Pharmacodynamics II

Question 1

What is structural specificity?

Answer 1

– there will be some degree of specificity for the drug

Question 2

What is the pharmacophore?

Answer 2

The part of the receptor that recognizes and “binds” the drug is the “pharmacophore” or drug recognition site.

Question 3

How do receptors exhibit stereospecificity?

Answer 3

Receptors generally exhibit stereospecificity for drugs containing asymmetric carbon atoms.

Stereospecificity – either all activity will reside in one isomer or one of the isomers will be more potent than the other

Question 4

How will increasing dose of a drug affect response of receptors?

Answer 4

Saturability – receptors exist in finite numbers and can be saturated by high concentration (doses) of drugs. Increasing dose will increase response- only up to some maximal effect.

Question 5

Pharmacological Response – there will be some quantitative relationship between the magnitude of the response and the total number of receptors occupied.

This will depend on:

Answer 5

1. the amount of drug reaching its site of action
2. the specific drug-receptor interaction at that site (e.g. coupling efficiency)
3. the functional status of the receptor and/or target cell (e.g. desensitization or supersensitivity)

Question 6

What is Bmax? How can it be altered?

Answer 6

receptors are dynamic entities whose cellular steady state levels (Bmax) can be affected by pharmacologic, physiologic and pathologic factors.

Question 7

What are the possible effects of a drug binding to an intracellular receptor?

(What kind of drug can bind? Where are these receptors?

Answer 7

They exist in the cytosol and can bind
biologic compounds that are sufficiently lipid soluble to cross the plasma membrane

The binding of the compound may:
(1) stimulate an intracellular enzyme (e.g. soluble guanylyl cyclase) or
(2) regulate cellular localization of the receptor and alter transcription of genes (e.g.
the glucocorticoid receptor).

Question 8

What are “gene active” receptors?

Answer 8

When binding of a drug to intracellular receptor regulates the cellular localization of the receptor and alters transcription of genes.

“GENE ACTIVE” receptors since they bind to promoters to
stimulate the transcription of genes in the nucleus.

Question 9

What are the Therapeutic Consequences of 
Gene Active Receptors ?

There is a lag period (30 min – few hours) before the effects may be observed. Why ?

Answer 9

– this is due to the time to synthesize new proteins; much longer than the time for other receptors to produce their effects.

Question 10

What are the Therapeutic Consequences of 
Gene Active Receptors ?

The effects of gene active receptors may persist for hours or days after the agonist is gone. Why?

Answer 10

this is due to the slow turnover of enzymes or proteins synthesized in response to receptor activation

Question 11

What is the implication of “gene active” receptors in regards to therapeutic or toxic effects?

Answer 11

• the therapeutic or toxic effects will decrease slowly.
• there is no simple temporal relationship between plasma drug levels and the magnitude of the effect, therefore; - activation of the gene, and its effects, may long outlast the presence of the drug in the body.

Question 12

What are the 3 types of Plasma Membrane receptors?

Answer 12

1. Ligand-Regulated Transmembrane Enzymes including Protein Tyrosine Kinase and Cytokine Receptors
2. . Ligand-Gated Channel Receptors.
3. G-Protein Family of Transmembrane Enzymes

Question 13

Protein Tyrosine Kinase (or Serine Kinase/ Guanylyl Cyclase) is an example of what type of receptor? Describe.

Answer 13

A. Receptor polypeptides that cross the membrane once and consist of an extracellular binding domain and an intracellular enzymatic domain (may be tyrosine or serine kinase or guanylyl cyclase)

B. Once activated, these receptors can phosphorylate tyrosines or serines on various downstream proteins.

C. Autophosphorylation of tyrosines on the receptor’s cytoplasmic side can intensify or prolong the duration of receptor activation (e.g. autophosphorylation of the insulin receptor persists long after insulin dissociates from the receptor).

Question 14

How might ligand binding affect the response of ligand-regulated TM enzyme receptors?

Answer 14

Subject to receptor down-regulation via endocytosis and degradation of receptors –ligand binding may also induce an accelerated endocytosis that could limit the intensity or duration of the drug effects.

Question 15

Describe the cytokine receptor. What does it respond to?

Answer 15

Closely resemble the tyrosine kinase receptors but utilize a separate protein tyrosine kinase that binds non-covalently and is not intrinsic to the receptor.

These receptors respond to a heterologous group of peptide ligands such as growth hormone and other regulators of growth and differentiation.

Question 16

Describe the cytokine receptor mechanism.

Answer 16

1. Ligand binding induces conformational change and receptor dimerization.
2. Dimerization allows JAKs to be activated & phosphorylate tyrosine residues on the receptor.
3. Phosphorylation of tyrosine on the receptor facilitates the binding of STAT proteins(Signal Transducers and Activators of Transcription).
4. The bound STATs are then phosphorylated by the JAKs
5. Two STATS dimerize & the dimer dissociates, travels to the nucleus and regulates gene transcription.

Question 17

What is an example of the ligand gated channel receptor?

Answer 17

the Nicotinic Cholinergic Receptor

Question 18

What are the signaling characteristics of the ligand gated channel receptors?

Answer 18

1. A pentamer consisting of 4 types of glycoprotein subunits (alpha2 beta gamma delta) that form a cylindrical structure containing the channel.
2. Acetylcholine binding to the α subunits produce a conformational change and transient opening of the channel.
3. The open channel allows sodium ions to pass from the extracellualr fluid into the cell.
4. The time between binding and response is in milliseconds which provides for rapid information transfer; much quicker than other signaling mechanisms that require seconds, minutes or hours to produce their effects.

Question 19

What is the quickest signaling mechanism? Slowest?

Answer 19

Ligand gated channel receptors - The time between binding and response is in milliseconds which provides for rapid information transfer; much quicker than other signaling mechanisms that require seconds, minutes or hours to produce their effects.

slowest- Gene active?

Question 20

Describe G- protein linked receptors. What are some key aspects about them?

Answer 20

1. A single polypeptide chain that traverses the plasma membrane 7 times (aka serpentine receptors)
2. The amino terminus is in the extracellular side while the carboxy terminus resides on the intracellualr side.
3. The extracellular region contains the ligand or drug recognition site (pharmacophore).
4. The third intracellular loop regulates the ability to interact with specific G-proteins while the carboxy terminus contains sites (serine residues) that are subject to phosphorylation and regulation of receptor function.
5. Activation of G proteins conveys the effects of the drug to the second messenger enzymes.

Question 21

What is the role of G proteins?

Answer 21

proteins that act as intermediates in the
transfer of information between the receptor and the second messenger. They are composed
of alpha, beta and gamma subunits that exist together as a trimer. Different G proteins mediate
the stimulatory and inhibitory effects on adenylyl cyclase and the activation of phospholipase C.
These G proteins are referred to as Gs, Gi and Gq and differ primarily in their alpha subunits

Question 22

What is the mechanism of activation of G protein coupled receptors?

Answer 22

a) Agonist binds to receptor and facilitates its association with a G‐protein (i.e. formation of a ternary complex)
b) Formation of the Ternary Complex facilitates the binding of GTP rather than GDP to the Gprotein.

c) Binding of GTP to the alpha subunit dissociates it from the beta‐gamma subunits, receptor and
agonist.

d) The GTP‐bound G‐protein is the active intermediate which changes the activity of the effector
component, usually an ion channel or enzyme such as adenylyl cyclase or phospholipase.

e) The G‐protein remains active until a GTPase converts GTP to GDP reforming the original nonreactive
G‐protein.

The separation of receptor activation from G‐protein mediated activation of the effector
facilitates amplification of the transduced signal.

Question 23

Reversible phosphorylation is a common theme in these signaling mechanisms. Why?

Answer 23

provides for amplification (activation of multiple substrates) and flexible regulation (e.g.
via cellular availability of particular kinases or kinase substrates).

Question 24

What is the following an example of?
A. actions at same receptor
B. action at identical receptor but in different tissues or affecting different effector pathways
C. actions mediated by different types of receptors)

Ex:
direct pharmacologic extension of the therapeutic
actions of the drug (e.g. excessive bleeding caused by anticoagulant therapy).

Answer 24

Actions at the same receptor ‐ direct pharmacologic extension of the therapeutic
actions of the drug (e.g. excessive bleeding caused by anticoagulant therapy).

manage dose
monitor effect

toxicity may be minimized or prevented by careful management of dose and
monitoring of effect, or by not administering the drug at all.

Question 25

What is the following an example of?
A. actions at same receptor
B. action at identical receptor but in different tissues or affecting different effector pathways
C. actions mediated by different types of receptors)

Glucocorticoid congeners used to treat asthma or inflammatory
disorders can produce protein catabolism, psychosis, etc. (all mediated by similar or
identical glucocorticoid receptors)

Answer 25

Actions at identical receptors but in different tissues or affecting different effector
pathways

Add other drugs to lower dose of 1st drug

Give lowest dose to achieve effect

Limit effects via route of administration

a) Administer the lowest dose that produces an acceptable benefit

b) Administer adjunctive drugs ‐ may allow lowering the dose of the first
drug

c) Limit the drug’s effects to specific parts of the body (e.g. aerosol
administration of a glucocorticoid to the bronchi)

Question 26

What is the following an example of?
A. actions at same receptor
B. action at identical receptor but in different tissues or affecting different effector pathways
C. actions mediated by different types of receptors)

(e.g. selective serotonin uptake
blockers rather than tricyclic antidepressants)

Answer 26

Actions Mediated by Different Types of Receptors

minimize toxic or side effects by
prescribing drugs with greater receptor selectivity

Question 27

What is an idiosyncratic drug response?

Answer 27

1. Idiosyncratic Drug Response – an unusual response that is not frequently observed in the majority of patients.

Question 28

Idiosyncratic Drug Response – an unusual response that is not frequently observed in the majority of patients.

Quantitative variations in a drug response are more common; what are these?

Answer 28

– the intensity of effect for a given dose of drug may be greater (hyperreactive) or less (hyporeactive) in comparison with the response observed in most individuals.

• the intensity of response may vary (decrease or increase) during the course of therapy.

Question 29

What accounts for variations in receptor responsiveness to drugs?

Answer 29

• these are compensatory responses, invoked to counter the effect imposed on system, in order to re-establish some degree of homeostatic function

Receptor Desensitization (in response to over-stimulation)

Receptor Supersensitivity (in response to under-stimulation)

Question 30

Describe the effect seen with pharmacodynamic tolerance.

Answer 30

(Desensitization) – there is a decreased responsiveness to hormonal stimulation that occurs slowly over with time.

Question 31

What is tachyphalaxis?

Answer 31

describes the rapid development of diminished responsiveness to a drug.

Question 32

How will receptor down-regulation affect dose-response curve/potency/Emax?

Answer 32

All of these will result in a shift to the right in the agonist dose-response curves (an increase in the ED50) and generally no change in Emax,…. unless “receptor reserve” is exceeded.

Question 33

What might explain a desensitization-induced reduction in Emax ?

Answer 33

Slide 28

1. Receptor reduction exceeding receptor reserve.
2. Post-receptor defects (changes in G-proteins, enzyme activity, etc, required to maintain Emax)

Question 34

Describe the process of homologous desensitization of the beta-adrenergic receptor?

Answer 34

beta‐adrenergic receptors are phosphorylated via beta‐adrenergic receptor kinases (aka GRK2, GRK3)
that functionally uncouple the receptors and can trigger their sequestration from the cell.
There is a loss of activity only to agonists interacting with the modified receptor.

B-adrenergic receptors are phosphorylated by specific kinases.

These kinases only recognize and phosphorylate sites on the agonist occupied receptor

This is followed by the binding of beta arrestin to the phosphorylated receptor.

(so there is a loss of activity only to agonists interacting with this modified receptor)

Question 35

Are drugs selective or specific in their actions?

Answer 35

selective

Drug Selectivity – will be dependent on the relative affinities of a drug for various receptors (i.e. comparative KDs for various receptors).

for any drug selectivity will decrease as drug dose is increased

Question 36

The following is an example of what type of pharmacodynamic principle?

• the loss of bronchiodilating effects of beta‐adrenergic agonists in asthmatics;
• the decreased vasoconstricting response to alpha‐adrenergic agonists used as
  decongestants.

Answer 36

Pharmacodynamic tolerance (Desensitization Phenomenon) ‐ a decreased
responsiveness to pharmacologic or hormonal stimulation that occurs slowly with time.

Question 37

What is heterologous desensitization?

Answer 37

Agonist activation of one receptor subtype results in a decreased responsiveness of one or more different receptor subtypes ( i.e. receptors that were not activated by the agonist).

Several protein kinases seem to be capable of promoting phosphorylation of other “non-activated” receptors. These kinases include; cAMP dependent protein kinase (PKA) and protein kinase C (PKC).

Heterologous desensitization may be associated with functional modifications at post-receptor intermediates in the signal transduction pathway (e.g. G proteins).

Question 38

What is the key difference between homologous and heterologous desensitization?

Answer 38

Homo- Desensitization is restricted to
only the receptor population that was activated by the drug

Hetero- This type of Desensitization is NOT restricted to only the receptor population activated by the drug.

Question 39

How can we differentiate between homlogous vs heterologous if we get desensitization following long-term administration of an agonist ?

Answer 39

v difficult unless saw desensitization of another R population following drug that activated a diff type of receptor.

Question 40

What is receptor supersensitivity?

How is dose response curve affected?

Answer 40

Supersensitivity – a compensatory receptor mechanism in which the loss of activity on receptors leads to an increase in receptor density and/or an enhanced receptor-effector coupling.

This results in an increased responsiveness to subsequent receptor activation and a shift to the left in the dose response curve

Question 41

What is the therapeutic implication of supersensitivity?

Answer 41

Any given dose of agonist will produce an exaggerated response !