Block E

Question 1

What is pharmacokinetics?

Answer 1

Refers to a drug’s journey within the body

Question 2

ADME

What are the four stages of pharmacokinetics?

Answer 2

• Absorption: Observes how a drug travels from the site of administration to site of action
• Distribution: Observes the passage of a drug through the bloodstream to different tissue in the body
• Metabolism: Observes the activity that breaks down a drug
• Excretion: Observes the elimination of a drug from the body

Question 3

What does pharmacodynamics refer to?

Answer 3

What the drug does to the bodY

Question 4

What is used for measurement in pharmacokineticsa?

Answer 4

Blood/ Plasma concentrations- Easy to access

Question 5

Suggest 3 sites of action for a drug.

Answer 5

• Anatomical: compaartment drug has to reach
• Cellular: The cell type the drug must reach
• Molecular: The molecular target to which the drug must bind

Question 6

Explain how Direct Oral Anti Coagulants work

Answer 6

• Target the central plasma compartment
• DOAC’s are small molecules that occupy the catalytic site of either FXa or thrombin, preventing their capacity to cleave and activate their substrates.

Question 7

What receptor does carffeine target?

Answer 7

Adenosine receptors.

Question 8

Outline the 3 adenosine receptors

Answer 8

• Adenosine A2A receptor is mainly present in the brain, heart, lungs and spleen.
• Adenosine A2B receptor has its major distribution in the large intestine and bladder.
• Adenosine A3 receptor is present in the lungs, liver, brain, testis and heart.

Question 9

What is the function of temozolomide?

Answer 9

Targets the DNA of brain tumour cells.

Question 10

Through what systems are drugs distributed througout the body?

Answer 10

circulatory and lymphatic systems.

Question 11

Suggest 3 Biological barriers which drugs must cross to reach their receptor.

Answer 11

1. Gastrointestinal mucosa
2. Blood brain barrier
3. Placenta

Question 12

What is a (simplistic) formula to work out drug concentration in the body?

Answer 12

Concentration= Dose/Volume

Question 13

Suggest how different drugs may vary in their volume distribution

Answer 13

• Large molecules will mainly stay in plasma- Very small VD
• Hydrophilic/ Highly polar small molecule drugs will distribute into extraceullular fluid and have a relatively small VD.
• Highly lipid soluble drugs distribute far more widely- Lerge VD

Question 14

At what volume distributions will drugs be considered to be confined to various parts of the body.

Answer 14

• VD-0.04 L/Kg are less thought to be confined to plasma
• VD-0.06L/Kg are considered to be distributed to all tisseues in the body including fatty tissue
• VD-10L Most of the drug is considered to be within the tissue with very little criculating in the plasma.

Question 15

Name the body fluid compartments alongside the %volume they take up

Answer 15

• Plasma-5%
• Extracellular Fluid-15%
• Intracellular Fluid-35%
• Intracellular Fat-20%

Question 16

What does partitioning of drugs refer to?

Answer 16

The fact that some drugs will accumulate in specific compartments of the body.

Question 17

Give 3 examples of drug partitioning.

Answer 17

1. Tetracycline accumulates in bones and teeth as they have a high affinity for calcium
2. Amiodarone can accumulate in the liver and lung causing hepatitis and intersitial pulmonary fibrosis
3. Chloroquine has a high affinity for melanin and can accumulate in the retina and lead to ocular toxicity

Question 18

Why can drugs partitioning into body fat cause issues?

Answer 18

Certain drugs e.g. benzodiazepines/ insecticides may accumulate in fat. Some drug doses are measured in mg/kg and must therefore be adjusted for obese patients.

Question 19

Why is grug efficacy reflected only by unbound drugs in the bloodstream?

Answer 19

Bound drugs may not passively diffues to extravascular/ tissue sites where pharmacologic drug effects occur

Question 20

What is drug elimination?

Answer 20

The loss of the drug from the body

Question 21

What are the main routes of drug elimination?

Answer 21

• Excretion- kidneys
• Metabolism- Liver

Question 22

What is the purpsoe of ther mass balance clinical study?

Answer 22

To understand how drugs are absorbed, metabilised and excreted after dosing

Question 23

Outline metabolism as a route of elimination for drugs

Answer 23

Most commonly occurs in the liver. Phase 1 rections introduce a reactive group into the molecule.
Phase 2 reactions allow conjucation to the molecule making it hydrophulic and suitable for elimination via the kidney.

Question 24

What does a pro drug molecule do?

Answer 24

Becomes converted into an active drug via metabolism

Question 25

Whare are CYP450?

Answer 25

A super family of enzymes. Distinct but have some overlapping features Typically involved in phase 1 oxidation, reduction and hydrolysis reaction in the liver

Question 26

How does liver disease affect CYP450

Answer 26

Reduction of activity in complex and undpredictable ways, therefore drugs metabolised in the liver should be used with caution.

Question 27

Why are CYP450 enzyme so important?

Answer 27

Responsible for the metabolism of ~70-80% of all drugs in clinical use

Question 28

Where is CYP3A4 most abundant?

Answer 28

In the liver where is ocmprises 15-20% of enzymes

Question 29

Suggest 2 common drug-drug interactions involving CYP3A4

Answer 29

1. Clarithromycin/erythromycin and simvasrarin causing myopathy/rhabdomyolysis 2. Diltiazem/veraspamil and prednisone causing immunosupression

Question 30

What does first pass metabolism refer to?

Answer 30

Drugs which pass through the liver and undergo metabolism before reaching the rest of the body

Question 31

what is the bioavailability of a drug?

Answer 31

The proportion of a drug which enters circulation when introduced into the body

Question 32

What is hepatic extraction ratio

Answer 32

The fraction of the drug entering the liver in the blood which is irreversibly removed during one pass through the liver

Question 33

How do you calculate the extraction ratio?

Answer 33

(Amount in- Amount out)/Amount in

Question 34

Name 3 important drugs metabolised in the intestine

Answer 34

* Cyclosporine * Midazolam * Verapamil

Question 35

Give a brief outline fo renal excretion of drugs

Answer 35

* Nearly all water+electrolytes are reabsorbed from renal tubes back to circulation * Large polar compounts (Most drug metabolites) cannot diffuest back into circulation unless a specific transport mechanism exists

Question 36

What is drug clearance?

Answer 36

The volume of plasma cleared of a drug over a specified time period.

Question 37

How do you calculate drug clearance?

Answer 37

Rate that drug is removed from plasma/Concentration of drug in plasma

Question 38

Suggest 3 factors affecting absorption

Answer 38

1. Barriers to absorption: * IV-none * Oral-GI mucosa * Topical-Skin epithelium, Subcuatneous tissue 2. Drug factors-affecting the rate and extend of absorption: * Molecular size/ lipid solubility/ chemical form 3. Patient factors- affecting rate of absorption: * Surface area of absorptive surface * Blood flow to site of absorption

Question 39

What is an IND?

Answer 39

Investigational New Drug document- tells the story about the potential new substance