Download DRUG ABSORBPTION

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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:
1. Lipid diffusion
2. Aqueous diffusion
3. Co absorption with lipids
4. Facilitated diffusion/active transport
*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.
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P = [lipid] / [water]
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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.
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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]
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For bases:
BH+ B + H+
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.
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.

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.