Pharmacokinetics

Question 1

Describe the process of drugs being taken orally to entering the bloodstream.

Answer 1

Disintegration, dissolution, small intestine, liver, bloodstream.

Question 2

What does the symbol ‘ka’ denote?

Answer 2

The absorption rate constant.

Question 3

What is the symbol used to show the absorption rate constant?

Answer 3

Ka.

Question 4

What does the term ‘F’ denote?

Answer 4

Oral Bioavailability.

Question 5

What symbol is used to show oral bioavailability?

Answer 5

F.

Question 6

What route of administration excludes the absorption step?

Answer 6

Intravenous.

Question 7

What routes of administration include the absorption step?

Answer 7

Oral, topical, SC, IM, inhalation.

Question 8

What is the ideal molecular weight for absorption?

Answer 8

<500.

Question 9

How can pH affect drug absorption?

Answer 9

Changes in pH in the intestines and the blood change the ionization states of drugs in each area. Ionized drugs have a harder time passing from the intestines to the blood. Non-ionized drugs can pass from the intestines to the blood easier. Hence, ionized drugs have a slower absorption rate.

Question 10

What are the pH of the stomach and intestinal fluids?

Answer 10

1.2.

Question 11

What is the pH of the blood?

Answer 11

7.4.

Question 12

How does a weakly acidic drug exist in the intestinal fluid and the blood respectively?

Answer 12

It will exist in its unionized form in the intestinal fluid. It will exist in the ionized form in the blood.

Question 13

How does a weakly basic drug exist in the intestinal fluid and the blood respectively?

Answer 13

It will exist in its ionized form in the intestinal fluid. It will exist in its unionized form in the blood.

Question 14

How does salt formation affect the absorption of drugs?

Answer 14

Salt formation can increase the solubility of weakly soluble drugs. Increased solubility leads to increased absorption.

Question 15

How is lipophilicity measured?

Answer 15

LogP.

Question 16

How does lipophilicity affect drug absorption?

Answer 16

The greater the lipophilicity of the drug, the greater the absorption of the drug. This is because the barrier for absorption is also lipophilic.

Question 17

List the 4 drug absorption pathways.

Answer 17

Paracellular, transcellular, cerrier mediated, endocytosis.

Question 18

Describe the paracellular drug absorption pathway.

Answer 18

Drug molecules pass through gaps between cells. Molecules must be of a small molecular weight.

Question 19

Describe the transcellular drug absorption pathway.

Answer 19

A passive process where the drug passes from one side of the cell to the other. Drug molecule must be lipophilic.

Question 20

Describe the carrier-mediated drug absorption pathway.

Answer 20

The drug molecule is transported by active carrier proteins that require ATP.

Question 21

Describe the endocytosis drug absorption pathway.

Answer 21

Drug molecules are taken up in vesicles to be passed across the cell.

Question 22

Is the blood flow in the brain, liver, kidneys, and heart fast or slow?

Answer 22

Fast.

Question 23

Is the blood flow in the bones, muscles, and skin fast or slow?

Answer 23

Slow.

Question 24

What is the volume of distribution?

Answer 24

The theoretical volume which helps you to convert the dose of drug into its systematic plasma concentration.

Question 25

What symbol is used to denote the volume of distribution?

Answer 25

Vd.

Question 26

What does the symbol 'Vd' denote?

Answer 26

The volume of distribution.

Question 27

If the volume of distribution is high, what does this mean?

Answer 27

That the drug is concentrated in the tissues.

Question 28

If the volume of distribution is low, what does this mean?

Answer 28

That the drug is concentrated in the blood.

Question 29

What are the two main plasma proteins involved in drug binding?

Answer 29

Albumin and alpha-1 acidic glycoprotein.

Question 30

What drugs do albumin bind?

Answer 30

Acidic and neutral drugs.

Question 31

What drugs do alpha-1 acidic glycoprotein bind?

Answer 31

Basic drugs.

Question 32

How does high protein binding affect the distribution of drugs?

Answer 32

Highly protein bound drugs will take a longer time to reach their intended site of action. They will also have a longer action.

Question 33

Where does drug metabolism typically occur?

Answer 33

The liver.

Question 34

Name the group of enzymes that are responsible for drug metabolism.

Answer 34

Cytochrome P450.

Question 35

What is believed to be the reason humans (and other organisms) have evolved cytochrome P450 enzymes?

Answer 35

To defend the body from ingested toxins.

Question 36

What percentage of drugs on the market are metabolised by Cytochrome P450 enzymes?

Answer 36

60%.

Question 37

What does a high metabolism and excretion mean for the dosage regimen of the drug?

Answer 37

More doses must be given daily.

Question 38

What does a low metabolism and excretion mean for the dosage regimen of the drug?

Answer 38

Fewer doses can be given per day.

Question 39

Through what means can drugs be excreted from the body?

Answer 39

Urine (kidneys), faeces (liver, small intestine), sweat, tears, hair, lungs.

Question 40

Excretion through which route is the primary route used when a breathalyzer test is administered?

Answer 40

The lungs.

Question 41

Define clearance.

Answer 41

The volume of blood or fluid from which drug is completely removed per unit time.

Question 42

What two clearance measurements is total clearance (CL Total) made up of?

Answer 42

CL hepatic and CL renal.

Question 43

Clinically, how can information on blood concentrations be gained?

Answer 43

By sampling blood levels over time.

Question 44

If one had no capacity for drug clearance, what would be the outcome?

Answer 44

Build up of drug and metabolites, leading to toxicity and death.

Question 45

What can concentration vs time graphs show us?

Answer 45

How long absorption takes, how long distribution takes, how effective elimination is, how long is the duration of action, is the drug toxic (MTC), how can one maintain the duration of action.

Question 46

What is an IV bolus dose?

Answer 46

An IV bolus dose is a direct injection of a full dose of drug into systematic circulation.

Question 47

What is the bioavailability of an IV bolus dose?

Answer 47

100%.

Question 48

What order kinetics does the pharmacokinetics of an IV bolus dose follow?

Answer 48

First order.

Question 49

On a concentration vs time graph for an IV bolus dose, what does the intercept represent?

Answer 49

The starting dose.

Question 50

On a concentration vs time graph for an IV bolus dose, what does the gradient of the line represent?

Answer 50

The rate of elimination.

Question 51

Once the gradient and intercept of a concentration vs time graph are established, what other parameters can be determined?

Answer 51

Half-life, clearance, the volume of distribution.

Question 52

What does a shorter half-life suggest?

Answer 52

The drug has a faster clearance.

Question 53

Define an IV infusion.

Answer 53

The slow pushing of a drug into the blood over a set time.

Question 54

Why are IV infusions prefered over an IV bolus dose?

Answer 54

They are more appropriate when repeated doses are required or when the drug concentration must be kept constant. IV infusions are used in a hospital to maintain a constant level of therapy in an individual. IV infusions can also be stopped if there are adverse drug reactions with fewer negative results compared to an IV bolus dose.

Question 55

Define steady state.

Answer 55

The balance between the infusion of drug in and the clearance f drug out. Maintaining a plasma concentration.

Question 56

How long, in half-lives, does it take for steady state to be reached for a drug?

Answer 56

4 to 5 half-lives.

Question 57

A drug with a long half-life will take an unacceptably long time to reach steady state concentration. In many clinical settings, we require a rapid clinical onset. How can this be achieved?

Answer 57

By starting the patient with a loading dose to artificially reach steady state concentration.

Question 58

What is the same as when an IV infusion is stopped?

Answer 58

Giving an IV bolus dose.

Question 59

What does the area under the curve (AUC) represent?

Answer 59

The residency of the drug in the body and is used to calculate the bioavailability (F). It is also very useful in calculating the clearance of the drug.

Question 60

How can the area under the curve (AUC) be calculated?

Answer 60

AUC = dose/clearance.

Question 61

Within what margins should the bioavailability of generic drug be, compared to the innovator?

Answer 61

within 10-15%.

Question 62

How does the volume of distribution differ for an overweight patient?

Answer 62

Their volume of distribution will be higher.

Question 63

How does the volume of distribution differ for an underweight patient?

Answer 63

Their volume of distribution will be lower.

Question 64

How can the dosage regimen be changed to provide an adequate therapeutic effect for an overweight patient? Why is this necessary?

Answer 64

The dose must be increased. This is because the volume of distribution is greater so more drug is needed to reach the target area.

Question 65

How can the dosage regimen be changed to provide an adequate therapeutic effect for an underweight patient? Why is this necessary?

Answer 65

The dose must be decreased. This is because the volume of distribution is lower so less drug is needed to reach the target area.

Question 66

Using different formulations can affect the shape of the concentration vs time graph. If all other parameters are maintained the same, what portion of the concentration vs time graph will change when the formulation is changed?

Answer 66

The rate of change of the ascending limb.

Question 67

In terms of pharmacokinetics, what can diseases of the liver and kidneys change?

Answer 67

The rate of elimination of the drug.

Question 68

What does a reduction in the production of plasma proteins do to the metabolism?

Answer 68

The extent of metabolism is increased.

Question 69

How is the metabolism of drugs affected by a reduction in blood flow to the liver?

Answer 69

The metabolism is reduced as less drug is brought to be acted upon by the enzymes.

Question 70

As well as the liver, where else are CYP450 enzymes found hence drug metabolism also occurs?

Answer 70

The small intestine.

Question 71

How many main groups are CYP450 enzymes split into? How many sub-classes are there?

Answer 71

3. Split into classes A-E.

Question 72

CYP2D6 makes up 2% of all CYP450 enzymes however metabolises what percentage of drugs? Especially what type of drug?

Answer 72

25% of all drugs, especially basic drugs.

Question 73

What drugs show non-linear kinetics?

Answer 73

Phenytoin and carbamazepine.

Question 74

What can inhibitory drug-drug interactions lead to?

Answer 74

Reduced metabolism, increased plasma concentration, AUC increases, elimination rate increases, increased Cmax.

Question 75

Define clearance.

Answer 75

The rate at which the liver eliminates drugs from the body.

Question 76

What is the maximum liver blood flow?

Answer 76

1500ml/min.

Question 77

How is hepatic clearance (CL H) calculated?

Answer 77

CL H = hepatic blood flow (Q) x Extraction ratio (E)

Question 78

What effect does an age-related reduction in cardiac output have on drug metabolism?

Answer 78

Reduced liver blood flow leading to reduced metabolism.

Question 79

What effect does age-related reduced hepatic function have on drug metabolism?

Answer 79

Reduced enzymes leading to reduced metabolism.

Question 80

Describe cirrhosis.

Answer 80

Permanent loss of liver cells. Different levels of cirrhosis lead to different levels of dose adjustment.

Question 81

Describe hepatitis.

Answer 81

Inflammation of the liver. If mild it is nothing significant. If it is major it will require dose adjustments.

Question 82

What 5 laboratory tests are used to generate the Child-Pugh score for liver function?

Answer 82

Serum albumin, total bilirubin, prothrombin time, ascites, hepatic encephalopathy.

Question 83

When are genetic differences in drug metabolism often first seen?

Answer 83

When the drug enters the market and has been subjected to the wider population.

Question 84

Metabolism of which drugs are affected by polymorphisms in the enzyme CYP2B6?

Answer 84

Doxorubicin, Nicotine.

Question 85

Metabolism of which drugs are affected by polymorphisms in the enzyme CYP2C9?

Answer 85

Warfarin, doxorubicin.

Question 86

Metabolism of which drugs are affected by polymorphisms in the enzyme CYP2C19?

Answer 86

Benzodiazepines, PPIs.

Question 87

Metabolism of which drugs are affected by polymorphisms in the enzyme CYP2D6?

Answer 87

Beta-blockers, anti-depressants, codeine.

Question 88

Metabolism of which drugs are affected by polymorphisms in the enzyme CYP3A4?

Answer 88

Erythromycin, HIV protease inhibitors.

Question 89

How is a person with two normal alleles for a specific CYP enzyme described? Describe their metabolism?

Answer 89

They are described as an extensive metaboliser. Their metabolism is normal.

Question 90

How is a person with one normal allele for a specific CYP enzyme described? Describe their metabolism?

Answer 90

They are described as an intermediate metabolizer. Their metabolism is decreased.

Question 91

How is a person with two poorly functioning alleles for a specific CYP enzyme described? Describe their metabolism?

Answer 91

They are described as a poor metaboliser. Their metabolism is close to none.

Question 92

How is a person with one normal and one overactive allele for a specific CYP enzyme described? Describe their metabolism?

Answer 92

They are described as an ultrarapid metaboliser. Their metabolism is increased.

Question 93

SNPs in which CYP enzyme are less prominent in Chinese/Japanese subjects compared to Caucasian subjects?

Answer 93

CYP2D6.

Question 94

SNPs in which CYP enzyme are more prominent in Chinese/Japenese subjects compared to Caucasian subjects?

Answer 94

CYP2C19.

Question 95

How many SNPs have been found for the CYP that metabolises Warfarin; CYP2C9? How many reduce metabolism?

Answer 95

3 SNPs. 2 reduce metabolism.

Question 96

What is the prevalence of CYP2C9 SNPs in Caucasians?

Answer 96

8-15%.

Question 97

What is the prevalence of CYP2C9 SNPs in Chinese populations?

Answer 97

80%.

Question 98

How many SNPs have been found for the CYP enzyme that metabolises Clopidogrel; CYP2C19?

Answer 98

3.

Question 99

As well as drugs, what other products can interact with drugs?

Answer 99

Food (milk, grapefruit), Herbals (SJW), Lifestyle (smoking, drinking).

Question 100

Patients of which groups are more susceptible to drug interactions?

Answer 100

Pregnant women, geriatric patients, patients suffering from renal or hepatic failure.

Question 101

Describe beneficial drug interactions.

Answer 101

Interactions that can potentiate the actions of one or more drugs. They can also be beneficial antagonistically.

Question 102

What can undesirable drug interactions lead to?

Answer 102

Toxicity and loss of efficacy.