L17&18: Pharmacodynamics: Receptor Theory Flashcards
What is pharmacodynamics?
Action of the drug on the body
Influence of drug concentration on magnitude of response
What is the difference between endogenous and exogenous ligands?
Endogenous–> from within the body
Exogenous–> from outside the body
What are the different targets for drugs?
RITE
- Receptor (KING)- (kinase linked receptor, ion channel (ligand gated), nuclear/intracellular, GPCR)
- Ion channel
- Transporter
- Enzyme
What is an orphan receptor?
Protein–> similar structure to other receptors
Potential drug targets
What does Molarity mean?
1 mole of substance contains 6 x 10^23 particles
1 molar solution contains 1 mole of substance, in 1 Litre of solvent
Why is concentration important?
Determine the number of drug molecules around the receptor at the site of action
What equations are useful for comparing drugs and concentrations?
Moles= mass/ Mr (molecular weight)
Molarity or Concentration= moles/ volume
What is significant about drug-receptor interactions?
Reversible (usually)
Association-dissociation rate important
–> more reactant reaction goes forward
–> more products reaction goes backwards
What are the two main classification of drugs on receptors?
Agonist–> compete for the receptor site, activate the receptor
Antagonist–> block the binding of endogenous agonists, bind elsewhere to the receptor
What determines whether a agonist binds to the receptor?
Affinity
Receptor must have affinity to bind ligand
What has to happen for a response to occur at a receptor?
Affinity–> ligand must bind
Intrinsic efficacy–> must be able to produce a conformational change to activate receptor
Coupled with other changes in a cell to produce a measurable response
Define intrinsic efficacy?
The ability of a agonist to produce a conformational change activating the receptor
Results in a fully or partially activated receptor state
Define efficacy?
The intrinsic efficacy and other things that influence the response (things within the cell/tissue)
Causes a measurable response
What is the difference between agonists and antagonists?
Agonists have affinity, intrinsic efficacy and efficacy
Antagonists have affinity but no intrinsic efficacy or efficacy
What is the difference between pharmacological efficacy and clinical efficacy?
Pharmacological–> what happens within the body e.g. blood vessels dilate
Clinical–> indication of how well a treatment succeeds in achieving its aim, what changes can be seen e.g. lower blood pressure
How can the binding of a ligand be measured?
Radioligands–> radioactively labelled ligands
Measure the radioactive levels in a cell or tissue
More binding = larger radioactive signal
How is ligand binding quantified?
Plot bound vs ligand concentration graph
Usually use logarithmic graphs
What is the Bmax?
The maximum binding capacity
Information on receptor number
What is the Kd?
The dissociation constant
Concentration when 50% of available receptors in a define tissue or cell expressing the target protein are occupied
What does the Kd tell you?
Affinity of ligand
Low concentration= high affinity
High concentration= low affinity
Why is it important to know the affinity of a ligand?
Given two drugs can determine which will bind better to a receptor–> out compete a drug
Useful in drug overdose
How is response to a drug measured?
Concentration response curves
Response require efficacy
Usually plotted on logarithmic scale
What is the Emax?
The concentration of drug required to produce 100% response
What is the EC50?
Effective concentration that results in 50% of the maximal response
What is the EC50 a measure of?
The potency of a drug It includes all the sequential stages leading up to a therapeutic response including the- - affinity - intrinsic efficacy - cell/tissue dependent effects
What is the difference between concentration and dose?
Used interchangable HOWEVER
- concentration–> used in vitro when precise concentration of drug around receptor can be manipulation
- dose–> used when measuring response in whole animal/human when precise concentration around a receptor is unknown
What is important about the potency of a drug?
Variable –> cell/tissue dependent factor affect overall efficacy
Affinity and intrinsic efficacy are fixed
What can affect the potency of a drug?
Receptor number
cell/tissue dependent factors
How does the receptor number affect the potency?
No receptors–> no binding–> no response
More receptors–> more binding–> bigger response
Why do you get spare receptors?
Other cell/tissue factors affect the response to ligands
e.g. muscle can only contract so much, gland can only secrete so quickly
Eventually an increase in the number of receptors doesn’t affect the response level
What is the point of spare receptors?
Increases the sensitivity
Allows the maximal response at a lower concentration of drug
How do you get a full response if you have spare receptors?
Exists because of amplification in the signal transduction pathway e.g. GPCR and tyrosine kinase
Cascade of events after receptor binding
Is receptor number fixed?
NO
Varies with cell type
Low activity–> up regulation of receptors
High activity–> down regulation of receptors (linked to negative feedback–> leads to tolerance to drugs and withdrawal symptoms)
What is the difference between full and partial agonists?
Partial agonists are unable to produce a maximal response even with full receptor occupancy
They have a decreased intrinsic efficacy (relationship between the Kd (binding affinity) and EC50 (response))
Unable to produce a fully activated receptor so gave lower intrinsic efficacy
Give an emaple of how partial agonist can be used clinically?
Treatment of opioid addiction (heroin) Herion is a full agonist Buprenophine is a partial agonist Both work on the opioid receptor Buprenophine has a higher affinity and inhibit the effect of heroin--> doesn't produce a full response because it is a partial agonist
What are the effects of buprenophine in heroin addiction?
Buprenophine doesn’t produce a full response only partial so patient becomes ill–> withdrawal symptoms
What is withdrawal or abstinence syndrome?
Sustained drug taking leads to tolerance–> reduced receptor number
When drug is withdrawn the endogenous ligands are less effective and can’t produce same full response
How do antagonists work?
Block the affect of agonists
Prevent receptor activation
What are the three main methods of action of antagonists?
1- Reversible competitive antagonism
2- Irreversible competitive antagonism
3- Non-competitive antagonism
How do reversible competitive antagonists work?
Dynamic equilibrium between the agonist and antagonist
Both associate and dissociate continuously
In competition with each other
Increase conc of the antagonist will inhibit the effect of the agonist as more antagonist will bind e.g.
How do irreversible competitive antagonists work?
Dissociate from the binding site slowly or not at all
e.g. covalent bond formed- effectively non-surmountable once bound
However agonist and antagonists compete for the free binding sites
How do non-competitive antagonist work?
Antagonist doesn’t bind to the orthosteric site (natural binding site for ligand)
Non competition for binding site
What is the Ki?
The Kd but for an antagonist
Binding affinity of an antagonist
What is the IC50?
The concentration of antagonist that will produce a 50% reduction from the Emax
What is the effect of adding a reversible competitive antagonist to a concentration response curve?
(Note: Effects of antagonists cannot be measured without agonist present)
Shift in the agonist response curve to the right
Higher concentration of agonist will be required to produce a response
Emax can still be achieved
What is the effect of irreversible and non-competitive antagonists?
Both cause a right shift
Depression in Emax
Irreversible binding so agonist unable to occupy sufficient binding sites to cause a full response
What are some clinical examples of where antagonists are used?
NSAIDs such as Iburprofen–> competitive antagonist of enzymes that synthesis prostaglandins
Hypertension treatment–> ACE inhibitors prevent ACE converting angiotensin I to angiotensin II
Hypertension treatment–> block VOCC in arteriolar smooth muscles –> limit opening of channels after depolarisation resulting in vasodilation
How is herion overdose treated?
Naloxone–> high affinity competitive antagonist at the opioid receptors
Competes with agonist (herion)
Reverses respiratory depression
Also used after surgery where fentanyl (powerful pain relief) is used
