Antipsychotics - drdhriti

Dr. D. K. BrahmaDepartment of Pharmacology

NEIGRIHMS, Shillong

• Drugs having primary effects on Psyche (mind) and – osis (diseased or abnormal condition) – overall the mental process and used for treatment of Psychiatric disorders

• History of psychopharmacology:– Treatment – to “Dope”– 1952 – Chlorpromazine (Reserpine - research)– TCA and MAOI – 1957– Benzodiazepines – 1960– 1980 onwards – novel drugs

• The disease - often imprecise, overlap and depends on predominant symptoms – to decide drug therapy types

• Types of disorders: DSM IV and ICD 101. Psychoses (Disorder of thought, behaviour and to

comprehend reality)2. Affective disorders (Disorder of Mood)3. Neuroses (less serious) – no loss of comprehending of

reality

• Defn.: These are serious Psychiatric illness with serious distortion of thought, behaviour, capacity to recognize reality and of perception (delusion and hallucinations) - Misperception and misevaluation (Loss of contact with reality - loss of ability to comprehend reality)

• Classification:1. Acute and chronic Brain syndromes

(cognitive): Delirium and Dementia. Toxic or pathological basis is present - Brain tumor, Drugs etc. Confusion, disorientation and defective memory and disorganized behaviors.

2. Functional disorders: No underlying cause Schizophrenia (split mind): splitting of

perceptions and interpretations from reality – inability to think coherently and auditory hallucinations

Paranoid states: Paranoid individuals constantly suspect (persecutory) the motives of those around them, and believe that certain individuals, or people in general, are "out to get them."

– Delusion: These are fixed, false beliefs that are outside patient`s culture firmly held. Types – grandeur/persecutory etc.

– Hallucinations: Abnormal sensations. It is a sensory perception without a source in the external world. May be visual, auditory, olfactory and tactile etc.

– Illusion: It is a mistaken or false interpretation of a real sensory experience

False Belief Delusion of Persecution

Pic. 1 Pic. 2

Little Voice Inside My Brain.

The real shadow of the hallucinating person transforms into the corporal image.

Disorders of MoodMania: elation or irritable mood, reduced

sleep, hyperactivity, uncontrollable thought and speech. Associated with violent behaviour

Depression: sadness, loss of interest and pleasure, worthlessness, guilt, physical and mental slowing, self-destructive ideation Bipolar Unipolar

Less severe and ability to comprehend reality is not lost: (mild disorder - anxiety, depression, or hypochondria)

1. Anxiety – unpleasant emotional state - concern for future

2. Phobic states – fear of specific persons/objects/situations

3. Obsessive-compulsive – limited abnormality of thoughts and behaviour, but recurrent intrusive thoughts or ritual like behaviour

4. Reactive depression – physical illness/loss5. Post-traumatic stress disorder – war, riots,

earthquakes and tsunami6. Hysterical

(Neurotransmitters of mental Illness: Dopaminergic and NA and 5-HT)

1. Phenothiazines (S(C6H4)2NH.) : Aliphatic side chains: Chlorpromazine (CPZ),

Triflupromazine Piperidine side chain: Thioridazine and

Mesoridazine Piperazine side chain: Trifluoperazine,

Fluphenazine and Perphenazine2. Butyrophenones:

Haloperidol, Trifluperidol3. Thioxanthenes: Flupenthixol4. Other heterocyclics: Pimozide,

Loxapine, Clozapine5. Atypical antipsychotics: Risperidone,

Olanzapine, Quetiapine, Aripiprazole and Ziprasidone

chondrium

• Tricyclic structure – 2 Benzene rings are linked by a sulfur and a nitrogen atom• Nature of substitute at position 10 influences pharmacological activity• Divided into 3 groups on the basis of substitution at position 10

Effect of CPZ and Reserpine on laboratory animals and psychiatric patients

Differ in Normal and psychotic individuals In Normal: (Neuroleptic syndrome)

Effects are appreciated as neutral or unpleasant (different from typical Barbiturate action)

Indifference to surroundings, paucity of thoughts, psychomotor slowing, emotional quietening, and tendency to go off to sleep (easily aroused)

Minimized spontaneous movements, but no ataxia or slurring of speech

In psychotics:Typical Psychotic patients – less agitated,

more communicative and responsiveAggressive and impulsive behaviour

diminishesOver a period of days –

hallucinations/delusions and others come to normal

Neuroleptics – emotional quietening with neurological effects – tremor, rigidity, bradykinesia etc.

Ataxia and dysarthria do not develope in normal doses

Tranquilizers – major and minor (!)

All phenothiazines, Butyrophenones and Thioxanthenes have same antipsychotic efficacy – but potency differs in equieffective doses Low potency (Aliphatic and piperidines) and high potency

(others)1. Antipsychotic effects: Low potency – more sedation

Prompt sedative action (tolerance develops) Antipsychotic effects take weeks to develop, but no tolerance Valuable in early treatment - added value in agitated psychotic

patients But, not used as anxiolytic or sedative Performance and intelligence are unaffected relatively, but

impaired vigilance – high potency drugs2. Extrapyramidal effects: More with high potency drugs (less

in thioridazone and atypical ones)3. Lowers seizure threshold – low potency drugs (piperazines

- lower propensity)4. Loss of temperature control: High doses – Poikilothermic,

medullary and other vital centres5. Antiemetic action – all except thioridazine

Drugs Sedative Extrapyramidal

Hypotensive

Aliphatic side chain

+++ ++ +++

Piperidine +++ + +++

Piperazine + +++ +

Haloperidol

+ +++ +

• Low Potency: Fewer EPS H1, α1, and muscarinic• High Potency: Higher EPS but lower H1, α1, and muscarinic

Behavioural Effects:Conditioned avoidance response inhibited(Remember, what is it ??)

Dopamine Hypothesis: Dopamine theory of schizophrenia Over activity of DA in limbic area Drugs which increase dopaminergic activity

(amphetamines, levodopa and bromocriptine etc.) – induce or exacerbate schizophrenia

Density of Dopamine receptors in post mortem of untreated – increased

PET in treated and untreated – untreated increased Homovanillic acid (HMV) – changed in treated patients

in CSF and urine Most antipsychotics block postsynaptic D2 receptors in

CNS except clozapine like atypical ones Site of action being limbic system and mesocortical areas But, initial rise in firing of DA neurones and DA activity increases

initially Followed by tolerance to increased activity of DA in Basal ganglia –

Parkinson like effect But, no such effect in limbic area - continued blockade

Hypothesis - Not complete, several atypical ones do not interact with D2 – other receptors - serotonin

ANS: α-blocking activityCPZ = Tflprmzn > thioridazine > clozapine

> fluphenazine > haloperidolMore potent compounds – lesser alpha-

blocking property - weak anticholinergic property

Additionally, Phenothiazines - Weak H1 and anti-5HT property

α-blocking, anticholinergic, weak H1 and anti-5HT

Local anaesthetic action

Skeletal muscle – no prominent action, spinal reflexes are not affectedReduce certain types of spasticity (Basal

ganglia action)

Drugs Receptors blocked

CPZ α1, D2 and H1

Haloperidol, Fluphenazine and Thioxanthenes

D2 only

Promethazine D2 and H1

Clozapine, Risperidone Serotonin

CVS: Postural hypotension – By central and peripheral actionAlmost equal to α-blocking drugs Less prominent in psychotics

Endocrine: Increase in release of prolactin – galactorrhoea and GynaecomastiaReduction in gonadotropin secretionACTH release in response to stress

decreasedGH release reducedDecreased ADH release

Absorbed orally, but unpredictable and parenterally - better

Bioavailability low – enterohepatic circulation Long biological half life Bound to plasma protein and tisue protein - Large

Vd – 20 L/kg (higher CNS entry than plasma) Metabolized by liver by hydroxylation Cumulation action – once a day dose maintenance Excreted in urine and Bile (6 to 12 months) Available as tablets 10, 25, 50 and 100 mg tabs, Syr.

and injections

1. CNS: Drowsiness, lethargy and mental confusion Increased appetite and weight gain Aggravation of seizures

2. CVS: Postural hypotension, palpitation, inhibition of

ejaculation – more with thioridazine and low potency drugs

3. Anticholinergic: Dry mouth, constipation, blurring of vision and

urinary hesitancy - more common with thioridazone

Hypersalivation - clozapine

4. Endocrine: Hyperprolactinemia. Lowers Gn hormones but infertility, amenorrhea and gynaecomastia is uncommon

5. Extrapyramidal disturbances: Parkinsonism – rigidity, tremor, hypokinesia (1-4

wks) Dose reduction or anticholinergics rabbit syndrome – years after therapy

Acute muscular dystonia (acute onset) – grimacing, tongue thrusting, torticollis and locked jaw etc. – initial therapy – resolve spontaneously

Akathisia (1-8 weeks): 20% cases- restlessness, agitation, compulsive desire to move about

Anticholinergics/Propranolol - stoppage Tardive dyskinesia: constant chewing, pouting, lip

licking etc. – accenuated by anticholinergics – uncommon with newer ones

Malignant neuroleptic syndrome – Rare, high doses of potent agents – rigidity, tremor, immobility, semiconsciousness, fluctuation in BP and Myoglobinemia – must stop, Dantrolene

6. Weight gain: risk of diabetes worsening – clozapine, less with Haloperidol. Blue pigmentation of exposed skin, lenticular opacities and degeneration

7. Hypersensitivity reactions: Cholestatic jaundice – common with CPZSkin rash, urticaria, photosensitivity etc.Agrannulocytosis – clozapineMyocarditis - clozapine

1. Triflupromazine: More potent than CPZ, used mainly as antiemetic

causes muscle dystonia in children

2. Thioridazone: Marked Anticholinergic action, but less EPS

cardiac arrhythmia and sexual function retardation

3. Trifluoperazine and fluphenazine: High potency, less sedation, more EPS effect

Butyrophenone derivative, Potent antipsychotic Strong D2 blocker Preferred in acute schizophrenia in highly

agitated patients Less autonomic effects, no weight gain and less

epiletogenic Marked EP effects to produce parkinsonism Irreversible toxic encephalopathy – used along

with lithium Orally 1.5 mg to 7.5 mg and 2 – 10 mg IV and

repeated every Hrly upto 30 mg Available as 0.5 mg, 1.5 mg and 5 mg tablets E1/2 is 24 hrs

Positive scale Delusions Conceptual disorganization Hallucinations Hyperactivity Grandiosity Suspiciousness/persecution Hostility

Relieved by Antipsychotics

Negative scale Blunted affect Emotional withdrawal Poor rapport Passive/apathetic social

withdrawals Difficulty in abstract

thinking Lack of spontaneity and

flow of conversation Stereotyped thinking

Less Relieved by Antipsychotics

• Better control of positive symptoms than negative symptoms

Cognitive, affective and Motor disturbances – relieved overall

Little improvement in judgment, memory and orientation

Some patients do not respond (90% responds)

Only symptomatic relieve, does not remove the cause – lifelong treatment may require

Choices of Drugs: Patient dependent, empirical and guided by presenting symptoms

Individual patients differ in response to different drugs

Symptoms Drugs

Agitated and violent CPZ, Thioridazine and Haloperidol

Withdrawn and apathetic

Trifloperazine and Fluphenazine

Negative symptoms Clozapine and olanzapine, risperidone and aripiprazole

Mood elevation Haloperidol, fluphenazine and olanzepine

Mania: CPZ or Haloperidol – IM or IV Organic Brain Syndromes:

Not very effective, used as short term therapy

Acute cases to control aggressionAs adjunct to nonsedatives to control

exacerbations of violent behaviourTCAs in depressed ones

Antiemetic and anti-anxiety Other Uses: Potentiation of

anaesthetics, Intractable Hiccough, Tetanus and Alcoholic hallucinations

Pharmacological actions, Mechanism of action and Adverse effects of CPZ /Haloperidol