Pharmacodynamics & Pharmacokinetics

Question 1

Pharmacology vs Therapeutics

Answer 1

At a basic level, pharmacology is the study of drug action. We need to understand how a drug interacts with living organisms and how this influences physiological function. As such, pharmacology is more focused on the ‘drugs’. Therapeutics is concerned with drug prescribing and the treatment of disease. As such, therapeutics is more focused on the ‘patient’.

Question 2

Pharmacodynamics vs Pharmacokinetics

Answer 2

At a basic level, pharmacodynamics deals with ‘what the drug does to the body’ and pharmacokinetics deals with ‘what the body does to the drug’.

Question 3

3 questions to ask on how a drug exerts its effects on the body

Answer 3

Where is this effect produced?
What is the target for the drug?
What is the response that is produced after interaction with this target?

Location, target, response

Question 4

4 classes of drug target proteins

Answer 4

Receptors
Enzymes
Ion channels
Transport proteins

Question 5

How is the dosage and specificity of a drug linked?

Answer 5

The greater the dosage, the lower the specificity the drug will have to its intended target. At high dosages, the ‘key’ (drug) will start to fit different ‘locks’ (targets), leading to adverse effects.

Question 6

4 different chemical interactions drugs can have with receptors

Answer 6

Electrostatic interactions - this is the most common mechanism and includes hydrogen bonds and Van der Waals forces.

Hydrophobic interactions - this is important for lipid soluble drugs.

Covalent bonds - these are the least common as the interactions tend to be irreversible

Stereospecific interactions - a great many drugs exist as stereoisomers and interact stereospecifically with receptors.

Question 7

Agonist vs Antagonist

Answer 7

Agonists activate their receptors, antagonists block them

Question 8

2 key properties of agonists

Answer 8

Affinity and efficacy

Question 9

Describe the relationship between affinity and receptor occupancy

Answer 9

The affinity of a drug determines strength of binding of the drug to the receptor. The strength of each drug-receptor complex is determined by the affinity of the drug. As a result, affinity is strongly linked to receptor occupancy.

It is very important that you understand that each individual drug receptor interaction is transient, with many interactions only lasting milliseconds. If you were to focus on one individual drug molecule amongst the many thousands that might be present, then at any given moment that particular drug molecule might be bound to a receptor, or it may have unbound and may currently be free with the potential to bind another receptor. It then follows, that if you have two drugs that could be added to the tissue (i.e. same number of receptors available), then the drug with the higher affinity will form stronger drug receptor complexes and thus at any given moment, it is more likely that more of this drug will be bound to receptors.

Question 10

Define efficacy

Answer 10

Efficacy refers to the ability of an individual drug molecule to produce an effect once bound to a receptor.

The important thing to grasp here is that when a drug occupies a receptor, it does not necessarily produce one standard unit of response. It may produce a complete response, or no response, or some partial response.

Question 11

What is the affinity and efficacy of a receptor antagonist to its receptor?

Answer 11

Affinity but no efficacy

Question 12

What is the affinity and efficacy of a full agonist to its receptor?

Answer 12

Affinity and maximal efficacy

Question 13

What is the affinity and efficacy of a partial agonist to its receptor?

Answer 13

Affinity and sub-maximal efficacy

Question 14

Describe potency, EC50 and ED50

Answer 14

Potency refers to the concentration or dose of a drug required to produce a defined effect. However, this is a little vague as a definition. As a result, the standard measure of potency is to determine the concentration or dose of a drug required to produce a 50% tissue response. The standard nomenclature for this measure is the EC50 (Half maximal effective concentration) or the ED50 (Half maximal effective dose)

Question 15

How to go about practically measuring EC50 and ED50 (with an example)

Answer 15

Imagine you are conducting an in vitro experiment to test drug effectiveness. You might be working with a piece of lung tissue to text smooth muscle relaxation. You would add specific ‘concentrations’ of the drug to your in vitro preparation to test effectiveness. The concentration that produced a 50% response would be the EC50.

Imagine you are conducting a clinical trial to test drug effectiveness. You might be looking at the ability of the drug to relieve breathlessness. In this case, you would give individuals a specific ‘dose’ of the drug to test effectiveness. It is very difficult to determine a 50% response in one individual (what is a 50% improvement in breathlessness?). Instead, you would look for the dose of drug that produced the desired effect in 50% or the individuals tested. This dose would be the ED50.

Question 16

Relationship between dose/ED50 and potency

Answer 16

The greater the potency, the lower the ED50

Question 17

Difference between potency and efficacy

Answer 17

A highly potent drug produces a large response at relatively low concentrations.

A highly efficacious drug can produce a maximal response and this effect is not particularly related to drug concentration.

For example, drug B is only a partial agonist with a lower ED50 whilst drug C is a full agonist with a higher ED50. However, the difference between a partial agonist and a full agonist is a difference in efficacy. Therefore, drug B is more potent than drug C, but drug B is not as efficacious as drug C.

At a very basic level, potency is related to dose, whereas efficacy is not

Question 18

Between potency and efficacy, which is more important and why?

Answer 18

Efficacy is more important. You want to know if the drug you are giving can induce a maximal response. The potency simply determines the dose that you will need to administer to produce a response. If you have two drugs that have equal efficacy, then it doesn’t really matter if one is more potent than the other, since you can still produce the maximal response with the less potent drug – you just need to administer a slightly higher concentration.

Question 19

Define absorption

Answer 19

The passage of a drug from the site of administration into the plasma.

Question 20

Define bioavailability

Answer 20

The fraction of the initial dose that gains access to the systemic circulation.

Question 21

Absorption vs Bioavailability

Answer 21

Overall, absorption deals with the process for drug transfer into the systemic circulation, whereas bioavailability deals with the outcome of drug transfer into the systemic circulation (i.e. how much).

Question 22

What is the biggest determinant of absorption and bioavailability

Answer 22

Site of administration e.g. for intravenous administration: absorption - the process for drug passage is injecting the full dose straight into the circulation, bioavailability - 100%.

Other examples include:
Oral
Inhalational
Dermal (Percutaneous)
Intra-nasal

Question 23

2 ways drugs can move around the body

Answer 23

1. Bulk flow transfer (i.e. in the bloodstream)
   or
2. Diffusional transfer (i.e. molecule by molecule across short distances)

Question 24

What are the 2 main ways drugs diffuse across membranes?

Answer 24

Diffusion across lipid membranes or carrier mediated transport

Question 25

Are most drugs more water or lipid soluble and why?

Answer 25

Water soluble - This makes sense, since a large proportion of drug molecules are given orally, and need to be water soluble to dissolve in the aqueous environment of the gastrointestinal tract and thus be available for absorption in the first place.

Question 26

1) Most drugs are either weak acids or weak bases. Given this information, what 2 states can they exist in?
2) Out of those 2 states, which is more lipid soluble?

Answer 26

1) Ionised or unionised
2) The unionised form of the drug retains more lipid solubility and is more likely to diffuse across plasma membranes.

Question 27

Detail what 2 things determine whether a drug is unionised or not?

Answer 27

1. the dissociation constant (pKa) for that drug
2. the pH in that particular part of the body.

If the pKa of the drug and the pH of the tissue are equal, then the drug will be equally dissociated between the two forms i.e. 50% ionised and 50% unionised.

As a result, a weak acid is going to be more unionised in areas of low pH like the stomach and a weak base is going to be more unionised in areas of higher pH like the blood and urine, leading to better absorption for those respective drugs in those areas.

Look at metformin example in ‘Pharmacology of Diabetes’ Lecture as an example

Question 28

Explain the concept of ‘ion trapping’.

Answer 28

When weak bases are trapped in areas of low pH (e.g. stomach) and weak acids are trapped in areas of high pH (e.g. blood and urine) as they are highly ionised here and therefore can’t be absorbed/have poor absorption (poor lipid solubility)

Question 29

How does the body work around ion trapping?

Answer 29

A weak base will indeed be poorly absorbed from the stomach due to the low pH leading to a high drug ionisation. However, once the drug eventually reaches the small intestine, it will be able to access a huge number of transport proteins that will enable absorption from the gastrointestinal tract.

A weak acid could potentially be absorbed from the stomach in its unionised state. However, it would then become more ionised at physiological pH and potentially become ‘trapped’ in the blood. Once again, however, most tissues possess transport proteins that could potentially move the ionised drug from the blood into the tissue.

i.e. mainly transport proteins

Question 30

Different tissues will be exposed to different amounts of the drug depending on what 4 factors?

Answer 30

1) Regional blood flow - more of the drug will be distributed to tissues that receive greater blood flow. Note that this can change e.g. after a meal more blood will go to the GIT
2) Plasma protein binding - Once drugs reach the systemic circulation, it is very common for them to bind to plasma proteins. In fact, with some drugs, they can be up to 99% bound to proteins. The most important plasma protein in this regard is albumin, which is particularly good at binding acidic drugs.
3) Capillary permeability - e.g. Continuous, BBB, Fenestrated, Discontinuous
4) Tissue localisation - e.g. since the brain has high fat content, a highly lipid-soluble drug will prefer retention there and hence be ‘localised’ in more fatty tissues than a water soluble drug would

Question 31

Can drugs bound to plasma proteins leave the blood?

Answer 31

No - only free drugs are able to diffuse out of the blood and into surrounding tissue. Drugs bound to PP can’t leave until they dissociate from that protein

Question 32

Give an example of the body where discontinuous capillaries are used.

Answer 32

Liver

Question 33

Give an example of the body where fenestrated capillaries are used.

Answer 33

Kidney

Question 34

What does the process of drug metabolism mainly involve?

Answer 34

The conversion of drugs to metabolites that are as water soluble as possible and easier to excrete.

Question 35

What 2 main kinds of biochemical reaction does drug metabolism involve?

Answer 35

Phase 1 – main aim is to introduce a reactive (polar) group to the drug
Phase 2 – main aim is to add a conjugate to the reactive group

Both stages together act to decrease lipid solubility (less diffusion across lipid soluble membranes) which then aids excretion and elimination.

As a general rule, the end result of phase 1 metabolism is to produce metabolites with functional groups that serve as a point of attack for the conjugating systems of phase 2.

Question 36

What is the most common form of phase 1 metabolism?

Answer 36

Oxidation

Question 37

What can often be a consequence of phase 1 metabolism?

Answer 37

Before we move onto phase 2, we must first consider the fact that phase 1 will often produce pharmacologically active drug metabolites. In some instances, the parent drug has no activity of its own, and will only produce an effect once it has been metabolised to the respective metabolite – these drugs are known as pro-drugs. In this case, metabolism is required for the pharmacological effect.

Of course, it can also be true, that active metabolites can have negative unintended effects. Liver damage as a result of paracetamol overdose, is due to a certain metabolite and NOT paracetamol itself.

Question 38

What is the result of phase 2 metabolism?

Answer 38

Phase 1 adds the functional groups that are susceptible to conjugation in phase 2. The result of phase 2 metabolism is the attachment of a substituent group, and the resulting metabolite is nearly always inactive and far less lipid soluble than the phase 1 metabolite. This facilitates excretion in the urine or bile (due to decreased ability to diffuse across lipid membranes)

Question 39

Which enzymes facilitate each phase of metabolism?

Answer 39

Phase 1 - mainly cytochrome p450
Phase 2 - mainly transferases

In the liver, mainly cytochrome p450

Question 40

Explain first pass (presystemic) metabolism

Answer 40

One final thing to consider with regard to drug metabolism is first pass hepatic metabolism. This is a particular problem for orally administered drugs.

Orally administered drugs are predominantly absorbed from the small intestine and enter the hepatic portal blood supply where they will first pass through the liver before they reach the systemic circulation.
- At this point, the drug can be heavily metabolized and as a result, little active drug will reach the systemic circulation (although first pass metabolism is a prerequisite for activity of prodrugs).

Remember if drugs are metabolised, they become more water soluble and less lipid soluble, making it harder for them to be absorbed and hence the effect to be felt.

Solution – administer a larger dose of drug to ensure enough drug reaches the systemic circulation.

Problem – the extent of first pass metabolism varies amongst individuals, and therefore the amount of drug reaching the systemic circulation also varies. As a result, drug effects and side effects are difficult to predict.

Question 41

What are the 2 most important routes of drug excretion? List some others.

Answer 41

Via the kidney (urine) or via the liver (bile)

Others include lungs and breast milk

Question 42

What are the 3 major routes of drug excretion via the kidney?

Answer 42

1. Glomerular filtration
2. Active tubular secretion (or reabsorption)
3. Passive diffusion across tubular epithelium

Question 43

Consider the following example. You are taking Drug A as an analgesic – it is a weak acid. The urine pH suddenly increases from 6.5 to 8. Will the drug effect be prolonged or reduced over the next few hours?

Answer 43

Drug A is a weak acid. If the urine pH increases to 8, then Drug A will become more ionised in the alkaline environment. This will decrease the lipid solubility of Drug A. As a result, less of the drug will be reabsorbed in the kidney tubule, and more will be excreted. The drug effect will be reduced due to this more effective excretion.

Question 44

Explain how biliary excretion works

Answer 44

Liver cells transport some drugs from plasma to bile – primarily via transporters similar to those in the kidney. Drugs transported to the bile are then excreted into the intestines and will be eliminated in the faeces.

Question 45

What is biliary excretion particularly good at removing?

Answer 45

Phase 2 glucuronide metabolites.

Question 46

Explain enterohepatic recycling with an example.

Answer 46

However, a process called enterohepatic recycling can take place which can significantly prolong drug effect. An example of enterohepatic recycling;

1. A glucuronide metabolite is transported into the bile.
2. The metabolite is excreted into the small intestine, where it is hydrolysed by gut bacteria releasing the glucuronide conjugate.
3. Loss of the glucuronide conjugate increases the lipid solubility of the molecule.
4. Increased lipid solubility allows for greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver.
5. The molecule returns to the liver where a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body.