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BMS317 - Pharmacology > LECTURE: 2-4 PHARMACODYNAMICS > Flashcards

LECTURE: 2-4 PHARMACODYNAMICS Flashcards

1
Q

Receptor definition

A

broadly, any target molecule with which a drug molecule must combine in order to elicit an effect. Usually, a site through which some molecule (drug, hormone, neurotransmitter) acts to initiate a biochemical or physiological chain of events

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2
Q

Ligand definition

A

any molecule that binds to another biological entity, regardless of effect

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3
Q

Agonist

A

a molecule that acts at a receptor to initiate a response

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4
Q

Antagonist

A

a molecule that binds to a receptor without causing activation

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5
Q

Ways to measure drug-receptor interaction

A
  1. direct measurement of biological repsonse (concentration effect or dose effect curves)
  2. Indirect measurement of biological response (e.g. receptor binding)
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6
Q

C-E and D-E curves should not be used to measure affinity because

A

1) Response is not always directly proportional to occupancy
2) The concentration of a drug at a receptor is usually unknown

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7
Q

Graded dose reponse curves

A
  • The response of a system is measured against increasing concentrations of a drug
  • Continuous: e.g. smooth muscle contraction, change in blood pressure, change in rate of urine production
  • Change in biological effect is plotted against the dose of the drug administered
  • Gives us some information on the properties of the drug relevant to the system
  • Referred to as concentration-effect, dose-effect, or dose-response curves (all the same thing)
  • Doesn’t tell us occupancy or affinity
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8
Q

Emax

A

maximum effect drug has on the system

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9
Q

EC50/ED50

A

concentration of a drug that will elicit 50% of the maximum effect

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10
Q

Quantal dose response curves

A
  • Quantal dose-response: effect is all or nothing
  • E.g. live or dead, seizure or no seizure, conscious or unconscious
  • Gives a population (normal) distribution
  • Can be used to determine the lethal dose of a drug
  • An example from the lab: murine tail flick test
  • An experiment to test analgesics in mice, which flick the tail in response to pain (e.g. to heat)
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11
Q

LD50

A

dose which kills 50% of the population

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12
Q

difference in ED50 between graded and quantal dose-response curves

A
  • In the graded dose-response curve, the ED50 refers to the concentration of a drug that will elicit 50% of the maximum effect
  • In the quantal dose-response curve, the ED50 refers to the concentration of the drug that produces an effect in 50% of the population
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13
Q

difference in ED50 between graded and quantal dose-response curves

A
  • In the graded dose-response curve, the ED50 refers to the concentration of a drug that will elicit 50% of the maximum effect
  • In the quantal dose-response curve, the ED50 refers to the concentration of the drug that produces an effect in 50% of the population
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14
Q

TI

A

the window between the effective (therapeutic) dose and the lethal dose, which tells us the safety of the drug

TI = LD50/ED50

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15
Q

efficacy

A

the ability or “strength” of a single drug-receptor complex in evoking a response in tissue. This applies only to those compounds that elicit a response (agonists). For antagonists, efficacy is zero

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16
Q

affinity

A

the ‘tightness’ with which a ligand and receptor will bind (in general, a drug with low affinity for a receptor will need a higher concentration of drug to exert maximum effect and vice versa). Doesn’t comment on effectiveness of the drug and applies to agonists and antagonists. Measured by the equilibrium constant Kd.

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17
Q

potency

A

the amount of drug required to produce a given effect. In general, this is influenced by the combination of efficacy and affinity

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18
Q

efficacy vs. potency graph

A
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19
Q

Drug specificity

A

can be biological specificity or chemical specificity

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20
Q

Targets of drug action

A

1) drugs that depend on chemical properties and do not interact with cellular components
2) drugs that combine with specific molecular components
* lipids
* DNA
* protein - main focus

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21
Q

4 classes of protein receptors

A
  1. enzymes
  2. carrier molecules
  3. ion channels
  4. classical receptors
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22
Q

Enzymes (protein receptors)

A
  1. Inhibitor:
    - A substrate analogue that acts as a competitive or non-competitive inhibitor
  2. False substrate:
    - The drug competes for the enzyme’s binding site, but produces an abnormal metabolite (e.g. different from the endogenous product) which ‘hijacks’ the normal pathway
  3. Prodrug:
    - These drugs are inactive when administered and are converted into the active compound by an enzyme (usually in the liver). Many drugs are prodrugs!
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23
Q

Carrier molecules (protein receptor)

A
  • Transport molecules across lipid membranes (or blood brain barrier)
  • Drugs may either utilize or block these carriers
  • Normal transport: transport of ions and small molecules across membrane requires transporter protein- facilitated transport systems
  • False substrate: similar to enzymes, hijacks carrier molecule to get across barrier
24
Q

Ion channels

A
  • Ion channel blockers: permeation of the channel blocked, ions cannot move through the channel
  • Ion channel modulators: promote or repress normal function by binding to a specific site on the channel

Voltage-gated ion channels
- Target for many drug classes and toxins

Ligand-gated ion channels
- Target for many drug classes and toxins

25
Q

Classical receptors (protein receptor)

A
  • receptors found on cell membranes or inside the cell
  • can be activated or inactivated
  • G-protein coupled receptors (cAMP pathway and Phosphatidylinositol pathway)
  • Enzyme-linked receptors
  • Nuclear receptors
26
Q

Classical receptors - activation by agonist leads to

A

o Ion channel modulation
o Enzyme activation or inhibition
o Activation or suppression of cell signaling molecules
o DNA transcription

27
Q

Classical receptors - inactivation by an antagonist causes

A

activity to be blocked

28
Q

G-protein coupled receptors involved in two main signal transduction pathways

A

o cAMP pathway
o Phosphatidylinositol pathway

29
Q

G-protein coupled receptors are only found in

A

eukarytoes

30
Q

what are G proteins

A
  • Guanine nucleotide-binding proteins
  • Transmit signals from stimuli outside cell to inside cell
  • Turned ON when bound to GTP
  • Turned OFF when bound to GDP
31
Q

Occupancu of receptors refers to

A

the proportion of receptors occupied by a drug

32
Q

Kd

A

dose that results in binding to 50% of the receptors

33
Q

Spare receptors

A

receptors that do not bind drug in order for the maximum biological effect to be produced

34
Q

spare receptor theory

A
  • This means that the maximum biological response often occurs when fewer than 100% of receptors are activated
35
Q

full agonist

A

Only a few receptors are activated for maximum response

36
Q

Partial agonist

A

All receptors are occupied but maximum response is not reached

37
Q

Inverse agonist

A

Bind to constitutive receptors and reduce activity

38
Q

What happens when a full and partial agonist are given together

A

the partial agonist acts as a competitive antagonist and decreases net activation

39
Q

Co-agonists

A

require two ligands to activate a receptor

40
Q

Allosteric modulators

A
  • Drugs that bind to an allosteric site (or regulatory site) and not the active site of a receptor
  • This allows them to enhance or inhibit the effects of the endogenous ligand
  • Conformational change by drug binding changes the binding affinity of the endogenous ligand, to regulate the ‘strength’ of its effects
41
Q

irreversible agonists

A
  • These permanently and irreversibly bind to a receptor by forming covalent bonds
42
Q

Physiological agonists

A
  • These are molecules that produce the same effects in the body as another molecule without binding to the same receptor
43
Q

Mixed agonist-antagonists

A
  • Drugs that act as an agonist in some tissues and antagonist in other tissues (e.g. selective oestrogen receptor modulators)
    OR
  • Is an agonist at some receptor subtypes and an antagonist at other subtypes (e.g. lots of opioids)
44
Q

Do antagonists have affinity and efficacy?

A

they have affinity for receptors, but dont have efficacy

45
Q

Where do antagonists bind

A
  • active site
  • allosteric site
46
Q

competiive antagonists

A
  • The antagonist competes with the agonist for the binding site
  • Reverdsible or irreversible
47
Q

Reversible competitive antagonism

A
  • Surmountable
  • Bind via non-covalent bonds and will eventually dissociate from the receptor
  • Addition of enough agonist will displace the antagonist, allowing a full response to occur
  • Expressed as a parallel shift in the agonist dose-response curve
48
Q

Irreversible competiitve antagonism

A
  • Non-surmountable
  • Bind via covalent bonds and will permanently antagonize the receptor (until it is ubiquitinated or the drug metabolized)
  • No amount of agonist will displace the antagonist from the receptor, so no full response can occur
  • Expressed as a decrease in the agonist dose-response curve
49
Q

Non competitive antagonists

A
  • These bind somewhere other than the active site and block the chain of events that leads to an agonist response
  • Reduce the magnitude of the maximal response that can be achieved by an agonist
  • May be reversible or irreversible
50
Q

Uncompetitive antagonists

A
  • Not the same as non-competitive antagonists
  • Require the receptor to be activated by an agonist before they can bind to an allosteric site
  • Somewhat paradoxical kinetics: the same concentration of antagonist is better able to block higher concentrations of an agonist than it is lower concentrations
51
Q

Chemical antagonists

A
  • Chemical antagonism occurs when two substances combine in solution (e.g. the body) and the agonist is inactivated, thereby reducing the concentration of active drug circulating
  • An important class of chemical antagonists are chelating agents used to treat heavy metal poisoning
52
Q

Pharmacokinetic antagonists

A
  • This refers to a drug reducing or inhibiting the effect of another by interfering with its absorption, distribution, metabolism or elimination
  • Lots of drugs do this by accelerating the hepatic metabolism of others
53
Q

Physiological antagonists

A
  • Physiological antagonism refers to the interaction of two drugs whose opposing actions cancel each other out
54
Q

Inverse agonists

A
  • Drugs that bind to a receptor and have the opposite effect to an agonist
  • Receptors must have an intrinsic level of activity in the absence of a ligand for an inverse agonist to induce a ‘negative’ effect
  • Inverse agonists are considered to have negative efficacy
  • Many drugs previously assumed to be antagonists are actually inverse agonists (e.g. most antihistamines)
55
Q

Inverse agonists: mechanism

A
  • Theoretically, G protein-coupled receptors exist in an equilibrium of either active or inactive states whilst no ligand is present
  • Inverse agonists induce conformational changes that shift this equilibrium and switch the receptor from an active to inactive state
  • The inactive state is ‘stabilized’ by the inverse agonist, which suppresses agonist-independent activity of the receptor
  • The magnitude of effect of the inverse agonist depends on the intrinsic activity of the receptor
  • Also may depend on other drugs: e.g. Naloxone is an antagonist of the mu opioid receptor under basal conditions, but in the presence of morphine acts as an inverse agonist

BMS317 - Pharmacology (22 decks)

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