Drug Mech: Quiz 1

a) converting the administered dose of the drug into a drug concentration at the site of action

...because pharmacokinetics deals with what the body does to the drug, and the above description sounds like part of metabolism from the ADME (Absorption, Distribution, Metabolism & Excretion) properties, all of which are actions the body takes on the drug.

Pharmacdynamics is described by the "pharmacological effect."

The occupancy-response coupling process is another way of saying a signal transduction pathway. PK has nothing to do with this pathway, although PD does.

If you wanted to plot PK, you would do concentration vs. time. PD would be plotted by concentration vs. effect.

a) they are inert binding sites

When you bind to a receptor, you alter biologic function, while if you bind to an inert binding site, you do NOT alter biologic function.

The rest of them are true about drug receptors.

d) drug efficacy

E_max is the highest value on the drug scale. E_max is a measure of drug efficacy.

• a) an increase in the sensitivity of that tissue to the agonist
• Fishing analogy: you increase the likelihood of catching a fish when you go to a lake with a ton of fish.

When you have more receptors in a tissue, you increase the sensitivity or likelihood that the agonist will bind with a receptor.

c) both its own concentration and the concentration of the endogenous agonist

...because a competitive antagonist is one that binds in the same site that the antagonist would bind to. In this particular case, the antagonist is stated as pharmacologic, and therefore can be assumed to be the exogenous drug, and therefore, the thing it would naturally be competing with would be the endogenous agonist since you wouldn't administer two competing drugs.

a) It binds to the receptor but does not activate it

...because, just as this answer states, an antagonist does not activate a receptor. But note that it cannot be any of the other options because an "irreversible" antagonist is different from a "competitive" antagonist.

There is no competition with irreversible antagonist, so it wouldn't compete with agonist, which rules out a couple of the other choices.

It doesn't matter it's rate of elimination because once it binds with drug-receptor complex, it must degrade the entire complex, so the duration of the action of the drug depends not on its own elimination, but the turnover rate of making new receptor molecules.

a) Drug A: KD = EC50 = 0.5 mcg/mL

Look for the lowest EC50 to find the most potent drug. Pay attention to units. A mcg is smaller than a mg.

EC50 measure potency. When EC goes up, potency goes down and visa versa. EC50 is a concentration...that is what EC50 is.

A drug can have very high efficacy, but low potency and visa versa.

c) Drug C

Affinity is measured by KD. Highest KD will give you lowest affinity.

• Which one would have spare receptor molecules?
• If they are equal, there are no spare receptors. Drug B and Drug C would have spare receptors because EC<KD.

c) receptor-specific antagonism (a pharmacologic antagonist)

A chemical antagonist has to bind to another drug, and inactivates that other drug.

A physiologic antagonist binds to a different receptor than what another drug binds to.

In this case, Clopidogrel is binding to a specific receptor. ADP binds to the ADP receptor, so both of them bind to the same receptor, which is a pharmacologic antagonist, aka a receptor specific antagonist.

b) it is a noncompetitive pharmacologic antagonist for the ADP-receptor in platelets

It binds irreversibly to receptor, so there is no competition.

e) none of the above

Specificity refers to how many effects the drug is producing...it has nothing to do with selective binding.

The drug molecule has nothing to do with this question.

d) degree of spareness of receptor types/subtypes in tissues

Everything else definitely affects selective binding.

The effect of a full agonist is greater than that of a partial agonist because the full agonist has better (not necessarily more) connections.

For example, in using the "tickle" analogy, a full agonist is not just "tickling" the receptor, it is tickling the receptor in the right spot...making the receptor laugh.

Compare this to a partial agonist where although the partial agonist is tickling (making connections) just as the full agonist, the partial agonist is not making the receptor laugh...and therefore not tickling in the right spot.

When the full agonist binds, it is able to stabilize the receptor in the active conformation because it has high intrinsic efficacy...it does everything right in the binding site. Everything is in the RaD form.

With the partial agonist, it doesn't stabilize because it has low intrinsic efficacy. You end up getting a mixture of RaD and RiD, so you get less of an effect.

• Which ligand stabilizes it in the RiD form?
• The inverse agonist (takes it to the left for RiD) while the full agonist takes it to the right (RaD).

When you increase binding affinity, you increase tissue sensitivity. You only need a small amount of drug if your drug is potent and visa versa.

One might think, at first glance, that an antagonist may not be useful because it does not activate the receptor. However, there are many clinical uses for antagonists. For example, take the GABA receptor found in the neurological tissue. The GABA responds to the endogenous GABA (gamma butyric acid). However, if we administer a competitive pharmacologic antagonist, all of a sudden we can slow or prevent the GABA receptor from being activated as it competes with the drug for the receptor site.

Concentrations need to be taken into account because of individual differences. Therefore, we must monitor the effects of the drug and adjust the dose based on the primary outcome. For example, propranolol must be monitored and it is a competitive pharmacologic antagonist. If HR and BP reach the target, then that worked great. Otherwise they increase or decrease the dose accordingly.

Irreversible antagonists are irreversible, and therefore you cannot quickly terminate the effects. You must wait for that turnover rate of the receptor-molecule complex. Therefore, they must be used carefully and much more rarely.

The advantages are you don't have to worry about the concentration of the agonist.

An RTK is very important in medicine, particularly in cancer because there is over-expression of these growth factor receptors, which are RTKs. Therefore, lots of drug factors on market that are RTK-inhibitors.

There are two domains, extra and intracellular domain (the intra is where the enzymatic activity is, which is intrinsic to the receptor...part of the receptor molecule). This activates the kinase, which will then phosphorylate tyrosine residues, which are then activated, and then produce pharmacologic effect.

A cytokine receptor, which is similar to an RTK. The major difference is that the enzymatic activity (aka the kinase activity) is not intrinsic. It will then phosphorylate intracellular proteins, so then it is similar to an RTK.

Recall an effector is a sort of secondary messenger that carries on a pathway or signal after the initial ligand-receptor complex has been activated and initiated. Because there are thousands of G protein-coupled signaling pathways, it really depends on the cell as to what an effector does.

A GPR coupled pathway has 7 transmembrane domains. Classic example is Beta-adrenergic receptor...common GPR. The effector is the final molecule that starts the process of producing an effect. The effector molecule is usually an enzyme or an ion channel. It's job is to increase the concentration of intracellular secondary messengers. Now the secondary messenger will produce a pharmacologic effect. Who is the first messenger? The ligand! It starts the whole thing.

GP-coupled receptors are highly efficient signal transduction pathways and amplify the signal. They convert the signal into a highly efficient signal that has been amplified. GTP replaces GDP. Recall it is active when GTP is attached. Once the G-protein is active, it will take time to de-activate it because it has to de-phosphorylate. As long as the G-protein is active, the effector molecule it is interacting with will be active. It takes time to de-phosphorylate.

Efficacy is E_max, but what about clinical efficacy? There is a difference.

• Clinical efficacy has to do with:
• 1) E_max
• 2) The ability of the drug to reach its site of action (or its receptor), or in other words, the pharmacokinetic properties of the drug.

How do we get the drug to it's receptor? Pharmacokinetics!

Pharmacokinetics and Pharmacodynamics are both vital!

Quantal Dose-Response Curve: different than a graded-dose response curve. X-axis is dose. Y-axis is how many individuals are responding to the drug effect being studied. This is the curve compiled by clinical trials of the drug. It will tell you drug information as a function of dose. We learn parameters from this curve.

ED50 is different than what we determined from graded-dose response curve. It is the dose of the drug required to produce an effect in 50% of the population. Example: 1000 people in a clinical trial, ED50 is when 500 people experience a clinical effect from the drug.

Sometimes these trials are performed in animals. LD50 can be determined: what is the dose that will kill 50 rats out of 100 rats. If it's very high, your drug is fairly safe. It gives a great idea of the toxicology of a drug.

• Therapeutic index of the drug?
• A ratio of TD50 and ED50. Gives you rough idea of how safe your drug is. Usually done in mammal animals.

Therapeutic Window: gives an idea of minimum toxic concentration and max toxic concentration. Drugs that have a wide therapeutic window is considered fairly safe.

Digoxin has a very narrow therapeutic window, so it's a very toxic drug. You could very easily go into toxicity if you give the wrong dose of these drugs. Therapeutic window more useful that Therapeutic index. Thus, therapeutic window much more clinically useful.