Introduction

Antipsychotics are also sometimes called neuroleptics or major tranquilisers.They are typically used for the treatment of psychosis, including schizophrenia, and also in delirium – particularly in the elderly when related to dementia and in patient in intensive care. Occasionally quetiapine may be used for anxiety.

There are two types of antipsychotic drugs; typical antipsychotics (first generation) and atypical antipsychotics (second generation).
There is debate about how to classify a drug as typical or atypical, but atypical antipsychotics typically have fewer motor side effects. Also, the typical antipsychotics all tend to be from one class, whilst atypical ones have a wider range of mechanisms.
First generation anti-psychotics e.g. chlorpromazine, haloperidol, fluphenazine (depot (long acting) injection), clopenthixol
Atypical antipsychotics e.g. clozapine, risperidone, sertindole, aripiprazole, zotepine, olanzapine, quetiapine
 
Antipsychotic drugs generally have 4 important qualities:
  • Sedation
  • Anticholinergic activity
  • Extrapyramidal activity
  • Hypotensive effects
The only real differences between the drugs are their differing efficacies in these four areas. Atypical antipsychotics also appear to be more effective at combating the negative symptoms seen in schizophrenia.

Mechanism of action

Most of the activity of these drugs is through blockade of dopamine receptors, although they have also been noted to block receptors for other neurotransmitters, including histamine, acetylcholine and 5-HT (serotonin). The activity at serotonin receptors is thought to affect their clinical efficacy, but the effect at other receptors is not, and is often responsible for side effects.
Dopamine receptors – there are 5 types of dopamine receptors (D1-D5), which are classed into 2 main categories – D1 and D2Antipsychotics mainly block D2 receptors. First generation drugs tend to have effect on D1 and D2, whilst atypical drugs have varying effects.
  • Mesolimbic and Mesocortical regions – the blockade at these regions is thought to be responsible for the antipsychotic effects
  • Nigrostriatal pathways – the blockade at these regions is thought to cause the motor side effects.
When the drug is first administered, dopaminergic neuron activity increases, but over time (after about 3 weeks), this activity decreases. This is thought to be related to the number of dopamine receptors – and that over time, due to the blockade, the number of receptors greatly increases, thus in an inverse relationship, dopaminergic neuron activity decreases.
The drugs take several weeks to become effective – even though the blockade of dopamine receptors is immediate.
You can also cause unwanted extrapyramidal effects if the blockade of dopamine receptors exceeds 80% (the therapeutic range is 65-80%).
Aytpical drugs have better compliance than their first generation counterparts – probably because they cause fewer side effects.

Clinical effects

  • Depression of emotional responses – this is useful for treating delusions, thought disorders and perception problems
  • Sedation – useful for treating confusion and restlessness. This effect is achieved by reducing input to the reticular activating system, but the normal spontaneous activity of this system is preserved, thus the overall effect is that external stimuli produce a reduced response.
  • Antiemetic effect – useful for treating vomiting – that is often associated with drug use in these patients. This effect is caused by dopamine blockade at the chemoreceptor trigger zone (CTZ)
  • Antihistamine effects – can be used to treat allergies in some people.

Uses of antipsychotics

They are mainly used in schizophrenia and acute behavioural disturbances, but they may also be used as adjuvant therapy in many other psychiatric disorders, such as mania and psychotic depression.
  • Antipsychotics are only effective in about 70% of patients. For any given drug, this % is lower – the 70% is the number of patients that will respond to the group of drugs as a whole. It is thought that polymorphic 5-HT receptors are the cause for this non-responsiveness
  • They control the positive symptoms – delusions, hallucination etc, but not the negative symptoms – e.g. social isolation, low mood. Atypical antipsychotic may also help to control negative symptoms.

Pharmakokinetics

  • They tend to undergo extensive first pass metabolism
  • The plasma concentration does not correlate to the clinical response
  • The plasma concentration can vary widely between individuals
  • Eliminated by liver metabolism
  • Administration – commonly given orally, but can also be given by intra-muscular injection. Due to the nature in which these drugs are given, they can also be given in special pro-drug formulations (also by intramuscular injection) which release the drug slowly into its active for up to 12 weeks after administration.
  • note that the intramuscular dose is lower than the oral dose – due to first pass metabolism

Unwanted Effects

Extrapyramidal Effects – these result fro D2 blockade in the nigrostriatal pathways – examples of the side effects include:

  • Akathisia – restlessness
  • Acute dystonia – Often bizarre and unwanted muscle movements e.g. tongue protrusion, torticollis (a head tilt to one side, also with chin lift) and oculogyric crisis (abnormal rotation of the eyeballs).
  • Parkinsonism – tremor, rigidity, ‘mask-like’ faces, bradykinesia
  • One or more of these effects can occur in about ½ of those treated, but they usually reverse when the drug is stopped. With prolonged use of the drug, the likelyhood of these effects becoming permanent is increased.
  • Some of these effects may not be seen until the drug has been used for several months. These are known as tardive dyskinesia. The acute onset events are known as acute dystonias.
    • Trade dyskinesia can be particularly difficult to treat and may persist indefinitely
    • Prevention is the best policy – hence starting with low doses and titrating upwards
  • It is thought that these effects are mainly due to damage to GABAergic neurons.
  • These effects DO NOT occur with clozapine – and are also far less likely with atypical drugs.
  • These effects are less prominent with atypical antipsychotics.

Other side effects include:

  • Weight Gain – this is relatively common, and is probably the result of 5-HT antagonism, mainly with atypical agents
  • Drowsiness and cognitive impairment
  • Insomnia and agitation (Risperidone only)
  • Galactorrhoea (milk discharge from the nipples not associated with pregnancy/childbirth), gynaecomastia, amenorrhoea, impotence. Again, these tend to be less common with atypical antipsychotics. The painful breast swelling and growth can occur in both men and women.
  • Antimuscarinic effects – e.g. dry mouth, constipation, blurred vision, increased ocular pressure and trouble micturating. As well as these peripheral effects, a CNS muscarinic blockade can cause confusion.
  • Postural hypotension, problems ejaculating, nasal stuffiness – due to α1 blockade
  • ↑ risk of seizures – especially in those already with epilepsy
  • Hypothermia – possibly due to altered 5-HT effect on the hypothalamus
  • Hypersensitivity
  • Photosensitivity
  • Agranulocytosis – only really with clozapine – but there is a 1-2% risk and regular checks are needed
  • Prolonged Q-T – predisposing to ventricular arrhythmias
  • Neuroleptic malignant syndrome – this is rare – it occurs with a certain genetic variant of the D2 receptor, and results in abnormal blockade of D2 in the striatum and hypothalamus. It causes fever, rigidity, hypertension, sweating, urinary incontinence, altered consciousness.
    • It can cause death – you should withdraw treatment immediately, and give a dopamine agonist. Symptoms can take longer than 2 weeks to disappear.
  • Sudden withdrawal of the drugs – this can cause nausea, vomiting, anorexia, diarrhoea, paraesthesia, insomnia, agitation. These symptoms normally go within 2 weeks.
NMS – neuroleptic malignant syndrome
  • Rigidity
  • Delirium
  • Fluctuating bp
  • Tachycardia
  • Sweating
  • Extrapyramidal side effects (EPSE’s)
  • Bloods: creatinine kinase – very high!
Caused by an adverse reaction to neuroleptics. It is rare, but is a medical emergency and can be life-threatening. It results in death in about 10% of cases.
Treatment basically involves stopping the drug, and aggressively treating the hyperthermia e.g. with ice packs. May also often require circulatory and ventilator support. Benzodiazepines can be used to control agitation. It is also important to recognise the syndrome early to treat it as soon as possible.

References

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