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DRUG ABSORBPTION
Drug absorption
In order for a drug to be absorbed, it must be able to pass through cell ?•
membranes (which is a lipid barrier). Lipid soluble drugs would be ideal to
pass through the membrane easily, but not all drugs can be lipid soluble to a
:great extent. There are 4 main ways drugs can be absorbed
Lipid diffusion .1
Aqueous diffusion .2
Co absorption with lipids .3
Facilitated diffusion/active transport .4
Lipid diffusion*
Highly lipid soluble drugs are able to pass across cell membranes quite ?•
easily. The movement is driven by passive diffusion down a concentration
.gradient
The lipid partitioning coefficient is a numerical value of how lipid soluble a ?•
.drug is
P = [lipid] /
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If the concentration of the drug is higher in a lipid medium than in an ?•
.aqueous medium, it will have a high P and hence have a high lipid solubility
Aqueous diffusion**
There are such things as aquaporins – special protein channels designed for ?•
the movement of water into and out of cells. Drugs which are small and easily
dissolved in solution will be able to pass through the cell membrane via this
.route, in conjunction with water which naturally diffuses
Co absorption with lipids
Some drugs can be absorbed in conjunction with lipids via micelles. E.g. ?•
.Vitamin A, digitoxin
A micelle is formed with the drug incorporated into its structure. Therefore, ?•
.when the micelle is absorbed, so is the drug
Facilitated diffusion/active transport***
All cells have specialized transport systems and channels which allow the ?•
active (requiring energy) uptake of materials from the ECF into the cell. These
materials are often nutrients required by the cell. If a drug is structurally
similar to the compound a transport system normally takes up, the drug will be
able to enter the cell by making the cell think it is someone else. e.g. Levodopa
(used to treat Parkinsons) is taken up via the aromatic amino acid transport
.system
Features of drugs which affect their absorption
Molecular weight?•
Drugs with a small size are absorbed well?•
Drugs which are large (often proteins) are absorbed poorly. These drugs are ?•
often administered
.intravenously to avoid any absorption barriers
Chemical and enzymatic stability?•
The drug must be able to withstand the acid conditions in the stomach and ?•
also the gut enzymes. e.g. Penicillin G (a ??lactam antibiotic) is highly acid
.labile, which means that it is not stable to acid
Aqueous and lipid solubility?•
A drug cannot be totally lipid soluble, otherwise it would not be able to ?•
dissociate in the circulation to remain in solution. On the other hand, we don’t
want a drug to be totally soluble because it may have problems in absorption.
.What is needed is a balance between these 2 properties
2
pH and lipid solubility
Most drugs are either weak acids or weak bases and can exist in either the ?•
ionized (less lipid soluble) or unionized (more lipid soluble) form, depending
.on the pH of the surrounding environment
)Acidic drugs have a carboxylic functional group (- COOH?•
)Basic drugs have an amine group (-NH2?•
:For acids?•
A-H ??A- + H+
ionization const. (Ka) = [A-] [H+] / [AH] or?•
]pKa = pH + log [unionized] / [ionized
:For bases?•
ionization const. (Ka) = [B] [H+]/ [BH+] or?•
]pKa = pH – log [unionized] / [Ionized
The ionization constants give an indication of how strong the acid is. If Ka is ?•
large (and hence pKa is small), then at equilibrium, more of the acid will exist
.in the ionized form
The opposite can be said for bases. If pKa is small for a base, then at ?•
equilibrium, more of the base will be in the unionized form. Hence a stronger
.base will have a large pKa rather than a small one
BH+ ??B + H+
If an acid drug lives in an acid environment, then the proton which it has ?•
.(the H+) will be retained and it will exist preferably in its unionized form
If pH = pKa: Equal amounts of the ionized and unionized forms?•
If pH < pKa: More of the drug is in the unionized form?•
If pH > pKa: More of the drug is in the ionized form?•
If a basic drug lives in a basic environment, then it will not want to accept a ?•
.H+ and so it will exist preferably in its unionized form
If pH = pKa: Equal amounts of the ionized and unionized forms?•
If pH < pKa: More of the drug is in the ionized form?•
If pH > pKa: More of the drug is in the unionized form?•
REMEMBER THAT A DRUG IS ABSORBED BETTER IN THE ?•
UNIONISED FORM
e.g. Aspirin is an acidic drug. In the stomach, the pH is from 1 - 3, which ?•
.means that it is an acidic environment
Hence most of the drug will exist in the unionized form and be better at
passing through the lipid membranes (i.e. better absorbed - around 30% of the
oral dose, the rest is absorbed in the small intestine). Do not confuse this with
the solubility of aspirin. A drug in the ionized form is better soluble but not
.necessarily better absorbed
Remember that the majority of a drug is absorbed in the small intestine, but ?•
acidic drugs also have a relatively large proportion of their concentration
.absorbed in the stomach
On the other hand, basic drugs such as MIPRAMINE (an antidepressant), ?•
.has 100% absorption in the small intestine
pH changes in the gut
There is a 10 fold change in the pH as we move from the stomach to the ?•
:small intestine
Stomach pH: 1 - 3?•
Duodenum pH: 5?•
Small intestine pH 5 - 7?•
Factors affecting gastrointestinal absorption
Gastrointestinal contents?•
Generally, an empty stomach = better absorption since some drugs may ?•
.interact with food
Gastric retention time?•
Drugs which are well absorbed from the small intestine (e.g. ethanol) will ?•
benefit from an increased gastric emptying rate since more of the drug will be
.ejected from the stomach into the small intestine
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Intestinal transit, GIT motility?•
First pass effect?•
Blood supply from the gut goes directly to the liver via the portal vein. ?•
Therefore, orally absorbed drugs will reach the liver before entering the
systemic circulation. This will be bad if the drug is heavily metabolized by the
.liver, which in most cases inactivates the drug
Bioavailabilty
The amount of drug reaching its site of action?•
If a drug is administered intravenously, and then the bioavailability will be ?•
.)100% (provided we want the drug to be present in the plasma
.The bioavailability can be much less for other routes of administration?•
e.g. 500?g of a drug is administered but only 100?g enters the circulation. ?•
.That means 400?g is lost (wasted) in bodily excretions
:Factors affecting bioavailability?•
Incomplete absorption?•
See the factors which affect absorption above?•
First pass effect?•
You should know what this is by now?•
Enterohepatic shunt?•
Lipid soluble drugs can make their way into bile and be excreted along with ?•
it. The drug can be excreted with the bile or reabsorbed with some bile which
.is reabsorbed via the enterohepatic circulation