Dr Philip Larkman Flashcards
What is the name of the drug which treats general anxiety?
Serotonin selective reuptake inhibitors antidepressants
Name of the axis which have a role in anxiety and depression
HPA axis (hypothalamic - pituitary - adrenal)
Which part of the brain regulates the release of corticotropin releasing factor (CRF)?
Amyglada and hippocampus
which part of the brain exerts an excitatory influence on CRF release? and which exerts an inhibitory effect?
hippocampus: inhibitory
amyglada: excitatory
what changes in the HPA pathway may udnerlie the cause of GA?
chronic activation of the HPA pathway
name three main drugs used to treat generalised anxiety
benzodiazepiene, 5-HT1A partial agonists, SSRIs (serotonin selective reuptake inhibitors)- antidepressants
what is thought to underlie chronic anxiety?
overactivation of the amyglada
where does the main activity of benzodiazepines lies? what is the effect of substituting the four main substituent groups?
activity lies in the aromatic ring and substituting the subtituent group would not alter the activity but do affect the pharmacokinetics
what type of modulator is BDZ? and how does BDZ have an effect on GABA-A receptor?
BDZ is a positive allosteric modulators which enhances GABA action by increasing Cl- conductance
which receptor does BDZ binds to?
GABA-A
what is need to be present in order for BDZ binding to work and why is this the case?
agonist needs to be present. BDZ works by altering the action of agonist by binding to an accessory site.
Does BDZ modulates the affinity or efficacy?
modulates affinity - because it enhances GABA affinity to its receptor (in fact BDZ and GABA enhance each other’s affinity)
whereas efficacy modulators affect channel activity (activation/gating)
How does BDZs increase Cl- conductance?
increase the number of open channels without altering individual channel conductance or opening time.
REMEMBER: the amount of Cl- going through the channel is still the same but conductance is higher because more channel opens
which subunit has sensitivity to BDZ?
the adjacent alpha and gamma subunit
which GABA-A receptors alpha subunit does not confer sensitivity to BDZ?
alpha-4 and alpha-6
what class of drug is flumazenil? Does it have an effect on GABA activity?
competitive antagonist for BDZ binding site, therefore it blocks BDZ. Neutral allosteric modulator, does not alter GABA activity
what does the ligand beta-carbolise-3-carboxylate do?
it is an inverse agonists. It has opposite effect of BDZ although binds to the BDZ binding site (induced anxiety)
explain how BDZ enhances GABA affinity and how inverse agonist counteract this effect
GABA only binds to one configuration of the receptor. BDZs stabilises this configuration. Whereas inverse agonist binds to the non-GABA-binding configuration
which drug can be used for alcohol-withdrawal syndrome?
BDZs, because alcohol also has a binding site in the GABA-A receptor
list down the 4 main clinical uses of BDZs
- reduce anxiety
- hypnotic/sedative effect (pre-operative sedation)
- anti-convulsant effects (reduces hyper excitability, for epilepsy)
- muscle relaxants
- use for alcohol-withdrawal syndrome
what amino acid substitution is found to underlie the insensitivity of alpha-4 and 6 subunit to BDZs?
substitute histidine for arginine at position 101 (H101R)
diazepam is benzodiazepeine
ok.
what was observed in the knock-in mutation when alpha-1 subunit is made insensitive to BDZ?
No sedative effect and anticonvulsant effect but the anxiolytic and muscle relaxant effect is still present. This demonstrate that the alpha-1 subunit mediates the sedative and anticonvulsant effect
How does barbiturates treat anxiety?
enhance Cl- influx by PROLONGING channel opening time. Therefor it modulates the efficacy
How does barbiturates treat anxiety?
enhance Cl- influx by PROLONGING channel opening time when activated by GABA. Therefor it modulates the efficacy
how does the substituent groups in BDZ affect its pharmacokinetics?
It can prolong the metabolic route resulting in long action duration
diazepam, alprazolam, oxazepam and chlordiazepoxide arrange them starting with the shortest half-life, which one do not have active metabolite?
oxazepam, alprazolam, diazepam and chlordiazepoxide.
oxazepam do not have any active metabolite
name three properties of BDZs
- bind strongly to plasma protein
- high lipid solubility therefore cross the blood-brain barrier rapidly
- well absorb from the gut
what are the two factors that taken into consideration when treating elderly with BDZs which affect the pharmacokinetics? how do these factors influence the half-life of BDZs?
- activity of hepatic microsomal enzymes
- a greater proportion of body mass is fat in the elderly
these factors increase the half-life of BDZs because:
- metabolism is decreased
- more is sequestered by fat reserves because of its lipid solubility
which drug is use to reverse the effect of BDZs in case of acute overdose?
flumenazil
list down the unwanted side effects of BDZs
- acute overdose: not lethal unless associated with alcohol
2. therapeutic use: sedative, hypnotic, amnesia,
list down the unwanted side effects of BDZs
- acute overdose: not lethal unless associated with alcohol
- therapeutic use: drowsiness, amnesia, confusion and impaired motor function
- tolerance: tissue tolerance does occur due to receptor changes
- dependence: withdrawal symptoms include elevated anxiety, insomnia. short acting BDZs like Oxazepam shows more abrupt withdrawal symptoms
name an example of 5-HT1A agonists, what does it treat? what type of agonist is this drug?
buspirone for treating anxiety, it is a partial agonist
which type of 5-HT receptor was implicated to be associated wit anxiety and depression?
5-HT1A
Where does the 5-HT1A located and what does it do?
5-HT1A is located pre- (as auto receptor) and post-synaptically in neurons releasing 5-HT. pre synaptically, it limits 5-HT release (inhibitory). post-synaptically it has an inhibitory actions on excitability predominantly.
explain briefly the mechanism of 5-HT1A receptor
5-HT1A receptor inhibits adenylate cyclase, activation of K+ channels and inhibition of Ca2+ channels
how does the expression and function of 5-HT1A receptor change in anxiety? and how does busporine and SSRI act on this change?
abnormal expression and function lead to reduce post-synaptic 5-HT release
busporine and SSRI normalise this by promoting desensitisation of auto receptors without affecting post-synaptic receptors
list the unwanted side effects of busporine
nausea, dizziness, headache and restlessness
what are the two explanations which explains why the effect of busporine on 5-HT1A takes several weeks to achieve maximal therapeutic effect?
- slow effects on autoreceptor function
- neurogenesis
this also demonstrate that busporine and SSRI act through indirect mechanism
ion channels are important in:
- neuronal excitability
- excitation-contraction coupling in muscle
- volume (cell size) control
name the largest molecule that could go through the voltage gated Na channel
Guanidinium
where does the energy of permeation which allows passage of ions in a stable state come from?
it comes from stripping water molecules off Na ions
which part of the alpha subunit in NaVGC come together to form the selectivity filter?
P-loop
what substitution causes NaVGC to be insensitive to TTX?
which substitution in mammalian heart causes insensitivity to TTX?
Glutamate387 substitute for glutamine, E387Q (in the P loop of domain I)
C385F
which side of NaVGC does TTX binds to?
extracellular
describe the chemistry of local anaesthetics
local anaesthetics constitute an aromatic ring liked by either an ester or amide bond but both possess basic side chain
definition of pKa
the relative proportion of ionised and unionised form of local anaesthetics is governed by which equation and state the equation
value of pH at which 50% of drug is ionised
Henderson-Hasselbach equation
Log10 GA+/GA = pKa-pH
what makes local anaesthetics able to exist in equilibrium?
due to the basic side chain, they are weak bases
which experiment demonstrate the importance of non-ionised LA and ionised LA in having an effect in blocking Na channels?
with QX314 which carries a permanent positive charge.
can only have a potent effect when applied inside the cell.
this suggests non-ionised form is important to cross the cell membrane but it is the ionised form that is the active channel blocker
name two drugs which blocks NaVGC
procaine and lidocaine
what is the difference between the hydrophilic and hydrophobic pathway?
hydrophilic pathway: requires ionised LA (charged) because channel is access from the inner mouth
hydrophobic: requires the unionised form because channel is access via the plasma membrane (can alter even when channel is close)
what is meant by use-dependent block, what enhances the blocking of LA and which pathway exhibit a use-dependent block?
this means that blocking increases when channel is open therefore block depends on depolarisation frequency
blocking activity is enhance when channel is inactivated which the LA prefers to bind to. his results in less channel recover therefore opening
hydrophilic pathway because channel needs to be open
which amino acid residue determines the high affinity binding of lidocaine? what does the experimental evidence suggests?
F residue on the S6 region of domain 4
when channel is inactivated, the F residue is more accessible to LA
describe two possible mechanism in which lidocaine can inhibit the channel
because they bind close to the cytoplasmic side of the selectivity filter:
- physical block of the pore
- electrostatic repulsion of Na+ by positive charge on LA+
what does experimental result showed when F residue is mutated with positively charged residue?
significantly abolished the ability of LA to block Na(v) but STILL ALLOWS Na permeation
there are two classes of affective disorder syndromes, name and describe them
UNIPOLAR depressive syndrome:
- depression without associated amnia
- common in older patients
- associated with anxiety and agitation
BIPOLAR depressive syndrome:
- oscillation between mania and depression
- hereditary link
- biochemical imbalance (?)
name two symptoms that are necessary to be present in diagnosing major depressive episode
- depressed or irritable mood
- decreased interest in, or unable to experience pleasurable activities (they don’t feel pleasure from doing what was suppose to be pleasurable activities)
name the brain regions involved in mood and depression
frontal cortex and hippocampus
- memory impairment, suicidality, hopelessness
hypothalamus
- sleep, appetite, reduced interest in pleasurable activities
nucleus accumbent and amygdala
- anxiety, anhedonia
name drugs of first and second generation of antidepressants
FIRST:
- tricyclic antidepressants
- monoamine oxidase inhibitor
SECOND:
- SSRI
- noradrenaline and serotonin-specific antidepressants NaSSA
- receptor-targeted actions
state the cause of depression and mania using the basis of monoamine theory of depression
what is the main evidence for the monoamine theory of depression?
depression is due to functional deficit of monoamine neurotransmission
mania is due to the opposite mechanism i.e. functional execs of neurotransmitters
drugs that alleviate symptoms of affective disorders are known to have effect on the 5-HT and NA systems
list three monoamine neurotransmitters
serotonin (5-HT), noradrenaline and dopamine
name the effect of tricyclic antidepressants (TCAs) and SSRIs in the monoamine pathway
inhibiting re-uptake of 5-HT and NA
name the drug which inhibits the breakdown of monoamine
monoamine oxidase inhibitor
what does alpha-methyltyrosine and reserpine does to the level of monoamine?
alpha-methyltyrosine inhibits the synthesis of 5-HT
reserpine depletes vesicular stores, less neurotransmitter release
these drugs decrease monoamine levels and increase depressive symptoms
name the drug which has weak effects on monoamine systems and is part of evidences inconsistent with the monoamine theory of depression
iprindole
what are the two main problems with the monoamine theory of depressions
- biochemical actions of drugs are very rapid but antidepressant effects usually take weeks to develop
- current antidepressant do not remove symptoms in all patients
what are the two hormones elevated in many depressed patients? where are they both release from?
what effect does the hippocampus and amygdala have on the release of CRF?
CRF (corticotrophin releasing hormone) and cortisol
CRF is released from the hypothalamus which stimulates the release of cortisol in the adrenal gland
hippocampus have an inhibitory effect, amygdala excitatory
what causes the damage and reduced hippocampal volume in depressed humans?
chronic release of cortisol which interferes with the negative feedback pathway this can lead to cell death
how does antidepressant act through the monoamine pathway to reduce CRF and cortisol level?
increasing monoamine levels may help in hippocampus repair through growth factor production (e.g. brain derived neurotrophic factor (BDNF)) through genomic mechanism
in other words - induced neurogenesis
more dendritic spine is observed
in the pharmacokinetics of imipramine, which metabolic step thought to underlie the varying response to tricyclic in different patients?
during hydroxylation, of imipramine carried out by CYP2D6 which has different allelic variants with variable activity
name one TCAs unwanted side effect
atropine-like autonomic side effects related to macho block
why is it important to be cautious when prescribing TCA?
TCAs may interact with other drugs and cause severe side effects.
- microsomal metabolism inhibited by competition with antipsychotics and steroids. This may result in increase TCA plasma levels
- TCA potentiate effects of alcohol (respiratory depression)
- can interact with some anti-hypertensive drug like ACE inhibitors -> causes large and dangerous swings in blood pressure
name the two isoforms of MAOI and which class of drug dot why fall into? name an example for both isoforms
first gen antidepressant
- MAO-A (5-HT selective)
- MAO-B (NA and DA preference)
MAO-A selective clorgyline (good antidepressant)
MAO-B selective selegiline, no antidepressant effect
list down the unwanted side effects of MAOIs
- hypotension
- weight gain
- atropine like side effects
explain the cheese reaction
caused when taking monoamine oxidase inhibitors and tyramine-containing food. this leads to build up of NA in the synaptic cleft and causes acute hypertension may be fatal because it can also cause intracranial haemorrhage
what is the mechanism of action of SSRI? what are their advantages over the 1st gen and what are their side effects?
highly selective 5-HT re-uptake inhibitor
advantages:
- no weight dain
- no anti-cholinergic effect
- low acute toxicity
- no food reactions
side effects:
- nausea, anorexia, anxiety, sexual dysfunction, insomnia
serotonin specific reuptake inhibitor (SSRI) and noradrenaline and serotonin specific antidepressants (NaSSA) are both second gen antidepressant drugs. How is NaSSA better than SSRIs?
less undesirable side effects compared with SSRIs
Mirtazapine is a NaSSA which do not cause nausea and reduce unwanted effects on anxiety, sleep and sexual dysfunction. how does it mediate this effect?
no nausea - block 5-HT3 receptors
reduced anxiety - block 5-HT2
what is ketamine? and explain why ketamine might be a good alternative for anti-depressant
ketamine is a widely used general anaesthetic, it is an NMDA glutamate receptor antagonist. blocking of NMDARs on GABAergic inhibitory neutrons increase glu release
glu release activates AMPARs in post-synaptic cells resulting in BDNF (growth factor) which induces neurogenesis
describe the control of voluntary movement and which dysregulation of a region of the brain associated with PD?
voluntary movement controlled by signals from the cortex -> travel down to PYRAMIDAL TRACT -> initiate motor neurone activity.
signals are fine tuned by influences from EXTRAPYRAMIDAL regions such as BASAL GANGLIA
PD is associated with dysregulation of basal ganglia
which structure receive input from the basal ganglia?
hypothalamus
what is thought to be associated with PD?
degeneration of dopamine-containing cells in the substantia nigra of the basal ganglia
name the components of the basal ganglia
Substantia Nigra (reticulata and compacts)
Subthalamic nucleus
Globus pallidus (interna and externa)
striatum
name two pathways in which the striatum can modulate GPi/SNr output
direct pathway - inhibitory, GABA
indirect pathway - excitatory, GLU
dopamine facilitates and inhibits which transmission?
what happened to this mechanism in PD?
facilitates the direct pathway through stimulating D1 receptor
inhibits the indirect pathway through D2 receptors
alteration of this balance lead to movement disorder such that in PD
what happened to the output of the basal ganglia in PDs?
the output increases therefore the thalamus inhibition increases as well
what happened to the GPi/ SNr output in the direct and indirect pathway in PDs?
direct pathway: less inhibition to the output nuclei
indirect pathway: increase excitation (disinhibited) in the output nuclei
name a drug use to treat PD which acts on dopamine synthesis
why only 1% of this drug actually reach the brain?
so what other drug is used to tackle this problem?
L-DOPA (levodopa) which can cross the blood-brain barrier
due to peripheral metabolism the enzyme dopa decarboxylase is present in other cells outside the brain as well
carbidopa, dopa decarboxylase inhibitors which does NOT cross the blood-brain barrier. hence, allows lower and less frequent doses of L-DOPA to be used
name the enzyme which converts L-DOPA to dopamine
dopa decarboxylase
what are the side effects of L-DOPA?
L-DOPA induces dyskinesia, involuntary writhing movement of the head and neck
on-off effect, unpredictable switches between symptomatic relieve and symptoms of PD
what are the drugs used in which DOPA concentration in the cleft increases without increasing the dosage of L-DOPA given?
name the target molecules
using MAO-B selective inhibitors such as selegiline. prevents metabolism of L-DOPA, increasing [DOPA] in the cleft
target catechol-O-methyl transferase with entacapone
direct acting dopaminergic agonists (D1/D2)
all these drugs increases the effectiveness of L-DOPA therapy
which neurones does muscarinic Ach receptors excite?
stratal neurones
explain the oxidative stress theory
oxidative stress is when reactive oxygen species is not metabolised due to compromised oxidative phosphorylation
this can lead to damage in important intracellular components such as DNA, enzymes and membrane lipids
describe the effects of MPTP
how is this finding associated with PD?
where is this compound found?
MPTP can cross blood brain barrier
in glial cells, MPTP converted MPP+ by MAO-B
MPP+ inhibit oxidative phosphorylation in dopaminergic neurons, reducing production of ATP
causes similar symptoms to PD but DOES NOT cause PD
environment (pesticides)
what is the characteristic of the pathology of dopaminergic neurons?
characterised by formation of aggregates of protein, Lewy bodies in the brain stem and substantia nigra
alpha-synuclein accumulation lead to defective endosomal trafficking -> oxidative stress -> neural death
name two factors hypothesised to contribute to the susceptibility of SNc neurones in PD?
- calcium entry during autonomous pacemaking of DA SNc neurones (therefore need a lot of ATP to sequester Ca into intracellular storage)
- DA SNc neurones have massive, complex, unmyelinated axonal arbours -> high energetic cost of AP propagation places metabolic demands
Where is the 5-HT1A receptors located within the body?
In the CNS and blood vessels
What is an autoreceptor?
A type of receptor located in the pre synaptic nerve cells. Serves as part of the negative feedback loop in signal transduction
