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Paige - Pharmacology > Lecture 2 > Flashcards

Lecture 2 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

Enzymes

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

kinase linked and related receptors

A

receptors for various growth factors and thus for some anticancer drugs

23
Q

cytoskeletal and structural proteins

A

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

24
Q

transporters or carrier proteins

A

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

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

26
Q

Occupancy Theory

A

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

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

28
Q

low Kd

A

binding affinity is high

29
Q

high Kd

A

low binding affinity

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

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

32
Q

Partial agonist

A

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

33
Q

Second limitation of Clark’s occupancy theory:

A

it assumes the relationship between 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)

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 vs drug response

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 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

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

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
52
Q

Competitive antagonist

A

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

53
Q

nuclear receptors

A

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

Paige - Pharmacology (16 decks)

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