pharmacodynamics

Question 1

what is pharmacokinetics?

Answer 1

How the body handles & processes drugs

Question 2

what is pharmacodynamics

Answer 2

Mechanisms of drug action

Question 3

all drugs have these 3 types of names

Answer 3

-chemical name
-generic name
-commercial / trade / brand name

Question 4

most important drug name to know, for those that you administer

Answer 4

generic name

Question 5

multicellular organisms rely on what to control tissue function? How does this work?

Answer 5

intracellular signalling molecules
-These interact with proteins (receptors) in the plasma membrane to regulate biochemical pathways in the cytoplasm

Question 6

how many different types of cellular receptors are there? Why is this relevant for drugs?

Answer 6

Each cell type expresses a unique selection of receptors
More than 1,000 plasma membrane receptors are known, in more than 20 families
Most drugs (a.k.a. ligands) act by stimulating or blocking membrane receptors

Question 7

what is the signal transduction pathway?

Answer 7

The receptor, its cellular target and any intermediary molecules are referred to as the signal transduction pathway (a.k.a. receptor-effector system)

Question 8

what do drugs need in order to interact with receptors?

Answer 8

In order for drugs to interact with receptors, they need to possess adequate:
* Size
* Charge
* Shape & atomic composition

Question 9

what size range do drugs need to fit within, generally? What if they are bigger?

Answer 9

Size (100-1000 MW)
* Lower limit (~100 MW): minimum size needed to
impart specificity of action
(some drugs are smaller, e.g., N2O MW 44)
* Upper limit (~1,000 MW): size limit allowing
reasonable movement in the body to sites of action (some drugs are larger, e.g., human chorionic gonadotropin MW 2321.6; enfuvirtide MW 4491.9)
* Very large drugs must be administered directly into the compartments where the target receptors are located

Question 10

how is charge related to drug-receptor interactions? which pairings are more selective? what is affinity?

Answer 10

Drugs & receptors interact by means of chemical forces or bonds
* Drugs that interact with receptors through weak bonds are more selective
(Not enough energy to ‘dock’ if fit is not optimal)
* A drug may interact with receptors that do not have the optimal fit if the D-R bond is strong enough to overcome poor fit
* Relative ability to bind to receptor is called
affinity

Question 11

main types of bonds important for drug-receptor interactions and their properties

Answer 11

Covalent (uncommon)
* Very strong; typically irreversible
E.g., acetylation of cyclooxygenase by aspirin; DNA-alkylating anti-cancer agents

Electrostatic (common)
* Weaker than covalent
* Include electrostatic, hydrogen, van der Waals bonds
* Many D-R interactions involve such bonds

Hydrophobic (common)
* Usually quite weak
* Probably most important with lipid interactions and highly lipid-soluble drugs
* Many D-R interactions involve such bonds

Question 12

Drugs modify signal transduction after binding to receptors to do what? How long do effects take to appear and what do they depend on?

Answer 12

• initiate
• enhance
• diminish
• terminate (block)
  cellular biochemical pathways

-Effects can be immediate (ms to s) or delayed (min to hours)
-Effects depend on actions of effector proteins and often second messengers that modulate cellular targets

Question 13

drug effect is generally proportional to what, regarding receptors? what does this depend on?

Answer 13

-Drug effect is generally proportional to the percentage of receptors occupied by drug
-The fraction of drug receptors occupied by drug is dependent on drug concentration in extracellular fluid

Question 14

Five main mechanisms of transmembrane signalling account for the majority of drug effects:

Answer 14

1. Lipid-soluble drug binds to cytoplasmic receptor
2. Transmembrane enzyme
3. Transmembrane non-enzyme
4. Drug binds to and opens or blocks ion channel
5. G-protein coupled receptors (GPCRs)

Question 15

what type of drugs bind to cytoplasmic receptors? How do they do so, and what happens next ie. how do they effect change?

What is an example of this type of drug, and how long will effects take to appear, and then last?

Answer 15

Lipid-soluble drug binds to cytoplasmic receptor
* Receptor possesses a DNA-binding domain as well as a ligand-binding site
* D-R complex translocates to nucleus > binds to response elements > modulates gene transcription

Example: steroids (progesterone, estrogen, glucocorticoids)
Hormones typically have a lag time for their effects
* Minutes to hours before onset of effects
* Time required for synthesis of new proteins
* Biological effects persist after drug has left body (hours, days)

Question 16

how does a transmembrane enzyme effect change due to drug interaction

Answer 16

Transmembrane enzyme
D-R complex activates enzymatic activity on cytoplasmic face of receptor

Question 17

how do transmembrane non-enzymes effect change due to drug interaction? what is an important type of these? How do they work?

Answer 17

Transmembrane non-enzyme
Includes cytokine receptors

• Enzyme activity is not intrinsic to receptor, rather receptor activation allows mobile enzymes to bind to the cytoplasmic face of the receptor

Question 18

how are ion channels important in receptor-drug interactions? How do they work, and how quickly? What are some important examples?

Answer 18

Drug binds to and opens or blocks ion channel
Key neurotransmitters that modulate ion channels:
* e.g., GABA, 5-HT, ACh, glutamate
* Effects very rapid (ms)
* Transduce signal across membrane by allowing ions (effectors) to cross membrane and alter cell excitability

Question 19

what is the most abundant receptor type? How does this receptor work, and what types of ligands does it interact with?

Answer 19

G-protein coupled receptors (GPCRs)
* The most abundant receptor type (close to 1,000 known)
* GPCRs bind to a family of heterotrimeric GTP-binding regulatory proteins termed G-proteins
* Activation of GPCRs results in exchange of GDP for GTP and subsequent downstream effects
* Many ligand types (ACh, NE, hormones, opioids, atropine, etc.)
* Many effectors

Question 20

what is an important G-protein coupled receptor type?

Answer 20

• Beta-adrenergic receptors are one important G-protein coupled receptor type

Question 21

what are second messengers in the signal transduction pathway? What do they do?

Answer 21

• Cytoplasmic molecules that translate D-R interaction
  into a change in cellular activity
• Most second messenger signalling entails reversible phosphorylation of key targets (enzymes)
• Allows for amplification of signal
  e.g. 1 ligand molecule may lead to millions of enzymes being activated within cell
• Allows for flexible regulation of signalling

Question 22

most drugs act on receptors that have this cytoplasmic feature

Answer 22

endogenous lignad (neurotransmitter, hormone)

Question 23

drugs are often given therapeutically to interact with receptors in these respects:

Answer 23

• Stimulate receptors in hypofunctional states
• Block receptors in hyperfunctional states

Question 24

how do receptors play a role in cell activity levels?

Answer 24

Usually, integration of signals from multiple receptor types determines activity level of cell

Question 25

what is an agonist?

Answer 25

activates receptor > cellular response

Question 26

what is a partial agonist?

Answer 26

agonist that is not able to fully activate the receptor

Question 27

what is an antagonist?

Answer 27

Binds to but does not activate the receptor
(simply prevents agonists from stimulating receptor)

Question 28

what is an inverse agonist?

Answer 28

Reduces basal activity of receptor

Question 29

what is a dose response curve? what does the semi-log plot help with?

Answer 29

The dose-response curve (DRC) is a depiction of the observed drug effect (% maximal response) as a function of drug concentration

Semi-log plot is used to identify EC50 (the steepest slope on the curve); also makes it easier to see the changes occurring at low concentrations

Question 30

what is a drug’s potency? notmally defined by what?

Answer 30

-The concentration of drug required to produce a given effect (i.e., a measure of a drug’s affinity for & activity at the receptor)
-Normally defined by the half-maximal effective concentration (EC50)

Question 31

The relative potency of different drugs acting at the same receptor can be measured by comparing what?

Answer 31

EC50 values

Question 32

is the most potent drug always the most efficacious?

Answer 32

no

Question 33

when is low potency a problem?

Answer 33

if the volume of the required dose is too large to be convenient

Question 34

what is the definition of drug efficacy? What is it defined by?

Answer 34

-The magnitude of the cellular response produced when all receptors of a given type are occupied by the ligand
-Defined by maximal response (Emax) of the drug

Question 35

how do we get a measure of relative efficacy?

Answer 35

Comparison of maximal responses of drugs acting at the same receptor gives a measure of
relative efficacy

Question 36

is potency or efficacy of greater interest to the clinician?

Answer 36

efficacy

Question 37

what is competitive receptor antagonism? how can we overcome the effects of a fixed dose of antagonist? how does an antagonist effect the dose response curve?

Answer 37

• Antagonist has affinity for receptor but no efficacy, competes with agonist at site
• A higher agonist concentration can overcome the effects of a fixed dose of antagonist
• Antagonist produces parallel rightward shift in dose-response curve

Question 38

how does the presence of a fixed dose of antagonist effect the EC50? Emax?

Answer 38

• EC50 value larger in presence of fixed dose of antagonist; i.e., competitive antagonist decreases the agonist’s potency
• No change in Emax

Question 39

what is non-competitive antagonsim? can we overcome the effects of a fixed dose of this antagonist?

Answer 39

• Antagonist binds irreversibly to receptor (or only very slowly dissociates)
• A higher agonist concentration cannot overcome the effects of a fixed dose of antagonist

Question 40

how does a non-competitive antagonist change Emax? EC50?

Answer 40

• Emax is reduced in presence of fixed dose of antagonist; i.e., the agonist’s efficacy is reduced by the antagonist
• May or may not be a change in EC50

Question 41

what is allosteric antagonism?

Answer 41

• Primary ligand/drug binds to main binding site on
  receptor (1)
• Allosteric antagonist binds to a different site on the receptor (2), a conformational change in the receptor then inhibits binding of drug at the main receptor (1)
• An example of non-competitive antagonism

Question 42

what is a positive allosteric modulator?

Answer 42

increase ligand affinity at main receptor site

e.g., benzodiazepines increase affinity of GABAA receptors for the neurotransmitter GABA

Question 43

what is drug tolerance? what are some mechanisms of its action? is it permanent?

Answer 43

The effect of a drug often diminishes when it is given repeatedly
Tolerance is the gradual decrease in responsiveness to chronic drug administration (days, weeks)
* a.k.a. desensitization or down-regulation
* temporary inactivation of receptor (phosphorylation)
* sequestration of receptors in cell (internalization)
* reduced synthesis of new receptors
Responsiveness returns to basal levels after drug has been discontinued for some time (time required depends on drug)

Question 44

what is tachyphylaxis?

Answer 44

a more rapid (acute) form of tolerance
* Can occur with some drugs on the second dose