PHRM 845 Module #1 > Lecture 52 + 53 - Antipsychotics > Flashcards

Lecture 52 + 53 - Antipsychotics Flashcards

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1
Q

HISTORY AND BACKGROUND OF TREATING SCHIZOPHRENIA

A

 Early 1900’s: Brain disease
 Now: Disease of nature/nurture
 Before 1950’s: Treatments included sedation, lobotomy, ECT, and Rauwolfia alkaloids used in Hindu Medicine
 1950’s: Reserpine
 1952: Phenothiazines (chlorpromazine): Out-patient therapy-emptying mental hospitals

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2
Q

GENERAL CONSIDERATIONS OF SCHIZOPHRENIA

A

 Antipsychotic = Neuroleptic = Anti-Schizophrenic
 Severe illness, most debilitating of psychotic
disorders
 Affects 1% of population
 Onset age 15-20 years old
 Not Split personality

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3
Q

ETIOLOGY OF SCHIZOPHRENIA

A

Neurodevelopmental/anatomical In utero/adolescence-increased ventricle size and changes in gray and white matter
Genetics-neuronal growth, migration of neurons (twin studies, families-multiple genes)
 Environmental- Birth complications, infections
Gene-Environment Interaction COMT-marijuana
Neurodevelopment-Environment Interaction

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4
Q

SYMPTOMS

A

postive
negative
cognitive

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5
Q

Postive Symptoms

A

Respond well to drug therapy – Examples: hallucinations, delusions, bizarre behavior, thought disorders

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6
Q

Negative Symptoms

A

Little response to drug therapy, newer agents are better
– Examples: blunted emotion, poor self care, social withdrawal, poverty in speech

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7
Q

Cognitive Symptoms

A

decrease in cognitive function
Involves D1 receptors and glutamate receptors

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8
Q

NEUROTRANMITTER HYPOTHESES

A

 Dopamine: First to be developed, but incomplete
 Serotonin: Based on mechanism of LSD and mescaline
 Glutamate: Based on phencyclidine and ketamine

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9
Q

SEROTONIN HYPOTHESIS OF SCHIZOPHRENIA

A
  1. LSD and mescaline were identified as 5HT agonists, inspired search for ‘endogenous’ hallucinogens
  2. Pharmacological studies with 5HT receptors identified 5HT2A receptor as mediator of hallucinations
  3. Antagonism and inverse agonism linked to antipsychotic activity
  4. 5HT2A receptors modulate dopamine release in cortex, limbic region, and striatum
  5. 5HT2A receptors modulate glutamate release and NMDA receptors
  6. 5HT2C agonists may be beneficial in schizophrenia
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10
Q

GLUTAMATE HYPOTHESIS OF SCHIZOPHRENIA

A
  1. Glutamate is major excitatory neurotransmitter
  2. Phencyclidine and ketamine, noncompetitive inhibitors of NMDA receptors exacerbate psychosis and cognition deficits
  3. LY2140023-mGLuR2/3 agonist effective in schizophrenia
  4. Ampakine (AMPA receptors)-effective in animal models
  5. GlyT inhibitors (under development
    as adjuncts)
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11
Q

DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

A
  1. D2 receptor antagonists - Binding and therapeutics; strong correlation receptor binding affinity vs. clinical effectiveness
  2. Dopaminergic agents (e.g. L-DOPA, amphetamine, bromocriptine) exacerbate symptoms of schizophrenia
  3. Increased D2 receptor density in treated and untreated patients of schizophrenia
  4. Imaging studies-increased DA release and receptor occupancy in patients
  5. Dopamine metabolites in CSF - D2 receptor antagonists initially increase metabolites in the CNS and later decrease metabolites in CNS
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12
Q

DETERMINING BINDING AFFINITY

A

 Binding Affinity: Intermolecular force between ligand and receptor
 Kd/Ki: Estimated concentration at which 1⁄2 of the receptors are occupied
 Saturation binding experiments – Vary concentration of radio-labeled ligands
 Competition binding experiments
– Constant radioligand (hot) concentration competing with unlabeled ligand (cold)

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13
Q

RECEPTORS ANTAGONIZED BY ANTIPSYCHOTICS: major

A

Dopamine (5 dopamine receptors)
D1-like receptors (D1 and D5)
D2-like receptors (D2, D3, and D4)

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14
Q

RECEPTORS ANTAGONIZED BY ANTIPSYCHOTICS: newer agents

A

Serotonin (5HT):
5HT2A Receptor Antagonists: clozapine, olanzapine, and risperidone
Older Agents: chlorpromazine, haldol, thioridazine

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15
Q

RECEPTORS ANTAGONIZED BY ANTIPSYCHOTICS: minor

A

Norepinephrine (NE): alpha1 Receptor Blockade: hypotension, sedation; alpha2 Receptor Blockade: may be helpful in therapy
Acetylcholine (ACh): Muscarinic receptors -anticholinergic effects (clozapine, thioridazine)
Histamine: H1 Receptor Antagonists: sedation, weight gain

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16
Q

Which receptor is key for therapeutic effectiveness?

A

There is no clear pattern: multiple receptors; individualize therapy based on patient response; unable to predict effectiveness of each therapy for individual patient
multiple receptors –> many SE –> poor adherence

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17
Q

BINDING AFFINITY VS. CLINICAL DOSE

A

Correlation between binding potency and clinical effectiveness for D2 receptors, therefore more effective drug target
Most antipsychotic drugs are receptor antagonists
Dopamine (D1, D2)

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18
Q

Antagonist actions at synapse

A

D2 receptors: Modulates synthesis and release of dopamine, block D2 receptor antagonist, get an increase in the synthesis and release of DA

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19
Q

DOPAMINE PHYSIOLOGY & FUNCTION

A

Actions of D2 Antagonists in CNS:
 Basal Ganglia (Nigrostriatal Pathway): Motor effects, extrapyramidal symptoms (EPS)
 Mesolimbic: Primary therapeutic effects (only ones we really want to block)
 Mesocortical: Hypofunction in schizophrenia, antagonists may exacerbate cognitive deficits
 Hypothalamus and Endocrine Systems: D2
receptor blockade in endocrine system
 Medulla: Chemoreceptor trigger zone; D2 antagonists are anti-emetics

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20
Q

Receptor Occupancy and PET

A

PET scan using [18F] fallypride in the absence (baseline) or presence of increasing doses of the antipsychotic drug aripiprazole

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21
Q

Receptor Occupancy and Antipsychotic Effects

A

see antipsychotic effect threshold at 70%; EPS threshold at 80%, start to see extrapyramidal sx

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22
Q

DRUG-INDUCED MOVEMENT DISORDERS (D2 Antagonism) - extrapyramidal symptoms

A
  1. Extrapyramidal Symptoms (EPS) 30-50%:
     Occur early, days/weeks, reversible
     Symptoms:
    – Dystonia – Increased muscle tone
    – Pseudoparkinsonism – Muscle rigidity
    – Tremor
    – Akathisia – Restlessness
    Unfortunately most patients will experience EPS as a result of long term antipsychotic drug therapy; important monitoring parameter
     Drug Therapy for EPS:
    – Benztropine (Cogentin), trihexyphenidyl (Artane), or akineton (Biperiden) – Anticholinergic agents
    – Diphenhydramine (Benadryl) – Antihistamine
    – Amantadine (Symmetrel) – Dopamine releasing agent
    – Propranolol – used for akathisia
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23
Q

NEURONS INVOLVED IN EPS:

A

dopamine: inhibitory
acetylcholine: excitatory

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24
Q

DRUG-INDUCED MOVEMENT DISORDERS (D2 Antagonism) - tradive dyskinesia

A
  1. Tardive Dyskinesia (20-40%):
     Occur late, months to a year, IRREVERSIBLE!!!
    Symptoms:
    – Mouth – Rhythmic involuntary movements
    – Choreiform – Irregular purposelessness
    – Athetoid – Worm-like
    – Axial hyperkinesias – “To-and-fro” movements
     Unknown MOA: Neuroadaptive response- Antagonist- induced supersensitivity of receptors to dopamine?
    Monitoring: AIMS (Abnormal Involuntary Movement Scale) rating scale; check every 6 months
    Treatment: Prevention! Use the least risky agent at the lowest dose possible and monitor
  2. Reduce dose of current agent
  3. Change to a different drug; possibly a newer agent
  4. Eliminate anticholinergic drugs
  5. VMAT inhibitors
     Newer Drug Therapies for TD: VMAT2 Inhibitors
    – Tetrabenazine (Xenazine) for Huntington’s chorea
    – Valbenazine (Ingrezza) for TD
    – Deutetrabenazine (Austedo) for TD and Huntington’s chorea
    prevent dopamine from being packaged into synaptic vesicles
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DRUG-INDUCED MOVEMENT DISORDERS (D2 Antagonism) - neuroleptic malignant syndrome
3. Neuroleptic Malignant Syndrome (NMS):  SeriousandRAPID;10%Fatality  Symptoms: – EPS symptoms with fever – Impaired cognition – Agitation, delirium, coma – Muscle rigidity  Treatment: Restore dopamine balance – Discontinue drug – DA agonists, diazepam, or dantrolene (skeletal muscle relaxant
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THERAPEUTIC USES OF ANTIPSYCHOTIC DRUGS
 Treatment of psychosis: – 2-3 weeks for effectiveness – 6 weeks to 6 months maximal efficacy  Other Mental Disorders – Anxiety = Overkill! – Mood Disorders: Mania = Secondary to lithium, used in combination; Depression = When accompanied by agitation and delusions – Tourette’s syndrome-tics, vocalizations: Treat with Pimozide (Orap)
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MISCELLANEOUS USES: huntington's chorea
tetrabenazine, deutetrabenazine
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MISCELLANEOUS USES: intractable hiccups
chlorpromazine
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MISCELLANEOUS USES: alcohol withdrawal (hallucinations)
haloperidol
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MISCELLANEOUS USES: nausea and vomiting
metoclopramide, promethazine
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MISCELLANEOUS USES: potentiation of opiates and sedatives
droperidol
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PHARMACOLOGICAL EFFECTS OF THE ANTIPSYCHOTIC DRUGS
 Behavioral Effects: Unpleasant in normal subjects or reversal of signs and symptoms of psychosis in affected individuals  “Neuroleptic” Syndrome: Suppress emotions, reduce initiative and interest, affect; may resemble negative symptoms  Block conditioned avoidance responses in animal studies  Decreased spontaneous activity, aggressive, and impulsive behavior
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Adverse Pharmacological Effects types
autonomic CNS endocrine system other
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Autonomic mechanism and manifestations
Muscarinic cholinoceptor blockade: Loss of accomodation, dry mouth, difficulty urinating, constipation Alpha adrenoceptor blockade: Orthostatic hypotension, impotence, failure to ejaculate
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CNS mechanism and manifestations
Dopamine receptor blockade: parkinson's syndrome, akathasia, dystonias Supersensitivity of dopamine receptors: tardive dyskinesia Muscarinic blockade: toxic-confusional state Histamine (H1) receptor blockade: sedation
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Endocrine system mechanism and manifestations
Dopamine receptor blockade resutling in hyperprolactinemia: amenorrhea-galactorrhea, infertility, impotence
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Other mechanism and manifestations
Possibly combined H1 and 5HT2c blockade: weight gain
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PRECAUTIONS AND CONTRAINDICATIONS
 Cardiovascular  Parkinson’s Disease  Epilepsy (e.g. Clozapine will lower seizure threshold)  Diabetes (for newer agents)
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Typical First Generation Antipsychotics
More movement problems Increased EPS and tardive dyskinesia due to strong D2 block
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PHENOTHIAZINE NUCLEUS
1st antipsychotic: chlorpromazine R10: requires 3 atom chain (allows nitrogen to bind receptor) 2 atom chain = antihistamine R2: important for potency
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PHENOTHIAZINE NUCLEUS examples
 Aliphatic Phenothiazines  Piperidine Phenothiazines  Piperazine Phenothiazines
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Aliphatic phenothiazines
 Aliphatic Phenothiazines: – *Chlorpromazine (Thorazine) - No longer 1st line therapy  Aliphatic Phenothiazines: Used for H1 antagonist properties – *Promethazine (Phenergan) - Also other indications, N/V
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Piperidine Phenothiazines
 Piperidine Phenothiazines: – *Thioridazine (Mellaril) - Sedation, hypotension; anticholinergic, many SE
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Piperazine Phenothiazines
 Piperazine Phenothiazines: – *Fluphenazine (Permitil, Prolixin) - EPS – *Prochlorperazine (Compazine) - Antiemetic – *Perphenazine (Trilafon) -  CATIE studies: Perphenazine and anticholinergic vs. several newer agents
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ANTIPSYCHOTICS
thioxanthines butyrophenones
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Thioxanthines
*Thiothixene (Navane) - Modest EPS
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Butyrophenones
*Haloperidol (Haldol) - EPS
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Miscellaneous Antipsychotics
 *Molindone (Moban) – ModerateEPS – Zyprexa or Risperidal vs. Moban + Benztropine: Found weight gain/metabolic problems in newer agents; adherence issues  *Pimozide (Orap) – Tourette’sdisease-tics,vocalizations
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Key points of chlorpromazine
1st Antipsychotic, antihistamine side effects
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Key points of promethazine
Antihistamine, antiemetic
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Key points of thioridazine
Many SE: anticholinergic, sedation, sexual dysfunction, cardiovascular
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Key points of fluephenazine
EPS
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Key points of proclorperazine
antiemetic
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Key points of perphenazine
CATIE studies: combo with anticholinergic
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Key points of thiothixene
modest EPS
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Key points of haloperidol
EPS
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Key points of molindone
moderate EPS
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Key points of pimozide
tourette's disease, suppress motor and vocal tics
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Atypical/Second Generation Antipsychotics
Reduced EPS Efficacy for Negative symptoms? Similar or enhanced 5HT2A receptor antagonism vs D2 (see “Serotonin Hypothesis of Schizophrenia”) More metabolic problems Linked to diabetes (greater risk in patients < 50)  Olanzapine, Clozapine,  Less evidence in Quetiapine and Risperidone
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ATYPICAL/2nd GENERATION ANTIPSYCHOTICS
clozapine olanzapine loxapine quetiapine ziprasidone asenapine lurasidone pimavanserin aripiprazole
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Clozapine
*Clozapine (Clozaril) -1st atypical antipsychotic -Very effective  Agranulocytosis – Occurs in 1-2% within 6 months (weekly blood monitoring) – 2nd or 3rd line therapy  Side Effects: Anticholinergic, Antihistamine – Reduced D2 potency = decreased movement disorders – Risk of diabetes
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Olanzapine
-Weight gain -Less likely to causes N&V -Less likely to cause movement disorders -Risk of diabetes
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Loxapine
-Older agent -Metabolite = Amoxipine (Ascendin) Inhibits NET --> Antidepressant
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Quetiapine
-Metabolite w/ antidepressant activity -5HT2A and D2 (low antimuscarinic) -Low EPS -Hypotension (α1) -Sedation (H1) -Risk of diabetes
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Ziprasidone
-5HT2A , D2, α1 affinity -Prolongs QT interval -Long acting formulation under study
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Asenapine
-5HT2A and D2 (nM affinity at most 5HT, α, DA, and histamine receptors)
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Lurasidone
5HT2A and D2 Less weight gain and metabolic effects (vs olanzapine) Fast onset (days without titration) Low doses similar effectiveness to high doses
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Pimavanserin
Inverse agonist 5HT2A (40x vs 5HT2C) Used for Parkinson disease psychosis
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Aripiprazole
-High affinity for 5HT2 and D2 (D2 actions are dopaminergic-state dependent and/or it is functionally selective) -Partial agonist at 5HT1A receptors (being used in depression) -Moderate affinity for D4, α, and histamine receptors -Side Effects: Weight gain, low risk for D2 effects -Prodrug: aripiprazole lauroxil, given q 4-8 weeks
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ATYPICAL ANTIPSYCHOTICS examples
risperidone paliperidone iloperidone
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Risperidone
-Specifically and structurally designed to be both a 5HT2A and D2 receptor antagonist! (Rational drug design) -Relatively low EPS at <8 mg/day -Weight gain; some sedation
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Paliperidone
9-hydroxyrisperidone
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Iloperidone
- structurally related to risperidone - very potent at alpha1 receptors (0.5 nM vs 5 nM at 5HT2A and D2)
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D2/D3 receptor partial agonists
brexiprazole cariprazine lumateperone
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Brexpiprazole
a D2/D3 partial agonist with supposedly less akathisia vs. aripiprazole. Schizophrenia and as an adjunct to antidepressants for major depression Partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors
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Cariprazine
also a D2/D3 partial agonist with greater affinity for D3. Weak partial agonist activity at 5-HT1A. Akathisia is high Schizophrenia, mania, bipolar disorder
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Lumateperone
partial D2 agonist presynaptic receptors/antagonist at postsynaptic receptors (5HT2A antagonist)
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Clozapine key points
1st Atypical antipsychotic, agranulocytosis, risk of diabetes, superior efficacy
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Olanzapine key points
Weight gain, risk of diabetes
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Quetiapine key points
Metabolite w/ antidepressant activity; hypotension, sedation
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Risperidone key points
5HT2A/D2 receptor antagonist
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Ziprasidone key points
5HT2A/D2, α1 affinity; prolongs QT interval
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Lurasidone key points
5HT2A/D2, reduced metabolic effects, rapid titration
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Aripiprazole key points
High 5HT2A/D2 affinity, partial agonist activity
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