S2) Pharmacokinetics

Question 1

What is pharmacokinetics?

Answer 1

Pharmacokinetics is the study of the movement of a drug into and out of the body

“What the body does to the drug”

Question 2

What is pharmacodynamics?

Answer 2

Pharmacodynamics is the study of drug effect and mechanisms of action

“What the drug does to the body”

Question 3

What is pharmacogenetics?

Answer 3

Pharmacogenetics is the effect of genetic variability on the pharmaco- kinetics/dynamics of a drug on an individual

Question 4

What are the two forms of drug administration?

Answer 4

• Enteral – delivery into internal environment of body (GI tract)
• Paraenteral – delivery via all other routes that are not the GI

Question 5

What are the 9 different types of drug administration into the body?

Answer 5

• Oral
• Intravenous
• Intramuscular
• Transdermal
• Inhalation
• Subcutaneous
• Sublingual
• Intrathecal
• Rectal

Question 6

Briefly, identify and describe the four main processes involved in drug therapy?

Answer 6

• Pharmaceutical process – “Is the drug getting into the patient?”
• Pharmacokinetic process – “Is the drug getting to its site of action?”
• Pharamcodynamic process – “Is the drug producing its required pharmacological effect?”
• Therapeutic process – “Is the pharmacological effect being translated into a therapeutic effect?”

Question 7

What are the four processes involved in pharmacokinetics?

Answer 7

• Drug in:

I. Absorption

II. Distribution

• Drug out:

I. Metabolism

II. Excretion

Question 8

What is bioavailability?

Answer 8

Bioavailability is the fraction of a dose which finds its way into a body compartment (usually the circulation)

Question 9

How does one calculate oral bioavailability?

Answer 9

Oral Bioavailability (F) = AUC_oral / AUC_IV

Question 10

What are the factors which affect bioavailability?

Answer 10

• Absorption – drug formulation, age, food, vomiting / malabsorption
• First pass metabolism

Question 11

What is first pass metabolism?

Answer 11

First pass metabolism is any metabolism occurring before the drug enters the systemic circulation

Question 12

Identify three common locations where first pass metabolism occurs

Answer 12

• The Gut Lumen
• The Gut Wall
• The Liver

Question 13

What is drug distribution?

Answer 13

The distribution of a drug refers to its ability to ‘dissolve’ in the body

Question 14

What are the two factors affecting drug distribution?

Answer 14

• Protein binding
• Volume of Distribution (V_d)

Question 15

In three steps, explain how protein binding determines drug distribution

Answer 15

⇒ In systemic circulation, many drugs are bound to circulating proteins

⇒ Most drugs must be unbound to have a pharmacological effect

⇒ The free fraction of the drug can bind to cellular receptors, then gain access to cellular enzymes

Question 16

Once in the systemic circulation, many drugs are bound to circulating proteins.

Provide four examples of this

Answer 16

• Albumin (acidic drugs)
• Globulins (hormones)
• Lipoproteins (basic drugs)
• Acid glycoproteins (basic drugs)

Question 17

What happens when a drug is displaced from its binding site?

Answer 17

Displacement of drugs from binding sites causes protein binding drug interactions

Question 18

Changes in protein binding can occur, causing changes in drug distribution. However, these are only important if 3 criteria are met.

What are these criteria?

Answer 18

• High protein binding
• Low V_d
• Has a narrow therapeutic ratio

Question 19

Identify four factors which affect protein binding

Answer 19

• Hypoalbuminaemia
• Pregnancy
• Renal failure
• Displacement by other drugs

Question 20

If a drug is not bound to plasma proteins, it is available for distribution to the tissues of the body.

How can one measure the tissue distribution of a drug?

Answer 20

Volume of distribution

Question 21

What is volume of distribution?

Answer 21

Volume of distribution is a measure of how widely a drug is distributed in body tissues

Question 22

How can one calculate volume of distribution?

Answer 22

Volume of distribution (V_d) = Dose / [Drug]_t0

Question 23

Identify six factors which might affect the tissue distribution of a drug

Answer 23

• Specific receptor sites in tissues
• Regional blood flow
• Lipid solubility
• Active transport
• Disease states
• Drug interactions

Question 24

What are the end products of drug metabolism (usually)?

Answer 24

• After conjugation, water-soluble metabolites are formed
• Usually, they are pharmacologically inactive

Question 25

Describe two circumstances where drug metabolism produces active metabolites

Answer 25

- Pharmacologically inactive compound → pharmacologically active compound *e.g. pro-drugs* - Pharmacologically active compound → other active compounds *eg. codeine to morphine*

Question 26

Phase I metabolism involves oxidation and reduction reactions. Which group of enzymes control these reactions?

Answer 26

Cytochrome p450 family of enzymes

Question 27

Explain how drugs can control the activity of Cytochrome P450 enzymes

Answer 27

**Enzyme-inducing** and **enzyme-inhibiting drugs** that alter the rate of metabolism of other drugs

Question 28

Identify five other factors, apart from drugs, which influences the activity of cytochrome p450 enzymes

Answer 28

- Age - Liver disease - Hepatic blood flow - Cigarette use - Alcohol consumption

Question 29

What are Cytochrome P450 isoenzymes and what do they do?

Answer 29

- **CYP450s** are a super family of isoforms responsible for approximately 90% human drug metabolism through oxidative reactions - They metabolise toxins such as carcinogens and pesticides

Question 30

Where are Cytochrome P450 isoenzymes found?

Answer 30

CYP450s are present mainly in the **liver** (some gut and lung)

Question 31

Identify 5 factors which might affect drug metabolism

Answer 31

- Race (development of pharmacogenetics) - Age (reduced in aged patients & children) - Sex - Species - Clinical / physiological condition

Question 32

What is the main route of drug elimination?

Answer 32

The main route of drug elimination is the **kidney**

Question 33

Identify 5 other routes of drug elimination

Answer 33

- Lungs - Breast milk - Sweat - Tears - Genital secretions

Question 34

Three processes determine the renal excretion of drugs. Identify these

Answer 34

- Glomerular Filtration - Passive tubular reabsorption - Active tubular secretion

Question 35

What is clearance?

Answer 35

**Clearance** is the ability of body to excrete drug (mostly = GFR)

Question 36

Describe the relationship of clearance with GFR and t_1/2

Answer 36

- **GFR** is directly proportional to clearance - **t**_1/2 is inversely proportional to clearance **i.e. a reduction in clearance (/ GFR) increases t_1/2 **

Question 37

Describe the features of 1st Order kinetics – linear

Answer 37

- **Rate of elimination** is proportional to drug level - Constant fraction of drug eliminated in unit time - **t_1/2** can be defined

Question 38

Describe the features of Zero Order kinetics – non-linear

Answer 38

Rate of elimination is constant

Question 39

How does one calculate the elimination rate constant (k)?

Answer 39

**k** = Cl / V_d

Question 40

How does one calculate half life (t_1/2)?

Answer 40

**t**_1/2 = ln2 / k

Question 41

Most drugs exhibit zero order kinetics at high doses. Why is this?

Answer 41

Because the receptors / enzymes become **saturated**

Question 42

Zero order drugs are more likely to result in toxicity, hence, drug monitoring essential. Why does this occur?

Answer 42

- **Fixed rate of elimination** per unit time - **“Small” dose changes** may produce large increments in [plasma] which may lead to toxicity

Question 43

Provide 5 reasons for drug monitoring

Answer 43

- Zero order kinetics - Long half-life - Narrow therapeutic window - Greater risk of drug-drug interactions - Known toxic effects *e.g. bone marrow suppression*

Question 44

What is the steady state (CpSS) of the drug?

Answer 44

- **Steady state** (CpSS) refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination - Usually, 4-5 half lives are required to reach steady state

Question 45

Loading doses are employed to reach CpSS more rapidly. What are loading doses?

Answer 45

- A **loading dose** is an initial higher dose of a drug that is given at the start of a drug course before dropping down to a lower maintenance dose - Useful for drugs that have a long systemic half-life (eliminated slowly)

Question 46

How does one calculate loading doses?

Answer 46

**Loading Dose** = V_d x [Drug]_target