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MP221 Normal Function of the GI Tract > Lecture 12 > Flashcards

Lecture 12 Flashcards

1
Q

What is bioavailability ?

A

The amount of drug that reaches the systemic circulation and is able to interact with its biological target and give a therapeutic effect and be accessible at the site of action.

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2
Q

Different formulations of a drug have…

A

… different bioavailabilities.

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3
Q

What happens if the dissolution process is too slow ?

A

This would mean that not all the drug is solubilised and solid parts of the drug will be excreted from the GI tract which means that less of the drug will be available to accumulate in the plasma.

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4
Q

What does bioavailability depend on ?

A

It depends on the solubility and the dissolution rate of the drug.

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5
Q

What needs to happen for a drug to be absorbed ?

A

The drug needs to be a single molecular entity in solution after dissolution.

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6
Q

What happens if there is poor bioavailability ?

A

This would mean that the drug is poorly soluble and will tend to be eliminated by the GI tract before dissolution is complete.

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7
Q

Factors that affect the drug concentration in solution in GI fluids ?

A

Complexation, adsorption, chemical stability, micellar solubilisation.

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8
Q

Complexation

A

If a large molecule/enzyme binds with the drug molecule, it no longer becomes a single molecular entity and because of the added weight, passive diffusion will become more unlikely and will not diffuse across the layer.

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9
Q

Adsorption

A

If there is co-administration of drugs and medicines that contain solid adsorbents, this may result in the adsorbents interfering with the absorption of drugs from the GI tract.
So the drugs are attached to the surface (i.e. adsorbed) which prevents absorption, and the drug molecules are no longer single molecular entities.

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10
Q

Chemical stability

A

It is a key factor in how much drug remains in the GI tract.
Drugs that will breakdown in the GI fluids will result in reduced absorption and bioavailability because they decomposed by the surroundings.
Instability caused by: stomach pH (acidic hydrolysis), enzyme degradation like pepsin.

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11
Q

Micellar solubilisation

A

This increases the solubility of drugs in the GI tract. The lipophilicity of the drug is what allows the bile salts to solubilise the drugs.

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12
Q

What are bile salts ?

A

They act as micellar solubilisers of the drug molecules in the GI tract, they are produced in the liver.

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13
Q

What does a surfactant molecule contain ?

A

A hydrophilic head and hydrophobic tail.

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14
Q

Why does a surfactant molecule contain these two components ?

A

Because they satisfy the need for complimentary interactions.

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15
Q

What are surfactant molecules used for ?

A

They are used in formulations and are designed specifically for their surface-activity, they do not interact with any targets but they help poorly soluble drug molecules become soluble.

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16
Q

What is a common feature in many surfactant molecules ?

A

The long-chain hydrophobic chain.

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17
Q

How else can surfactant properties help drug molecules ?

A

They may optimise the pharmacological activity and the pharmacodynamic interactions ?

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18
Q

What could happen is a drug molecule has polar and non-polar region ?

A

The drug molecules may adsorb at interphases.

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19
Q

What do bile salts act as in the GI tract ?

A

They act like surfactants.

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20
Q

What is the critical micelle concentration (CMC) ?

A

The point where the surface of the interface is completely filled with surfactant molecule.

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21
Q

What happens if more surfactants are added pass the CMC ?

A

The surfactants have to enter the bulk solution and accumulate there instead of the surface and their concentration increases.
This allows for the surfactants in the bulk to associate and form micelles.

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22
Q

What are micelles ?

A

They are associated colloids of small molecule surfactants.

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23
Q

What happens when the surfactants enter the bulk phase ?

A

The surfactants in the bulk associate and form micelles, which results in the hydrophobic tail being in contact with the aqueous environment which is not ideal.
The surfactant molecules aggregate into micelle structures which hides the hydrophobic tails from the aqueous environments.

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24
Q

What are micelles composed of ?

A

A large number of small molecules (surfactants) that have aggregated together to form discrete spherical particles.

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25
Q

What can be contained within the micelles ?

A

Lipophilic structures can be contained in the hydrophobic core of the micelle and therefore can be transported around aqueous solutions.

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26
Q

Drug absorption from the GI tract - step 1

A

The molecules partition between the GI fluid (aqueous) and the GI membrane (non-aqueous).

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27
Q

Drug absorption from the GI tract - step 2

A

Diffusion occurs across the membrane from the LHS (higher concentration of drug molecules) to the RHS (lower concentration of drug molecules).
The RHS will always have a lower concentration of drug molecules because of the constant removal of the drug into the bloodstream and therefore the drug molecules are not given the chance to accumulate there.

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28
Q

Drug absorption from the GI tract - step 3

A

The molecules partition between the GI membrane (non-aqueous) and the extracellular fluid (aqueous), prior to entering the bloodstream.

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29
Q

What is defined by Fick’s 1st law of diffusion ?

A

The rate of diffusion.

This governs the rate at which molecules will move across the membrane.

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30
Q

What is the pH partition hypothesis ?

A

It is the non-ionised form of the drug (not the ionised form) which partitions into the membrane, with the extent of ionisation dependent on the pH of the GI tract fluid.

31
Q

What can influence the extent of absorption ?

A

The amount of non-ionised drug as only this portion of the drug is able to cross the membrane.

32
Q

Why must the SA of the GI membrane, across which absorption can occur, must be considered ?

A

This is because if non-ionised drug is removed from the GI tact, the equilibrium must be adjusted so that more non-ionised molecule are produced in the GI fluid.
There still is significant absorption from highly ionised molecule over the whole length of the GI tract, but there is better absorption for molecules which are predominantly un-ionised at the pH appropriate for absorption.

33
Q

Why does ionisation cause an increase in the solubility of an organic compound in the GI fluid ?

A

This is because it will interact better with water and therefore will have better solubility.

34
Q

What happens to the solubility of an organic compound in the GI membrane if they are ionised ?

A

The solubility will be decreased.

35
Q

What determines the extent of ionisation ?

A

The pH of the GI fluid and the pKa of the drug.

36
Q

What does pH describe ?

A

pH describes the environment.

37
Q

What is pKa ?

A

It is a proper of drug molecule.

38
Q

What will not be favoured by ionisation ?

A

Partitioning between the GI fluid and the membrane will not be favoured.

39
Q

What is the total polar surface area ?

A

It describes how polar a molecule is.

40
Q

What havens if the molecules are too polar ?

A

The molecules will not be able to enter the GI tract.

41
Q

What is Ka ?

A

It is the acidity constant that is also referred to as the dissociation constant.
It is a measure of strong or weak an acid or base is relative to water.
Tends to be a small number.

42
Q

What does Ka dictate ?

A

It dictates the equilibrium position between the unionised and ionised form of a drug at a particular pH.

43
Q

What is p in pKa ?

A

p is -log10.

44
Q

What is pKa ?

A

It is the pH at which exactly half of the acid/base is dissociated.
If the pH is is raised 2 units above or below the pKa value gives 100% ionised or unionised.

45
Q

What are pKa values ?

A

They are thermodynamic at a given temperature, meaning that pKa is a feature of the molecule and not dependent on the environment.

46
Q

What does pKa have an influence on ?

A

pKa influences the lipophilicity, solubility, permeability and the pharmacokinetics characteristics.

47
Q

pKa and drug absorption properties are directly related to…

A

… their chemical structures, which allows useful estimates of pKa to be made based on functional group chemistry alone.

48
Q

The lower the pKa,…

A

… the stronger the acid.

49
Q

What happens if there are electron withdrawn substitutes, for acids ?

A

The OH bonds are weakened and is made more acidic.

50
Q

What happens if there are electron withdrawn groups on the ring, for amines ?

A

This reduces the availability of the lone pairs n the nitrogen which reduces its basicity.

51
Q

What is log P ?

A

It is a measure of a compound’s lipophilicity in its unionised state, it is not dependent on pH

52
Q

What is log D ?

A

It is the distribution co-efficient.
It takes into account all the forms of the drug - unionised and ionised.
Log D is dependent on pH.

53
Q

Is log P or log D greater ?

A

log D < log P.

54
Q

Log D =

A

log P + log (Funionised).

55
Q

Passive transport

A

Is concentration driven, where diffusion is key and molecular size does matter.

56
Q

Other types of absorption

A

Facilitated diffusion, active transport.

57
Q

Migrating myoelectric complex - phase 1

A

There is no activity for 40-60mins which gives time fo r the acids and enzymes in the GI fluid to work on the food stuffs and break down the peptide bonds etc. to release the nutrients for the body to absorb.

58
Q

Migrating myoelectric complex - phase 2

A

Moderate mixing contractions in the stomach and the small intestine which homogenises the mixture and further breaks it down and refines it.

59
Q

Migrating myoelectric complex - phase 3

A

Powerful contractions empty the digestible food into the small intestine from the stomach where distally migrating peristalsis occurs and moves the food through the GI tract.

60
Q

Migrating myoelectric complex - phase 4

A

The stomach is empty and there is no digestible food and so the contractions stop at this point.

61
Q

What is the size of the stomach in the fasted state ?

A

~50ml.

62
Q

What is the size of the stomach in the fed state ?

A

~1L

63
Q

How does the body react to different formulations in the fed state ?

A

Liquids, pellets, disintegrated tablets empty with food which are held in the stomach until the food is released into the small intestine, so there is delay before the absorption process can occur.
Controlled release drugs are retained for longer because they are not being exposed to the GI fluids/environment to the same extent.

64
Q

How does the body react to different formulations in the fasted state ?

A

There is little discrimination between the formulation types so they all behave relatively in the same.

65
Q

Gastric emptying occurs at…

A

… a regular rate, so when the stomach is empty to recycle the contents, so the drug products move with the natural rhythm.

66
Q

What effect can fatty food have on gastric emptying ?

A

Fatty foods delay gastric emptying which effects drug absorption.

67
Q

What is the effect of fatty foods on the fundus ?

A

The presence of fatty foods in the fundus to relax which then relieves some of the pressure which causes the trigger to empty the food to the small intestine.

68
Q

What is the effect of fatty food on the pH in the stomach ?

A

Fatty foods in the stomach result in an increase in pH and so the stomach is made less acidic.
If the drug molecules are present and rely on the acidity to be ionised in order to become water soluble, this increase in pH will result in less of the ionised drug being available for absorption.

69
Q

Why are most medications prescribed to be taken on a full stomach ?

A

In order to protect the stomach lining and reduce irritation.

70
Q

Effect of food on the pH

A

Carbohydrate meal - little change in the acidity.
Protein meal - elevates pH.
Liquid mixed meal - elevates pH but returns to base levels.

71
Q

What happens if the pH is increased above 5?

A

The pepsin will be denatured and would stop breaking down the foodstuff and the gastric acid production will also be reduced.

72
Q

Do tablets disintegrate immediately ?

A

No they do not.

73
Q

What can cause stomach irritation ?

A

Sediment on the bottom of the stomach.

NSAIDs can cause erosion in the mucus layer which is associated with GI discomfort.

MP221 Normal Function of the GI Tract (13 decks)

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