9. antipsychotics

Antipsychotics/Major Tranqullizers/Neuroleptics Antipsychotics/Major Tranqullizers/Neuroleptics or or

Anti-schizophrenic drugsAnti-schizophrenic drugs• Psychosis

1. Schizophrenia

2. Organic Psychosis

3. Affective disorders – Depression – Mania – Manic depressive illness (bipolar

depression)

• Etiology:

• Not known

• Strong but incomplete genetic pre-disposition

• (1st degree relatives – 10%)

• (2nd monozygotic twin – 50%)

• suicide is about 10% cases

• Symptoms:

• 1.Positive symptom: (result from Neurochemical Abnormality)

• Increase do paminergic transmission Respond well to Rx

• Delusions often paranoid in nature:

cann’t be rectified by reasoning

• Hallucinations:

• They may be

• Visual

• Auditory

• Tactile (CD Canine bugs)

•  

• c) Thought disorder

• Wild train of thoughts

• Draw irrational conclusion with the feeling that thoughts are inserted or withdrawn by an outside agency.

• Usually not like to be interfered, flight of ideas from one thought to other thought.

• Broadcast of ideas.

• d) Abnormal stereotypical behavior, usually aggressive.

• e) Defectiveness in selective attention unnecessary voices are ignored but he can’t ignore unnecessary voices

• 2. Negative Symptoms: •

• Result from brain atrophy

• Don’t respond / less responsive to Rx

•  Emotional blunting.• Poor Socialization• Cognitive deficit (Dementia)• more irritable.

• Neurochemical Basis:• 1) Dopamine Theory (Hypothesis by Carlson

awarded noble prize in year 2000)• Dopamine hyperactivity in mesolimbic and

mesocortical pathway & amygdale positive symptoms of schizophrenia.

• Proof:• Dopamine agonists – produce these symptoms of

schizophrenia e.g. central sympatholytics Amphetamines)

• Block Dopamine recap Improve the symptoms

• 2) Glutamate Theory– Glutamate and DA exert excitatory and inhibitory effects

respectively on GABA ergic striatal neurons which project to thalamus and constitute “sensory Gate”

– Glutamate or DA disables the gate and uninhibited sensory input reaches the cortex.

– Glutamate NMDA (N-methyl deaspartate) recep antagonists:

• Phencyclidine • Katamine Produce Psychotic Symtoms• Dizoclipine

• 3) 5 – HT Theories:

• 5 – HT dysfxn

• LSD & 5-HT2 Receptors agonists produced schizophrenia like syndrome.

•  

• Mostly of Anti-psychotics in addition to affect dopamine also back serotonin receptors.

• 4) Current views:

• Combination of DA hyperactivity with 5-HT & glutamate dysfxn.

• 1) Nigrostriatal Pathway: • 75% of dopamine in brain • 2) Mesolimbic mesocortical pathway:• Projects from neurons near S.N to limbic system &

Neocortex• Behaviorial effects• Hyperactivity leads to schizophrenia.• 3) Tuberoinfundibular (Tubrohypophy Scal) Pathway:• Connects arcuate nuclei & prevent nuclei

hypothalamus and post pituitary. Regulation endocrine control – control MSH, GH, Prolactin.

• 4) Medullary Perventricular Pathway:• From neurons of Motor Nucleus of Vagus ___

Periventricular nuclei • Eating behavior• Satiety center ____ Bolimia Nervosa • Appetite Cetre _____ Anorexiz Nervosa• 5) Incertohypothalamic Pathway:• From medial zone incerta to hypothalamus & Amygdala.• Sexual drive, Microvasculatory function and

temperature regulation

• 5) Incertohypothalamic Pathway:• From medial zone incerta to hypothalamus & Amygdala.• Sexual drive, Microvasculatory function and

temperature regulation.• 6) Many local Dopaminergic Neurons in olfactory

cortex & retina:• 7) Dopaminergic transmission in periphery:• - Renal Vasculatory• - Mesenteric pathway• - CVS

Classification of Antipsychotic Classification of Antipsychotic DrugsDrugsA: Classical / Typical Antipsychotics.

I. Phenothiazine Derivativesa. Aliphatic compounds

Chlorpromazine Promazine.

b. Piperazine Compounds:Procholorperazine Perphenazine

Fluphenazine Trifluperazine

c. Piperidine Compounds:Thioridazine

Mesoridazine

• A) Classical Typical Nemoleptics:

• 1. Phenothiazines:

• a) Aliphatic Comp• (less potent,sedation & weight gain)

• Chloropromazine (Largactil)• Promazine• Triflupromazine

• b) Piperidine Derivative:• Thioridazine (Melleril, less potent, Anti-Cholinergic)• Mesoridazine (metabolite of thioridazine)

• c) Piperazine Derivative:• Fluphenazine (I/V preparation, slowly, release, • Perphenazine • Trifluperazine • Prochlorperazine • Thioperazine .

• 2. Thioxanthines: (also available as DEPOT preparation)

• Thiothixene

• Clopenthixol

• Flupenthixol

• Chlorprothixine

• 3. Butyrophenones:

• Haloperiodol

• Properidol

• Benperidol

• B) Atypical Neuroleptics:

• Their mechanism of action is different from anti-psychotics

• Loxapine

• Clozapoine (Clozanl) ___ A/E: Cause agranulocyctosis ___ Bone marrow depression

• Risperidone ____ commonly used D2 5HT2 selective activity for D4 receptors

• Olanzapine __ Disadv: cause agranulocytosis

• Ziprasidone(patients resistant to other drugs. Also Rx of negative effects)

• Sulpirdie (D2 selective)

• Remazopride• Remoxipride

• Pimozide (D2 selective) long acting indole

• Quetiapine• Aripiprazole

II. Butyrophenone Derivatives Haloperidol Droperidol

III. Thioxanthenes Thiothixene Flupenthixol

IV. Rauwolfia Alkalois Reserpine

B. Newer / Atvpical AntipsychoticsMiscellaneous Structures. Clopazine Olanzapine Quetiapine Pimazole Pimazole Sulpiride Risperidone

C: Drugs used for Manic-Depressive Disorders: Lithium carbonate

Phenothiazines• Chemistry & Structure

• Pharmacokinetics

MOAMOA

Act on a variety of CNS & Peripheral receptors – Post synaptic D2 receptor blockade – 5 HT2 receptor blockade – Muscarinic receptor blockade – Ganglion blockade– Quinidine like effects– Alpha-1 adrenergic blockade – Local anaesthetic like activity

MOA of Antipsychotic effect:-MOA of Antipsychotic effect:-

Acts by blocking Post Synaptic D2 receptors in Dopaminergic pathways in CNS.

Three important Dopaminergic pathways • Mesolimbic mesocortical pathway• Nigrosticatad pathway• Tuboinfundibuar pathwayAdditional Pathways • Medullary periventricular pathway• Incertohypothalamic pathway

Dopamine Receptors

Ph. ActionsPh. Actions• a) PTS:

• No loss of intellectual functions and performance (clear sensorium)

• Alteration of deranged thought process

• Emotional quietening

• Psychomotor slowing

• Antagonism of behavior eff. of amphetamine

• Decreased paranoid idea

• Decrease initiative

• Decrease aggressiveness

• b) NORMAL (NON -PSYCHOTICS)• unpleasant feelings due to • Sleepiness, restleseness• Autonomic effects : b/c of muscarinic blockade• unpleasant feelings due to • Sleepiness, restleseness• Autonomic effects : b/c of muscarinic blockade

2. Effect on motor activitya.Decreased spontaneous activity b.Extra Pyramidal symptoms • Parkinsonism • Acute dystonias• Neuroleptic malignant syndrome • Akathisia• Tardive Dyskinesia • Perioral tremor (Rabbit syndrome)

• ) DECREASE SEIZURE THRESHOLD:• Convulsive potential• High dose: cause convulsion cause seizure in

patients of epilepsy• Aggrevate epilepsy• If anti-epilepsy is taken by epilepsy potent, he

has to increase the dose• Potentiate cause of seizure latent epilepsy

patient

6. Effect on CTZ

7. Endocrinal Effects

8. Hypothermia/ Hyperthermia

• a) ANTICHOLINERGIC• b) ADRENOCEPTORS BLOCKADE• Orthostatic hypotension• Less less with halo oeriod of flupenthixol and

eluphenazine and other non phenothiazines except clozapine

• c) WEAK GANGLIONIC BLOCKADE:• Both symp and P/symp ganglionic blockade . Non

blockade cz transmission in both is cholinergic

B: B: PERIPHERAL EFFECTSPERIPHERAL EFFECTS

1. Effect on ANS 2. Effect on CVS 3. Quinidine like anti-arrhythmic effect on heart 4. Miscellaneous

– LA effect– Renal effects – Effect on Liver– Antihistaminic action– Skeletal muscle relaxant effect

• v) RESP. CONTROL:

• Depressant effect

• No permanent effect in N individual

• No prominent effect in psychotic pt having N respiration

• But if he suffers from resp. diseases such as Asthama them resp. depression

• vi) ENDOCRINE EFFECT:

• hyper prolactinemia and inflextility DA, control prolactin (check its release),if block hyper prolactinemia manifested by Gynecomastia in infertility in male and female

• ix) ANTIEMETIC ACTION:

• Because of DA recep blockade in CRTZ. Useful in drug induced vomiting and other vomiting except motion sickness and vomiting in pregnancy

• x) TEMP. REGULATION:

• Dopaminergic transmission to hypothalamus is blocked. Temperature regulation is lost person because poikelothermic

• xiii) SK.MUSCLES:• in high doses themselves cause convulsion and spasm• 2) CVS• -ve isotropic effects more thioridazine cause death in

young children• Decrease stroke volume and decrease CO• Decrease TPR and alpha adrenergic blockade

vasodilation decrease B.P.• Decrease B.P • Increase H.R barorecceptor, increase QT interval

Adverse effects1. Neurological side effects• Parkinsonism • Acute dystonias• Neuroleptic malignant syndrome • Akathisia• Tardive Dyskinesia • Perioral tremor (Rabbit syndrome) 2. ANS effects3. ECG Changes 4. Tolerance & Physical Dependence5. Reverse Tolerance or super sensitivity.4. Cholestatic Jaundice

5. Endocrinal effects

6. Hypothermia / Hyperthermia

7. Dermatitis

8. Opacities in lens and cornea

9. Blood Dyscrasias

10.Drug Interactions

Therapeutic UsesTherapeutic Uses

A. Treatment of Psychiatric patient

1. Schizophrenia

2. Organic Psychosis

3. Bipolar depression

B. Nausea & vomiting

C. Alcoholic hallucinition

D. Intractable Hiccough

• NEUROLEPTIC POISONING:• Can be homicidal less common suicidal less

chances occure in extreme of disease.• Rarely fatal except thio & mesoridazine duer

jto cacdio depressive neuro musculal, excitability. Convulsions.

• Pt. comatosed.• Hypothermia, miosis, deep• Tendon reflexes.• Tachycacdia• Thioridazine.• RX:

• *Monitos vcital fxns.

• * Gastric lavage with activated charcoal

• *Saline catharsis (Na2SO4Mgo)

• * Fluid replacement

• * Pressor agents.

• Diaqzepam for seizerres I/V.

•  

• PIPERIDINE DERIVATIVE:• THIORIDAZINE:

– Block D2,x-1 & 5HT-2– More potent anti muscacinics

• Extrapyramidal (packinsonian) symptoms duer jto blockade of D2 and balance is disturbed, in this case balance is notr distubedf when cholinergicx activity es.– Sinilac B.A (2s-30%)– More cacdiotoxic– Less extra pyramidal eff.

– More macked occulax eff.

• Deposit in retina browning of vision.

• Picture res emble that of retinitis pigmentosa pt.

• Potency—related to dose.

Newer/ Atypical anti-psychotics Newer/ Atypical anti-psychotics