Pharmacodynamics Flashcards
What unit do we use to consider drug concentration?
Molarity
What is a ligand ?
A molecule or ion that binds specifically to a receptor
If a drug is an antagonist, what effect does it have on the receptor?
Block the binding of its endogenous ligand
If a drug is an agonist, what effect does it have on the receptor?
Activate the receptor to bind its ligand, alters receptor conformation (switches On)
Receptor activation is governed by intrinsic efficacy. What does this mean?
the relative ability of a drug-receptor complex to produce a maximum functional response.
What is the ligands efficacy?
The ability of a ligand to cause a measurable response
What two factors is efficacy governed by?
Intrinsic efficacy
Plus cell/tissue dependent factors
Do antagonists have affinity, efficacy and/or intrinsic efficacy?
Recess affinity for the receptor only. Block the effects of agonists (no intrinsic efficacy)
How do we measure drug-receptor interactions by binding?
Often by binding of a radioactively labelled ligand to cells or membranes prepared from cells
Low ligand concentration = low binding
What is Bmax?
Maximum binding capacity (receptors saturated). Independent of ligand concentration. Gives information on receptor number
What is Kd?
The drug dissociation constant, drug concentration that’s required to occupy 50% of available receptors gives an idea of affinity.
Lower Kd = higher affinity
What is the effect of drugs with high affinity?
High affinity allows binding at low concentrations, reflects the amount of drug regard needs to be given
If you plot log[drug] vs proportion of bound receptors, what is the shape of the curve?
Sigmoidal
What is the EC50 of a drug?
The effective concentration which gives 50% of the maximal response
What is the difference between drugs dose and concentration?
The concentration is known for a drug at the site of action
The dose is when the concentration at the site of action is unknown - give a toeing a specific dose in mg for example, but don’t know concentration at site
What is Ec50 a measure of?
Potency (how well a drug works)
What three things are required for a ligand to have potency?
- Affinity - ligand binding to receptor
- Intrinsic efficacy - receptor activation
- Cell/tissue specific components
2+3 = efficacy
What are spare receptors?
Receptors that don’t contribute to response (where less than 100% occupancy = 100% response)
Often seen when receptors are catalytically active (e.g. Tyrosine kinase of GPCR)
Why do spare receptors exist?
Because of amplification in the signal transduction pathway (response limited by a post-receptor event)
What is the benefit of having spare receptors?
Spare receptors increase sensitivity- allow response at low concentrations of agonist
Receptor number can be altered by what?
Activity (increase with low activity, decrease with high activity)
Also physiological, pathological and drug-induced changes
What is a full agonist?
Where EC50 is less than/equal to Kd (spare receptors)
Often endogenous ligand
What is a partial agonist?
Where EC50 is approx = Kd. So no spare receptors, all receptors occupied, insufficient intrinsic efficacy for maximal response (cannot change into right shape)
Lower efficacy that full agonists
What is the relevance of partial agonist? (3)
Allow a more controlled response
Work in the absence or low levels of (endogenous) ligand
Can act as antagonist if levels of full agonist
What are opioids?
Used for pain relief and also recreationally (e.g. Heroin)
Action primarily as an agonist to μ-opioid receptor (GPCR)
Changing the number of receptors can change a partial agonist into a full agonist, how?
Partial agonist still has low intrinsic efficacy at each receptor BUT sufficient number of receptors to generate a full response
The maximal possible response is limited, meaning that equal responses …….
Do not mean equal strength (efficacy)
What are the three types on antagonist?
Reversible competitive
Irreversible competitive
Non-competitive
What does reversible competitive antagonism depend on?
Relied on dynamic equilibrium between ligands and receptors (greater [antagonist] = greater inhibition)
What effect do reversible competitive antagonists have in the agonist-response curve?
Cause parallel shift to the right of the agonist concentration-response curve (further right with increased agonist concentration)
What is Naloxone?
is a high affinity, competitive antagonist at μ-opioid receptors. (Competes (successfully) with heroin and other opioids for receptors)
What is irreversible competitive antagonism?
When the antagonist dissociates from receptor slowly or not at all. With increased [antagonist] or increased time, more receptors blocked
(Can’t be overcome by increasing agonist conc)
What is the effect of irreversible competitive antagonists on the agonist concentration-response curve?
cause a parallel shift to the right and at higher concentrations suppress the maximal response (as spare receptors filled by antagonist)
What is non-competitive antagonism?
Binds at an allosteric site (no competition for binding site)
Similar effects to irreversible competitive antagonism
