Pharmacology: Block 1: Pharmacodynamics 1, 2, 3

Front 1

Where are most drugs absorbed?

Back 1

In the small intestine.

Front 2

What is the formula for the acid dissociation constant, Ka?

Back 2

HA <--> H+ + A-

Front 3

What is the formula for the pKa?

Back 3

pKa = -log ([H+][A-] / [HA])

Front 4

What is the Hendersen-Hasselbalch Formula?

Back 4

pH = pKa + log (cong base/cong acid).

Front 5

If an acid has a small pKa, what does it indicate about that acid?

Back 5

That the acid has a "small" affinity for protons and thus gives them up readily --> it is a strong acid.

Front 6

What are some ways to think about the pKa?

Back 6

1. That pH below which the ionisable group is protonated. That pH above which the ionisable group is unprotonated.

2. The pH at which there are equal protonated and unprotonated forms.

3. The inverse indication of acid strength.

4. The mid-point of the acid titration curve.

5. ***Think of the pKa as a measure of "Proton binding affinity." If a group has a low pKa, then it has a low affinity for protons --> it binds protons weakly and thus gives them up readily.

Front 7

Explain the phenomena of ion trapping. What is a typical example of this?

Back 7

Only uncharged species can cross the cell membrane. If a species becomes charged it will remain on that side of the membrane.

Example: trapping of a weak base (methamphetamine) in the urine by making the urine more acidic than the blood. The base will bind the free H+ and will trap itself in the urine. (Note that in the interstitium where it is not acidic, the base will tend to give up its proton and become the uncharged form of methamphetamine).

Front 8

How do you make the urine acidic?

Back 8

Give ammonium chloride.

Front 9

How do you make the urine basic?

Back 9

Give bicarbonate.

Front 10

Would an acid of pKa = 2 be absorbed well in the GI tract?

Back 10

No, because having a "low" pKa means that the acid has a "low" affinity for protons (is thus a strong acid) and is therefore most often in its CHARGED form in a blood of pH 7.4.

Front 11

Would an acid of pKa = 8 be absorbed well in the GI tract?

Back 11

Yes, because having a "high" pKa means that the acid has a "high" affinity for protons (is a weak acid), and is therefore mainly in its UNCHARGED state in the blood of pH 7.4.

Front 12

Would a base of pKa = 12 be absorbed well in the GI tract?

Back 12

No, because pKa of 12 is "high" and indicates that the species wants to HOLD onto H+. When a base holds onto H+ it is CHARGED! Thus it will not be able to cross membranes efficiently.

Front 13

What is an agonist?

Back 13

A drug that mimics an endogenous ligand and binds to that ligand's receptor, activating a response.

Front 14

What is a full agonist?

Back 14

An agonist that can produce the maximal response of he system that it is mimicking.

Front 15

What is a partial agonist?

Back 15

An agonist that produces a SUB-maximal response of the system that it is mimicking.

Front 16

What is an antagonist?

Back 16

An antagonist blocks a ligand (or agonist) from binding to its receptor. The antagonist binds instead and blocks the normal effect that the ligand would have.

Front 17

What is an inverse agonist?

Back 17

An inverse agonist binds to the INactive form of the receptor, inhibiting what would otherwise be constitutive activity. Inverse agonists usually look like a competitive antagonists.

Front 18

The relationship between the drug concentration and the magnitude of the effect it produces is mediated by what?

Back 18

1. Proportional to the number of receptors occupied by the drug.

2. Proportional to the concentration of the drug.

Front 19

Put the rate constants into this equation:

L + R <--___-- --___--> LR

Back 19

L + R <--k-1-- --k+1--> LR

k+1 = the "on" rate constant
k-1 = the "off" rate constant

Front 20

What is denoted by the EC50?

Back 20

The EC50 (effective concentration) is the drug concentration at which the drug has half of its maximal effect.

Front 21

What is denoted by Kd?

Back 21

The Kd is the drug concentration at which half of the maximum number of receptors are bound.

Front 22

What is the mathematical equation that models the receptor theory invovled with the action of agonists?

Back 22

Basically the Michaelis-Menten equation:

Effect = Emax[A] / Kd + [A]

v0 = vmax[S] / Km + [S]

Front 23

What is the relation between Kd and EC50 when 50% of the receptors are occupied?

Back 23

Kd = EC50.

Front 24

Describe the shape of these two curves:

1. % of max effect vs. [Drug]
2. % of max effect vs. log [Drug] (where is the EC50 found on this graph?)

Back 24

1. hyperbolic
2. sigmoid (EC50 is at the inflection point)

Front 25

What is meant by potency? Use an example with curves A and B.

Back 25

Potency is exhibited on the x-axis of the dose response curve.

If curve A is shifted more to the left than B, then it is more potent.

Front 26

What is meant by efficacy? Use an example with curves A and B.

Back 26

Efficacy is exhibited on the y-axis of the dose response curve. If the Emax of curve B is of lower magnitude than curve A, then A is more efficacious.

Front 27

What is a chemical antagonist?

Are receptors involved?

Give two examples.

Back 27

One drug might bind to another drug and inactivate it.

Receptors are NOT involved.

Examples: protamine and heparin, Gastric acid (HCl) and Al(OH)3.

Front 28

What is a physiologic antagonist?

Give an example.

Back 28

An antagonist that produces effects that are opposite that which are produced by a naturally-occurring physiologic agonist. This anatagonist may act at a different receptor than the agonist.

Example: Beta blockers and vasopressors

Front 29

What is a pharmacologic receptor antagonist?

What is another word for this?

Back 29

An antagonist that binds to the active site or to an allosteric binding site on a receptor.

Also called a "neutral antagonist".

Front 30

Where does a competitive antagonist bind?

What are two other terms for competitive antagonist?

Back 30

Binds to the active site, preventing agonist binding.

Also called a reversible or surmountable antagonist.

Front 31

What is another term for an unsurmountable antagonist?

What does "unsurmountable" refer to?

Back 31

Noncompetitive or irreversible.

Even high concentrations of agonist can't activate the receptor because antagonist is covalently bound.

Front 32

What is an allosteric antagonist?

Back 32

An antagonist that binds to a site other than the active site. Can be reversible or irreversible.

Front 33

What effect does adding competitive antagonist [B] have on the DRC of [A]?

Back 33

By adding a competitive antagonist, the DRC of [A] is shifted to the right. Higher concentrations of A are needed to produce the same response. The potency has decreased.

Front 34

What is the formula for the dose ratio?

Back 34

Dose ratio = ([A] in presence of B)/([A] in absence of B)

Front 35

What is the Shild Plot used for?

Back 35

To determine the Kb of competitive antagonists.

Front 36

At low concentrations of irreversible antagonists, DRC may be ______ ___ ____ without a change in _______ ______.

Provides evidence for ______ ______.

Back 36

At low concentrations of irreversible antagonists, DRC may be SHIFTED TO THE RIGHT without a change in MAXIMUM EFFECT.

Provides evidence for SPARE RECEPTORS.

Front 37

How many receptors need to be occupied by full agonists to produce a maximum response?

Back 37

"Relatively few"

Front 38

Giving a competitive antagonist does what to the DRC?

Back 38

Shifts it to the right.

Front 39

Giving a noncompetitive antagonist at high levels does what to the DRC?

Back 39

Decreases the maximum effect.

Front 40

A partial agonist and look like a ______ _______ of a full agonist.

Back 40

A partial agonist can look like a NONCOMPETITIVE INHIBITOR of a full agonist.

Front 41

What are two things that make a partial agonist "partial"?

Back 41

1. The agonist may not be able to promote efficient signal transduction.

2. The agonist may have affinity for both active and inactive states of the receptor. "Pulling equilibrium in both directions"

Front 42

What is an inverse agonist?

Back 42

Inverse agonists inhibit the intrinsic activity of constitutively active receptors by stabilizing the receptors in a drug occupied but inactive form.

An inverse agonist has a greater affinity for the inactive state.

Front 43

In systems with no constitutively activity, inverse agonists will act like _____ _______.

Back 43

In systems with no constitutively activity, inverse agonists will act like COMPETETIVE ANTAGONISTS.