Pharmodynamics : Receptor Theory Flashcards
How to calculate g/L of acetylcholine that has a molecular weight of 146 in 1M solution ?
MWt x Molarity = g/L
146 x 1 = 146g/L
- molecular weight means molecular weight in GRAMS.
How does binding of a ligand obey the law of mass action ?
L + R = RLIgand receptor complex
- reversible reaction
- as you add more ligand or more receptor the eq would shift to the right and more ligand -receptor complexes would be made.
Define affinity
Measure of strength of interaction between a ligand and a receptor
How does an agonist work ?
- an agonist binds to a receptor.
- binding of the agonist depends on AFFINITY
- an agonist-receptor complex is made
- receptor activation is governed by intrinsic efficacy which results in the receptor being activated conformation.
- to generate a biological response EFFICACY is required
Explain how an antagonist works ?
- antagonist binds to receptor
- this requires AFFINITY
- an antagonist blocks the binding of the agonist which prevents the receptor being activated.
- they have NO intrinsic efficacy which explains why there is no response
How can we measure binding of a ligand to a receptor experimentally ?
- often by binding of a radioactively labelled ligand to cells or membranes
- incubate radioligand and receptors
- we separate the ligands that are bound and free and then measure the ligands that are bound.
What is kd?
The concentration of drug at which 50% of receptors are occupied.
- gives a measure of affinity
The lower the kd the ….. greater/lower the affinity ?
Greater the affinity because the lower the kd the less concentration required to occupy all 50% of receptor sites
How can we treat heroin or morphine overdose ?
Naloxone is used to treat overdose
- it has a very high affinity ( thus lower kd) than heroin
- high affinity antagonist of u-opioid receptors
- and eventually outcompetes heroin in the body
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What is fentanyl and why is it very difficult to treat overdose in it ?
- fentanyl is an opioid that causes euphoria
- it has an agonist which has an extremely high affinity towards opioid receptors
- often medications like naloxone cannot outcompete fentanyl.
Log10 of number =
Power by which 10 has to be raised to get that number
Eg log10 ( 1000) = 3 because 10^3 = 1000
What does a response require in order to happen ?
EFFICACY
Define EC50
Effective concentration giving 50% maximal response
What is intrinsic efficacy ?
Ability to activate receptor
Define potency
Effective concentration that gives 50% of the maximal response
What does potency depend on ?
- BOTH AFFINITY
- intrinsic efficacy
- PLUS cell/tissue components eg number of receptors
Define concentration and dose
Concentration - known concentration of drug at site of action
- dose : concentration at site of action generally unknown eg dose to a patient in mg or mg/kg
Why when treating asthma we need a highly selective drug ?
-drugs that act as agonists tend to target b2-adrenoreceptors in the airways , however because b-adrenoreceptors are elsewhere in the body eg b1-adrneoreceptors are found in the heart , non-selective drugs may increase force and rate of contraction!
How does Salbutamol achieve selective specificity ?
Kd for b2- 1micromoles
Kd for b1- 20micromoles
- this shows that there is only a 20 fold difference between the affinity towards beta1 and beta2 adrenoreceptors. Which suggests that selectivity is not that great. HOWEVER…
- when salbutamol binds to beta2- adrenoreceptors, the receptors are activated very well compared to beta1-adrenoreceptors which suggests that salbutamol is enhanced by b2-selective efficacy.
How does salmeterol achieve selective specificities
- long acting drug
- kd b1- 1900nm
- kd b2- 0.5nm
= there is a 3455 fold difference in affinity which suggests that salmeterol selectivity is based on affinity , not selective efficacy
What are the problems with salbutamol in people who have cardiovascular disease ?
the b1-adrenoreceptors are also activated resulting in heart rate increasing.
- this could lead to problems such as angina
- hypertension
Give an example of one cell/tissue dependant factors that influence agonist potency ?
Number of receptors
How does an increase in the number of receptors increase agonist potency ?
- because we often have spare receptors left over
- for example : if there were no spare receptors ( there were 10,000 receptors in a cell ) , a full response requires 100% occupnacy . This would mean it requires»_space;»> kd concentration of drug. Eg if kd of drug is 1nm it would need 10-100 Nm of drug instead.
- HOWEVER, with spare receptors ( if we have 20,000) . Only 50% occupancy required for full response (10,000). So it requires kd of drug. Eg if kd=1nm, it requires 1nm.
Does changing receptors number affect maximal response ?
Yes it can
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