Download Anti-psychotics

Pharmacology: Antipsychotic Drugs (Bannon)
SCHIZOPHRENIA:
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Epidemiology:
Affect 1% of the population worldwide
30% of all homeless people
30% of all hospitalizations
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Disease Characteristics:
Psychotic Symptoms (Positive/Cognitive Symptoms): emerge in late teens
o Loss of reality
o Delusions and hallucinations (usually auditory)
o Disordered thinking and memory
Prodromal Signs (Negative Symptoms): poorer prognosis associated with prominent negative symptoms
o Social isolation and withdrawal
o Poverty of speech
o Odd behavior/ideas
o Blunted affect
o Lack of motivation
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Biological Findings: especially associated with negative symptoms
Decreased blood flow in frontal lobe and caudate during working memory tasks
Reduced hippocampal and medial temporal lobe volume
Enlarged ventricles
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Genetic Predisposition:
15% incidence in first degree relatives (compared to 1% incidence in the general population)
17% concordance in DZ twins; ~50% concordance in MZ twins
Complex polygenic disorder (as evidenced by high frequency and partial penetrance)
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Dopamine Hypothesis:
Evidence for the Involvement of DA:
1. Dopamine agonists can induce/exacerbate psychosis
2. Clinically effective APDs block DA receptors
3. DA receptor expression increased in schizophrenia (has since been proven UNTRUE)
Dopamine Receptors: G-protein coupled receptors
o D1 Family: includes D1 and D5 (less prominent)
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Location:
 D1: striatum and neocortex*
 D5: hippocampus and hypothalamus
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Second Messengers (Gq):
 Increase cAMP
 Increase PIP2 hydrolysis (PKC activation and Ca++ mobilization)
o D2 Family: D2, D3 and D4 (latter 2 less prominent)
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Location:
 D2: striatum, substantia nigra and pituitary gland*
 D3: olfactory tubercle, nucleus accumbens, hypothalamus
 D4: frontal cortex, medulla, midbrain
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Second Messengers (Gi):
 Decrease cAMP
 Increase K+ currents
 Decrease voltage-gated Ca++ currents
Dopamine Pathways: single source divergent systems
o Nigrostriatal DA: modulates movement and learned habits; 80% of total DA
o Mesolimbic DA: modulates motivation, goal-directed thinking, affect and reward
o Mesocortical DA modulates cognition
o Hypothalamic DA: hormone regulation
o Area postrema: located outside the BBB; mediates emesis (very sensitive to DA drugs)
Dopamine Pathways and their Relation to Psychotic Symptoms:
o Mesolimbic/Mesocortical DA: overactive  possibly related to positive Sx
o Mesocortical DA: hypofunction  possibly related to negative Sx (DA blockade not helpful for these)
o Nigrostriatal DA: highest DA content and related to extrapyramidal (motor) SEs and tardive dyskinesia
o Tuberoinfundibular/Hypothalamic DA: related to endocrine effects
ANTIPSYCHOTIC DRUGS:
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D2R Blockade and Clinical Efficacy: strong correlation between blockage for these R and efficacy
Original D2 Blocking Agents (ie. Chlorpromazine): not a real high affinity for D2 receptors and therefore needed
very high doses to achieve desired effects (lots of SE)
Newer D2 Blocking Agents with Higher Affinity (ie. Spiroperidol): although higher affinity, do not have
improved efficacy over earlier agents; however, will have different SE profiles
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Commonality in APDs Relevant to Antipsychotic Effects:
Possibilities:
o 5HT2A: typical APDs occupy most striatal D2 receptors while atypical APDs occupy a lower proportion
of D2 R and more 5HT2A; however, role for 5HT2A receptors in psychosis not clear
o D4 in cortex: but not all block here (ie. quetiapine)
o Fast dissociation relative to R binding allows better modulation of function (ie. high Kd at D2): but
then atypical APDs should look lie low-affinity typical APDs (not the case)
Another issue: blockade of receptors is immediate but effects are delayed
BOTTOM LINE:
o Antipsychotic MOA(s) still not really understood
o However, D2 DA receptor blockade is a commonality to all agents
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Pharmacokinetics of APDs:
Absorption: most are READILY but INCOMPLETELY absorbed
o Highly lipid soluble and protein bound
o Long clinical duration relative to plasma half life
Administration: parenteral forms (IM depot injections) available (especially older APDs); often used when
compliance is an issue
Metabolism: significant FIRST PASS metabolism by P450; conjugation for urinary excretion
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Adverse Effects of APDs:
Relatively high therapeutic index: pretty safe in overdose
Autonomic Effects:
o Muscarinic Block: dry mouth, urinary retention, constipation
o Alpha Adrenergic Blockade (α1): orthostatic hypotension, impotence
Cardiovascular Effects:
o Phenothiazines (chlorpromazine and others): ↑HR, abnormal ECG
o Atypical APDs (esp. ziprasidone): significant risk of QT prolongation
o Overall: ~2x increased risk of sudden cardiac death with both typical and atypical (dose-dependent)
Endocrine Effects:
o Hyperprolactinemia: manifest as amenorrhea, galactorrhea, infertility, impotence
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Due to decreased action of DA (normally suppresses prolactin release from anterior pituitary)
Metabolic Effects:
o Atypical APDs (esp. clozapine and olanzapine): weight gain leading to insulin resistance and diabetes
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Possible cause: H1 and 5HT blockade
Extrapyramidal Effects:
o Seen in proportion to D2R affinity (drugs with higher affinity for this receptor cause more EP effects)
o Some effects are short term and limiting, while others are long-term and irreversible
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Adverse Neurological Effects of APDs (Extrapyramidal Effects):
Early Adverse Effects:
o Acute Dystonic Reaction: of face or back (1-5 days after starting medication); NOT seizures or hysteria
o Akathisia: uncontrollable restlessness (5-60 days after starting medication); NOT agitation
o Parkinsonism: looks like idiopathic PD (5-30 days after starting medication)
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Treatment of Acute Dystonic Reaction/Akathisia/Parkinsonism:
 Reduce dose of APD
 Anti-muscarinics/anti-histaminics (bring system back into balance by reducing ACh)
o Neuroleptic Malignant Syndrome: very rare sensitivity to DA blockade by all types of APDs
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When: first few weeks of taking medication OR after increasing dose
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Manifestations:
 Hypothalamic DA block leads to very high dangerous fever
 Basal ganglia DA block leads to parkinsonism
 Others symptoms include autonomic instability and muscle breakdown
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Treatment:
 Bromocriptine (DA agonist) and dantrolene
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Late Adverse Effects:
o Tardive Dyskinesia: occurs months to years after starting medication
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Most important side effect of APDs (20-40% of patients chronically treated with typical will
develop TD)
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Advanced cases are difficult to reverse (early recognition is important)
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Masked by increasing APD dose and worsens upon drug withdrawal
Special Adverse Effects with Clozapine:
Seizures (1-4% of patients)
Agranulocytosis (1-2% of patients)
o Potentially fatal
o Develops between weeks 6-18 and reversible if caught early
o Therefore, need to do weekly blood counts for the first 6 months and every 3 weeks after that
Studies of APD Efficacy:
CATIE Study:
o Basics: first generation perphenazine vs. second generation olanzapine, quetiapine, risperidone and
ziprasidone
o Phase I:
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¾ of patients switched mediations because of adverse side effects
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Olanzapine showed a modest advantage in terms of duration of treatment and symptom
relief (but substantial weight-related SEs)
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Other atypicals (second generation) showed no advantage over perhpenazie
o Phase II:
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Patients who stopped APDs due to SEs/no response (and who refused to take clozapine)
given one of the 4 atypicals mentioned above
 Patients continued on olanzapine and risperidone significantly longer
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Patients who stopped APDs because of inadequate symptom relief were given clozapine,
olanzapine, risperidone or quetiapine
 Clozapine significantly more effective and patients stayed on it longer
o Issues with the Study:
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Subject selection limitation (most patients had no EPS/TD and those that had TD were
assigned to second generation APDs only)
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Therefore, study deals with side effects and efficacy but does not really address the issue of
tardive dyskinesia
CUtLASS Study:
o Basics:
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Clinicians and patients UNBLINDED and initiated drug changes (better mimicked the clinical
situation BUT less control of variables)
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Assessed by a blind rater after 1 year on the medications
o Overall Results:
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Typicals and atypicals equivalent in quality of life, efficacy and side effects
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Clozapine between in managing symptoms than other second generation drugs in treatment
resistance patients (overall quality of life also somewhat better)
TEOSS Study:
o Basics:
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Study of young patients on APDs (8-19 years old)
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Looked at olanzapine, risperidone or molindone PLUS benztropine (anticholinergic)
o Overall Results:
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Roughly equivalent efficacy
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Side effects differed:
 Weight gain (olanzapine>risperidone>molindone)
 Increase in cholesterol and other metabolic disturbances (olanzapine- this arm of
the trial was terminated)
Determining the DOC for your Patient:
Cost: newer atypicals 10-100x more costly than generics
Adverse Side Effects: profile of typical vs. atypical; short term vs. long term use
Compliance: depot injections or drug changes
Treatment-resistance
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Important Examples of APDs:
Chlorpromazine (and other phenothiazines):
o Receptor Affinities: α1=5HT2A>D2=D4=H1>D1=M
o Pros:
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Generic and inexpensive
o Cons:
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Many adverse autonomic effects (dirty drug- action at many different receptors)
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Some risk of EPS and TD (action at D2 receptors)
Haloperidol:
o Receptor Affinities: D2>α1>D4>5HT2A>D1>>H1>>M
o Pros:
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Generic and inexpesive
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Parenteral form available (depot injection)
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Less autonomic effects (does not have a high affinity for these receptors)
o Cons:
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Strong D2 block means higher risk of EPS and TD
Risperidone:
o Receptor Affinities: 5HT2A>D2=α1>D4>H1>D1>>M
o Pros:
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Generic and inexpensive
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Depot preparation available
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Borderline atypical and therefore LESS 5HT-related weight gain compared to other atypicals
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More tolerable than most others APDs (maybe)
o Cons:
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Borderline atypical and therefore MORE DA-related side effects (hyperprolactinemia, EPS)
Olanzapine:
o Receptor Affinities: 5HT2A=M>H1>D4>D2>α1>D1
o Pros:
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More tolerable than other APDs (clozapine-like structure without risk for agranulocytosis or
seizures)
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May be somewhat more effective than other APDs (subtle)
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Less risk of EPS and TD (less action at D2)
o Cons:
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Expensive (no generic)
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Several metabolic adverse effects including weight gain and diabetes (more action at 5HT2A)
Clozapine:
o Receptor Affinities: 5HT2A>D4=α1=M=H1>D2>D1
o Pros:
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Clearly the most efficacious drug available for refractory cases
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Less risk for EPS and TD (less action at D2)
o Cons:
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Expensive (no generic)
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Risk for weight gain and diabetes (more action at 5HT2A)
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More serious side effects of agranulocytosis and seizures
Traditional Use of APDs:
Schizophrenia: primary indication
Schizoaffective Disorder:
o Characteristics of schizophrenia PLUS affective disorders (depression, BPD)
o Treat with APD plus antidepressants, lithium or valproate
Neuroleptoanesthesia:
o Droperidol (short-acting and highly sedating) + fentanyl
Pre-Surgical Use:
o Older APDs (with H1 blockade) used due to strong anti-emetic effects (via CTZ and GI), sedation and
relief of pruritis (itching)
Other Uses of APDs:
Depression and Bipolar Disorder: some justification for the use of APDs in treatment
o Atypical APDs: FDA-approved for acute mania and mixed episodes of BPD
o Risperidone/Lithium Combination: FDA-approved for maintenance in refractory BPD
o
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Atypical APD + Antidepressants: tested for drug-refractory depression (fluoxetine/olanzapine tested
first); mixed results depending on the drug combination used
Agitation in Alzheimer’s Disease and Dementias:
o Rationale: calming, sedative, antipsychotic effects
o Black Box Warning: both typical and atypical APDs increase death due to CV accidents and infections in
patients with AD/dementia (therefore, really need to be careful/limit use in this population)
Control of Aggressive Behavior in Pediatrics:
o Risperidone: FDA-approved for use in autistic children over the age of 5 with aggression or selfinjurious behavior
o Quetiapine and Aripiprazole: FDA-approved for children over the age of 10 with BPD
o General Issues:
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Use especially high in Medicaid children (poor)- especially off label use for ADHD (cheaper
than the drugs for ADHD)
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Off-label use in privately insured children aged 2-5 has also doubled