Lecture 2: drug-receptor interactions

Question 1

Examples of drugs that don’t require a target receptor to evoke biological responses

Answer 1

osmotic diuretics (e.g., mannitol),
antidotes for heavy metal poisoning, and most laxatives (e.g., lactulose, polyethylene glycol),
antacids neutralizing the hydrochloric acid in stomach)

Question 2

Where did the concept of receptor evolve from

Answer 2

pioneering work of Lanley and Ehrich

Question 3

how do most drugs work?

Answer 3

in a structurally specific way (their therapeutic and toxic effects stem from their interactions with specific cellular target molecules collectively known as receptors

Question 4

What determines the concentration of drug required to form a significant number of drug-receptor complexes?

Answer 4

affinity for binding a drug

Question 5

high affinity =

Answer 5

less drug dose

Question 6

what limits the maximal effect a drug may produce?

Answer 6

the total number of receptors

Question 7

what provides the specificity of the overall drug-receptor interaction

Answer 7

the ensemble of the interactions

Question 8

receptor is associated with

Answer 8

enzyme(?)

Question 9

van der Waals

Answer 9

hydrophobic (dislikes water)
weak bond

Question 10

how is affinity measured/reported?

Answer 10

by the Kd value

Question 11

affinity contributes to overall..

Answer 11

potency
efficacy
duration of drug action

Question 12

Non-covalent bonds

Answer 12

Ionic Bonds
Dipole Interactions
Hydrogen Bonds: a specialized type of Dipole-Dipole bond
van der Waals Interactions
Hydrophobic Bonding
Chelation and Complexation
Charge Transfer Interactions

Question 13

ionic bond

Answer 13

complete transfer of valence electron to attain stability

Question 14

Dipole interaction

Answer 14

partial charge bonded with opposite partial charge

Question 15

Hydrogen bond

Answer 15

H–F,O,N

Question 16

van der Waals

Answer 16

all Carbons
hydrophobic

Question 17

hydrophobic interaction

Answer 17

arise as a consequence of the interaction of their hydrophobic (i.e., “water-disliking”) amino acids with the polar solvent, water.

the tendency of nonpolar molecules to minimize their contact with water.

Question 18

chelation and complexation

Answer 18

Chelation is the complexation process by which a metal ion is bound to more than one atom in a single ligand.

Question 19

What is a charge transfer interaction

Answer 19

an electron donor acceptor complex can be defined as an association of two or more molecules, or of different parts of a large molecule, in which a fraction of electronic charge is transferred between the molecular entities.

Question 20

which bonds are permenant

Answer 20

covalent

Question 21

most drugs are…

Answer 21

proteins

Question 22

What is Kd?

Answer 22

a concentration and it quantifies the ‘affinity’ for a particular drug for its receptor.

If the Kdis low, the binding affinity is high, and vice versa.

Question 23

It is the ____ of the drug that produces a fractional occupancy of 50%…

Answer 23

concentration

Question 24

According to the Clark’s occupancy theory, the maximal response to the drug …

Answer 24

is equal to the maximal tissue response, leading to the expectation that all agonists would produce the same maximal response.

For some drugs, e.g., the partial agonists, maximum response can never be achieved even at extremely high doses. (Limitation 1 of the theory)

Question 25

examples of Therapeutic index (TI)

Answer 25

penicillin (high window) and warfarin (low window)

Question 26

list of protein receptors

Answer 26

enzymes ionotropic/ion channels metabotropic kinase linked and related receptors nuclear receptors cytoskeletal or structural proteins transporters/carrier proteins

Question 27

example of enzyme receptors

Answer 27

dihydrofolate reductast: receptor for antineoplastic drug methotrexate

Question 28

example of iontropic receptors/ion channels

Answer 28

ligand gated channels and voltage gated channels

Question 29

example of metabotropic receptors

Answer 29

G-protein coupled receptors binding to endogenously produce hormones neurotransmitters

Question 30

what are kinase linked and related receptors

Answer 30

receptors for various growth factors and for some anticancer drugs

Question 31

examples of nuclear receptors

Answer 31

receptors for thyroid hormone some fat-soluble vitamins and steroids

Question 32

examples of cytoskeletal or structural proteins

Answer 32

tubulin, the receptor for colchicine, and anti-inflammatory agent

Question 33

examples of transporters or carrier proteins

Answer 33

NA+, K+, ATPase, the receptor for cardiac glycosides

Question 34

examples of non-protein receptors

Answer 34

nucleic acids (DNA/RNA) membranes fluid compartments

Question 35

____ receptors can be coupled to respective executioner or effector components that orchestrate diverse cellular effects which may occur over a wider time scale

Answer 35

GPCR

Question 36

how fast are effects produced by the following receptors channels: - ion channels: - steroid and thyroid hormones: - GPCRs:

Answer 36

- ion channels: (milliseconds) - steroid and thyroid hormones: (several minutes) - GPCRs: (seconds to minutes)

Question 37

laws of occupancy theory:

Answer 37

The drug (D) and receptor (R) bind reversibly to form a drug-receptor complex (DR) in 1:1 stoichiometry.  The DR complex generates a response (E): D + R ↔️ DR → E. The magnitude or intensity of the response is directly proportional to the amount or concentration of the DR complex ([DR]) formed: (E ∝ [DR]).  The maximum possible response (Emax) is elicited when all the receptors (RT) become occupied by the drug, forming the DR complex: (when [DR] = [RT], E = Emax).

Question 38

equation for fractional occupancy

Answer 38

Question 39

Limitations of occupancy theory

Answer 39

1.) According to the Clark’s occupancy theory, the maximal response to the drug is equal to the maximal tissue response, leading to the expectation that all agonists would produce the same maximal response. For some drugs, e.g., the partial agonists, maximum response can never be achieved even at extremely high doses. (Limitation 1 of the theory) 2.) Second, the occupancy theory assumes that the relationship between occupancy and response is linear and direct. Therefore, a 50% receptor occupancy will result in a half-maximal response and thus KD equals to EC50 (i.e. the concentration of drug producing 50% of Emax). This is rarely seen in biological systems. Nickerson (1956) first showed that agonists such as histamine could produce a maximal tissue response at extremely low receptor occupancies (far less than maximal). (Limitation 2 of the theory)

Question 40

According to the Clark’s occupancy theory, the maximal response to the drug is equal to

Answer 40

the maximal tissue response

Question 41

what are spare receptors?

Answer 41

receptors that remain unbound when an agonist is producing its maximal biologic response receptor reserve’ --> and drugs need to occupy only a minor proportion (≤10%) of the total receptor population to evoke a maximum response.

Question 42

Are Kd and EC50 always equal?

Answer 42

NO

Question 43

what is the overall transduction process that links drug occupancy of receptors and pharmacologic response?

Answer 43

coupling

Question 44

what is coupling determined by?

Answer 44

downstream biochemical events that transduce receptor occupancy into cellular responses

Question 45

define efficacy

Answer 45

the ability of a ligand to initiate receptor activation

Question 46

what kind of ligand has both affinity and efficacy?

Answer 46

agonist

Question 47

types of agonists

Answer 47

1.) Full agonists: mimic the physiologic agonist, e.g., isoproterenol (β-adrenergic agonist). 2.) Partial agonists: activate receptors but are unable to elicit the maximal response of the receptor system; e.g., Dobutamine (a partial agonist at β-adrenergic receptor). 3.) Inverse agonists: Inverse agonists cause constitutively active targets to become inactive; e.g., antihistamines are considered as inverse agonists of H1 receptor.

Question 48

types of antagonists

Answer 48

1.) Competitive or reversible inhibition - bound to active site (noncovalent) - Examples: ACEI, rennin inhibitors, angiotensin receptor inhibitors. 2.) Non-competitive or irreversible inhibition - bound to active site (covalent) - Examples: inhibitors of acetylcholine esterase such as physostigmine, neostigmine etc., cyclooxygenase (COX) inhibition by aspirin, phenoxybenzamine antagonism of α-adrenergic receptor. 3.) Allosteric inhibition - different binding site which morphs the active site (noncovalent mostly) - Examples: nonnucleotide reverse transcriptase inhibitors, antihistamines binding to histamine H1 receptor.

Question 49

what kind of ligand has affinity but lacks efficacy?

Answer 49

antagonists

Question 50

advantages and disadvantages of noncompetitive (irreversible) antagonism

Answer 50

Advantages: duration of action is independent on the drug half life. e.g. Aspirin and proton pump inhibitors (esomeprazole, omeprazole) Disadvantage: reversal of drug effect in case of toxicity is complicated.

Question 51

less commonly know antagonists that act as antagonists of particular receptors without direct interaction with these receptors

Answer 51

Physiological antagonists: two drugs acting on different cognate receptors have opposing pharmacological actions; e.g., histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton pump; the two drugs can be said to act as physiological antagonists. Pharmacokinetic antagonists: decreases another drug's concentration at the site of action----> reduce bioavailability, and thus the concentration of an agonist at its site of action through induction of drug metabolizing enzymes in the liver (e.g., Phenobarbital reducing the anticoagulant effect of warfarin this way), impaired absorption from GI tract or enhancement of renal excretion.

Question 52

___ produce a lower response at full receptor occupancy than do ___

Answer 52

partial agonist; full agonist

Question 53

when there is [ ] of a full agonist and partial agonist together, what is the relationship?

Answer 53

inverse

Question 54

potency refers to ...

Answer 54

the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect. 

Question 55

the potency of the drug depends on ...

Answer 55

affinity Kd coupled response

Question 56

what is the therapeutic window?

Answer 56

the range between the minimum toxic dose and the minimum therapeutic dose - of greater practical value in choosing the dose for the pt

Question 57

define idiosyncratic drug response

Answer 57

unusual and infrequent response mostly due to genetic factors

Question 58

define pharmacodynamics and describe its role in therapeutics

Answer 58

The drugs effect on the body pharmcotherapeutics , our drug choice is dictated by what we need our drug to do, its pharmcodynamics if you will. Example, tissue plasminogen activator TPA is a powerful medicine that can break down blood clots. It is useful for a situation like ischemic stroke where a blood clot is the problem. However we wouldn't use it for a cold since we have no reason to assume it will alleviate cold symptoms or otherwise combat rhinovirus

Question 59

what is TD50

Answer 59

TD50 is the dose required to produce a toxic effect in 50% of the population

Question 60

LD50 is

Answer 60

the amount of a material, given all at once, which causes the death of 50% (one half) of a group of test animals

Question 61

What is ED50

Answer 61

The ED50 (median effective dose) is the dose of a medication that produces a specific effect in 50% of the population that takes that dose.

Question 62

Define Therapeutic Index

Answer 62

defined as the ratio of the TD50 to ED50 from some therapeutically relevant effect

Question 63

narrow therapeutic index is observed with_____

Answer 63

highly potent drug

Question 64

example for when therapeutic drug monitoring (TDM) is recommended

Answer 64

use with lithium (bipolar disorder) due to its narrow therapeutic range and phenytoin