Unit 3: Pharmacokinetics

Question 1

How do drugs work?

Answer 1

Drugs are distributed throughout the body by the blood and other fluids.
When they are at the site of action, they act by binding to receptors, usually located on the outer membrane of cells//enzymes within the cells.
Receptors ‘turn on’ when stimulated/blocked by a drug which binds to the receptor.

Question 2

How do narcotic pain relievers like morphine work?

Answer 2

Bind to receptors in the brain that sense pain and decrease the intensity of that perception

Question 3

How to non-narcotic pain relievers like aspirin or ibuprofen work?

Answer 3

Bind to an enzyme (cyclooxygenase) located in cells outside of the brain close to where pain is localised (not brain).
Decrease the formation of biologically-active substances known as prostaglandins, which cause pain/inflammation

Question 4

What is onset, duration and intensity of action of a drug after administration controlled by?

Answer 4

The rate at which the drug reaches site of action
The concentration of the drug
The metabolism of the drug in the body
The rate of excretion of the drug
The sensitivity of the individual to the drug

Question 5

ADME processes occur at the same time until…

Answer 5

• All of the drug is absorbed and there is no more absorption phase
• All the drug has been metabolised and there is no more parent drug and it is no longer detectable in the blood.

Question 6

Absorption

Answer 6

The process by which a drug is made available to the fluids of distribution in the body (blood, plasma, lymph)

Question 7

In the fasting state, how long does it take for most orally administered drugs to reach the peak blood conc?

Answer 7

1-2 hours

Question 8

Most rapid route to least rapid route of administration

Answer 8

Intravenous administration (IV)
Intranasal
Inhalation
Sublingual (under tongue)
Intramuscular (IM)
Subcutaneous (under skin)
Percutaneous (through skin)

Question 9

Distribution

Answer 9

Circulated by some degree to all areas of the body to which there is blood flow.

Question 10

What organs are the first to accumulate drugs

Answer 10

Organs with high blood flow (e.g. heart, liver, kidneys) are first, while drugs accumulate more slowly into connective tissue

Question 11

Metabolism

Answer 11

Altering the chemical structure of the drug to promote its excretion.
Transformation of the drug molecule into a chemically related substance that is more easily excreted from the body

Question 12

What do urine drug screens usually determine in terms of drugs and use the example of cocaine.

Answer 12

Determine metabolites in urine not original ‘parent’ drug which was ingested/taken.
E.g. if cocaine is snorted/injected, a urine drug screen will most often detect the cocaine metabolite called benzoylecgonine in the urine, not cocaine.

Question 13

Excretion

Answer 13

Process by which drug is eliminated from the body

Question 14

How is a drug absorbed if administered orally?

Answer 14

There are layers of protective mucus in many parts of the gastrointestinal tract, which must be traversed before the drug reaches the cell membranes of the epithelial cells lining the tract.
Several membranes may have to be penetrated before the drug eventually reaches the bloodstream.

Question 15

Two mechanisms that drugs are absorbed by

Answer 15

Passive diffusion of unionised drug
Active transport

Question 16

peristalsis

Answer 16

the involuntary muscle movement that moves food through your gastrointestinal tract.

Question 17

Major site of absorption

Answer 17

Small intestine

Question 18

Why is the small intestine the major site of drug absorption?

Answer 18

high peristalsis,
a high surface area,
high blood flow
optimal pH (pH 5–7) for the absorption of most drugs all of which result in a high absorption rate.
absorption tends to be much less rapid from other parts of the gastrointestinal tract.

Question 19

Which type of drugs are absorbed in the stomach and give examples

Answer 19

Largely acidic drugs that are un-ionised in the low pH (pH 1–3) environment in this organ.
Drugs include aspirin, nonsteroidal anti-inflammatory drugs and some angiotensin-converting enzyme inhibitors.

Question 20

What happens to drugs following absorption by the GI tract and what are the exceptions?

Answer 20

drug molecules are taken up by hepatic portal system
exceptions are lipids, which normally enter the lymphatic system and are eventually deposited in the blood via that thoracic duct into the superior vena cava.

Question 21

high hepatic first pass effect

Answer 21

when metabolism may be very rapid so that the drug never ‘makes it’ past the liver

Question 22

an example of high hepatic first pass effect and why is it administered the way that it is

Answer 22

glyceryl trinitrate, used to treat angina pectoris; almost 96% is destroyed by the liver on its first journey through.
This is why glyceryl trinitrate is administered by placing the tablet under the tongue (sublingual) or by an oral spray so that it is absorbed through the mucous membranes of the mouth directly into the blood stream

Question 23

an example of comparing the effects of a drug given orally with those resulting from parenteral administration

Answer 23

Pethidine, for example, when given parenterally, may require an injection of only 25 mg to produce an analgesic effect equivalent to 100 mg taken orally.

Question 24

sites of absorption

Answer 24

lungs
mucous membranes
skin
sublingual
buccal
vaginal
ocular

Question 25

How can the extent of ionisation be calculated?

Answer 25

by the Henderson-Hasselbach equation and whether the molecule is acidic or basic in nature

Question 26

How is the extent of the equillibrium between the ionised and unioned form of a molecule determined?

Answer 26

Diffferent between pH of the solution and pKa of the solution

Question 27

What does the pH partition hypothesis say?

Answer 27

that only the unionised form can cross a membrane and that the concentration of the unionised form on each side of the membrane will be equal.

Question 28

partition coefficient

Answer 28

coefficient (P or logP) which is a measure of how a drug molecule partitions (divides) itself between an organic layer (normally octanol) and an aqueous (water) layer.

Question 29

what is the value of partition coefficient dependent on?

Answer 29

the pH of the aqueous layer, indicating that the absorption potential of a drug will vary with pH.

Question 30

where in the body is the pH highly acidic

Answer 30

fasted stomach

Question 31

where in the body is the pH basic

Answer 31

intestine

Question 32

what does the extent of ionisation of a drug molecule depend on

Answer 32

pH

Question 33

when can gastric emptying be delayed?

Answer 33

following severe trauma and in any condition producing nausea or vomiting

Question 34

Which drugs are more readily absorbed from upper regions of the GI tract and why

Answer 34

Acidic drugs- Non ionised (more lipid soluble) form of a drug is more readily absorbed than the ionised form. Acidic drugs usually in a non-ionised form in the upper regions

Question 35

Characeristics of a drug needed so that it can cross a membrane barrier.

Answer 35

Must normally be lipid soluble to the membrane to get into the membrane Soluble in the aqueous phase to get out of the membrane

Question 36

For drugs that are weak acids/bases, what will control the solubility of the drug and therefore the rate of absorption through membranes lining GI tract?

Answer 36

pKa of drug pH of GI tract fluid pH of bloodstream

Question 37

Why is distribution usually uneven?

Answer 37

Due to differences in blood perfusion (local fluid flow), tissue binding (due to lipid content), regional pH, and permeability of cell membranes.

Question 38

what does entry rate of a drug into tissue depend on

Answer 38

rate of blood flow to tissue tissue mass partition characterisitics between blood and tissue

Question 39

where is distribution equillibrium reached more quickly?

Answer 39

in richly vascularised areas, unless diffusion across cell membrane is the rate determining step.

Question 40

after equilbrium, drug concentrations in tissues and extracellular fluid are reflected by...

Answer 40

plasma concentration

Question 41

xenobiotics

Answer 41

non essential foreign compounds

Question 42

what is an integral part of xenobiotic elimination?

Answer 42

metabolism

Question 43

what does metabolism do to a drug?

Answer 43

facilitates excretion may also affect pharmacological response by altering potency/duration of action

Question 44

charactersistics of metabolites of drugs

Answer 44

with few exceptions, they are more polar and water soluble than parent drug- more likely to be excreted from body.

Question 45

in general what does metabolism do?

Answer 45

converts active compounds into less active and less toxic compounds

Question 46

where does drug metabolism take place

Answer 46

primary site= liver but may be metabolised in blood, brain, kidneys, lungs, skin, gastrointestinal tract

Question 47

biotransformation reactions

Answer 47

individual chemical reactions of drug or foreign compound metabolism

Question 48

main organs responsible for drug excretion

Answer 48

kidneys - renal excretion liver- biliary excretion other organs can be involved- lungs for volatile/gaseous agents

Question 49

what compounds can slightly concentrate in milk and why, why is this important?

Answer 49

basic compounds- milk is more acidic than plasma this is important to estimate the amount of drug administered to the breastfed baby

Question 50

what drugs cannit be excreted before metabolism into more polar compounds?

Answer 50

lipophillic drugs

Question 51

what is the excretory system made up of?

Answer 51

2 kidneys ureter bladder urethra branches of two renal arteries and veins

Question 52

glomerular filtration

Answer 52

small drug and metabolite molecules and those not bound to plasma proteins are filtered from the blood. large molecules or those bound to plasma proteins are poorly excreted by glomerular filtration.

Question 53

tubular secretion

Answer 53

most drugs enter the kidney tubule by tubule secretion rather than glomerular filtration the process involves active transport against a concentration gradient and therefore requires energy and carriers for acidic drugs such as furosemide and penicillin

Question 54

tubule reabsorption

Answer 54

some drugs and metabolites are absorbed back into the bloodstream. this doesnt require energy- it is passive transport

Question 55

initial phase

Answer 55

the delivery of the drug to the body in a dosage form from which the drug molecule has to be released (dissolution). The drug then absorbs, is distributed around the body before elimination.

Question 56

Cmax

Answer 56

maximum/peak concentration of drug after administration

Question 57

Tmax

Answer 57

time after administration when max concentration is reach rate of absorption= rate of elimination

Question 58

area under curve

Answer 58

total drug exposure over time

Question 59

Cmax is affected by

Answer 59

first pass metabolism (can inactivate drug) losses due to route (does not dissolve) excretion/elimination

Question 60

what does t max depend on

Answer 60

absorption rate

Question 61

how can the time taken for the drug to show an effect/duraction of action of the drug be assessed?

Answer 61

if the minimum effective conc (MEC) where the drug is effective at any level is above threshold and the maximum tolerated concentration (MTC) are known

Question 62

bioavailability

Answer 62

is the fraction (%) of an administered drug that reaches the systemic circulation.

Question 63

when is a drugs bioavailability 100%, when is it lower and why?

Answer 63

when a medication is administered intravenously (IV), its bioavailability is 100% Routes other than IV due to incomplete release from the dosage form, incomplete absorption and first-pass metabolism.

Question 64

how is bioavailability calculated?

Answer 64

by comparing the AUC for the particular dosage form in question to that obtained when the drug is administered intravenously, taking any differences in the amount administered into account

Question 65

what does it mean if two products are said to be bioequivalent

Answer 65

means that they would be expected to behave in the body, for all intents and purposes, the same.

Question 66

volume of distribution

Answer 66

expresses how the administered drug has distributed itself throughout the body. the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma.

Question 67

what does a larger vD suggest

Answer 67

indicates a greater extent of drug distribution in the tissues have a tendency to leave plasma and enter extravascular compartments of the body- so higher dose of a drug is required to achieve a given plasma conc.

Question 68

what does a drug with a lower vD suggest

Answer 68

indicates a lower extent of drug distribution in the tissues have a tendency to remain in plasma- so lower dose of a drug is required to achieve a given plasma conc.

Question 69

what concentration is required from the concentration time graph for volume of distribution

Answer 69

extrapolate backwards to concentration at time zero

Question 70

plasma protein binding classified into...

Answer 70

restrictive and non restrictive binding

Question 71

restrictive binding

Answer 71

important drug-plasma binding and thus limits the extensive distribution of the drug to tissues

Question 72

non-restrictive binding

Answer 72

does not limit the drug distribution to tissues due to a greater binding capacity to tissues than that to the plasma proteins

Question 73

vD and description for Warfarin

Answer 73

vD= 0.14 L/kg Very strongly bound to plasma protein (approximately 99% bound). Shows limited distribution into body tissues.

Question 74

vD and description for Paracetamol

Answer 74

vD= 0.9 L/kg Distributes rapidly and evenly throughout most tissues and fluids

Question 75

vD and description for Digoxin

Answer 75

vD= 7.3 L/kg Widely distributed and extensively bound in varying degrees to tissues throughout the body (skeletal and cardiac muscles intestines and kidney)

Question 76

What will influence the effect of a highly bound drug?

Answer 76

Changes in the concentration of plasma proteins

Question 77

when may low plasma protein levels occur and what occurs?

Answer 77

may occur in old age or in malnutrition. a sharp increase in the free drug concentration in the plasma may occur. greater amount of free drug may produce a greater therapeutic effect or side effect and reduced drug dosages may be indicated in these cases.

Question 78

what happens when a highly protein bound is given to a patient who is already recieving another highly bound protein drug

Answer 78

the second drug may displace the first drug from the plasma proteins leading to increased free drug concentration that may cause an increased therapeutic effect and/or adverse effects – this is an important mechanism of drug – interactions.

Question 79

clearance

Answer 79

is the efficiency of the irreversible elimination of drug from the systemic circulation

Question 80

if the clearance is high

Answer 80

the drug is removed quickly

Question 81

if the clearance is low

Answer 81

the drug remains in the body for a longer period of time

Question 82

what does the clearance value indicate

Answer 82

indicates the theoretical volume of plasma from which a substance would be completely removed per unit time. Usually, clearance is measured in L/h or mL/min.

Question 83

total body clearance equation

Answer 83

dose// area under the curve (mg x hours/L)

Question 84

half life

Answer 84

the time taken for the concentration of the drug in the plasma to have dropped by half

Question 85

first order reaction

Answer 85

concentration vs time graph is an exponential decay, where the gradient of the line is equal to the rate of drug loss. If the natural log (ln) of the concentration is plotted against time a straight line is obtained with a gradient of –k, which is the rate constant the rate of drug elimination proportional to the concentration (C) in the systemic circulation, i.e. the higher the concentration of drug in the systemic the faster the rate of elimination

Question 86

general equation for first order reaction

Answer 86

ln [A]t = ln [A]0 − kt [A]t is the concentration after time, t [A]0 is the initial concentration (at time=0) k is the rate constant t is the elapsed time 0.693/k

Question 87

is the half life dependent or independent of concentration for first order

Answer 87

independent

Question 88

half life equation, vD, and clearance

Answer 88

0.693 x vd/clearance

Question 89

what happens if a drug is being infused into a patient?

Answer 89

initially the rate that the drug is being added is higher than the rate it is being eliminated, so the plasma concentration rises. If the rate of drug elimination is 1st order, then the rate of elimination is dependant on the concentration (rate=clearance x concentration) so as more drug is added to the body, the elimination rate rises. At some point the rate drug is being added= rate that it is being eliminated, so the concentration reaches steady state (constant concentration). When the infusion is stopped, then the concentration will fall.

Question 90

how many half life does it take for a drug to be eliminated/reach steady state

Answer 90

5-6

Question 91

time taken to achieve steady state is..

Answer 91

still independent of dose (half life dependent).

Question 92

what must we assume to calculate the steady state conc

Answer 92

you assume that at steady state, rate of the drug entering the body is equal to the rate of the drug leaving the body

Question 93

what does a loading dose do?

Answer 93

rapidly increase the plasma concentration up to the level that is required in steady state and give immediate efficacy.

Question 94

how do we calculate the initial plasma concentration reached by the loading dose

Answer 94

Concentration = dose/volume of distribution Typically loading doses and twice that of the subsequent maintenance dose.

Question 95

what may cause non linear pharmokinetics and what order reaction does it tend to follow?

Answer 95

due to the saturation of one of the ADME steps for that drug. tends to follow zero order kinetics.

Question 96

zero order reaction

Answer 96

kinetics the rate is a constant value a plot of concentration against time is linear the half life depends on the concentration

Question 97

zero order reaction- half life independent/dependent on concentration

Answer 97

dependent

Question 98

example of non-linear behaviour

Answer 98

phenytoin epileptic patient who has not responded to phenytoin after 2 weeks on 300 mg/day is observed to have a plasma concentration of 4 mg/ml. Twenty days after the daily dose is subsequently increased to 500 mg/day, the patient develops severe toxicities. The plasma concentrations of phenotoin is now 36 mg/L caused by the saturation enzymes that are responsible for metabolism in the liver, so after a certain amount of drug is in the blood stream, the liver is now working at its maximum rate and cannot process it any faster, so a constant amount of drug is eliminated per unit time no matter how much drug is in the body. This means that an increased dose cannot be metabolised any faster and so there is a higher concentration of free drug in the body.

Question 99

what happens if the absorption process is saturated so the drug is absorbed at a fixed rate and what is an example of this?

Answer 99

If the absorption process is saturated, so that the drug is only absorbed at a fixed rate, independent of the drug concentration on the GI tract, the bioavailability (F) is affected example of this is amoxicillin where the transport across the gut wall is saturated with a decrease in bioavailability

Question 100

what happens if the distribution step is saturated and give an example

Answer 100

normally protein binding that restricts the drug to the blood stream), then more free drug is available & the volume of distribution are affected. example is naproxen causing an increase in the fraction unbound & increase in the volume of distribution.

Question 101

what can happen to the metabolic process in the liver and give an example?

Answer 101

either be restricted (inhibited) or enhanced (induced) and the clearance by the liver (CLH) is affected example of phenytoin has already been given, but high doses of propanolol decreases the blood flow to the liver and so reduces the clearance. High doses of carbamazepine can increase the metabolism rate (induced) and so increase the clearance.

Question 102

what does penicillin G do in the kidney

Answer 102

penicillin G an saturate the active secretion, reducing the clearance, whilst ascorbic acid (vitamin C) saturates the active reabsorption, where the drug passes back from the nephrons back into the blood, causing an increase in the clearance.

Question 103

Therapeutic Drug Monitoring

Answer 103

When drugs exhibiting non-linear pharmacokinetics show disproportionate increases (or decreases) in steady state concentration with increased dose and for drugs with a narrow therapeutic index, a small change in daily dose can easily cause side effects (are become non therapeutic), so for these, regular monitoring of the patients plasma concentration is vital