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Psych Week 2 > ICL 8.3: Psychopharmacology of Antipsychotic Medications > Flashcards

ICL 8.3: Psychopharmacology of Antipsychotic Medications Flashcards

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1
Q

what treatments have been used throughout history to treat psychosis?

A
  1. tranquilizers
  2. neuroleptics
  3. ataractics
  4. anti-schizophrenic agnes
  5. antipsychotics; typical and atypical
  6. dopaminergic blocking or dopamine-serotonin antagonists
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2
Q

which drugs were the first drugs found to be useful as antipsychotics?

A
  1. reserpine
  2. chlorpromazine

reserpine is no longer used as an antipsychotic

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3
Q

what is the MOA of clozapine?

A

it was the first atypical antipsychotic

it blocked both dopamine and serotonin receptors unlike chlorpromazine which just blocked dopamine

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4
Q

what are the psychiatric uses of antipsychotics?

A
  1. schizophrenia and schizophrenia spectrum disorders
  2. all psychotic disorders
  3. Tourette’s syndrome
  4. bipolar affective disorder
  5. unipolar depression
  6. agitation
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5
Q

what are the nonpsychiatric uses of antipsychotics?

A
  1. antiemetic (first generation antipsychotics)
  2. antipruritic/itching (Phenothiazines, promethazine)
  3. anesthesia (Droperodol)
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6
Q

what are the 5 dopaminergic pathways in the brain?

A
  1. mesolimbic-mesocortical pathway
  2. nigrostriatal pathway
  3. tuberoinfundibulnar pathway
  4. medullary-periventricular pathway
  5. incertohypothalamic pathway
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7
Q

what is the function of the mesolimbic-mesocortical pathway?

A

it’s a dopaminergic pathway in the brain

the mesocortical pathway is associated with working memory, motivation and emotion

mesolimbic pathway-referred to as the reward pathway of the brain (important in addiction)

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8
Q

what is the function of the nigrostriatal pathway?

A

it’s a dopaminergic pathway in the brain from the substantia nigra to the dorsal striatum

it’s associated with movement

blockade of the D2receptors in the nigrostriatal pathway is responsible for EPS (extrapyramidal symptoms)

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9
Q

what is the function of the tuberoinfundibulnar pathway?

A

it’s a dopaminergic pathway in the brain that arises in the arcuate nuclei and periventricular neurons and releases dopamine into the pituitary portal circulation

it regulates the secretion of the hormone prolactin from the anterior pituitary gland

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10
Q

what is the function of the medullary-periventricular pathway?

A

it’s a dopaminergic pathway in the brain that involves eating behavior

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11
Q

what is the function of the incertohypothalamic pathway?

A

it’s a dopaminergic pathway in the brain that forms connections from the medial zona incerta to the hypothalamus and the amygdala

it appears to regulate the anticipatory motivational phase of copulatory behavior in rats

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12
Q

what is the effect of antipsychotic medications on the dopaminergic pathways of the brain?

A

antipsychotic medications nonspecifically block dopamine everywhere in all the dopaminergic pathways in the brain

it blocks the dopamine in the mesolimbic system which is great because this reduces positive symptoms however….it also blocks dopamine in all the other dopaminergic systems which isn’t so good and leads to a lot of the side effects of antispychotic medications

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13
Q

what type of dopamine receptors do antipsychotics mostly block?

A

D2

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14
Q

what are the 2 groups of dopamine receptors?

A

D2-like = D2, D3, D4 –> these all decrease cAMP

D1 like = D1, D5 –> these increase cAMP

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15
Q

where are D2 receptors found?

A
  1. caudate-putamen
  2. nucleus accumbens
  3. olfactory tubercle

D2 receptors decrease calcium channels but open K channels

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16
Q

where are D3 receptors found?

A
  1. frontal cortex
  2. medulla
  3. midbrain
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17
Q

where are D4 receptors found?

A

they’re concentrated in the cortex

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18
Q

where are D1 receptors found?

A
  1. putamen
  2. nucleus accumbens
  3. olfactory tubercle
  4. cortex
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19
Q

where are D5 receptors found?

A
  1. hippocampus

2. hypothalamus

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20
Q

what is the serotonin hypothesis of psychosis?

A

when you use LSD which is a serotonin agonists, patients exhibited psychotic symptoms

this made researchers look for serotonin-antagonists to prevent psychosis

atypical antipsychotics work on 5-HT(2A) and 5-HT(2C) receptors

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21
Q

which serotonin receptors are associated with psychosis?

A

5-HT(1A)

5-HT(2A)

5-HT(2C)

22
Q

what is the function of 5-HT(2A) receptors?

A

these are the main serotonin receptor for second generation antipsychotic agents

they are inverse agonists aka they don’t totally block and have a little bit of basal activity

important for regulation of DA, NE, Glutamate, GABA, Ach modulation at cortex, limbic region and striatum

23
Q

what is the function of 5-HT(2C) receptors?

A

they modulate the secretion of dopamine in the limbic system and cortex

24
Q

which drugs effect NMDA receptors and how is it linked to psychosis?

A

phencyclidine and ketamine are non-competitive inhibitors of NMDA glutamate receptors

we saw worsening cognitive impairment and psychosis in schizophrenia patients who were using these drugs

the hypothesis is that decreased NMDA receptors leads to decreased GABA neurons which then leads to increased glutamate activity and hyper stimulation of cortical neurons

25
Q

how are antipsychotics classified?

A
  1. based on chemical structures
  2. typical vs. atypical
  3. first generation vs. second generation

before clozapine is considered first generation and after clozapine is second generation

26
Q

how are antipsychotics classified based on chemical structure?

A
  1. phenothiazines

chlorpromazine, thioridazine, mesidazine, fluphenazine, prochlorperazine, triflupromazine, perphenazine

  1. thioxanthene

thiothixene

  1. butyrophenone

haloperidol, droperidol

  1. dibenzoxapines

loxapine, molindone

  1. biphenybutylpiperidines

pimozide

27
Q

what are first generation antipsychotics?

A

aka typical antipsychotics

they work on dopamine receptors; specifically, they’re D2 receptor antagonists

they have higher incidence for extra pyramidal symptoms (EPS) because they also block dopamine in the nigrostriatal pathway

higher incidence for prolactin elevation because dopamine normally inhibits prolactin but when you inhibit dopamine then there’s elevated prolactin levels

28
Q

what are second generation antipsychotics?

A

aka atypical antipsychotics

they’re dopamine (D2 receptor) and serotonin (5HT2A5HT2C)receptorantagonists

there’s a lower incidence of EPS and prolactin elevation

less likely to cause EPS, TD or neuroleptic malignant syndrome and
more effective in treating negative symptoms

however, there’s a higher risk for metabolic syndrome

they are also efficacious for neurocognitive symptoms

29
Q

which drugs are first generation antipsychotics?

A

Chlorpromazine (Thorazine)

Perphenazine (Trilafon)

Fluphenazine (Prolixn)*

Thioridazine (Mellaril)

Thiothixene (Navane)

Trifluoperazine (Stelazine)

Haloperidol (Haldol) Prototype*

Loxapine(Loxitan)*

Pimozide (Orap)

30
Q

which drugs are second generation antipsychotics?

A

Aripiprazole (Abilify)

Asenapine (Saphris)

Caripiprazine (Vraylar)

Clozapine (Clozaril) Prototype*

Iloperidone (Fanapt)

Lurasidone (Latuda)

Olanzapine (Zyprexa)

Paliperidone (Invega)

Quetiapine (Seroquel)*

Risperidone (Risperdal)

Ziprasidone (Geodon)

31
Q

how are antipsychotic drugs metabolized in the body?

A

most are metabolized by oxidation or demethylation in the liver

liver microsomal cytochrome P450 enzymes–> CYP2D6, CYP1A2, and CYP3A4 are the major isoforms involved

drug-drug interactions should be considered when combining antipsychotic drugs with various other psychotropic drugs

ex. fluoxetine is an SSRI that’s a CYP2D6 inhibitor and it you’re also giving an antipsychotic that uses that pathway then you have to be careful that the antipsychotic drug levels don’t get too high

32
Q

what is important about the parmacokinetics of antipsychotics?

A
  1. most are readily but incompletely absorbed
  2. many undergo significant first-pass metabolism

this is important because when you give this medication, as they go through the liver most of them are lost in the liver and their bioavailability decreases to 25-35% –> except haloperidol which has a bioavailability of 65%

so this could be a problem if a patient’s liver isn’t working well and you dose thinking that the bioavailability will only be 25-35%, you’ve got a problem

  1. highly lipid soluble and protein bound

this is important because all the antipsychotics have to cross the BBB

basically all of this just means that antipsychotics general have a much longer clinical duration of action than would be estimated

33
Q

how much antipsychotics should you take?

A

patients often think if they take more medication it will work better – not true! it’s an exponential curve that eventually plateaus

the goal is 60 - 80% of the dopamine receptors to be blocked for clinical efficacy

higher than 80% just increases the risk of side effects

34
Q

what is the relative affinity of haloperidol vs. chlorpromazine to the various D2 and 5HT receptors?

A

haloperidol: D2> α1> D4> 5-HT2A> D1> H1
chlorpromazine: α1= 5-HT2A> D2> D1

these are 1st generation antipsychotics

35
Q

what is the relative affinity of clozapine, olanzapine, aripiprazole, and quetiapine to the various D2 and 5HT receptors?

A

clozapine: D4= α1> 5-HT2A> D2= D1
olanzapine: 5-HT2A> H1> D4> D2> α1> D1
aripiprazole: D2= 5-HT2A> D4> α1= H1» D1
quetiapine: H1> α1> M1,3> D2> 5-HT2A

these are all 2nd generation antipsychotics

36
Q

what is the relative affinity of chlorpromazine to various D2 and 5HT receptors?

A

α1, H1, M1 = 5-HT2A> D2> D1

it’s a low potency, first generation antipsychotic

37
Q

what are the side effects of chlorpromazine based on its relative affinity to various D2 and 5HT receptors??

A

α1, H1, M1 = 5-HT2A> D2> D1

before it can be clinically effective, patients will start having antiadrenergic (orthostatic hypotension), anticholinergic (dry mouth, constipation) and antihistamine (sedation) side effects due to the greater affinity of chlorpromazine to α1, H1, and M1 receptors over dopamine receptors

since it’s anticholinergic you have to watch for prolonged QT interval, heart block and ventricular arrhythmias

rare risk of agranulocytosis and higher risk of seizures

however, one good thing about it having lower dopamine affinity and its effect on cholinergic receptors, it has lower EPS and less risk of neuroleptic malignant syndrome (NMR) risk

38
Q

why do we care about the relative affinities of antipsychotics to certain receptors?

A

so you can educate the patients about side effects and titrate the medication and slowly work them up

39
Q

what is the relative affinity of haloperidol to various D2 and 5HT receptors??

A

D2> α1> D4> 5-HT2A> D1> H1

it’s a high potency, first generation antipsychotic

40
Q

what are the side effects of haloperidol based on its relative affinity to various D2 and 5HT receptors??

A

D2> α1> D4> 5-HT2A> D1> H1

greater affinity for dopamine receptors so a relatively small dose is needed

  1. less sedation, orthostatic hypotension and anticholinergic effects compared to chlorpromazine
  2. greater risk for extrapyramidal symptoms and likely TD because it blocks dopamine so highly
  3. IV haloperidol can cause QTc prolongation and torsade
41
Q

which drugs are types of haloperidol?

A
  1. Haloperidol (Haldol)

2 .Fluphenazine (Prolixin)

  1. Trifluoperazine (Stelazine)
  2. Pimozide (Orap)
42
Q

which drugs are mid-potency first generation anti-psychotics?

A
  1. Loxapine (Loxitane)
  2. Thiothixene (Navane)
  3. Molindone (Moban)
  4. Perphenazine (Trilafon)
43
Q

what are some of the alternate uses of atypical antipsychotics?

A
  1. acute mania, bipolar disorder
  2. adjunctive medications for bipolar depression
  3. adjunctive medications forUnipolar depression
44
Q

what is the relative affinity of clozapine to various D2 and 5HT receptors??

A

D4= α1> 5-HT2A> D2= D1

it’s a 2nd generation antipsychotic and it has the most complex pharmacological profile because it effects so many different receptors

45
Q

why use clozapine?

A

aka clozaril

  1. less likely to cause EPS and Tardive dyskinesia; used in patients with TD
  2. used in treatment refractory schizophrenia (gold standard)**
  3. only antipsychotic known to decrease suicide risk

when everything else fails, use clozaril!!!! it’s the gold standard

46
Q

what are the side effects of clozapine?

A
  1. anticholinergic effects = tachycardia and hypersalivation
  2. agranulocytosis (0.5 to 2%), seizures, myocarditis
  3. excessive salivation (M1), sedation (M1, H1and α1), constipation
  4. cardiometabolic risk,weight gain (5HT2C ,H1,)
47
Q

what is the relative affinity of quetiapine to various D2 and 5HT receptors??

A

H1> α1> M1,3> D2> 5-HT2A

48
Q

what are the characteristics of quetiapine?

A
  1. seroquel has a ceiling effect of the DA blockade like Clozapine; even if you increase the dose it doesn’t block more than 60% of dopamine receptors
  2. has different properties depending on the dose –> at low doses it has sedative hypnotic effects but at high doses it can be used as an antipsychotic
  3. active metabolite nor quetiapine
  4. causes no EPS or elevation of prolactin
49
Q

what are the side effects of quetiapine?

A

seroquel can cause sedation, weight gain and orthostatic hypotension

H1> α1> M1,3> D2> 5-HT2A

50
Q

what is the relative affinity of olanzapine to various D2 and 5HT receptors??

A

5-HT2A> H1> D4> D2> α1> D1

51
Q

what are the side effects of olanzapine?

A

zyprexa is notorious for serious weight gain

other common side effects are weight gain, sedation and dyslipidemia

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