Lecture slide week 3

Question 1

What does xenobiotic mean?

Answer 1

substances that are foreign to the body or to an ecological system
(She uses this term in her slides, so I just thought we should know…)

Question 2

T/F lipophilic drugs can be excreted without metabolic alterations. What about hydrophilic drugs?

Answer 2

False:
Hydrophobic(/lipophilic) drugs, to be excreted, must undergo metabolic modification making them more polar. Hydrophilic drugs, on the other hand, can undergo excretion directly, without the need for metabolic changes to their molecular structures.

Some drugs (a type of xenobiotic) are hydrophilic enough and/or have small enough molecular volumes that they possess physicochemical properties that allows them to be excreted without much alteration.

Question 3

T/F Every tissue has some ability to metabolize drugs

Answer 3

TRUE!

Question 4

T/F The liver is the only organ that contributes to the first pass effect

Answer 4

False - intestinal metabolism also relevant here…

• some drugs are absorbed intact from the small intestine
  and transported first via the portal system to the liver where they undergo extensive metabolism.
  Still some other drugs are more extensively metabolized in the intestine than in the liver - so intestinal metabolism can contribute to the overall first pass effect.

Question 5

Name 3 abnormalities of the gut/liver that could influence how much of a drug is bioavailable following the first pass effect (very general)

Answer 5

1) Altered intestinal metabolism
2) Altered gut pH
3) Altered liver function

** this will put them at risk of enhanced
or inhibited drug action

Question 6

T/F All drugs goes through phase I and phase II of biotransformation

Answer 6

False
Metabolism and biotransformation of xenobiotics may go through Phase I and possibly Phase II reactions

Question 7

What occurs in Phase I biotransformation? What enzymes are involved and where are they located?

Answer 7

Phase I reactions usually convert the parent drug to a more polar metabolite.

Many drug-metabolizing enzymes are located in the endoplasmic reticulum membranes of the liver (and other tissues).

The enzymes responsible for most phase I reactions (NADPH-cytochrome P450 oxidoreductase and cytochrome P450), are found specifically in smooth microsomes (vesicles derived from smooth endoplasmic reticulum).

Phase I reactions are generally described as oxidation reactions (can involve oxidation, hydrolysis or reduction)

Question 8

After a phase I reaction, a metabolite may be readily excreted. What qualities of the metabolite would allow this?

Answer 8

sufficiently polar/hydrophilic

Question 9

What occurs in Phase II biotransformation?

Answer 9

If metabolites from Phase I are still too lipophilic, can undergo phase II, a subsequent reaction to form a highly polar conjugate. This occurs by addition of a polar group, which yields drug conjugates which can be excreted.

= CONJUGATION REACTIONS

Question 10

What enzymes are responsible for catalyzing the bulk of the hepatic drug and xenobiotic metabolism?

Answer 10

The P450s

Question 11

What are the possible effects of drugs we prescribe on the P450s?

Answer 11

Can be inducers, competitive inhibitors or inactivators of P450s.

(our text calls them P450 substrates, inducers, and inhibitors)

Question 12

Induction of enzymes by substrates results in _______(slower/faster) metabolism of other substrates

Answer 12

Faster

Question 13

Induction can occur when two drugs are co-administered and can lead to….?

Answer 13

metabolite-mediated toxicity or, a decrease in pharmacologic action, or both

Question 14

T/F environmental chemicals and pollutants can induce P450 isoforms

Answer 14

True!

Question 15

What is typically faster - phase I or II biotransformation?

Answer 15

Phase II reactions are generally faster than CYP450 catalyzed reactions (phase I) thus effectively accelerating drug biotransformation

Question 16

T/F all drugs are inactive/harmless after phase II metabolism?

Answer 16

false
- Drug conjugations do not represent terminal inactivation…these phase II reactions may lead to the formation of reactive metabolites responsible for toxicity

Drug induced toxicity can occur with seemingly benign substrates like acetaminophen so it is
crucial that as a prescriber you understand the process of metabolism and biotransformation
for the drugs you prescribe.

Question 17

What are genetic polymorphisms? Do they affect phase I, II, or both?

Answer 17

Genetic polymorphism is defined as the occurrence of a variant allele of a gene at a population frequency of >1%, resulting in altered expression or functional activity of the gene product or both.

There are several polymorphisms that have been identified to affect drug metabolism and therefore drug effect.

Polymorphisms can be relevant to phase I and phase II drug metabolizing enzymes.

Question 18

Genetic polymorphisms can be categorized according to how they influence metabolism. What are the 3 classifications?

Answer 18

1) Extensive metabolizer (EM)
2) Poor metabolizer (PM)
3) Ultrarapid metabolizer (UM)

Question 19

If drugs are lipophilic when they reach the kidneys, what happens?

Answer 19

They are passively reabsorbed

Question 20

What is pharmacodynamics?

Answer 20

study of what the drug does to the body. More specifically, it is the study of the relationship between concentration of a drug and the response obtained in the patient.

Question 21

Why are drug receptors important for understanding pharmacodynamics?

Answer 21

Receptors form the basis for the actions and clinical uses of drugs:

1. Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects;
2. Receptors are responsible for selectivity of drug action;
3. Receptors mediate the actions of pharmacologic agonists and antagonists

Question 22

Most drug receptors are ______ (lipids/carbs/proteins)

Answer 22

Proteins

Question 23

Describe how receptors influence dosage of a drug and the extent to which you will see an effect? Does the effect of a drug continue to grow infinitely as you administer more and more of it?

Answer 23

A receptor’s affinity for binding a drug determines the concentration of drugrequired to form a significant number of drug-receptor complexes.

The total number of receptors may limit the maximal effect a drug may produce.
- Responses to low doses of drug usually increase in direct proportion to dose. However, as doses increase, the response increment diminishes. Eventually, doses may be achieved at which no further increase in response can be achieved.

Question 24

What are agonists?

Answer 24

substances (drug in our case) that have an affinity for
a receptor and by binding with that receptor, they initiate a response

Question 25

What are antagonists?

Answer 25

substances that interfere with or inhibit the physiologic action of
another substance

Receptor antagonists bind to receptors but do not activate them; the primary action of antagonists is to reduce the effects of agonists

When there is an antagonist present, the drug:effect curve (and effect in the patient) may be different as the drug agonist action will be interfered with by the antagonist

Question 26

If an antagonist is present, is it guaranteed that your drug won’t be able to achieve desired effect?

Answer 26

No, not necessarily. If the drug is still able to occupy enough ‘spare’ receptors, it could still reach full effect without needing to occupy the receptors occupied by the antagonist.

Question 27

What is the difference between competitive and non-competitive antagonists

Answer 27

COMPETITIVE antagonists work to inhibit the effect of the agonist by competitively binding with the agonist receptor site:
● The degree of inhibition produced by a competitive antagonist depends on the concentration of antagonist.
● Clinical response to a competitive antagonist also depends on the concentration of agonist that is competing for binding to receptors.

NON-COMPETITIVE ANTAGONISTS
may not compete for the agonist receptor site but binds elsewhere (on the receptor) and still influence the action of the agonist.

Question 28

At times, a non-competitive antagonist inhibits the action of an agonist and does this in an irreversible fashion by forming a covalent bond with the receptor. What is the effect of this?

Answer 28

Once such an antagonist is present, agonists may not be able to surmount the inhibitory effect, irrespective of their concentration

(meaning no matter how high the drug, won’t see as big of an effect (= lower efficacy)

Question 29

What is the difference between partial and full agonists?

Answer 29

Partial Agonists: bind to the same receptors as full agonists and activate them in the same way but do not evoke as great a response, no matter
how high the concentration

• Partial agonists produce concentration-effect curves that resemble those observed with full agonists in the presence of an antagonist that irreversibly blocks some of the receptor sites

Failure of partial agonists to produce a maximal response is not due to decreased affinity for
binding to receptors…it can bind fully but just has less of an effect

A full agonist reaches the maximal response capability

Question 30

Describe what occurs in terms of receptor occupancy if you begin with full occupancy of full agonist binding, but then add increasing amounts of partial agonist?

(see slide 13 of pharmacodynamics to make sense of next couple of questions)

Answer 30

As occupancy by the partial agonist
increases, binding of the full agonist
decreases

Question 31

What occurs when you have simultaneous treatment with a single concentration of full agonists and increasing concentrations of a partial agonist?

Answer 31

each drug competes to bind to
the receptor - eventually sum of the
responses reaches the value produced
by partial agonist alone.

Question 32

There are five basic mechanisms of of transmembrane (across membrane drug:receptor
coupling) signaling and each represents a different family of receptor protein and strategy to
circumvent the plasma membrane. Can you describe them?
(Sorry this is a hard one!)

Answer 32

1. Lipid soluble ligand that crosses the membrane and acts on an intracellular receptor;
2. A transmembrane receptor protein whose intracellular enzymatic activity is allosterically
   regulated by a ligand that binds to a site on the protein’s extracellular domain;
3. A transmembrane receptor that binds and stimulates an intracellular protein tyrosine
   kinase;
4. A ligand-gated transmembrane ion channel that can be induced to open or close by the
   bind of a ligand;
5. A transmembrane receptor protein that stimulates a GTP-binding signal transducer
   protein (G protein), which in turn modulates production of an intracellular second
   messenger.

Question 33

What is the ED50?

Answer 33

Dose of the drug at which we see therapeutic response in 50% of the population

Question 34

What is TD50?

Answer 34

Dose of drug at which we see toxic effect in 50% of population

Question 35

Formula for therapeutic index (TI)? WHat is it?

Answer 35

TI = TD50/ED50

Therapeutic Index relates to the dose of a drug required to produce a desired effect to that which produces an undesired effect.

In order for therapeutic index to be understood, drugs are tested on animals and
then humans; our clinical guidelines are then developed to reflect the therapeutic
index that is identified from these trials.

Question 36

How does a competitive antonist change the potency of the drug?

Answer 36

Decreased potency, because you need more of the drug to elicit a response… so EC50 is higher than it would be without the competing drug.

Question 37

What does Emax stand for?

Answer 37

Maximum efficacy

Question 38

WHat is maximum efficacy vs potency?

Answer 38

Maximal efficacy: reflects the limit of the dose-response relation and is often determined by the drug’s mode of interactions with receptors.

Potency: refers to the concentration or dose of a drug required to produce 50% of that
drug’s maximal effect (usually denoted clinically in relation to a therapeutic end point).

Question 39

What is the “therapeutic window”?

Answer 39

Therapeutic Window reflects the range between the MINIMUM toxic dose and the MINIMUM therapeutic dose.

Question 40

Are drug effects directly related to plasma concentrations?

Answer 40

In the simplest cases, drug effects are
directly related to plasma concentrations.

But…most relationships between drug
concentration and effect are not linear!
So, drug going into the body does not
necessarily increase plasma concentration
and effect 1:1.
Depending upon the drug and the patient,
drugs can have immediate, delayed and
cumulative effect.

Question 41

What is the DELAYED EFFECT?

Answer 41

Changes in drug effect are often delayed in
relation to changes in plasma concentration

The delay may reflect the time required for the
drug to distribute from plasma to the site of
action (which is the case for most drugs), but it
could also be due to slow turnover of a
physiologic substance that is involved in the
expression of the drug effect

Question 42

What is the CUMULATIVE EFFECT?

Answer 42

From internet: The condition in which repeated administration of a drug may produce effects that are more pronounced than those produced by the first dose.

From lecture slides: Some drug effects (negative) are more obviously
related to a cumulative action whereby side
effects or negative effects occur as a result of
accumulation of the drug.

This concept of accumulation of drug may also useful in therapy whereby the extent of binding of drug to receptors is proportional to concentration. So the higher the drug
concentration that is maintained (cumulatively)
maintains drug:receptor effect

Question 43

When might be want to use a loading dose?

Answer 43

In situations whereby the time to reach steady state is appreciable (as it is for drugs with long
half-lives), it may be desirable to administer a loading dose that promptly raises the
concentration of drug in plasma to target concentration

Question 44

What is the maintenance dose?

Answer 44

dose needed to maintain steady state of a drug in the body