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Psychopharm > Antipsychotics > Flashcards

Antipsychotics Flashcards

1
Q

Phenothiazines were derived from ____

A

methylene blue

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2
Q

Chlorpromazine was created in what year?

A

1951

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3
Q

Typical antipsychotic affect on seizure threshold.

A

Lowers seizure threshold

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4
Q

D2 blockade is this brain region is thought to diminish psychosis

A

Mesocortical and mesolimbic

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5
Q

D2 blockade in this system causes derangements in prolactin levels

A

Tuberoinfundibular system, increases prolactin

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6
Q

D2 blockade in this brain area causes movement disorders

A

Nigrostriatal (basal ganglia, caudate). Causes EPS, PD, tremor

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7
Q

Typical antipsychotics are metabolized by ___ and ___

A

2D6 and 3A4

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8
Q

Levels of typical antipsychotics are increased by ______

A

fluoxteine, paroxetine, fluvoxamine (Prozac, paxil, luvox)

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9
Q

Levels of typicals are reduced by ____

A

Carbamazepine

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10
Q

Absorption of typicals is reduced by ____

A

antacids

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11
Q

Cigarettes tend to ____

A

decrease blood concentrations of typicals

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12
Q

Typicals effect on valproic acid

A

Increase the blood concentration of valproic acid

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13
Q

List of high-potency typicals

A

fluphenazine (Prolixin), haloperidol (Haldol), thiothixine (Navane), trifluoperazine (Stellazine)

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14
Q

List of medium-potency typicals

A

perfenazine (Trilafon), molindone (Moban), loxipine (Loxitane)

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15
Q

List of low-potency typicals

A

chlorpromazine (Thorazine), thioridazine (Mellaril)

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16
Q

Pseudoparkinson

A

bradykinesia, rigidity, masked face, cogwheeling, tremor. Women are 2x more likely.

Treat with anticholinergics, Benadryl, or amantadine

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17
Q

Dystonia

A

muscle spasms of jaw, tongue, eyes. Laryngospasms possible. More common in young males. Treat with anticholinergics or Benadryl

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18
Q

Akathisia

A

pacing, restlessness, described as feeling the urge to move around or having “crawling” sensation under skin.

Treated with propranolol, BZD, or clonidine

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19
Q

Tardive Dyskinesia

A

occur about 6 months after initiation of the medication. Is related to increased sensitivity to DA due to receptor changes. Thus, appears to be closer to a movement disorder that occurs due to excess DA despite presence of DA blocking medication. Presents with abnormal muscular jerking of limbs, trunk and periorbital. Increases with stress. More common in older females.

Treat by decreasing the medication or discontinuing. Anticholinergics worsen TD

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20
Q

Neuroleptic Malignant Syndrom

A

fever, muscle rigidity, autonomic symptoms, increased CPK and acute mental status change. More common in males. Can be lethal.

Treat with cooling, dantrolene or bromocriptine, and discontinue the inciting medication

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21
Q

Alpha Blockade can cause

A

orthostatic hypotension

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22
Q

Anticholinergic side effects

A

dry mouth (treat with sugarless gum), constipation, sore throat, urinary retention (treat with bethanechol), blurred vision, confusion

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23
Q

Antihistamine side effects

A

weight gain and sedation

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24
Q

Endocrine side effects

A

prolactin causes sexual side effects like erectile dysfunction, priapism, increased time to ejaculation, gynecomastia, impotence, and anorgasmia

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25
Q

Hepatic side effects

A

jaundice and elevated LFTs (less severe than with atypicals)

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26
Q

Cardiac side effects

A

arrhythmia and prolonged QTc

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27
Q

Hematologic side effects

A

agranulocytosis (monitor for fever, sore throat)

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28
Q

Neurologic side effects

A

epilepsy due to lowered seizure threshold

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29
Q

Dermatologic side effects

A

skin discoloration and photosensitivity in chlorpromazine

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30
Q

Opthomologic side effects

A

retinitis pigmentosa and blindness in thioridazine

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31
Q

Typical associations: Cardiac patients

A

avoid low potency, especially thioridazine (Mellaril)

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32
Q

Typical associations: Elderly

A

avoid low potency due to anticholinergic confusion

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33
Q

Typical associations: Weight gain

A

molindone (Moban) and loxipine (Loxitane) have the least weight gain. High potency have less weight gain. Currently molindone is off the market due to lack of high-volume clinical use

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34
Q

Typical associations: Sexual side effects

A

most common in thioridazine (Mellaril)

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35
Q

Typical associations: Sleep

A

chlorpromazine is a sedating typical and is a good choice for aiding sleep in a patient with mania or psychosis

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36
Q

Typical associations: Mood

A

loxipine (Loxitane) has mild 5-HT antagonism, making it similar to atypical. Additionally, it is metabolized to the TCA amoxepine. It is useful when a patient cannot get quetiapine or aripiprazole due to cost. DA blockade is similar to quetiapine and the mood component is like aripiprazole. Additionally, Stahl notes the use of loxipine for the augmentation of schizophrenia management with an atypical antipsychotic

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37
Q

Typical associations: Compliance

A

Haloperidol has a depot formulation that lasts 3-4 weeks to ensure compliance. Fluphenazine (Prolixin) has a depot formulation that lasts 2 weeks. Always do an oral test dose before giving a depot injection due to risk of irreversible EPS once depot is given. Consider avoiding fluphenazine depot in med-naïve young muscular males due to EPS risk

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38
Q

Typical associations: Dysphagia

A

Haloperidol has a liquid formulation to aid in ease of administration and an IV formulation. Reminder that IV formulations are much higher potency due to lack of first pass in the liver. Thus, start with lower doses than would use in PO or even IM (2-5mg IV)

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39
Q

Role of serotonin in atypical antipsychotics

A

If excessive DA blockade leads to EPS, then less severe DA blockade would cause less EPS. The best way found to modulate the amount of DA blockade was through 5-HT. Normally, serotonin binds to 5-HT receptors on DA neurons and inhibits DA release. By blocking these 5-HT receptors, DA release is not inhibited. The combination of DA receptor blockade plus 5-HT blockade (less inhibition) leads to a net increase in free DA compared with straight DA blockade in the typicals. Thus, the atypicals have less EPS.

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40
Q

Atypical side effects (general)

A

atypicals appear to have more metabolic side effects (weight gain, diabetes) than the typicals do due to effects on other receptors. Additionally, the atypicals may have more liver effects and leukopenia than the typicals do

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41
Q

Risperidone indications

A

In addition to mania and psychosis, it is approved for the treatment of aggression and self-injurious behavior in autistic children. It can be used in children with tic disorders (consider also using haloperidol) or impulsive/disruptive behaviors.

Useful in severe OCD, impulse control issues, and body dysmorphic symptoms.

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42
Q

Risperidone pharmaco stuff

A

Half-life is 20 hours; thus once-daily dosing is fine.

Equivalent to haloperidol in D2 binding affinity with less incidence of EPS when kept below 6 mg per day. Minimal alpha and muscarinic affinity.

Has an active metabolite that is formed by 2D6, thus inhibiting 2D6 (paroxetine, fluoxetine) may lead to less efficacy of risperidone.

43
Q

Antipsychotic with most prolactin increase

A

Risperidone

44
Q

Other risperidone side effects

A

Watch for pedal edema and increased LFTs. Weight gain is #3 after clozapine and olanzapine

45
Q

Paliperidone is related to

A

it is the isolated active metabolite of risperidone

46
Q

Paliperidone side effects

A

considered to have less side effects than risperidone, paliperidone has more QTc prolongation and requires lower dosing in renal impaired patients (as it is excreted unchanged through the kidneys).

47
Q

Paliperidone formulations

A

It exists as an immediate release and a delayed release medication (avoid in gastric bypass) and also occurs in a depot formulation (Sustenna). Sustenna requires no continued oral dosing once the depot is given. Injection into deltoid has nearly 30% higher plasma concentration that gluteal

48
Q

Olanzapine half life

A

31 hours, once dialy dosing is cool

49
Q

Olanzapine is metabolized by ____

A

1A2, so fluvoxamine, cimetidine, and ciprofloxacin increase olanzapine concentrations (inhibitors of 1A2), while carbamazepine and smoking reduces olanzapine

50
Q

Atypical with the best adherence

A

Olanzapine (surprisingly given weight gain/metabolic SEs)

51
Q

Olanzapine formulations

A

Formulation includes pill, dissolving Zydis tabs, IM, and depot Relprevv (injections q 2-4 weeks), however it requires monitoring due to Post-Injection Delirium/Sedation Syndrome.

52
Q

Quetiapine half-life

A

7 hours, bid or tid dosing recommended

53
Q

Major quetiapine side effects

A

weight gain and sedation. Also can cause orthostatic hypotension

54
Q

Quetiapine drug interactions

A

Dilantin increases Quetiapine’s clearance 5-fold, thus consider higher dosing in patients on Dilantin.

55
Q

Ziprasidone half life

A

5-10 hours. BID dosing is recommended.

56
Q

How to take ziprasidone

A

Bioavailability doubles when taken with food, preferably a 500-calorie meal.

57
Q

Why is ziprasidone thought to be helpful for treating depression?

A

Due to 5-HT1A agonism and SSRI/SNRI properties, it has some benefit in treating or augmenting depression treatment

58
Q

Ziprasidone formulations

A

Ziprasidone has BID dosing and exists as a capsule (cannot be broken in half), liquid, and IM.

59
Q

Aripiprazole mechanism

A

unlike the other atypicals, is a D2 partial agonist, competing with endogenous DA (both postsynaptic and presynaptic) and binds less robustly. This is considered to be modulation of the DA receptor rather than blockade. The net result is diminished DA activity in the limbic system (which is elevated in schizophrenia) and increased DA activity in the frontal and prefrontal areas (which is considered low in schizophrenia).

Is a strong 5-HT2C agonist (unlike the other atypicals), which means less weight gain. It is also a strong 5-HT7 antagonist, improving mood.

60
Q

Aripiprazole indications

A

In addition to mania and psychosis, it is indicated for augmentation of depression treatment

61
Q

Aripiprazole half life

A

The half-life is about 75 hours; thus once-daily dosing is fine

62
Q

Aripiprazole side effects

A

Side effects include akathisia, orthostatic hypotension (alpha blockade), nausea/GI effects, somnolence or insomnia

63
Q

Aripiprazole side effects

A

Side effects include akathisia, orthostatic hypotension (alpha blockade), nausea/GI effects, somnolence or insomnia

64
Q

Arsenapine (Saphris) mechanism

A

like clozapine, has higher affinity for D3 and D4 receptors than D2 receptors

65
Q

Arsenapine side effects

A

It has minimal anticholinergic side effects. Is associated with akathisia, dizziness, sedation, and weight gain (histamine affinity).

66
Q

Arsenapine metabolism and dosing

A

Metabolized by 1A2 and is dosed BID in a sublingual formulation. The patient may not eat or drink for 10 minutes after dosing

67
Q

Arsenapine bottom line

A

Preliminary drug company data reports results from 1,500 patients but there is paucity of published data on actual efficacy (the main published study only evaluated 174 patients). Thus, asenapine has weight gain, sedation, must be dosed sublingually, and is very expensive. There is limited published data on the efficacy on this medication as compared with other atypicals.

68
Q

Iloperidone (Fanapt) mechanism

A

Has mixed D2 and 5-HT2 antagonism with low affinity for histamine and muscarinic receptors.

69
Q

Iloperidone metabolism

A

Metabolized by 2D6 and 3A4 and the half-life varies between 18-37 hours based on the strength of 2D6 enzymes (longer half-life in poor metabolizers). Avoid in hepatic impairment

70
Q

Iloperidone side effects

A

Prolongs QTc interval as much as ziprasidone. It is also associated with orthostatic hypotension (alpha blockade), dizziness, and somnolence. Iloperidone has minimal weight gain. Prolactin is increased in over 25% of patients

71
Q

Iloperidone dosing

A

Due to risk of orthostatic hypotension, dosing must be gradual over 4 days in BID scheduling.

72
Q

Iloperidone bottom line

A

this medication is similar to ziprasidone in QTc prolongation with less akathisia but more weight gain. It must be titrated slowly due to orthostatic hypotension and many studies do not show it to be any better than existing atypicals.

73
Q

Lurasidone (Latuda) mechanism

A

Strong D2/5-HT2 antagonist with minimal histamine interaction (thus low weight gain). It does have sedation, which may be related to strong 5-HT7 antagonism

74
Q

Lurasidone side effects

A

Minimal weight gain, no QTc issues. EPS is equivalent to other atypicals

75
Q

Lurasidone metabolism

A

Metabolized by 3A4

76
Q

Is lurasidone “pro-cognitive”?

A

One study suggested that it upregulates BDNF in the prefrontal cortex, suggesting that the medication may be “pro-cognitive.”

77
Q

How to take lurasidone

A

Has once-daily dosing but must be taken with food to be absorbed.

78
Q

5-HT7

A

some of the new antipsychotics are boasting 5-HT7 antagonism. While not fully understood, the 5-HT7 receptor may be associated with depression. Medications that block 5-HT7 improve depression. Additionally, they may improve hippocampus-mediated actions, like memory. Many of the atypicals (risperidone, ziprasidone) are potent 5-HT7 antagonists.

79
Q

Pimavanserin (Nuplazid)

A

FDA approved in 2016 for psychosis within the context of Parkinson’s Disease. Unlike other antipsychotics, Nuplazid reduces hallucinations without worsening parkinsonism

80
Q

Pimavanserin dosing

A

recommended 34 mg once daily with or without food, no titration needed. No dose adjustment of carbidopa/levodopa is required

81
Q

Pimavanserin mechanism

A

non-dopaminergic atypical antipsychotic, inverse agonist and antagonist activity at serotonin 5-HT2A receptor. While traditionally we think of treatment of hallucinations by D2 blockade, in PD this mechanism substantially worsens the underlying movement disorder

82
Q

5-HT2A receptors?

A

Consider that the mechanism for LSD induced hallucinations is through cortical 5-HT pathways. Pimavanserin works as an antagonist and inverse agonist specifically at 5-HT2A receptors. There is minimal binding at 5-HT2C and no appreciable affinity for 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors

83
Q

Pimavanserin drug interactions

A

Pimavanserin is highly protein bound (~95%) in human plasma. Pimavanserin is predominantly metabolized by CYP3A4 and CYP3A5.

84
Q

Pimavanserin side effects

A

Nausea (7%), Constipation (4%), Peripheral edema (7%), confusional state (6%), possible QTc prolongation.

85
Q

Brexpiprazole indications

A

schizophrenia and adjunctive treatment for depression

86
Q

Brexpiprazole dosing

A

start at 0.5mg-1mg once daily and titrate.

For schizophrenia: 2–4 mg once daily. For depression: 2 mg once daily. Can be taken with or without food

87
Q

Brexpiprazole mechanism

A

related to aripiprazole, is also a D2 partial agonist, along the agonism spectrum. It is closer to the antagonist end than aripiprazole. Is also a partial agonist at 5-HT1A receptors (improve mood and cognition). Acts as a 5-HT2A receptor antagonist (see Nuplazid).

88
Q

Brexpiprazole and BDNF

A

Brexpiprazole also thought to increase BDNF

89
Q

Brexpiprazole is metabolized by ___

A

2D6 and 3A4

90
Q

Brexpiprazole side effects

A

weight gain and dose-dependent akathisia. Others include upper respiratory infection, nasopharyngitis, somnolence, tremor, fatigue, headache, hyperglycemia, theoretical risk of tardive dyskinesia, NMS (rare), seizures (rare).

91
Q

Brexpiprazole in pregnancy

A

: In animal studies, brexpiprazole did not demonstrate teratogenicity. There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester. In the newborn, symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding.

92
Q

Cariprazine (Vraylar) indication

A

schizophrenia and bipolar 1- manic/mixed episodes

93
Q

Cariprazine dosing

A

starting dose 1.5 mg, max 6 mg per day for both BMD and Schizophrenia. Has the longest half-life of the atypical antipsychotics, half-life of 2-4 days with an active metabolite that has a half-life of 1-3 weeks.

94
Q

Cariprazine mechanism

A

D2 partial agonist like aripiprazole and brexpripazole, unique high affinity for D3 receptors. D3 agonism is associated with wakefulness, thus partial agonism is associated with the treatment of mania. Additionally, effects at D3 may be precognitive and diminish negative symptoms of schizophrenia. Also has high affinity for the 5-HT1A (partial agonist) and moderate affinity for the 5-HT2A receptor (antagonist).

95
Q

Cariprazine is metabolized by ____

A

3A4

96
Q

Cariprazine

A

akathisia, EPS, may cause dose-dependent weight gain, GI symptoms (N/V), sedation

97
Q

Clozapine half-life

A

12 hours

98
Q

Clozapine is metabolized primarily by ___

A

1A2 (increased in presence of fluvoxamine or ciprofloxacin and smoking)

99
Q

Clozapine side effects

A

include severe sedation, weight gain, sialorrhea, agranulocytosis, QTc prolongation, and requires weekly blood draws for 6 months to monitor the ANC

100
Q

When do you hold clozapine (regarding WBC and ANC)

A

Dosing is held if WBC <3000 or granulocytes <1500. Additionally, this medication is only dispensed at certain pharmacies and requires proof of labs to dispense

101
Q

What is the risk of agranulocytosis in the first year of clozapine treatment?

A

< 1%

102
Q

Clozapine dosing

A

pill and dissolving tablet formulations and is BID dosing. Dosing starts at 25mg BID and can increase by 25mg per day maximum

103
Q

Try treating clozapine-induced sialorrhea with ____

A

clonidine

104
Q

Medication that can help raise the ANC

A

Lithium (600mg qhs)

Psychopharm (9 decks)

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