Antipsychotic Agents - Filtz Flashcards
Define Psychoses
Mental disorders characterized by rifts in rational thought, inappropriate processing of sensory information, and disturbed views of reality and self. Psychotic symptoms are generally not recognized as such by the sufferer.
Define Nueroses
Abnormal reaction to an external state that is generally recognized as abnormal by the sufferer.
Psychotic markers, “positive” or overt symptoms
Delusions and/or paranoia, hallucinations (mostly auditory), Disordered thoughts/loose ideation, inappropriate emotional responses
Psychoses in disease states
Schizophrenia, delirium in dementia, manic psychoses, secondary to severe depression, post-traumatic stress disorders, drug-induced
Drug Induced psychoses
Amphetamine, steroid, LSD, ketamine, PCP, sedative/hypnotics
Schizophrenia
Disease with psychotic symptoms affecting 1% of the population (men and women affected equally; there are multiple and varied subtypes)
Age of onset varies from 15-25 years (odd behaviors and other symptoms often precede onset of psychoses)
Clinical presentation and course are highly variable
High mortality (10%) with poor long term prognosis
Negative or residual symptoms of schizophrenia
Flat affect; anhedonia and apathy; anxiety; lack of volition; social and emotional withdrawal; disorganized speech, thinking and behavior; impaired attention; poor self-care
Etiology of schizophrenia
Neurodevelopmental disorder (cause unknown)
Genetic and environmental factors in causation (twin studies show a genetic predisposition, perinatal insults and traumatic early life events increase susceptibility)
Anatomic irregularities (enlarged cerebral ventricles, reduced cortical mass, hypofrontality)
Hypofrontality
Reduced processing in the prefrontal cortex
Treatment options for Schizophrenia
Frontal lobotomy (used in 40s and 50s, calmed patients but was permanently debilitating)
Psycotherapy (ineffective by itself)
Cognitive behavioral therapy (improves social skill, life skills and may improve ability to self-assess)
Self medication with nicotine
Antipsychotics
Antipsychotic Agents
AKA Neuroleptics or major tranquilizers
Most effective means of treating psychotic symptoms with much less effect on emotional and social problems
Effective in 70% of psychotic patients (reduces frequency and obtrusiveness of hallucinations and delusions; reduces the 12 month relapse rate from 90% without drugs to 40% with drugs; additional affects included improved mood, reduced anxiety and improved sleep)
Not anesthetics but can supplement anesthesia
Do NOT cure schizophrenia and are usually life-long treatments
Latency of effectiveness of anti-psychotics
Calming (tranquilizing) effects may be seen within minutes to hours
Diminished psychotic symptoms within 24-28 hours
Full antipsychotic effects evolve over 2-8 weeks
Improvement may continue for up to 6 months (fewer hallucinations, less paranoia and more rational thinking can significantly improve functioning)
D2 Antagonism correlation with antipsychotic pharmacology
All antipsychotics are D2 dopamine receptor antagonists or weak partial agonists
Antipsychotic affinity for D2 receptors correlates wtih average clinical dose (an approximation of potency)
Dopaminergic Pathways
Mesocortical (VTA to frontal and prefrontal cortex)
Mesolimbic (VTA to nucleus accumbens in limbic area)
Nigrostriatal (Substantia nigra to striatum in the basal ganglia)
Tuberoinfundibular (hypothalamus to pituitary)
Dopamine Theory of Psychosis
Psychoses resulting from over-stimulated dopamine receptors in the cortex (reasoning) and limbic (emotional) areas
> drugs that increase dopamine levels (e.g. amphetamine) can induce or exacerbate psychoses
drug that block dopamine release decrease psychoses (reserpine)
Dopamine “hypofrontality” refers to a hypothesized lack of dopamine in the mesocortical pathway
Positive symptoms seem to be a result of dopamine hyperactivity
Serotonin signaling in psychosis
LSD is a serotonin partial agonist
Newer antipsychotics have higher affinity for serotonin 5HT2 receptors
Negative symptoms may be associated with dysfunction in the serotonin (and dopamine) systems
Glutamate signaling in psychosis
NMDA receptors:
> Glutamate antagonists (Ketamine and PCP) can exacerbate or produce psychoses
Potential new antipsychotics affecting glutamate signaling have not moved beyond Phase 3 clinical trials yet
1st Generation Antipsychotics
Phenothiazines and related thioxanthines (Chlorpromazine - the grandparent of all antipsychotics, Thioridaine, Fluphenazine, Thiothixene)
Butyrophenones and related are more D2 selective (Haloperidol, Pimozide)
2nd Generation Antipsychotics
Dibenzapines (Clozapine, Loxapine, Olanzapine, Quetiapine)
Others (Risperidone, Ziprasidone, Aripiprazole, Iloperidone, Paliperidone, Lurasidone, Asenapine, Brexpiprazole, Cariprazine)
Side Effects: Nigrostriatal Pathway
Initiation and control of movement and muscle tone
Selectively degenerated in Parkinson’s disease
Involved in obsessive and compulsive disorders
Antagonism of D2 receptors in the basal ganglia produces extrapyramidal side effects (EPS)
Toxic Dose-Limiting Effects: EPS/Acute Dyskinesias
Akathisia (after a few months) - motor restlessness and distress compels constant movement
Dystonia (early on, within 1-2 doses) - spasms of neck and face muscles including grimacing, torticollus, ocular dysfunction; involuntary, often painful movements and bodily distortions
Respiratory disress - pharyngeal/laryngeal dysfunction
Pseudo-Parkinsonism (occurs around 6 months) - bradykinesia and rigidity, resting treomr of head and hands, flat affect)
EPS or Motor Side Effects
Dose related - most common with high dose bolus or initial depo injection
Treat by decreasing dose, changing drugs, adding anti-Parkinson agent
Women more sensitive than men
Lead to irreversible tardive dyskinesias
Less selective antipsychotics (the dirty drugs) cause fewer EPS
In general, 2nd generation drugs cause less EPS than 1st generation drugs
Muscarinic Receptor Affinity and EPS
Inverse relationship
In order of increasing EPS frequency:
(Thioridazine < Clozapine < Chlorpromazine < Promazine < Thiothixene Fluphenazine < Haloperidol)
Haloperidol is often given in combination with benzotropine, a muscarinic antagonist, to reduce EPS
Muscarinic antagonists in combo with dopamine antagonists (or as properties of dopamine antagonists) work by…
Helping to reset the motor output imbalance caused by D2 antagonists
Tardive Dyskinesias
Involuntary movement of the tongue, lips, head and neck (grimacing, tongue rolling, lip smacking, eye rolling)
Occurs in up to 50% of patients long-term (after a few years) of treatment with antipsychotics - resulting from increase of D2 receptors
Frequently irreversible
Severity is related to dose, duration of treatment, and gender
Mechanism for Tardive Dyskinesias
Resulting from too many Dopamine (D2) receptors as a result of long term treatment with antipsychotics
Can occur short term
Treatment: Withdraw or reduce antipsychotic, consider a cholinomimetic; Vitamin B6 supplements (100mg pyridoxine/day) used as prevention
Tuberoinfundibular Pathway SIde Effects
Pituitary D2 receptors normally inhibit prolactin
Blockade of D2 inhibition leads to increased prolactin (gynecomastia and increased lactation; disturbed thermal regulation; amennorhea, inretility and sexual dysfunction)
Prolactin levels above 100 ng/mL lead to prolactinomas and increased risk of breast cancer (usually don’t see this in antipsychotics)
2nd Generation Antipsychotics (general)
Relative to FGAs, SGAs:
One average have a higher affinity for 5HT2 receptors
Have somewhat lower affinity for D2 dopamine receptors (by 5-50 fold)
Generally have lower incidence of EPS and endocrine side effects
Recommended as first line therapies (have other side effects)
Serotonergic CNS pathways/antipsychotic theory
Projection from the raphe to the pre-frontal cortex, hypothalamus, limbic areas, spinal reflex areas, and basal ganglia
5HT2 receptors modulate dopamine release
Theory is that there are fewer EPS with antipsychotics that combine 5HT2 antagonism with lower affinity D2 antagonism because 5HT modifies dopamine release in the basal ganglia
*the best possible drug is a DA/HT/muscarinic antagonist but is dirty in nature (blocking of 5HT2 heteroreceptors will result to increased dopamin in cleft with every signal)
Autonomic Effects of antipsychotics
A1 adrenergic antagonism
Muscarinic cholinergic antagonism (blind, hot, dry, red, confusion/crazy and other anticholinergic effects)
Sedation in Antipsychotics
H1 antagonism leads to drowsiness and sedation, weight gain, and anti-nausea effects on vestibular apparatus
Difficult for patients on prophylactic or chronic therapy
Very useful for acute treatment of florid psychoses with agitation
Weight gain/metabolic disorder with antipsychotics
Serotonin, H1 and alpha1 adrenergic receptor blockade causes:
Increased appetite, increased fat storage, sleep apnea, hypocholesterolemia, insulin insensitivity and hypoglycemia
*lipids, weight, HbA1c, and BP should all be monitored in all patients on antipsychotic therapy
**susceptibility varies and we don’t know why
Antipsychotics with large weight gain
Clozapine, Olanzapine, Chlorpromazine, Thioridazine
Antipsychotics with moderate weight gain
Risperidone, Quetiapine, Paliperidone, Iloperidone
Antipsychotics with no weight gain (weight neutral)
Ziprasidone, Aripiprazole, Molindone, Haloperidol, Asenapine
Potentially fatal cardiotoxicities with antipsychotics
Increased risk of sudden cardiac death (prolonged QT interval may cause Torsades de pointe arrythmias; highest risk with ziprasionde, pimozide and thioridazine)
Muscarinic and a1 adrenergic antagonist activities
Weight gain and CV disease increase
Smoking
Black Box Warning for Antipsychotics
Increased mortality in elderly patients with dementia related psychosis (1.6-1.7 times placebo)
Most deaths appeared to be either CV or infectious in nature (these drugs are not approved for the treatment of patients with dementia-related psychosis)
Neuroleptic malignant syndrome
Rare, recurrent with 10% mortality, patients with severe EPS are more vulnerable (could be related to D2 antagonism)
Manifestations include: Hyperthermia and diaphoresis; altered mental status, including catatonia and stupor; flucutating blood pressure and pulse; tremor and muscle rigidity; acute renal failure
Treatment: Immediate discontinuation of all antipsychotic medication; dantrolene may be helpful; bromocriptine may be helpful
Hypersensitivity reactions to antipsychotics
Primarily with phenothiazines (5%): Dermal reactions including rash and photosensitivity, ocular opacities of the cornea and lens, jaundice
Alert for Asenapine: Serious hypersensitivity and anaphylaxis alert
Clozapine unique efficacy and toxicities
Significant advantage (uniquely effective in 25-30% of treatment-resistant patients; no reported EPS)
Serious toxicities make it a third line agent (Leukopenia can lead to agranulocytosis in 1.3% which can be fatal in 4-16% of patients; myocarditis; CV collapse including hypotension, respiratory or cardiac arrest)
Decreased seizure threshold
Sedation, antimuscarinic effects (severe constipation), etc.
Olanzapine
Very similar in structure and profile to clozapine but lacking the unique toxicities
2nd most effective antipsychotic of all
Weight gain is very problematic at effective doses making it a third line agent
Quetiapine (Seroquel)
Sedating - making it useful to reduce anxiety and agitation
Low EPS (active metabolite is an anti-muscarinic)
Low adrenergic blockade
Moderate weight gain/risk of metabolic syndrome
Risperidone
Lack of sedation is attractive for some patients
Restlessness/agitation is a problem
Dose needs to be controlled to avoid EPS
Approved for irritability in autism spectrum disorders at age 5 and up
Used more often as a maintenance therapy for those looking to function in normal society
Paliperidone
Hydroxy metabolite of risperidone (similar pharmcologic profile, including restlessness and EPS)
Sustained release form leads to once monthly dosing
Ziprasidone and Lurasidone
Low weight gain, low EPS
Problems including QT prolongation (less with Lurasidone)
Iloperidone
Low EPS, low-anticholinergic effects, low weight gain, low tendency for metabolic syndrome
Hypotension is a problem and requires dose titration
Asenapine
Minimal weight gain and metabolic disturbance
Extreme sedation from histamine receptor antagonism
Off-label use to treat PTSD
Serious hypersensitivity reactions including anaphylaxis alert issued by FDA in 2011
Concern with EPS due to relatively low affinity for muscarinic receptors
No better efficacy than other antipsychotics and noto as good in some trials
Aripiprazole
D2 partial agonist (~30%)
Transient nausea
No endocrine disturbances (slight decrease in prolactin)
No receptor sensitization (low risk for EPS or TD)
Good efficacy (but may increase psychoses in a subset of patients)
Agitating (may be a problem in some patients)
Alpha 1 antagonist (increasing reports of weight gain with time)
Brexipiprazole
Newer to market
Similar to aripiprazole but weaker D2 partial agonism (partial agonist at 5HT1, antagonist at 5HT2 receptors; low risk for EPS or TD)
Alpha 1 antagonism
Low affinity for histamine receptors
Common side effects include akathisia and moderate weight gain
Cariprazine
Newer to market
Pharmcology similar to Aripiprazole (D2 partial antagonist, 5HT1A partial agonist, 5HT2 antagonist)
D3 partial agonist with higher affinity for D3 than D2
Extrapyramidal side effects in 1/4 to 1/3 patients
Low weight gain
American Psychiatric Association top 5 recommendations from the “Choosing Wisely” initiative
Don’t prescribe antipsychotic medications to patients for any indication without appropriate initial evaluation and appropriate ongoing monitoring
Don’t routinely prescribe 2 or more antipsychotic medications concurrently
Don’t use antipsychotics as first choice to treat behavioral and psychological symptoms of dementia
Don’t routinely prescribe antipsychotic medications as a first-line intervention for insomnia in adults
Don’t routinely prescribe antipsychotic medications as a first-line intervention for children and adolescents for any diagnosis other than psychotic disorders
Additional Antipsychotic Indications
Tourette’s (uncontrolled vocal outbursts, tics and repetitive movements | too much dopaminergic activity in the nigrostriatial pathway | treat with high affinity D2 antagonist like pimozide)
Neuroleptanesthesia (Innovar = Droperidol plus fentanyl)
Adjunct treatment to anti-depressants (not alone | approved for aripiprazole, quetiapine and olanzapine)
Behavioral problems, including irritability, in autism spectrum disorders (approved for risperidone and aripiprazole)
Bipolar disorder
Additional indications-more on these in the GI unit
Severe nausea and vomiting (Promethazine and Prochlorperazine, D2 antagonists block the chemoreceptor trigger zone and increase GI motility, antihistamine and anticholinergic effects block motion sickness)
Intractable hiccups (Thorazine)
Insufficient lactation (Metoclopramide, inhibit D2 inhibition of prolactin release)
