Download - Antipsychotic drug
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