Antipsychotic agents [3]

Question 1

Clinical features of schizophrenia

Answer 1

overactivity of DA neurons in limbic system (MESOLIMBIC PATHWAY)
- present with positive symptoms (delusions, halluc, disordered thoughts)

• so antipsychotics block D2 DA receptor or 5HT 2A
• negative symptoms seen later (hypoactivity of DA neurons)

Question 2

Too much Glutamate making you psychotic or too little?

which drugs makes you psychotic, NMDA agonist or antagonists?

Answer 2

Antagonist

ketamine, phencyclidine

Question 3

DA hypothesis of schizophrenia

Answer 3

overactivity in brain DA pathways
- virtually all antipsychotic drugs block DA D2 receptors

(but Glu and 5HT and ACh also seem to play role, and blocking D2 receptors occur immediately, but psychoses improvement isnt for 3-6 weeks)

Question 4

Brain DA pathways

Answer 4

1. Mesolimbic pathway
2. Mesocortical pathway
3. Nigrostriatal pathway
4. Tuberoinfundibular pathway

Question 5

Mesolimbic pathway

Answer 5

Brain DA pathway

integration of sensory input and motor responses with
AFFECTIVE or EMOTIONAL data

Question 6

Mesocortical pathway

Answer 6

Brain DA pathway

involved in COMMUNICATION and SOCIAL abilities

Question 7

Nigrostriatal pathway

Answer 7

Brain DA pathway

part of basal ganglia (extrapyramidal tract)
plays central role in PLANNED, COORDINATED MOVEMENT

Question 8

Tuberoinfundibular pathway

Answer 8

Brain DA pathway

hypothalamic neurons release DA in pituitary to INHIBIT PROLACTIN RELEASE
- antipsychotic D2 receptor blockers side effects: hyperprolactinemia

Question 9

Serotonin hypothesis

5HT2A receptor effect on Mesocortical vs Mesolimbic pathway

Answer 9

Mesocortical: 5HT2A receptors on DA neurons in PFC (heteroreceptor) → DECREASES (breaks) DA release
- get negative symptoms

Mesolimbic: 5HT2A on glutamate pyramidal cells in PFC→ INCREASE DA release
- get positive symptoms

Can block these receptors w/ atypical agents → increased DA release

Question 10

Typical vs Atypical antipsychotics

Answer 10

Block D2 receptors with typical → decreased DA release

Can block 5HT2A receptors w/ atypical agents → increased DA release

(therapeutic utility of antagonist of both D2 and 5HT2A receptors in schizo - improvement in both positive and negative symptoms)

Question 11

Glutamate hypofunction hypothesis

- mesolimbic pathway

Answer 11

Normally:
cortical glutamate → activates cortical GABA neurons → inhibits cortical Glu neurons → regulates DA (keeps it from accumulating)

so. . .
with Hypofxn of cortical glutamate →
 loss of cortical GABA inhibition →  
increased activity of Glu neurons →  
HYPERactivity in MESOLIMBIC pathway (↑DA) → 
POSITIVE symp of schizo

Question 12

Glutamate hypofunction hypothesis

- mesocortical pathway (regulates DA release indirectly)

Answer 12

Hypofxn of cortical glutamate →
 loss of cortical GABA inhibition →  
increased activity of Glu neurons →  
HYPOactivity in MESOCORTICAL  pathway (↓DA) → 
NEGATIVE symp of schizo

Question 13

POSITIVE symp of schizo result from?

Answer 13

overactivity of DA neurons in the mesoLIMBIC system (↑DA)

Question 14

NEGATIVE symp of schizo result from?

Answer 14

HYPOactivity in MESOCORTICAL pathway (↓DA)

Question 15

Typical antipsychotic agents

Answer 15

D2 antagonist
(D2 blocks - High D2/5HT2A)

Good efficacy against POSTIVE symptoms

• Chlorpromazine
• Haloperidol

Question 16

ATypical antipsychotic agents

Answer 16

5HT2 Antagonist
(and slight D2 block so low D2/5HT2A ratio)

Good efficacy against Negative symptoms
Reduced indicence of extrapyramidal toxicity (EPSE)
- Clozapine
- Quetiapine

Question 17

Haloperidol vs Chlorpromazine

Answer 17

Typical antipsychotic agents

Haloperidol

• high potency
• high extrapyramidal toxicity (DA block)
• -> dystonia, akathisia, pseudoparkisonium, dyskinesia

Chlorpromazine

• low potency (need so much, so it spills over and causes ANS effects)
• antimuscarinic (no pee, no spit), anti Histamine, alpha 1 block (M-H-a1 block)

Question 18

Atypical antipsychotic agents such as clozapine are distinguished from typical agents such as haloperidol bc they are associated with lower incidence of:

Answer 18

Extrapyramidal side effects

clozapine, aka wet pillow syndrome - hypersalivation

Question 19

Typical low potency drug side effects

Answer 19

Chlorpromazine (low potency - use so much it spills over)

• muscarinic block (no pee . . .)
• a1 block (orthostatic HYPOtension)
• H1 histamine block (weight gain –> Type II diabetes)

Question 20

Diff between treating Parkinsons vs Pseudoparkinsonium

Answer 20

Parkinsons: DA enhancing drugs

Pseudoparkinsonium: anticholinergic agents

• extrapyramidal side effect with typical high potency antipsychotic agent (Haloperidol)
• due to antipsychotic block of D2 (blocking D2, increases ACh)

Question 21

Appetite increase, weight gain, diabetes are common side effects of antipsychotics use that result from block of DA rctprs at which site?

Answer 21

Hypothalamus

Block hypothalamic DA receptors - esp with atypical agents

Question 22

Agranulocytosis (low white blood cell count) think

Answer 22

clozapine

ATypical antipsychotic agents
5HT2 Antagonist

but Good efficacy against Negative symptoms

Question 23

Low potency Typical antipsychotic agents have significant effects on which receptor blocking activity (other than D2)?

Answer 23

Chlorpromazine (low potency - use so much it spills over)

alpha adrenergic receptor

(so if you give EPI, which acts on a1-b2, a1 usually wins out. but if pt is on chlorpromazine, which is a1 blocker, then b2 wins and you get paradoxical b2 vasodilation + hypotension)

(but dont forget typicals are D2 antagonist )

Question 24

which of following therapeutic actions of antipsychotic agents does not result from blockade of DA receptors?

Answer 24

Orthostatic Hypotension (a1)