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Antipsychotic Drugs

 

  • Psychosis denotes a variety of mental disorders: the presence of delusions (false beliefs), various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory, and grossly disorganized thinking in a clear sensorium.
  • Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance.
  • Psychosis is not unique to schizophrenia and is not present in all patients with schizophrenia at all times. 

Cause:
 

1. Serotoneric Hypothesis 5-HT2A-receptor and possibly 5-HT2C stimulation is the basis for the hallucinatory effects.
2. Dopaminergic Hypothesis Relevant to understanding the major dimensions of schizophrenia, such as positive and negative symptoms (emotional blunting, social withdrawal, lack of motivation), cognitive impairment, and possibly depression.
3. Glutamate Hypothesis Hypofunction of NMDA receptors, located on GABAergic interneurons, leading to diminished inhibitory influences on neuronal function, contributed to schizophrenia.

Drugs:

  • Two types:

Typical (1st generation, Older drugs)  - Atypical (2nd generation, New drugs)

  1. Typical antipsychotics:
  1. Phenothiazines
    1. Aliphatic
      i. Chlorpromazine (LARGECTIL)        
      ii. Prochlorperazine
    2. Piperazines
       
      i. Trifluperazine                        
       
      ii. Fluphenazine
    3. Piperadines
      i. Thioridazine                  
      ii. Mesoridazine
  1. Thioxanthenes
    Thiothexene
  1. Butyrophenones
    i. Haloperidol   
    ii. Droperidol           
    iii. Penfluridol           
    iv.
    Flupenthixol
  1. Miscellaneous
    i. Pimozide               
    ii. Molindone            
    iii. Amisulpride         
    iv. Sulpride

 

B. Atypical antipsychotics

  • New drugs (2nd generation)
    i.Risperidone               
    ii. Iloperidone               
    iii. Paliperidone     
    iv. Clozapine                             
    v. Olanzapine               
    vi. Quetiapine       
    vii. Sertindole         
    viii. Ziprasidone              
    ix. 
    Aripiperazole

 

Mechanism:

Older / Neuroleptics

Newer

D-2 Receptor Blockage

Extrapyramidal Syndrome

Epileptogenic

Antiemetic

Prolactin Release

5-HT2, α Blockers, D-4 Blockers

Weight Gain

Hyperlipidemia

Dm

  1. Older drugs-D2 block (mesolimbic system, nigrostrial, tubuloinfundibular pathyway), new drugs, 5-HT2 & D4 blockers
  2. Aripiperazole (D2), ziprasidone (D1)-partial agonists

Dopamine receptors

  1. Dopaminergic receptors are GPCRs; D1, D5, are similar.

D1, D5

Brain; Renal vascular bed

Stimulation of adenylyl cyclase and increased cAMP.

D2

Brain, smooth muscle; presynaptic nerve terminals

Inhibition of adenylyl cyclase; increased potassium conductance

D3

Brain.

Inhibition of adenylyl cyclase

D4

Brain, cardiovascular system

Inhibition of adenylyl cyclase

 

P/K

  1. Well absorbed
  2. Lipid soluble
  3. High volume of distribution
  4. Metabolized quickly to inactive products
  5. Do not induce or inhibit microsomal enzymes
  6. Two antipsychotics are prodrugs:
  • Thioridazine forms mesoridazine
  • Loxapine forms amoxapine
  1. Half life of chlorpromazine (2 hours), penfluridol longest acting

Variations

  1. Rate of metabolism varies
  2. Indians require low dose, compared to westerners.

Uses:

  1. Chlorpromazine (Laborit’ 1951)
    1. LEAST POTENT D-2 BLOCKER                        
    2. S/E Heatstroke, hiccups, Cholestatic jaundice
  2. Haloperidol (DOC)
    Highly Potent D-2 Blocker (also TRIFLUPERAZINE, FLUPHENAZINE), hence greatest Chance Of EPS

USE:

  1. Gilles de la Trourette                    
  2. Delirium                      
  3. Psychosis in renal & hepatic   failure
  4. Huntington’s disease                  
  5. Acute schizophrenia      
  6. Acute mania
  1. Thioridazine
    Least potent D-2 blocker, have Alpha-2 blocking property also.

S/E:

  • Inhibit ejaculation,
  • QTC Prolongation,
  • Retinal damage
  1. Penfluridol - longest acting
    Atypical Antipsychotics: 
  2. Clozapine
  • 5-HT2, α , D-4 blocker
  • Suppress both positive and negative symptoms

Uses:

  1. Refractory schizophrenia
  2. Schizophrenia with negative symptoms
  3. Schizophrenia with extrapyramidal symptoms (EPS)
  4. Late onset psychosis
  5. Schizophrenic symptoms in Alzheimer’s or Parkinson’s disease
  6. Antisucidal drug (only drug approved for this condition)

                        

S/E:

  1. Convulsion (Dose Dependant)
  2. Agranulocytosis (Dose Independent)
  3. Myocarditis
  4. Antimuscarinic Effects
  5. Severe Ileus, Sialorrhea
  1. Risperidone
  • Potent D-2 blocker than clozapine,
  • Causes Hyperprolactinemia
  1. Olanzapine
  • Similar to risperidone (POTENT D-2 BLOCKER)
  • Causes: SEIZURES, WEIGHT GAIN, STROKE, and SUDDEN DEATH.
  • Also used in: ACUTE MANIA, BIPOLAR DISORDER  
  1. Ziprasidone
  • Does Not Cause Seizures, Weight Gain, Stroke
  • S/E: QTC Prolongation

Uses:

  1. Generalized anxiety disorder
  2. SSRIs are also used in Generalized anxiety disorder
  1. Quetiapine
  • S/E: Cataract formation
  • Shortest acting atypical antipychotic 
  1. Aripiprazole
  • SEROTONIN-DOPAMINE STABILIZER
  • Partial agonist at 5-HT1A and D-2 receptors. Antagonist at 5-HT2A receptors
  • USE: Autistic disorder in children 
  1. Other antipsychotics
    1. Antiemetics except thioridazine (No such action)
    2. Asenapine is used sublingually for Schizophrenia

Toxic Potential

Highly

Clozapine, Olanzapine

Intermediate

Quetiapine

Low

Resperidone, Paliperidone

Least

Ziprasidone, Aripiprazole, Asenapine

 

Side effects

  1. Sedation is MC
    1. Maximum with Chlorpromazine, minimum with Haloperidol
  2. Weight gain
    1. Maximum with olanzapine, least with Haloperidol;
    2. Weight gain may be a part of metabolic syndrome
      1. Also seen with clozapine
  3. Autonomic symptoms
    1. Maximum with CPZ, minimum with Haloperidol
  4. Seizures
    1. Denovo seizures occur with clozapine (2%)
    2. Other drugs reduce seizure threshold
    3. Bromides are used in seizure disorder with psychosis
  5. Cardiotoxicity
    1. myocarditis with clozapine, QT interval prolongation [quetiapine, aripiperazole, sertindole, ziprasidone (max)]
  6. Ocular toxicity
    1. quetiapine (cataract), thioridazine (browning of vision)
  7. Agranulocytosis - clozapine, Chlorpromazine
  8. Hepatitis-Chlorpromazine, pimozide, fluphenazine
  9. Osteoporosis
  10. Impotence
    1. Both are newly described side effects
  11. Hyperpigmentation
    1. Chlorpromazine
  12. Hyperprolactinemia
    1. Seen with D2 blockers; also with risperidone
  13. Extra Pyramidal Syndromes:

Acute Muscular Dystonia

WITHIN FEW HOURS

Grimacing, Torticollis (In Children)

ANTICHOLINERGICS

Parkinsonism

1-4 WEEKS

Tremors, Akinesia

ANTICHOLINERGICS

Akathisia

8 WEEKS

Discomfort, Agitation

PROPANOLOL, DIAZEPAM

Tardive Dyskinesia

VERY LATE

Purposeless Wrigling- Chorea (Due To Supersensivity Of D2 Receptors)

NO TREATMENT, (CLONAZEPAM/DIAZEPAM CAN BE TRIED)

neurolept malignant syndrome

EMERGENCY

Hyperthermia, Fever, Unconciousness, Rigidity, Tremors

DANTROLENE, BROMOCRIPTINE, SUPPORTIVE T/T

 

 





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