Drug Absorption

Question 1

What is the difference between pharmacodynamics and pharmacokinetics?

Answer 1

• Pharmacodynamics is the effect that drugs have on the body.
• Pharmacokinetics is the study of the way in which drugs move through the body during ADME and the effects the body has on drugs.

Question 2

What is ADME and why is it important?

Answer 2

ADME stands for:
Absorption - Process by which unchanged drug enter the circulation
Distribution - Dispersion of a drug among fluids and tissues of the body - it is reversible
Metabolism - Transformation of a drug into daughter components
Excretion - Removal of drugs from the body

They are key factors in determining the speed of onset of a drug’s effects, their duration of action and the potential for problems in special cases.

Question 3

Define drug absorption.

Answer 3

the process by which unchanged drugs get from the site of delivery to circulation.
AIM: drug must travel in a timely/predictable manner from site of administration to site of action

Medicines need to be absorbed unless they are given directly into circulation.

Question 4

The choice of the delivery route in drugs is a compromise. List some factors that it compromises between.

Answer 4

• speed of onset
• route of administration
• bioavailability (proportion of administered drug reaching the systematic circulation, 100% for iv-administered drugs)
• side effects, specificity of action

Question 5

How do drugs get through cellular barriers during absorption?

Answer 5

Absorption requires drugs to cross biological barriers (layers of cells with semi-permeable, lipophilic membranes).
Most absorption occurs through the cells (transcellular), some occurs between the cells (paracellular). Most drugs are absorbed paracellularly. This means the drugs need to be able to dissolve in the aqueous medium, but not to a great extent.

Question 6

What are the three ways in which absorption can occur by?

Answer 6

• active transport through cells (very few medicines) e.g choline uptake for ACh synthesis - blocked by hemicholinium which therefore inhibits ACh synthesis
• facilitated diffusion through the cells (few medicines) e.g amino acid transporter transports β-lactam, ACE inhibitors
• passive diffusion (most medicines) e.g GI absorption of orally administered drugs

Question 7

What does Fick’s Law state?

Answer 7

EQUATION:
rate of diffusion = surface area x concentration difference x permeability

Factors affecting the rate of diffusion of a drug:
* Size of the drug molecule and its configuration
* Chemical structure (lipid solubility, ionisation) of the molecule
* Surface area of absorption site
* Cell membrane is lipid – diffusion occurs more readily if the drug is lipid-soluble (lipophilic)

Question 8

What does permeability depend on?

Answer 8

• molecular size
• lipid solubility
• presence of uncharged/ionisable groups

Question 9

Are drugs ionisable?

Following up on drug ionisability, how does it affect the drug’s permeability to membranes?

Answer 9

Most drugs are weak acids or bases and are thus ionisable.
A weak acidic drug is a proton donor, while a weak basic drug is a proton acceptor.

The extent of ionisation depends on the pH of the environment and the acid-base dissociation constant of the drug.

HOW PERMEABILITY IS AFFECTED:
To diffuse across cell membranes, medicines must be uncharged.
- non-ionisable, lipophilic drugs are absorbed most efficiently due to being more able to cross the membrane.
- ionised (charged) drugs are absorbed least efficiently due to greater polarity. These compounds must change to their uncharged form to cross the membrane, then they may change back if necessary.

Question 10

What is the use of the Henderson-Hasselbach equations?

Answer 10

The Henderson-Hasselbach equations predict the extent of ionisation.
FOR ACIDS:
pH = pKa - log[non-ionised]/[ionised]

FOR BASES:
pH = pKa + log[non-ionised]/[ionised]

pH = pKa when drug is 50% ionised

Question 11

How does the pH affect the ionisation of different drugs?

Answer 11

ACIDIC DRUGS: more of the drugs stay unionised as pH becomes more acidic/drops
BASIC DRUGS: more of the drugs stay unionised as pH becomes more basic/increases

Question 12

What is ion trapping, and what does it have to do with the drug’s site of absorption?

Answer 12

• Ion trapping is the concept of ions staying in a certain area due to them staying in their charged form, based on the environment they are in. Based on the idea that drugs are absorbed more efficiently when the pH of the environment is similar to the pH of the drug

Question 13

What are the Lipinsky rules, and what do they state?

Answer 13

It is a rule-based approach to ADME optimisation but don’t predict pharmacological activities (i.e pharmacodynamics).

An orally-active drug has no more than one violation of the following:
- molecular weight < 500
- no more than 5 H-bond donors
- no more than 10 H-bond acceptors
- log P < 5 (partition coefficient). This relates to lipid solubility – a higher lipid solubility means it is more likely to be absorbed.

H bonds related to metabolism, regulates its sensitivity to certain enzymes, particularly Cytochrome P450.

ADME optimisation might minimize desirable properties like receptor binding

Question 14

Give 5 reasons why a drug can be removed from development

Answer 14

• Pharmacodynamics
• Side effects
• Toxicity
• Commercial reasons
• Lack of efficacy

Question 15

What factors affect rate of drug absorption?

Answer 15

• Physicochemical properties of the drug
• Permeability of the epithelial membrane at the site of action
• Surface area of the membrane exposed to the drug
• Concentration gradient between the site of absorption (donor site) and the blood stream (received site)

Question 16

Describe the absorption of aspirin

Answer 16

Aspirin: quite well absorbed in the unionised form in the stomach, but much better absorbed in the small intestine. But the pH is 5.5-7.5 in the small intestine; & therefore, the degree of ionisation is increased.

The reaction: HAsp (unionised) —> H+ + Asp- (both ionised)

In stomach:
* Environment pH = ~1.4
* Reaction is driven to the left, forming un-ionised HAsp
* Unionised HAsp is lipid-soluble, crosses gastric mucosa into plasma
* Much of the aspirin is absorbed in GI tract due to large surface area

In plasma:
* Environment pH = ~7.4 (>pKa, aspirin acts as a proton donor)
* Reaction is driven to right, forming ionised Asp-
* Asp- cannot pass back into stomach

Question 17

What are the different ways a drug can be administered?

Answer 17

Can be administered:
-subcutaneous
-intravenous - injected
-intramuscular
-orally - passes through the liver (hepatic portal vein). Hepatocytes might metabolise a lot of the drug, so only a small fraction of the drug is admitted to the rest of the circulation. First-pass metabolism is the name of this process.

Question 18

Explain why acidic drugs are absorbed effectively in the stomach?

Answer 18

• Acidic drugs are absorbed efficiently from the stomach (pH: 1-2) because when they pass the membrane into a relatively more basic environment (circulation, pH: 7.4), they will exist in their charged form, preventing them from being absorbed back, essentially ‘trapping’ them.

Question 19

Why are basic drugs not absorbed effectively in the stomach?

Answer 19

• Basic drugs are absorbed less efficiently from the stomach, but are absorbed better from the intestine (pH: 6.6-7.5). This is due to the larger surface area so greater rate of absorption (this is why many drugs absorbed at intestine) and the fact that it’s slightly more alkaline (i.e more ideal pH).

Question 20

Why might a living organism not be able to reach a maximum rate of drug absorption?

Answer 20

• due to the presence of efflux pumps - pump drugs away from target cells
• Elimination of drug by lacrimal drainage
• Drug metabolism by tear and tissue proteins