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Pharm S1 > Lecture 2- E1 : drug-receptor interactions > Flashcards

Lecture 2- E1 : drug-receptor interactions Flashcards

1
Q

what is pharmacodynamics (PD)

A

how the drug affects the body (drug fixes disease)

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2
Q

what is pharmacokinetics (PK)

A

the effect of the body on the drug (the body reacting to a foreigner what it does to metabolize, eliminate)

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3
Q

what is PK sometimes referred to as

A

ADME
absorption, distribution, metabolism, excretion

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4
Q

what are some drugs that do NOT require a target receptor to evoke their response

A

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

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5
Q

Where did the concept of receptor evolve from

A

pioneering work of Lanley and Ehrich (early 20th century)

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6
Q

how do most drugs work?

A

most drugs work in a structurally specific way stemming from how they react at each target molecule (receptor) to excrete their therapeutic or toxic effects

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7
Q

what can bind to a receptor?

A

specific molecules such as neurotransmitters, hormones, metabolites, or drug molecules

all initiating some type of cellular response

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8
Q

how do biological actions of drug come to be enforced?

A

a drug can cause biological and biophysical changes in the receptor site which then create physiological changes in the body that show the drugs actions/effect

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9
Q

what do receptors largely determine

A

the relations between the dose/ concentration of drug and its pharmacological effects

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10
Q

what determines the drug concentration needed to form an adequate amount of drug receptor complexes

A

affinity for (attraction for) binding a drug

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11
Q

what can limit the maximal effect a drug may produce

A

the total amount of receptors
( which is determined by the concentration of drug needed)

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12
Q

van der waals bond strength

A

very weak

also hydrophobic

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13
Q

high affinity

A

less drug dose

(because its easier for the drug to bind and produce a strong cellular signal so you don’t need as many receptors- which the number is determined by concentration)

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14
Q

the specificity of the overall drug-receptor interaction is determined by what?

A

the ensemble of the interactions between chemical interactions (different types/strengths of bonds)

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15
Q

how is affinity measured/reported?

A

by the Kd value

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16
Q

what is the Kd value

A

a concentration

a measure of the favorability for a particular drug for its receptor

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

kd is the value it will take to fill 50% of receptors (E50)

can tell us how well a drug can bind to a receptor

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17
Q

affinity contributes to overall..

A

potency
efficacy
duration of drug action

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18
Q

what can significantly alter binding interactions of drugs

A

even a minor variation in functionality of the drug molecule

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19
Q

Non-covalent bonds

A
  • Ionic Bonds
  • Dipole Interactions
  • Hydrogen Bonds: a specialized type of Dipole-Dipole bond ( a hydrogen and individual atoms)
  • van der Waals Interactions
  • Hydrophobic Bonding
  • Chelation and Complexation
  • Charge Transfer Interactions

hydrophobic and van der waals work closely together

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20
Q

ionic bond

A

complete transfer of valence electron to attain stability

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21
Q

Dipole interaction

A

partial charge bonded with opposite partial charge

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22
Q

Hydrogen bond

A

H–F,O,N

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23
Q

van der Waals

A

all Carbons
hydrophobic

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24
Q

hydrophobic interaction

A

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.

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25
Q

chelation and complexation

A

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

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26
Q

What is a charge transfer interaction

A

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.

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27
Q

which bonds are permenant

A

covalent

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28
Q

most drug receptors are…

A

proteins

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29
Q

what produces a fractional occupancy of 50%

A

the concentration of a drug

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30
Q

Categories of protein receptors

A

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

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31
Q

example of enzyme as a protein drug receptor

A

dihydrofolate reductase, the receptor for the antineoplastic drug methoxetrate

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32
Q

example of metabotropic receptors as a protein drug receptor

A

G protein coupled receptors that bind to endogenously produced hormones, neurotransmitters, etc

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33
Q

example of kinase linked and related receptors as a protein drug receptor

A

receptors for various growth factors and thus for some anticancer drugs

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34
Q

example of nuclear receptors as a protein drug receptor

A

receptors for thyroid hormone, some fat soluble vitamins and steroids

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35
Q

example of cytoskeletal or structural proteins as a protein drug receptor

A

tubulin, the receptor for colchicine, anti inflammatory agent

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36
Q

example of transporters or carrier proteins as a protein drug receptor

A

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

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37
Q

what are the non protein receptors

A

nucleic acids (DNA, RNA) membranes, and fluid compartments

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38
Q

what receptor classes can be coupled as executioners or effector components and what do they do?

A

G protein couple receptors and growth factor receptors can be coupled as effector components as they create diverse cellular effects which can occur over a wider time scale

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39
Q

speed of effect production by ion channels

A

very fast (milleseconds)

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40
Q

speed of effect production by steroid and thyroid hormones

A

very slow ( several minutes to hours)

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41
Q

speed of GPCR effect production

A

intermediate time scale - seconds to minutes

42
Q

what does the occupancy theory really mean?

A

that a response or effect is only elicited when a drug or ligand is BOUND to the receptor- it isn’t the receptor that elicits this response

% bound = % response

43
Q

Emax values

A

full Emax =1
partial Emax <1
super Emax >1

44
Q

Occupancy theory ( laws of mass action) variables

A

D+R bind reversibly to form DR complex

DR complex creates E (effect)

45
Q

in the occupancy theory, the magnitude or intensity of the response (E) is directly proportional to what

A

the amount or concentration of the DR complex

46
Q

how is Kd derived from occupancy theory graphs?

A

where the fractional occupancy is quantified by using the equilibrium

  • the graph will flatten out even if you continue to increase concentration of drug because you met the equilibrium where the effect (response) maximum has hit showing where the drug concentration (x axis) needs to be for that effect
47
Q

When is Emax hit

A

when all of the receptors (Rt) are occupied by the drug (forming the DR complex)

48
Q

For an agonist in the occupancy theory, what is E

A

E can only come from the DR complex, and E is a function of the fractional occupancy ( which is determined by the concentration of a drug)

49
Q

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

A

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)

50
Q

examples of Therapeutic index (TI)

A

penicillin (high window) and warfarin (low window)

51
Q

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

A
  • ion channels: (milliseconds)
  • steroid and thyroid hormones: (several minutes)
  • GPCRs: (seconds to minutes)
52
Q

equation for fractional occupancy

A
53
Q

Limitations of occupancy theory

A

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)

54
Q

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

A

the maximal tissue response

55
Q

what are spare receptors?

A

“receptor reserve”
- likely play a role in amplifying signal intensity and duration

-these remain unbound when an agonist produces its full effect ( so agonists don’t need to fill every receptor to maximize effect)

  • may never come into play
  • may allow cell activation by weak ligands
  • allows for higher maximal effect when there are spare receptors present
56
Q

Agonist vs Antagonist on a dose response curve graph

A

a pure agonist will reach maximal effect at a lower concentration (EC50 at lowest and equal to Kd)

pure antagonist will need more dose because it needs a higher concentration in order to reach Kd and maximum effect ( still able to reach this max because there are an adequate number of spare receptors

  • as more antagonist is introduced, the number of spare receptors decreases and eventually can no longer hit the maximal effect
57
Q

Are Kd and EC50 always equal?

A

NO

58
Q

what is coupling

A

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

59
Q

what is coupling determined by?

A

downstream biochemical events that transduce receptor occupancy into cellular responses

60
Q

when are receptors said to be spare for a given pharmacological repsonse

A

if its possible to elicit a maximum biologic response (Emax) at a concentration of agonist that doesn’t result in occupancy of every available receptor

61
Q

what does an agonist do

A

mimics body function or function of endogenously produced ligands

62
Q

what does an antagonist do

A

opposed body function or can oppose biological effects of endogenous ligands

63
Q

in the presence of a fixed agonist concentration what can inhibit this response

A

increasing the concentrations of competitive antagonist

high antagonist concentrations prevent the response almost completely

antagonist binds at the same place as agonist so they’re now competing for a place

64
Q

define efficacy

A

the ability of a ligand to initiate receptor activation

65
Q

what kind of ligand has both affinity and efficacy for cognate receptors?

A

agonists

66
Q

what is a full agonist

A

mimic the physiologic agonist, e.g., isoproterenol (β-adrenergic agonist).

67
Q

what is a partial agonist

A
  • activate receptors but are unable to elicit the maximal response of the receptor system;
  • e.g., Dobutamine (a partial agonist at β-adrenergic receptor).
  • doesn’t keep the max effect on the curve- can act as a full agonist, or antagonist
68
Q

what is an inverse agonist

A

-Inverse agonists cause constitutively active targets to become inactive
- e.g., antihistamines are considered as inverse agonists of H1 receptor.- very potent only need low dose
- powerful antagonist

69
Q

competitive or reversible inhibition antagonist

A

bound to active site (noncovalent) - Examples: ACEI, rennin inhibitors, angiotensin receptor inhibitors.

70
Q

what are non competitive or irreversible inhibitor antagonists

A

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.

agonist and noncompetitive antagonist on a graph- EC50 is the same but cant get as high of effect as agonist alone

71
Q

what are allosteric inhibition antagonists

A

different binding site which morphs the active site (dont bind to same active site in receptor)
-noncovalent mostly, can be covalent - Examples: nonnucleotide reverse transcriptase inhibitors, antihistamines binding to histamine H1 receptor.

72
Q

what kind of ligand has affinity but lacks efficacy?

A

antagonists

73
Q

advantages of noncompetitive (irreversible) antagonism

A

duration of action is independent on the drug half life. e.g. Aspirin and proton pump inhibitors (esomeprazole, omeprazole)

74
Q

disadvantages of noncompetitive (irreversible) antagonism

A

reversal of drug effect in case of toxicity is complicated.

75
Q

what are physiological antagonists:

A

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.

  • antagonist of particular receptor without direct interaction with that receptor
76
Q

what are pharmacokinetic antagonists

A

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.

-antagonist of particular receptor without direct interaction with this receptor

77
Q

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

A

partial agonist; full agonist

78
Q

failure of partial agonists to produce max response is NOT due to

A

decreased affinity for binding to receptors

79
Q

what do partial agonists do to full agonists

A

partial agonists competitively inhibit responses produced by full agonists…. “agonist-antagonist” property

can be beneficial or deleterious

ex-buprenorphine, partial agonist for u-opioid receptors, is gen. safer analgesic drug than than morphine bc less respiratory depression in overdose. however buprenorphine is effectively anti analgesic when administered with more efficacious opioid drugs

80
Q

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

A

inverse

81
Q

potency refers to …

A

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

82
Q

how is potency stated

A

in dosage units (50 mg for mild sedation)

83
Q

the potency of the drug depends on …

A

affinity Kd
coupled response

84
Q

what is a quantal dose response

A

drug effect which is either present or absent

85
Q

what do quantum dose effect curves show

A

-therapeutic index, median effective dose, median lethal dose, and other parameters to determine safe dose recommendations

  • potential variability of responsiveness among individuals
86
Q

limitations of quantal dose effect curves

A

-cant construct if pharmacological response is a quantal (either or) event such as prevention of convulsions, arrhythmia, death

  • relevance of response in one patient is limtited in application to other patients
87
Q

what is the therapeutic window?

A

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

88
Q

define idiosyncratic drug response

A

unusual and infrequent response mostly due to genetic factors

89
Q

define pharmacodynamics and describe its role in therapeutics

A

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

90
Q

what is TD50

A

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

91
Q

LD50 is

A

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

92
Q

What is ED50

A

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.

93
Q

Define Therapeutic Index

A

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

94
Q

narrow therapeutic index is observed with_____

A

highly potent drug
(digoxin has small window while aspirin has large window)

  • bigger window is safer
95
Q

example for when therapeutic drug monitoring (TDM) is recommended

A

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

96
Q

what are quantitative variations

A

hyper reactive or hypo reactive

97
Q

what is tolerance

A

decrease in the intensity of response to a given dose (usually over time)

98
Q

what is tachyphylaxis

A

rapid tolerance

99
Q

mechanisms of variation in drug responsiveness

A

variation in drug concentration at active site, variation in receptor coupling effect

100
Q

what is therapeutic drug monitoring (TDM)

A

-drugs with narrow therapeutic range may have dosage adjusted according to actual blood levels in the person taking it

-recommended for use with lithium (bipolar disorder) and phenytoin (anticonvulsant)

  • may do this in hospital before discharge

Pharm S1 (18 decks)

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