Neuroleptics(Anti-psychotic Drugs)

Kaukab Azim, MBBS, PhD

Drug ListTypical Neuroleptics

(First generation anti-psychotics) Atypical Neuroleptics (second Generation anit-

psychoticsPhenothiazines Butyrophenones Others

Chlorpromazine Haloperidol Thiotixene Clozapine

Thioridazine Molindone Olanzapine

Fluphenazine Qietiapine

Prochlorperazine* Risperidone

Aripiprazole

* Will be covered in another lecture

Learning OutcomesBy the end of the course the students will be able to

☛ Outline the dopamine hypothesis of schizophrenia.

☛ Explain the mechanism of action of each drug in each class.

☛ Describe the antipsychotic action of neuroleptics.

☛ List the main pharmacokinetic features of neuroleptics

☛ Outline the use of depot preparations of fluphenazine and haloperidol

☛ Describe the main adverse effects of neuroleptics

☛ List the main contraindications of neuroleptics

☛ Outline the main therapeutic uses of neuroleptics.

Pharmacodynamics of NeurolepticsMechanism of action

☛ Neuroleptics block many different receptors.

☛ The therapeutic effects of neuroleptics are though to result from competitive blockade of dopamine (mainly D2) and/or serotonin (mainly 5-HT2A) receptors.

☛ The adverse effects of neuroleptics seem to result from the blockade of D2 receptor in the substantia nigra as well as from blockade of a variety of receptors both in the central and autonomic nervous system

Pharmacodynamics of NeurolepticsNeuroleptic can be broadly classified into the following groups:

1. Typical agents ☛ (which can be further subdivided in low potency and

high potency agents)☛ These drugs have high D2 antagonism and low 5-HT2A

antagonism.

2. Atypical agents

☛ These drugs have low (clozapine) or moderate D2 antagonism and high 5-HT2A antagonism.

Pharmacodynamics of NeurolepticsPharmacological effects

a.In normal individuals:

☛ Dysphoric effects are common (this can explain why this drugs have negligible abuse liability)

b. In schizophrenic patients☛ Positive schizophrenic symptoms(delusion,hallucinations &

thought disorders) usually subside in 1-4 weeks and are about equally affected by typical and atypical agents.

☛ Negative schizophrenic symptoms(withdrawal,blunted emotions & reduce ability to relate to people) are minimally affected by typical neuroleptics but more so by atypical neuroleptics (the higher blockade of 5-HT2 receptors may contribute to this effect).

Pharmacodynamics of NeurolepticsOther effects

☛ Inhibition of nausea and vomiting (due to blockade of D2 receptors mainly in the CTZ, but also in the stomach

☛ Inhibition of thermo-regulation (due to inhibition of the hypothalamic thermostat)

Pharmacokinetics of Neuroleptics☛ Variable oral bioavailability (0.25-0.70)

☛ Large Vd.

☛ Extensive metabolism by the liver.

☛ Long half-lives (12-55 hours) for most compounds .

☛ Administered PO, IM , IV. For some compounds depot preparations are available (i.e. fluphenazine decanoate, haloperidol decanoate)(depot:It is a special preparation of the medication, which is given by injection. The medication is slowly released into the body over a number of weeks)

Receptor Affinity of Typical and Atypical Neuroleptics

D2 D4 5-HT2A H1 M Alpha1

Typical agents (first generation neuroleptics)

Chlorpromazine +++ 0 ++ ++ +++ +++

Thioridazine +++ 0 ++ + +++ +++

Fluphenazine +++ 0 + 0 0 +

Haloperidol +++ 0 + 0 0 +

Atypical agents (second generation neuroleptics)

Clozapine ++ ++ +++ + +++ +++

Aripiprazole +++ 0 ++ + 0 ++

Quitiapine + + ++ + + ++

Olanzapine ++ + +++ ++ +++ ++

Risperidone +++ + +++ + 0 +++

Relative incidence of Adverse Effects of Neuroleptics

DrugExtra

PyramidalSymptoms

ProlactinElevation Sedation Anticholinergic

EffectsPostural

Hypertension

Chlorpromazine Medium Present High High High

Thioridazine Low Present High High High

Fluphenazine High Present Low Low Low

Haloperidol High Present Low Low Low

Clozapine Very Low None High High High

Quetiapine Very Low None Medium Low Medium

Olanzapine Very Low None Medium High Medium

Risperidone Medium Present Medium Low Medium

Aripiprazole Very Low None Low Low Medium

Extrapyramidal Adverse Effects of Neuroleptics

Syndrome Features Proposed mechanism Treatment

Acute dystonia Spasms of muscles of tongue, face, and neck Unknown Anti-Parkinson

Drugs

Akathisia Motor restlessness UnknownAnti-ParkinsonDrugsBenzodiazepinesPropranolol

Parkinsonism Bradykinesia, rigidity, tremor

DopamineAntagonism

Anti-ParkinsonDrugs

Tardive dyskinesiaOral-facial, dyskinesia, choreoathetosis,Dystonias

Up-regulation of D2 receptors

Prevention.Treatment is unsatisfactory

Tardive DyskinesiaEtiology

Long term treatment with typical neuroleptics endowed with strong extrapyramidal effects (the risk of the syndrome is much lower with atypical neuroleptic)

Symptoms and signs☛Tardive dyskinesia is characterized by:

a. The buccal-lingual masticatory syndrome (grimacing(foul smell), chewing, tongue protrusion, lip smacking(make a noise with the lip), puckering(gather into a small wrinkles)

b. Choreiform(jerky involantary movement), athetoid(Twist) or rhythmic movements of neck and trunk (torsion and torticollis) arms and legs (pill rolling, toe tapping and writhing(Twist)

Tardive DyskinesiaClinical course and prognosis

☛ Early signs of tardive dyskinesia can be reversible

☛ If the disease is not detected or allowed to persist, it can become irreversible even with drug discontinuation.

Therapy

☛ Prevention is important

☛ No drug treatment is satisfactory.

☛ Switching to an atypical neuroleptic (clozapine) is the favored first-line therapeutic strategy.

Adverse Effects of NeurolepticsCNS☛ Sedative effects, usually perceived unpleasant by normal individuals (dysphoria,

dizziness).☛ Extrapyramidal effects.☛ Seizures,(neuroleptics lower the convulsive threshold).The risk is substantial with

clozapine (2-5%).

☛ Neuroleptic malignant syndrome (catatonia(person become mute or stuporous), stupor(a condition of near unconsciousness), fever, unstable blood pressure, myoglobinuria). It can be fatal. Dantrolene is the drug of choice, bromocriptine may help.

Gastrointestinal system☛ Xerostomia, constipation.☛ Cholestatic jaundice (mainly with chlorpromazine)☛ Sialorrhea (with clozapine. Up to 70 %)

Adverse Effects of NeurolepticsGenitourinary system☛ Urinary retention, urinary incontinence.☛ Sexual dysfunction (erectile dysfunction, ejaculatory

abnormalities).

Metabolic/Endocrine system☛ Hyperprolactinemia (can lead to amenorrhea, galactorrhea,

anovulation in women, gynecomastia and azoospermia in men)☛ Weight gain (mainly with clozapine and olanzapine)☛ Hyperglycemia, diabetes (mainly with clozapine and

olanzapine)☛ Poikilothermia (with high doses)

Adverse Effects of NeurolepticsCardiovascular system

☛Orthostatic hypotension (manly with lower potency drugs)

☛ Cardiac arrhythmias (mainly with thioridazine) [patients with long Q-T intervals are at greater risk]

☛Myocarditis (with clozapine. The disease can be lethal)

Other adverse effects

☛ Cornea, lens and retinal deposits (mainly with thioridazine)☛ Blurred vision☛Urticaria, skin rash (phenothiazines, 1-5%).☛ Photosensitivity (phenothiazines)☛ Agranulocytosis (with clozapine. About 1%)

Neuroleptic Drug Interactions of Clinical Importance

Neuroleptic Interacting drug Effect of the interaction

All☛ Class 1 and class 3

anti-arrhythmics☛ Quinolones

Life threatening arrhythmias

Low potency typical and most atypicals Anti-cholinergics Increased anti-muscarinic effects

Phenothiazines SSRIs Inhibition of phenothiazine metabolism

Haloperidol Azoles Inhibition of haloperidol metabolism

Haloperidol Lithium Extrapyrimidal effects and/or lithium toxicity are increased

Clozapine Caffeine Inhibition of clozapine metabolism

Clozapine SSRIs Inhibition of clozapine metabolism

Clozapine Ritonavir Strong inhibition of clozapine metabolism

Risperidone SSRIs Inhibition of risperidone metabolism

Summary of Adverse Effects of Neuroleptics

Typical neuroleptics

☛ Low potency drugs (most phenothiazines and thioxanthenes) have low extrapyramidal effects and high or intermediate sedative, antimuscarinic and hypotensive effects.

☛ High potency drugs (fluphenazine, prochlorperazine, butyrophenones) have high extrapyramidal effects and low sedative, antimuscarinic and hypotensive effects.

☛ All drugs increase serum prolactin levels.

☛ All drugs, but thioridazine, have good antiemetic effects.

☛ All drug can cause cardiac arrhythmias, due to an increase in QT intervals.

Atypical neuroleptics

☛ All drugs have low or negligible extrapyramidal effects

☛ All drugs have negligible effects on serum prolactin levels.

☛ All drugs can cause cardiac arrhythmias, due to an increase in QT intervals

☛ Most drugs have significant sedative, antimuscarinic and hypotensive effects.

Summary of Adverse Effects of Neuroleptics

Contraindications and Precautions of Neuroleptics

Contraindications / Precautions Explanations

States of CNS depression Addictive effects

Parkinson’s disease Blockade of D2 receptors can worsen the disease

Seizure disorders Neuroleptic lower the seizure threshold

Catatonia The risk of neuroleptic malignant is increased

Long Q-T intervals, cardiac arrhythmias The risk of polymorphic ventricular tachycardia is increased

Glaucoma Several neuroleptics have pronounced anti-muscarinic effects

Catatonia is a state of neurogenic motor immobility, and behavioral abnormality manifested by stupor.

Contraindications and Precautions of Neuroleptics

Contraindications / Precautions Explanations

Bone Marrow suppression(clozapine)

The risk of clozapine induced agranulocytosis is increased

Hypovolemia, hypotension Several neuroleptics have alpha1 blocking activity

Prostatic hypertrophy Several neuroleptics have pronounced anti-muscarinic effects

History of breast cancer Some breast cancers are prolactin-dependent

Elderly Sensitivity to anti-cholinergic effects is increased.

Therapeutic Uses of NeurolepticsPsychiatric indications

☛ Acute psychosis (manic phase of bipolar disorder, etc.)

☛ Agitation, delirium (in mentally retarded or demented patients)

☛ Irritability, in autistic children and adolescents (risperidone)

☛ Schizophrenia, schizoaffective disorders

☛ Tourette’s syndrome

☛ Huntington’s disease

☛ Alcoholic hallucinosis

Therapeutic Uses of NeurolepticsNonpsychiatric indications

☛ Nausea and vomiting (some phenothiazines)

☛ Neuroleptanalgesia (droperidol & fentanyl)

☛ Pruritus (promethazine)

Notes

☞ Atypical neuroleptics seem to have higher efficacy, particularly for negative symptoms, cognition and mood. However the issue is still controversial.

☞ Only clozapine has shown superiority over other neuroleptics in randomized clinical trials for the management of treatment resistant schizophrenia.