Pharmacokinetics

Question 1

Define Pharmacokinetics?

Answer 1

Factors which determine the concentration of the drug at the target receptors.

Question 2

4 factors that determine concentration at target site?

Answer 2

1. Absorption
2. Distribution
3. Metabolism
4. Excretion

Question 3

Therapeutic Window

Answer 3

Difference between the minimum effective concentration and the minimum toxic concentration

Question 4

Absorption following intramuscular and subcutaneous injections

Answer 4

Blood flow to the muscle is higher than the skin, so absorption from intramuscular is more rapid than for subcutaneous. Exercise increases muscle blood flow thus further enhancing rate of absorption

Question 5

Most absorption of drugs occurs in…

Answer 5

The small intestine, due to its large surface. Stomach has a relatively small surface area and thick mucosa - due to this very little absorption

Question 6

Tetracyclines

Answer 6

Soluble at acidic pH but insoluble at neutral pH - due to this absorbed in the stomach

Question 7

Levodopa

Answer 7

Used in treating Parkinson’s –> Uses phenylalanine’s transporter

Question 8

ATP Binding Cassette (ABC transporters)

Answer 8

Use ATP to drive drug efflux from cells. e.g. MDR1 (p-glycoprotein)

Question 9

Whats special about the SERT transporter? (Part of the SLC Superfamily)

Answer 9

1. Acts as the receptor for Serotonin

2. Has very high substrate selectivity

Question 10

Gentamicin

Answer 10

Amimoglycoside antibiotic is hydrophilic and cannot readily cross cell membranes. However is small enough to cross endothelium between cells and therefore distributes in plasma and interstitial compartments

Question 11

Effect of drug binding to tissue or partitioning into fat on Vd (Volume of Distribution)

Answer 11

Increases Vd –> Eg Morphine has a Vd of 250litres. Note: Partitioning in fat is particularly important for lipophilic drugs such as the general anaesthetic, Thiopental

Question 12

Effect of drug binding to plasma proteins on Vd

Answer 12

Decreases apparent Vd, as plasma now carries a higher concentration of drug

Question 13

Define Volume of Distribution

Answer 13

It is the volume that would contain the total amount of drug in the body at a concentration equal to the plasma concentration
Vd = Total amount of drug in body (X) / Plasma concentration (C)

Question 14

Albumin as a plasma binding protein

Answer 14

Present in high concentration = 0.6mmol/litre. Its concentration is much higher than the therapeutic concentration of drugs.

• Has 2 binding sites fro acidic drugs (Warfarin, Silacylic Acid, Phenytoin)
• Also binds many neutral and some basic drugs

Question 15

Albumin levels fall in… (4)

Answer 15

• Old age
• Liver disease
• Nephrotic disease
• Major burns

Question 16

Alpha1-Glycoprotein (plasma binding protein)

Answer 16

• Normally expressed at low levels
• Acute phase reactant increased in inflammation or stress
• Binds many beta-blockers and antidepressants as well as other basic drugs

Question 17

Why is saturation of plasma proteins a problem?

Answer 17

When a low percentage of binding sites are occupied, an increase in dose produces a proportionate increase in Cfree and Cbound. However once binding sites have become saturated, further increase in dose produces a disproportionate increase in Cfree. Important for drugs such as Phenytoin that will saturate albumin in their therapeutic range.

Question 18

Function of Sulphonamides in neonates

Answer 18

Displace bilirubin from plasma protein binding sites –> accumulation of bilirubin in brain can cause neurological damage + jaundice

Question 19

Clearance (CL)

Answer 19

Rate of Elimination/ Plasma Concentration

- Note: Independent of the route of administration

Question 20

Xenobiotics

Answer 20

Foreign chemical substances that are not formed by the normal metabolism of the organism - Drugs are metabolised by the same enzyme systems that defend us from Xenobiotics (Detoxification)

Question 21

Major sources of xenobiotics?

Answer 21

Plants - contain secondary metabolites involved in the production of pigments/odourants/phytoalexins

• Environmental pollution
• Agrochemicals/ Cosmetic Drugs
• Pharmaceutical drugs

Question 22

Hydrophillic Xenobiotics

Answer 22

Cell membrane acts as a barrier - so readily excluded. Hydrophillic xenobiotics that have been absorbed can be readily excreted - so not a problem.

Question 23

Lipophillic Xenobiotics

Answer 23

Not excluded by membranes. Not readily excreted - so accumulate in fat + phospholipid bilayers in the absence of effective metabolism

Question 24

First pass metabolism

Answer 24

Liver is the main site of drug metabolism, as it contains very high concentrations of metabolic enzymes. Small intestine is also a site of xenobiotic metabolism.

• Metabolism produces a marked decrease in the concentration of drug reaching the systemic circulation
• Reduced bio-availability

Question 25

Phase 1 Hepatic Drug Metabolism

Answer 25

Functionalisation - introduce/unmask reactive chemical group e.g. OH/COOH/SH. Little effect on water solubility but alters biological properties of the drug

• Catabolic
• Makes a more reactive drug metabolite if prodrug (often drug is inactivated, but not always)

Question 26

Phase 2 Hepatic Drug Metabolism

Answer 26

Conjugation - reactive functional group is used to add another molecule; increases water solubility (hydrophilic) and molecular weight

• Anabolic
• Less reactive metabolite

Question 27

What’s special about Paracetamol with reference to hepatic drug metabolism?

Answer 27

Paracetamol already has an appropriate functional group - and therefore does not require Phase 1