Psychopharmacology: Antipsychotis

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ANTI PSYCHOTICS
Antipsychotics are used in the treatment of psychotic disorders and psychotic symptoms.
CHLORPROMAZINE is considered to be, the first anti psychotic drug. Introduced by Delay and Paul Denikar in 1952.
FIRST-GENERATION ANTIPSYCHOTIC (low potency)
·         Chlorpromazine
·         Prochlorperazine
·         Thioridazine
FIRST-GENERATION ANTIPSYCHOTIC (high potency)
·         Fluphenazine
·         Haloperidol
·         Pimozide
·         Thiothixene
SECOND GENERATION ANTIPSYCHOTIC
·         Aripiprazole
·         Asenapine
·         Clozapine
·         Iloperidone 
·         Lurasidone
·         Olanzapine
·         Quetiapine
·         Paliperidone 
·         Risperidone
·         Ziprasidone
CHEMICAL CLASSIFICATION
l . Phenothiazines
·         Aliphatic Side Chain: Chlorpromazine, Triflupromazine
·         Piperidine Side Chain: Thioridazine
·         Piperazine Side Chain: Trifluoperazine, Fluphenazine
2. Butyrophenones: Haloperidol, Trifluperidol, Penfluridol
3. Thioxanthenes: Flupenthixol
4. Diphenylbutylpiperidines : Pimozide, Penfluridol
5. Dibenzoxapines :Loxapine
6. Dihydroindolones : Molindone

ATYPICAL
           Dibenzodiazepines: Clozapine
           Benzisoxales: Risperidone, Iloperidone
           Thieno- Benzodiazepine :Olanzapine
           Dibenzothiazepine : Quetiapine    Benzithiazolyl : Ziprasidone
NOVEL / THIRD GENERATION
Phenylpiperazine : Aripiprazole
Dibenzo-Oxepino Pyrrole Derivative : Asenapine Maleate
Phenyl-Pyridine : Blonanserin
First-generation antipsychotics
·         The first-generation antipsychotic drugs (also called conventional, typical, or traditional antipsychotics) are competitive inhibitors at a variety of receptors, but their antipsychotic effects reflect competitive blocking of D2 dopamine receptors.
·         First-generation antipsychotics are more likely to be associated with movement disorders, particularly for drugs that bind tightly to dopaminergic neuroreceptors, such as haloperidol.
Second-generation antipsychotic
·         The second generation antipsychotic drugs (also referred to as "atypical" antipsychotics) have fewer Extra Pyramidal symptoms (EPS) than the first-generation   agents, but are associate with a higher risk of metabolic side effects, such as diabetes, hypercholesterolemia, and weight gain.
·         The second-generation drugs appear to owe their unique activity to blockade of both serotonin and dopamine receptors.

a) Mechanism of action
Typical Antipsychotics: Block D2 receptors, the dopamine receptors which are mainly  present in the mesolimbic system and the nigro-striatal system
Atypical antipsychotics are serotonin-dopamine antagonists

b)Pharmacokinetics
·         Absorption- from GIT
·         Distribution- highly protein bound
·         Metabolism- from liver (hepatic microsomal enzymes)
·         Excretion- by kidneys
c)Injectable drugs
·         Fluphenazine decanoate: Dose- 12.5-50mg Duration-2-3 weeks
·         Haloperidol decanoate: Dose- 50 to 300mg Duration- 3 to 4 weeks 
They are depot antipsychotic with long duration of action.
d) Indications
A.Organic Psychiatric Disorders:
·         Delirium
·         Dementia
·         Delirium tremens
·         Drug induced psychosis        
·         Other organic mental disorders(organic hallucinosis, organic delusional disorder, secondary mania etc)
B.Non organic psychotic disorders:
·         Schizophrenia
·         Schizo-affective disorder
·         Acute psychoses
·         Mania
·         Major depression
·         Delusional disorder
C.Child psychiatric disorders:
·         ADHD
·         Pervasive developmental disorders   
·         Conduct disorders     
D.Neurotic and other psychiatric disorders:
·         Anorexia nervosa
·         Severe, intractable, and disabling anxiety
·         OCD
E. Medical disorders:
·         Huntington's chorea
·         Intractable hiccups
·         Nausea and vomiting
·         Tic disorders
·         Eclampsia
·         Heat stroke
·         Tetanus, intractable pruritus, severe pain, pre-anesthetic medication
e) Contraindications
·         Pregnancy- cross the placental barrier and cause EPS in some newborns.
·         Lactation- transient neonatal toxicity.
·         Hepatic and renal problem
·         Older adults-heightened EPS and anti cholinergic effect.
f) Side Effects
 Extra pyramidal or neurological Side effects:
l.Parkinsonism- basal ganglia is affected. symptoms are
·         Tremors
·         Bradykinesia
·         Rigidity 
·         Anti parkinsonian drugs are indicated
2.Dystonia:
·         These are abnormal postures caused by involuntary muscle spasms
·         They elicit a sustained, twisted, and contracted positioning of the limbs, trunk, neck, or mouth
Types:
·         Torticollis: contracted positioning of neck
·         Oculogyric crisis: contracted positioning of the eugs upward
·         Laryngial-pharyngial constriction
·         Writer's cramp: fatigue spasms affecting a hand
Management is by benztropine or diphenhydramine

3. Akathesia
·         It is a subjective feeling of restlessness demonstrated by restless legs, jittery feelings, and nervous energy.
·         Management is by change of medication or reduction of dose
4. Akinesia-
·         absence of movement; responds to anticholinergics
5.Tardive dyskinesia:
·         late onset oro-facial dyskinesia. Typical symptoms include tongue writhing, tongue protrusion, teeth grinding, and lip smacking
Rx- valium (diazepam), sodium valporate

6. Rabbit syndrome:
·         Peri-oral tremors, Management by antiparkinsonian medication
7. Neuroleptic malignant syndrome:
·         Rise of temperature, impairment of consciousness, rigidity, high CPK, catatonic symptoms, autonomic dysfunction etc. 
·         Management: bromocriptine, dantrolene, baclofen, general supportive care, add on lorazepam, occasionally ECT
Autonomic Side Effects:
·         Dry mouth
·         Constipation 
·         Cycloplegia
·         Mydriasis
·         Urinary retention       
·         Delirium
·         Orthostatic hypotension
·         Impotence
·         Impaired ejaculation
 Other CNS Effects
·         Seizures         
·         Sedation
Metabolic and Endocrine side effects:
·         Weight gain
·         Diabetes        
·         Galactorrhea with or without amenorrhea
  Allergic side effects:
           Cholestatic jaundice o agranulocytosis
Cardiac side effects
·         ECG changes            
·         Sudden death
Ocular side effects:
·         retinopathy
 Dermatological side effects:
·         Contact dermatitis
·         Photosensitive reaction
·         Blue-gray metallic discoloration
g) Client education
·         Caution while driving or operating dangerous machine Drowsiness and dizziness can occur.
·         Do not stop drug abruptly after long term use. withdrawal symptoms like nausea,  vomiting, headache, tremors can occur.
·         Use sun screen or wear protective clothing when out doors.   Report weekly if receiving Clozapine therapy.
·         Report to physician any other symptoms like sore throat, fever, unusual bleeding, headache, dark colored urine, skin rash,
·         Rise slowly from sitting or lying down position to prevent sudden drop in blood pressure.
·         Take frequent sips of water, sugarless gum or candy to avoid dry mouth.
·         Dress appropriately to weather to avoid exposure to very high or low temperature.
·         Be aware of possible risk during pregnancy.
·         Protocol for Clozapine therapy
·         If base line WBC count is less than 3500/mm3, do not start Clozapine.
·         Once started monitor WBC count weekly.
·         If WBC level is below 3000/mm3 discontinue Clozapine.
·         If WBC level is below 2000/mm3 permanently discontinue.


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Psychopharmacology: Antipsychotis
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