Week 1: Pharmacodynamics II

Question 1

What are the pharmacodynamics of a neutral antagonist?

Answer 1

If a drug D has an equal affinity for R and R*, it is a neutral antagonist. This will lead to no effect on the receptor.

Question 2

What occurs when a drug has much higher affinity for R than R*? What is an example of a situation where this would be useful?

Answer 2

This refers to a competitive antagonist, but when there is constitutive activity (receptor is active without agonist), the drug acts as an inverse agonist and reverses/lowers constitutive activity of constantly active receptors.

An example is when there is a genetic defect in the vasopressin receptor that makes it constitutively active. Vasopressin helps the body retain water, raising blood pressure. A competitive vasopressin antagonist would help lower BP.

Question 3

Describe the two generic state model involving agonists, antagonists, and inverse agonists

Answer 3

In this model (see photo)…

Inverse agonists mostly bind the R state, and can bind the R* state minimally

Antagonists bind the R and R* states with equal preference

Agonists preferentially bind the R* state

Question 4

What are the two generic states of a receptor? Can there be more than two states?

Answer 4

Resting (R) and Active (R*)

There can be, however, many relevant conformations of a receptor

Question 5

How does the number of receptors affect the effect of a drug?

Answer 5

When the number of receptors is low, most drugs can act as full/partial agonists or as neutral antagonists

When the number of receptors is much higher, you can detect inverse agonism activity in a drug’s effects

Question 6

How do antagonists and inverse agonists affect binding sites? How do we know inhibitors are binding to the receptor?

Answer 6

These drugs bind at orthosteric sites, competing for those sites with endogenous ligands.

We know inhibitors bind to the receptor because more of a given drug is required to elicit a similar response curve in a receptor’s effects. In other words, having to compete against I increases the EC₅₀ of a drug.

Question 7

What are some examples of competitive antagonists?

Answer 7

Propranalol is a beta blocker that helps lower BP

Rispiridone is an antipsychotic medication that is an antagonist at dopamine receptors in the brain

Question 8

When increasing the concentration of I in the presence of a saturating concentration of D, what is the IC₅₀?

Answer 8

The IC₅₀ is the concentration of an inhibitor that inhibits 50% of the maximum drug response (this is NOT a constant because it shifts based on the drug concentration)

Question 9

What is the Cheng & Prusoff equation?

Answer 9

It allows us to correct for the amount of drug within an experimental paradigm when inhibitor is added. This assumes binding is competitive.

K_i = IC₅₀

1 + D/EC₅₀

Question 10

How do we know an antagonist is binding to a receptor?

Answer 10

The IC₅₀ of an inhibitor depends on the concentration on D via Cheng & Prusoff’s equation. When D increases, IC₅₀ increases in a compensatory manner to maintain the value of K_i mathematically. Thus, [I] and [D] are interrelated.

Question 11

What are the two main kinds of modulators and what do they do?

Answer 11

Negative Allosteric Modulators (NAM)
and

Positive Allosteric Modulators (PAM)

Allosteric antagonism is non-competitive (not binding at activee site) and saturable.

Question 12

What do NAMs do to dose-response curves, and what is an example?

Answer 12

NAMs shift dose-response curves rightward, and can decrease E_max and/or EC₅₀

An example is maraviroc, a NAM for the CCR5-receptor, which decreases the affinity of HIV binding to cell receptors

Question 13

What do PAMs do to dose-response curves? What is an example?

Answer 13

PAMs decrease the EC₅₀ and make the same concentration of drug “more” efficacious.

An example is diazepam, a PAM for GABA_A receptors, which decrease nerve activity. Diazepam is an agonist for GABA_A receptors, and help downregulate nerve pathways involved in anxiety.

Question 14

What do NAMs and PAMs modulate?

Answer 14

They modulate the affinity (alpha) of an orthosteric agonist for it’s receptor, or the efficacy (beta) of an orthosteric agonist

Question 15

What does propranalol do?

Answer 15

It acts as a competitive antagonist at a beta adrenergic receptor, blocking the effects of Epi/NE on beta receptors, and decreasing blood pressure

Question 16

What are pharmacological antagonists?

Answer 16

It is an antagonist that works on the same receptor as the agonist

Question 17

What are physiological antagonists?

Answer 17

These are two or more drugs that bind to two or more receptors that have opposite physiological responses

For example

NE + betaR = increased HR

ACh + muscarinicR = decreased HR

Question 18

What is chemical antagonism? What is an example?

Answer 18

Chemical antagonism occurs when drug binds to another drug or molecule.

An example of this is when toxic heavy metals like lead, cadmium, or mercury are bound by chelating agents like EDTA (EthyleneDiamineTetraAcetic acid), which grabs onto the heavy metal and allows it to be excreted

Question 19

What are additivity and synergism?

Answer 19

If two drugs work at the same orthosteric site and are given at less than maximal doses, their effects will be additive (i.e. enkephalins and opioids at opiate receptors)

Two drugs acting on distinct sites that potentiate one another are termed synergistic (i.e. NSAIDS acting on COX enzymes and opioids acting at opiate receptors, aka different sites)

Question 20

What are some examples of synergy?

Answer 20

1) SSRIs and serotonin release from neurons
2) AChE and ACh release from neurons
3) Benzodiazepines acting allosterically and GABA release from neurons
4) Probenecid and penicillin–probenecid inhibits tubular excretion via kidneys, prolonging the action of penicillin

Question 21

What is the difference between an antagonist and an inverse agonist?

Answer 21

Antagonists bind with equal affinity to the R and R* conformations

Inverse agonists have more affinity for the R (the inverse of agonists, which usually have affinity for R*)

Question 22

What are the general classes of drug receptors?

Answer 22

“NED”

(1) NT or hormone receptors (most common)

Ion channels (nicotinic cholinergic, glutamate, GABA), ions are Na, K, Ca, Cl

GPCRs (adrenergic, muscarinic), second messengers are cAMP, IP₃ and prostaglandins

Growth factor (EGF) and cytokine (interferon), cause protein kinase activity and phosphorylated proteins

Transcription factors (estrogen), cause transcriptional regulation

(2) Enzymes - HMG-CoA, PDE (phosphodiesterase), MEK (tyrkin inhibitors), cholinesterase
(3) Protein-protein interactions
(4) DNA or RNA - siRNA, antisense, CRISPR-cas9, may combat COVID

Question 23

What is the concept of a receptor reserve?

Answer 23

The number of receptors can change as a function of physiological state, disease states and even gender

Receptor reserve is the idea that not all receptors need to be occupied by agonist to get to E_max. This introduces non-simple systems. It explains why EC₅₀ and K_D may not be equal.

Question 24

What is a physiological example of receptor reserve? What does it mean for the corresponding physiological response?

Answer 24

When NE activates a beta adren. receptor, cAMP is produced. Only 1% of cAMP production is needed to meet the EC₅₀ of PKA, so the very small requisite cAMP production means you will see a huge shift in physiological response (increased HR) with just a small amount of receptor activation.

Question 25

Where, physiologically, do K_D and EC₅₀ derive from and why are they different?

Answer 25

K_D depends on occupancy, and therefore only depends on the number of sites occupied. EC₅₀ relates to function, and can be affected by things like constitutive activation, receptor reserve, and other things that require either a smaller or larger dose to elicit a certain response.

Question 26

What is the concept of receptor regulation and what are some examples?

Answer 26

Receptor regulation occurs when chronic drug administration can alter responsiveness

(1) Disuse supersensistivity occurs when denervation or chronic antagonist use (i.e. beta blockers) can lead to an increase in response to an agonist (because the # of overall receptors increases), so receptors are much more sensitive to agonists
(2) Desensitization or down-regulation occurs when loss of receptor response or decrease in receptor # due to chronic administration of an agonist. This means more and more agonist is required to elicit the same response, as receptors are lost due to overstimulation.

Question 27

What is the ED₅₀?

Answer 27

The dose of a drug that causes an effect in 50% of people. This is influened by affinity, absorption, distribution, biotransformation and excretion, which differs from person to person. This is why people respond to the same dose in different ways. The EC₅₀ is also called the median effective dose.

Question 28

What separates the drug from a poison, given that all drugs are technically poisonous?

Answer 28

The dose!

Question 29

What is the therapeutic index (TI) of a drug, and what does it compare? What does a larger TI mean?

Answer 29

Therapeutic Index = TxD₅₀

ED₅₀

The larger the TI, the safer the drug

orrrr, for lethal doses… LD₅₀

TD₅₀

Question 30

What is the Standard Margin of Safety and how is it calculated?

Answer 30

The SMS is the dose that negatively affects 1% of the population and positively affects 99% of the population. THis is calculated via…

SMS = TxD₁

ED₉₉