• 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c) Thought disorder• Wild train of thoughts• Draw irrational conclusion with the feeling that thoughts are inserted or withdrawn by an outside agency.• Usually not like to be interfered, flight of ideas from one thought to other thought.• Broadcast of ideas.• d) Abnormal stereotypical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,
• 2. Negative Symptoms:•• Result from brain atrophy• Don’t respond / less responsive to R x• 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
• 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
• 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:
• 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.
• 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:
Classification of Antipsychotic DrugsA: Classical / Typical Antipsychotics.I. Phenothiazine Derivatives a. Aliphatic compounds Chlorpromazine Promazine. b. Piperazine Compounds: Procholorperazine Perphenazine Fluphenazine Trifluperazine c. Piperidine Compounds: Thioridazine Mesoridazine
MOAAct 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:-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
Ph. 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
• ) 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 CTZ7. Endocrinal Effects8. 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
B: PERIPHERAL EFFECTS1. 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
• 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
Adverse effects1. Neurological side effects• Parkinsonism• Acute dystonias• Neuroleptic malignant syndrome• Akathisia• Tardive Dyskinesia• Perioral tremor (Rabbit syndrome)2. ANS effects3. ECG Changes4. Tolerance & Physical Dependence5. Reverse Tolerance or super sensitivity.4. Cholestatic Jaundice
5. Endocrinal effects6. Hypothermia / Hyperthermia7. Dermatitis8. Opacities in lens and cornea9. Blood Dyscrasias10. Drug Interactions
• 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.
• 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
– More macked occulax eff.• Deposit in retina browning of vision.• Picture res emble that of retinitis pigmentosa pt.• Potency—related to dose.