M&R Session 8 Flashcards
What equation is used to calculate molarity?
Grams per litre/molecular weight
Which drugs do not bind to proteins?
Anti microbial
Anti tumour
Why must drug concentrations be considered in molarity?
Using equal weights of substances w/ different molecular weights leads to different concentrations of molecules
What is the critical determinant of drug action?
The molarity of drug molecules around receptors
What law does drug binding obey?
Mass action
What forms the dynamic equilibrium between ligand, receptors and the complex they form upon binding?
Association and dissociation
What is related to the binding of drug molecules to receptors?
[reactants]
[products]
Le Chatelier’s principle
What two characteristics do agonists have?
Affinity
Intrinsic efficacy
What governs receptor activation to give intracellular effects?
Intrinsic efficacy
What is intrinsic efficacy?
The ability to turn a receptor on by forming an activated receptor
What is efficacy?
Ability to cause coupling leading to cellular action
Ability to generate a biological response
What determines efficacy?
Cell/tissue-dependent factors
Why can an antagonist not cause a response?
It only has affinity so cannot convert the receptor to an active form - no conformational change
How do antagonists prevent receptors being turned on?
Prevent agonist binding
What two methods are used to measure drug-receptor interactions?
Binding w/radioligand
Relation b/w [drug] and response
Describe the process of radioligand binding.
Bind radioligand to cells/prepared membranes –> separate bound and free radioligand –> low [ligand] = low binding,
What is B(max)?
The concentration at which all receptors are full
What is Kd?
The dissociation constant = 50% occupancy
Measure of affinity
Is Kd affected by receptor number?
Nope
What does a low Kd indicate?
High affinity
What is K(A)?
Index of affinity determined by functional assay
What is the definition of a logarithm?
The exponent by which a fixed (base) value has to be raised to give a particular number
How is [drug] usually expressed?
On a logarithmic scale giving a sigmoidal curve
Can Kd be used for agonists and antagonists?
Yes, it can be used for any type of ligand
What does receptor response require?
Efficacy
What type of ligand must be used to measure drug-receptor interactions by relation b/w [drug] and response?
An agonist
What is E(max)?
Effect maximum; a tissue can only secrete/contract so much
What is EC50?
Effective concentration giving 50% of the maximal response
Define concentration in relation to drug action.
Known [drug] at site of action e.g. in cells and tissues
Define dose.
Concentration at an unknown site of action e.g. dose to a patient (mg or mg/kg)
What is potency?
How good a drug is at generating a biological response
What does potency depend on?
Affinity
Intrinsic efficacy
Efficacy
What is the key determinant of efficacy?
The number of receptors present
What factors must be considered in drug action?
Affinity Efficacy Selectivity Pharmacokinetics Physiochemical properties
What is the therapeutic target used in asthma treatment?
Beta 2-adrenoreceptors
Why do agonists for asthma treatment need to have specificity rather than just their usual high selectivity?
So they do not act on beta 1-adrenoreceptors in the heart
What is functional antagonism?
Where the antagonist of the action not the receptor
How is Salbutamol utility increased?
Beta 2-selective efficacy
Route of administration
Describe the action of Salbutamol.
Binds slightly preferentially to beta 2 and is particularly good at turning beta 2 on
Describe the action of Salmeterol.
Long acting
Selectivity based on affinity as it has no selective efficacy
What problems are associated with Salbutamol and Salmeterol respectively?
Salbutamol: can act on beta 1-adrenoreceptors in heart –> increases HR –> angina (common in elderly w/asthma)
Salmeterol: insoluble so cannot be given IV when nebuliser no longer an option
When are spare receptors often seen?
When receptors are catalytically active
Give two examples of receptor types you would expect to see spare receptors with.
Tyrosine kinase
GPCRs
Why do spare receptors exist?
B/c of amplification and response limited by post-receptor event
In asthma what percentage of M3 muscarinic receptors are activated to give maximal contraction?
10%
Describe the relationship b/w drug concentration and its Kd if there are no spare receptors.
For full receptor response requires»_space; Kd of drug
What effect do spare receptors have on sensititvity?
Increase
Describe the response when there are spare receptors present.
Occurs at lower [agonist]
Occurs at Kd
Decreased [drug] for full response
What does changing receptor number do?
Changes agonist potency
Can affect the maximal response
Describe the relationship b/w [drug], its effects and receptor number.
Same [drug] has different effects depending on receptor number
What happens if receptor number is low?
There is 100% occupancy but insufficient receptors for a full response
What can cause up-regulation of receptors w/low activity and down-regulation w/high activity?
Physiological, pathological or drug-induced changes
What is tachyphylaxis?
Desensitised receptors
How can partial agonists not elicit maximal response with full receptor occupancy?
Insufficient efficacy creates a different activated receptor so it is turned on but not fully
What tends to happen with the binding curve and function curve for a partial agonist?
Overlap so EC50 ~ Kd
What type of receptors do opioids primarily bind to?
Mu-opioid
Why is buprenorphine sometimes used clinically instead of morphine?
It has a higher affinity but lower efficacy so can give sufficient pain control with a lower risk of breathing depression
What type of agonist is heroin?
Full
Which mixed agonist/antagonist is used to aid heroin withdrawal?
Buprenorphine
What can cause a partial agonist to act as a full agonist?
Increased receptor number (low efficacy but enough receptors –> full response)
What indicates intrinsic activity?
Maximal response
Can full agonists w/identical intrinsic activities have different efficacies?
Yes
What can be said about the response of two full agonists with equal intrinsic activity?
They have the same maximum response
In which direction does the response curve of a drug move with increasing potency?
Left
What does reversible competitive antagonism rely on?
A dynamic equilibrium b/w ligands and receptors
What is K50?
The concentration of antagonist which gives 50% inhibition
Index of antagonist potency determined by [agonist]
What is the difference between Kd and KB?
Kd = antagonist affinity derived from radioligand KB = antagonist affinity derived pharmacologically
How do reversible competitive antagonists affect agonist concentration-response curves?
Cause parallel shift to right
Which drug can be used clinically to reverse opioid-mediated respiratory depression?
Naloxone
When does irreversible competitive antagonism occur?
When the antagonist dissociates slowly or not at all
How does irreversible competitive antagonism affect the agonist concentration-response curve?
Parallel shift to right and suppresses maximal response
How does irreversible competitive antagonism suppress maximal response?
Spare receptors are filled by antagonist therefore there are insufficient receptors for a full response
How does phenoxybenzamine work?
Non-selective alpha 1 adrenoreceptor blocker that binds covalently so no matter how much adrenaline/NA present vasoconstriction is not caused
What mechanism of action does Clopidogrel use to prevent thrombosis?
Irreversible P2Y12 antagonist which prevents cytochrome P450 metabolism
What is non-competitive antagonism?
Endogenous ligand binds to orthosteric site on extracellular part of GPCR
What are allosteric sites?
Binding sites for agonists and molecules that enhance or reduce ability of endogenous ligand to turn receptor on
What type of antagonism does non-competitive antagonism resemble when comparing [agonist]-response curve?
Irreversible competitive antagonism
Describe an NMDA (excitatory glutamate) receptor.
Inotropic receptor
Ligand gated ion channel
Distinct glutamate and ketamine binding sites
What effects can binding at an NDMA produce?
Analgesia
Decreased central excitation
Describe the allosteric sites of GPCRs.
High specificity
High receptor subtype selectivity
Are GPCRs competitive?
No
What do GPCRs often require to function?
Orthosteric ligand
