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

Lecture 52 + 53 - Antipsychotics Flashcards

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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25
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
26
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)
27
MISCELLANEOUS USES: huntington's chorea
tetrabenazine, deutetrabenazine
28
MISCELLANEOUS USES: intractable hiccups
chlorpromazine
29
MISCELLANEOUS USES: alcohol withdrawal (hallucinations)
haloperidol
30
MISCELLANEOUS USES: nausea and vomiting
metoclopramide, promethazine
31
MISCELLANEOUS USES: potentiation of opiates and sedatives
droperidol
32
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
33
Adverse Pharmacological Effects types
autonomic CNS endocrine system other
34
Autonomic mechanism and manifestations
Muscarinic cholinoceptor blockade: Loss of accomodation, dry mouth, difficulty urinating, constipation Alpha adrenoceptor blockade: Orthostatic hypotension, impotence, failure to ejaculate
35
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
36
Endocrine system mechanism and manifestations
Dopamine receptor blockade resutling in hyperprolactinemia: amenorrhea-galactorrhea, infertility, impotence
37
Other mechanism and manifestations
Possibly combined H1 and 5HT2c blockade: weight gain
38
PRECAUTIONS AND CONTRAINDICATIONS
 Cardiovascular  Parkinson’s Disease  Epilepsy (e.g. Clozapine will lower seizure threshold)  Diabetes (for newer agents)
39
Typical First Generation Antipsychotics
More movement problems Increased EPS and tardive dyskinesia due to strong D2 block
40
PHENOTHIAZINE NUCLEUS
1st antipsychotic: chlorpromazine R10: requires 3 atom chain (allows nitrogen to bind receptor) 2 atom chain = antihistamine R2: important for potency
41
PHENOTHIAZINE NUCLEUS examples
 Aliphatic Phenothiazines  Piperidine Phenothiazines  Piperazine Phenothiazines
42
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
43
Piperidine Phenothiazines
 Piperidine Phenothiazines: – *Thioridazine (Mellaril) - Sedation, hypotension; anticholinergic, many SE
44
Piperazine Phenothiazines
 Piperazine Phenothiazines: – *Fluphenazine (Permitil, Prolixin) - EPS – *Prochlorperazine (Compazine) - Antiemetic – *Perphenazine (Trilafon) -  CATIE studies: Perphenazine and anticholinergic vs. several newer agents
45
ANTIPSYCHOTICS
thioxanthines butyrophenones
46
Thioxanthines
*Thiothixene (Navane) - Modest EPS
47
Butyrophenones
*Haloperidol (Haldol) - EPS
48
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
49
Key points of chlorpromazine
1st Antipsychotic, antihistamine side effects
50
Key points of promethazine
Antihistamine, antiemetic
51
Key points of thioridazine
Many SE: anticholinergic, sedation, sexual dysfunction, cardiovascular
52
Key points of fluephenazine
EPS
53
Key points of proclorperazine
antiemetic
54
Key points of perphenazine
CATIE studies: combo with anticholinergic
55
Key points of thiothixene
modest EPS
56
Key points of haloperidol
EPS
57
Key points of molindone
moderate EPS
58
Key points of pimozide
tourette's disease, suppress motor and vocal tics
59
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
60
ATYPICAL/2nd GENERATION ANTIPSYCHOTICS
clozapine olanzapine loxapine quetiapine ziprasidone asenapine lurasidone pimavanserin aripiprazole
61
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
62
Olanzapine
-Weight gain -Less likely to causes N&V -Less likely to cause movement disorders -Risk of diabetes
63
Loxapine
-Older agent -Metabolite = Amoxipine (Ascendin) Inhibits NET --> Antidepressant
64
Quetiapine
-Metabolite w/ antidepressant activity -5HT2A and D2 (low antimuscarinic) -Low EPS -Hypotension (α1) -Sedation (H1) -Risk of diabetes
65
Ziprasidone
-5HT2A , D2, α1 affinity -Prolongs QT interval -Long acting formulation under study
66
Asenapine
-5HT2A and D2 (nM affinity at most 5HT, α, DA, and histamine receptors)
67
Lurasidone
5HT2A and D2 Less weight gain and metabolic effects (vs olanzapine) Fast onset (days without titration) Low doses similar effectiveness to high doses
68
Pimavanserin
Inverse agonist 5HT2A (40x vs 5HT2C) Used for Parkinson disease psychosis
69
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
70
ATYPICAL ANTIPSYCHOTICS examples
risperidone paliperidone iloperidone
71
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
72
Paliperidone
9-hydroxyrisperidone
73
Iloperidone
- structurally related to risperidone - very potent at alpha1 receptors (0.5 nM vs 5 nM at 5HT2A and D2)
74
D2/D3 receptor partial agonists
brexiprazole cariprazine lumateperone
75
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
76
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
77
Lumateperone
partial D2 agonist presynaptic receptors/antagonist at postsynaptic receptors (5HT2A antagonist)
78
Clozapine key points
1st Atypical antipsychotic, agranulocytosis, risk of diabetes, superior efficacy
79
Olanzapine key points
Weight gain, risk of diabetes
80
Quetiapine key points
Metabolite w/ antidepressant activity; hypotension, sedation
81
Risperidone key points
5HT2A/D2 receptor antagonist
82
Ziprasidone key points
5HT2A/D2, α1 affinity; prolongs QT interval
83
Lurasidone key points
5HT2A/D2, reduced metabolic effects, rapid titration
84
Aripiprazole key points
High 5HT2A/D2 affinity, partial agonist activity

PHRM 845 Module #1 (50 decks)

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