1. Neuroleptics (Anti-psychotic Drugs) Kaukab Azim, MBBS, PhD

2. Drug List Typical Neuroleptics (First generation anti-psychotics) Atypical Neuroleptics (second Generation anit- psychotics PhenothiazinesButyrophenonesOthers ChlorpromazineHaloperidolThiotixeneClozapine ThioridazineMolindoneOlanzapine FluphenazineQietiapine Prochlorperazine*Risperidone Aripiprazole * Will be covered in another lecture

3. 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.

4. 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 D 2 ) and/or serotonin (mainly 5-HT 2A ) receptors. ☛ The adverse effects of neuroleptics seem to result from the blockade of D 2 receptor in the substantia nigra as well as from blockade of a variety of receptors both in the central and autonomic nervous system

5. Pharmacodynamics of Neuroleptics 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 D 2 antagonism and low 5-HT 2A antagonism. 2.Atypical agents ☛ These drugs have low (clozapine) or moderate D 2 antagonism and high 5-HT 2A antagonism.

6. 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(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-HT 2 receptors may contribute to this effect).

7. Pharmacodynamics of Neuroleptics Other 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)

8. 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)

9. Receptor Affinity of Typical and Atypical Neuroleptics D2D2 D4D4 5-HT 2A H1H1 MAlpha 1 Typical agents (first generation neuroleptics) Chlorpromazine+++0++ +++ Thioridazine+++0++++++ Fluphenazine+++0+00+ Haloperidol+++0+00+ Atypical agents (second generation neuroleptics) Clozapine++ ++++ Aripiprazole+++0+++0 Quitiapine++++++ Olanzapine+++++++++++++ Risperidone++++ +0

10. Relative incidence of Adverse Effects of Neuroleptics Drug Extra Pyramidal Symptoms Prolactin Elevation Sedation Anticholinergic Effects Postural Hypertension ChlorpromazineMediumPresentHigh ThioridazineLowPresentHigh FluphenazineHighPresentLow HaloperidolHighPresentLow ClozapineVery LowNoneHigh QuetiapineVery LowNoneMediumLowMedium OlanzapineVery LowNoneMediumHighMedium RisperidoneMediumPresentMediumLowMedium AripiprazoleVery LowNoneLow Medium

11. Extrapyramidal Adverse Effects of Neuroleptics SyndromeFeatures Proposed mechanism Treatment Acute dystonia Spasms of muscles of tongue, face, and neck Unknown Anti-Parkinson Drugs AkathisiaMotor restlessnessUnknown Anti-Parkinson Drugs Benzodiazepines Propranolol Parkinsonism Bradykinesia, rigidity, tremor Dopamine Antagonism Anti-Parkinson Drugs Tardive dyskinesia Oral-facial, dyskinesia, choreoathetosis, Dystonias Up-regulation of D2 receptors Prevention. Treatment is unsatisfactory

12. Tardive Dyskinesia Etiology 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)

13. Tardive Dyskinesia 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.

14. Adverse Effects of Neuroleptics CNS ☛ 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 %)

15. Adverse Effects of Neuroleptics 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 (with high doses)

16. Adverse Effects of Neuroleptics Cardiovascular 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%)

17. Neuroleptic Drug Interactions of Clinical Importance NeurolepticInteracting drugEffect of the interaction All ☛ Class 1 and class 3 anti-arrhythmics ☛ Quinolones Life threatening arrhythmias Low potency typical and most atypicals Anti-cholinergicsIncreased anti-muscarinic effects PhenothiazinesSSRIsInhibition of phenothiazine metabolism HaloperidolAzolesInhibition of haloperidol metabolism HaloperidolLithium Extrapyrimidal effects and/or lithium toxicity are increased ClozapineCaffeineInhibition of clozapine metabolism ClozapineSSRIsInhibition of clozapine metabolism ClozapineRitonavirStrong inhibition of clozapine metabolism RisperidoneSSRIsInhibition of risperidone metabolism

18. 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.

19. 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

20. Contraindications and Precautions of Neuroleptics Contraindications / PrecautionsExplanations States of CNS depressionAddictive effects Parkinson’s disease Blockade of D 2 receptors can worsen the disease Seizure disordersNeuroleptic 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 GlaucomaSeveral neuroleptics have pronounced anti- muscarinic effects Catatonia is a state of neurogenic motor immobility, and behavioral abnormality manifested by stupor.

21. Contraindications and Precautions of Neuroleptics Contraindications / PrecautionsExplanations Bone Marrow suppression (clozapine) The risk of clozapine induced agranulocytosis is increased Hypovolemia, hypotension Several neuroleptics have alpha 1 blocking activity Prostatic hypertrophy Several neuroleptics have pronounced anti- muscarinic effects History of breast cancerSome breast cancers are prolactin-dependent Elderly Sensitivity to anti-cholinergic effects is increased.

22. Therapeutic Uses of Neuroleptics Psychiatric 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

23. 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.