ANTIPSYCHOTIC DRUGS

Writing prescription is easy, understanding people is hard

Franz Kafka, (1883-1924)

Overview

History Introduction Different hypothesis for schizophrenia Classification Mechanism of action Uses Adverse effects Recent advances

History

1931 Sen and Bose – publish therapeutic effect of reserpine in Hypertension and Insanity

Hans Laborit – note the antipsychotic effect of chlorpromazine, which was being tried as preanesthetic medication

1950 - Jean Delay and Piere Deniker conducted trial

1960-1970: identification of D2 blockade as the key mechanism, development of these first-generation of antipsychotic agents

Janssen introduced Haloperidol & Pimozide

Introduction

Neuroleptics/ Major tranquillisers/ Dopamine antagonist

Psychoses and Neuroses Psychotic disorders – Schizophrenia, severe forms of

depression and mania

Symptoms of SchizophreniaPositive symptoms: the presence of inappropriate behaviors

Delusions

Hallucinations

Disorganized talking

Movements

Negative symptoms: the absence of appropriate behaviors

Flat affect

Anhedonia

Catatonia

Dopamine hypothesis

Excessive dopaminergic activity: • Drugs which increase dopamine activity• Postmortem – receptor density high in nucleus

accumbens, caudate, putamen• Imaging studies – amphetamine – high

dopamine in striated areas Diminished dopaminergic activity• Cortical/hippocampal – cognitive and negative• Postmortem – cortical, limbic, nigral, striatal

Serotonin hypothesis

5HT2A and 5HT2C – hallucination 5HT2A- depolarization of glutamate receptors

stabilization of NMDA 5HT 2C- inhibition of cortical dopamine release 5HT1C- anxiolytic effect, exert procognitive effects in

schizophrenia

Glutamate hypothesis

Hypofunctioning of NMDA receptors located on GABAergic interneurons, leading to diminished inhibitory influence on neuron function

GABA ergic activity induce disinhibiton of downstream glutamate activity hyperstimulation of cortical neuron through non NMDA receptor

NMDA requires glycine In schizophrenia, glycine site is not fully occupied

Antipsychotic drugs

Classical neuroleptics

Phenothiazines Thioxanthenes Butyrophenones Miscellane

ous

Novel or atypical

neuroleptics

Phenothiazines

With aliphatic tertiary amine side

chainChlorpromazine

With piperadine moiety in side chain Thioridazine

With piperazine moiety in side chain

Trifluperazine, fluphenazine

Thioxathenes

Flupenthixol

Thiothixene

Butyrophenones

Haloperidol

Benperidol

Droperidol

Domperidone

Miscellaneous

Pimozide

Penfluridol

Molindone

Loxapine

Sulpiride

Remoxipride

Atypical neurolepticsTypical or first generation antipsychotics (FGA)

Atypical antipsychotics or second generation antipsychotics (SGA)

D2 receptor blockade 5HT and Dopamine receptor block

Less effective against negative symptoms

More effective against negative symptoms

Not effective in refractory cases

Effective in refractory cases

More side effects (EPS) Less side effects profile

ClozapineOlanzapine Quetiapine ZotepineRisperidone Ziprasidone Paliperidone Aripiprazole Sertindole

Increased dopamine

Rise in Number of brain D2 receptors

Receptor supersensitivit

y Excess availability of

dopamine due to over production

Reduced destruction through enzyme

deficiency

SCHIZOPHRENIA

MOA of FGA

Typical/ FGA – D2 antagonist Initially – increased synthesis of DA – later

decreases HVA and DOPAC level in blood & urine Molindone, loxapine, sulpiride and amisulpiride In between typical and atypical antipsychotics

Most of the antipsychotics are given orally but incompletely absorbed.

Significant first-pass metabolism. Bioavailability is 25-65%. Most are highly lipid soluble. Most are highly protein bound (92-98%). High volumes of distribution (>20 L/Kg).

Absorption and distribution

Plasma half life • Quetiapine – 7h• Clozapine – 12h• Fluphenazine- 20h (depot – 14.3days)• Haloperidol – 24-48h (depot – 21days)• Olanzapine – 33h

Depot preparation – 2-4 weeks Measurable plasma concentration with I.M route is seen within 15-30min

Most antipsychotics are almost completely metabolized- phase 1 and subsequent phase 2

Exceptions are asenapine(phase 2), ziprasidone(aldehyde oxidase system) and paliperidone(oxidized metabolite)

Most metabolites- inactive. Chlorpromazine – 160 metabolites, 70 have been

identified.

Metabolism & excretion

Uses Psychiatric indication: • Schizophrenia – advantage V/s disadvantage• First psychotic episode – start with atypical• Olanzapine (10mg), risperidone (4mg), quetiapine

(25mg)• 2 weeks later increase the dose

• Previously treated with typical – continue• Long acting depot preparations – haloperidol,

fluphenazine• Rapid tranquillizers – lorazepam – 1-2mg i.v• Haloperidol – 2-10mg i.m

Drug Dose Maximum

Chlorpromazine 25-100mg TDS 1g/day

Thioridazine 50-100mg TDS 800mg/day

Fluphenazine 1-3mg TDS 20mg/day

Trifluoperazine 2-5mg BD 40mg/day

Flupenthixol 3-9mg TDS 18mg/day

Zuclopenthixol 20-50 mg daily 200mg I.M depot

Haloperidol 0.5-5mg TDS 60mg /day

Penfluridol 20-60mg once a week

250mg once a week

Pimozide 2-4mg /day 12mg/day

Loxapine 10-25mg BD 75mg/day

Drug Dose Maximum dose

Sulpiride 400-800mg

Amisulpride 200-400mg/day 1g/day

Levosulpride 200-300mg/day

Aripiprazole 10-15mg/day 30mg/day

Clozapine 12.5mg OD/BD 300mg/day

Olanzapine 5-10mg/day 20mg/day

Risperidone 1mg BD 3mg BD

Paliperidone 6mg/day 12mg/day

Ziprasidone 20mg BD 80mg BD

Quetiapine 25mg BD 300mg BD

• Drug induced psychoses –LSD , amphetamine• Schizo-affective disorder – schizo part – antipsychotic,

affective part – anti depressant or lithium

Neuro psychiatric indication• Tourette’s syndrome – haloperidol or pimozide• Huntington’s disease – haloperidol or chlorpromazine

Non psychiatric indication:• Antiemetic – D2 block at CTZ,GIT – prochlorperazine,

domperidone • Preanaesthetic medication - promethazine • Intractable hiccups – parenteral haloperidol, CPZ

Adverse effects CNS side effects: • Behavioral effects – sedation more with

phenothiazines, thioxanthenes, olanzapineLess with butyrophenones, pimozide

• Tolerance and dependence – tolerance develops to sedation and autonomic side effects

Treatment: Promethazine, Diphenhydramine

Treatment: non selective b-blocker like Propranolol

Treatment: Trihexyphenidyl, Procyclidine

Treatment: withdraw neuroleptic drug and add diazepam

*Parkinsonism • Due to disturbance in

DA-Ach imbalance• Treatment with

anticholinergic- antiparkinsonian drugs•Trihexyphenyidyl,

procyclidine•DO NOT START WITH

LEVODOPA

*Neurolept malignant syndrome•Hyperpyrexia, muscle

rigidity, fluctuating BP, increase CK, myoglobin•Central mechanism•Peripheral mechanism•Stop neuroleptic•Supportive care•Dantrolene•Diazepam, bromocriptine

Autonomic (ANS) side effects:• Alpha adrenergic blockade- Postural hypotension• Antimuscarinic effects- dryness of mouth, constipation

etc. (except clozapine) Endocrinal side effects: chlorpromazine, thioxanthene Agranulocytosis - clozapine Photosensitivity – UV rays oxidizes phenothiazines –

accumulates in melanin containing tissues Retinal pigmentation, , corneal opacities- thioridazine Epileptogenic effects- clozapine, chlorpromazine Poikilothermic effects- impair the ability of hypothalamic

thermoregulation

Mechanism Therapeutic effects

Adverse effects

α1 block -- Dizziness, orthostatic hypotension, reflex tachycardia.

D2 block +ve symptom ↓ EPS & ↑ Prolactin

D1 & D4 block

-ve symptom & EPS ↓

--

H1 block Sedation Drowsiness & ↑ appetite & weight

M block -- Dry mouth, etc.

5-HT2 block

-ve symptom & EPS ↓

Anxiety & insomnia

Toxicities

Thioridazine: ventricular arrythmias, cardiac conduction block, sudden death

Pimozide, ziprasidone: prolong QT, hypokalemia Quetiapine: cataract formation, priapism,

peripheral edema, hyperventilation

Drug Effects

Antacids Decrease absorption of antipsychotics

Anticholinergics Increased anticholinergic effect

Alcohol More sedation

Antithyroid drugs Agranulocytosis

Barbiturates Decreased effect but more sedation

Carbamazepines and phenytoin Decreased effect but lower threshold

Chloroquine May precipitate EPS

Lithium Enhancement of neurotoxicities

Levodopa Decrease efficacy

Oral contraceptives Hyperprolactinemia

Cigarette smoking Increased metabolism

Recent advances

Aspirin Minocycline Raloxifene Estrogen N-acetyl cysteine

Raloxifene

Raloxifene Exhibit agonistic and protective

action on the brain by modulating the

monoaminergic neurotransmission of dopamine,

serotonin and GABA

Addition of Raloxifene (60 mg/day) to regular

antipsychotic treatment ↓ negative, positive &

general psychopathological symptoms in

comparison with women receiving antipsychotic

medication alone (Usall et al., 2011)

Estrogen Short term Rapid membrane effects by altering

functional activity in the dopaminergic synapse (Di

Paolo, 1994)

Long term Modifies synthesis in dopamine receptors

(Di Paolo, 1994)

Estrogen alters serotonergic system (Moses et al.,

2000)

Estrogen promotes neuronal regeneration & blocks

mechanisms of neuronal death (DonCarlos et al., 2009)

N acetyl cysteine

Glutathione is a major antioxidant that protects

cells against oxidative stress (Meister and

Anderson, 1983)

Glutathione potentiates NMDA receptors (Choi

and Lipton, 2000)

Potential future targets

Targeted gene therapy Dysbindin, Neurogelin 1,

COMT, DISC1 Enhancement of BDNF Targets GSK 3, PKC , GABAA receptor PDE inhibitors (particularly at PDE1B) Cannabinoid receptor antagonist Currently glycine transport inhibitors are in trials Preliminary study with LY2140023 (agonist at

glutamate receptor) is also been tried

Thank you