Pharmacodynamics: Drug Effects and Mechanisms

• The following notes are for Basic Pharmacodynamic Concepts

Basic Pharmacodynamic Concepts

• Pharmacodynamics describes what a drug does to the body
• Pharmacodynamics studies a drug's effects in the body.
• This is the relationship between drug concentration at the action site and the effect.
• It determines the relationship between a drug's plasma concentration and effect intensity.
• Concentrations vs effect is usually a sigmoidal relationship
• If the response is delayed it may be down to biochemical processes

Onset and Duration of Drug Effect

• Correct dosing intervals help prevent plasma levels from dropping too low or rising too high.

Efficacy and Potency

• Efficacy is the maximum response a drug can produce.
• Potency is the concentration (EC50) or dose (ED50) needed to produce 50% of the drug's maximum effect.

Relative Potencies of Morphine and Codeine

• The potency ratio of Morphine and Codeine is 13

Agonists and Antagonists

• An agonist activates a receptor to produce a response.

• An antagonist has receptor affinity but no efficacy, and can prevent agonists from activating receptors.

  • Antagonists block receptors by binding, not activating them

• Competitive antagonists reduce the potency of an agonist

  • Effects can be overcome by increasing the concentration of the agonist.

• Non-competitive antagonists reduce an agonist's efficacy and usually do not affect potency.

  • The effects of a non-competitive antagonist cannot be completely overcome by increasing the concentrations of the agonist

Why individuals vary in their response to a drug

• Physiologic factors
  • Differences in the number or function of receptors
  • Changes in the effector mechanism coupled to the receptor.
• Pharmacologic factors
  • Variations in the concentration of drug that reaches the receptor at the site of action.
  • Variations in the concentration of competing substances

Polymorphisms in pharmacodynamics

• Variations in DNA result in Polymorphisms in pharmacodynamics

PD Drug Interactions

• Warfarin drug interactions:
  • Warfarin is a CYP 2C9 substrate.
    • CYP 2C9 inhibitors and inducers influence warfarin exposure, requiring dosage adjustments.
  • Aspirin, salicylates (including topical), and NSAIDs increase bleeding risk in patients taking warfarin.
    • The mechanism is unclear, but both warfarin and aspirin/NSAIDs are highly protein-bound.
      • Albumin binding competition makes more warfarin available to tissues; however the result is most likely a PD interaction.
    • Nonselective NSAIDs increase bleeding risk due to an antiplatelet effect without increasing INR, while COX-2 inhibitors increase INR
    • Clinical monitoring and dose adjustments are required when these drugs are combined

Age

• Paediatric (0 – 12 y):
  • Pharmacodynamics are not well understood, but maturational changes occur.
• Elderly (> 65 y):
  • Impaired homeostatic mechanisms reduce protection against orthostatic hypotension.
  • This may increase the drug sensitivity

PK – PD - Dose Selection

• Extrinsic factors such as other medications can effect PK
• Intrinsic Factors such as age, disease, and genetic variations can effect PD