ICPP - Pharmacokinetics

Question 1

What are the four main processes in pharmokinetics?

Answer 1

Absorption, distribution, metabolism and elimination

Question 2

Summarise the drug administration routes.

Answer 2

ENTERAL (oral, sublingual, rectal) and PARENTERAL (intravenous, subcutaneous, intramuscular)

Question 3

Where does most drug absorption occur in the oral route?

Answer 3

Most is absorbed from small intestine

Question 4

What is the typical transit time of the small intestine?

Answer 4

3-5 hours, but motility varies 1-10 hours

Question 5

What is passive diffusion?

Answer 5

The mechanism by which lipophilic drugs and weak acids/bases diffuse directly down concentration gradient into GI capillaries.

Question 6

What are SLCs?

Answer 6

Solute Carrier transport, which move anions and cations through the GI epithelia. It is a passive process driven by electrochemical gradient.

Question 7

Give some examples of factors in the GI tract that can affect drug absorption?

Answer 7

• GI length
• Density of SLC expression
• Blood flow to GI
• Motility of GI
• Whether there is food present/ pH

Question 8

What are phase I and II enzymes?

Answer 8

Enzymes found in the liver that metabolise enzymes. Phase I = cytochrome P450s.
Phase II = conjugating

Question 9

What is “first pass” metabolism?

Answer 9

When drugs pass through the liver, which reduces the availability of the drug reaching systemic circulation.

Question 10

What is bioavailability?

Answer 10

The fraction of a defined dose which reaches its way into a specific body compartment.

Question 11

Why is the circulatory compartment a common reference compartment?

Answer 11

Because an IV bonus has 100% delivery to veins

Question 12

How is oral bioavailability (F) calculated?

Answer 12

F = amount reaching systemic circulation (area under curve on oral graph) / total IV drug given (area under curve on IV graph)

F is between 0 and 1, and informs choice of administration route

Question 13

What are the three varying levels of capillary permeability?

Answer 13

• continuous
• fenestrated
• sinusoid

Question 14

If a drug is lipophilic, is it easy or difficult to move across the membrane barriers?

Answer 14

Easy

Question 15

If a drug binds to plasma/tissue proteins, can it bind to the target site?

Answer 15

Not initially, as it must be free to bind. However, bound drug often acts as a “reservoir”, so it would be able to dissociate and bind to target site.

Question 16

What are the three model body fluid compartments?

Answer 16

Plasma water (3 litres), interstitial water (11 litres) and intracellular water (28 litres). Drugs move from plasma to interstitial to intracellular.

Question 17

What is apparent volume of distribution?

Answer 17

A (made up) concept that the main body fluid compartments can be grouped together.

Vd = drug dose / [plasma drug] at time=0. Units are litres or litres/kg

Smaller Vd values = less penetration of intracellular fluid compartment, higher Vd values = more penetration

Question 18

Can the Vd change from person to person?

Answer 18

Yes - it is affected by many factors, for example pregnancy, pediatrics, geriatrics, renal failure

Question 19

What is the evolutionary advantage of recognising xenobiotics?

Answer 19

They are potential toxins

Question 20

Which reactions do CYP450 (phase I) enzymes catalyse, and where are they found?

Answer 20

Redox, dealkylation and hydroxylation.

Found on external face of ER.

Question 21

What are pro-drugs?

Answer 21

A precursor to drugs which must be activated in order to work, eg codeine to morphine

Question 22

Where are phase II enzymes found and what do they do?

Answer 22

In the cytosol, they enhance hydrophilicity by further increasing ionic charge which allows better renal elimination.

Question 23

What are the three super families of cytochrome P450 enzymes?

Answer 23

CYP 1, 2 and 3. Six of these isozymes metabolise around 90% of prescription drugs.

Question 24

Give some factors affecting speed of drug metabolism in humans.

Answer 24

• age
• sex
• general heath/dietary/disease

Question 25

What is CYP450 induction?

Answer 25

Certain drugs can induce CYP450, leading to faster metabolism of other drugs.

Question 26

Give an example of CYP4450 inhibition.

Answer 26

Grapefruit juice inhibits CYP3A4, which metabolises Verapimil which is used to treat high blood pressure. Consequence can be much reduced BP and fainting.

Question 27

Do CYP450s show genetic variation?

Answer 27

Yes - some may not be expressed, or are overexpressed. Eg 1% of Caucasians and Africans are unable to metabolise NSAIDs.

Question 28

What is the main route of drug excretion?

Answer 28

Via kidneys. Other routes include bile, lung, breast milk, sweat, tears, genital secretions, saliva.

Question 29

Which sort of drug molecules are NOT filtered out by the kidneys?

Answer 29

Lipophilic, unionised molecules. These leave the tubule due to solute conc being higher inside than outside. Hydrophilic, ionised drug is filtered out and excreted in urine.

Question 30

In the proximal tubule, anions and cations are actively transported in. Give some examples of these.

Answer 30

OATs: urate, penicillin, NSAIDs, antiviral
OCTs: morphine, histamine, chlorpromazine

Question 31

What is clearance?

Answer 31

The volume of plasma that is completely cleared of the drug per unit time. Units are ml/min

Total body clearance = hepatic clearance + renal clearance

Question 32

What can clearance (CL) and Vd indicate when combined?

Answer 32

They predict how long the drug will stay in the body.

Question 33

What is drug half life?

Answer 33

The amount of time over which the concentration of a drug in plasma decreases to one half of the concentration value it had when it was first measured.

T1/2 = 0.693xVd / CL

Question 34

The curve of plasma half-life decreases exponentially, so what happens if we plot concentration on a log axis?

Answer 34

It becomes linear

Question 35

What happens when elimination processes become saturated?

Answer 35

They become rate limited and cannot go any faster. They are known as zero order. In this situation, a graph of [drug] against time would be a straight line.

Question 36

Why is it better to avoid drugs having zero-order kinetics?

Answer 36

All processes are saturated, so more likely to result in ADRs/toxicity as. Relatively small dose changes can cause huge plasma [drug] changes. Half-life is not easily calculable so cannot predict dosage regimes.