Pharmacodynamics lecture

Discussion of basic pharmacodynamic concepts.
Acknowledgment of traditional owners of the land where QUT stands and respect paid to elders past, present, and emerging.

Pharmacodynamics defined as the study of the effects of drugs in the body.
Characterizes the relationship between drug concentration at the site of action and the effect produced.
Due to the invasiveness of tissue collection to determine effect site concentration, plasma concentration is used as a proxy.
- It is assumed that plasma concentration is in equilibrium with effect site concentration.
- Intensity of effects is often measured as a function of plasma concentration.

The concentration-response curve is typically sigmoidal.
- Y-axis: Response.
- X-axis: Concentration.
At zero drug concentration: no effect is observed.
As concentration increases, response rises to a maximum, due to homeostatic mechanisms.

The curve is characterized by:
- Emax: The maximum response achievable.
- EC50: The plasma concentration that produces 50% of the maximum response.
- Example:
- For warfarin, there is a delayed response because it inhibits prothrombin synthesis, needing time for the coagulation cascade to equilibrate (response delay on the order of days).

When studying an orally administered drug, the plasma concentration over time for repeated doses will follow a specific profile:
- Plasma concentrations rise to a maximum and then decline to a minimum.
Regularly scheduled doses can achieve steady state where plasma concentrations remain stable.
Onset of response: Occurs when plasma concentrations exceed the minimum effective concentration, typically around 24 hours for the discussed drug.
Duration of response: Lasts until the concentration drops below the minimum effective concentration.

Efficacy is the maximum effect achievable by a drug.
Potency is measured by the EC50, which is the concentration required to achieve 50% of the maximum effect.
Comparisons of drugs A, B, and C demonstrated the relationship:
- Drug A: Greater efficacy than B, which is greater than C.
- Drug A's EC50 = 0.5, Drug D's EC50 = 120, proving A is more potent than D.
Example of opioid analgesics:
- Morphine is shown to be 13 times more potent than codeine based on relative ED50s.

Agonists: Activate receptors to produce a response.
Antagonists: Have affinity for receptors but no efficacy, blocking agonist activity.
- Competitive antagonists: Compete with agonists at the binding site, thus reducing potency of the agonist, necessitating higher concentrations for effect.
- Non-competitive antagonists: Bind to receptors, thus blocking access for agonists and reducing maximum efficacy.

Individual variability in drug response due to:
- Differences in receptor numbers or function.
- Variation in effector mechanisms linked to receptors.
- Differences in drug concentrations that reach receptors.
- Presence of endogenous/exogenous substances competing for receptors.
Example: Warfarin dose variability due to genetic variations (e.g., polymorphisms in the Vitamin K epoxide reductase complex gene (VCORC1)).
- Prevalence of these polymorphisms is race-dependent:
- 37% of Caucasians.
- 14% of Africans.

Concomitant medication use can result in pharmacodynamic interactions that require careful monitoring.
Warfarin interactions:
- CYP2C9 substrates' exposure can be affected by inhibitors and inducers leading to dosage adjustments.
- Aspirin and NSAIDs may increase bleeding risk due to pharmacodynamic interactions.
- Antiplatelet effects of these drugs could heighten bleeding risk without increasing INR, necessitating avoidance of combinations to prevent adverse outcomes.

Aging can impair homeostatic mechanisms such as those defending against orthostatic hypertension.
Increased risks of side effects from drugs such as NSAIDs and CNS depressants among the elderly due to sensitivity changes.

Principles of pharmacodynamics and pharmacokinetics are reviewed emphasizing their importance for developing effective dosing regimens.
Highlights the need for individualization of drug therapy based on intrinsic and extrinsic factors affecting drug response.
A well-tuned approach increases the likelihood of therapeutic success while reducing risks of therapeutic failure.