Pharmacodynamics

Question 1

What determines the upper and lower bounds of sizes of a drug?

Answer 1

Lower bound - needs to be large enough to have some specificity for the target receptor

Upper bound - needs to be small enough to be able to move through the body

Most drugs are between 100 and 1000 molecular weight units in size

Question 2

What are the three types of drug-receptor interactions and which is most common?

Answer 2

1. Covalent - i.e. irreversible
2. Electrostatic - most common, varying strength
3. Hydrophobic - mostly lipid soluble drugs

Question 3

What is hydrophobicity important for drugs?

Answer 3

The greater the hydrophobicity, the greater ability to cross biological membranes

Question 4

What are the three types of intracellular receptors? What is the general length of action?

Answer 4

1. Enzymes - alter production of a metabolic molecule
2. Transcription factors - i.e. steroids and thyroid hormones
3. Structural proteins

Generally have a lag-time of about 30 minutes, and then persist for hours or days

Question 5

What are the four types of non-intracellular receptors?

Answer 5

1. Receptor Tyrosine kinases
2. Cytokine receptors
3. Ligand / Voltage-gated ion channels
4. G-protein coupled receptors

Question 6

How is the activity of a transmembrane receptor regulated? What is the structure of these receptors?

Answer 6

Via downregulation -> endocytosis from cell surface and degradation

They work via extracellular hormone-binding domain and a cytoplasmic tyrosine kinase, serine kinase, or guanylyl cyclase

Question 7

How does a cytokine receptor differ from a receptor tyrosine kinase?

Answer 7

They still dimerize upon ligand binding, however, the protein kinase activity is not intrinsic and comes from a JAK kinase which is bound non-covalently to the receptor.

Question 8

What is the mechanism by which a Jak kinase carries signal downstream and give one receptor example?

Answer 8

Jak kinases will bind and phosphorylate STAT receptors, which dimerize and regulate transcription of target genes

I.e. growth hormone

Question 9

What is the relative response time of ligand and voltage-gated channels?

Answer 9

Very fast - milliseconds

Question 10

What are the three elements of the G-protein coupled receptor?

Answer 10

1. Cell surface receptor
2. G-protein on cytoplasmic face of membrane
3. Effector element

Question 11

What are the mechanisms of inactivation of Gq GPCR’s?

Answer 11

1. Dephosphorylation of IP3
2. Phosphorylation or acetylation of DAG
3. Ca+2 efflux via pumps

Question 12

What is desensitization and resensitization? What could prevent this from happening?

Answer 12

Desensitization - cAMP response via a ligand is diminished after a few minutes with continued presence of an agonist

Resensitization - cells recover to full response of a stimulus following agonist removal

Can not happen if cells are exposed to agonist repeatedly or over a more prolonged time period

Question 13

What are the molecular mechanisms underlying desensitization and resensitization?

Answer 13

Desensitization - phosphorylation of GPCR via GPCR kinases when activated allows binding of Beta-arrestin, which diminishes the receptor’s ability to interact with Gs subunit, terminating the response.

Resensitization - GPCR activation is terminated, disallowing further GPCR kinase activation, and phosphatases will subsequently cause removal of Beta-arrestin

Question 14

What are the functions of Beta-arrestin?

Answer 14

1. Blocks Gs binding
2. Accelerated endocytosis of receptors, which allows quicker resensitization via phosphatases. However, endocytosis also means that cells may be degraded by the lysosome more readily.

Question 15

In what situation is there not a 1:1 correspondence between ligand binding and response?

Answer 15

Signalling systems where downstream effectors are enzymes that can provide biological amplification of the signal - i.e. spare receptors

Question 16

What do Kd and Response in in drug-receptor complex formation correspond to in enzyme kinetics?

Answer 16

Kd - corresponds to Km (concentration of ligand at which 50% of the receptors are occupied)
Response - Velocity / Vmax - the maximal response via the receptor

Question 17

What is the definition of an agonist?

Answer 17

A ligand (drug or endogenous) that binds to a receptor to directly activate a signalling pathway and produce a response

Question 18

What is efficacy vs potency?

Answer 18

Efficacy - maximum response obtained with the highest concentrations of the agonist

Potency (EC50) - concentration of agonist required to achieve 50% of the maximum response (Usually equal to Kd, except will be lower whenever spare receptors are in place)

EC = Effective concentration

Question 19

What is a partial agonist? How does this happen moleculary?

Answer 19

A drug that produces a lower efficacy than a full agonist

This is not well understood -> partial agonist is thought to trigger a conformational change in receptor, but not large enough to create a full response

Question 20

How can partial agonists sometimes work as antagonists?

Answer 20

If they are competing for receptor binding with the full agonist, there will be an overall decrease in receptor response even with the partial agonist bound

Question 21

What are the two types of non-receptor antagonism? Define them.

Answer 21

1. Physiological antagonist - Agonist and antagonist act and two independent sites and produce two independent but contradicting effects (i.e. glucocorticoid activation + insulin secretion)
2. Chemical antagonist - chemical directly interacts with the agonist to inactivate it

Question 22

What is needed in order to see an antagonist’s effect?

Answer 22

The presence of an agonist (in order to be blocked). Addition of antagonist without agonist present does nothing. This is why they are called “blockers”?

Question 23

What are the two types of receptor antagonists? How does each work?

Answer 23

1. Competitive - bind to the main receptor site but do not trigger downstream effects
2. Non-competitive - bind allosteric site or irreversibly to agonist site, but do not produce conformational change necessary to trigger downstream effects

Question 24

How does a competitive antagonist change the dose response curve for the agonist?

Answer 24

Shifts the curve to the right.

Efficacy remains unchanged because the antagonist binding is reversible and can become oversatured with agonist.

Potency will be decreased -> need higher concentrations of agonist for the same effect

Question 25

What is the primary functional difference between a non-competitive and competitive antagonist?

Answer 25

Non-competitive agonists are irreversible ->, increasing agonist concentrations will not overcome the blocking effect

Can be an issue if overdose occurs -> need to unblock via an alternate pathway

Question 26

What is the big advantage to using non-competitive antagonists?

Answer 26

Competitive antagonists must be kept at relatively constant blood concentrations and are subject to varying clearance and excretion.

Non-competitive antagonists must simply bind the receptor and do not need to remain in blood -> activity is just dependent on rate of turnover of receptor molecules rather than rate of elimination

Question 27

What is an inverse agonist and what are they active against? Give an example?

Answer 27

They are chemicals which produce effects opposite to an agonist. They act on receptors that are constitutively active to reduce the basal firing (antagonist would leave it unchanged).

They stabilize the receptor in its inactive form

Example: GABA-A inverse agonist will cause anxiogenic effect

Question 28

What is the definition of spare receptors?

Answer 28

When a maximal biological response can be achieved without a full occupancy of all receptors, the extra receptors are “spare”

Question 29

How does a spare receptor modify the dose-response curve for non-competitive antagonists?

Answer 29

Until all spare receptors have been neutralized, the dose response curve will appear to simply shift to the right (agonist becomes less potent)

Once the spare receptors are gone, the maximum efficacy will begin shifting downward (typical effect of a non-competitive antagonist)

Question 30

What is the typical response to a non-competitive antagonist on the dose-response curve?

Answer 30

Efficacy will shift downward, but potency will not be affected because receptor affinity has not been changed (receptors have simply been suicide-inactivated)

Question 31

What systems typically utilize spare receptors?

Answer 31

Neurotransmitters and signal transduction pathways.

Question 32

What is a quantal dose response curve?

Answer 32

Plots based on the dose response of a drug for a large number of individuals or experimental animals. It is called “Quantal” because it is discrete and measures an “all-or-nothing” response to a drug -> i.e. relief of headache, sleep, etc

Question 33

What is the typical distribution of a quantal dose response curve? What is it distributed around?

Answer 33

Lognormally distributed - few individuals will be affected at low doses, followed by large numbers in the middle, and few need the highest doses to get a quantal response

It is distributed around the ED50 or effective dose 50 -> dose required to make 50% of individuals respond
“median effective dose”

Question 34

What is the median toxic dose?

Answer 34

TD50 - the dose required to produce a particular toxic effect in 50% of animals

Question 35

What is the median lethal dose?

Answer 35

LD50 - dose at which toxic effect is death of animal in 50% of cases

Question 36

What is the therapeutic index?

Answer 36

TI = LD50/ED50, where a higher number is better (proportion of lethal to effective dose is much higher)

Question 37

Where are the problems with therapeutic index?

Answer 37

Data is collected in animals, so meaning is uncertain. Lethal dose in mice does not necessarily mean toxic dose in humans which we care about, and also we want the ED99.

Question 38

What is the certain safety factor?

Answer 38

TD1/ED99

The greater the ratio, the less toxic the drug. TD1 = dose which is toxic in 1% of population. ED99 = dose which is therapeutic in 99%. If the ratio is greater than 1 that’s pretty good

Question 39

What factors contribute to drug response?

Answer 39

Sex, age, percent body fat, genetics

Question 40

What is an idiosyncratic drug response?

Answer 40

Drug response rarely observed in most patients, usually caused by genetic differences in metabolism or immunologic mechanisms

Question 41

What is tachyphylaxis?

Answer 41

When responsiveness diminishes rapidly after administration of a drug -> rapid tolerization

Question 42

What is typically rate limiting clearance by the liver?

Answer 42

Drug delivery via hepatic blood flow, rather than P450 enzymes

Question 43

What accounts for the majority of drug toxicities in clinical practice?

Answer 43

A direct pharmacological extension of the therapeutic effects of the drug -> i.e. bleeding caused by anticoagulant therapy (this is where drug monitoring is important).

Also for instance when beneficial and toxic effects are mediated by different types of receptors (adrenergic receptors which are nonselective)

Question 44

What is one major way to decrease adverse drug effects?

Answer 44

Increase selectivity of the drug’s actions by manipulating concentrations of drug available to receptors in different parts of the body