4. Pharmacodynamics

Question 1

1. Define agonist (full, partial, inverse), antagonist (competitive, non competitive), affinity, intrinsic activity and efficacy (objective)

Answer 1

Answer later

Question 2

2. Know the types and relative strengths of the bonding forces involved in drug-receptor interactions (objective)

Answer 2

Answer later

Question 3

3. Understand the relationship between the amount of drug-receptor complex, the Kd, and concentrations of the receptor and the drug (objective)

Answer 3

Answer later

Question 4

4. Understand receptor desensitization and receptor down-regulation (objective)

Answer 4

Answer later

Question 5

5. Be able to use sigmoid concentration-response (or dose-response) curves to compare drugs (objective)

Answer 5

Answer later

Question 6

6. Be able to use linear (probit) dose-response curves to compare ED50, TD50 and clinical responses (objective)

Answer 6

Answer later

Question 7

7. Understand therapeutic index and margin of safety (objective)

Answer 7

Answer later

Question 8

Pharmacodynamics (levels)

Answer 8

1. Molecular level: 
Drug-Receptor Interactions
2. Cellular and Tissue Physiology Level:
Graded Dose-Response Curves
3.Clinical Therapeutics Level:
Quantal Dose-Response Curves

Question 9

1. Molecular Level: Drug-Receptor Interactions (history)

Answer 9

1690, John Locke

1897, Paul Ehrlich, drug receptor concept, similar to lock and key (“side-chain” on cells bound toxins, chains could be released into blood where they could act as antitoxins or antibodies)

1905, John Langley, termed receptive substance (nicotine and curare on skeletal muscle), idea that drugs elicit inhibitory response

Question 10

Receptor (definition)

Answer 10

Structure that recognizes endogenous or exogenous compounds (ligands) with high selectivity

Binding of appropriate ligand to receptor initiates/terminates a physiologic process

Question 11

Not all drug actions mediated by receptors

Answer 11

Neutralization of stomach acid with a base (antacid)

Osmotic diuretic action of mannitol

Question 12

Agonist

Answer 12

Drug that mimics the effects of the endogenous ligand for a receptor

Question 13

Antagonist

Answer 13

Drug which does not have intrinsic activity, but which interferes with the binding of the endogenous ligand (or agonist) to a receptor

Question 14

Bonding Forces (list from weakest to strongest)

Answer 14

Van der Walls (weakest)
Hydrophobic
Hydrogen
Ionic
Covalent (strongest)

Question 15

Affinity (affinity of a receptor for a particular drug is determined by)

Answer 15

1. Number of interacting sites

2. The types of forces that are involved in the binding interactions

Question 16

Equation Describing Reversible Drug-Receptor Interaction (Reaction 1)

Answer 16

[D]+[R] forward arrow [DR]
k1 is on arrow

[DR] forward arrow [D]+[R]
k2 is on arrow

Reaction is double arrow/reversible

Question 17

Equations describing the dissociation constant (Kd); note that the Kd called the “affinity” constant

Answer 17

Kd=k2/k1
=rate of DR dissociation/rate of DR association
=”off” rate/”on” rate

When [DR]=0.5[Rtotal] then Kd=[D]
Thus, Kd is concentration of drug which one-half of total # of receptors are bound by drug. Kd units of moles liter-1

Question 18

Affinity (Kd)

Answer 18

Kd of a drug for a receptor is the concentration of drug that occupies half of the total number of available receptors [Rt]

Lower the molar concentration value of Kd for a given drug, the higher drug’s affinity for the receptor

Question 19

DR=(([Rt])([D]))/((Kd)+([D]))

Answer 19

Like Michaelis-Menten equation

Rt=receptor total

Question 20

Drug Receptor Binding [DR] vs Drug Concentration [D] Graph

Answer 20

Upward slope until it plateaus.

Halfway mark in slope is Rt (1/2 DR) and Kd

Question 21

Drug Bound/Drug Free [DR]/[D] vs Drug-Receptor Binding [DR] Graph

Answer 21

Kd=-1 slope
Downward slope with x intercept at Rt
*Just to compare things linearly (Kd is slope)

Other graph shows data points but with a curve going downwards (example there exists receptor subtypes)

Question 22

Raymond Ahlquist (1914-1983)

Answer 22

Concept of receptor subtypes

1948, proposed existence of alpha and beta subtypes of adrenergic receptors

Question 23

Decreasing Response to Drugs with Sustained Exposure

Answer 23

Receptor Desensitization:
Time-Seconds to Minutes
Mechanism-Receptor Phosphorylation
Effect-Decreased Affinity

Receptor Down-Regulation:
Time-Hours to Days
Mechanism-Receptor Turnover
Effect-Decreased Receptor Number

Question 24

2. Cellular and Tissue Physiology Level: Graded Dose-Response Curves (miscellaneous)

Answer 24

Efficacy- clinical response
y= intrinsic activity in tissue or lab

[DR] forward arrow with y to Re (response)

Re=y[DR]

Question 25

Re=[y([Rt])([D])] / [(Kd)+([D])]

Answer 25

Michaelis-Menten version for response

Question 26

% response (Re) vs Drug Concentration [D] Graph

Answer 26

``` Hyperbolic curve (upward until plateau) Now just compared response to drug concentration instead of receptors ``` Then graph of sigmoid curve (just log of drug concentration): Kd is the point where 50% response

Question 27

Comparing Re vs Log Drug Concentration Curves

Answer 27

Sigmoid curves Kd is way to compare drugs Sigmoid curve to the left has higher affinity then one on the right

Question 28

Effect of a positive allosteric modulator on an agonist log drug-response curve (Diazepam example)

Answer 28

With diazepam, the sigmoid curve shifts to the left (high affinity) Gamma Amino Butyric Acid (GABA)

Question 29

Agonist

Answer 29

Drug that can elicit response after interaction with receptor has intrinsic activity greater than zero (y>0)

Question 30

Full agonist (graph)

Answer 30

Every receptor you bind, get some level of response, y=1. %response and receptor binding curves overlap

Question 31

Partial Agonist (graph)

Answer 31

In case of opioids, you don't want to give them full agonist (addiction, respiratory arrest...) Y=0.5 Receptor binding is normal curve, % response curve is shifted to the right with a lower max plateau (lower drug receptor binding)

Question 32

Spare Receptors (graph)

Answer 32

Rate limiting step can be downstream of receptor binding, doesn't need to bind to all of the receptors to get a full response. %response curve is shifted to the left with same max plateau

Question 33

Receptor Antagonist

Answer 33

Drug that can bind to receptor but has y=0. | Occupies receptor but does not elicit response

Question 34

Agonist and Competitive Antagonist Graph

Answer 34

Agonist + competitive antagonist sigmoid curve shifted to the right of just agonist curve: competes and overcomes agonist, binding to the same site. Need more agonist to overcome bound antagonist for same response as just against with agonist alone.

Question 35

Agonist and Noncompetitive Antagonist Graph

Answer 35

Agonist with noncompetitive antagonist sigmoid curve shifted to the right (same Kd) and lower max plateau than agonist sigmoid curve: inactive portion of receptors bound by antagonist, changes maximal response (lowers)

Question 36

Therapeutic Examples of Noncompetitive Antagonist

Answer 36

Phenoxybenzamine: binds a-adrenergic receptors; blocks catecholamine-induced vasoconstriction, used to treat pheochromocytoma (tumor of adrenal medulla) Aspirin: irreversibly acetylates cyclooxygenase; block prostaglandin synthesis Losartan and Candesartan: act as both comp and noncomp antagonists at angiotensin type 1 receptors; maintains endothelial function in patients with non-insulin-dependent diabetes mellitus Penicillins: covalently bind bacterial transpeptidases, involved in cell wall synthesis

Question 37

Other Forms of Antagonism

Answer 37

Physiological Therapeutic Windows (at some point get a decreased response)

Question 38

Inverse Agonist

Answer 38

Receptor doesn't need to be bound to have a response. Binding of inverse agonist to a receptor that has constitutive (basal/ligand independent) activity results in inhibition of agonist-independent activity Long term treatment with inverse agonist may lead to receptor up-regulation

Question 39

Concept of agonist-directed trafficking of receptor signaling

Answer 39

Some receptors (GPCRs) have been shown to couple to more than one signal transduction pathway (more than one G-protein)

Question 40

3. Clinical Therapeutics Level: Quantal Dose-Response Curves

Answer 40

``` ED50=effective dose in 50% population (half people that show response at certain dose) # of responders vs Log Drug Dose Graph: Bell configuration (curve) ```

Question 41

Comparing different drug bell curves (# of responders vs Log of drug dose graph)

Answer 41

Width of bell curve is inter patient variability. (Higher amplitude=smaller bell curve width) Slide 51 A and C have similar variability, but takes less of A than C amount of drug for ED50 response Same ED50 dose for B as A, but less variability in B than A.

Question 42

Comparing different drug sigmoid curves (cumulative percent of population responding vs log drug dose graph)

Answer 42

Drug A and B E50 is the same dose (potency) Drug C sigmoid curve is to the left of A and B and is thus less potent Plateaus of each sigmoid curve is the efficacy of the drugs

Question 43

Probit Scale vs. Log Drug Dose (conversion of sigmoid curves to linear curves; comparing new drugs A and B)

Answer 43

Drug A desired line, Drug A toxic line, Drug B desired line, Drug B toxic line (left to right, Drug B lines are more steep than A lines) Drug A lines are flatter, thus if you draw 100% point of desired drug A line down, large percentage (60%) of people will have toxic side effects. Drug B desired line drawn down has less people with toxic side effects TI for A greater than TI for B

Question 44

Therapeutic Index

Answer 44

TI=TD50/ED50 TD-toxic dose ED-effective dose Higher TI is better and implies safety generally

Question 45

Margin of Safety

Answer 45

Margin of Safety=TD1/ED99

Question 46

Summary Chart

Answer 46

1.Drug-Receptor Binding Reactions: Affinity (Kd); Receptor Number (Rt) 2.Graded Biochemical Physiological Responses: Affinity/potency; maximal response (REmax); intrinsic activity y (agonist, antagonist) 3. Quantal Responses: Potency(ED50); Efficacy; biological variation; therapeutic index