Neuropharmacology of Antipsychotics Flashcards
Potency of first generation antipsychotics
Low potency
Chlorpromazine (Thorazine)
Chlorprothixene
Levomepromazine
Mesoridazine (Serentil)
Periciazine
Thioridazine (Mellaril)
Ridazine
Medium potency
Loxapine (Loxitane)
Molindone (Moban)
Perphenazine (Trilafon)
High potency
Droperidol
Fluphenazine (Prolixin)
Haloperidol (Haldol)
Pimozide (Orap)
Prochlorperazine
Trifluoperazine (Stelazine)
Zuclopenthixol
Thiothixene (Navane)
- High potency risks/benefits:
a. increase in EPS
b. increase in D2 affinity
c. requires lower dosing - Low potency risks/benefits:
a. increased sedation
b. hypotension
c. weight gain.
d. anticholinergic effects
Trilafon
- Piperizine phenothiazine – piperizine group at R1
Greatly increased D2 blockade (better antipsychotic)
Lower affinty at muscarinic, α1 and histamine receptors, so…
Muscarinic - less anticholinergic effects (dry mouth, blurry vision, constipation, memory issues)
α1 - less orththostatic hypotension
H1 - less sedating
- …in comparison with Thorazine
Thorazine
- Aliphatic phenothiazines are low potency antipsychotics
- anticholinergic-it is attaching to acetylcholine receptor but acting as an antagonist there
- apha1 aadrenergic is attaching to a norephinephrine receptor but specifically the alpha 1 subtype as an antagonist
- At R1 they have the long chemical structure you see above
- anti-histamine has sedating properties.
Very sedating due to anti-cholinergic, α1 adrenergic, and anti-histamine effects (antagonist)
Haldol
- Not a phenothiazine…a butyrophenone
- Due to it’s receptor affinity profile, has greater EPS issues than Trilafon
- And somewhat greater prolactin issues
4, Hyperprolactanemia: can cause breast enlargement and lactation in both sexes - Gynecomastia: cannot be reversed by drug withdrawal, must use surgical correction
Haloperidol (Haldol)
Indications
- -Schizophrenia/psychotic disorders
- -Tourette’s
- -Severe behavioral disturbances (2nd line)
- -Short term treatment of hyperactive children (2nd line)
- -Behavioral disturbances in dementia
- -Bipolar disorder
Dosing
- -1-40 mg daily
- -Start 1-15 mg daily; generally should start low due to risk of EPS
Evidence
- -Long history of well documented efficacy for positive symptoms
- -Few recent studies available
- -Data has not shown efficacy for negative symptoms
- -EPS have been well documented in multiple RCTs
Particulars
- -Blocks D2 receptors
- -BMI, FBG, BP, lipids need to be monitored regularly
- -Half-life is 12-38 hours (oral); 3 weeks for injection
- -Most preferred antipsychotic prior to SGAs
- -Most widely used FGA today
- -High doses can induce negative symptoms
- -Many patients can tolerate low dose if can’t afford SGA
- -Less sedating than other FGAs
- -Often used to treat delirium along with lorazepam
- -Good choice for patients with violent/aggressive tendencies
- -Does little to nothing for cognitive or affective symptoms
- -Limb deformities have been reported
Side Effects/ADRs
–Neuroleptic induced deficit syndrome
–Akathisia, EPS, parkinsonism, TD, galactorrhea, amenorrhea, hypotension, dizziness, sedation, dry mouth, decreased sweating
– Seizures, NMS, jaundice, leukopenia, agranulocytosis
Interactions
–Additive effects with alcohol
–May increase intraocular pressure when combined with anticholinergic agents
–Reduces effects of anticoagulants
Medical Considerations
–Caution in renal, hepatic, and cardiac impairments
–Use with caution in elderly patients with dementia
To mitigate the side effects of D2 antagonist we can:
- Add a 5ht2a antagonist
- Add a 5HT1a partial agonist
- add a 5ht2a antagonist.
Side effects of 1st generation antipsychotics.
- D2 – dopamine, almost all typicals are strong antipsychotics in the proper dose range
- 5HT2A – serotonin, you see some differences here
- Muscarinic – acetylcholine, you see marked differences here. Thorazine and Mellaril have strong anticholinergic action, and the least EPS side effects among the typicals
a. side effects are blurred vision, dry mouth, constipation, drowsiness - Alpha 1 adrenergic – norepinephrine, again, you are seeing differences. You would predict orthostatic hypotension would be strongest with Thorazine and Mellaril – if you go back to our previous chart, you’ll see this is true
a. alpha 1 side effects are orthostatic hypotension and drowsiness. - antihistamine – specifically the H1 subtype, we also see differences. Even though Haldol is less sedating than, say, Thorazine, it is still quite sedating for non-psychotic patients. This is one reason it is often given in emergency rooms for highly agitated jor combative patients (regardless of psychotic symptoms)
a. histamine side effects are weight gain and drowsiness.
Second-Generation Antipsychotics
Overview
- -Referred to as “atypicals”
- -First line treatment for psychosis
- -Equal effectiveness for positive symptoms
- -Low extrapyramidal symptoms
- -Less hyperprolactinemia
- -Serotonin-dopamine antagonists
- -Partial agonism
2nd generation antipsychotics mechanisms of action
- Greater affinity for 5HT in general, and 5-HT2A specifically (acts as an antagonist)
- Initially thought low value of 5-HT2A/D2 ratio for atypicals vs typicals explained EPS protection
- Low 5-HT2A/D2 ratio thought to improve negative symptoms of schizophrenia (Meltzer, 2004)
- Other research supported selective D2 action with atypicals – w/little effect on the nigrostriatal pathway (Strange, 2001), later research calls this into question
- Atypical binding with D2 is looser, more on-off action (newer accepted thought process).
- Greater anticholinergic action coupled with transient D2 action may have the best support to explain improved EPS (Stahl, 2013)
- Idea is that dopamine normally acts as an inhibitor of ACh in the nigrostriatal pathway
a. Therefore, if you reduce DA, then ACh goes up and leads to an increase in EPS increases
b. However, if you simultaneously have anticholinergic properties, then EPS risk goes back down (e.g. Haldol & Cogentin given together)
c. Demonstrated by the idea that if you give a typical antipsychotics with high anticholinergic action have lower EPS (Thorazine & Mellaril)
Side effects (effect on EPS) of 2nd generation antipsychotics
- Very little EPS risks, Risperdal/Invega & Latuda have some.
- In general, sedation risks parallel metabolic syndrome risks (H1, 5HT2A & α1 antagonism).
- Clozaril & Zyprexa are very sedating w/problematic weight gain.
- Very little EPS risks, Risperdal/Invega & Latuda have some.
- Invega is the primary metabolite of Risperdal w/almost identical profile, prolactin isues remain (D2 tuberoinfidibular).
Risperidone
Indications
- -Schizophrenia
- -Relapse in Schizophrenia
- -Other psychotic disorders
- -Acute/mixed mania
- -Behavioral disturbances in autism
- -Bipolar maintenance
Dosing
- -2-8 mg daily
- -Start 1mg bid
- -Maximum dose is 16 mg daily
Evidence-General
- -A few studies have indicated increases from 1 to 2 to 3 mg over a few days is acceptable
- -One study has shown that risperidone, over a one year period, is as equally effective as clozapine for treatment resistant schizophrenia
- -Data indicating EPS is worse than other SGAs above 6 mg daily
- -CATIE trial revealed that risperidone was often under dosed <3 mg which explains poorer response in clinical settings
Evidence-Specific
- -Two combined studies totaling 513 patients with chronic schizophrenia who were assigned to an 8 week double-blind, fixed dose, placebo controlled study (2, 6, 10, or 16 mg daily) or haloperidol (20 mg daily) showed that risperidone was more effective than haloperidol in positive and negative symptoms (Chouinard et al. 1993; Marder and Meibach, 1994)
- -No difference in cognitive symptoms were found when compared to olanzapine in patients with schizophrenia (Keefe et al. 2006)
Particulars
- Alpha 2 antagonist properties may be responsible for antidepressant effects
- -Blocks D2 and 5HT 2A receptors
- -Psychotic symptoms can improve in one week
- -Available in depot formulation
- -Can cause hyperprolactinemia, particularly in adolescent boys
- -BMI, FBG, BP, lipids need to be monitored regularly
- -Metabolized by CYP450 2D6
- -Half-life is 24 hours; long acting has 3-6 day half-life
- -Less weight gain than some other SGAs
Side Effects/ADRs
–Increases risk of diabetes and dyslipidemia
–Dose-dependent EPS
–Dose-dependent hyperprolactinemia
– Diabetic ketoacidosis, seizures, NMS
Interactions
–May increase effects of antihypertensives
–Carbamazepine may reduce levels
–Fluoxetine and paroxetine may increase levels
Medical Considerations
–Use with caution in patients with renal, hepatic, and cardiac problems
–Use with caution in elderly patients with dementia
Quetiapine (Seroquel)
Indications
- -Schizophrenia
- -Maintaining response in schizophrenia
- -Agitation in schizophrenia
- -Other psychotic disorders
- -Acute mania
- -Bipolar depression
- -Bipolar mainteance
- -Depression
Dosing
- -400-800 mg qd or bid
- -Increase in 25-50 mg each day until desired dose is reached
Evidence-General
- -FDA approval in 1998
- -Several large RCTs have shown efficacy when compared to placebo and FGAs
- -Data indicates efficacy for negative symptoms, but can take several weeks
- -Open label trials have shown efficacy for treatment resistant psychotic disorders
- -Studies have consistently shown that quetiapine produces modest weight gain
- -Data supports reduced side effects with XR
Evidence-Specific
- -Rapid titration study comparing rapid dosing (starting at 200 and going to 800 mg daily over four days) to conventional dosing (50 mg one day and up to 400 mg over five days) showed that rapid dosing was slightly more effective and that patients tolerated both schedules equally (Pae et al. 2007)
- -Study comparing quetiapine to risperidone found that both were equally effective, but quetiapine had fewer sexual side effects, lower prolactin levels, and fewer EPS (Zhong et al. 2006)
Particulars
- -Blocks D2 and 5HT 2A receptors ; also has high affinity for D4 receptors
- -5HT1A action may explain improvement in cognitive and affective symptoms at moderate to high doses
- -BMI, FBG, BP, lipids need to be monitored regularly
- -Half-life is 6-7 hours
- -Modest amount of weight gain; not the best…not the worst
- -May be best choice for Parkinson’s Disease and Lewy Body Dementia
- -May be more effective than we think; often under dosed
- -Active metabolite (norquetiapine) may explain affective improvement through NEPI effects
- -More sedation than other SGAs
- -Pregnancy category C
- -No motor side effects noted; initial studies show may have less metabolic issues
Side Effects/ADRs
–Increases risk of diabetes and dyslipidemia
–Dizziness, sedation, dry mouth, GI effects, orthostatic hypotension, tachycardia,
– Diabetic ketoacidosis, seizures, NMS
Interactions
–CYP450 3A and 2D6 inhibitors may increase plasma levels; generally don’t need to adjust dose
–Enhance antihypertensive effects
Medical Considerations
–Use with caution in patients with hepatic and cardiac problems (particularly because of OH)
–No dose adjustments needed for renal problems
–Use with caution in elderly patients with dementia
Olanzapine (Zyprexa)
- -Schizophrenia
- -Maintaining response in schizophrenia
- -Agitation in schizophrenia
- -Other psychotic disorders
- -Acute/mixed mania
- -Bipolar depression
- -Acute agitation in bipolar disorder (Symbyax-fluoxetine and olanzapine)
- -Treatment resistant depression (Symbyax)
Dosing
- -10-20 mg daily; 6-12 mg olanzapine and 25-50 mg fluoxetine
- 5-10 mg qd; generally in evening
Evidence-General
- -FDA approval in 1996
- -CATIE trial found it may be more efficacious than other SGAs and less rate of discontinuation (moderate doses)
- -One study showed olanzapine as effective as clozapine in treatment resistance schizophrenia; CATIE trial did not support this notion
- -Olanzapine has consistently shown in studies that it has less EPS than all other first generations
- -Studies have consistently shown that olanzapine produces more weight gain than most other SGAs
Evidence-Specific
- -Flexible dosing study showed that olanzapine was more effective than haloperidol in schizophrenia; mean dose was 13 mg daily (Tollefson et al. 1997)
- -Study showed that olanzapine was more effective than haloperidol with regard to global symptoms of schizophrenia (Leucht et a. 1999)
- -Other studies have shown than olanzapine did no better than haloperidol with regard to cognitive symptoms (Buchanan et al. 2005)
Particulars
–Blocks D2 and 5HT 2A receptors
–5HT2C antagonism may explain improvement in cognitive and affective symptoms
–Combined formulation with fluoxetine (Symbyax)
–BMI, FBG, BP, lipids need to be monitored regularly
–Half-life is 21-54 hours
–More weight gain than some other SGAs; less than clozapine, but more than quetiapine and risperidone
–Pregnancy category C
–Very effective, but weight gain is very limiting
Side Effects/ADRs
–Increases risk of diabetes and dyslipidemia
–Dizziness, sedation, dry mouth, GI effects, peripheral edema, orthostatic hypotension, tachycardia, rash on exposure to sunlight (rare)
– Diabetic ketoacidosis, seizures, NMS
Interactions
–May need to be raised in smokers (1A2)
–May increase risk of antihypertensives
Medical Considerations
–Use with caution in patients with renal, hepatic, and cardiac problems
–Use with caution in elderly patients with dementia
Aripiprazole (Abilify)
Aripiprazole Indications --Schizophrenia --Maintaining response in schizophrenia/delaying relapse --Other psychotic disorders --Acute/mixed mania --Bipolar maintenance --Depression (adjunct) --Autism related irritability --Behavioral disturbances
Dosing
- -15-30 mg qd
- -Start 10-15 mg qd; increase in 2.5-5mg thereafter
Evidence-General
- -Meta-analysis showed aripiprazole to be more effective than placebo and as effective as risperidone and FGAs in schizophrenia
- -It was not evaluated in CATIE trial (too new)
- -Studies have shown side effect profile to be better than other SGAs and lower dropout rates
- -Studies have shown it to be as effective as haloperidol in preventing relapse
Evidence-Specific
- -In a study of 307 schizophrenics with a recent relapse, assignment of patients to doses of 2, 10, and 30 mg of aripiprazole did better than those assigned to haloperidol (Daniel et al. 2000)
- -Aripiprazole has been shown to delay time to relapse compared to placebo, 57% to 34% respectively (Pigott et al. 2003)
Particulars
- -Partial agonism at D2 receptors; an atypical atypical
- -Action at D3 receptors may also explain effiacy
- -Blocks 5HT 2A
- -BMI, FBG, BP, lipids need to be monitored regularly
- -Half-life is 75 hours
- -Considered to be weight neutral; may have less risk of metabolic problems; good choice for patients at risk of diabetes or that have lipid abnormalities
- -Less sedating than other SGAs; less activating than ziprasidone, but is still activating in some patients
- -Short acting IM formulation available
- -Similar to ziprasidone, can add benzo to manage agitation
- -Not a good choice if insomnia is an issue
- -Good choice in schizoaffective, but limited data
Side Effects/ADRs
–Activation and akathisia; avoid in highly agitated patients
–Increases risk of diabetes and dyslipidemia (less than others)
–Dizziness, GI upset, OH
– Seizures, NMS
Interactions
–CYP3A4 inhibitors may increase plasma levels (fluoxetine)
–Carbamazepine may reduce plasma levels
Medical Considerations
–No dose adjustments needed for renal or hepatic problems
–Limited data with cardiac patients; use with caution due to risk of OH
–Use with caution in elderly patients with dementia
Ziprasidone (Geodon)
Indications
- -Schizophrenia
- -Maintaining response in schizophrenia/delaying relapse
- -Agitation in schizophrenia
- -Other psychotic disorders
- -Acute/mixed mania
- -Bipolar maintenance
- -Bipolar depression
- -Behavioral disturbances
Dosing
- -40-200 mg bid
- -Start 20 mg bid; however, 40 or 60 mg bid may be better tolerated
Evidence-General
- -FDA approval in 2000
- -CATIE trial found modest effects; better tolerated
- -Studies have shown modest dose of ziprasidone is as effective as 15mg of haloperidol
- -No large RCTs done with treatment resistance psychotic disorders
- -Data does not suggest significant dropout from activation, but clinical practice shows it is a problem
Evidence-Specific
- -Studies have shown that rapid titration provides greater benefits due to staying in treatment longer and being able to reach therapeutic doses (Kane, 2003; McCue et al. 2006)
- -Compared to olanzapine, ziprasidone did not do as well in a sample of 548 patients with regard to improvement on standardized screenings for schizophrenia over 28 weeks (Breier et al. 2005)
Particulars
- -5HT1A and 5HT2C action may explain improvement in cognitive and affective symptoms at moderate to high doses
- -5HT1D influence NEPI and dopamine receptors theoretically leading to improvement in anxiety and depression
- -Anecdotal evidence supports effectiveness in treating anxiety and mood; some research support
- -BMI, FBG, BP, lipids need to be monitored regularly
- -Half-life is 6-7 hours
- -Considered to be weight neutral; may have less risk of metabolic problems; good choice for patients at risk of diabetes or that have lipid abnormalities
- -May be more effective than we think; often under dosed
- -More activation than other SGAs; can add benzo
- -Short acting IM formulation available
- -Concern over QTc prolongation; fears may not be warranted
Side Effects/ADRs
–Activation; avoid in highly agitated patients
–Increases risk of diabetes and dyslipidemia (less than others)
–Dizziness, EPS, dystonia at high doses
– Seizures, NMS
Interactions
–Risk of QTc prolongation when given with other medications that increase QTc
–Enhance antihypertensive effects
Medical Considerations
–No dose adjustments needed for renal or hepatic problems
–Avoid in patients with history of QTc prolongation and other heart issues
–Use with caution in elderly patients with dementia
