Pharmacokinetics II

Question 1

What are the 4 major water compartments in the body?

What percentages of the body weight do these conribute to?

Answer 1

1) Extracellular fluid
2) Intracellular fluid (20-40%)
3) Transcellular fluid (2.5%)
4) Fat (20%)

Question 2

How does the volume of a compartment affect a drug?

Answer 2

Concentration of a drug in that compartment at equilibrium

Question 3

What percentage do the water compartments contribute to the body weight?

Answer 3

50-70%

Question 4

What are the 3 components of extracellular fluid and how much body weight percentage?

Answer 4

1) Plasma (4.5%)
2) Interstitial fluid (30-40%)
3) Lymph (1-2%)

Question 5

What is interstitial fluid?

Answer 5

Extracellular fluid which bathes cells and tissues

Question 6

How are drugs distributed to different parts of the body?

Answer 6

In the plasma

Question 7

Where is the bioavailability of a drug measured?

Answer 7

In the plasma

Question 8

How does fat impact the pharmacokinetics of a drug? (4)

Answer 8

• Made of lipids
• Non- polar drugs can easily enter and accumulate here
• Poorly perfused
• Varies between different people

Question 9

Examples of the compartments of the body which are tightly regulated and why(2)

Answer 9

The foetus
- Protected by the placenta

The CNS
- Protected by the BBB

Question 10

What is the distribution of the drug based upon?

Answer 10

• Permeability

- Lipid solubility

Question 11

What is the BBB impermeable to and why?

Answer 11

Water soluble molecules, they have poor lipid solubility

Question 12

Examples of drugs which can’t cross the BBB?

Answer 12

• Antibiotics
• Chemotherapy drugs

(poor lipid solubility)

Question 13

Examples of which molecules easily cross the BBB?

Answer 13

Lipid soluble

• Ethanol
• Caffeine

Question 14

What happens to tight junctions during inflammation?

Answer 14

Become ‘leaky’

Question 15

Where is the chemoreceptor zone in the body and what does this do?

Answer 15

• Outside of the BBB

- Induces vomiting - can happen during drug treatments

Question 16

How does the protein albumin affect the free concentration of drugs in the plasma?

Answer 16

• Binds to acidic drugs

- Reduces the concentration of drug in the plasma

Question 17

What are the 3 considerations of drug dose, regarding albumin?

Answer 17

When low doses of free drug are needed- need to increase dose to overcome binding to albumin

When high doses of free drug are needed - already taking a high dose
- Binding to and from albumin can decrease/increase the concentration of drug in the plasma - dangerous

Taking another drug can displace the original drug from albumin - increasing free concentration of the original drug

Question 18

How does the partition into body fat effect the free concentration of drug in compartments why is this a disadvantage?

Answer 18

• Drug accumulates in the body fat
• Changes the amount and duration of drug in the body
• Difficult to predict the concentration of drug where you want it to act

Question 19

What drugs are more likely to partition into the body fat?

Answer 19

Lipid soluble drugs

Question 20

What affects drug concentration in the body?

Answer 20

Absorption (permeability, lipid solubility, into fats)
Distribution
Metabolisation
Excretion

Question 21

Where does drug metabolism mostly occur?

Answer 21

In the liver

Question 22

What are the 2 biochemical reactions in the liver?

Answer 22

Phase 1 - catabolic reaction

Phase 2 - synthetic (anabolic) reactions

Question 23

What happens in phase 1 in the liver?

Answer 23

• Produce more reactive compound
• By oxidation, reduction or hydrolysis
• Adds a reactive group (-OH) which serves as a point of attack for phase 2 reaction

Question 24

What happens in phase 2 in the liver?

Answer 24

• Conjugation to produce an inactive product

-

Question 25

What is conjugation?

Answer 25

Attachment of a substituent group

Question 26

What are the microsomal enzymes present in the liver?(3)

Answer 26

- Cytochrome P450 - Alcohol dehydrogenase - MAO

Question 27

Where is cytochrome P450 found?

Answer 27

Embedded in the membrane of the smooth muscle endoplasmic reticulum of the liver

Question 28

Which enzyme can cause drug concentration to increase and why?

Answer 28

Alcohol dehydrogenase as it is easily saturated

Question 29

What does enzyme induction cause?

Answer 29

- Increase metabolic enzyme in the body | - Cause drug to have a less effect as concentration decrease

Question 30

What does drug metabolism depend upon?

Answer 30

The ability of the drug to cross the membrane into the liver

Question 31

What are pro-drugs?

Answer 31

Drugs which only become active after undergoing phase 1 of metabolism Drugs which concentrations rise slower in the body

Question 32

How do drugs get into the liver? (2)

Answer 32

Through the portal system | Through the plasma

Question 33

How may the metabolism of drugs decreased as they go through the portal system?

Answer 33

They join up with bile

Question 34

How do drugs escape metabolism? What happens instead?

Answer 34

They bind with food in the gut - go straight out of the body through excretion

Question 35

How is aspirin eliminated from the body?

Answer 35

Phase 1 - Gain OH group - Make salicylic acid Phase 2 - Large sugar molecule added to the free -OH group - Forms glucuronide - Drug can no longer bind to target - drug action stopped - Facilitate excretion out of the body

Question 36

What is important about the intermediate of paracetamol when it is being metabolised?

Answer 36

It it poisonous

Question 37

Why is there differences between how individuals metabolise drugs?

Answer 37

- Polymorphisms between individuals in P450 enzyme | - Different isoforms of P45 react with different drugs

Question 38

What are inducers of P450 drug metabolism?

Answer 38

Certain food activate/ inhibit P450

Question 39

What are the 3 routes of drug excretion from the body?

Answer 39

1) Renal excretion 2) GI excretion 3) Lung excretion

Question 40

When are drugs excreted in the urine?

Answer 40

After undergoing phase 2 of metabolism and after glomerular filtration etc. into the urine

Question 41

Which drugs go through urine excretion and which drugs don't?

Answer 41

Small drugs do Drugs bound to albumin don't

Question 42

What happens if a person has kidney disease?

Answer 42

Concentration of drug in the blood may be higher

Question 43

What % of drugs are excreted through the kidneys?

Answer 43

80%

Question 44

What does the time course of clearance of a drug from the body follow and what is this?

Answer 44

Mono-exponential decay

Question 45

What does exponential decay depend upon?

Answer 45

Rate of metabolism and rate of excretion

Question 46

What is the half-life of a drug dependant on?

Answer 46

- The concentration of drug taken | - The drug taken

Question 47

Describe saturation kinetics of a drug

Answer 47

- Enzyme cannot keep up with the metabolism of the drug - When exceed the rate of which drug can be administered (set by the metabolism of the drug) - Linear increase in concentration of the drug in the plasma - Unexpected increase of the drug concentration causing toxicity

Question 48

What are some advantages of prodrugs? (4)

Answer 48

- Prevent damage to the GI tract - Selective toxicity (eg. only cleaved in HIV cells) - Cross BBB quicker than active form - Greater bioavailability than active from

Question 49

What determines the rate of which a drug can be administered?

Answer 49

The metabolism of the drug

Question 50

Are strong bases absorbed well in the GI tract? Why?

Answer 50

NO | Favours dissociation of the drug - poor absorption

Question 51

What is sublingual administration? What does this avoid?

Answer 51

Placing a tablet underneath the tongue Avoids first pass metabolism in the liver