Pharmacodynamics Flashcards
What is a ligand?
Molecule that binds specifically to a receptor.
What is the law of mass action?
Rate of a chemical reaction is proportional to the concentrations of the substances.
What must ligands have to bind to a receptor?
Affinity (= strength of binding to receptor)
What is the difference between agonist and antagonist ligands?
- Agonists: activate receptors.
- Antagonists: block the binding of an endogenous agonist.
- Both have affinity for receptors.
What properties do agonists have but not antagonists?
- Intrinsic efficacy
- Efficacy
What is intrinsic efficacy of a ligand?
- Its relative ability to activate a receptor.
- Determined by the conformational change of the receptor upon ligand binding.
What is efficacy of a ligand?
- Its ability to cause a response.
- Determined by intrinsic efficacy + cell/tissue-dependent factors.
What is potency of a ligand?
Affinity + efficacy
Why is affinity and intrinsic efficacy of any ligand-receptor combination fixed, whereas potency is variable?
Because of the cell/tissue-dependent factors that affect efficacy.
What is the effect of drug concentration on affinity?
Increasing the amount of drug increases the amount of binding until saturation (Bmax) is reached.
What is Bmax? What does it give us information on?
- Bmax = maximum binding capacity.
- Gives info about R number.
What is the dissociation constant Kd?
- Kd = concentration of ligand required to occupy 50% of available receptors.
- Is an index of affinity.
Does a ligand have high affinity for a R if it has a high or a low Kd.
A low Kd - less drug required to saturate 50% of receptors.
What is the effect of drug concentration on functional response (potency)?
Increasing drug concentration leads to an increase in response % until Emax is reached.
What is Emax?
- Emax = maximum possible response (e.g. Muscle is as contracted as can be).
- Indicator of intrinsic activity.
What is EC50?
- EC50 = effective drug concentration giving 50% of maximal response.
- Is a measure of agonist potency.
Name an important cell/tissue-dependent factor affecting ligand potency.
Number of receptors.
Why does 100% receptor binding not always generate 100% response?
The response is controlled/limited by other factors, e.g. A muscle can only contract so much, a gland can only secrete so much.
What are spare receptors? When are these commonly seen?
- The left over receptors when <100% binding = 100% response.
- Often seen when receptors are catalytically active (e.g. Tyrosine kinases or GPCRs).
Why do spare receptors exist?
- Amplification of the signal transduction pathway.
2. Response limited by a post-receptor event.
Give an example of signal amplification.
- A few adrenaline molecules binding to cell surface beta-adrenoreceptors can cause a relatively massive cellular response.
- Because activation of adenylyl cyclase generates many molecules of cyclic AMP - activate many PKA - etc.
Give an example of spare receptors in the body.
10% occupancy of mAChRs generates maximal contraction of smooth muscle in airways.
Why have spare receptors?
Spare receptors increase sensitivity - allow responses at lower concentrations of agonist.
- If no spare receptors, full response requires 100% occupancy - must have > Kd conc. of drug.
- If spare receptors (e.g. Double amount of receptors), full response requires only 50% occupancy - much have Kd conc. of drug.
What is the effect of changing receptor number?
Changes agonist potency and can affect maximal response.
Give examples of when receptor numbers can change.
Physiological, pathological or drug-induced changes:
- tend to increase with low activity (up-regulation)
- tend to decrease with high activity (down-regulation)
What is the effect of receptor number down-regulation on drug treatment?
Can contribute to tolerance/tachyphylaxis: more drug is required to stimulate same effect.
