pharmacology principles + receptors

• what does pharmacodynamics mean?

  what the drug does to the body
• how does a drug influence an intracellular process?

  unoccupied receptor -> drug binds -> receptor activates -> signal transduction = biological response
• how does a drug produce an effect?

  • the drug interacts with its target
  • target forms tight bonds with the drug
  • the target-drug complex produces a response
• the nature of a response depends on what?

  the type of target - ion channels, enzymes, receptors etc

  and what the target is linked to
• what do we need to have for anything to occur (a response)

  affinity and efficacy
• what is affinity?

  degree of attraction - the capacity to bind
• what is efficacy of a drug?

  degree of response - what does it actually do to the target once bound
• what can determine the affinity/efficacy of a drug and how tightly it binds to its receptor?

  functional groups that the drug is made up of
• what properties can functional groups of drugs determine?

  • how it interacts with the target
  • mechanism of action
  • route of administration
  • route of metabolism
  • ability to cause side effects
  • 3D shape
  • specificity
• what is target interaction dependant on?

  on functional groups and charge distribution - different environments can effect the ionisation and how strong the bond is
• what type of bonding is avoided in drugs?

  covalent
• Target interactions due to ions:

  • eg–COO- ; -NH3+
  • Related to drugs being weak acids or bases
  • pH and pKa are important as they influences the degree of ionisation
  • Will form strongest bonds between drug and target
• target interaction due to dipoles:

  • e.g. -OH
  • uneven distribution of electrons between atoms in a molecule
• type of target interactions:

  A) Van der Waals

  B) hydrogen

  C) ionised

  
• what can happen if there's a change in the functional group of a drug?

  changes the specificity of the ligand
• what are the terms for drugs when talking about binding to receptors? (the behaviour of the ligand at the target)

  Agonist and antagonist.
• what are the terms for drugs when talking about binding to enzymes? (the behaviour of the ligand at the target)

  activator and inhibitor
• what are the terms for drugs when talking about binding to a transporter? (the behaviour of the ligand at the target)

  activator and inhibitors
• what are the terms for drugs when talking about binding to ion channels? (the behaviour of the ligand at the target)

  openers and blockers
• what is the importance of understanding drug-receptor interactions and behaviours?

  • These are fundamental principles which help us understand how a drug works, what effects it will have, how side effects occur and what potential interactions there may be.
  • These principles therefore need to be understood by pharmacists prescribing, dispensing or advising drugs & medications.
• what are the terms that are used in relation to the target: receptors?

  • orthosteric binding
  • allosteric binding
  • affinity
  • intrinsic efficacy
  • rate of dissociation
• what are orthosteric binding and allosteric binding?

  O - binding to the main active binding site

  A - binding to the alternative binding site
• what does intrinsic efficacy mean?

  capacity to excite
• what does the rate of dissociation mean?

  how quickly the drug comes off the receptor (how long is the duration of action)
• what are the different keys that unlock or block a biological effect?

  • agonist
  • antagonist
  • allosteric modulators
• what are agonists?

  They activate - enhance a physiological response

  • they have affinity and efficacy - it’s attracted to the receptor + has the efficacy to produce a conformational change
  • all types of agonists bind too the same active site
• what are the types of agonists?

  • full agonist - full response
  • partial agonist - response but never a full response
  • biased agonist - activates a subset of a receptor’s signalling cascade - depends on the cell
  • inverse agonist - produces the opposite effect of natural ligand - decreases activity and so will have an effect
• where do competitive and non-competitive antagonists bind?

  C - binds to the same site as agonist

  N - binds to different site from agonist
• what do allosteric modulators do?

  They bind to a different site on receptors to alter the affinity and/or efficacy of the drug binding to the main site.
• What can allosteric modulators be?

  • positive (PAM)
  • negative (NAM) - reduces the agonist response
  • neutral (SAM) - prevents a PAM or NAM from binding
• occupation of a target site is governed by affinity
• activation of the target site is governed by efficacy
• greater the affinity, the greater the association and the smaller the dissocciation
• why does the binding of an antagonist not produce a response?

  antagonists have no efficacy
• describe the conformational states of receptors...

  • at equilibrium - receptor is in rest state
  • when a ligand binds, the receptor concerts to active state and when it dissociates it goes back to rest state
• what does a constitutively active receptor mean?

  • these receptors can go between the active state and the rest state without the need for a ligand and so independent
  • can produce a biological effect without a ligand
• what does a dose-response (concentration-response) graph tell us?

  • the effects of increasing dose/concentration of drug to see what it does to the size of the response
  • The properties of drugs can also be determined
• With agonists - the greater the concentration of drug = the greater the response

  There's a maximal response - so a full agonist maximal response is 100%

  
• what is potency and how is it usually quantified?

  A measure of how much drug is needed to produce a certain size of effect.

  Quantified by the concentration required to produce 50% of the maximal response (EC50)
• what does the EC50 value allow?

  comparisons between drugs at the same receptor