Pharmacokinetics

Front 1

Places that drugs are metabolised (excluding the liver).

Back 1

° Lungs

° Plasma

° Intestinal Flora

Front 2

What is meant by the term 'truly absorbed'?

Back 2

° When a drug has entered lymphatic or vascular system.

Front 3

What is Pharmacokinetics?

Back 3

° The study of absorption, distribution, metabolism and excretion (ADME) of a drug/xenobiotic.

° Evolutionary advantage to void potentially dangerous substances from the body.

Front 4

What is meant by the term 'voiding'?

Back 4

° A term used to describe how a drug leaves the body, and it used as the GI tract is said to be on the outside of the body.

° Excretion occurs via urine, faeces, bile or breath (low concentrations sometimes in sweat e.g fish odour syndrome).

Front 5

Enteral Routes:

Back 5

° Sublingual/Buccal

° Oral

° Rectal

Front 6

Parenteral Routes:

Back 6

° Intravenous (IV)

° Intramuscular (IM)

° Subcutaneous (SC)

° Epidural

° Spinal Tap

Front 7

What is meant by the term 'absorption'?

Back 7

° The extent to which an intact drug is absorbed from the intestinal lumen into the portal circulation.

° Expressed as f(G), meaning the fraction of drug absorbed from the gut.

Front 8

What are the factors affecting absorption?

Back 8

° Formulation of the drug.

° Surface area for absorption at drug target.

° Physicochemical properties (pKa, pH, P values etc).

° Blood circulation of absorption site.

° Amount of enzymes/efflux proteins present.

° Gastric emptying rate.

Front 9

What is meant by 'first pass metabolism'?

Back 9

° Amount of drug that is lost due to liver metabolism via hepatic portal vein.

° Expressed as f(H), fraction of the drug lost to first pass metabolism.

Front 10

How do drugs enter hepatic circulation?

Back 10

Via the Hepatic Portal Vein

Front 11

Name two formulations of the same drug that give different therapeutic responses.

Back 11

° Modified/Sustained release tablets.

° Gastro-resistant/Enteric coated tablets.

Front 12

What is meant by the term 'bioavailablity'?

Back 12

° F = f(G) + f (H)

° The sum of the fraction absorbed and the fraction lost due to first pass effect.

° Measured against the bioavailablity of IV administrations as this is always 100%.

•Plot 2 graphs and calculate the area under the curve for each one

•F (other route)= AUC(other)/AUC(IV) × 100.

Front 13

When is first pass metabolism beneficial?

Back 13

° When administering drugs that require metabolising to become active, known as pro-drugs.

° Activated due to the actions of certain enzymes known as cytochromes P450.

° Codeine -------> Morphine

CYP2D6

Front 14

What are some implications of first pass metabolism?

Back 14

° Reduces drug bioavailability.

° Higher dose required to give therapeutic effect (therapeutic window).

° May cause problems with poor metabolisers (PM) as the drug may accumulate and become toxic.

Front 15

Why are most drugs weak acids or weak bases?

Back 15

° Weak acids/bases tend to exist in an unionised state so can be absorbed easier than they can in their ionised form.

° Have a log P value between 3-6.

Front 16

What is a p-glycoprotein?

Back 16

° ATP-dependent efflux pump used as an evolutionary defence mechanism to expel xenobiotics.

° If a drug target contains are large concentration of p-glycoproteins then a higher dose is required to ensure complete absorption.

Front 17

What is 'depot therapy'?

Back 17

° Injection (usually intramuscular) of a drug together with a substance that slows the release and prolongs the action of the drug.

° Good for drugs such as contraceptives e.g Depo Provera and drugs with low patient compliance to regular doses e.g antipshycotic Haloperidol.

Front 18

What are the factors affecting bioavailablity?

Back 18

° Drug formulation e.g sustained release.

° Physicochemical properties (pKa, pH, P values etc).

° Route of administration.

° First pass metabolism.

Front 19

What is Fick's Law?

Back 19

° Absorption of the drug is proportional to the concentration gradient (C1 - C2) across cell membranes.

° Faster with lipid soluble drugs.

Front 20

What is facilitated diffusion for absorption?

Back 20

° Occurs via carrier proteins across cell membranes (passive).

° Requires a concentration gradient.

° Saturable due to the finite number of carrier proteins present.

Front 21

What is meant by 'filtration' as a method of drug absorption?

Back 21

° The movement of a drug across a membrane due to a hydrostatic pressure gradient created by the cardiovascular system.

° Drugs may move through spaces between cells (paracellular).

Front 22

What is meant by 'Volume of Distribution' (Vd)?

Back 22

° Vd is 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.

° Indicative of the extent of distribution of a drug.

° Low Vd value indicates a high amount of plasma protein binding.

Front 23

What would it meant if a Vd value was greater than total body water?

Back 23

° The drug is widely distributed through tissues.

Front 24

What would a high distribution rate mean?

Back 24

° The drug is highly lipid soluble so able to enter cells rapidly.

° Includes entry across the blood brain barrier.

Front 25

Why does Iodine have a high Vd?

Back 25

° It is highly concentrated to one area (the thyroid gland).

Front 26

Following intravenous administration, drugs are distributed fastest to?

Back 26

° The liver, kidney and brain.

Front 27

What characteristic is the most important determinant of the pharmacological activity of a drug which is administered orally?

Back 27

°Susceptibility to metabolic enzymes

Front 28

What is the half-life of adrug with a volume of distribution of 100L/70kg and a clearance of 7L/hr/70kg?

Back 28

° Method:
Cl = Vd x Kel
Kel = 7/100 = 0.07

t1/2 = ln2/Kel
t1/2 = 0.693/0.07

t1/2 = 10 hours.

Front 29

What is the description of Phase II metabolism?

Back 29

°Reactions which add a polar molecule to a functional group already present on a drug or one of its metabolites.

Front 30

What dose of i.v. amoxycillin would give a plasma concentration of 7mg/L assuming S=1 Vd = 0.25L and a 70kg patient?

Back 30

°Method:
7 x 0.25 x 70 = 122.5ug

Front 31

What does drug transport by lipid diffusion NOT depend on?

Back 31

°Density of transporters

Front 32

Transdermal drug administration:
a) is most suitable for highly polar drugs
b) is not subject to first-pass hepatic metabolism
c) provides rapid and complete absorption
d) is only used for localized effects
e) is most suitable for unconscious persons

Back 32

b) is not subject to first-pass hepatic metabolism

Front 33

Which of the following characteristics is most likely to be associated with a very high apparent volume of distribution?
a) High hepatic extraction ratio
b) Penetration across the blood:brain and blood:testes barriers
c) Extensive binding to plasma protein
d) Extensive binding to tissue constituents
e) Distribution into total body water

Back 33

c) Extensive binding to tissue constituents

Front 34

What would receive a hydrophilic drug slowly?

Back 34

Fat

Front 35

What would receive a lipophilic drug quickly?

Back 35

Fat

Front 36

What type of substance are xenobiotics?

Back 36

Exogenous

Front 37

Bioavailability (F) is the fraction or percentage of administered drug that reaches the systemic circulation via a given route as compared to what route?

Back 37

I.V (intravenous)

Front 38

After a single dose of a drug which has a half-life of 8 hours, what percentage of the dose is still in the body of a 70kg patient after 1 day?

Back 38

°Method:
24/8 = 3
100/2^3 = 12.5%

Front 39

Using the Fick Law of Diffusion, how will flux change if the permeability coefficient is quadrupled?

Back 39

°It will quadruple

Front 40

Using the Fick Law of Diffusion, how will flux change if the membrane thickness is quadrupled?

Back 40

°It will quarter

Front 41

A drug is administered by infusion at 2 mg/min toachieve a steady state concentration of 8mg/L. Assuming S=1, and a 70kg patient, what is the clearance rate?

Back 41

° Method:
2/8 = 0.25L/min

Front 42

The binding of drugs to plasma albumin:
a) is usually irreversible
b) is most important for basic drugs
c) accelerates drug metabolism
d) accelerates drug excretion
e) is saturable

Back 42

e) is saturable

Front 43

Apatient is administered 400mg of a drug to achieve a plasma concentration of20mg/L. If the clearance is 2.5L/min, calculate the half-life.

Back 43

° Method:
Vd = amount of drug in body/Cplasma
Vd = 400/20 = 20L

Cl = Vd x Kel
Kel = Cl/Vd
Kel = 2.5/20 = 0.125

t1/2 = ln2/Kel
t1/2 = 0.693/0.125

t1/2 = 5.5 hours

Front 44

Fill in the blanks: Drug bio transformation phase I makes drugs ____ polar for metabolism and phase II makes drugs ____ polar for excretion.

Back 44

More, More

Front 45

Apatient receives an infusion dose of penicillin 150 mg, what oral dose F(tab)=0.7 would give the same bioavailability?

Back 45

° Method:
150ug/0.7 = 214ug

Front 46

Of the top 15 global pharmaceutical companies in 2015, how many relied upon pharmaceutical sales for more than 50% of their income?

Back 46

13

Front 47

Of the top 15 global pharmaceutical companies in 2015, how many DIDN'T rely upon pharmaceutical sales for more than 50% of their income?

Back 47

2

Front 48

According to Rang & Dale’s Pharmacology, thesuccess rate of a typical drug (synthetic empirical compound) progressing from identification of a drug candidate to Phase IV clinical trials is what?

Back 48

1 in 20

Front 49

The reason why 30% of biopharmaceuticals fail in phase III of clinical trials compared to only 20% of traditional empirical style pharmacology drugs is most likely to be a consequence of what?

Back 49

° The physiological roles of the targets for biopharmaceuticals tends to be less well characterised and understood.

Front 50

The number of new molecular entity (drug) approvals bythe FDA for new drugs has begun to stagnate in recent years: explanations for this could include which of the following:
a) More rigorous regulations and scrutiny by the FDA and EMA
b) Higher costs of clinical trials in recent years
c) Many drugs are not first in class and it is therefore difficult to make improvement on already good existing treatments
d) Approximately one third of new drugs do not recoup their development costs
e) All of the above are correct

Back 50

e) All of the above are correct

Front 51

What is the Kd of this Hill Plot?

Back 51

° Method:
x-intercept =Ln -19
Kd = e^-19
Kd = 5.6nM
or 5600pM

Front 52

What is the Hill Coefficient (nH) of this Hill Plot?

Back 52

° Method:
nH = slope
nH = 6/(13-19)
nH = 1

Front 53

What does the value of nH suggest about these results?

Back 53

There is 1 ligand : 1 receptor stoichiometry

Front 54

What is the approximate IC50 value ofthe displacing ligand in this displacement binding curve?

Back 54

° Method:
IC50 = EC50
At ~2750dpm, draw a line across to the graph, and then draw one downwards so it connects with x-axis.
IC50 = 3000nM
or 3uM

Front 55

What is the Kd at the binding site (Kc)?

Back 55

° Method:
Kc = IC50/(1+L/Kl)
Kc = 3000/(1+400/800)

Kc = 2uM
or 2000nM

Front 56

What is the Kd of the high affinity site of this Scatchard Plot?

Back 56

° Method:
Draw a triangle connecting the upper linear part of the graph to the x-axis.
Calculate the gradient of this line
Slope = 85/4500 = 0.0189
Kd = 1/slope, Kd = 1/0.0189
Take into consideration the amount of protein present and change it to 1mg, so 0.25mg protein in 1ml, so 1mg in 4ml
To calculate Kd:
(52.94x1000)/4

Kd = 13235pM
or 13.2nM

Front 57

What does the steep slope denote on this Scatchard Plot?

Back 57

° High affinity of binding

Front 58

What does the shallow slope denote on this Scatchard Plot?

Back 58

° Low affinity of binding

Front 59

What is the pA2 value of the antagonist at the receptor agonistA acts on?

Back 59

° Method:
Agonist A intercepts the x-axis at -9.2
pA2 = -log[antagonist], so antilog the x-intercept value
pA2 = 10^-9.2

pA2 = 630pM
or 0.63nM

Front 60

What is the pA2 value of the antagonist at thereceptor agonist B acts on?

Back 60

° Method:
Agonist B intercepts the x-axis at -7.45
pA2 = -log[antagonist], so antilog the x-intercept value
pA2 = 10^-7.45

pA2 = 35.5nM

Front 61

What is the pA2 value of the antagonist at the receptor agonist C acts on?

Back 61

° Method:
Agonist C intercepts the x-axis at -7.7
pA2 = -log[antagonist], so antilog the x-intercept value
pA2 = 10^-7.7

pA2 = 20nM

Front 62

What can you conclude about the interactionbetween Agonists A, B and C and their receptors?

Back 62

°Agonists B and C are likely to be acting on the same receptor as they are antagonised with similar affinity bya single antagonist.

°Agonist A acts on a different receptor to that which B and C act on as the sameantagonist has much higher affinity at the receptor that agonist A acts on.

Front 63

What characteristic does this Schild Plot represent?

Back 63

° Competitive Binding

Front 64

What characteristic does this Schild Plot represent?

Back 64

° Heterogenous Receptors

Front 65

What characteristic does this Schild Plot represent?

Back 65

° Non-Competitive Binding

Front 66

What characteristic does this Schild Plot represent?

Back 66

° Cooperative Binding

Front 67

What characteristic does this Schild Plot represent?

Back 67

° Non-Equilibrium

Front 68

Regarding Fick's Law, which one of these options is True?
a) Flux will double if membrane thickness is doubled
b) Flux will halve if the surface area is doubled
c) Flux is inversely proportional to the concentration gradient
d) Flux is not energy dependent

Back 68

d) Flux is not energy dependent

Front 69

What are the correct definitions of clearance from these options?
a) the volume of blood/plasma irreversibly cleared of drug per unit time
b) the time taken to reduce the plasma concentration by half
c) the constant relating the rate of elimination of a drug to plasma concentration
d) the amount of drug metabolized per unit time
e) the amount of drug excreted per unit time

Back 69

a) the volume of blood/plasma irreversibly cleared of drug per unit time

c) the constant relating the rate of elimination of a drug to plasma concentration

Front 70

Which of these options are correct for describing half life?
a) increases as clearance increases
b) decreases as volume of distribution increases
c) decreases as clearance increases
d) increases as Vd increases
e) increases as elimination rate constant decreases

Back 70

c) decreases as clearance increases

d) increases as Vd increases

e) increases as elimination rate constant decreases

Front 71

If a drug is administered repeatedly at the same dose and dosage intervals, the time required to reach steady-state plasma drug concentration is proportional to what?
a) dose
b) route of administration
c) dosage interval
d) bioavailability
e) elimination half life

Back 71

e) elimination half life

Front 72

The main determinant(s) of the hepatic clearance of a high hepatic extraction ratio drug are:
a) intrinsic clearance
b) hepatic blood flow
c) elimination rate
d) protein binding
e) dose

Back 72

b) hepatic blood flow

Front 73

The main determinant(s) of the hepatic clearance of a low hepatic extraction ratio are:
a) intrinsic clearance
b) hepatic blood flow
c) elimination rate
d) Vd
e) dose

Back 73

a) intrinsic clearance

Front 74

A drug has a hepatic clearance of 50L/hour and liver blood flow is 90L/hour. What is the maximum oral bioavailability?

Back 74

Method:
50/90 = 0.56
1-0.56 = 0.44
44%

Front 75

Phase II metabolism usually:
a) includes hydrolytic enzymes
b) produces low MW products
c) results in inactive metabolites
d) takes place mainly in kidneys
e) requires NADPH as a co-factor

Back 75

c) results in inactive metabolites

- unless the drug is a prodrug

Front 76

An increase in drug-plasma protein binding will lead to which of the following?
a) no change in unbound drug concentration
b) decrease in free drug
c) decreased drug activity
d) decrease in Vd
e) no change in free drug plasma concentration

Back 76

b) decrease in free drug

Front 77

In first-order elimination:
a) drug half-life is directly proportional to drug concentration
b) the rate of elimination is directly proportional to drug concentration
c) drug clearance is directly proportional to plasma drug concentration
d) the rate of elimination is constant
e) the rate of elimination is unpredictable

Back 77

a) drug half-life is directly proportional to drug concentration