topic 15 - absorption and distribution

Question 1

what is absorption?

Answer 1

the process by which a drug move from its site of administration to the systemic circulation.

Question 2

what is distribution?

Answer 2

the reversible transfer of a drug to and from the systemic circulation.

Question 3

what is metabolism?

Answer 3

any chemical alteration of a drug by the living system to enhance water solubility and hence excretion.

Question 4

what is excretion (elimination)?

Answer 4

the irreversible transfer of a drug from the systemic circulation

e.g. renal excretion or sweat

Question 5

absorption through membranes?

Answer 5

Apart from injection - intra-venous / muscular delivery etc. drugs generally must pass through membranes.

Various membranes can be used to absorb drugs…

Gastric mucosa – oral drugs

Buccal cavity e.g. sub-lingual

Rectal membranes - suppositories

Vaginal membranes - pessaries

Skin – transdermal patches

Pulmonary epithelium - inhaled drugs

Question 6

how much drug is really delivered?

Answer 6

An oral drug must be able to:

dissolve

survive a range of pHs (1.5 to 8.0)

survive intestinal bacteria

cross membranes

survive liver metabolism

avoid active transport to bile

avoid excretion by kidneys

partition into target organ

avoid partition into undesired places (e.g. brain, foetus)

Question 7

what is the bioavailability of the drug?

Answer 7

Bioavailability – refers to the fraction of the drug that is available in the blood supply after administration.

dose –> destroyed in gut –> not absorbed –> destroyed by gut wall –> destroyed by liver –> systemic circulation.

Question 8

what is the typical plasma conncentration / time profiles? (oral dose)

Answer 8

Oral dose of a compound.

Absorbed and enters the bloodstream the concentration rises

Compound distributes into tissues and absorption rates start to slow

Drug is metabolised and excreted from the systemic circulation

Question 9

factors affecting absorption?

Answer 9

Factors Affecting Drug Absorption :

Acid stability

Solubility

Permeability

Lipophilicity

Metabolism.

mouth –> stomach (pH 2) –> intestine (pH 7)

Question 10

what are the components of the intestinal wall structure?

Answer 10

epithelium
central capillary network
microvilli
apical surface
brush border membrane
epithelial cell (entrerocyte)
basolateral surface

Question 11

intestinal wall structure epethelial cells

Answer 11

Intestinal wall epithelial cells have many finger-like projections on their luminal surface called microvilli which form the brush border membrane

Compounds which pass across the gut wall are then taken by a network of capillaries via the hepatic portal vein to the liver.

Question 12

factors affecting absorption pt 2

Answer 12

Acid stability

Tablet - pass through the stomach (pH ~ 2) before it gets into the systemic circulation.

Drug needs to be stable to these acidic conditions at body temperature.

The pH of the small intestine is ~ 7 (Majority of absorption often takes place here, due to the comparatively large surface area).

Question 13

factors affecting absorption pt 3

Answer 13

Solubility

The drug requires sufficient aqueous solubility for dissolution, as only dissolved compound can be absorbed. Fat globules – low surface area – poor surface contact.

Permeability

Poor permeability, gut wall metabolism and/or efflux can all lead to poor absorption across the intestinal wall.

Lipophilicity

Drugs which are absorbed passively through the gut wall also need to be sufficiently lipophilic to cross cell membranes but polar enough to be sufficiently water soluble, i.e. log P = 1 – 4 (octanol/water partition coefficient; measure of extent of ionization as well as intrinsic lipophilicity).

Question 14

factors affecting absorption pt 4

Answer 14

Metabolism – gut wall / first pass metabolism

All blood from the stomach, small and large intestine passes to the liver via the hepatic portal vein.

Some of the compound may be metabolised (first pass metabolism) before the compound reaches the systemic circulation.

Question 15

how does pH vary in the body?

Answer 15

It is the neutral form of compounds that is absorbed passively - lipophilic

So the same compound will be ionised to different extents in different parts of the body.

This means that, for example, basic compounds will not be so well absorbed in the stomach compared to acidic compounds since it is generally the unionised form of the drug which diffuses into the blood stream.

Question 16

why are Un-ionised drugs passively absorbed?

Answer 16

1. This is because the compound has to pass through a lipophilic membrane and this process will be unfavourable for charged molecules.
2. In a more acidic medium, such as the stomach, the percentage of an acidic compound ionised will be less at pH 7.4 and so more compound will have the capacity to be passively absorbed.
3. In comparison, a basic compound in an acidic medium will be more ionised and so less of the compound will be in the neutral form and have the capacity to undergo passive absorption.

This may well be the reason for the observation that acidic compounds generally have better fraction absorbed (hence bioavailability) than bases with neutral compounds lying between them.

Question 17

what are the absorption mechanisms?

Answer 17

Transcellular absorption
Main route for most oral drugs
Drug must be in solution at cell surface
pKa important - drug must be un-ionised
Lipophilicity important
H-bonds - solvation shell needs dispersing
Along concentration gradient.

Paracellular absorption
Drug passes through gaps between cells
Inefficient – pores have &laquo_space;surface area than cellular surface
Restricted to low MW hydrophilic molecules
MW < 200

Active Transport
Drugs carried through membrane by a transporter – requires energy (ATP)
Against a concentration gradient
Many transporters exist for nutrient molecules, e.g. glucose, amino acids
SAR (Structural Activity Relationship) specific – few drugs absorbed by this route

Question 18

distribution and the reversible transfer of a drug to and form the systemic circulation

Answer 18

Distribution: the reversible transfer of a drug to and from the systemic circulation.

Compounds can distribute out of plasma into tissues:

Main factors influencing distribution are pKa, lipophilicity, plasma protein binding (only unbound drug in the tissue is free to distribute).

Tissue pH is slightly lower than plasma (blood) pH.

Therefore: Basic compounds tend to distribute out of plasma into tissue more than acidic compounds.

Question 19

interactions with blood proteins

Answer 19

• Drugs can bind to macromolecules in the blood – known as plasma protein binding (PPB) or serum protein binding.
• Compounds with high PPB are retained in the plasma and cannot therefore distribute into the tissues.

Only unbound compound is available for distribution into tissues = bioavailable

0-50% bound = negligible 90-99% = high

50-90% = moderate >99% = very high

Blood also contains enzymes which may degrade drugs

Question 20

what is plasma protein binding?

Answer 20

Serum albumin is the most abundant protein in blood. It binds various hydrophobic molecules in a non-specific fashion, with a preference for acids (e.g. fatty acids in nature) and steroids.

Basic drugs tend bind to alpha-1 acid glycoprotein.

Drug-drug interactions: effects which arise when multiple drugs are given to a patient.

These can arise when the drugs compete for binding of blood proteins, changing their baseline binding levels and usually increasing the bioavailability of one or both of them.

Co-administration of probenecid can increase bioavailability of penicillin

However, this is usually a risk – sudden increase of bioavailability can lead to toxicity

Albumin binding can also be used to increase the long-term solubility and release of hydrophobic drugs

Question 21

summary of absorption and distribution

Answer 21

Drugs need to get to their targets in order to have the desired effects

They can be administered in a range of ways to provide either direct access to the tissue of interest, or through the circulatory system

Drugs also need to be absorbed by the appropriate tissues

This requires tuning of their physicochemical properties such that they can pass through the right membranes, taking into account physiological variations in conditions.

The distribution of drugs throughout the body is determined by physicochemical properties of tissues (e.g. pH) and by blood plasma proteins