Antipsychotics Flashcards
When is the onset of schizophrenia?
Late adolescence or early adulthood
Which kind of symptoms respond the best to antipsychotic medications?
Positive symptoms
What are the three kinds of symptoms schizophrenics have?
Positive, Negative, Cognitive
What are the positive symptoms?
Those that appear to reflect an addition to or an excess of normal functions
-Hallucinations
-Delusions
-Disorganized thinking
What are negative symptoms?
Those that are absent from normal behavior
-Flat affect
-Anhedonia
-Social Withdrawal
What re the cognitive symptoms?
Altered thinking, concentration and memory
-Slowed thinking
-Difficulty understanding
-Poor concentration
-Poor working memory
What are the etiologies of schizophrenia?
Genetics, neurons, systems, behavior
What are the genetical information regarding schizophrenia?
Identical twins have a 50% chance of also being schizophrenic.
However, if the parent has it, only 10% of children have it.
What are the environmental etiologies that have been associated with schizophrenia?
-Prenatal infections
-Perinatal hypoxia
=Adolescent drug abuse
=Stress
Who is neurologist Ugo Cerletti?
Italian neurologist Ugo Cerletti who developed electroconvulsive therapy ECT (electroshock therapy)
Describe the Lobotomy
Anestesia using 2 quick shots to the head.
Insert an ice pick through the upper eyelid in the pt’s head
Use hammer to position device into frontal lobe
Move icepick back and forth
Did anyone improve from lobotomy?
only 1/3 improved, and by improved they were left unresponsive, lethargic, and in a vegetative state
What does the lobotomy aim to do?
Disconnect the connection of the frontal lobe
How many lobotomies were done?
40-50,000
When were lobotomies done?
1940-1950s
What is methylene blue?
Biological stain that had clinical utility for malaria
Who first synthesized methylene blue and when?
Heinrich Caro 1976
Who started making derivatives of methylene blue and when?
Paul Charpentier in 1940s
What was a potent, centrally activing H1 antagonist derivative found from methylene blue?
Promethazine- it causes extreme sedation and prompted use as an adjunt anesthetic
What medication was discovered in the late 1940’s that produced a more “calming” effect than promethazine?
Chlopromazine- the first antipsychotic
What are the first generation of antipsychotics? How do they work?
Phenothiazines-
-Haloperidol
-Chlorpromazine
-Perpehazine
Block DOPAMINE D2R -> treats POSITIVE symptoms of schizophrenia
What is one of the older hypotheses of schizophrenia?
Increased dopamine transmission
How long does it take for first generation antipsychotics to work?
Weeks for maximum therapeutic efficacy, but the D2 blockade occurs rapidly
Postsynaptic D2 receptors are what?
The target of dopamine transmission
Presynaptic D2 receptors do what?
Regulate dopamine transmission- meaning if theres too much dopamine it uses negative feedback to lower dopamine
What is important to know about D2 blockade acute versus chronic.
Acute injections of D2 antagonists increases dopamine because the presynaptic D2 receptor that helps turn it off prevents the negative feedback from occurring.
However, chronic use (>3 weeks) dramatically reduces dopamine neuron activity by depolarization block.
What are the dopamine pathways?
-Mesolimbic Pathway
-Mesocortical pathway
-Nigrostriatal pathway
-Tuberoinfundibular pathway
Blocking activity in the mesolimbic pathway causes what?
Decreases dopamine, decreases positive symptoms.
What does the mesolimbic pathway regulate?
-Emotion and pleasure
Constant long term stimulant abuse that effects the mesolimbic pathways causes what?
Paranoia and psychosis indistinguishable from schizophrenia
Hyperactivity of which pathway underlies positive symptoms of schizophrenia?
Mesolimbic pathway
What does the mesocortical pathway regulate?
cognitive function
Which pathway contributes negative and cognitive symptoms?
Mesocortical
What kind of fluctuation of dopamine in the mesocortical pathway causes negative and cognitive symptoms?
DECREASE in dopamine! Which goes against the current treatment of trying to lower ALL dopamine
Which pathway controls movements?
Nigrostriatal pathway
Parkinson’s disease is attributed to?
Loss of nigral dopamine neurons, resulting in tremor, rigidity, and bradykinesia
A _ in dopamine in the _ pathway produces parkinson-like phenotype and Tardive dyskinesias?
A decrease in the nigrostriatal
Which pathway inhibits prolactin release?
Tuberoinfundibular pathway
D2 blockade in the tuberoinfundibular pathway can cause what?
-Galactorrhea (milky discharge)
-Amenorrhea (absense of menstruation)
-Sexual dysfunction
What is neuroleptic malignant syndrome?
Rare but life threatening
Severe form of parkinsonism
Leads to increased serum creatine kinase and myglobin
MAY persist for weeks following discontinuance of APD
What can reverse neuroleptic malignant syndrome? What is the downside?
Dopamine AGONIST- Bromocriptine and a muscle relaxant Dantrolene….
Induces psychosis
Are antipsychotics abused?
No- not tolerable
What is an example of an atypical neuroleptic?
Clozapine
What are benefits of clozapine- an atypical neuroleptic?
-Doesn’t cause parkinsonian symptoms
-No dystonia
-No Tardvie dyskinesia
Why don’t atypical neuroleptic cause severe parkinsonian symptoms like the 1 gen antipsychotics do?
Their ratio of 5HT2A/D2
5-HT inhibits dopamine in the nigrostriatal pathway but NOT the mesolimbic pathway.
Explain the relationship between 5HT2A receptors and D2 receptors.
When 5HT2A receptor receives serotonin signal, it inhibits dopamine vesicle release from the presynpatic neuron. This means no dopamine in the synaptic cleft.
In the mesolimbic pathway, the 5-HT2 anatognist binds to the receptor which allows the dopamine to be release; however, the dopamine antagonists are completely binded to the postsynaptic receptors- not allowing the dopamine in the cleft to bind.
In the nigrostratial pathway, the 5-HT2 antagonist binds to the receptor on the presynaptic neuron, triggering vesicle release of dopamine… and the dopamine antagonists weakly bind in this area, so overall you have an INCREASE in dopamine which is needed to lower parkinsonian symptoms.
Blocking D2 causes what side effects?
EPS (extrapyramidal symptoms) and prolactin elevation
Blocking 5-HT2A causes what?
Anti-EPS (extrapyramidal symptoms)
5-HT2C causes what?
Satiety blockade
What is another problems associated with antipsychotics?
Weight gain
Qt prolongation
What were the results of the CATIE (Clinical antipsychotic trials of intervention effectiveness) experiment?
out of 1500 patients,
74% discontinued the study due to inefficacy and intolerable side effects
In the CATIE experiment, what can you say about olanzapine?
Slightly better than the other drugs, but still associated with weight gain as a side efffect
In the CATIE experiment, what can you say about perphenazine?
Even though it was a first gen antipsychotic it was equally effective and tolerated as second generation drug.
