principles of drug action psychosis exam 3 Flashcards
WHAT IS PSYCHOSIS?
“Psychotic” means out of touch with reality, or unable to separate real from unreal experiences.
Psychoses may include hallucinations and / or delusions.
Diagnosis based on degree and length of symptoms:
Reactive or Brief Psychotic Disorders Schizoaffective Disorder
Schizophreniform Disorder
Schizophrenia
what are the positve and negative symtoms of schiz
negative :
Flattened affect
Social withdraw
Lack of motivation
Poverty of speech (alogia) Anhedonia
Positive
Hallucinations
Negative Symptoms
Flattened affect
Social withdraw
Lack of motivation
Poverty of speech (alogia) Anhedonia
- Delusions
- Agitation
- BizarreBehavior • Catatonia*
DOPAMINERGIC HYPOTHESIS:
dopaminergic antagonists to treat psychotic symptoms
Classical Neuroleptics block dopamine D2 receptors
Reduces symptoms of schizophrenia
what drugs increase dopmaine and causes positive symptoms?
L-dopa
amphetamine
SEROTONERGIC HYPOTHESIS
Based on the serotonergic receptor (blocks the 5HT2A receptor) binding profile of the atypical antipsychotics, and serotonergic interactions with dopaminergic neurotransmission.
Serotonin stimulation decreases DA release in striatum
Administration of m-chlorophenylpiperazine (mCPP) a 5-HT agonist:
Exacerbates symptoms in unmedicated schizophrenics - Has no effect in healthy volunteers
D1-Like Receptors (Increase cAMP)
Increases cAMP by activation of adenylyl cyclase. Increases PKA activity in cell
Long carboxyterminal sequence
D1 Receptors
Localized in Striatum (putamen, nuclelus accumbens) &
olfactory tubercle
Renal and enteric NS (GI tract)
D5 Receptors
Localized in Limbic system (hippocampus) & hypothalamus Vasculature and heart
D2 - Like Receptors (Decrease cAMP)
Decreases cAMP by inhibiting adenylyl cyclase
Opens potassium channels (What effect?)
Blocks calcium channels (What effect?)
Long cytoplasmic loop sequence G-protein binding site
d2 receptor
Localized in striatum, substantia nigra, and pituitary
Kidney and presynaptic nerve terminals in vasculature
d3 receptor
Localized in N. accumbens, olfactory tubercle, hypothalamus.
d4 receptor
Localized in frontal cortex, substantia nigra, medulla & midbrain
Highly polymorphic, but not associated with disease
Mesolimbic System:
Dopaminergic neurons originating in the ventral tegmental area (VTA) and terminating in the nucleus accumbens, amygdala, and hippocampus.
Influences limbic and cognitive function, and behavior
Hyperactivity in this pathway is associated with positive symptoms of schizophrenia
Ventral tegmental area
Associated with BEHAVIOR
Mesocortical System:
Hyperactivity may cause
Mesocortical Pathway
psychomotor agitation
Hypoactivity may cause slowed thinking in Parkinson’s disease, reduced concentration in patients with ADHD, and negative symptoms of schizophrenia
Provides negative feedback to the
mesolimbic pathway to the nucleus
accumbens. Diminished activity may
cause overactivity of limbic system, tegmental causing or exacerbating the positive
symptoms of schizophrenia
Nigrostriatal system
Dopamine neurons originating in substantia nigra and terminating in corpus striatum (basal ganglia).
controls motor function
Deficiency of dopamine associated with MOVEMENT Disruptions
Dopamine D2 receptor antagonists cause side effects of extrapyramidal reactions (EPS):
Produces a movement disorder similar to Parkinson’s disease (pseudoparkinsonism)
Substantia nigra
Muscle spasms or dystonias
Hyperkinetic movements seen as akathisia and tardive dyskinesia
Tuberoinfundibular pathway
uberoinfundibular pathway is one of the major dopamine pathways in the brain originating from hypothalamus. The release of dopamine in this pathway regulates prolactin secretion by the pituitary gland
Blockade of D2 receptors (as seen with the use of antipsychotic medications) increases prolactin secretion and may cause:
Females: Galactorrhea (breast engorgement), lactation (inappropriate milk production), amenorrhea, and infertility
Males: Gynecomastia and impotence
Prolactinomas: Most Common Hyperfunctioning Pituitary
Adenoma
Hypersecretion
Hypofrontality
is a state of decreased cerebral blood flow (CBF) in the prefrontal cortex of the brain. Hypofrontality is symptomatic of several neurological medical conditions, such as schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and major depressive disorder.
The most prominent neurochemical entity associated with schizophrenia is
the monoamine neurotransmitter dopamine.
Dopamine hypothesis of __schizophrenia_________
Symptoms of schizophrenia are due to INCREASED dopamine
transmission
Dopamine hypothesis of ________________
Therapeutic effects of anti-psychotics result from their action on dopamine transmission
Not all anti-psychotics are created equal
Regional selectivity and differential effects on dopaminergic systems
TYPICAL ANTIPSYCHOTICS: DOPAMINE RECEPTOR ANTAGONISTS
Pharmacological Actions
Block dopamine D2 receptors, as well as
cholinergic muscarinic, adrenergic, and
histaminergic receptors
Blockade of D2 receptors in the mesolimbic track, decreases positive symptoms.
Blockade of D2 receptors in the mesocortical track which is already deficient in schizophrenia, may increase negative symptoms.
Blocks D2 receptors in the extrapyramidal motor system, resulting in extrapyramidal symptoms.
Blockade of other receptors subtypes associated with ADRs
how is negative symptoms worsened
Negative symptoms may be worsened or caused by higher doses of medications which decrease dopamine activity in the prefrontal areas
TYPICAL ANTIPSYCHOTICS:
THERAPEUTIC INDICATIONS
Second line agents
for treatment of schizophrenia and other psychotic disorders
Approximately one-third of schizophrenic patients fail to respond to typicals
Limited efficacy against negative symptoms and cognitive deficitsHigh proportion of patient relapse (see earlier graph)
Side effects and compliance issues
TYPICAL ANTIPSYCHOTICS: DOPAMINE RECEPTOR ANTAGONISTS
Low Potency Agents (100mg equivalents)
Bind to dopamine D2 receptors at ≈60-70%
occupancy
Produce higher incidence of anticholinergic side effects (muscarinic), sedation (histamine) and orthostatic hypotension ( adrenergic)
TYPICAL ANTIPSYCHOTICS: DOPAMINE RECEPTOR ANTAGONISTS
High Potency Agents (1-10mg equivalents)
Bind to dopamine D2 receptors at >80% occupancy
High incidence of extrapyramidal symptomsFewer non-dopaminergic side effects
TYPICAL ANTIPSYCHOTICS: DOPAMINE RECEPTOR ANTAGONISTS
Phenothiazines (D2 vs D1: 5x selectivity)
list the three categories of phenothiazine and drugs of each category
Aliphatic :
Chlorpromazine (Thorazine)
Triflupromazine (Vesprin)
Piperidines
Thoridizine (Mellaril)
Piperizines
Fluphenazine (Prolixin)
Perphenazine (Trilafon)
Trifluoperazine (Stelazine)
Low potency typical antipsychotics have significant
histamine, muscarinic, and adrenergic receptor activity, leading to many of the undesired ADRs with these drugs
TYPICAL ANTIPSYCHOTICS: DOPAMINE RECEPTOR ANTAGONISTS
Thioxanthenes and Butyrophenones
list subcategories and slectivity to which dopamine receptor
Aliphatic (Selective for D2 vs D1)
Chlorprothixene (Taractan)
Piperizines (Selective for D2 vs D1)
Thiothixene (Navane)
Butyrophenones (HIGHLY D2 selective)
Haloperidol (Haldol)
High potency typical antipsychotics have significant dopamine______ receptor activity, leading to the extrapyramidal side effects of these drugs
D2
TYPICAL ANTIPSYCHOTICS: DOPAMINE RECEPTOR ANTAGONISTS
Others
Dibenzodiazapines:
High potency (10 mg eq) Loxapine (Loxitane)
Low Potency (100 mg eq) Clozapine (Clozaril)
Indolone:
Low potency: Molindone (Moban)
Diphenylbutylpiperidine: High potency:
Pimozide (Orap)
a1 agrenergic receptor antagonism adverse reaction
Orthostatic hypotension, dizziness, reflex tachycardia
D2 receptor antagonism
teraputic and adverse reactions
t_eraputic actions_ :Alleviation of positive symptoms of schizophrenia
_adverse reaction:_Extrapyramidal side effects (akathisia, pseudoparkinsonism dystonia), elevated serum prolactin
Muscarinic antagonism
Blurred vision, constipation, dry mouth, urinary retention, cognitive effects, sinus tachycardia
H1 receptor antagonism
Sedation, increased appetite and weight gain
EXTRAPYRAMIDAL MOTOR TRACTS
- Include all motor pathways NOT part of the corticospinal tract (aka “pyramidal” tract”)
- Motor neurons that are part of the extrapyramidal tracts descend to spinal cord but do NOT pass through the pyramids
- Descending motor neuron tracts that control or regulate
- Axial muscles responsible for balance and posture
- Muscles controlling movements of proximal portions of limbs
Head, neck and eye movements
TWO MAJOR DESCENDING PATHWAYS
PYRAMIDAL VS. EXTRAPYRAMIDAL
Pyramidal system
- Pathway for voluntary movement Brain stem centers
- Most fibers originate in motor cortex and cross to contralateral side in the medulla to affect voluntary movement
Extrapyramidal system
•Pathways for postural control / certain reflex movements
- Originates in brainstem
- Fibers do not cross
- Cortex can influence this system via inputs to brain stem
MOST COMMON NON-NEUROLOGICAL SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS
Sedation (serotonin and antihistamine activity) 70%
- More common with low potency agents
-Orthostatic Hypotension (1 anti-adrenergic activity) 10-30%
- More common with low potency agents
- Patients should be advised to get up slowly from recumbent positions
Anticholinergic reactions (anti-muscarinic activity) >60%
-Constipation, tachycardia, dry mouth, urinary retention, blurred vision
Cardiac Toxicity
Can occur with several neuroleptics
Causes cardiac conduction delays
Can cause arrhythmias, QT prolongation, and tachycardia
SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS
{Extrapyramidal effects - motor}
Dystonic reactions - Slow sustained contractions or spasms that result in involuntary movement, mostly seen in face, neck, tongue, back spasm
Akathisia –
Subjective or observable restlessness & urge to move “Ants in the Pants”
May persist until the AP dose is lowered, or treated with propranolol
Anticholinergic and antiparkinsonian drugs are less effective
(Pseudo) Parkinsonian symptoms - shuffle, tremor, facial rigidity,
bradykinesia, cogwheel rigidity
ANTIPSYCHOTICS - TYPICAL ADRS
Tardive Dyskinesia
The risk of tardive dyskinesia increases with duration of neuroleptics exposure
- Syndrome of abnormal involuntary movements
- Buccolingual masticatory movements
- Involuntary movement involving the tongue and mouth (NOT A DYSTONIA)
- Choreoathetoid movements of limbs or trunk / neck
- Facial grimacing or tics
- Can affect respiration
Treatment includes discontinuation and often switching to clozapine
- Temporarily masked by increasing dose of AP and worsens acutely with decreased dosage
- Antiparkinsonian drugs are of no benefit and may actually increase symptoms of tardive dyskinesia.
SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS
Neuroleptic Malignant Syndrome
Characterized by:
Fever >38, and up to 42°C
Autonomic dysfunction, tachycardia, labile BP, respiratory distress, arrhythmias
Altered level of consciousness
Severe muscle rigidity
Usually within two wks of initiation or dose change
risk factors: high-potency antipsychotics; recent increase in drug dosage;
previous episodes of NMS
Treatment involves discontinuing the neuroleptics immediately along with supportive treatment:
Aggressive cooling
IV benzodiazepines for agitation, psychomotor hyperactivity, and muscular rigidity
Dopamine agonists (bromocriptine and amantadine) or dantrolene
SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS
- Galactorrhea, gynecomastia, menstrual irregularities*
- Due to elevated prolactin levels due to DA blockade
- Greatest risk with typical antipsychotics and risperidone
Sexual Side Effects
Retrograde ejaculation, erectile dysfunction, and inhibition of orgasm are common side effects
Photosensitivity
Photosensitivity and a predisposition to sunburn is not uncommon
Chlorpromazine
Seen more with low potency agents
Retinitis Pigmentosa
irreversible blindness seen with high dose thioridazine
TYPICAL ANTIPSYCHOTICS – ADME
- Protein binding ranges from 90 to 99%
- Peak levels in 1-4 hr; half-lives from 8-36 hr
- Extensively metabolized in the liver
Many have active metabolites
- Variable oral bioavailability (first pass effect), therefore IM doses can result in 2 - 3X higher blood levels
Haloperidol ≈ 60% AND Loxapine ≈ 30%
DEPOT INJECTABLE ANTIPSYCHOTICS
Haloperidol decanoate
Use an immediate-release antipsychotic before
considering a conversion to haloperidol decanoate
Recommended that patients be treated with and tolerate short-acting haloperidol due to adverse reactions
Fluphenazine decanoate
Initial 12.5-25 mg for IM or SC use
Subsequently administered every 2 to 3 weeks Fluphenazine PO overlap for 1 week
Hypersensitivity reactions:
Test orally BEFORE administering decanoate
ATYPICAL ANTIPSYCHOTICS
-Generally bind to D2 receptors with lower affinity than typicals (≈ 50-70% occupancy).
- Drugs have a higher affinity for 5-HT2 compared to the dopamine D2 receptors. A low ratio of [5HT2A binding affinity] / [D2 binding affinity] is predictive of atypical antipsychotic activity
Haloperidol = ~3.9
Clozapine = 0.02;
Olanzapine = 0.2;
Risperdal = 0.25
RECEPTOR BINDING PROFILES RESPONSIBLE FOR THERAPEUTIC RESPONSE AND ADVERSE DRUG REACTIONS
ATYPICAL ANTIPSYCHOTICS
Therapeutic Indications
First-line agents for the initial and maintenance treatment of schizophrenia and psychotic symptoms of any cause, in both adolescents and adults
Also effective for:
mood disorders with psychotic or manic features; psychosis secondary to head trauma;
psychosis and aggressiveness secondary to dementia; agitation and aggression;
drug-induced psychoses
ATYPICAL ANTIPSYCHOTICS
Improve positive symptoms of schizophrenia
May improve negative symptoms of schizophrenia
May improve cognitive impairment
Improve positive symptoms of schizophrenia
Hallucinations
Delusions
Disordered thoughts
Agitation
May improve negative symptoms of schizophrenia
Withdrawal
Flat affect
Anhedonia
Catatonia
May improve cognitive impairment
Perceptual distortions
Memory deficits Inattentiveness
ATYPICAL ANTIPSYCHOTICS VERSES TYPICALANTIPSYCHOTICS
Adverse Effect profiles
Relatively small risk for extrapyramidal symptoms
Mostly with risperidone when used at higher doses (>8 mg/day)
Neuroleptic malignant syndrome
Rarely seen compared to typical APs
Anticholinergic effects
Seen mostly with clozapine and olanzapine
Tardive dyskinesia
Some atypical agents can reduce the risk and symptoms of TD, unlike typical agents that have a high incidence of TD.
Caution should be exerted with higher doses of risperidone.
EVIDENCE FOR SEROTONIN-DOPAMINEINTERACTION IN PSYCHOSIS
Clozapine
binds with high affinity to 5-HT2A receptors
increases dopamine levels in the mouse PFC with smaller increases in subcortical regions
- Mixed 5-HT2A/D2 receptor antagonists, cause a marked rise extracellular dopamine concentrations in mesocortical projection regions
- This finding suggests that concomitant blockade of 5-HT2A and D2 receptors may prominently stimulate the mesocortical dopamine pathway compared to the nigrostriatal and mesolimbic pathways.
ATYPICAL ANTIPSYCHOTICS: CLOZAPINE (CLOZARIL)
Clozapine titrated slower than other antipsychotics due to risk of orthostatic hypotension
Initiate at low dose (12.5 mg qd or bid) and raise dose gradually by 25-50mg/day as tolerated until a target dose of 300-450mg/day is reached (~2 weeks)
Predominantly metabolized by the CYP3A4 and CYP1A2.
Risk of cardiomyopathy & agranulocytosis… (Block Box Warning)
ATYPICAL ANTIPSYCHOTICS: RISPERIDONE (RISPERDAL)
Potent antagonist at 5-HT2A and D2 receptors
Affinity for alpha-1 adrenergic and H1 receptors
Low affinity for beta-adrenergic and muscarinic receptors
Typically dosed bid or qd (4-6mg/day)
Dose dependent risk for EPS
Dose dependent risk for prolactin elevation (especially at
higher doses)
Minimal anticholinergic side effects
Fatigue and sedation are most commonly reported side effects.
Metabolized by CYP2D6
Likely to interact with SSRIs and other antidepressants.
PALIPERIDONE (INVEGA®)
9-OH risperidone = principal active metabolite of risperidone
80% renally eliminated, <10% metabolized through CYP2D6 hence fewer drug interactions expected
Effects similar to Risperidone…
Potent antagonist at 5-HT2A and D2 receptors
Affinity for alpha-1, alpha-2 adrenergic and H1 receptors
Low affinity for beta-adrenergic and muscarinic receptors
Dose dependent risk for EPS (similar to risperidone)
High risk for elevated prolactin levels (similar to risperidone)
LURASIDONE (LATUDA®)
Potent antagonist at 5HT2A and D2 receptors
◦ Alsobindα1,α2receptors
◦ NoaffinityforH1andmuscarinicreceptors
◦ Highaffinityatthe5-HT7receptor,andmaythereforehavea unique effect on cognition
Half-live ~ 18 hrs, Css ~ 7 days Metabolized by CYP3A4
ILOPERIDONE (FANAPT®)
Potent antagonist at 5-HT2A and D2 receptors
Low to moderate affinity for alpha-1, alpha-2 adrenergic and H1 receptors
No discernable affinity for mAChRs
Metabolized through P450 2D6 and 3A4
T1⁄2 ~ 18 hr, Css ~ 3 - 4 days
Available in 1, 2, 4,6, 8, 10 and 12mg tablets
Potent antagonist at 5-HT2A and D2 receptors
Low to moderate affinity for alpha-1, alpha-2 adrenergic and H1 receptors
No discernable affinity for mAChRs
Metabolized through P450 2D6 and 3A4
T1⁄2 ~ 18 hr, Css ~ 3 - 4 days
Available in 1, 2, 4,6, 8, 10 and 12mg tablets
Minimal ADRs:
extrapyramidal side effects, weight gain
prolactin elevation dizziness, dry mouth, fatigue
orthostatic hypotension
somnolence
tachycardia
ATYPICAL ANTIPSYCHOTICS: ZIPRASIDONE (GEODON)
Low incidence of EPS
Somnolence, dizziness, nausea, and postural hypotension are most common side effects
May raise prolactin
Low weight gain liability
Cardiac conduction problems (↑QTc interval). EKG Recommended for examination of QT interval Torsade de Pointes (ventricular tachycardia)
Metabolized by CYP3A4
Available as Capsules and an IM injectable formulation
ATYPICAL ANTIPSYCHOTICS: OLANZAPINE (ZYPREXA)
Chemical analogue of clozapine without the ADR liability of clozapine (e.g. agranulocytosis)
Substantial affinity for 5-HT2A, alpha1, D2, D4, M1, and H1 receptors
Typically dosed qd due to drowsiness (10-20mg) & long half-life.
Relatively free of serious side effects: Most common side effects include drowsiness, dry mouth, weight gain and development of type-2 diabetes, and insomnia. Less common side effects include orthostatic hypotension, and nausea.
Low incidence of EPS.
Mainly direct glucuronidation with minor metabolism by the CYP1A2
and CYP2D6.
Drug-drug interactions are less likely to occur with this medication
ATYPICAL ANTIPSYCHOTICS: QUETIAPINE (SEROQUEL)
Dosed bid or tid (50-250mg; most effective at 300mg/day) Short half-life (~6 hours)
Drug has a remarkable absence of binding preference to any of the receptor systems thought to correlate with clinical efficacy
Low incidence of EPS.
Side effects include orthostatic hypotension, somnolence, and weight gain. Dyspepsia, abdominal pain and dry mouth may also occur
Can cause cataracts in very high doses so initial and periodic eye exams are recommended
Predominantly metabolized by sulfoxidation and CYP3A4 (minor).
ASENAPINE (SAPHRIS®)
Potent antagonist at 5-HT2A and D2 receptors
Affinity for alpha-1, alpha-2 adrenergic and H1 receptors
Metabolized through P450 1A2 and 3A4 (Minor)
T1⁄2 ~ 24 hr, Css ~ 3 days with BID dosing
Available in 5 and 10mg sublingual tablets
5mg PO BID for schizophrenia; 10mg PO BID for bipolar D/O
Place under tongue…
Do NOT swallow and do NOT eat/drink for 10 min
Side effects: See antipsychotic comparison chart
ARIPIPRAZOLE (ABILIFY®)
Partial agonists: Different class of antipsychotic agent
Classified as a partial dopamine agonist
~90% D2 occupancy; 20-30% partial agonist activity
Ki~0.5nMatD2andD3
D2 receptor blockade is considered necessary and sufficient for antipsychotic activity
Also has 5-HT2A antagonist activity (Ki ~3.4 nM)
WHY MIGHT ARIPIPRAZOLE’SDOPAMINE STABILIZING PROPERTY BE IMPORTANT?
-Theories suggest schizophrenia is a problem with both too much and too little dopamine
In the hypodopaminergic environment, aripiprazole increases dopaminergic tone in areas where neurotransmitters are LOW (acts as an agonist).
In the hyperdopaminergic environment, aripiprazole decreases dopaminergic tone in areas where transmission excessive (acts as an antagonist).
WHY IS ARIPIPRAZOLE DOPAMINE STABILIZING PROPERTY IMPORTANT?
In the hyperdopaminergic environment, aripiprazole decreases dopaminergic activity by acting as an functional antagonist, reducing psychosis.
In the hypodopaminergic environment, aripiprazole increases dopaminergic action when it binds to the D2 receptor (acts as an agonist), reducing EPS and hyperprolactinemia.
BREXPIPRAZOLE (REXULTI®)
Approved for psychosis for Sz and bipolar
Provides alternative to D2 selective FGA and SGAs
Classified as a partial dopamine agonist
CARIPRAZINE (VRAYLAR®)
-approved for psychosis for Sz and bipolar
Classified as a partial dopamine agonist with selectivity
for D3 vs D2 receptors ( as opposed to Abilify and Rexulti) Provides alternative to D2 selective FGA and SGAs
minimal effect on prolactin
relative lack of effect on metabolic parameters, including weight
PIMAVANSERIN (NUPLAZIC)
For use with psychosis in Parkinson’s Disease
Classified as a partial inverse agonist and antagonist at
5HT-2A
Approved for delusions and hallucinations associated with Parkinson’s Disease
Limited affinity at dopamine receptor
study second generation antipsychotics table
ESTIMATED MEAN WEIGHT GAIN (at 10 weeks)
Some atypical agents can increase appetite and cause weight gain Antipsychotic drugs may have direct actions on glucose metabolism, causing or exacerbating diabetes
agents include
clozapine
olanzapine
quetiapine
effects WEIGHT GAIN WITH ANTIPSYCHOTICS
- Increased risk of morbidity and mortality
- Type-2 Diabetes
- Cardiovascular disease
- Hypertension
- Increased cholesterol
- LDL increase, triglycerides increase, HDL decrease
- Dissatisfaction with medication and problems with adherence
- Diminished self esteem
summary
Atypicals, pioneered by Clozapine, have mixed pharmacology profiles targeting primarily dopamine and 5-HT2 receptors
Atypicals are as good as typicals at alleviating positive symptoms of psychosis and MAY be more effective with negative symptoms
Atypicals are generally safer and less likely to induce neurological side effects common of high potency typicals
Aripiprizole is a neuromodulator and is theorized to work by partial agonism at different dopaminergic terminal fields in the CNS
Clozapine is clinically determined to be the most effective atypical but severe side effects dictate it be reserved for refractory symptoms and requires regular WBC monitoring
