Exam 1 - Antipsychotics Flashcards
Dopamine
Produced in the Ventra Tegmental Area(Reward Pathway)
Associated with reward and pleasure
Involves 4 major pathways
Mesolimbic Pathway “reward/pleasure”
Associated with positive symptoms of schizophrenia (i.e. hallucinations, delusions etc)
However, excess DA in this pathway will produce positive psychotic sx (even in people abusing substances which increase DA and other disorders with psychosis)
Note: Dopamine inhibits prolactin.
Dopamine
Mesocortical Pathway
Associated with the negative symptoms of Schizophrenia (i.e. cognition, affect, apathy, behavior etc.)
It is believed that negative sx are related to a deficit of dopamine in this particular pathway
FGA can induce negative and cognitive symptoms as they block DA
Dopamine
Tuberoinfundibular Pathway
When functioning normally, the neurons in this pathway are active and INHIBIT prolactin release
Sx of elevated prolactin levels: galactorrhea, amenorrhea, possible sexual dysfunction
Note: Dopamine inhibits prolactin.
Therefore, blockade of dopamine= ↓DA= ↑ Prolactin
Dopamine
Nigrostriatal Pathway
Blockade of DA in this pathway produces increased motor movements
Deficient DA in this pathway causes movement disorders
e.g. EPS (Pseudo parkinsonism, Akathisia, dystonia & TD)
Neurotransmitters in schizophrenia
↑Dopamine in the mesolimbic area
↓Dopamine activity in the Mesocortical area
↓Serotonin (down regulation) in the frontal cortex
Most patients experience prodromal phase so symptoms before their first psychotic break (i.e. negative symptoms, cognitive deficits and social awkwardness (2-3 years before psychotic break)
10+% incidence with one parent with schizophrenia and 35+% with both parents with schizophrenia.
Antipsychotic polypharmacy can increase the risk ofor re-hospitalization, diabetes, EPS, sedation, seizures, metabolic effects, mortality and sudden cardiac death.
Red part
Antipsychotic polypharmacy can increase the risk ofor re-hospitalization, diabetes, EPS, sedation, seizures, metabolic effects, mortality and sudden cardiac death.
Psychotic Disorders:
Brief Psychotic Disorder
Schizophreniform disorder
Schizophrenia
Schizoaffective disorder (Bipolar type or depressive type)
Antipsychotics (Up to 6-8 weeks for response)
Etiology:
Impaired neuronal communication
↑ DA in mesolimbic pathway = positive symptoms
↓ DA in mesocortical pathway = negative symptoms
Excessive Glutamate
↓ GABA
↓ 5HT
NOTE: Majority of patients require lifelong medication.
Indication(s): Schizophrenia, schizoaffective disorder, depression w/ psychotic features, bipolar w/ psychotic features,
Positive Symptoms of Schizo/Psychotic disorders:
Delusions
Conceptual disorganization
Excitement
Grandiosity
Hostility
Hallucinations
Negative Symptoms of Schizo/Psychotic disorders:
Affects (generally flat, constricted)
Alogia (relative absence of speech
Avolition/Apathy ( lack of emotions, initiative)
Attention (poor or lacking)
Anhedonia (absence of pleasure/motivation
Asociality- withdrawal from normal social contact
Cognitive Symptoms
Manifestation of Positive Symptoms of Schizo/Psychotic disorders:
Delusions
Hallucinations
Conceptual disorganization
Hostility
Grandiosity
Manifestation of Negative Symptoms of Schizo/Psychotic disorders:
Affect (generally flat, constricted)
Alogia (relative absence of speech)
Avolition/Apathy(lack of emotion enthusiasm)
Attention (poor or lacking)
Anhedonia (absence of pleasure)
Antipsychotics: overview
Not just used for psychosis or schizophrenia
Used for mania and depression in bipolar d/o
Augmentation for mood
Off-label for many disorders including mood, anxiety, PTSD
Typical/1st Generation /Neuroleptics /Coventional
Introduced in the 1950’s
Block D2 receptors
Effective for positive symptoms
Can worsen negative symptoms secondary to ↓DA in the Mesocortical pathway
Long-acting forms available (Decanoate)
Atypical/2nd Generation
First line treatment
Fewer neurological S/E
Effective for both positive and negative symptoms
Serotonin-Dopamine antagonist (D2/5HT2A)
Can cause EPS but at a lower risk
↓ incidence of Tardive dyskinesia
Metabolic side effects : Weight gain, HLD, hyperglycemia, Diabetes, HTN, Cardiac and respiratory S/E
Some Antihistaminic, antiadrenergic and antimuscarinic effects
Elevated Liver function tests (LFTs)- check yearly
QTC Prolongation
Atypical/2nd Generation Antipsychotics are first line treatment.
NOTE: Antipsychotics can take up to 6-8 weeks for response
Factors affecting choice of antipsychotic medication
Side effect profile
Available route of administration (e.g. liquid vs. disintegrating forms)
Patient’s medical hx
Current medications
Preference
Low Potency Typical (1st Generation Antipsychotics)
Low affinity to DA receptors= ↑doses required
High incidence of antiadrenergic, anticholinergic and antihistaminic s/e
Lower risk of EPS
More lethal in overdose d/t QTC prolongation
e.g. Thorazine, Mellaril
Recap: Low potency= Low EPS= High antiadrenergic, anticholinergic and antihistaminic s/e
High Potency Typical (1st Generation Antipsychotics)
Greater affinity to DA receptors= ↓doses needed
Less incidence of antiadrenergic, anticholinergic and antihistaminic s/e
Greater risk of EPS
e.g. Haldol, Prolixin, Stelazine
Recap: High potency= High EPS= Low antiadrenergic, anticholinergic and antihistaminic s/e
Typical Antipsychotics
Chlorpromazine (Thorazine)
Can cause blue-gray skin discoloration and corneal/lens deposits
Causes orthostatic hypotension
Also used for N/V and intractable hiccups
Comes in po and IM formulation (effective for agitation in emergencies
Typical Antipsychotics
Thioridazine (Mellaril)
Associated with retinitis pigmentosa
Typical Antipsychotics
Loxapine (Loxitane)
Higher risk of seizures
Typical Antipsychotics
Haloperidol (Haldol)
Can be given PO/IM/IV; Decanoate (LAI)
Given in Acute agitation or psychosis
Typical Antipsychotics
Fluphenazine
PO/IM; Decanoate (LAI) available
Typical Antipsychotics
Trifluoperazine (Stelazine)
Approved for nonpsychotic anxiety
Side Effects of Typical Antipsychotics (blockade of histamine, acetylcholine, alpha 1 and other receptors)
High antiadrenergic, anticholinergic and antihistaminic s/e (e.g. sedation, weight gain)
Elevated liver enzymes, jaundice
Seizures – all antipsychotics lower the seizure threshold
Orthostatic hypotension
QTC prolongation – obtain baseline EKG
Sexual dysfunction
Rashes, photosensitivity
Elevated liver enzymes, EPS (Akathisia, dystonia, Parkinsonism)
**Hyperprolactinemia (decreased libido, galactorrhea, gynecomastia, impotence, amenorrhea)
Tardive dyskinesia
Neuroleptic Malignant Syndrome(FALTERED)
Muscarinic cholinergic blocking
Conventional antipsychotics also block M1-cholinergic receptors
Side effects: blurred vision, dry mouth, constipation, cognitive blunting, urinary retention
Antipsychotics that have weaker anticholinergic properties tend to cause more EPS and vice versa
Dopamine and acetylcholine have a reciprocal relationship in the nigrostriatal pathway
Therefore, you may see anticholinergics given along with conventional AP to decrease EPS, but it does nothing to mitigate risk of tardive dyskinesia
Other actions of conventional AP
Conventional AP also can block H1 receptors
Side effects: weight gain, drowsiness
Blockade of alpha-1 adrenergic receptors
Side effects: orthostatic hypotension, drowsiness
Key point: while conventional antipsychotics vary in their degree of blockade of various secondary receptors (and thus vary in degree of certain side effects), their efficacy in positive Sx via DA blockage is thought to be equivalent within the class.
Extrapyramidal Symptoms (EPS)
Acute Dystonia
Sudden onset
Fixed/Sustained painful contraction of the neck muscles (torticollis), tongue, eyes (oculogyric crisis)
Can be life threatening if it affects airway
Txt: Cogentin, Artane, Benadryl, Benzos- Ativan
Lower dose if possible
Hours to days
Extrapyramidal Symptoms (EPS)
Akathisia
Internal and external restlessness
Subjective anxiety, restlessness, inability to remain still
Constant need to pace or walk
Txt: Drug of choice= Beta blocker (Propranolol), Benzos (Klonopin, Ativan)
Lower dose if possible
Change to an atypical
Days to months
Extrapyramidal Symptoms (EPS)
Pseudo-Parkinsonism
Bradykinesia(shuffled gait), masklike face, cogwheel rigidity, pill-rolling tremor
Txt: Cogentin, Artane, Benadryl, Symmetrel (Amantadine)
Lower dose if possible
Days to months
Do not co-prescribe drugs in efforts to prevent EPS. Associated w/ high anticholinergic side effects
Caution w/ Elderly patients.
If necessary, anticholinergics should be prescribed at the lowest dose possible.
Bruxism (involuntary teeth grinding)
Occurs especially during sleep
Can result in destruction of teeth structure, TMJ dysfunction, sleep disturbances.
Management
Reduce dose or switch
Dental guards
First line: Buspar
2nd line: Benzos (Clonazepam); Gabapentin
Tremor
More prominent in the hands
?? Fine vs. Coarse; resting vs. postural vs. intentional
Common meds: Lithium, valproic acid, lamotrigine, SSRIs etc.
Management
Educate about caffeine intake – can worsen tremors
Reduce or switch agent
First-line: Propranolol, Inderal, Benztropine (Cogentin)
Tardive Dyskinesia
Tardive= D2 Blockade in the Nigrostriatal Pathway =late occurring
Involuntary Choreoathetoid movements of face, mouth, lips (lip smacking) tongue (fly catcher tongue) and other body parts (facial grimacing, eye blinking, trunk, limbs etc. )
Occurs in patients who have used neuroleptics for months to years ( Sooner in older adults)
Risk factors: older age, women, patients with affective disorders, FGA, duration of txt, higher dose, African American
Affects about 20-30% of patients who on antipsychotics or months or years.
Up to 50% of cases will remit (without further antipsychotic use)
Mostly irreversible
Management: Dose reduction; D/C med; switch to an atypical antipsychotic; Clonazepam, Amantidine, Tetrabenazine.
2017: First FDA approved treatment for TD (Valbenazine=Ingrezza); Deutetrabenazine (Austedo)
AIMS (Abnormal Involuntary Movement Scale) testing initially then Q3-6 months
Risk factors: High doses, long duration, old age, women, hx of EPS, substance abuse (heavy smoking), diabetes
Patient Education: TD symptoms may initially worsen transiently as medication dosages are lowered.
Consider switching to Clozaril (Lowest risk of TD)
Neuroleptic Malignant Syndrome (NMS)
Life-threatening idiopathic reaction to antipsychotic medications (more common w/ FGAs)
Medical Emergency w/ 20% mortality rate if untreated
Generally apparent 2 weeks of treatment initiation
F= Fever
A= Autonomic Instability (Tachycardia, HTN, Diaphoresis)
L= Leukocytosis
T= Tremor
E= Elevated CPK
R= Rigidity (lead pipe)
E= Excessive sweating (diaphoresis)
D= Delirium (mental status changes)
Risk factors: High doses, high potency, LAIs
Risk factors: Young males early in treatment with high potency antipsychotics
Management
D/C medication
Supportive care (hydration, IV benzos- for relaxation; cooling blankets)
Administer sodium dantrolene, bromocriptine, amantadine
ECT can be effective
General Information of Atypical (2nd Generation Antipsychotics)
Accounts for 80% of total antipsychotics prescribed.
MOA: Blocks both dopamine and serotonin receptors
Less likely to cause EPS, TD or NMS
May be more effective than typical antipsychotics in treating negative symptoms of schizophrenia
Used to treat acute mania, bipolar disorder and as adjunctive in unipolar depression
Also used in treating borderline personality disorder, PTSD and certain childhood psychiatric disorders (e.g., tic disorders)
Atypical antipsychotics/2nd generation
Pines(Olanzapine, quetiapine, asenapine, clozapine)= ↑risk of weight gain, metabolic syndrome, diabetes
Dones (risperidone, lurasidone, ziprasidone, iloperidone)= ↑risk of movement disorders, cardiac conduction problems ↓
S/E: Metabolic syndrome = Obtain baseline and monitor BMI,weight, fasting glucose, waist circumference, BP, HbA1c and fasting lipids
Features: obesity, elevated triglycerides, low HDL levels, BP greater than 135/85
Weight gain, HLD, Hyperglycemia, elevated LFTs, QTC prolongation,
Quetiapine (Seroquel)
Strongest H1 antagonism*
Comes in XR
Rare cataract formation
Weight gain, Sedation and orthostatic hypotension
Olanzapine (Zyprexa)/ Zydis (Disintegrating from)
Causes significant weight gain, sedation and dyslipidemia (strong H1 antagonism)
Acute agitation IM acts within 15min
Monitor for dose-related hyperprolactinemia
PO/IM/LAI formulation
Relprevv (Injection)= Monitor 3 hours post injection d/t risk of delirium & sedation syndrome (Post injection syndrome)
Risperidone (Risperdal)
LAI- Consta (Watch for lump at injection site= may persist for several weeks)
Doses > 6mg = increase EPS risk
Greatest prolactin elevation among atypical
Often used also in children (behavioral, autism spectrum d/o) and older adults (major neurocog with behavioral disturbances), aggression, irritability
Ziprasidone (Geodon)
Injectable form
QTC prolongation
Take with food to ↑absorption (300 calorie meal)
PO/IM formulation
Weight neutral
Paliperidone (Invega)
LAI(Sustenna- Monthly) (Trinza- every 3 months)
Metabolite of Risperdal
Do not use if hx of qtc prolongation, recent myocardial infarction, heart failure
Aripiprazole (Abilify)
Partial D2 agonist
Can be activating (Akathisia) and less sedating
PO/IM, LAI formulation (Maintenna)
Weight neutral
Watch for orthostatic hypotension
Adjunctive tx of depression, bipolar
Brexpiprazole (Rexulti)
Similar to aripiprazole
Slightly lower risk of akathisia
Lumateperone (Calypta)
Relatively new
Approved for schizophrenia
Lauroxil (Aristada)
441mg, 662 mg, 882 mg IM Q month
Iloperidone (Fanapt)
Similar class s/e, metabolic, motor, prolactin increase, dose-dependent weight gain, orthostatic hypotension
Asenapine(Saphris)
Sublingual administration (cannot eat or drink x 10 min after taking), fairly rapid onset of action (utility as PRN inpatient vs IM)
Still very expensive, not commonly used
Lurasidone (Latuda)
Take w/ food (350 calories) for absorption
Approved for bipolar depression
Low risk for metabolic syndrome
Criprazine (Vraylar)
Also approved for the acute treatment of mania, mixed episodes of bipolar 1 d/o
Long half life
Associated w/ EPS (Akatisia, parkinsonism-like features)
Clozaril:
Perform WBC/ANC weekly for first 6 months of treatment and can decrease frequency there-after
Clozapine(Clozaril)
Fazaclo (ODT)- Denigrating form
Agranulocytosis in 1% of patients
Neutropenia in about 3%
Off label use
Treatment resistant bipolar disorder
Dementia
Parkinson’s related psychosis or agitation
Common adverse effects
HTN
Hypotension
Tachycardia
Dislipidemia
Weight gain
Constipation
Sialorrhea
Drowsiness/sedation
Used to treat refractory schizophrenia(i.e., treatment resistant)
Only antipsychotic shown to decrease SI risk
Less likely to cause TD
Weight gain is most prominent
More anticholinergic s/e- tachycardia, constipation etc.
Hypersalivation (sialorrhea) occurs in 30-80%
Agranulocytosis( highest first 3 months of treatment)= Monitor WBC and Absolute neutrophil count (ANC)
D/C med if ANC is <1.5 (1500)
ANC
General Management of Sialorrhea
Chew sugarless gum
Place towel over pillow especially if nocturnal sialorrhea is a problem
Med: Glycopyrrolate (Robinul) -fewer Anticholinergic side effects)
Benztropine, Artane etc.
Note: Associated with myocarditis and cardiomyopathy typically in early stages of treatment (e.g., SOB, chest pain and swelling in LE)
Clozaril
Note: Associated with myocarditis and cardiomyopathy typically in early stages of treatment (e.g., SOB, chest pain and swelling in LE)
Clozapine Risk Evaluation and Mitigation Strategy (REMS)
A centralized point of access for providers and pharmacists to certify before dispensing Clozapine.
Severe neutropenia is and ANC less than 500/mcL
Must be enrolled in the Clozapine risk eval & management strategy program (Clozaril REMS program)
Prescribers are required to submit patient’s ANC levels to the Clozapine REMS program for every prescription of Clozapine.
Once started ANC weekly x first 6 months
Then Q2 weeks x 6 months
Then Q4 weeks thereafter
May check blood levels ≥ 350g/ml
Atypical common side/adverse effects
Typically described as food craving and binging
Weight gain: ≥7% increase in weight from baseline
Common with Clozapine, Olanzapine, Quetiapine
Least with Aripiprazole, haloperidol, ziprasidone and lurasidone
Monitoring: Weight, BMI, waist circumference per guidelines
Management: Switch to weight neutral medication
May add to regimen: Topiramate, Metformin, Orlistat, Aripiprazole.
Atypical common side/adverse effects
Metabolic Syndrome
H1 receptor antagonism is associated with sedation and weight gain
Weight gain – Metformin can be used to reduce or prevent
Hyperlipidemia
Hyperglycemia
Monitor Baseline and ongoing;
Weight
Waist circumference
BP
HbA1c
Fasting lipids
NOTE: For patients established on antipsychotic medications, yearly labs should be considered.
Note:
Antipsychotics are metabolized primarily in the liver. Many metabolites are active and peak plasma concentrations is usually reached 2-3 hours after an oral dose.
Atypical common side/adverse effects
Elevated Prolactin Levels
D2 blockade in the Tuberoinfundibular pathway= Hyper-prolactin
Men= Gynecomastia, erectile dysfunction, low libido, galactorrhea
Women = galactorrhea and absence of menses, low libido, galactorrhea
Management
Reduce or discontinue med
Switch to a different medication
If the above techniques are not feasible, add Aripiprazole to the regimen
Smoking and antipsychotic medications
An estimated 60-90% of schizophrenia patients smoke cigarettes for anxiolytic effects, enhanced attention and pro-cognitive effects
Note: Smoking induces CYP1A2 enzymes and lowers the levels of certain antipsychotic medications
Smoking cessation options should be routinely offered to patients.
Medication Non-compliance
Estimated 50+% of patients are non-compliant with medications
Consider Long-acting injectables (LAIs)
May need to initiate an oral form of the medication to demonstrate tolerance before starting a LAI.
Oral form should be continued until the LAI has been established
NOTE: Haldol and Prolixin dec use sesame oil – watch for allergic reactions in patients sensitive to sesame.
Long Acting Injectables (LAIs)
Fluphenazine Decanoate (dosed every 2 weeks)
Haldol Decanoate (dosed monthly)
Abilify Maintena (dosed monthly)
Abilify Aristada (dosed monthly, every 6 weeks or every 2 months)
Olanzepine Relprevv (dosed every 2 weeks or monthly- note post-injection delirium/sedation syndrome
Invega Sustenna – dosed monthly
Invega Trinza – dosed every 3 months
Risperdal Consta – dosed every 2 weeks
Risperdal (Perseris) dosed monthly; no oral overall required; SubQ injection
Black-box warning for ALL antipsychotics
Increased risk of death when used in the elderly and those with dementia related psychosis.
Antipsychotics can be used for txt of agitation or psychosis in patients with dementia when symptoms are severe, dangerous and cause significant distress to the patient
Increased risk of falls and non-vertebral fractures in patients 65+
No antipsychotic medication is approved in patients with dementia.
Withdrawal Dyskinesia
Occurs when stopping or reducing an antipsychotic medication
Symptoms look like TD ( lip puckering, tongue movements etc)
Though transient it can persist
Management
Watch and wait – see if symptoms go away
May introduce a small dose of the antipsychotic med to quiet the movements
Risk Mitigation Strategies
Educate all patients, caregivers and/or surrogate decision makers on the effects, possible risks and benefits and recommended monitoring.
Document…..document…..document
Obtain appropriate parameters and labs as part of good practice
AIMS testing
EKG
Weight, waist circumference
Vitals (BP)
Labs (HA1C, BMP, CBC, prolactin levels, fasting blood glucose, Lipid profile)
Suicidality in children, adolescents and young adults
Some antipsychotics are approved or used for the txt of depressive episodes in bipolar disorder or adjunctive txt for unipolar depression
Monitor for risk of suicidal thinking and behavior for children, adolescents and young adults (< 24 years) for the first 3 months of treatment.
