Medwiki

L02 Clinical Pharmacology Pharmacodynamics introduction

Pharmacodynamics introduction

Objectives:

  1. 4 main types of of proteins targeted by drugs
  2. how drugs interact with enzymes, transporters and ion channels to change their activity
  3. why do drugs need selectivity for the target
  4. how is drug binding to a receptor described
  5. how is the relationship between drug concentration and response described
  6. what is the difference between and agonist and an antagonist
  7. how can you differenctiate between a competitive reversible and irreversible antagonist

Content:

4 main types of of proteins targeted by drugs

Receptors are the most common drug target

  1. Receptors
    1. ligand gated ion channels
    2. g protein coupled receptors
    3. kinase linked receptors
    4. nuclear receptors
  2. Enzymes
  3. Transporters
  4. Ion channels
How can drugs interact with enzymes, transporters or ion channels to change their activity?

Drug binding and target activation are 2 different processes

Concentration response curves

Affinity

Drug which highly bind at low concentrations have high affinity basically how much the drug likes to bind to targets

Potency

A measure of drug activity expressed as the amount of drug required to give a certain effect

A common one is the EC50 or the dose required to hit 50% of maximal response. The more potent the drug the lower the EC50

Efficacy

This is the ability of the drug to cause a change in the activity of a target once bound. it is also from this measure we define: (Note the level of activity of these are also dictated by affinity) (also all of these bar allo bind to orthosteric binding site (site for endogenous ligand)

  • agonists (positive efficacy)
    • Partial - Does not produce the full effect even when it has full receptor occupancy
    • Full (or very high) - Produced full or extremely high tissue response
  • inverse agonists (negative efficacy)
  • Antagonist (bind to receptor and cause nothing except blocking site)
    • Reversible (can unbind from active site)
      • effect on response concentration chart a rightward shift
      • means that with enough dilution full tissue response can be achieved
    • Irreversible (does not unbind from active site)
      • downward shift. basically the same as reducing number of receptors
  • allosteric modulators (does not bind to active site, but rather allosteric binding sites)
    • receptor proteins may have multiple allosteric binding sites
    • binding to allosteric sites may
      • increase or decrease affinity or efficacy of orthosteric ligand

non receptor mechanisms of drug antagonism

Chemical antagonism infliximab neutralisation of TNF Pharmacokinetic antagonism reduce the concentration of the drug at the active site interrupt receptor response block receptor downstream eg blocks cAMP from activating calcium influx as to stop upstream processes from working physiological receptor response canceling other drugs out. histamine and adrenaline

Specificity at drug targets

we generally want our drugs to be pretty specific for targets. no drug is completely specific

less potency a drug has the more needs to be given and the more side effect it will have

not all adverse effects are off target though. opioids cause respriatory depression and constipation as the lungs and gut have mu opioid receptors which are on target.

drugs tend to have nanomolar EC50s

Desensitisation, tolerance, resistance

Drug effect can diminish following continuous or repeated administration:

  • Desensitisation – drug effect reduces in a few minutes
  • Tolerance – drug effect reduces over hours to days
  • Resistance – loss of sensitivity to cytotoxic/antimicrobial drugs
  • Mechanism:
    • Receptor phosphorylation
    • Receptor internalisation
    • Intracellular feedback loops
    • Drug metabolism
    • Physiological adaptation

Summary

Graph View