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(D) Pharmacology > Lecture 2- PD and drug-receptor interactions > Flashcards

Lecture 2- PD and drug-receptor interactions Flashcards

1
Q

Pharmacodynamics (PD)

A

The effect of the drug on the body

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2
Q

Pharmacokinetics (PK)

A

Effect of the body on the drug (ADME)
- absorption
- distribution
- metabolism
- excretion

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3
Q

Is a target receptor necessary?

A

A few clinically useful drugs do not require a target receptor to evoke biological response (osmotic diuretics i.e. mannitol, antidotes for heavy metal poisoning

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4
Q

How do drug receptors function?

A

Most drugs have a specific structural interaction with specific cellular target molecules (receptors)

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5
Q

Who pioneered the concept of receptor?

A

Langley and Ehrlich in early twentieth century

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6
Q

Where is a receptor located pharmacologically?

A

Mostly on the cell membrane, but also within the cytoplasm or cell nucleus that binds to a specific molecule such as a neurotransmitter, hormone, metabolite, or a drug molecule and thereby initiating cellular response

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7
Q

What is the result of drug-induced changes in the biochemical and biophysical properties of the receptor?

A

physiological changes that constitute the biological actions of the drugs

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8
Q

What does a receptor’s affinity for binding a drug determine?

A

The concentration of drug required to form a significant number of drug-receptor complexes

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9
Q

What might the total number of receptors limit?

A

the maximal effect a drug may produce

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10
Q

Ensemble

A

Multiple chemical interactions (ie van der Waals, covalent..)

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11
Q

What does ensemble provide?

A

Specificity of the overall drug-receptor interaction

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12
Q

What is affinity (KD value)?

A

A measure of the favorability of a drug-receptor interaction

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13
Q

What contributes to the overall potency, efficacy, and duration of drug action?

A

Minor variation in the functionalities of the drug molecules can significantly alter the binding interactions

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14
Q

Bond Types

A

Covalent Bond
Non-covalent bonds
- ionic
- dipole
- hydrogen bonds (specialized dipole dipole)
- van der waals
- hydrophobic
- chelation and complexation
- charge transfer interactions

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15
Q

Covalent Interaction examples

A

alkylation and acylation

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16
Q

Receptor Classes

A

Protein and Non-protein

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17
Q

Types of protein drug receptors

A

Enzymes
Ionotropic
metabotropic
kinase
nuclear
cytoskeletal or structural
transporters or carrier

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18
Q

Types of non-protein receptors

A

nucleic acids (dna, rna), membranes, and fluid compartments

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19
Q

Enzyme example

A

dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate

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20
Q

ionotropic receptors or ion channels

A

ligand gated channels and voltage gated channels

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21
Q

metabotropic receptors

A

G-protein coupled receptors that bind to endogenously produced hormones, neurotransmitter, etc.

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22
Q

nuclear receptors

A

receptors for thyroid hormone, some fat-soluble vitamins and steroids

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22
Q

kinase linked and related receptors

A

receptors for various growth factors and thus for some anticancer drugs

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23
Q

cytoskeletal and structural proteins

A

ie tubulin, the receptor for colchicine, an anti-inflammatory agent

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24
Q

transporters or carrier proteins

A

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

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25
Q

Effector components

A

Can be coupled with a receptor (particularly GPCR) orchestrate diverse cellular effects which may occur over a wider time scale.
Also known as a respective executioner

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26
Q

Occupancy Theory

A

The maximal response of the drug is equal to the maximal tissue response

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27
Q

KD

A

It is the concentration of the drug that produces a fractional occupancy of 50%
Concentration: quantifies the ‘affinity’ of particular drug for its receptor

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28
Q

low Kd

A

binding affinity is high

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29
Q

high Kd

A

low binding affinity

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30
Q

What occurs with a large increase in drug concentration

A

Concentration of a receptor is finite within a tissue, so will saturate the receptor pool leading to secondary, less affinity binding to various non-specific sites other than the receptor protein. This may create unwanted side effects

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31
Q

1st limitation of Clark’s occupancy theory:

A

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, ie partial agonists, maximum response can never be achieved even at extremely high doses

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32
Q

Partial agonist

A

activate receptors but are unable to elicit the maximal response of the receptor system

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33
Q

Second limitation of Clark’s occupancy theory:

A

it assumes the relationship btwn occupancy and response is linear and direct.
(ie a 50% receptor occupancy will result in a half-maximal response and thus KD equals to EC50 –> the concentration of drug producing 50% of Emax)

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34
Q

What did Nickerson (1956) first show regarding agonists in occupancy theory?

A

that they could produce a maximal tissue response at extremely low receptor occupancies (far less than maximal)

35
Q

Spare receptors

A

receptor reserve, drugs need to occupy only a minor proportion (<10%) of the total receptor population to evoke a maximum response

36
Q

Dose-response curves

A

drug effect (y-axis) against the log of the dose or concentration (x-axis), transforming the hyperbolic curve into a sigmoid curve with a linear mid-portion

37
Q

hyperbolic curve

A

drug dose and drug response are plotted in a linear way, produces a hyperbolic curve (plat

38
Q

coupling

A

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

39
Q

By what is coupling determined?

A

“downstream” biochemical events that transduce (causes) receptor occupancy into cellular response

40
Q

What defines a receptor as “spare”

A

if it is possible to elicit a maximal biologic response at a concentration of agonist that does not result in occupancy of all of the available receptors

41
Q

Two actions drugs can elicit upon binding at specific binding sites on their receptors

A
  1. Mimic the action of endogenously produced ligands as agonists
  2. Oppose the biological effects of the endogenous ligands as antagonists
42
Q

Competitive antagonist

A

Increasing concentrations can progressively inhibit the (fixed concentration) agonist response.
High antagonist concentrations prevent the response almost completely

42
Q

High agonist concentrations

A

Can surmount the effect of a given concentration of the antagonist (Emax for the agonist remains the same for any fixed concentration of antagonist)

43
Q

Agonist of a receptor action:

A

activates the receptor (the binding of a drug induces changes in the structure of that receptor in such a way that a biologic response is elicited)

44
Q

Efficacy

A

the ability of a ligand to initiate receptor activation

45
Q

Full agonists (agonist subtype)

A

mimic the physiologic agonist (ie isoproterenol (B-adrenergic agonist))

46
Q

Partial agonists (agonist subtype)

A

activate receptors but are unable to elicit the maximal response of the receptor system (ie dobutamine (partial agonist at B-adrenergic receptor))

47
Q

inverse agonists (agonist subtype)

A

constitutively active targets to become inactive (ie antihistamines considered inverse agonists of H1 receptor)

48
Q

cognate receptor

A

two typical biomolecules interacting

(ie ligand and receptor)

49
Q

Two things agonists have

A

affinity and efficacy for cognate receptors

50
Q

Antagonists

A

Have affinity but lack efficacy

51
Q

Ways a drug can antagonize a receptor

A

Competitive or reversible inhibition
Non-competitive or irreversible inhibition
Allosteric inhibition

52
Q

Competitive inhibitor

A

Occupies the active site and prevents binding of the physiological (ie endogenously produced) ligands. (ie ACEI, rennin inhibitors, angiotensin receptor inhibitors

53
Q

Non-competitive or irreversible inhibitor

A

covalently binds at the active site of the enzyme and irreversibly inhibits it.
(ie inhibitors of acetylcholine esterase such as physostigmine, neostigmine, COX inhibition by aspirin, phenoxybenzamine antagonism of a-adrenergic receptor)

54
Q

Allosteric inhibitor

A

binds at sites other than the active site, causing a conformational change in the enzyme that prevents it from binding to its physiological substrate.
(ie nonnucleotide reverse transcriptase inhibitors, antihistamines binding to histamine H1 receptor)

55
Q

Agonist concentration-effect curves produced by a competitive antagonist or by an irreversible antagonist

A
56
Q

Advantages Irreversible Antagonism

A

duration of action is independent on the drug half life (ie aspirin and proton pump inhibitors: esomeprazole, omeprazole)

57
Q

Disadvantage Irreversible Antagonism

A

reversal of drug effect in case of toxicity is complicated

58
Q

Physiological antagonists

A

two drugs acting on different cognate receptors have opposing pharmacological actions
(ie 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)

59
Q

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

60
Q

Partial agonists vs full agonists

A

partial produces a lower response at full receptor occupancy and competitively inhibits the responses produced by full agonists.

61
Q

Percentage of receptor occupancy resulting from full agonist (present at a single concentration) binding to receptors in the presence of increasing concentrations of a partial agonist.

A
62
Q

How many main signaling mechanisms are there?

A

Five basic mechanisms of transmembrane signaling are well understood

63
Q
  1. transmembrane signaling mechanism
A

A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor

64
Q
  1. transmembrane signaling mechanism
A

the signal binds to the extracellular domain of a transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain

65
Q
  1. transmembrane signaling mechanism
A

signal binds to the extracellular domain of a transmembrane receptor bound to a separate protein tyrosine kinase, which it activates

66
Q
  1. transmembrane signaling membrane
A

the signal binds to and directly regulates the opening of an ion channel

67
Q
  1. transmembrane signaling mechanism
A

signal binds to a cell-surface receptor linked to an effector enzyme by a G protein

68
Q

Potency

A

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

69
Q

What 2 things does potency depend on?

A

Affinity (Kd)
Coupled response

70
Q

Maximal Efficacy

A

Max effect it can have while occupying the lowest proportion of receptors
(even if you add more drug, it won’t cause more response)

71
Q

Graded dose-response curves limitations

A

impossible to construct if pharmacological response is an either-or (quantal) event (such as prevention of convulsions, arrhythmia, or death)
variability amongst patients in dose-response relation

72
Q

Quantal dose-effect curves

A

plotting the cumulative frequency distribution of responders versus the log dose and the dose of drug required to produce a specified magnitude of effect
(variability in persons dose to elicit same response)

73
Q

Therapeutic Index (TI)

A

the ratio of the TD50 (or LD50) to the ED50 for some therapeutically relevant effect.

74
Q

TI examples

A

Digoxin has a narrow TI
Aspirin has a high TI

75
Q

LD50 (TD50)

A

median lethal (toxic) dose

76
Q

ED50

A

median effective dose

77
Q

Therapeutic Window

A

range between minimum toxic dose and the minimum therapeutic dose

78
Q

Idiosyncratic drug response

A

unusual and infrequent response mostly due to genetic factors

79
Q

quantitative variations

A

hyper reactive or hyporeactive

80
Q

tolerance

A

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

81
Q

tachyphylaxis

A

rapid tolerance

82
Q

mechanisms

A

variation in drug conc. at active site, variation in receptor expression, variation in receptor-coupling effect, etc

83
Q

Therapeutic Drug Monitoring (TDM)

A

may have dosage adjusted according to measurements of the actual blood levels achieved in the person taking it

84
Q

When is TDM recommended?

A

Lithium (for bipolar disorder due to narrow therapeutic range)j
Phenytoin (anticonvulsant)

(D) Pharmacology (18 decks)

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