Pharmacodynamics: Potency, Efficacy, and the Therapeutic Index

pharmacokinetics:

the study of drug movement throughout the body

pharmacodynamics

- study of how a drug changes the body

- relationship between plasma drug concentrations and therapeutic response

- mechanisms of action of drugs

- influenced by pharmacokinetic processes

- pt responses to meds highly individualized

Quantal effects

yes/no questions

- did the drug reduce systolic BP by 20 mmHg or not?

- does not indicate the magnitude of effects

- frequency distribution curve

what is the ED50?

- median effective dose

- dose required to produce a specific therapeutic response in 50% of patients (yes/no question)

- often the standard dose

best way to present quantal effect data

logarithm, makes it easier to calculate ED50 instead of eyeballing a straight vertical line

therapeutic index

- ratio of a drug's LD50 (or TD50) to its ED50

- drugs with a narrow therapeutic index are considered high alert medications

median lethal dose (LD50)

- dose of drug that will be lethal in 50% of test animals

median toxic dose (TD50)

- dose that will produce a given toxicity in 50% of patients

graded effects: Dose response curves

- demonstrates the magnitude of biological response to a drug

- very different from a quantal yes or no response

- obtained by observing and measuring patient responses at different doses of drug

gives us:

- therapeutic range of a drug

- efficacy of a drug

- potency of a drug

what do dose response curves tell us?

- therapeutic range of a drug

- efficacy of a drug

- potency of a drug

Dose-response relationship: phase 1

- few target cells are affected by the drug

- no response, not enough concentration to elicit desired effect

Dose-response relationship: phase 2

- linear relationship between amount of drug administered and degree of client response

Dose-response relationship: phase 3

- plateau is reached

- increasing the dose has no therapeutic effect --> may even produce adverse effects

potency

- compares the doses of two or more drugs with respect to how much drug is needed to produce a specific response

- comparison usually based on the median effective dose (or concentration) of a drug (ED50 or EC50)

- if a drug is highly potent, it will not take much drug to produce a therapeutic response (eg: hydromorphone higher potency/affinity than morphine)

- potent drugs typically have a higher affinity for the receptor binding site

efficacy

- what is the capacity of the med to reach 100% of the therapeutic effect

- better measure than potency

K1 association

- rate of drug-receptor complex formation

K-1 dissociation

- rate of drug dissociation from receptors

high affinity

- rapid binding, slow dissociation

low affinity

- slow binding, rapid dissociation

Kd and affinity relationship

- inverse relationship

LOW Kd = High affinity and vice versa

Dissociation Constant

Kd

Full agonists

- bind to the same receptor site as the endogenous ligand and produce the same bio effect as the endogenous ligand at that receptor site

- if an agonist produces the full effect of the endogenous ligand, the drug is a full agonist with high efficacy

- ex: dexamethasone is a mimic for cortisol

Partial agonists

- if only a part of the endogenous effect is elicited, the drug is a partial agonist

- efficacy will always be lower than a full agonist

- ex: Aripiprazole produces a smaller bio effect at the dopamine receptor compared to dopamine

Inverse agonists

- bind to the same receptor as the endogenous ligand, but induce the opposite response

- only occurs when the receptors have a baseline level of activity (most don't)

- considered to have negative efficacy

- ex: GABA receptors are agonized by benzos, they have a sedative effect... inverse agonists are anxiogenic

antagonists

- bind to the same receptor site as the endogenous ligand, but DO NOT stimulate the receptor

- rather, antagonists occupy the receptor preventing the endogenous ligand from binding

- two main types: reversible and irreversible

Reversible antagonists

- competitive

- non-competitive

Irreversible antagonists

- bind to receptors and never let go

- cells have to make new receptors

- Kd very low --> very high affinity

- many biological weapons are irreversible antagonists

--> nerve gases

- some are very helpful though

- ASA (anti-inflamm, anti-platelet, analgesia) , Omeprazole (GERD)

Competitive antagonism

- antagonists compete for the same receptor binding site as the endogenous ligand

- when the antagonist is bound, it blocks the endog. ligand from binding

- a competitive antagonist always dissociates from the receptor

Non-competitive antagonism

- binds to a site other than the endogenous receptor binding site "allosteric modulation" --> change the shape of the seat for the ligand

- prevents the endogenous ligand from binding at the receptor binding site

- PCP and Ketamine are non-competitive antagonists for the NMDA receptor