Drug Receptor Interactions and Cell Signaling- 5&6

Question 1

What is a receptor?

Answer 1

any cellular macromolecule with which a drug interacts resulting in the change of one or more on-going cellular processes. Drugs do not initiate new processes. Responds to endogenous as well as exogenous substances. Usually coupled to an effector (transducer) or ion channel. Responsible for mediating the actions of many but not all classes of drugs.

Question 2

Example: Epinephrine adrenergic receptors

Answer 2

alpha 1 subtype- constricts vascular smooth m.

beta 2 subtype- relaxes vascular smooth m.

Question 3

-olol

Answer 3

beta blocker

Question 4

Properties of receptors

Answer 4

a cell can only respond to a drug if it has the receptor for that drug. Receptors, like any other protein, undergo synthesis and degradation with variable lifespans. Receptors on a cell can be altered by diseases or chronic drug treatment, source of concern.

Question 5

“Down regulation”

Answer 5

Excessive receptor stimulation leading to decreased receptor density.

Question 6

“Up regulation”

Answer 6

Decreased receptor stimulation leading to increased receptor density.

Question 7

Is drug binding reversible?

Answer 7

most drug-receptor binding is readily reversible. Binding and unbinding of the drug receptor complex is very fast

Question 8

Types of binding

Answer 8

ionic, hydrophobic, ect.
Strength of the interaction determines the concentration of the drug required to interact with the receptor (binding affinity). Stronger interaction -> lower concentration required -> higher affinity.

Question 9

Drug- receptor interactions exhibit…

Answer 9

Saturable response, reversibility, good potency, chemical selectivity, competitive blockade by antagonists, amplified responses.

Question 10

4 receptor categories

Answer 10

Ion channels.
Guanine Nucleotide Binding Protein (G protein)- Coupled Receptors (GPCR).
Receptor Tyrosine Kinases (TRK).
Intracellular Receptors.
Ion channels and GPCR are common therapeutic targets

Question 11

G protein coupled receptors

Answer 11

adrenergic, cholinergic, dopaminergic, histamine, opiate, serotonergic.

Question 12

Ion channel coupled receptors

Answer 12

Nicotinic receptor gated Na+ channels, GABA- receptor gated Cl- channels, Glutamate (NMDA)- coupled cation channels.

Question 13

Receptor ligands

Answer 13

ligands are small molecules that interact with or bind to a cellular macromolecule (receptor). Receptor ligands, aka drugs, are classified by the nature of the response they produce.
Two main types: Agonists and Antagonists.

Question 14

Agonists

Answer 14

Full- 100% stimulation.

Partial- 1-99% stimulation.

Question 15

Antagonists

Answer 15

Competitive- No stimulation, reversible.

Non competitve- No stimulation, irreversible.

Question 16

Properties of receptor agonists

Answer 16

bind very rapidly to target receptors. After dissociating from receptor, the response dissipates quickly. Prolonged stimulation of receptors can lead to a diminished response. Produce changes that are independent of other ligands. A full agonist produces a complete or maximal effect. Sigmoidal dose-response plot.

Question 17

Common receptor agonists

Answer 17

alpha 2 adrenergic: xylazine, detomidine, medetomidine.
alpha 1 adrenergic: phenylephrine.
beta 1/2 adrenergic: isoproterenol.
opiate receptors: morphine, fentanyl, butorphanol.
beta 1 receptors: dobutamine.
mucscarinic cholinergic: bethanecol.
beta 2 adrenergic: terbutaline

Question 18

Properties of antagonists

Answer 18

drugs that bind to a receptor and block or prevent the action of a agonist. Zero efficacy. Bind and unbind from receptor slower than agonists. may be reversible or irreversible. Pure anatgonists are unable to elicit cellular action when given alone.
3 major types- competitive, noncompetitive, irreversible.

Question 19

Competitive antagonists

Answer 19

antagonists that bind reversibly to a receptor. Binding happens at same site agonist would. They two are mutually competitive. One drug can override the other when present in excess.
A low concentration of competitive antagonist yields a modest parallel rightward shift.

Question 20

Non-competitive antagonists

Answer 20

antagonists that bind irreversibly or bind to an alternate site of the receptor- agonists do not compete. Extent of receptor blockade is fixed and related to the dose of antagonist administered. Blockade cannot be overcome.

Question 21

Dissociation constant (Kd)

Answer 21

a mathematical relationship that predicts the relative concentration of the drug-receptor complex at any concentration of drug.
Kd = K-1/K1 = DR/D.
Is independent from any cellular response and therefore can be determined for both agonists and antagnists.
Kd is the drug concentration at which half of the receptors are occupied by drug.

Question 22

Practical relevance of Kd

Answer 22

indicates the relative drug concentration that is required in order for a drug to bind to a receptor. No relationship with efficacy. But measure of drug affinity.
High affinity= low Kd.
Low affinity= high Kd.

Question 23

Potency

Answer 23

dose of drug needed to produce a desired level of effect.

High affinity doesn’t equal high potency.

Question 24

Affinity

Answer 24

drug concentration required to occupy a target receptor.

High potency doesn’t equal high affinity.

Question 25

Specificity

Answer 25

a measure of a drug’s ability to produce one effect (desireble) relative to its ability to produce another effect (undesirable).
Specificity= ED50 (undesirable)/ ED50 (desirable).
where ED50 is the dose that produces that effect in 50% of the target.
If ED of undesirable is greater than desirable that drug has good specificity. If it is about or equal it has poor specificity.

Question 26

Measure of drug

Answer 26

most commonly determined by comparing drug doses that produce a desired effect relative to doses that are lethal. Can exhibit substantial species variation.

Question 27

Therapeutic Index (TI)

Answer 27

a quantal response (yes or no) that is measured at the 50percent level.
TI= LD50/ED50

Question 28

Margin of safety (MOS)

Answer 28

more stringent measure of drug safety. Avoids problems associated with non-parallel dose relationships for efficacy and lethality dose-response relationships.
MOS= LD1/ED99.