Lecture 52 + 53 - Antipsychotics Flashcards
HISTORY AND BACKGROUND OF TREATING SCHIZOPHRENIA
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
GENERAL CONSIDERATIONS OF SCHIZOPHRENIA
Antipsychotic = Neuroleptic = Anti-Schizophrenic
Severe illness, most debilitating of psychotic
disorders
Affects 1% of population
Onset age 15-20 years old
Not Split personality
ETIOLOGY OF SCHIZOPHRENIA
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
SYMPTOMS
postive
negative
cognitive
Postive Symptoms
Respond well to drug therapy – Examples: hallucinations, delusions, bizarre behavior, thought disorders
Negative Symptoms
Little response to drug therapy, newer agents are better
– Examples: blunted emotion, poor self care, social withdrawal, poverty in speech
Cognitive Symptoms
decrease in cognitive function
Involves D1 receptors and glutamate receptors
NEUROTRANMITTER HYPOTHESES
Dopamine: First to be developed, but incomplete
Serotonin: Based on mechanism of LSD and mescaline
Glutamate: Based on phencyclidine and ketamine
SEROTONIN HYPOTHESIS OF SCHIZOPHRENIA
- LSD and mescaline were identified as 5HT agonists, inspired search for ‘endogenous’ hallucinogens
- Pharmacological studies with 5HT receptors identified 5HT2A receptor as mediator of hallucinations
- Antagonism and inverse agonism linked to antipsychotic activity
- 5HT2A receptors modulate dopamine release in cortex, limbic region, and striatum
- 5HT2A receptors modulate glutamate release and NMDA receptors
- 5HT2C agonists may be beneficial in schizophrenia
GLUTAMATE HYPOTHESIS OF SCHIZOPHRENIA
- Glutamate is major excitatory neurotransmitter
- Phencyclidine and ketamine, noncompetitive inhibitors of NMDA receptors exacerbate psychosis and cognition deficits
- LY2140023-mGLuR2/3 agonist effective in schizophrenia
- Ampakine (AMPA receptors)-effective in animal models
- GlyT inhibitors (under development
as adjuncts)
DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA
- D2 receptor antagonists - Binding and therapeutics; strong correlation receptor binding affinity vs. clinical effectiveness
- Dopaminergic agents (e.g. L-DOPA, amphetamine, bromocriptine) exacerbate symptoms of schizophrenia
- Increased D2 receptor density in treated and untreated patients of schizophrenia
- Imaging studies-increased DA release and receptor occupancy in patients
- Dopamine metabolites in CSF - D2 receptor antagonists initially increase metabolites in the CNS and later decrease metabolites in CNS
DETERMINING BINDING AFFINITY
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)
RECEPTORS ANTAGONIZED BY ANTIPSYCHOTICS: major
Dopamine (5 dopamine receptors)
D1-like receptors (D1 and D5)
D2-like receptors (D2, D3, and D4)
RECEPTORS ANTAGONIZED BY ANTIPSYCHOTICS: newer agents
Serotonin (5HT):
5HT2A Receptor Antagonists: clozapine, olanzapine, and risperidone
Older Agents: chlorpromazine, haldol, thioridazine
RECEPTORS ANTAGONIZED BY ANTIPSYCHOTICS: minor
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
Which receptor is key for therapeutic effectiveness?
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
BINDING AFFINITY VS. CLINICAL DOSE
Correlation between binding potency and clinical effectiveness for D2 receptors, therefore more effective drug target
Most antipsychotic drugs are receptor antagonists
Dopamine (D1, D2)
Antagonist actions at synapse
D2 receptors: Modulates synthesis and release of dopamine, block D2 receptor antagonist, get an increase in the synthesis and release of DA
DOPAMINE PHYSIOLOGY & FUNCTION
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
Receptor Occupancy and PET
PET scan using [18F] fallypride in the absence (baseline) or presence of increasing doses of the antipsychotic drug aripiprazole
Receptor Occupancy and Antipsychotic Effects
see antipsychotic effect threshold at 70%; EPS threshold at 80%, start to see extrapyramidal sx
DRUG-INDUCED MOVEMENT DISORDERS (D2 Antagonism) - extrapyramidal symptoms
- 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
NEURONS INVOLVED IN EPS:
dopamine: inhibitory
acetylcholine: excitatory
DRUG-INDUCED MOVEMENT DISORDERS (D2 Antagonism) - tradive dyskinesia
- 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 - Reduce dose of current agent
- Change to a different drug; possibly a newer agent
- Eliminate anticholinergic drugs
- 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
DRUG-INDUCED MOVEMENT DISORDERS (D2 Antagonism) - neuroleptic malignant syndrome
- 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
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)
MISCELLANEOUS USES: huntington’s chorea
tetrabenazine, deutetrabenazine
MISCELLANEOUS USES: intractable hiccups
chlorpromazine
MISCELLANEOUS USES: alcohol withdrawal (hallucinations)
haloperidol
MISCELLANEOUS USES: nausea and vomiting
metoclopramide, promethazine
MISCELLANEOUS USES: potentiation of opiates and sedatives
droperidol
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
Adverse Pharmacological Effects types
autonomic
CNS
endocrine system
other