drug disposition/pharmacokinetics

Question 1

what is pharmacokinetics

Answer 1

how drugs get into and move around and are removed from body systems / the processes that determine drug movement

Question 2

what is pharmacodynamics

Answer 2

the interaction of drug molecules with receptors, cells, etc how effects are produced at a level
How the effects that are produced depend on these concentrations, is considered in pharmacodynamics.

Question 3

dose‑concentration

Answer 3

(pharmacokinetics)

Question 4

concentration‑effect

Answer 4

(pharmacodynamics)

Question 5

A.D.M.E stands for?

Answer 5

a - administration

d - distribution

m - metabolism

e - excretion

Question 6

Practically, is measuring plasma concentrations easy or hard

Answer 6

easiest to measure

Question 7

In addition, plasma concentrations are important in?

Answer 7

• delivery of drugs to tissues/organs/receptors
• for the removal of drugs / drug metabolites from body systems

Question 8

As a general rule, changes to the drug plasma concentration will lead to changes in

Answer 8

• the concentration of drug at the site of action
• and that will have an effect on clinical outcome (assumed) e.g. a small conc, will have little clinical effect, or a large may even have a toxic effect

Question 9

however, this assumption for the general rule has many exceptions, including

Answer 9

• effects caused by drug metabolites, rather than the molecule we are giving to the patient
• we might not see it if there is slow penetration of the drug e.g. there might be a slow release if we are giving it intramuscularly
• irreversible effects of drugs (’hit and run effects’ e.g. with antibiotics, killing off all the bacteria = job done), like toxic effects
• however, aside from this, we basically assume the more drug we give = the more effect

Question 10

summary: what is pharmacokinetics:

Answer 10

Pharmacokinetics is the science of the relationships between the movement of a drug through the body and the processes acting upon it; it describes the time-course of drug movement into, around and out of the body.

Question 11

how are drugs transported into the body

Answer 11

via the blood, and hence need to obtain entry into the circulation

Question 12

how do we get them into the body: 2 ways

Answer 12

• via absorption: extravascular administration e.g oral, rectal etc
• via intravenous routes like infusion: here it’s directly into the system vascularly, but there is no absorption

Question 13

d = drug

d is in the body system in the circle: let’s call that the central compartment - this is all of the tissues that are in equilibrium with our blood plasma

the arrow represents absorption

Answer 13

https://www.notion.so/drug-disposition-pharmacokinetics-1ae00bb3982d8046adedd8ddf9d368cf?pvs=4#1cd00bb3982d80d6a702cbf202561507

Question 14

capillaries are very porous. what are they in equilibrium with and why is that key

Answer 14

with extracellular fluid / extravascular volumes

this equilibrium means that we can get drugs there as well

Question 15

what is moving drugs around the body about?

Answer 15

distribution (ensuring we get drugs to tissues, organs and other receptor sites of action)

Question 16

drugs must penetrate tissues in order to act on target receptors. Drugs are not usually specific, so?

Answer 16

will therefore reach a large number of different tissues and organs.

Question 17

drug movement around the body
https://www.notion.so/drug-disposition-pharmacokinetics-1ae00bb3982d8046adedd8ddf9d368cf?pvs=4#1cd00bb3982d800a8762eed3b95bfae2

Answer 17

there are levels of distribution e.g. the 2nd circle is the peripheral part: it has 2 arrows so we know it is a reversible distribution equilibrium - most drugs (as they are partly lipid soluble etc) exhibit this 2 compartment model (the central compartment and the tissue, peripheral compartment)

Question 18

what is the removal of drug from the body called

Answer 18

elimination of drugs (a combo of metabolism and excretion)

Question 19

where does elimination of drugs happen/via what?

Answer 19

the liver and/or the kidneys

Question 20

what is actually being eliminated?

Answer 20

The elimination may be of the unchanged drug molecule or various metabolites.

Question 21

we often give drugs via inhalation e.g. gaseous and removing it from (where?) is also a route of elimination

Answer 21

from the lungs

Question 22

image to show it:
https://www.notion.so/drug-disposition-pharmacokinetics-1ae00bb3982d8046adedd8ddf9d368cf?pvs=4#1cd00bb3982d801b859ac9f50f8980f3

Answer 22

• removal of drug clearly not reversible
• elimination = product of metabolism and renal excretion

Question 23

not all routes of administration are suitable for all drugs, largely because of issues relating to?

Answer 23

their formulation, physico-chemical properties and sites of action.

Question 24

Routes of drug administration can be divided into two broad categories:

Answer 24

ENTERAL and PARENTERAL.

Question 25

enteral meaning

Answer 25

- (extravascular) drug entering the body via the gastro-intestinal tract (oral)

Question 26

parenteral meaning

Answer 26

(vascular) refers to all other routes.

Question 27

what is bioavailability?

Answer 27

Bioavailability is the proportion of an administered drug that reaches the systemic circulation and is therefore available for distribution to the intended site of action.

Question 28

IV bioavailability and pros and cons

Answer 28

100% Rapid onset of action, controlled rate of administration, avoids GI tract and first pass metabolism but requires trained personnel and sterile technique.

Question 29

IM/SC bioavailability and pros and cons

Answer 29

75 — 100% (typically) Advantages as above and suitable for depot preparations. SC administration can be performed by patient e.g. insulin. IM requires trained personnel and sterility, can also be painful. Common now in pharmacy practice (vaccination, for example)

Question 30

oral bioavailability and pros and cons

Answer 30

5 — 100% average of averages circa 70% Convenient, but some drugs are poorly absorbed through the gut wall, some may be denatured by acid and/or enzymes in the stomach or form complexes with food and all may be subject to first pass metabolism.

Question 31

inhalation bioavailability and pros and cons

Answer 31

5 — 100% Rapid onset of action and avoids first pass metabolism, but not all drugs can be formulated for inhalation, <10% absorption for solid/liquid formulations and particle size for solid formulations must be below 20 µm.

Question 32

rectal bioavailability and pros and cons

Answer 32

5 — 100% average of averages circa 70%   Allows targeting of large bowel, but variable absorption and patient acceptability are issues. Sometimes useful for systemic delivery when oral or parenteral delivery not available.

Question 33

sublingual bioavailability and pros and cons

Answer 33

75 — 100% Rapid onset of action and avoids first pass metabolism, but limitations on size of dose that can be given, holding dose in mouth can be inconvenient and taste may be unpleasant.

Question 34

transdermal bioavailability and pros and cons

Answer 34

80 — 100% Convenient and avoids GI tract and first pass metabolism, but not suitable for non-lipid soluble drugs and may cause local skin reactions.

Question 35

The KEY concept here is whether there is an absorption process or not (ie. crossing cell membranes in GIT): - e.g. which one has no absorption

Answer 35

IV – no absorption, therefore no modelling or parameters for absorption needed in the model description. In this case, we are concerned only with ELIMINATION processes (metabolism and excretion).

Question 36

which method does have an absorption process

Answer 36

- e.g. oral so for it we have to consider the absorption processes in addition to elimination processes.

Question 37

To minimise toxicity the concentration must not be

Answer 37

too high

Question 38

when treat­ment is complete what should happen to the concentration

Answer 38

it should fall rapidly.

Question 39

Drugs are eliminated from the body either by what 2 ways?

Answer 39

their direct **excretion** or by their conversion into other substances by **metabolism** followed by subsequent excretion.

Question 40

why doesn’t the plasma concentration hover at a constant level

Answer 40

because elimination occurs at all times not just at the end of treatment

Question 41

It goes up and then comes back down. To keep the concentration above a minimum level, what must be given?

Answer 41

top‑up doses must be given at regular intervals to replace the portion that has been eliminated. After each of these additional doses, the concentration again goes up to a peak and falls so that a more realistic concentration time curve looks a bit like the teeth of a saw (dotted line in Fig 2.)

Question 42

if the plasma conc isn’t changing what is equal

Answer 42

the amount of drug we put in is equal to the amount the body system is eliminating

Question 43

1)         What DRUG concentrations are required for the desired clinical effect?

Answer 43

balance between effective and toxic plasma conc (Cp) - this give rise to the concept of a therapeutic window.

Question 44

     At what rate (administration) must the drug reach the systemic circulation to maintain a desired concentration?

Answer 44

- this is about deciding on dosing schedules - what pharmacokinetic parameters do we need to be aware of e.g. the half life, the elimination rate constant, the clearance of the drug, the absorption rate

Question 45

3)         To what extent is an administered dose actually absorbed into the systemic circulation/body?

Answer 45

depends on / is bioavailability

Question 46

  How long should one dose follow another? (how rapidly do drug concentrations fall?)

Answer 46

based on elimination and all the extra stuff e.g. clearance, Ka, pathology etc

Question 47

TDM: therapeutic drug monitoring is based on

Answer 47

Changes in how a person's body handles a drug can alter the effects of the drug on the body. - the changes of clinical importance = those that alter mean concentrations.

Question 48

For most drugs the (minimum) effective concentration is defined as

Answer 48

the smallest maintained total plasma concentration that will sustain the desired response.

Question 49

For others with an effect that outlasts the plasma concentration, e.g. bactericidal antibiotics, the effective concentration is?

Answer 49

a concentration that must be exceeded at regular intervals.

Question 50

Toxic concentrations are those that will produce what effects

Answer 50

toxic effects if they are exceeded for too long.

Question 51

The most appropriate measure of successful administration of a drug is

Answer 51

clinical effect! e.g whenever the response to a drug is easily observed (eg. antihypertensives should cause a readily measurable reduction in diastolic blood pressure), plasma concentrations are measured "only" as a means to understand the many processes that intervene between dose and effects.

Question 52

For a target concentration strategy (TDM) to be worthwhile a number of conditions must be satisfied: what are these (5)

Answer 52

1)         **The clinical response must be difficult to measure in the short term;** 2)         **The therapeutic range of concentrations must be known (and should not vary greatly between individuals)** 3)         **The therapeutic range should correlate with pharmacological and therapeutic activity** 4)         **The therapeutic range must be sufficiently narrow to make an accurate plasma concentration important;** 5)         **It must be possible to measure the plasma concentration sufficiently soon after blood samples are drawn to allow subsequent doses to be adjusted.**

Question 53

Plasma concentration measurements are also used to investigate what?

Answer 53

unexpected results of standard doses. If the concentrations are as expected the variation usually reflects an unusual sensitivity to the drug.

Question 54

After a substance has been delivered to the system (in a body fluid), the individual molecules may be found in three diff places. what are these?

Answer 54

- may be found free in solution - bound to specific receptors (rarely more than a small proportion). - or bound to something else (eg. soluble plasma proteins, connective tissue, or cell membranes).

Question 55

does binding and unbinding happen rapidly or not? in what cases?

Answer 55

For almost all drugs, binding occurs rapidly and, provided the drug is not covalently bonded or metabolised, so does unbinding. In most instances if the concentration of free drug changes that of bound drug changes as well. It is a dynamic equilibrium.

Question 56

what forms are in equilibrium?

Answer 56

- ie. the free and bound forms remain at equilibrium with each other.

Question 57

what is the total concentration?

Answer 57

the sum of the concentration of the free and bound forms

Question 58

in plasma, the relative proportions free and bound are stated as either the percentage of the drug in plasma that is bound: what is the equation → % bound =

Answer 58

C bound/C total x 100

Question 59

the fraction of the drug in the plasma that is free also has it’s own equation which is:

Answer 59

fraction free = c free/c total = 1- bound/100

Question 60

what is Cfree

Answer 60

the plasma concentration of free drug

Question 61

what is C bound

Answer 61

the plasma concentration of the bound drug

Question 62

what is the total plasma concentration

Answer 62

this = C which = C free + C bound

Question 63

the rate of binding to a site or receptor is proportional to what? note - this is true of any cellular receptor or a circulating plasma protein (receptive protein).

Answer 63

to the free rather than the total concentration near the site.

Question 64

which concentration determines the drug effects, and the movement of the drug

Answer 64

The free concentration, rather than the total concentration, at the site of action Free concentrations also dictate the movements of the drug between plasma and the tissues.

Question 65

The amount present in a small region, or carried in a small volume of plasma is proportional to what?

Answer 65

the total concentration.

Question 66

free concentrations are key, but what is used in most equations instead, because of historical reasons

Answer 66

the total rather than the free plasma concentration is used in most of the equations, because when pharmacokinetic equations were first written, free concentrations were almost impossible to measure and even now total concentrations are usually much simpler to determine.  Fortunately descriptions based on total plasma concentrations are normally adequate.  (The exceptions occur when there are large changes in the percentage bound in plasma).