pharmacodynamic

• Pharmacodynamics


  A study of biochemical, physiologic, & molecular effects of drugs on the body, which involves receptor binding (receptor sensitivity), post receptor effects & chemical interactions
• Drugs


  • Majority of drugs bind to specific receptors
  • On the surface
  • Interior of cells
• Pharmacodynamics


  • Concerned with the mechanism by which drugs produce their effects
  • Dose-response relationship
• Mechanisms of Action


  1. Molecular

  2. Cellular

  3. Tissue

  4. System
• Molecular Level


  • Majority of targets are proteins / molecule
  • Most common target = receptor
  • Others = ion channels, enzymes
• Example: rifampicin (anti-TB)


  • At molecular level, rifampicin binds to a type of enzyme, called RNA polymerase, in the bacteria responsible for TB. This binding blocks the enzyme's activity.
• Drug-receptor complex


  When drug enters the body, it starts interacting with the cell receptors, which leads to a formation of signal transduction

  
• Nature of Receptors


  • Receptors are trans-membrane proteins that have a binding site on the external surface and an effector site on the internal surface
  • Specific binding sites, receives substrate, provides molecular communication between the drug & signaling (transduction)
  • Types: neurotransmitter, hormone

  
• Neurotransmitter Receptors


  • Allow the binding of neurotransmitter to suitable site

  
• Hormone Receptor


  • Interact with hormones to produce effects
• Drug-Receptors Interactions

  • Most drugs bind to their receptor site by forming weak bonds (H-bond, Van der Waals)
  • Binding is usually specific to a certain molecules only (drug, neurotransmitter, hormone)
  • In few cases, drugs can form covalent bonds (strong bonds)
  • Affinity: tendency of a drug to combine with its receptor
  • The number of receptors (R) occupied by a drug depends on drug concentration and drug-receptor association & dissociation rate constants (k1, k2)
• Association & Dissociation Rate Constants

  • Kd represents the [drug] required to occupy 50% of the receptors
  • High Kd = lower affinity
  • Low Kd = greater affinity
• Cellular Level


  • Biochemical & other components of cells participate in the process of transduction (signal delivery)
  • Potential biochemical: enzymes, ion channels, G-proteins
• Example: rifampicin (anti-TB)


  • At cellular level, rifampicin inhibits RNA synthesis & kills the bacteria responsible for TB.
• Signal Transduction


  • The process by which receptor binding initiates a sequence of biochemical events leading to physiologic effect
  • Receptors are often attached (coupled) to a G-protein, an ion channel or an enzyme

  
• 1. Proteins


  • G-protein have 3 subunits: Alpha (α), Beta (β), Gamma (γ)
  • Special functions: α-subunits hydrolyse GTP, αs-subunits increase cAMP production, αi-subunits decrease cAMP production
  • G-protein: activates phospholipase C, leading to formation of IP3 & DAG

  
• Hormone Receptors


  Interact with hormones to produce effects
• Second Messengers


  • Most common: cAMP, IP3 & DAG
  • Together with other second messengers, they can activate or inhibit unique cellular enzymes in each target cell
  • cAMP activates enzymes that regulate muscle contraction, ion channel activities, enzyme activities
  • IP3 & DAG stimulate the release of Ca from intracellular storage sites, which will augment muscle contraction, glandular secretion
• Tissue Level


  • The function of any tissue in the body such as the heart, skin, lungs etc. is altered
  • Types of function: contraction, secretion, metabolic activity, proliferation
• Example: rifampicin (anti-TB)


  • At tissue level, rifampicin prevents damage to lung tissue which would otherwise, caused by the bacteria.

  
• System Level


  • The function system is altered
  • System: cardiovascular, nervous, respiratory, GIT, etc.
• Example: rifampicin (anti-TB)


  • At system level, rifampicin prevents loss of lung function, which can affect respiratory system that caused by TB

  
• Intrinsic activity


  The ability of a drug to initiate a cellular effect
• Types of drugs


  • Agonist
  • Antagonist

  
• Agonist

  Have both receptor affinity and intrinsic activity

  
• Antagonist


  Have receptor affinity but lack intrinsic activity

  
• Drug responses


  • Agonists/activators (drugs that activate their molecular target)
  • Antagonists/blockers/inhibitors (drugs that prevent the action of agonists or deactivate a molecular target)

  
• Potency


  The amount of drug necessary to produce a biological response of a certain magnitude
• Efficacy


  The ability of the drug to produce a response by the activation of the receptor
• A higher potency does not necessarily mean a higher efficacy
• The importance of potency and efficacy depends on the objective of the treatment
• Agonist potency


  Depends on affinity (tendency to bind to receptors) and efficacy (ability to initiate changes once bound)

  
• Full agonist


  • Has high efficacy and can produce maximal effects
• Partial agonist


  • Has intermediate efficacy and produces only submaximal effects
• Antagonist


  Have zero efficacy
• Mechanisms of drug antagonism

  • Competitive antagonism
  • Non-competitive antagonism
  • Chemical antagonism
  • Pharmacokinetic antagonism
  • Physiological antagonism
• Competitive antagonist


  Receptor binding is reversible, effects can be compensated by increasing dose of agonist

  
• Non-competitive antagonist


  Maximal effect of agonist will be reduced

  
• Receptor regulation


  Receptors may undergo dynamic change in terms of their density (number per cell)
• Up-regulation


  Repeated/continuous exposure to antagonists can increase receptor density