What is Pharmacokinetics?
relationship between drug administration and exposure to drug
What is Pharmacodynamics?
relationship between exposure to drug and effect
What are receptor agonisms?
- agonists bind to receptors
- activate transmembrane events
- conc need to have % effect differs
- max response may differ
What are receptor antagonisms?
- bind to receptors
- do not signal transduction
- low [antagonist] little inhibition
- zero efficacy as it does not activate a receptor
What is efficacy?
how well drugs/ligands activate receptors once its bound
What are the quantitative aspects go drug-receptor interactions?
- noncov
- reversible
- competitive
- specific
- selective
- ligand
- reversibility (how easily the ligand bind and dissociate from receptors
What is the rate of dissociation?
- number of molecules dissociating per second proportional to the conc of receptor ligand complexes
What is the rate of association?
- number of molecules association er second proportional to the conc of receptor and ligand
What is Kd?
The concentration of ligands resulting in half receptors being occupied by ligand
EC50 is the drug conc thats gives 50% response
(See equation 1)
How do we measure Kd?
- receptor binding sites
- measure binding to cell membranes
- total binding = specific binding + non specific binding
What is specific binding?
binding to receptors
What is non-specific binding?
binding to anything else present
How does an agonist binding to a receptor lead to biological effect?
- law of mass action applies
- response related to receptor occupancy
- max tissue response obtained at lower occupancy or higher occupancy
- see equation 2
What is the Hill Equation?
See equation 3
- predicts what we should see most of effect over approximately 100 fold difference in conc
- reflects range of drug conc over which response occurs
- important because allows us to view consequences of using 3 drugs on a patient
- allows for calculation of EC50 and nH
- allows us to obtain KD for ligand binding
How does the Hill Equation explain partial agonism?
- isoprenaline and prenalterol activate beta adrenergic receptors
- isoprenaline = full agonist
- prenalterol = partial agonist
What are partial agonists?
- fully occupy all receptors
- cannot activate large enough proportion to elicit max response
- some tissues, this may be sufficient
- dependent on receptor reserve
What are spar receptors?
- full agonists elicit max response without all receptors being occupied
- Kd > EC50
How can receptor number and efficacy determine response?
- drugs are tested for max response in 2 diff. tissues
- two tissues have different number of receptors present needed to obtain max response
What is competitive antagonism?
- reversible
- agonist and antagonist cannot bind at the same time
- effect of antagonist overcome with higher conc of agonist
- increase EC50
- more agonists = overcome antagonist
- Kd increased by (1+ [B]/kB )
- dependent on [antagonist]
- see equation 3
What is the cheng prustoff equation?
see equation 4
What is irreversible antagonism?
- antagonists bind covalently to same site as agonist
- not dissociate
- receptors become inactivated
- reduces max response
- increases [Agonist] not overcome blockade
- KD unchanged
How does antagonism by partial agonists work?
- partial agonist competes with full agonist
- high [partial agonist] activity of partial agonist predominates
- add partial agonist on top of full agonist, antagonises the effect
What is allosteric antagonism?
- antagonist binds to diff. site on receptors
- receptors activated if binds to agonist alone
- effect on response curve is complicated and depends on receptor reserve
What are inverse agonists?
- receptors are constitutively active
- drugs bind to R to reduced amount of receptor available to spontaneously activate and reduce resting response of tissue
