pharmacodynamics

• Pharmacodynamics


  The study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect
• Drug-receptor interactions


  • Modeled by L=ligand (drug), R=receptor (attachment site), reaction dynamics that can be studied mathematically through tools such as free energy maps
• Pharmacodynamics vs Pharmacokinetics


  Pharmacodynamics is the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug
• Effects of drugs on the body

  • Mimic or inhibit normal physiological/biochemical processes or inhibit pathological processes in animals
  • Inhibit vital processes of endo- or ectoparasites and microbial organisms
• Main drug actions


  • Stimulating action through direct receptor agonism and downstream effects
  • Depressing action through direct receptor agonism and downstream effects (ex.: inverse agonist)
  • Blocking/antagonizing action (as with silent antagonists), the drug binds the receptor but does not activate it
  • Stabilizing action, the drug seems to act neither as a stimulant or as a depressant (ex.: some drugs possess receptor activity that allows to stabilize general receptor activation, like buprenorphine in opioid dependent individuals or aripiprazole in schizophrenia, all depending on the dose and the recipient)
  • Exchanging/replacing substances or accumulating them to form a reserve (ex.: glycogen storage)
  • Direct beneficial chemical reaction as in free radical scavenging
  • Direct harmful chemical reaction which might result in damage or destruction of the cells, through induced toxic or lethal damage (cytotoxicity or irritation)
• Types of drug receptors

  • Cell surface or intracellular regulatory proteins – mediate the effects of endogenous chemical signals such as neurotransmitters and hormones. e.g. adrenoreceptors, steroid receptors, acetylcholine receptors
  • Enzymes – cell surface, membrane-spanning or intracellular proteins inhibited (or less commonly activated) by the binding of a drug. e.g. Na+K+ATPase is the cell surface receptor for cardiac glycosides such as digitalis
  • Structural proteins – extra- or intracellular proteins inhibited (or less commonly activated) by the binding of a drug. e.g.tubulin is the receptor for colchicine - an anti-inflammatory agent
• Relation between Drug concentration and response

  Effect max is the maximum response of the system to the drug. EC50 is that concentration of drug that produces a response one-half of the maximum response
• Receptor-ligand binding


  1. The Law of Mass Action tells us that the equilibrium constant for R.L formation is given by [R.L]/([R][L]) = kon/koff

  2. The fraction of total receptor that exists as R.L is: [R.L]/([R]+[R.L]) = [L]/(KD+[L])

  3. Available receptors are 50% occupied by drug when [drug] = koff/kon
• Agonist


  A chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance
• Types of agonists


  • Full agonists - bind and activate a receptor, displaying full efficacy
  • Partial agonists - bind and activate a receptor, but have only partial efficacy relative to a full agonist
  • Inverse agonists - bind to the same receptor binding-site as an agonist and reverse constitutive activity of receptors
• Antagonist


  A type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses
• Types of antagonists


  • Competitive - reversibly bind to receptors at the same binding site as the agonist, but without activating the receptor
  • Non-competitive - reduce the magnitude of the maximum response that can be attained by any amount of agonist
  • Uncompetitive - require receptor activation by an agonist before they can bind to a separate allosteric binding site
  • Partial agonists - can act as a competitive antagonist in the presence of a full agonist
  • Inverse agonists - bind to the same receptor binding-site as an agonist and reverse constitutive activity of receptors
• Efficacy


  The maximum effect (Effect max) of a drug
• Potency


  A comparative measure, refers to the different doses of two drugs needed to produce the same effect
• General classes of antagonists

  • Chemical antagonists - one drug binds to and inactivates another drug
  • Physiological antagonists - drugs that take advantage of physiologic antagonism between endogenous regulatory pathways
  • Pharmacological antagonists - drugs that bind to receptors but do not act like agonists and, therefore, do not alter receptor function