Neuroleptics(Anti-psychotic Drugs)

Kaukab Azim, MBBS, PhD

Drug List

Typical Neuroleptics(First generation anti-psychotics) Atypical Neuroleptics

(second Generation anit-psychotics

Phenothiazines Butyrophenones Others

Chlorpromazine Haloperidol Thiotixene Clozapine

Thioridazine Molindone Olanzapine

Fluphenazine Qietiapine

Prochlorperazine* Risperidone

Aripiprazole

* Will be covered in another lecture

Learning Outcomes

By 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.

Pathways of Dopaminergic SystemPathway Connections Function

Mesolimbic

From midbrain ventral tegmentum to:☞ Amygdala☞ Olfactory tubercle☞ Septal nuclei☞ Nucleus accumbens

☞ Arousal☞ Memory☞ Stimulus processing☞ Motivational

behaviour

MesocorticalFrom midbrain ventral tegmentum to:☞ Prefrontal cortex☞ Frontal cortex

☞ Cognition☞ Communication☞ Social function☞ Response to stress

NigrostriatalFrom substantia nigra to:☞ Caudate Nucleus☞ Putamen

☞ Movement

Tubero-infundibular

From hypothalamic arcuate nuclei and periventricular neurons to:☞ Posterior pituitary

☞ Regulation of prolactin release

The Dopamine Hypothesis of Schizophrenia

• The dopamine hypothesis of schizophrenia proposes that the illness results from an abnormality in dopamine neurotransmission in mesolimbic and mesocortical pathways.

• The hypothesis is supported by the following observations:

1. Most antipsychotic drugs block D2 receptors and there is a very good correlation between clinical potency of these drug and their in vitro affinity for these receptors.

2. Dopaminergic agents (cocaine, amphetamines, levodopa, etc.) can induce a schizophrenic-like behavior and exacerbate the symptoms of schizophrenia.

3. An increased density of dopamine receptors has been found in caudate nucleus and a decreased density in the prefrontal cortex of untreated schizophrenics.

4. The earliest sign of brain disturbances in schizophrenia is a decrease in blood flow in a region of the basal ganglia (a region very rich in dopamine receptors)

The dopamine hypothesis has been further elaborated by Weinberger who proposed that:

1. An increase activity in the mesolimbic pathway would account for the positive symptoms of schizophrenia.

2. A decreased activity in the mesocortical pathway would account for the negative symptoms of schizophrenia.

3. The activity of the mesocortical pathway normally inhibits the mesolimbic pathway. Therefore the primary defect in schizophrenia should be a reduction in this activity.

The dopamine hypothesis of schizophrenia is not fully satisfactory but provide a useful model for future research.

The Serotonin Hypothesis of Schizophrenia

• The discovery that indole hallucinogens such as LSD (lysergic acid diethylamide) and mescaline that are serotonin (5-HT) agonists led to the search for endogenous hallucinogens in the urine, blood, and brains of patients with schizophrenia.

• This proved fruitless, but the identification of many 5-HT-receptor subtypes led to the crucial discovery that 5-HT-receptor stimulation was the basis for the hallucinatory effects of these agents.

• It has been found that 5-HT2A receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine.

• These drugs are inverse agonists of the 5-HT2A receptor; that is, they block the constitutive activity of these receptors. These receptors modulate the release of dopamine in the cortex, limbic region, and striatum.

• Stimulation of 5-HT2A receptors leads to depolarization of some glutamate neurons, but also postsynaptic NMDA receptors.

The Glutamate Hypothesis of Schizophrenia

• Glutamate is the major excitatory neurotransmitter in the brain.

• Phencyclidine and ketamine are noncompetitive inhibitors of the NMDA receptor that exacerbate both cognitive impairment and psychosis in patients with schizophrenia.

• This was the starting point for the hypothesis that hypofunction of NMDA receptors, located on GABAergic interneurons, leading to diminished inhibitory influences on neuronal function, contributed to schizophrenia.

• The diminished GABAergic activity can induce disinhibition of downstream glutamatergic activity, which can lead to hyperstimulation of cortical neurons through non-NMDA receptors.

• Ampakines are drugs that potentiate currents mediated by activation of AMPA-type glutamate receptors.

• In behavioral tests, ampakines are effective in correcting behaviors in various animal models of schizophrenia and depression.

• They protect neurons against neurotoxic insults, in part by mobilizing growth factors such as brain-derived neurotrophic factor.

Pharmacodynamics of Neuroleptics

Mechanism 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

Neuroleptic 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 Neuroleptics

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

• Negative schizophrenic symptoms are minimally affected by typical neuroleptics but more so by atypical neuroleptics (the higher blockade of 5-HT2 receptors may contribute to this effect).

Other effects

• Inhibition of nausea and vomiting (due to blockade of D2 receptors mainly in the CTZ

• 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)

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 +++

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, stupor, 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 %)Genitourinary 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: the inability to maintain a constant

core temperature (with high doses)

Cardiovascular system

• Orthostatic hypotension (mainly 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%)

Relative incidence of Adverse Effects of Neuroleptics

DrugExtra

PyramidalSymptoms

ProlactinElevation Sedation Anticholinergic

EffectsPostural

Hypotension

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-Parkinson DrugsBenzodiazepinesPropranolol

Parkinsonism Bradykinesia, rigidity, tremor

DopamineAntagonism Anti-Parkinson Drugs

Tardive dyskinesia

Oral-facial, dyskinesia, choreoathetosis,Dystonias

Up-regulation of D2 receptors

Prevention. Treatment is unsatisfactory

Tardive DyskinesiaOccurrence

Typical neuroleptics (with high extrapyramidal effects):

• Incidence is about 5% per year.• Prevalence is about 20% with long term treatment.

Atypical neuroleptic:

• Incidence is about 1% per year.

Etiology

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

Pathogenesis

• The exact cause is unknown. Proposed mechanisms are:A. Up-regulation of D2 receptors in caudate-putamen.

B. Disturbed balance between dopaminergic and cholinergic system

C. Dysfunction of GABAergic and noradrenergic systemD. Neurotoxicity (via free radicals).

Symptoms and signs

• Tardive dyskinesia is characterized by:

A. The buccal-lingual masticatory syndrome (grimacing, chewing, tongue protrusion, lip smacking, puckering)

B. Choreiform, athetoid or rhythmic movements of neck and trunk (torsion and torticollis) arms and legs (pill rolling, toe tapping and writhing)

Clinical 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.

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

Neuroleptic Interacting drug

Effect of the interaction

Haloperidol Lithium Extrapyramidal effects and/or lithium toxicity are increased

Clozapine Caffeine Inhibition of clozapine metabolismClozapine 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.

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 Neuroleptics

Nonpsychiatric 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.

GOOD LUCK