M&R Factoids and Definitions Flashcards
Define Therapeutic Ratio
Maximum tolerated dose/minimum effective dose
OR
LD50/ED50
Define Oral Bioavailability
Proportion of a dose given orally (or by any route other than IV) that reaches systemic circulation unchanged
Define Volume of Distribution
Theoretical volume into which drug has distributed assuming that this occurred instantaneously
Define Membrane
Continuous, selectively permeable barrier
Define Receptor
A molecule that recognises specifically a second molecule (ligand) or family of molecules and in response to ligand binding brings about regulation of a cellular process
Define ligand
Any molecule that binds specifically to a receptor site
Define affinity
Likelihood of a ligand binding to a receptor
Or Strength of ligand-receptor interaction
Activation of a receptor is governed by…
Intrinsic activity- measure of size of response
Kd is…
Measure of affinity. Conc of ligand that causes 50% receptor occupancy. Reciprocal of affinity
Bmax tells you about…
The maximum binding capacity (total number of receptors in a tissue)
Efficacy is…
Intrinsic activity plus cell and tissue dependent factors. The difference between affinity and response curve- how well, once bound, the ligand produces a cellular response
Affinity + efficacy is..
Just affinity is…
Agonist
Antagonist
Emax is…
Maximum response of a particular agonist. Crude measure of efficacy
EC50 is…
The effective concentration of ligand giving half the maximum response. Crude measure of potency
Define Potency
Dose range over which a response is produced. Measured by EC50.
Depends on affinity and intrinsic activity/efficacy AND number of receptors
If a tissue had reserve receptors, where would the response curve lie in relation to the binding curve?
To the left. EC50<Kd
Define Partial Agonist
Binding, even at 100% occupancy cannot produce a maximum response. EC50=Kd System dependent (high number of receptors can covert to full agonist)
Clinical use of affinity/efficacy
Salbutamol- poor affinity for B2 but high selective efficacy. Plus direct route of administration. (In high concs can increase HR)
Salmeterol- high affinity (so no need for selective efficacy)
Clinical use of partial agonist
Opioids act on u opioid receptor (GPCR). Can cause resp depression.
Morphine (full agonist) can give pain relief but also RD. Buprenorphine (partial agonist) has higher affinity and lower efficacy- still provides adequate pain control, but less RD
Why can giving Buprenorphine to a heroin addict (with heroin in their system) cause withdrawal symptoms?
Heroin in a full agonist. In high doses, Buprenorphine can act as a antagonist of heroin (efficacy is low but higher affinity so occupies receptor and limits response)- so can get withdrawal.
Therefore, partial agonists can act as antagonists of full agonists. (PA=mixed agonist/antagonist).
Buprenorphine can also be used in lower doses to enable gradual withdrawal from heroin.
Higher dose (with same antagonist) or greater affinities (with differing antagonists) both cause…
(Reversible competitive antagonism)
Response curve of [agonist] shifts to the right
Clinical example of reversible competitive antagonist
Naloxane- antagonist of u opioid receptors. Reverses resp depression
What happens in irreversible competitive antagonism?
Antagonist dissociates very slowly/not at all - non surmountable.
Clinical example of a irreversible competitive antagonist
Phenoxybenzamine- for pheochromocytoma. Irreversible a1 adrenoreceptor antagonist- good because even high adrenaline won’t outcompete it.
Where do non competitive antagonists bind?
To the allosteric site of a receptor. Reduce the effect of agonist binding to the orthosteric site (decreased efficacy and/or affinity)
Define Desensitisation
Define Tolerance
Desensitisation- when the effect of an agonist, when given continuously, is diminished as the tissue becomes less responsive. Develops over a few minutes.
Tolerance- more GRADUAL decrease in responsiveness
Define Supersensitivity
Adaptive response in cells (in an attempt to overcome the drug effect) which may result in a ‘rebound’ effect in response to endogenous agonists when drug therapy ceases
Define Homologous desensitisation
Only the receptor for the agonist that is signalling is desensitised
Define Heterologous desensitisation
When receptors for several different agonists are desensitised when only one has been stimulated by an agonist
Desensitisation of GPCRS can result from…
i) modification of the receptor by phosphorylation (most commonly associated with heterologous desen)
ii) reversible receptor internalisation (sequestered to a pool for later use when needed)
iii) down regulation (irreversible internalisation- to lysosome where agonist and receptor are degraded)
