1. antipsychotics Flashcards
true or false: antipsychotics are mainly antagonists
true - there are some instances where they may be a partial agonist
what is the amino acid precursor of dopamine
tyrosine
what are the two types of degrading enzymes found in the dopaminergic presynaptic axon terminal?
MAO and COMT
true or false: MAO degrading enzymes can be found intracellularly and extracellularly
true
true or false: COMT degrading enzymes can be found intracellular and extracellularly
false - only extracellular
What is the purpose of the dopamine transporter (DAT) or reuptake pump?
Transport dopamine back up into presynaptic neuron from the synaptic cleft therefore regulating the amount of dopamine in the cleft
What are the three fates of DA in the presynaptic axon terminal?
- DA can be stored in vesicles inside the neuron
- If the vesicle fuses with the neurons membrane, DA can get back out into the cleft
- DA can be broken down by MAO
Where in the synaptic cleft do drugs normally target?
Dopamine transporter (DAT)
This regulates the release of dopamine from the presynaptic neuron
Presynaptic D2 receptor
This is a post synaptic DA receptor involved in psychosis, movement and prolactin regulation. All antipsychotics has an action on this receptor
D2
Clozapine is a potent antagonist of this post synaptic DA receptor
D4
What are the 4 main DA pathways in the brain
- Nigrostriatal
- Mesolimbic
- Mesocortival
- Tuberoinfundinular
What kind of symptoms occur if there is too much DA present in mesolimbic pathway
Positive symptoms (e.g. hallucinations, hearing voices)
What symptoms occur if there is too little DA in the mesocortical pathway?
dorsolateral PFC & ventromedical PFC = negative sx’s
dorsolsteral PFC = cognitive sx’s (trouble focusing, learning)
Ventromedicsl PFC = Mood symptoms (depression)
True or false: treatment goals include increasing DA in nigrostriatal and tuberoinfundibular pathways
False - these pathways should be left alone
What type of antipsychotics are the following:
Chlorpromazine, perphenazine, loxapine, zuclopenthixol, fluphenazine, trifluoperazine, haloperidol
1st generation or typical/conventional antipsychotics
What type of antipsychotics are the following:
Risperidone, quetiapine, olanzapine, paliperidone, ziprasidone, clozapine, asenapine, lurasidone.
2nd generation
What type of antipsychotics are the following:
Aripiprazole, brexpiprazole, cariprazine
3rd generation antipsychotics
First generation antipsychotics may have different affinities and potencies for blocking what four receptors?
D2, M1, H1 and alpha1
If an FGA has a high potency for blocking D2, it will have inverse affinities for blocking M1, H1 and alpha1
True
What will happen if you add a D2 antagonist when there is too much dopamine in the mesolimbic tract
Decrease positive symptoms
What will happen if you add a D2 antagonist when there is too little dopamine in the mesocortical pathway
May aggravate negative symptoms
What will happen if you add a D2 antagonist that affects the nigrostriatal pathway
Cause motor side effects (EPS)
What will happen if you add a D2 antagonist that affects the tuberoinfundibular pathway
Increase prolactin release which can cause galatorrhea or amenorrhea
What type of side effects are seen with M1 antagonism
Anticholinergic side effects
E.g.dry eyes, confusion, constipation, dry mouth, urinary retention
4 CANT’s - can’t see, can’t pee, can’t spit, can’t shit
What type of side effects are seen with alpha1 adrenergic antagonism
Anti-adrenergic side effects
E.g. orthostatic hypotension, dizziness, reflex tachycardia (when blood pressure drops, HR increases)
What type of side effects are seen with H1 antagonism
Antihistaminic side effects
E.g. weight gain, drowsiness
True or false: SGA’s only block 5HT2
False - prefer to block 5HT2 but if no 5HT2 receptors available will block D2
Which SGA’s are more likely to cause anticholinergic side effects due to blocking M1?
Clozapine & olanzapine
Which SGA’s are more likely to cause orthostasis & dizziness due to blocking alpha1?
Clozapine, risperidone, paliperidone & asenapine
Which SGA’s are more likely to cause sedation and weight gain due to blocking H1?
Clozapine, olanzapine and quetiapine
What is a heteroreceptor/brake?
5HT receptor on dopamine neuron
How do the presynaptic serotonin heteroreceptors affect dopamine release?
When endogenous 5HT binds to the heteroreceptor, DA release is inhibited
How to SGA’s affect dopamine release?
SGA’s bind to the presynaptic 5HT heteroreceptor/brake and doesn’t let serotonin bind which then allows dopamine to be released
What effect do SGA’s have on the mesocortical tract?
In untreated schizophrenia, there is too little DA in the mesocortical tract which results in negative symptoms. SGA will block the brake allowing dopamine to be released and improve negative symptoms
What effect do SGA’s have on the nigrostriatal and tuberoinfundibular tracts?
In untreated schizophrenia, there is a normal level of dopamine in these tracts. An SGA will block the brake cause DA to be released. An increase in dopamine has no effect here so no EPS or hyper prolactin is present
What effect do SGA’s have on the mesolimbic tract?
THERE ARE NO PRESYNAPTIC 5HT BRAKES IN MESOIMBIC TRACT
In untreated schizophrenia there is too much dopamine in the mesolimbic tract which causes positive symptoms. Since there is no 5HT receptor for the SGA to block, it will block D2 and inhibit release of dopamine which will improve positive symptoms
SGA’s can block M3. What side effects can be seen because of this?
Impaired glucose tolerance (IGT) and T2DM
What are the top 3 SGA offenders for metabolic side effects
Olanzapine, clozapine & quetiapine
* if a patient is on one of these and not gaining weight be suspicious on whether or not they are taking it
Antagonism of which receptors are responsible for increased appetite, weight gain and dyslipidemia
H1 and 5-HT2c
Antagonism of which receptor causes impaired glucose tolerance and type 2 DM
M3
Based on the receptor profiles of SGAs, how can we tell whether or not a patient is more likely to experience increased appetite, weight gain and/or dyslipidemia
Agents that have a moderate affinity for H1 or 5-HT2c and moderate-high or high affinity for the other one are more likely to experience these problems
This SGA has:
- high metabolic risk
- anticholinergic effects
- postural hypotension
- sedating effects
- low QT risk
- seizures and agranulocytosis
Clozapine
This SGA has:
- high metabolic risk
- anticholinergic effects
- minimal postural hypotension
- sedating effects
- moderate QT risk
Olanzapine
This SGA has:
- low metabolic risk
- low postural hypotension
- no anticholinergic effects
- no sedation
- needs at least 500kcal meal
- high QT risk
Ziprasidone
This SGA has:
- moderate to high metabolic risk
- minimal anticholinergic effects
- minimal postural hypotension
- sedating effects
- moderate QT risk
Quetiapine
This SGA has:
- moderate metabolic risk
- no anticholinergic side effects
- postural hypotension
- minimal sedation
- low to moderate QT risk
*increased risk of EPS/TD and hyperprolactemia due to high affinity for D2
Risperidone
This SGA has:
- EPS - akathisia, Parkinson’s
- dose dependant sedation
- nausea
- needs at least 350 kcal
Lurasidone
This SGA has:
- EPS - akathisia
- postural hypotension
- sedation
- SL administration
Asenapine
This SGA has:
- dose dependant EPS
- hyperprolactemia
- some sedation
- postural hypotension
- ghost cap in stool
Paliperidone
True or false: TGA’s are antagonists
False - partial dopamine agonists
What effects do TGA’s have on the mesolimbic tract?
In untreated schizophrenia, there is too much dopamine in the mesolimbic tract which causes positive symptoms. A partial DA agonist will compete with endogenous DA for the receptors therefore it behaves kinda like an antagonists and improves positive symptoms
What effects do TGA’s have on the mesocortical tract
In untreated schizophrenia, there is too little dopamine in the mesocortical tract which causes negative symptoms. A partial agonist will act as an agonist and bind to the DA receptors and increase DA transmission thus improving negative symptoms
What effects do TGA’s have on the nigrostriatal and tuberoinfundibular tracts
Less risk of EPS/TD and hyperprolactemia
This TGA has:
- low metabolic risk
- no anticholinergic effects
- minimal postural hypotension
- not sedating
- can be activating (agitation, akathisia, insomnia)
Aripiprzole
This TGA is also a
- 5-HT1a partial agonist which improves mood, anxiety and cognition
- 5HT7 antagonist which helps with mood, cognitions and negative symptoms
- alpha 1 antagonist which can cause postural hypotension
May also see dose dependant akathisia
Brexpiprazole
This TGA is also a
- D3 partial agonist which may have improvements on negative e symptoms?
- 5HT1a partial agonist (high affinity) which improves mood, anxiety and cognition
- presynaptic 5HT2a antagonist
*May also see dose dependant akathisia
Cariprazine
