Pharm - Drug Absorption and Bioavailability

Question 1

What factors influence drug absorption?

Answer 1

1. Route of administration
2. Particle size
3. Pka + ionisation
4. Lipid solubility
5. Concentration gradient
6. Other (small details e.g. bacterial overgrowth can reduce gut absorption, milk chelates tetracyclines)

Question 2

How do manufacturers alter rate of drug absorption?

Answer 2

1. Particle size
2. Compounds used in formulation e.g. in modified release tablets
3. Coatings e.g. enteric coatings will not dissolve in acidic conditions

Question 3

What are the routes for drug administration?

Answer 3

From top to toe:

• Intranasal (rich blood flow, avoids first pass metabolism but has variable absorption due to mucus flow)
• Sublingual (rich blood flow, avoids first pass metabolism but has variable absorption due to saliva flow)
• Enteral (variable availability relies on formulation, pKa, gastric pH, GI transit time)
• Intrapulmonary (e.g. volatiles, rich blood flow and large surface area)
• Transdermal (suitable for small, potent, lipophillic drugs_
• Intramuscular (variable absorption by blood flow, formulations can allow for depot)
• Intravenous (bioavailability is 100%)
• Epidural+subarachnoid (in general has a localised effect with minimal systemic absorption, NB opiates can still induce respiratory depression)
• Rectal (avoids first pass metabolism, good blood flow, useful in N&V)
• Vaginal (avoids first pass metabolism, limited systemic absorption so primarily used for drugs aimed at local actions)

Question 4

What is pKa and how does it influence drug absorption?

Answer 4

• pKa is the negative log of the acid dissociation constant. In other words, it is the pH at which the drug is 50% unionised and 50% ionised
• A high pKa for an acidic drug describes a reluctance to dissociate
• Acidic drugs are ionised at a pH ABOVE their pKa
• Basic drugs are ionised at a pH BELOW their pKA
• Drugs cross membranes in an unionised state so acids are better absorped in acidic environments

-Examples of acids: weak-propofol pKa 11, strong- aspirin pKa 3
- Examples of bases: weak-diazepam pKa 3.7, strong- morphine pKa 8.6

• Dissociation of drugs by pH follows a sigmoid curve

Question 5

What is the Henderson-Hasselbach equation?

Answer 5

Equation which describes the ability of a drug to ionise at a specified pH

pH = pKa + log[conjugate base/acid]
OR
pH = pKa + log[A-/AH]

Worked example using thiopentone:

pKa of thiopentone is 7.6, its a weak acid

In an ampoule, pH = 11

11=7.6 + log[A-/AH]
log[A-/AH]= 3.4, so the ratio of ionised:unionised is between 10^3 and 10^4. So there is thousands more ionised thiopentone than unionised->helps solubility in storage

Physiological pH = 7.4

7.4=7.6 + log[A-/AH]
log[A-/AH]= -0.2, so there is hundreds more unionised thiopentone than ionised

Question 6

Define bioavailability

Answer 6

Bioavailability is the fraction of drug administered that reaches the blood stream

For orally administered drugs it can be calculated by drawing the graph plasma concentration on Y axis and time on x-axis for the drug when administered orally and when administered intravenously.
- The AUC oral/AUC IV gives the bioavailable fraction

Question 7

What is first pass metabolism? Give examples.

Answer 7

The process by which drugs absorbed through the GI system enter the hepatic portal circulation and are carried to the liver to be metabolised so that only a fraction of the drug returns to the systemic circulation.

Drugs that undergo extensive first pass metabolism have low oral bioavailability

Examples:

Aspirin 70%
Codeine 60%
Morphine 40%
Hydralazine 15-30%
Verapamil 20%

Question 8

What are the mechanisms of drug passage across a membrane?

Answer 8

Passive diffusion: either dissolution in lipid bilayer or down ion channels
Facilitated diffusion: combines with membrane bound carrier proteins to cross membrane (faster than passive diffusion)
Active transport: molecules transported against concentration gradient by an energy requiring molecular pump e.g. Na/K/ATPase. There is also secondary active transport - the pump is coupled to an ionic gradient which is actively maintained, e.g. Na/Glucose co-transporter
Pinocytosis: molecule invaginated by cell membrane and then released into cytosol (larger molecules)

Question 9

What factors affect the rate of diffusion?

Answer 9

1. Concentration gradient
   - Fick’s law: rate of diffusion proportional to concentration gradient
   - Protein binding affects proportion of available drug in the concentration gradient
   - Bowman’s principle: less potent NMB drugs are given in higher doses and so have a larger concentration gradient between plasma and active site so faster onset
2. Molecular size (Graham’s law)
3. Ionisation e.g. Alfentanil has a quick onset because it is a weak base with pKa 6. At physiological pH around 90% is unionised and so able to easily cross the cell membrane to its site of action. Fentanyl has a pKa of 8 so is 11% unionised at physiological pH so only a small proportion is available to cross the membrane.
4. Lipid solubility
5. Membrane thickness