Antipsychotics Flashcards
Phenothiazines were derived from ____
methylene blue
Chlorpromazine was created in what year?
1951
Typical antipsychotic affect on seizure threshold.
Lowers seizure threshold
D2 blockade is this brain region is thought to diminish psychosis
Mesocortical and mesolimbic
D2 blockade in this system causes derangements in prolactin levels
Tuberoinfundibular system, increases prolactin
D2 blockade in this brain area causes movement disorders
Nigrostriatal (basal ganglia, caudate). Causes EPS, PD, tremor
Typical antipsychotics are metabolized by ___ and ___
2D6 and 3A4
Levels of typical antipsychotics are increased by ______
fluoxteine, paroxetine, fluvoxamine (Prozac, paxil, luvox)
Levels of typicals are reduced by ____
Carbamazepine
Absorption of typicals is reduced by ____
antacids
Cigarettes tend to ____
decrease blood concentrations of typicals
Typicals effect on valproic acid
Increase the blood concentration of valproic acid
List of high-potency typicals
fluphenazine (Prolixin), haloperidol (Haldol), thiothixine (Navane), trifluoperazine (Stellazine)
List of medium-potency typicals
perfenazine (Trilafon), molindone (Moban), loxipine (Loxitane)
List of low-potency typicals
chlorpromazine (Thorazine), thioridazine (Mellaril)
Pseudoparkinson
bradykinesia, rigidity, masked face, cogwheeling, tremor. Women are 2x more likely.
Treat with anticholinergics, Benadryl, or amantadine
Dystonia
muscle spasms of jaw, tongue, eyes. Laryngospasms possible. More common in young males. Treat with anticholinergics or Benadryl
Akathisia
pacing, restlessness, described as feeling the urge to move around or having “crawling” sensation under skin.
Treated with propranolol, BZD, or clonidine
Tardive Dyskinesia
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
Neuroleptic Malignant Syndrom
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
Alpha Blockade can cause
orthostatic hypotension
Anticholinergic side effects
dry mouth (treat with sugarless gum), constipation, sore throat, urinary retention (treat with bethanechol), blurred vision, confusion
Antihistamine side effects
weight gain and sedation
Endocrine side effects
prolactin causes sexual side effects like erectile dysfunction, priapism, increased time to ejaculation, gynecomastia, impotence, and anorgasmia
Hepatic side effects
jaundice and elevated LFTs (less severe than with atypicals)
Cardiac side effects
arrhythmia and prolonged QTc
Hematologic side effects
agranulocytosis (monitor for fever, sore throat)
Neurologic side effects
epilepsy due to lowered seizure threshold
Dermatologic side effects
skin discoloration and photosensitivity in chlorpromazine
Opthomologic side effects
retinitis pigmentosa and blindness in thioridazine
Typical associations: Cardiac patients
avoid low potency, especially thioridazine (Mellaril)
Typical associations: Elderly
avoid low potency due to anticholinergic confusion
Typical associations: Weight gain
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
Typical associations: Sexual side effects
most common in thioridazine (Mellaril)
Typical associations: Sleep
chlorpromazine is a sedating typical and is a good choice for aiding sleep in a patient with mania or psychosis
Typical associations: Mood
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
Typical associations: Compliance
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
Typical associations: Dysphagia
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)
Role of serotonin in atypical antipsychotics
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.
Atypical side effects (general)
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
Risperidone indications
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.
Risperidone pharmaco stuff
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.
Antipsychotic with most prolactin increase
Risperidone
Other risperidone side effects
Watch for pedal edema and increased LFTs. Weight gain is #3 after clozapine and olanzapine
Paliperidone is related to
it is the isolated active metabolite of risperidone
Paliperidone side effects
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).
Paliperidone formulations
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
Olanzapine half life
31 hours, once dialy dosing is cool
Olanzapine is metabolized by ____
1A2, so fluvoxamine, cimetidine, and ciprofloxacin increase olanzapine concentrations (inhibitors of 1A2), while carbamazepine and smoking reduces olanzapine
Atypical with the best adherence
Olanzapine (surprisingly given weight gain/metabolic SEs)
Olanzapine formulations
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.
Quetiapine half-life
7 hours, bid or tid dosing recommended
Major quetiapine side effects
weight gain and sedation. Also can cause orthostatic hypotension
Quetiapine drug interactions
Dilantin increases Quetiapine’s clearance 5-fold, thus consider higher dosing in patients on Dilantin.
Ziprasidone half life
5-10 hours. BID dosing is recommended.
How to take ziprasidone
Bioavailability doubles when taken with food, preferably a 500-calorie meal.
Why is ziprasidone thought to be helpful for treating depression?
Due to 5-HT1A agonism and SSRI/SNRI properties, it has some benefit in treating or augmenting depression treatment
Ziprasidone formulations
Ziprasidone has BID dosing and exists as a capsule (cannot be broken in half), liquid, and IM.
Aripiprazole mechanism
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.
Aripiprazole indications
In addition to mania and psychosis, it is indicated for augmentation of depression treatment
Aripiprazole half life
The half-life is about 75 hours; thus once-daily dosing is fine
Aripiprazole side effects
Side effects include akathisia, orthostatic hypotension (alpha blockade), nausea/GI effects, somnolence or insomnia
Aripiprazole side effects
Side effects include akathisia, orthostatic hypotension (alpha blockade), nausea/GI effects, somnolence or insomnia
Arsenapine (Saphris) mechanism
like clozapine, has higher affinity for D3 and D4 receptors than D2 receptors
Arsenapine side effects
It has minimal anticholinergic side effects. Is associated with akathisia, dizziness, sedation, and weight gain (histamine affinity).
Arsenapine metabolism and dosing
Metabolized by 1A2 and is dosed BID in a sublingual formulation. The patient may not eat or drink for 10 minutes after dosing
Arsenapine bottom line
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.
Iloperidone (Fanapt) mechanism
Has mixed D2 and 5-HT2 antagonism with low affinity for histamine and muscarinic receptors.
Iloperidone metabolism
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
Iloperidone side effects
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
Iloperidone dosing
Due to risk of orthostatic hypotension, dosing must be gradual over 4 days in BID scheduling.
Iloperidone bottom line
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.
Lurasidone (Latuda) mechanism
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
Lurasidone side effects
Minimal weight gain, no QTc issues. EPS is equivalent to other atypicals
Lurasidone metabolism
Metabolized by 3A4
Is lurasidone “pro-cognitive”?
One study suggested that it upregulates BDNF in the prefrontal cortex, suggesting that the medication may be “pro-cognitive.”
How to take lurasidone
Has once-daily dosing but must be taken with food to be absorbed.
5-HT7
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.
Pimavanserin (Nuplazid)
FDA approved in 2016 for psychosis within the context of Parkinson’s Disease. Unlike other antipsychotics, Nuplazid reduces hallucinations without worsening parkinsonism
Pimavanserin dosing
recommended 34 mg once daily with or without food, no titration needed. No dose adjustment of carbidopa/levodopa is required
Pimavanserin mechanism
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
5-HT2A receptors?
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
Pimavanserin drug interactions
Pimavanserin is highly protein bound (~95%) in human plasma. Pimavanserin is predominantly metabolized by CYP3A4 and CYP3A5.
Pimavanserin side effects
Nausea (7%), Constipation (4%), Peripheral edema (7%), confusional state (6%), possible QTc prolongation.
Brexpiprazole indications
schizophrenia and adjunctive treatment for depression
Brexpiprazole dosing
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
Brexpiprazole mechanism
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).
Brexpiprazole and BDNF
Brexpiprazole also thought to increase BDNF
Brexpiprazole is metabolized by ___
2D6 and 3A4
Brexpiprazole side effects
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).
Brexpiprazole in pregnancy
: 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.
Cariprazine (Vraylar) indication
schizophrenia and bipolar 1- manic/mixed episodes
Cariprazine dosing
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.
Cariprazine mechanism
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).
Cariprazine is metabolized by ____
3A4
Cariprazine
akathisia, EPS, may cause dose-dependent weight gain, GI symptoms (N/V), sedation
Clozapine half-life
12 hours
Clozapine is metabolized primarily by ___
1A2 (increased in presence of fluvoxamine or ciprofloxacin and smoking)
Clozapine side effects
include severe sedation, weight gain, sialorrhea, agranulocytosis, QTc prolongation, and requires weekly blood draws for 6 months to monitor the ANC
When do you hold clozapine (regarding WBC and ANC)
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
What is the risk of agranulocytosis in the first year of clozapine treatment?
< 1%
Clozapine dosing
pill and dissolving tablet formulations and is BID dosing. Dosing starts at 25mg BID and can increase by 25mg per day maximum
Try treating clozapine-induced sialorrhea with ____
clonidine
Medication that can help raise the ANC
Lithium (600mg qhs)
