Antipsychotic agents [3] Flashcards Preview

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Flashcards in Antipsychotic agents [3] Deck (24):
1

Clinical features of schizophrenia

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)

2

Too much Glutamate making you psychotic or too little?
(which drugs makes you psychotic, NMDA agonist or antagonists?)

Antagonist
ketamine, phencyclidine

3

DA hypothesis of schizophrenia

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)

4

Brain DA pathways

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

5

Mesolimbic pathway

Brain DA pathway

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

6

Mesocortical pathway

Brain DA pathway

involved in COMMUNICATION and SOCIAL abilities

7

Nigrostriatal pathway

Brain DA pathway

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

8

Tuberoinfundibular pathway

Brain DA pathway

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

9

Serotonin hypothesis
5HT2A receptor effect on Mesocortical vs Mesolimbic pathway

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

10

Typical vs Atypical antipsychotics

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)

11

Glutamate hypofunction hypothesis
- mesolimbic pathway

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

12

Glutamate hypofunction hypothesis
- mesocortical pathway (regulates DA release indirectly)

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

13

POSITIVE symp of schizo result from?

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

14

NEGATIVE symp of schizo result from?

HYPOactivity in MESOCORTICAL pathway (↓DA)

15

Typical antipsychotic agents

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

Good efficacy against POSTIVE symptoms

- Chlorpromazine
- Haloperidol

16

ATypical antipsychotic agents

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


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

17

Haloperidol vs Chlorpromazine

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)

18

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

Extrapyramidal side effects

(clozapine, aka wet pillow syndrome - hypersalivation)

19

Typical low potency drug side effects

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)

20

Diff between treating Parkinsons vs Pseudoparkinsonium

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)

21

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

Hypothalamus

Block hypothalamic DA receptors - esp with atypical agents

22

Agranulocytosis (low white blood cell count) think

clozapine

ATypical antipsychotic agents
5HT2 Antagonist

but Good efficacy against Negative symptoms

23

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

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 )

24

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

Orthostatic Hypotension (a1)