Medications and their effects Flashcards
What is an agonist?
What is an antagonist?
Agonist:
- a compound that binds to a receptor and causes a biological response
- not all medications are agonists
- all endogenous ligands (NTs that come within the brain) are all agonists (e.g. Glu, GABA, serotonin, dopamine, …)
Antagonist:
- a compound that binds to a receptor and blocks a biological response
- many medications are antagonists
- e.g. antipsychotics are antagonists: block excess of dopamine in mesolimbic system
- > antagonists cause blockage -> positive therapeutic response (also side effects)
What characterises antipsychotics?
What is the most important pathway in psychosis?
What are the issues with antipsychotics in this pathway?
What do PET scans show regarding antipsychotics?
> All modulate the dopaminergic system
All are post-synaptic dopamine antagonists
Circulate widely, BUT should only affect dopamine receptors
> Mesolimbic system is the most important pathway in psychosis
- regulates reward processing and salience
- hyperactive in psychosis
- only salience is affected (reasons not understood)
(no excess in reward processing)
-> paranoia
> Antipsychotics must block 60-70% of dopamine to be effective
- we need some dopamine to go through for the limbic system to function well
- PET scans show we need an optimal amount of blockage (less -> meds don’t work ; more -> excess side effects)
- antipsychotics are “clumsy”: suppress both pleasure and threat evaluation (rapid decision making)
- > can cause dysphoria (loss of pleasure in life), which can lead to people abandoning their medication
How do antipsychotics affect the mesocortical system?
What are iatrogenic symptoms?
What is the action of new atypical antipsychotics?
Mesocortiyal system
- regulates PFC: cognition, motivation, social expression
- hypoactive in schizophrenia -> negative symptoms
- affects a variety of cognitive functions (neurotransmission is not effective because it’s only through Glu and GABA = ionotropic)
Classic or typical antipsychotics (all antagonists)
- suppress the mesocortiyal system further
- worsen negative symptoms (secondary or iatrogenic symptoms = caused by medication)
=> Antipsychotics are good for positive (mesolimbic) symptoms BUT bad for negative (mesocortical) symptoms
Newer atypical antipsychotics suppress the mesolimbic excess of dopamine input (hyperactive in psychosis) while stimulating the mesocortical system (hypoactive in schizophrenia)
How do antipsychotics affect the nigrostriatal and tuberoinfundibular systems?
What is amenorrhoea? Galactorrhea?
Nigrostriatal system
- regulates movement initiation
- degenerates in Parkinson’s
Tuberoinfundibular system
- part of hypothamalic-pituitary axis (HPA)
- regulates endocrine (hormonal) system
Both are normal in psychosis and schizophrenia
(presynaptic release of dopamine is normal)
Both are blocked by antipsychotics
- they can still communicate, because it is driven by Glu and GABA
BUT chronic use of antipsychotics leads to:
- in nigrostriatal system: Extrapyramidal Side Effects (ESPs) = movement problems
- in Tuberoinfundibular system: hormone dysfunction
(e.g. in women: amenorrhoea - cessation of menstruation ; or galactorrhea - inappropriate production of breast milk
(e.g. in both genders: reduced libido -> confusion with psychotic symptoms)
What are the target pathways of antidepressants?
Serotonin and noradrenaline pathways
- innervate similar regions: brain stem, amygdala (mood, fear processing), hypothalamus (appetite and libido), thalamus (sleep), prefrontal cortex, basal forebrain, midbrain
- can affect each other’s inputs
How were antidepressants discovered?
How did it lead to the monamine hypothesis?
What is that hypothesis?
How was it proved invalid?
What is the refined hypothesis concerning depressed people?
> 1950s: antidepressants discovered “accidentally” within a different class of drugs for improving mood
- these drugs increased serotonin and noradrenaline levels
- > Monoamine hypothesis: depression is caused by a lack of serotonin and noradrenaline (both monoamine NTs)
> Research showed this was incorrect:
- depressed people have normal levels of serotonin and noradrenaline NTs and their receptors
- > Antidepressants increase the binding (not the secretion) of serotonin and noradrenaline
> Refined hypothesis:
- Even though levels of serotonin and noradrenaline are ok, depressed people have abnormal intracellular responses to these NTs (metabotropic -> chemical cascades and changes in gene/DNA expression)
- above normal levels of the NTs compensate for this
What are the 3 mechanisms of antidepressants?
What are the classes of medication corresponding to each mechanism?
Antidepressants work indirectly:
- with the existing levels of serotonin and noradrenaline, they try and increase their time in the synapse and their binding to postsynaptic receptors
- Through a presynaptic autoreceptor antagonist
- all neurons are designed to shut themselves down if overactive -> if presynaptic neuron releases too much serotonin or noradrenaline NTs, it will shut itself down and stop its own release
- NaSSAs (Noradrenergic and Specific Serotoninergic Antidepressants) block this presynaptic off-switch
- Mirtazapine (only med in NaSSAs): does not allow the presynaptic neuron to shut itself down, so it keeps releasing its NT
-> Over time, we’re gonna get more signalling
(more serotonin and noradrenaline because the neuron is more active since it can’t shut itself down) - Through blocking the reabsorption of the NTs (most common mechanism of antidepressants)
- all NTs after they’re released, get recycled back into presynaptic cell
- SSRIs (serotonin specific re-uptake inhibitors): most common class of antidepressants
e.g. Fluoxatine, Paroxetine, Sertraline, Citalopram
-> there aren’t anymore NTs, but the existing ones spend more time binding with the postsynaptic neuron
- NARIs (noradrenaline re-uptake inhibitors): one drug - Reboxatine (same as SSRIs but for noradrenaline neurons)
- SNRIs (serotonine-noradrenaline re-uptake inhibitors: e.g. Venlafaxine and Duloxetine)
and TCADs (Tricyclic antidepressants: e.g. Amitriptyline) work the same way pharmacologically: block the re-uptake of serotonin and noradrenaline
BUT have different side effects
- SNRIs: newer class of drug ; produce fewer side effects in a therapeutic dose, safer in overdose - By stopping the breakdown in the synapse
- in the synapse, there’s an enzyme breaking the NTs into smaller parts (it’s the physiology of the synapse - normal)
- MAOIs (Monoamine oxidase inhibitors stop that process in the synapse: the enzyme oxidising monamines (serotonin and noradrenaline)
- > less breakdown of serotonin and noradrenaline NTs -> they are more available to bind the postsynaptic neurones dendrites
What happens to the released neurotransmitters during communication between neurons?
- Some bind to the postsynaptic neuron
- Some self shut-down and get recycled back in the pre-synaptic neuron
- Some break away in the synapse by an enzyme
To which mental disorders is acetylcholine (ACh) associated?
> Primarily used in treating dementia
> Acetylcholinergic pathways project into the frontal cortex and hippocampi
-> ACh plays important role in attention and memory
> Dysfunction of the acetylcholinergic system plays a role in Alzheimer’s, but not primary cause
Plays a role in psychosis
What are the acetylcholine (ACh) synthesis and breakdown processes?
- Inside the cell (pre-synaptic neuron):
- acetyl CoA and choline bind together to produce acetylcholine (ACh), which is released once neuron depolarises - Acetylcholine NT finds the cholinergic receptor of the postsynaptic cell and causes effects within the cell (metabotropic communication)
- when this happens in frontal cortex and hippocampi
- > affects attention and memory - In the synapse, the enzyme ‘acetylcholinesterase (AChE) breaks acetylcholine (ACh) NT into its constituent parts, which get taken back into the presynaptic cell to make more ACh
- > recycling process: ACh is made, released and binds, then is broken down and sent back, and process starts again
What are the 2 ways medication can enhance the functioning of acetylcholine (ACh)?
- A direct agonist of ACh
- acts in the same way as ACh: binding with postsynaptic receptor, causing effect within the cell
- such medications are under development, used in research, not clinically available - Stop the ACh breakdown within the synapse
- AChEIs (acetylcholinesterase inhibitors) stop the enzyme acetylcholinesterase from breaking down the existing ACh in the synapse
Why do medications have side-effects?
What are the major side-effect classes?
> Medications are large molecules that can bind to each other, other medications, and other receptor systems
Side-effects can arise from:
- Direct actions on other organs (e.g. heart, liver, kidneys)
- Binding with other NT systems in the brain and body
What are the 3 systems particularly important to monitor regarding side-effects (3 side-effect pathways)?
- Acetylcholinergic system
- Anticholinergic effects: dysfunction of attention and memory (common side-effects on antidepressants)
- ACh pathways exist throughout the body
- Anticholinergics can block receptors in the peripheral nervous system
includes neurons that innervate mucuous membranes (body parts that produce mucus : gastrointestinal tract, eyes, mouth) - mucus is necessary to good functioning
-> anticholinergic effects: lack of mucus secretion
- dry mouth, tacky eyes, constipation - Histaminergic system
- involved in processes including: Immune responses, sleep-wake cycle
- Histamine medications: many are “antihistamines” (block the histamine system)
- antagonists at the H_1 receptor, which is involved in alertness (keeping people alert and awake)
- > Antihistaminergic effects: drowsiness (sleepy) - Adrenergic system
- adrenaline is involved in many processes, including heart stimulation
- many medications are antiadrenergic
- > Antiadrenergic effects: hypotension, bradycardia, dizziness
What is (should be) the role of pharmacology?
Reverse pathway dysfunction, or compensate it in various ways
What are the limits of the biological model used in these lectures to explain the pharmacological interventions in mental health?
- Doesn’t give the whole picture
2. It does not always translate directly when we deal with mental disorders in the real world
