Antipsychotics

Question 1

Schizophrenia

General, symptoms, causes, mechanism

Answer 1

General:
psychotic illness, one of most common and debilitating

Symptoms:
Positive: Delusions, hallucinations, thought disorder
Negative: withdrawal, flattening of emotional resp
Common: deficit in cognitive function, anxiety, guilt , depression

Causes:
Mix: genetic and environmental causes

Mechanism:
   Dopamine theory: too much dopamine
    Amphetamine--> dopamine relase --> symptoms
    Overdose L DOPA--> symptoms 
    D2 Agonists--> worsen schizophrenia 

Glutamate theory: disruption glutaminergic NT
NMDA R antagonists—> positive and negative symptoms
NMDA R expression reduced in schizophrenia

Question 2

Dopaminergic Pathways and R

Answer 2

Pathways:
Nigrostriatal: control and coordination of movements
Subst Nigra –> corpus striatum

Mesolimbic and Mesocortial
Mesolimbic important in drug addiction (reward)
Mesocortical important in emotional control
Midbrain–> part of limbic system

Tubero-Hypophyseal: prolactin feedback
Ventral hypothalamus–> median eminence and pituitary

Receptors:
D1 and D5: stimulate adenylate cyclase (Gs–> increase cAMP)

D2/D3/D4: inhibit adenylate cyclase (Gi)

Question 3

Classification of Antipsychotics

Answer 3

First Generation (typical)

Second Generation (Atypical) (Lower D2 R effect): Less EP side effects, improve positive and negative symptoms

Question 4

Indications

Answer 4

Schizophrenia
Mania
Toxic psychosis (amphetamine intoxication)
Huntington Chorea
Tourtette's / Ticks
(Antiemetics)

Question 5

Mechanism of Action

Answer 5

First Generation
Antagonists on postsyn D2 –> increase cAMP as inhibition of inhibition

Second Generation
Antagonists on 5HT2 R + D2/D4 R

Question 6

General Targets for Antipsychotics

Answer 6

Dopamine R (Antagonists)
Serotonin R –> contribute to clinical efficacy
H1 R
Noradrenaline R (alpha)

Question 7

Kinetics

Answer 7

Oral, absorption highly variable 
Highly lipophilic 
Extensive first pass metabolism 
T1/2: 15-30 hrs
Exclusively eliminated via hepatic metabolism 
Excretion: biliary and renal

Question 8

Side Effects of Antipsychotics

Answer 8

Main cause thereof is antagonist action at D2 + H1

Extrapyramidal Synd: D2 blockage in basal ggl (nigrostriatal pathway)
Acute Dystonia: in first few weeks then decline
Reversible: invol movements, parkinsonism

Tardive Dyskinesia: after months/years of th
Irreversible: invol movements (face, tongue)

Endocrine (tubero hypophyseal pathway)
Hyperprolactinaemia

H1 Block–> Sedation; good for acute psychotic episode
M R Block–> Blurred vision, dry mouth, constipation
Alpha R Block–> orthostatic hypotension
5 HT R Block–> weight gain

All decrease seizure threshold–> increased occurance thereof

Question 9

First Generation Antipsychotics

Names and characteristics

Answer 9

Chlorpromazine
Prototype; antipsychotic and antiemetic (equally so)
Can cause cholestatic jaundice, increase PL

Promethazine
Antipsychotic, antiemetic, antihistamine (H1 Block)

Flupenthixol, Chlorprothixine
Flupenthixol is pure D antagonist–> low sedative and antiemetic effect

Haloperidol, Droperidol
Haloperidol also pure D antagonist

Question 10

Second Generation Antipsychotics

Names and characteristics

Answer 10

Clozapine, Olanzepine
Potent D4 R Antagonists
No EP symp; effective against +and - symp
Clozapine: risk of agranulocytosis

Sulpiride, Amisulpiride
Selective D2 and D3 Antagonists
Less EP symp

Sertindole
Long T1/2: 3 days–> effective against - symp too
Risk of arrythmia, weight gain, nasal congestion

Quietapine
No EP symp nor Prolactin increase
Short acting
Risk of tachycardia

Risperidone
Potent D4 Antagonist

Ziprasidone
Increase QT
Short acting