Session 8 - Drugs and Receptors Flashcards
What is the equation for molarity?
-M=g/L divided by Mwt
What is the main factor in determining drug action?
-The concentration of drug molecules around the receptors (site of action)
Do most drugs bind reversibly or irreversibly to receptors?
-Reversibly
Define Ligand
-A molecule which interacts specfically with a receptor
What two factors dictate drug-receptor interactions?
- Affinity
- Intrinsic Efficacy
What is meant by affinity of a ligand?
-The ability of the ligand to bind to the receptor
What is meant my intrinsic efficacy?
-The ability to convert the bound receptor to its active form
With regards to receptors, what must a ligand do to be an agonist?
- Cause a response
- Have both affinity and intrinsic efficacy
Define drug efficacy
-The ability to generate a biological response, with respect to the receptor itself and tissue/cell dependent factors (eg cellular machinery)
With regards to receptors, what makes antagonists different from agonists?
-Antagonists have affinity but no intrinsic activity. ie they bind the receptor but do not activate it
How do antagonists effect agonist action?
-Antagonists bind to the receptor but do not activate it. This means that they are blocking the receptor so an agonist cannot bind and thus prevent activation
How is drug-receptor binding usually measured?
-Radioligand binding
Define Bmax
-The maximum binding capacity, ie when all receptors are filled (100% occupancy)
Define Kd
-The concentration of ligand required to occupy 50% of the available receptors, ie it is a measure of affinity
What has a higher affinity, a lower or higher Kd?
-The lower the Kd the higher the affinity (the less conc it takes to fill 50% of available receptors)
Define Emax
-The maximum response which can be produced from a cell/tissue
define EC50
-The concentration of drug which gives 50% of the maximum response
What is the difference between concentration and dose?
- Concentration is the known concentration of drug at the site of action
- Dose is when the concentration at the site of action is unknown
What is EC50 a measure of?
-Potency
What factors effect the potency of a drug?
- Affinity
- Intrinsic efficacy
- Efficacy
What 5 factors are important when assessing a drug?
- Affinity
- Efficacy
- Selectivity
- Drug metabolism
- Physiochemical properties
How can drug selectivity produce side-effects?
-Drug binds off-target and produces other unwanted effects in the body
What is meant by specificity/selectivity of a drug?
- Specificity= drug only binds and activates one receptor subtype
- Selectivity= drug prefers to bind and activate to one receptor subtype but can effect others
How is specificity/selectivity achieved with salbutamol in asthma?
- Salbutamol has affinity for both B-adrenoreceptors in the heart (b1) and bronchi (b2) so binds to both
- Has high intrinsic efficacy for b2 receptors in the bronchi, but low intrinisic efficacy for b1 in heart -> this makes it selective as only b2 predominantly activated
Regarding the selectivity for b2-adrenoreceptors of salbutamol, why can high doses cause increased force and heart rate?
-Repeated high use allows enough receptors to be activated to generate a sufficient response
What are ‘spare’ receptors?
-Receptors which are unoccupied in cells where less than 100% receptor occupancy produces maximal response.
Where are spare receptors often seen?
-Catalytically active receptors such as receptor tyrosine kinases or GPCRs
Why is it possible to get maximal response with less than 100% occupancy?
- Amplification within the signal tranduction pathway means activation of one receptor can lead to multiple secondary messenger activation -> small number of receptors activated produces a large response
- Response may be limited by a post-receptor event
Why are ‘spare’ receptors beneficial?
-Increase the sensitivity of cells, allowing responses to be generated at low concentrations of drug (ie less % occupancy has to be reached before a response is generated)
How does changing the receptor number effect agonist potency?
- Increasing the receptor number, increases the potency of the agonist as a smaller %occupancy of the total receptor number has to be reached to generate a full response
- Decreasing the receptor number will decrease the potency of an agonist as a higher % occupancy of the total receptor number has to be reached to generate a full response
How can decreasing the receptor number affect the maximal response?
-If the receptor number is decreased beyond the amount of receptors needed to generate a full response
When do receptor numbers tend to change?
- Increase with low-activity (up-regulation)
- Decrease with high activity (down-regulation)
What is tachyphylaxis?
-Desensitisation/tolerance to the drug
Why does tachyphylaxis occur?
-The drugs administered produce high-activity on the receptors which then down-regulate and thus the cell becomes tolerant/tachyphylactic
What is a partial agonist?
-An agonist which, when all receptors are occupied, does not produce the maximal response
With regards to partial agonists, how is the maximal response related to intrinsic efficacy?
-Even with high affinity, the agonist may not fully activate the receptor/activate it in a different way, and thus the full response is not generated
Why might buprenorphine be advantageous over morphine in some clinical settings
- Using morphine for pain relief there is a risk of respiratory depression, buprenorphine can be used which is a partial agonist of the opioid receptor, so does not generate a full response, however generates an adequate pain relief response with a decreased risk of respiratory depression.
- NB. Buprenorphine is a partial agonist with higher affinity for the receptor but decreased intrinsic efficacy
Why is buprenorphine used in the treatment of heroin addicts?
- Buprenorphine is an opioid so binds to the same opioid receptors as heroin, however buprenorphine is a partial agonist and heroin is a full agonist, so does not deliver the same level of euphoria as efficacy is insufficient
- Buprenorphine binds to the receptors and becomes an antagonist to heroin effects as the drug blocks the receptor site so heroin cannot bind, even if injected.
- This enables the gradual withdrawal from heroin
Why is a partial agonist said to be compound and system dependant?
- If the receptor number is increased, the agonist can change from a partial agonist to a full agonist
- The low intrinsic efficacy at each receptor becomes sufficient enough to produce a full response
Do full agonists with the same intrinsic efficacy have the same efficacy?
-No, the drugs can have the same affinity and intrinsic efficacy but different efficacy as this takes into account how the drug causes a response with regards to the tissue-dependant factors
What are the three types of receptor antagonists?
- Reversible competitive
- Irreversible competitive
- Non-competitive
Describe reversible competitive receptor antagonists
- Relies on the dynamic equilibrium between ligands and receptors
- Increasing the concentration of antagonists will overcome the agonist and increase the inhibition
- The inhibition is surmountable by increasing the agonist
What is IC50?
-The concentration of antagonist needed to reduce the maximal response to 50%
What happens to the agonist concentration-response curve with increasing antagonist?
- The curve shifts to the right as more agonist needed to produce the same response
- The Emax stays the same
What is naxolone, and when is it clinically useful?
- A high affinity competitive antagonist of u-opioid receptors
- Useful to reverse opioid-induced respiratory depression as the high affinity competes effectively with other opioids
Describe irreversible competitive inhibition
- The antagonist dissociates very slowly or non at all so the antagonist cannot be competed off.
- Increasing the antagonist, increases inhibition
- The inhibition is non-surmountable
How do irreversible competitive antagonists effect the agonist concentration-response curve?
- Shift to right with increasing antagonist concentration
- Emax begins to decrease as surpass a point where not enough receptors are available to mount a full response
How are irreversible competitive antagonists used in pheochromocytoma?
- phenoxybenzamine is a non-selective irreversible competitive a1-adrenoreceptor antagonist
- Used in hypertensive episodes of pheochromocytoma
- tumour of adrenal chromaffin cells which produce excess adrenaline and act on a1 adrenoreceptors causing vasoconstriction
- phenoxybenzamine blocks receptors and reduces vasoconstriction
Describe non-competitive antagonism
- Antagonist binds to an allosteric site rather than orthosteric site of receptor
- alters the activity of the receptor (can be increased or decreased through altering efficacy or affinity
How is ketamine a non-competitive antagonist?
- Ketamine binds to allosteric site of NMDA receptors (glutamate receptors found in nerve cells)
- It antagonises the normal effects of the receptor when an agonist binds, and results in analgesia by reducing central excitation
