drug-receptor interactions 1 Flashcards
the majority of drugs ____/____ normal physiological/ biochemical processes or ____ pathological processes
mimic/inhibit
inhibit
the magnitude of a pharmacological response depends on (3)
nature of drug molecule
number/ avaliability of drug targets
amount of drug interacting with target
pharmacodynamics is the interaction of a ____ and the interaction with its ____ to form a ____ ____
drug (L)
receptor (R)
ligand receptor complex (LR)
what is psilocybin
hallucinogenic component in magic mushrooms
prodrug (psilocin is active metabolite)
partial agonist
what is psilocin structurally similar to
serotonin - difference in placement of hydroxyl group
(therefore psilocin mimicks serotonin’s endogenous function)
binds to serotonergic receptors
example of drug interfering with body’s pathogenic process
beta lactams e.g. penicillin inhibits peptidoglycan inactivating enzymes called penicillin-binding proteins (PBPs) - formation of bacterial cell wall and osmotic pressure, causing to burst
what are full agonists
produce max. response which system is capable of if given enough of full agonist
drugs that end in mab
monoclonal antibody
e.g. trastuzamab
example where avaliability of targets impacts pharmacodynamics
trustuzamab can only be given to patients with an overexpression of HER2 receptor (overexpressed in breast cancer)
overexpression allows antibodies to interact with cancer and not healthy cells containing HER2
full agonists have ___ affinity and ___ efficacy to their target
variable
high
what is an example of a full agonist
morphine
what receptor does the full agonist morphine act on
mu opioid receptor (MOR) which is a GCPR for pain relief
in sufficient doses, what endogenous function would morphine produce the same effect as?
enkephalins - endogenous opioid receptor ligands
neurotransmitters like dopamine and serotonin are ____ while GABA is ____
excitatory
inhibitory
what is an example of an endogenous agonist
serotonin of serotonergic receptors
what is an example of an exogenous agonist (serotonergic receptors)
psilobycin (psilocin technically) of serotonergic receptors
what is the mu opioid receptor (MOR)
GCPR
for pain relief
what drug is more potent than morphine that also is a full agonist of mu-opioid receptor (MOR)
heroin (diamorphine/ diacetylmorphine)
how are potencies typically measured
by comparing EC50
compare the EC50s of morphine and heroin (diamorphine/ diacetylmorphine)
heroin has a smaller EC50 - less drug is needed to elicit the same response
if codeine has a potency of 0.1, how big of a dose is needed to be equivalent to 10mg of morphine?
100mg
if heroin has a potency of 3, how big of a dose is needed to be equivalent to 10mg of morphine?
3.33mg
if morphine has a potency of 1, how big of a dose is needed to be equivalent to 10mg of morphine?
10mg
if fentanyl has a potency of 100, how big of a dose is needed to be equivalent to 10mg of morphine?
0.1mg
if oxycodone has a potency of 1.5, how big of a dose is needed to be equivalent to 10mg of morphine?
6.67mg
what is a partial agonist
produces a response but not fully activates to full response, regardless of dose
partial agonists have ____ affinity and ____ efficacy
variable
variable
what are two examples of a partial agonist
buprenorphine
psilocybin
what does buprenophrine bind to
mu opioid receptor (MOR) - high affinity, partially activated
lower efficacy than methadone
what is buprenophrine used for
decrease doses to wean patients off methadone - opioid replacement therapy
if not weaned off, sudden withdrawal causes shock and potential death
opioid disorder can cause respiratory depression
what are antagonists
bind with no effect - also called neutral antagonists
antagonists have ____ affinity and ____ efficacy
variable
no
what are the two types of antagonism
competitive and non competitive
what is competitive antagonism
surmountable
prevents activation of receptor
structurally similar to agonist
orthosteric site binding
what is non-competitive antagonism
insurmountable
as binds to separate allosteric binding site - no competition
only reversible if agonist added before antagonist covalently binds to receptor
what is an example of a competitive antagonist
naloxone
can be used to reverse opioid effects during overdose e.g. respiratory depression (as naloxone spray)
what does naloxone bind to
opioid receptors
prevents activation of mu opioid receptors MOR - would outcompete if administered with opioid
what is an example of a non competitive antagonist (2)
ketamine
cyanide
what does ketamine bind to
NMDA channel pore
vs
the agonist glutamate binds to the extracellular surface of NMDA
how does naloxone work to reverse opioid overdose
naloxone outcompetes opioids (morphine) for binding to the opioid receptors at the same orthosteric site as they are structurally similar, and outcompetes already bound opioids
reverses overdose symptoms e.g. respiratory depression
agonists and competitive antagonists bind to the ____
orthosteric site
what is meant by a competitive antagonist being surmountable
the competitive antagonist’s effects can be overcome by increasing dose of agonist
compare the dose response sigmoid curve of a agonist vs a competitive antagonist + agonist
antagonist shifts curves to right - more agonist needed to overcome antagonist
the orthosteric binding site is also called the ____
ligand binding site
what binds to the allosteric site
non competitive antagonists
what do non competitive antagonists look like on a dose response sigmoid curve
shifts to right but does not reach maximal response
how does cyanide work as a non competitive antagonist
C triple bond N
non competitive antagonist/ inhibitor of cytochrome c oxidase in ETC, inhibiting ATP production
insurmountable
due to smoke inhalation
treatment focused on intercepting cyanide before it reaches and covalently binds to receptor/ cytochrome c oxidase or displacing it
what are allosteric modulators
bind to receptor to change receptor’s responses to drug/ stimulus
cannot cause a response alone, only act on response from stimulus
what are the two types of allosteric modulators
negative allosteric modulator NAM - inhibit
positive allosteric modulator PAM - enhance
what is a type of NAM
non competitive antagonism
how do NAM/PAMs affect dose response curve
curve moves to the left as less agonist needed for same response (PAM)
right if NAM
what is an example of a negative allosteric modulator (NAM)
GABA neurotransmitter
what does GABA bind to
GABA a or GABA b
what is GABA a
ionotropic receptor - activation causes receptor to open and allow ions to flow through receptor
what occurs when GABAa is activated
Cl- ions flow into cell causing hyperpolarisation - inhibits action potential firing, signalling in brain
GABAa is activated by ____ (2)
GABA binding at orthosteric site
allosteric modulation at BZD allosteric site (PAM)
examples of GABAa PAMs
benziodiazepines, zolpidem, barbituates
what impact do PAMs have on GABAa
increase affinity for GABA of GABAa receptor so channel remains open for longer, more Cl- enters neuron, inc hyperpolarisation - the neuron action potential activity is further inhibited
what is an inverse agonist
inhibit agonist’s independent low-level signalling
dec response
examples of an inverse agonist - 3
anti histamine (histamine receptors work without histamine being bound)
beta-carboline derivatives at BZD receptor (which is part of GABA- A receptor complex) - reduce GABA transmission - lead to inc anxiety and seizure disorders - used in research
11-cis-retinal which binds to rhodopsin via a Schiff base linkage in the dark, which stabilises it and prevents it from constituent signalling, allowing the eye to remain adapted to the dark
how do anti histamine drugs function
prevent histamine activating receptor and inhibit constitutive/ independent activity - less effect result
what are superagonists
capable of producing maximal response beyond than capable max response - unknown how
example of superagonist
gaboxadol of GABAa receptors
a full agonist, if displayed as response vs log of conc, forms what
sigmoid curve
flumazenil
bzd competitive antagonist of GABAa receptor - used to treat bzd overdose or after surgery using bzd
but, has some partial inverse activity in patients with panic disorders - decreases the activity of GABA-A receptors- inc risk of panic attacks
suggests response depends on patient physiology
cinacalet
PAM
treating hyperpara thyroidism
targets calcium sensing receptor, inc its sensitivity to calcium so activates at low calcium levels
dec parathyroid hormone production
maraviroc
NAM - anti retroviral therapy
treating AIDS
targets CCR5
by binding to an allosteric site on the CCR5 receptor, maraviroc alters its conformation, preventing the HIV virus from binding and gaining entry into the cell
dec risk of resistance as allosteric site less prone to mutation
a low Kd refers to a ___ affinity
high
an example where efficacy is relevant in treatment
to treat opioid overdose, the full agonist morphine is administered, then buprenorphine to wean off and avoid shock from withdrawal
compare the ec50 between heroin and morphine
heroin has a smaller EC50 value than morphine, so has a higher potency
compare the ec50 between formoterol and salbutamol
for asthma treatment - helps wit bronchodilation
salbutamol has a smaller ec50 value than formeterol so has a higher potency - needs to be higher to achieve therapeutic effect in short duration of action
what is formoterol
long-acting β₂-adrenergic receptor agonist (LABA)
asthma treatment
what is salbutamol
short-acting β₂-agonist (SABA)
asthma treatment
example of cyanide treatment
vitamin B12a binds to cyanide
forming cyonocobalamin, non toxic
cyanide thus unable to bind to receptor
compare potencies of hydromorphine and morphine and clinical meaning
hydromorphine is at least 5x more potent than morphine, so patients can be switched to hydromorphine for analgesic effect if needed instead of inc morphine dose
1/5 of hydromorphine would have the same effect as of the full morphine dose
(oral)
