S3: Drug Absorption

Question 1

What is Pharmacodynamics and pharmacokinetics?

Answer 1

Pharmacodynamics is what the drug does to the body, whereas pharmacokinetics is what the body does to the drug.

Question 2

What are the 4 characteristics of pharmacokinetics?

Answer 2

ADME!
Absorption - The process by which the unchanged drug enters the circulation (blood) from site of delivery.
Distribution - Dispersion of a drug among different compartments of the body - fluids and tissues of the body (some will remain in circulation).
Metabolism - Transformation of a drug into daughter compounds (metabolism also called biotransformation).
Excretion - Removal of drugs (parent drug)/metabolites from the body.

Question 3

Why is ADME important?

Answer 3

ADME 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.

• It is essential for the safe and intelligent use of medicines by all doctors and is essential for treatment.
• It is important for designing dosing regimens e.g. in patient with liver failure.
• Monitor treatment compliance (by doing a urine or blood test to see concentration and if patient is following treatment).
• Substance of abuse monitoring.
• It is a medicine licensing requirement (medication has to go through lots of processes including pharmacokinetic testing).

Question 4

What is BNF (british national formulary)?

Answer 4

The BNF gives information on licensed medications including indications, cautions, dosage and side effects. It also tells us if there is any drug-drug interactions or liver effects.

Question 5

What is the most common reason for withdrawal of candidate drugs from development?

Answer 5

Pharmacokinetics. Example: It could be that it is too poorly absorbed from an oral dosage and only absorbed well through IV. However, IV is not a convenient method for everyday medications and therefore drug may have to be dropped.

Question 6

What routes can the drug take once adminsitered?

Answer 6

• The administered dosage we want to be absorbed into the blood stream. This will lead to reaching a particular drug concentration in the plasma, hopefully above threshold so it can have its effects at its site of action.
  From the plasma there are 3 routes the drug can take:
  1. The drug can get dispersed around to other tissues and remain there.
  2. The drug can be delivered to site of action.
  3. The drug can be delivered to the liver, kidneys and other sites to be metabolised or excreted.

Question 7

What determines the concentration of drug in the circulation (plasma)?

Answer 7

Supply rate, distribution and removal from the body.

Question 8

When do drugs not need to be absorbed?

Answer 8

When they are given directly into the circulation like IV.

Question 9

Why can drug absorption be tricky? Use oral drugs as an example.

Answer 9

• Drug absorption need to pass through multiple barriers (cells and their membranes).
• For example, the most common route of administration is oral so the drug first has to get to the stomach, go into the intestine and be absorbed through the intestinal wall and then pass through the liver.
• So drugs have to be lipophilic enough to pass through membranes but not so much they will go into membranes and stay there and get stuck.

Question 10

Explain how choice of delivery route of drug is a compromise

Answer 10

These are various factors that need to be considered:

• Speed of onset (how quickly do we want the drug to start acting?). If its an emergency, an IV would be the most direct route.
• Convenience which is also linked to the compliance of the patient. If the dosing regimen is too complicated the patient won’t follow it.
• Bioavailability which is the proportion of administered drug that reaches the systemic circulation. An IV drug is 100% bioavailability but anything other will be lower so we must consider this when giving a dosing regime to see how much drug is lost.
• Side effects and specificity of action.

Question 11

List and explain different routes of administration

Answer 11

• IM is into the muscle and SC is subcutaneous. These are not as direct but will be absorbed into the circulation. Some will be lost e.g. stuck in muscle.
• Oral drugs enter into the stomach and have to survive in this acidic enviroment as well as any enzymes. Then once absorbed in the gut, they enter into the blood and pass through the liver first via the hepatic portal vein before it travels around the rest of the body.
• Inhalers which are local acting drugs that are delivered close to site of action so they don’t always enter the systemic circulation.
• Topical applications like steroid creams do not need to enter the circulation.

Question 12

What is the problem with drugs that are extensively metabolised by the liver?

Answer 12

These drugs have a high first pass metabolism which means a lot of drug can be lost.

Question 13

2 options for the durg to go through single cellular barrier

Answer 13

1. Transcellular - it can go straight through the cell, through the plasma membrane,
2. Paracellular route where there can be gaps between cells in which certain drugs pass through. e.g. leaky capillaries

Question 14

List mechanisms by which drugs are absorbed

Answer 14

• Passive diffusion ( - Trancellular and paracellular route)
• Facilitated diffusion
• Active transport - rare

Question 15

What is Fick’s law and what does it govern ?

Answer 15

The rate of diffusion of the drug down its gradient is governed by Fick’s law.

Rate of diffusion = surface area x Conc. difference x permeability

Question 16

What determines permeability of membrane to a particular chemical?

Answer 16

• Molecular size - the smaller the molecule the more permeable the membrane will be to the molecule.
• Lipid solubility - The more lipophilic the molecule is, the easier it moves through the membrane.
• Presence of charged/Ionised groups -
• If you have a charged molecule, these tend to stay out of cells and not go through membranes/lipid layer unless there are specific transporters for it.

Question 17

Why are most drugs weak acids or bases?

Answer 17

Most drugs are weak acids or bases and thus can be ionised. Therefore they can exist in two forms, neutral or ionised! They act as buffers. This mean they can alter their permeability to move through membranes.

Question 18

How are drugs weak acids or bases? How do they behave in basic and acid enviroments?

Answer 18

With a weak acid, the neutral form is when it is holding onto the proton and when it donates its proton it becomes negatively charged. The lower the pH, the more H+ are present and around, so the weak acid will bind protons and be neutral, the higher the pH the less protons there are and so the weak acid will donate protons and become an anion.

Weak bases are neutral when on their own and can accept proton, to become positively charged.
The more basic the environment (higher pH) the more likely it will remain happy as a neutral base. The more acidic the environment (lower pH) then there will be more H+ kicking around so the base will accept protons and become positively charged.
- Acidic drugs = The more acidic the environment the more unionised the drug will be
- Basic drugs = The more basic the environment the more unionised the drug will be

Question 19

What two factors affect the extend of ionisation of drugs?

Answer 19

• The pH of the enviroment.
• The acid-based dissociation constant of the drug (how easily the drug will accept or donate a proton, this is a property of the drug based on its chemical structure).

Question 20

Describe how an acidic drug ‘AH’ can pass through membranes

Answer 20

The acidic drug “AH” is able to pass through the membrane because it is uncharged. However if it ionises by donating a proton (due to alkaline conditions), then the anion will be unable to move through the membrane and be stuck on that side.
Alternatively the AH could move through and get ionised on the other side, essentially trapping it until it becomes neutral again.
This all of course depends on the pH on either side of the membrane and the acid-dissociation constant.

Question 21

What is the Henderson Hasselbach Equation for acids and bases?

Answer 21

Acids:
pH = pKa - log [non-ionised]/[ionised]

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

pKa = acid-base dissociation constant,
When pH=pKa, half the drug is ionised.

Question 22

Describe the absorption of aspirin at the gastric mucosa (use Henderson-hasselbach equation)

Answer 22

Aspirin is a weak acid usually taken in oral form, landing in the stomach. it has to then move through the gastric mucosa.
- The henderson-hasselbach equation is used to estimate how much aspirin is absorbed or stays in the stomach.
- Only the uncharged form of aspirin can pass through the gastric mucosa to the circulation so pH on either side is different.
- Aspirin is a weak acid so it has a pKa of 3.5. This is the pH at which 50% is ionised and unionised. In the equation, it is found that 99.7% of aspirin in the stomach is uncharged due to the highly acidic form meaning aspirin is effectively absorbed in the stomach.
- Once it gets through into the circulation, the pH is much higher. Even though the pH is neutral, it is higher than that in the stomach and as a result the acid donates protons and the majority of aspirin is ionised (99.9%).
The important point is that although the pH is neutral, it is high enough for the weak acid to exist in its ionised form.
So a drug may be ionised (or not) in different compartments of the body.

Question 23

What is ion trapping?

Answer 23

This is where a drug is essentially trapped in a compartment of the body because of the pH making it ionised so it can no longer pass through cell barriers to adjacent compartments.

• Trapping can be useful in the excretion of a drug e.g. alkaline urine will trap and enhance the excretion of acidic drugs in the kidney.
• Although things may be trapped, absorption will still take place but slowly. This is because there is an equilibrium, so some uncharged drug will be absorbed and then some ionised drug will become neutral and be absorbed etc.

Question 24

What type of drug is more efficiently absorbed in the stomach?

Answer 24

Acidic drugs are absorbed efficiently from the stomach. Basic drugs are absorbed less efficiently (will bind protons and become positively charged).

Question 25

Can basic drugs be given orally?

Answer 25

Yes! We still given basic drugs orally unless they are very basic or permanently ionised! Basic drugs are (unsurprisingly) poorly absorbed from the stomach (where pH is 1-2).
However, basic drugs are absorbed better from the intestine (pH 6.6-7.5).
As well as this the surface area of the intestine compensates for the low absorption efficiency!
Many drugs are weak bases and absorbed in the intestine.

Question 26

What are Lipinski Rules?

Answer 26

They are rules to optimise drug absorption and present better pharmacokinetic properties (ADME).
His rules are that an orally-active drug has no more than one violation of the following:
1. Molecular weight of less than 500
2. No more than 5 H- bond donors
3. No more than 10 H-bond acceptors
4. Log P < 5 (partition coefficient)

The Lipinski rules are not to do with the pharmacodynamics and often contradict the desirable structures for activating or inhibiting receptors. ADME optimisation may minimise desirable properties (H bonding ) for receptor binding.

Question 27

What is the partition coefficient of a drug?

Answer 27

The partition coefficient is how well it dissolves in lipid, we want a decent amount so it passes through but not so much that it gets stuck in the bilayer.