Pharmacodynamics Flashcards
bioavailability
the concentration of bioactive drug in the systemic circulation
pharmacokinetics (ADME-T)
what the body does to the drug
pharmacodynamics
‘what the drug does to the body’
the relationship between drug concentration at the site of action and the intensity/duration of the effects
main drug targets
- voltage/ligand ion channels
- enzymes
- transporters
- receptors
drug targets at the synapse
- voltage gated calcium channels
- precursor transport channels
- synthesis enzymes
- vesicular transporters
- postsynaptic receptors (metabotropic/ionotropic)
- presynaptic regulatory receptors
- degradation enzymes
- reuptake channels
GPCRs
proteins composed of 7 transmembrane domains, with an extracellular N terminus and intracellular C terminus
G proteins
heterotrimeric proteins (aby) that change conformation upon receptor activation to dissociate into an alpha subunit and a beta-gamma dimer which can both exert effects
Affinity
the ability of a drug to bind to a receptor
defined by Kd: the concentration of a drug required to occupy 50% of receptors
potency
a measure of the concentration of a drug required to produce an effect
defined by EC50: the concentration of a drug required to produce 50% of the maximal response
Efficacy
the ability of a drug to produce a response
defined by Emax on a concentration-response curve
Define agonist & partial agonist, in terms of drug efficacy
agonists have 100% efficacy at full receptor occupancy, whereas partial agonists will never reach Emax
fractional occupancy
Fo = [A]/(Kd+[A])
describes the percentage of receptors occupied at a given time
Kd equation
Kd = (k-1)/(k+1)
a function of the dissociation constant (k-1) and the binding constant (k+1)
concentration response curve
defines efficacy and potency
Effect = Emax.[A] / (EC50+[A])
desensitisation of ion channels
phosphorylation by GRK facilitates recruitment of beta-arrestin
downregulation of ion channels
clathrin-mediated internalisation and subsequent sorting of vesicles for recycling or degradation
tolerance
the development of a diminishing response to the same dose of drug
mechanisms of tolerance
pharmacological down regulation of agonist receptors or up-regulation of antagonising receptors
pharmacokinetic altering of metabolism
competitive reversible antagonists
bind reversibly to orthosteric site, but do not activate the receptor
= affinity but no efficacy
shift the dose-response curve to the left
surmountable, as can be overcome with increasing concentration of agonist
examples of competitive reversible antagonists
naloxone (opioid antagonist)
haloperidol (dopamine receptor antagonist and antipsychotic)
clozapine (serotonin/dopamine antagonist and an atypical antipsychotic)
partial agonists as antagonists
partial agonists can prevent the full action of an agonist by occupying receptors to produce decreased efficacy
buprenorphine
a partial agonist that is used as an antagonist for opioid dependence, as it helps manage withdrawal and prevents effectiveness of full opioid agonists such as heroin
irreversible competitive antagonism
drug binds covalently to orthosteric site of receptor
flattens dose-response curve
not surmountable, and will reduce the number of receptors available to agonist
receptor reserve
the idea that some regions have excess receptors, such that the maximum response can be achieved without complete receptor occupancy
eg: the neuromuscular junction has a large amount of receptors, so high concentration of antagonists are needed to diminish response
why can irreversible antagonists resemble reversible antagonists
due to receptor reserve
inverse agonists
bind to the orthosteric of the site and decrease the constitutive activity of a receptor
= affinity and negative efficacy
allosteric modulators
drugs that bind to a site other than the orthosteric site that can modulate affinity or efficacy of endogenous ligands or indirectly (in)activate the receptor
advantages of allosteric modulators
- ceiling effect: a progressive inability to shift dose-response curve with increasing concentrations
- greater selectivity
- maintain the spatial and temporal nature of endogenous signalling
- probe dependence: have different responses depending on the agonist
ortho-allosteric ligands
linking of an allosteric modulator to an orthosteric ligand via an appropriate spacer moiety
allows subtype specificity with orthosteric action
