topic 15 - absorption and distribution Flashcards
what is absorption?
the process by which a drug move from its site of administration to the systemic circulation.
what is distribution?
the reversible transfer of a drug to and from the systemic circulation.
what is metabolism?
any chemical alteration of a drug by the living system to enhance water solubility and hence excretion.
what is excretion (elimination)?
the irreversible transfer of a drug from the systemic circulation
e.g. renal excretion or sweat
absorption through membranes?
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
how much drug is really delivered?
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)
what is the bioavailability of the drug?
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.
what is the typical plasma conncentration / time profiles? (oral dose)
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
factors affecting absorption?
Factors Affecting Drug Absorption :
Acid stability
Solubility
Permeability
Lipophilicity
Metabolism.
mouth –> stomach (pH 2) –> intestine (pH 7)
what are the components of the intestinal wall structure?
epithelium
central capillary network
microvilli
apical surface
brush border membrane
epithelial cell (entrerocyte)
basolateral surface
intestinal wall structure epethelial cells
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.
factors affecting absorption pt 2
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).
factors affecting absorption pt 3
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).
factors affecting absorption pt 4
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.
how does pH vary in the body?
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.
why are Un-ionised drugs passively absorbed?
- This is because the compound has to pass through a lipophilic membrane and this process will be unfavourable for charged molecules.
- 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.
- 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.
what are the absorption mechanisms?
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 «_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
distribution and the reversible transfer of a drug to and form the systemic circulation
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.
interactions with blood proteins
- 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
what is plasma protein binding?
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
summary of absorption and distribution
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
