.

- Patients at high risk: > 60 years of age, women, cerebral lesions (eg. mentally retarded).

- If possible, antipsychotics should be withdrawn.

- Dose reduction results in improvement of dyskinesia in about 50% of affected patients.

- Long-term use of an anticholinergic agent (to prevent/treat drug-induced movement disorders) may worsen dyskinesia.

- Anticholinergic side effects (eg. dry mouth, constipation).

- Postural hypotension ( - blockade).

- Increased sensitivity to sunlight - use sunscreens.

- Hepatic side effects - cholestasis.

- Blood dyscrasias.

 

Relative Incidence of Adverse Effects to Antipsychotics
Drug	Sedation	Antichol	Extrapyra	Hypotension
(a) Phenothiazines Side chain Aliphatic  Chlorpromazine  Piperidine Thioridazine Piperazine Trifluoperazine  Fluphenazine	High  High  Low Low	Mod  High  Low  Low	Low  Low   High  V. High	High  High  Low  Low
(b) Butyrophenones Haloperidol	Low	V. Low	V. High	Low
(c) Thioxanthenes   Thiothixene  Flupenthixol	Low	Low	High	Low
(d) Diphenylbutylpiperidones   Pimozide	Low	Low	Mod	V. Low

 

6. Plasma Level Monitoring:

There is considerable inter-individual variation in the bioavailability, apparent volume of distribution, and rate of elimination of the antipsychotics.

Hence, there is also considerable variability in the steady-state plasma concentrations that are produced from standard dosages in different patients. This is particularly so with the phenothiazines, where 40 to 100-fold differences in steady-state plasma levels have been reported.

As a result, there has been increased examination of the clinical utility of plasma level monitoring (TDM) of antipsychotics. To date, toxic or therapeutic ranges of plasma levels have been demonstrated for only a small number of antipsychotic drugs in relatively few patients.

The principal aims of TDM of antipsychotics are:-

(i) To improve patient compliance.

(ii) Lower the incidence of adverse effects (especially tardive dyskinesia).

(iii) Improve the antipsychotic effect.

At present, it seems that TDM may be useful in some situations when prescribing Chlorpromazine, Fluphenazine, Thioridazine and Haloperidol.

Current indications for TDM of antipsychotics:

- Check patient compliance.
- Insufficient clinical response to recommended dosage.
- Increase in or onset of adverse effects.
- Worsening psychosis.
- Elderly patients.
- Patients with chronic liver disease.
- suspected drug interaction.

Recommended Plasma Concentrations of Some Antipsychotics
Drug	Plasma Level
Fluphenazine	0.4-4nmol/L
Haloperidol Schizophrenia  Manic states  Senile psychosis	14-40nmol/L  60-70nmol/L  7-10nmol/L
Thioridazine  < 40 years  > 40 years	2-3mmol/L  1-2mmol/L
Chlorpromazine	The dose should be lowered in non-responders when levels are above 0.3-0.5mmol/L

7. Conclusion:

A rational approach to drug dosage and TDM during antipsychotic drug treatment, based on available clinical pharmacological data, may represent a valuable adjuvant to clinical judgments alone.

 

8. Appendices:

(a) Description:

The name schizophrenia was given by Bleuler in 1911 to a group of severe and common psychiatric illnesses characterised by a special type of thought disorder and disturbances in the volitional and emotional life of the patient.

The causes of the schizophrenic disorders are not known; it is likely that eventually a number of pathological brain processes will be discovered. All the drugs that relieve schizophrenic symptoms produce an extrapyramidal syndrome. These drugs block central dopamine receptors and this suggests a “dopamine hypothesis” for schizophrenia.

A diagnosis of schizophrenia will be made after a complete history is obtained from the patient, family and friends and from an examination of the patient’s mental state.

There are positive manifestations characteristic of the acute episode and usually responsive to antipsychotic drugs:-

- Delusions; particularly of a persecutory or jealous content.
- Auditory hallucinations.
- Disorganised thinking.
- Incongruous affect.
- Bizarre behaviour (including catatonia).

There are also negative manifestations characteristic of the chronic illness and usually with a poor response to antipsychotic drugs:-

- Blunted affect.
- Apathy and lack of motivation with social withdrawal.
- Poverty of thinking.
- Personality and social deterioration.

 

This Ready Reckoner gives theoretical equivalents only - the nearest smaller dose is appropriate, eg. 25mg rather than 26.7mg. It is only a guide as individual response varies greatly.

CPZ - Chlorpromazine	TFPZ - Trifluoperazine	HPD - Haloperidol
TRZ - Thioridazine	TTX - Thiothixene	FPZ - Fluphenazine
PIM - Pimozide

1. Based on Flupenthixol decanoate 40mg - Fluphenazine decanoate 25mg. A 4 weekly or 6 weekly dose is twice or thrice the 2 weekly or 3 weekly dose for Fluphenazine and Flupenthixol decanoates.

2. Haloperidol depot doses are measured as milligrams of Haloperidol (ie. not of the decanoate). Haloperidol depot is given FOUR WEEKLY. Patients should be stabilised on oral Haloperidol first. Haloperidol depot doses can be derived from two equivalents, either 10-15 times OR 20 times the daily oral Haloperidol dose. The range cited is the mid-point - 15 TIMES.

* Clinical experience with Haloperidol decanoate at doses greater than 300mg per month has been limited.

 

TABLE 1: Equiactive Doses (in mg) of Antipsychotic Drugs and the Relative Intensity of Common Side Effects (X = Least, XXX - Marked)
Drug	Equiactive Daily Doses	Sedation	Hypotension	Anti-cholinergic	Extra-Pyramidal
Phenothiazines Aliphatic Chlorpromazine	100	XXX	XXX	XX	X
Piperidine Pericyazine  Thioridazine	10  100	XXX  XXX	XXX  XXX	XXX  XXX	X  X
Piperazine  Fluphenazine  Fluphenazine decanoate¶ Perphenazine  Trifluoperazine	2  0.6  10  5	XX  XX  X  XX	X  X  X  X	X  X  X  X	XXX  XX  XXX  XXX
Butyrophenones Droperidol  Haloperidol	2  2	X  X	X  X	X  X	XXX  XXX
Thioxanthenes  Thiothixene	5	X	X	X	XXX
Diphenulbutylpiperidines Primozide	2	X	X	X	XXX
¶ Given intramuscularly every two to six weeks.