#10 Pharmacodynamics #2

Question 1

pharmacophore

Answer 1

the receptor recognition sites. Where the drug is recognized and binds to the receptor

Question 2

the response depends on

Answer 2

1. the amount of drug reaching its site of action (occupancy)
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 3

Intracellular Receptors

Answer 3

can only be activated by lipid soluble drugs that can cross plasma membrane. 

The binding of the drug may:

1. Stimulate an intracellular enzyme (e.g. nitric oxide stimulation of guanylyl cyclase)
2. Regulate the cellular localization of the receptor and alter gene transcription (referred to as “Gene Active” receptors)

Question 4

Therapeutic Consequences of 
Gene Active Receptors

Answer 4

1. lag period before effects are observed due to the time it takes to make new proteins
2. effects may continue for a period of time after the drug is gone

activation of the gene, and its effects, may long outlast the presence of the drug in the body.

Question 5

PLASMA MEMBRANE RECEPTORS

Answer 5

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

Question 6

Ligand-Regulated Transmembrane Enzyme Receptors 
including Protein Tyrosine Kinase

Answer 6

consist of an extracellular hormone binding domain and a cytoplasmic enzyme domain. (cross the membrane once)

may be tyrosine or serine kinase or guanylyl cyclase which phosphorylate downs stream receptors

autophosporylation of tyrosine residues on the receptor can intensify or prolong the duration of the activation of the receptor (even after the drug is no longer present ie insulin)

subject to down regulation via endocytosis and degradation of receptors

Question 7

The Cytokine Receptor Mechanism

Answer 7

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 & differentiation.

Question 8

Cytokine receptor activation steps

Answer 8

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 & regulates gene transcription.

Question 9

The Ligand Gated Channel Receptors

Answer 9

the Nicotinic Cholinergic Receptor

1. A pentamer consisting of 4 types of glycoprotein subunits (α2βδγ) 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 10

G-PROTEIN LINKED RECEPTORS

Answer 10

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 11

toxic effects of drugs can occur by 3 different means

Answer 11

1. actions at the same receptor. (eg excessive bleeding due to anticoagulant therapy)
2. actions at identical receptors in different tissues
3. actions mediated by different types of receptors

Question 12

Idiosyncratic Drug Response

Answer 12

an unusual response that is not frequently observed in the majority of patients.

Question 13

Quantitative Variations in drug response

Answer 13

more common
- the intensity of effect for a given dose of drug may be greater (hyper-reactive ) or less (hypo-reactive) in comparison with the response observed in most individuals.

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

Question 14

Tachyphalaxis

Answer 14

the rapid development of diminished responsiveness to a drug

Question 15

Pharmacodynamic Tolerance (Desensitization)

Answer 15

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

These are general mechanisms of cellular adaptation that limit the therapeutic effectiveness of a number of drugs.
 (e.g. the loss of vasoconstriction responses after  using α adrenergic agonists  as decongestants for a period of time)

Question 16

3 ways that desensitization occurs

Answer 16

Agonist-induced phosphorylation of the activated receptor & subsequent binding of β-arrestin (a readily reversible phenomenon).

Receptor down-regulation - there is an actual loss of membrane bound receptors responsible for eliciting the response.

Post-Receptor Adaptations – receptors become “functionally uncoupled” from post receptor components due to modification of G-proteins or 2nd messenger enzymes.

**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 17

What might explain a desensitization-induced reduction in Emax ?

Answer 17

1. Receptor reduction exceeding receptor reserve.

2. Post-receptor defects (changes in G-proteins, enzyme activity, etc required to maintain original Emax).

Question 18

HOMOLOGOUS DESENSITIZATION

Answer 18

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

Question 19

Heterologous Desensitization

Answer 19

Desensitization is NOT restricted to only the receptor population activated by the drug.

if you give a second drug after the first and get a diminished response then you have heterologous response

Question 20

Supersensitivity

Answer 20

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