Pharmacodynamics Flashcards
Definition of pharmacodynamics
Mechanisms of action of a drug
Therapeutic uses
Adverse or side effects
Definition of pharamcokinetics
Mechanisms by which body handles the drug Absorption Distribution Metabolism Elimination
Theory of drug interactions
Drugs do not create effects, they modify ongoing functions
Effects of the body of most drugs are a result of interactions between the drug and functional macromolecular components of the organism
Stages in receptor function
Binding (L+R LR)
Transduction (LR -> Effect)
Alternatives to receptor-mediated drugs
Enzyme inhibitors
Transport inhibitors
Ion channel inhibitors
Note all of these still tend to follow the same paradigm as receptor-mediation
Characteristics of receptors
Specificity: Receptors are targeted by specific drugs
Selectivity: Receptors target a specific subset of cell pathways
Sensitivity: Effects at receptors are amplified within the cell, therefore, only a small amount of drug is needed
Pharmacological Classification Schema
Structural features of ligands (Muscarinic, Nicotinic cholinergic receptors)
Biochemical Classification Schema
Based upon transduction mechanism (Metabotropic vs ionotropic)
Molecular/Structural Classification Schema
Families of similar gene products
Definition of Kd
Dissociation constant at equilibrium
Kd = [L][R]/[LR] = k2/k1
Inverse of affinity
Units of M
Equation of [LR]
[LR] = Rt*[L]/(Kd + [L])
Characteristics of Ionic Bonds
Receptors have charged amino acids
Ligands are weak acids or bases and are charged at physiological pH
Major determinant of k1
Characteristics of Hydrogen Bonds
Hydrogen bound to an electronegative atom will have a partial positive charge
Weaker than ionic bonds, and require close proximity
Characteristics of Van der Waals interactions
Hydrophobic interactions
Act only at very close distances
Greatly strengthen the binding interaction and are the major determinant of k2
Occupancy theory
Effect is directly proportional to [LR] E/Emax is proportional to [LR]/Rt E = (Emax * C)/(Kact + C) C = [Drug] EC50 = Kact
Efficacy in occupancy theory
Idea of intrinsic activity for a ligand (0 < α < 1)
E/Emax = α[LR]/Rt
Full agonist: α = 1
Antagonist: α = 0
Spare receptors
Effector units are limiting factor, not receptors
Results in EC50 not being equal to KD
Increases a cell’s sensitivity to low ligand concentration and low activation time
Classes of antagonists
Chemical: Combines with agonist to disallow interaction
Physiological: Activates an oppposing physiological target (ACh vs Norepi)
Pharmacological: Blocks effects of agonist at site of action
Competitive Antagonist
Blocks target site of the drug
If reversible then it can be surmounted by agonist
Apparent affinity loss
Equation for EC50’
EC50’ = EC50(1 + [I]/Ki)
Implications of competitive therapeutic use
Dependence upon both its concentration and the agonist concentration
Antagonist with highest affinity for the receptor will produce the greatest inhibition
Irreversible Competitive
Covalent binding to site or in an effectively irreversible rate
Reduces receptor pool
Assuming no spare receptors, no change in affinity (EC50), but efficacy decreases (Emax)
Implications of irreversible therapeutic use
New receptor synthesis is the only way to overcome the effects of the antagonist
Degree of inhibition produced is not influenced very much by the concentration of agonist present
Noncompetitive Antagonist
Binds to receptor at different target site
Decreases efficacy, completely irrespective of affinity even with spare receptors
Implications of noncompetitive therapeutic use
Independent of agonist concentration of receptor
Can be used to inhibit the effects of multiple agonists that use the same signal transduction cascade (inhibition of voltage operated calcium channels)
Partial agonist
Partial agonist decreases effect of agonist
Tonic Activity
Equilibrium between active and inactive receptor states
True antagonist does not have effect so it does not alter basal equilibrium
Agonist and partial agonists shift equilibrium towards active state
Inverse agonist shift equilibrium toward inactive state
Dose Response Theory
Ideally follows pharmacodynamical models in vitro
Issues from pharmacokinetics causes non-idealized behaviors (absorption, distribution, metabolism, excretion)
Definition of potency
Drug response equivalent of affinity (EC50 => ED50)
Result from site affinity, delivery to site
Definition of efficacy
Drug response equivalent of Ema
Determinants: intrinsic activity, characteristics of effector, limits on amount that can be actually given in dose (risks of adverse effects)
Deviations from sigmoid response curve
Additive effects of the drug
Threshold effects
Antagonist effects
Need to be considered for therapeutic purposes
Population dose response curves
Response frequency: Log-normal
Culmulative response: Log-sigmoid
You didn’t see that coming, did you?
Causes for dose response variations
Pharmacokinetic differences
Variations in the amount of endogenous agonist present
Changes in the number of functioning of the drug target
Differences in a component distal to the drug target
Definition of idiosyncratic drug responses
Unexpected based upon the mechanism of actions of the drug
Definition of hyporeactive and hyperreactive
Tails of frequency distribution
Definition of hypersensitivity
Allergic or inflammatory response to the drug
Definition of tolerance
Slowly developing resistance to the drug
Definition of tachyphylaxis
Rapidly developing resistance to the drug
Quantal dose response curves
Culmulative frequency relationships between drug dose and population response
Shape of curve reflects the variability in response the population
Parameters from quantal dose response curves
ED50 - Median effective dose TD50 - Median toxic dose LD50 - Median lethal dose Therapeutic index (Ti) = TD50/ED50
