Session 10.1 - Pharmacokinetics - 01

Question 1

What are the 4 main stages that can effect a drugs potency and how are these further classified?

Answer 1

“Drug In”:

1) Absorption
2) Distribution

“Drug Out”:

3) Metabolism
4) Excretion

Question 2

What are the 2 classifications for drug administration and what routes are classified by these?

Answer 2

Enteral:
Delivery into internal environment of body - GI tract (Oral, Sublingual, Rectal)

Parenteral:
Delivery via all other routes that are not GI (Intravenous, Subcutaneous, Intramuscular)

Question 3

What mnemonic can be used to highlight all the major routes of drug administration?

Answer 3

Oi! It is Sir!

Oral Intravenous! Intramuscular Transdermal - Intranasal Subcutaneous - Sublingual inhalation Rectal!

Question 4

What are the main methods of absorption at the molecular level?

Answer 4

• Passive diffusion = lipophilic drugs, weak acid/bases
• Facilitated diffusion = charges molecules diffuse down gradient via OATs or OCTs
• Secondary (indirect use of ATP) active transport - Cotransport with pre-existing chemical gradients

Question 5

How does a weak acid/base passively diffuse across the lipid bilayer?

Answer 5

• If pH is near its pKa - 50% will be protonated the remainder won’t
• A drug will pass through the membrane more readily if it is uncharged

Question 6

Name some factors that affect drug absorption

Answer 6

Physiochemical Factors:

• GI length
• Drug Lipophilicity / pKa
• Density of SLC expression in GI (OATs and OCTs)

GI physiology:

• Blood flow = reduced blood flow in shock/anxiety as blood is redirected
• GI motility = slow post meal : rapid in diarrhoea
• Food/Internal pH = food can absorb drugs, Low pH destroy drugs

First Pass Metabolism by GI and Liver:
- Gut Lumen: Gut/ Bacterial Enzymes can denature some drugs
- Gut wall/ Liver: some drugs metabolised by:
- Cytochrome P450s - Phase 1 enzymes
- Conjugation - Phase 2 enzymes
“First pass” metabolism effects availability of drugs reaching systemic circulation

Question 7

In the average male what are the general proportions of the small intestine?

Answer 7

6-7m long - 2.5cm diameter

Total SA for absorption ~ 30-35m^2

Question 8

Define Bioavailability

Answer 8

• The fraction of a defined dose which reaches its way into a specific body compartment
• The most common reference compartment is the CVS (circulation). As such IV delivery is 100% and comparisons for delivery are made by this intravenous bioavailability

Question 9

What is Oral Bioavailability?

Answer 9

• Represented as “F”

F- = (Amount reaching systemic circulation)/(total drug given IV)

Question 10

What are the 2 main factors that can affect drug distribution?

Answer 10

• Drug molecule lipophilicity/hydrophilicity (it’s ability to move across membranes, capillary, tissue)
• Degree of drug binding to plasma and/or tissue proteins

Question 11

How can degree of binding to plasma/ tissue proteins effect the drug distribution?

Answer 11

• Drugs will bind to plasma proteins with weak interactions. As such they have a bound/unbound equilibrium.
  If a drug is bound this removes it from the free drug concentration and as such it’s potency is reduced.
  N.B. the drug is not permanently bound so as the plasma level drops the drug will be released from the protein to reach equilibrium

Question 12

Plasma proteins have a discrete number of binding site which multiple drugs can bind to. What effect does this have?

Answer 12

Competition for binding sites affects free drug plasma concentration. If 2 drugs are taken together that bind to the same site the free concentration will increase

Question 13

What are the 3 body fluid compartments?

Answer 13

• Plasma water
• Interstitial water (tissue fluid)
• Intracellular water

Question 14

What effect does increasing penetration of drug through the fluid compartments have on plasma drug concentration and volume distribution?

Answer 14

• Decreasing plasma drug concentration

- Increasing Vd = Volume distribution

Question 15

What is the “apparent” volume distribution?

Answer 15

Vd = (drug dose)/[Plasma Drug]

Higher Vd values (lower plasma concentration) = greater compartment penetration

Lower Vd values (higher plasma concentration) = lower compartment penetration

The measure is “apparent” because it assumes that [plasma] is equal to all compartments (which it’s not)