Anti-Psychotics (General and Typical)

Question 1

What is the job of the D1 receptors? Where are they found in the brain?

Answer 1

Stimulatory dopamine receptors and stimulates adenyl cyclase. Found in the striatum and neocortex.

Question 2

What is the job of the D2 receptors? Where are they found?

Answer 2

They are the inhibitory receptors and inhibit adenyl cyclase. Found in the Striatum, substantia nigra and hypothalamus.

Question 3

Why does stimulation of D2 receptors trigger increased Ca?

Answer 3

Although D2 receptors will inhibit adenyl cyclase activity, it will also trigger the IP3 pathway to increase Ca.

Question 4

What does the stimulation of the D2/D3 receptors pre-synaptically do?

Answer 4

Inhibits adenyl cyclase pre-synaptically so no dopamine is released pre-synaptically.

Question 5

What are the general themes of the MOA of anti-psychotics even if their MOA is not understood?

Answer 5

Acts on multiple neurotransmitters to basically block (competetively) serotonin and dopamine receptors. Both pre/post synaptic neurons are blocked.

Question 6

How do D3 D4 and D5 receptors relate to D1 and D2?

Answer 6

D3/4 are both like D2, D1 and D5 are alike.

Question 7

Where are D5 receptors found?

Answer 7

Hippocampus and Hypothalamus.

Question 8

Where are D3 and D4 receptors found?

Answer 8

3 is found in olfactory tubercle, nucleus accumbens, and hypothalamus. 4 is found in Frontal cortex, medulla and midbrain.

Question 9

Name the 4 drugs that fall under the category of “typical antipsychotics”

Answer 9

Chlorpromazine, Thioridazine, Fluphenazine, and Haloperidol.

Question 10

How do typical antipsychotics relate to first pass metabolism? How are they metabolized?

Answer 10

They have extensive 1st pass metabolism, metabolized by 1A2, 2D6, and/or 3A4. All metabolized to inactive or weakly active drug.

Question 11

Which 3 typical antipsychotic drugs inhibit 2D6?

Answer 11

Chlorpromazine, Perphenazine, and Thioridazine.

Question 12

What is Thioridazine significant for in terms of its metabolism?

Answer 12

It inhibits 2D6 and in addition the metabolized compound (mezoridazine) is more active than the parent compound (this is the exception among the class), thus causing cardiotoxicity. Recall that TCA’s and other drugs that prolong the QT interval will also cause cardiotoxicities and arrythmias with Thioridazine.

Question 13

What is important to recall about CYP 2D6?

Answer 13

People have genetic variability of this enzyme some are fast and others are slow. Further, anti depressants like TCA’s and some SSRIs are metabolized by 2D6. Also Codiene is metabolized by 2D6 to its more active form, so if 2D6 is inhibited then the effect of codiene is reduced.

Question 14

How are typical anti-psychotics excreted, whats their half life and their rate of onset?

Answer 14

Renally excreted, 20-30 hr half life, and onset can be days to weeks.

Question 15

What are the 4 tx uses of Chlorpromazine?

Answer 15

Use in psychosis, it can be formulated as an anti-emetic, intractable hiccups, and hyperactivity in kids (short term to combat explosive behavior and combativeness).

Question 16

What are the 2 tx for Thioridazine?

Answer 16

Psychosis and agitated depression.

Question 17

Tx uses of Fluphenazine? What’s special about its administration?

Answer 17

Psychosis, acute agitation/mania. It comes in oral and IM depot administration.

Question 18

What are the tx uses of Haloperidol? Admin?

Answer 18

Psychosis, can be administered oral or IM depot. Acute agitation/delirium, aggression, tourrete, tic disorders. Also there is a short acting IM admin route, for acute emergencies.

Question 19

What is the receptor affinity of typical anti-psychotics?

Answer 19

It has greater affinity for D2R which is greater than 5-HT2 receptors.

Question 20

What is it about the typical anti-psychotics that is though to repress the positive symptoms?

Answer 20

Blockade of the D2R in the mesolimbic pathway.

Question 21

What are “Extrapyrimidal symptoms (EPS)” and how do typical anti-psychotics help prevent that?

Answer 21

EPS refers to various movement (motor) disorders associated to disease processes such as parkinson’s. This is because these patients have a reduced amount of dopamine. The typical anti-psychotics block the D2R in the basal ganglia to alleviate the EPS.

Question 22

Where do the typical antipsychotics act to block D2R’s that result in increased serum prolactin?

Answer 22

D2R in the tuberoinfundibular system.

Question 23

What are the receptors that typical anti-psychotics also hit to cause orthostatic hypotension (what is this?), failure to ejaculate, dry mouth, blurred vision, constipation, urinary retention, drowsiness, increased apetite and weight gain?

Answer 23

Orthostatic hypotension is caused when patients go from sitting to standing position and their body fails to equilibrate the BP. This is caused by blocking the alpha 1 receptors. which also causes failure to ejaculate. The dry mouth, urinary retention, constipation, blurred vision is caused by anti cholinergic effects by blocking the muscurinic ACh receptors, and the drowsiness is caused by blocking the H1 receptors. Also, chronic blockade of H1 receptors is associated with increased appetite and weight gain.

Question 24

What is the role of dopamine in relation to prolactin? What happens if dopamine receptors are blocked?

Answer 24

Dopamine has a tonic activity (meaning constantly leaves something “off”) of prolactin in the anterior pituitary unless the hypothalamus removes the tonic activity (hypothalamus normally secretes DA to act on the D2R of lactotrophs to inhibit prolactin secretion in AP). If D2R’s are blocked then the tonic activity is removed, thus there will be continued prolactin secretion, which results in amenorrhea, decreased libido and gynacomastia (as well as infertility).

Question 25

What is the effect of increased serum prolactin?

Answer 25

It leads to gynacomastia in men, and also increased prolactin inhibits GnRH secretion in the hypothalamus, resulting in decreased LH and FSH secretion –> Amenorrhea, decreased testosterone production and infertility. Also there is effects induced by prolactin in breasts and there is a decrease in libido.

Question 26

What do the effects of the typical anti-psychotics have on 5-HT2 receptors?

Answer 26

Blockade of 5-HT2 receptors might have something to do with blocking the negative effects (unknown), but it is associated with weight gain.

Question 27

In addition to the AE’s experienced by the blockade of the alpha 1 receptors, 5–HT2 receptors, muscurinic receptors and H1 receptors, what are other AE’s experienced by the typical antipsychotic drugs? What is the black boxed warning which relates to all antipsychotics?

Answer 27

Cardiotoxicity, decreased seizure threshold, “poikilothermic effects,” rash, photosensitivity INCREASED RISK OF STROKES IN PT’S WITH DEMENTIA RELATED DISORDERS (black box warning)

Question 28

What are “Poikilothermic effects?”

Answer 28

Body loses ability to maintain a stable internal body temperature and thus patient’s temperature mimics ambient temp: hot when hot outside and cold when cold outside.

Question 29

Use of antipsychotics in preggos?

Answer 29

If in the third trimester the fetus will have symptoms of EPS and withdrawal upon delivery. However one CANNOT ABRUPTLY REMOVE THE MOTHER FROM THE DRUG, must be managed from the outset of preggo.

Question 30

What is the rare AE of all anti-psychotics called “Neuroleptic Malignant Syndrome?”

Answer 30

FALTER!!! Fever, Autonomic instabilty, Leukocytosis, Tremor (also include agitation and delirium w/ tremor), Elevated CPK and Muscle rigidity.

This is characterized by muscle rigidity, elevated temperature, leukocytosis, agitation, delirium and UNSTABLE BP.

Question 31

How is neuroleptic malignant syndrome managed?

Answer 31

Offending drug is withdrawn, patient is put in supportive care, benzo, dantrolene, and dopamine agonists have been used with varying success.

Question 32

What’s interesting about the tolerance tendency of anti-psychotics?

Answer 32

There is tolarence to the sedative effects but NOT to the anti-psychotic effects.

Question 33

Dependance and anti-psychotics?

Answer 33

Might occur, withdrawal symptoms include malaise and difficulty sleeping. However there is no abuse potential of this drug.

Question 34

Rank the typical anti-psychotics in relation to their potency?

Answer 34

Chlorpromazine and Thioridazine are low potency, whereas Fluphenazine and Haloperidol have high potency. Potency here relates to affinity of the D2R,

Question 35

Which Typical Anti-Psychotic would we want to use to tx EPS?

Answer 35

The high potency ones, particularly Haloperidol (very high effect) and Phenazine.

Question 36

Which TAS is related to high sedative, anticholinergic and hypotensive effects? Whats the exception?

Answer 36

The low potency ones, such as Chlorpromazine and Thioridazine (because the low potency refers to low D2R affinity, meaning they have high affinity to the other receptors). Regarding anticholinergic effects, Chlorpromazine has medium effect but Thioridazine has a very high effect.