ic9 pharmacology of antidepressants and antipsychotics Flashcards
what are the sx of depression
emotional: misery, apathy, pessimism, low self esteem (guilt, inadequacy, ugliness), indecisiveness, loss of motivation
others: loss of libido, retardation of thoughts and action, sleep disturbances and loss of appetite
what are eg. of monoamine neurotransmitters
5HT, NA, dopamine
what is the monoamine theory
deficits in monoamine neurotransmitters (5HT and NA) can cause depression
what are the limitations of the monoamine theory
hypothesis was originally formulated for NA then subsequently shifted to focus on 5HT, also unable to explain for all pharmacological actions of depression thus mainly is monoamines important but also involves complex interactions with other neurotransmitter systems
where is monoamine oxidase found
found in nearly all tissues, incl nerve terminals, liver and intestine; found intracellularly mostly on mitochondrial surface
what is the function of monoamine oxidase
it breaks down monoamines
what types of monoamine oxidases are there and what are the differences between each type (in terms of what do they break down)
MAO-A and MAO-B
5HT mainly broken down by MAO-A
NA and dopamine are broken down by both MAO-A and MAO-B
what is the general moa of MAOi and list an example of MAOi
MAOi increases the biological availability of monoamines
eg. of MAOi is phenalzine
what class of drug is phenalzine and what is its moa
phenalzine is a non selective MAOi (MAO-A and MAO-B), is an irreversible MAOi and would result in incr of 5HT, NA and dopamine
what are neurotransmitters typically packed in when they are in the presynapse and what happens after
NT like 5HT would be packed into vesicles that would be released into the synapse to activate the post synaptic receptors
what happens if 5HT stays within the synapse and what is then the role of SERT
it can result in overactivation of the post synaptic neurons thus requiring serotonin reuptake transporter to terminate the signal by reuptaking 5HT back into the presynaptic terminal
eventually 5HT that was reuptake either broken down or recycled back for the next round of neurotransmission
what kind of NT is dopamine
both excitatory and inhibitory
what are the s/e of MAOi and what are the likely reasons behind these s/e
- postural hypotension likely due to the sympathetic block resulting from the accumulation of dopamine in the cervical (neck) ganglia where it acts as an inhibitory NT
- restlessness and insomnia due to stimulation of CNS
- serotoninergic effects (ddi if combi with other drugs that enhances serotoninergic func like pethidine)
what is an eg. of a drug that can enhance serotoninergic func
pethidine
what are sx of enhanced serotoninergic func
hyperexcitability, myoclonic (jerking and involuntary movements), incr muscle tone, loss of consciousness
what is the “cheese reaction” and which class of drug is affected by the “cheese reaction” and what are the sx of this reaction
MAOi has this drug food interaction as a major limitation for its use and when it occurs can result in acute hypertension, severe throbbing HA and occasionally intracranial hemorrhage
this reaction occurs when consumption of cheese or conc yeast products bc amines in food (like tyramine that is found in cheese) which are usually broken down by MAO in intestine and liver are now unable to be broken down bc of MAOis thus it leads to accumulation of tyramine and thus a sympathomimetic effect (bc it triggers release of NA from synaptic vesicles)
when there is an accumulation of tyramine, since tyramine has similar structure to NA, it is taken up into adrenergic terminals and competes with NA for vesicular compartment thus NA would be displaced by tyramine and the resulting outpouring of NA into the CNS results in NA related s/e like acute hypertension
*adrenergic terminals are just referring to nerve terminals of the sympathetic nervous system
how might the “cheese reaction” be overcome
less likely to occur with reversible MAO-A selective inhibitors like moclobemide (bc MAO-B would then still be available to degrade some NA)
what is the general moa of TCAs
TCAs are the first generation monoamine reuptake inhibitor antidepressants
what is the general structure of TCAs
three ringed chemical structure
what kinds of TCAs are there and list the drugs in each type of TCAs
non selective TCAs for SERT/NET: imipramine, amitriptyline, nortriptyline
selective for NET: desipramine
*SERT refers to serotonin transporter while NET refers to norepinephrine transporter
what are the benefits of nortriptyline compared to its similar counterparts
nortriptyline is a second generation TCA and has milder s/e compared to imipraline and amitryptiline (first gen counterparts) thus it has improved compliance
what are the s/e of TCAs and what are the likely reasons behind the s/e
- sedation due to blocking H1 receptor (H1 receptor in CNS is impt for attention) *tolerance to sedation can develop in 1-2w
- postural hypotension due to alpha-adrenoceptor sympathetic block
- anticholinergic s/e (dry mouth, constipation, blurry vision, incr urinary retention) due to blockage of M1 receptor
*link M1 to rest and digest parasynmpathetic nervous system
were MAOis and TCAs developed for the purpose of being an antidepressant
no, MAOis developed for antiTB while TCAs developed as being antipsychotic and antihistamine
but SSRIs are the first drug class developed for purposes of antidepressant tx
what are the advantages of SSRIs
- higher selectivity for 5HT reuptake compared to TCAs (fluoxetine has 50 fold selectivity while citalopram has 1000 fold selectivity)
- fewer s/e thus having better tolerability and thus improvement in compliance (low affinity for alpha adrenoceptor thus lack of CV effects, lack of effect at histamine receptor thus lower sedation, low affinity for muscarinic receptor thus minimal anticholinergic s/e)
- first line in tx (altho only 2/3 gets remission, adverse effects experienced esp at start and discontinuation can be a problem in some)
what are the s/e of SSRIs and which are likely withdrawal/ discontinuation sx
- nausea
- insomnia
- sexual dysfunction
- lower levels of sedation (esp for citalopram since it still has slight antagonistic effects on histamine receptor)
- serotonergic syndrome (ddi if combi with drugs that can enhance serotoninergic func like MAOis)
*nausea and insomnia are discontinuation/ withdrawal sx that likely occur due to dropped plasma levels of drug when between doses
what are some of the effects resulting from serotonin syndrome
tremer, hyperthermia, CV collapse
compare SNRIs to TCAs
similar dual 5HT and NA reuptake inhibition profiles to non selective TCAs
what are eg. of SNRIs
venlafaxine, desvenlafaxine (synthetic metabolite of venlafaxine), duloxetine
when is SNRIs typically considered
for if SSRIs did not work (eg. the 1/3 who did not get remission from SSRIs)
what are the benefits of SNRIs
- similar moa to non selective TCAs where there is dual 5HT and NA reuptake inhibition
- but different structure to TCAs thus there is fewer s/e compared to TCAs
- claimed to work slightly faster than other antidepressants
- claimed to work better in treatment resistant patients
what are the s/e of SNRIs
- nausea
- insomnia
- sexual dysfunction
- serotonin syndrome (ddi with other drugs that enhances serotoninergic func like MAOis)
- withdrawal effects may be more common and stronger than for SSRIs and TCAs
what are eg. of other antidepressants and their moa
- mirtazapine - norepinephrine and specific serotonin antidepressant (NaSSA); antagonist of alpha2 autoreceptor and 5HT2C receptor among others
- bupropion - norepinephrine-dopamine reuptake inhibitor (NDRI)
- agomelatine - agonist of melatonin MT1 and MT2 receptor (also has antagonism on 5HT2C); less TCA/ SSRI assoc s/e and helps in sleep disorders
- ketamine - glutamate NMDA receptor antagonist; currently used as an anesthetic
- vortioxetine - multimodal serotonergic antidepressant with (i) agonist activity 5HT1A receptor (ii) partial agonist activity 5HT1B receptor (iii) antagonism at 5HT1D, 5HT7, 5HT3 receptors -> additional receptor affinities may result in further release of serotonin and other NT
what do the fact that there are many other antidepressants with various moa show
shows the complex interaction of NT in terms of the pathophysiology of depression which is also reiiterated by how some people can be treated by SSRIs while others cannot bc maybe 5HT deficit is not the main reason behind that person’s depression
what is the moa of vortioxetine and what are the benefits and disadvantages of vortioxetine
vortioxetine is a multimodal serotonergic antidepressant with (i) agonist at 5HT1A (ii) partial agonist at 5HT1B (iii) antagonist at 5HT1D, 5HT7, 5HT3 receptors
the additional affinities for other receptors can result in incr release of serotonin and other NT
may be efficacious in pts resistant to other antidepressants, may have pro-cognitive effects
but while s/e profile generally similar to other antidepressants, there is potential in incr risk of suicidal thoughts or actions in children and teens thus close monitoring req in initial stages
when is the typical onset of schizophrenia
late adolescence/ early adulthood
what are the sx of schizophrenia (list the domains of sx)
there are five domains of schizophrenia
- pos sx
- neg sx
- anxiety/ depression
- aggressive sx
- cognitive sx
differentiate between pos and neg sx (definition)
pos sx meaning addition of abnormal behaviours (eg. hallucinations) while neg sx is the removal of normal behaviours (eg. becoming emotionally blunted)
pos sx incl hallucinations, delusions, thought disorders, abnormal behaviours like aggression or stereotypical
neg sx incl withdrawal from social contacts, flattening of emotional responses
how would you describe the presentation of sx for schizophrenia and how does this change as the disease progresses
periods of acute presentation with pos sx interspersed with periods during which the neg sx predominate
as the disease progresses, the neg sx generally become more dominant
which type of sx affects pt more vs which type of sx affects those around pt more
neg sx affects pt more while pos sx affects those around pt more
what is the etiology of schizophrenia
- genetic (incomplete hereditary tendency where 50% risk for a monozygotic twin of an affected individual; various chromosomal regions identified to have linkage; susceptible genes include DISC1, neuregulin1, dysbindin1, catechol-O-methyl transferase (COMT); but not all schizophrenics share the same mutations of susceptible genes)
- environmental (onset consistent with neurodevelopmental abnormalities involving myelination of cortico-cortical pathways
ultimately schizophrenia can be explained to occur resulting from the neurochemical theories
what are the various neurochemical theories and what do these theories suggest
- dopamine theory - found to be the most impt bc (i) amphetamine which is a CNS stimulant produces sx similar to acute schizophrenia and (ii) D2 receptor antagonism is found to correlate with better clinical efficacy
- serotonin theory - lysergic acid diethylamine (LSD) which acts primarily as an agonist to 5HT2 receptor has produced sx similar to acute schizo; most atypical antipsychotics have 5HT2 receptor antagonism
- glutamate theory - drugs that block the (N-methyl-D-aspartate) NMDA receptor channel (eg. ketamine and phencyclidine) have been found to produce sx similar to acute schizo
these three theories is suggestive of the pos sx
what does a low Kd value suggest (relate to correlation of D2 antagonism and clinical efficacy for acute schizophrenia)
low Kd = higher affinity
if low mean clinical dose means higher efficacy thus a linear Kd vs mean clinical dose suggests that higher affinity provides higher efficacy
fluphenazine > haloperidol > trifluperazine > clozapine > chlorpromazine
what are the various dopamine pathways of the brain
- mesolimbic - from ventral tegmental area (VTA) to the limbic (emotional) region of the brain; regulates reward and emotion
- mesocortical - from VTA to prefrontal cortex; regulates cognition and attention
- nigrostriatal - from substantia nigra to dorsal striatum; regulates involuntary movement since it forms a part of the extrapyramidal motor system
- tuberoinfundibular - from hypothalamus to anterior pituitary to regulate secretion of prolactin into the blood circulation
*note 1 and 2 are suggestive of reasons why the sx for schizophrenia are as such
is dopamine incr or decr in acute schizophrenia
dopamine incr in acute schizo
what kinds of antipsychotics are there (classify the antipsychotics)
- typical antipsychotics (first gen): chlorpromazine, haloperidol
- atypical antipsychotics (second gen): amisulpride, clozapine, olanzapine, risperidone
what do the antipsychotics mainly target
they mainly control pos sx of schizophrenia
what are the s/e of typical antipsychotics (list two eg. and compare between two of the typical antipsychotics)
- anticholinergic s/e (dry mouth, constipation, blurry vision, incr urinary retention) due to binding to muscarinic M1 receptor
- sedation and weight gain due to binding to histamine H1 receptor (recall that H1 receptor in brain impt for attention)
- postural hypotension and dizziness due to binding to alpha1 adrenoceptor
- extrapyrimidal s/e (acute dystonia, tardive dyskinesia and akathisia) due to blockade of D2 receptor in nigrostriatal pathway
comparing between chlorpromazine and haloperidol,
since chlorpromazine blocks H1, alpha1, M1 and D2 while haloperidol only blocks alpha1 and D2 -> haloperidol would not have anticholinergic and CNS s/e
why might typical antipsychotics result in EPSE and what are eg. of the EPSE
due to antagonism of D2 receptors in nigrostriatal pathway
EPSE incl acute dystonia and tardive dyskinesia and akathisia
differentiate between pyramidal and extrapyramidal motor systems
extrapyramidal motor systems controls both involuntary and voluntary movement while pyramidal motor system controls only voluntary movements
extrapyramidal motor systems has upper motor neurons that are located in the brain stem and do not directly innervate lower motor neurons but activate or inhibit them through interneurons vs pyramidal motor systems has upper motor neurons located in the cerebral cortex that activate lower motor neurons in the spinal cord and brain stem which innervate skeletal muscles
pyramidal motor pathway is the output from primary motor cortex in the cerebral cortex via the pyramids of the medulla oblongata to the spinal cord
extrapyramidal motor pathway involves the basal ganglia incl the striatum and susbtantia nigra (which is part of the nigrostriatal pathway since that path starts from substantia nigra to striatum)
EPSE incl acute dystonia which is cogwheel rigidity and tremor at rest, and tardive dyskinesia and akathisia which is [repetitive and stereotypes involuntary movements of face, tongue and limbs] and [involuntary movements and compulsion to act assoc w restlessness, anxiety and agitation] respectively
compare between the onset and reversibility of the two broad types of EPSE resulting from s/e of typical antipsychotics
acute dystonias occurs within the first few weeks of tx and is often reversible upon discontinuation of drug
tardive dyskinesia and akathisia occurs slowly and develops over months or years of tx and is often irreversible; akathisia unlike dyskinesia is correlated directly with duration on medication
what is the likely reasoning behind tardive dyskinesia and akathisia occurring
due to upregulation or supersensitivity of dopamine receptors in the nigrostriatal pathway
what is the likely reasoning behind tardive dyskinesia and akathisia occurring
due to upregulation or supersensitivity of dopamine receptors in the nigrostriatal pathway
what types of affinities do atypical antipsychotics generally have and what defines atypical antipsychotics
greater affinity at 5HT2, greater affinity at D4
with mixed antagonism at alpha, H1, M1 and 5HT2
most atypical antipsychotics have serotonin-dopamine antagonism (SDA) aka 5HT2 and D2 (but ofc still have other actions depending on what other receptors they bind to)
compare the receptors each atypical antipsychotic binds to and relate to the general s/e (note which s/e is most evident for which atypical antipsychotic)
clozapine binds to M1, H1, alpha1, alpha2 -> esp s/e incl anticholinergic and sedation
olanzapine binds to M1, H1, alpha1 -> esp s/e incl anticholinergic and sedation
risperidone binds to alpha1, alpha2 -> esp s/e incl postural hypotension and reflex tachycardia
what significant s/e does clozapine (and not other atypical antipsychotics) have and what is the req monitoring
clozapine-induced agranulocytosis
agranulocytosis is the lack of granulocyte type WBC
approx 1% affected but fatal, req to monitor regular FBC
does olanzapine have the same significant s/e as clozapine
no olanzapine does not produce agranulocytosis s/e
what are the other significant s/e to consider for atypical antipsychotics and which atypical antipsychotics is related to these s/e
drug-induced diabetes and drug-induced weight gain for clozapine, olanzapine and risperidone
drug-induced diabetes may be related to 5HT antagonism in hypothalamus and pancreatic beta cells
drug-induced weight gain may be related to sedation (bc of H1 receptor) and binding to alpha and 5HT2 on hypothalamus and feeding behaviour
*both mechanisms unsure
what is the difference between amisulpride compared to other antipsychotics and what impact does this have on the s/e of amisulpride
amisulpride is a selective D2/D3 antagonist (but recently also reported 5HT7 antagonism)
its selectivity results in few s/e (absence of alpha block, antihistaminergic and anticholinergic s/e)
but has s/e on mammary glands and tissues incl incr prolactin secretion due to block of dopamine receptors in anterior pituitary gland (tuberoinfundibular path) -> breast swelling, pain and lactation, may present as gynaecomastia in males
what can be deduced about the type of receptors in tuberoinfundibular path relating to s/e of amisulpride
amisulpride is a selective D3/D2 antagonist thus likely that tuberoinfundibular has even more D3 receptors since amisulpride causes incr prolactin secretion which is regulted by this path
(all other antipsychotics involve the D2 receptor antagonism)
why might atypical antipsychotics produce lesser EPSE
(all in relative to typical antipsychotics)
for clozapine and olanzapine: potent 5HT2A receptor antagonism vs weak D2 antagonism allows it to have lower EPSE and higher efficacy against neg sx
for amisulpride: high D3 to D2 antagonism ratio favours actions on the nucleus accumbens over the striatum (likely nigrostriatal path has lesser D3, striatum exclusively has D1 and D2 only)
for clozapine: high D4 to D2 antagonism ratio favours actions in prefrontal cortex (assoc w emotion and higher cognition; recall mesocortical pathway) over the striatum
for amisulpride and risperidone: high D2 to D1 antagonism ratio reduces impact of antagonism in striatum (thus D1 is the worst of the two that causes EPSE)
what is the ranking in decr order (from most causative to least) in causing EPSE
D1, D2, D3/D4
what are some additional benefits of atypical antipsychotics
- some are more effective against neg sx (clozapine, olanzapine, risperidone)
- some may ameliorate cognitive dysfunction better (clozapine, olanzapine)
- some may be better at mood stabilisation (clozapine, olanzapine, risperidone)
are antipsychotics generally useful currently
no
15-20% remain tx resistant to any antipsychotics
60-75% respond but remain severely disabled in social and occupational func
10-20% recover to near pre-illness levels of func
<1% able to come off medication and retain near pre-illness levels of func
