Quiz #2 (10/7-10/12) Flashcards
Law of mass action
At some point of adding drug into the system we will reach a steady-state in which [DR] is constant. This happens as drugs are binding to and dissociating from receptors at the same rate.
Law of mass action states that the ratio of rate of dissociation/rate of association which is defined as Kd = [D][R]/[DR].
Kd
Kd is the dissociation constant and is a measure of the drug’s affinity. Smaller values of Kd means the drug has higher affinity.
Fractional receptor occupancy
defined as how many receptors are bound to drug at any given [D]. Fractional receptor occupancy = [DR]/[Rt] = [D]/Kd+[D]
From this we note that the fraction of receptors bound is only dependent on the concentration of drug, [D] and the affinity of the drug, Kd.
When [D] = Kd half of the receptors are bound.
drug binding curve
log dose vs. percent of receptors bound.
Drug-receptor interactions strongest to weakest
covalent (irreversible) > ionic > hydrogen > hydrophobic > van der waals
Dose response curves
Theory is that the magnitude of the drug effect is proportional to the amount of DR complexes formed. Maximum effect is achieved when all receptors are occupied.
log dose vs response.
Emax = maximal effect of the drug and is the efficacy of the drug.
EC50 = drug dose that produces 50% of the maximal effect and is a measure of potency.
Potency is the indication of the amount of drug needed to produce a given effect. Smaller EC50 has greater potency
Occupancy model assumptions
- Binding of drug to the receptor is a simple, bimolecular reaction that is freely reversible
- The magnitude of the response is proportional to the concentration of DR complexes formed
- The maximal response occurs when all receptors are occupied.
- In this model the dose-response curve is the same curve as the drug binding curve. Therefore Kd = EC50
Agonists
- Agonist: any drug that binds a receptor and produces an effect. Activator. Example is morphine
- Full agonist: produces the maximal effect. Much higher affinity for Ra than for Ri.
- Partial agonist: cannot produce the maximal effect even when all receptors are bound. It will always have lower efficacy than full agonist. Somewhat higher affinity for Ra than for Ri.
- Inverse agonist: reduces the low level of constitutive/basal activity observed in the absence of the agonist. Much higher affinity for Ri than for Ra. Not considered an antagonist because it will actually lower the response % when given whereas antagonist simply prevents a change in response %.
Receptor conformations: - Ri: inactive form that produces no effect when bound by agonist or when not bound.
- Ra: active form that produces a small effect in absence of bound drug or a bigger effect when bound by drug
reversible competitive antagonist
- Antagonist binding does not activated the receptor.
- Shifts dose-response curve to the right, therefore lowers potency of agonist (increased EC50)
- No change in efficacy.
- Surmountable: effects of competitive antagonist can be overcome by increasing agonist concentration, increasing the potency of the agonist.
- Example is Chantix. It is a partial agonist at nicotinic receptors in the brain and competes with nicotine at the receptor.
Irreversible noncompetitive active site antagonist
- reduces total number of receptors available for agonist binding
- shifts the dose-response curve downward, decreasing efficacy. No change in potency
- Insurmountable: effects of irreversible antagonist cannot be overcome by increasing concentration of agonist
Allosteric Binding
Allosteric binding: reversible or irreversible is always a noncompetitive allosteric antagonist
- Binds to receptor at a different site from the agonist and not at the active site.
- Works to block the responsiveness of the receptor to the agonist by either preventing binding of the agonist to the active site of the receptor or altering the level of receptor activation after agonist binding
GABA and allosteric binding
GABAa receptor that is a chloride channel expressed on neurons that inhibits neuron function when activated.
All the drugs that act on GABA are allosteric. Propofol is a positive modulator because when it binds the channel opens and stays open longer. Midazolam is a positive affinity modulator because you need less GABA to bind to activate it when midazolam is bound.
Chemical antagonists
chemical antagonist: receptor independent
Interacts directly with the drug/agonist by either removing the drug from the system or preventing the drug from binding to its receptor.
Examples include protamine sulfate which stably binds to heparin and reverses anti-coagulant effect. Also, dimercaprol binds to toxic metals which are then excreted in the urine.
Physiological antagonist
Physiological antagonist: act at different receptor than the agonist
Agonist and antagonist bind to two different receptors. And activation of the two receptors produces opposing physiological effects.
Physiological antagonists bind to a receptor and produce an effect different from all other antagonists.
spare receptor in the presence of competitive antagonist
Spare receptors exist when maximal response to a drug can be achieved when less than all the available receptors are bound by drug.
The receptor occupancy vs % maximal effect curve is now no longer 1:1 linear. In the spare receptor example the % maximal effect increases much more rapidly with fewer % receptor occupancy until it reaches 100% in which case it plateaus at 100% effect in when % receptor occupancy continues to increase.
