Absorption of Drugs

Absorption:

Absorption is the process by which drug molecules cross biological membranes. It is usually associated with oral drugs and their absorption through the GIT. It also occurs by subcutaneous, intra muscular and transdermal routes of administration of drugs. However, the absorptive process does not occur during direct injection of drug by intravenous or intra arterial injection.

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Biological Membrane:

Biological membranes consist of a lipid bilayer separating different compartments, with protein molecules acting as enzymes, channels or carrier proteins.

Drugs have to cross the biological membranes to get absorbed.

Processes Determining Absorption:

Absorption, distribution and excretion of drugs overlap in the processes determining them. These processes include:

1. Passive Transport

a. Simple diffusion

b. Filtration/ Aqueous diffusion

c. Bulk flow

2. Active Transport

a. Primary active transport

b. Secondary active transport

c. Pinocytosis

d. Phagocytosis

3. Specialized Transport involving facilitated diffusion

Simple Diffusion:

Most of the drugs are absorbed by simple diffusion, which is the movement of molecules down the concentration gradient i.e. from higher concentration to lower concentration. This type of transport occurs mostly for the lipid soluble drugs.

Non-specific:

This type of transport is non-specific i.e. no carrier proteins are required.

Energy Expenditure:

No energy is required for this type of transport.

Factors affecting diffusion:

1. Concentration Gradient Across Membrane:

Fick’s law of diffusion explains the concentration gradient across the membrane. It is stated as the flux of molecules per unit time is equal to the concentration gradient times the area times the permeability coefficient divided by the thickness.

Flux (molecules/unit time) = (C1- C2) x Area x Permeability coefficient/Thickness

Where permeability coefficient is the motion of drug molecules across the membrane.

Thus Fick’s law indicates that the movement of molecules is directly proportional to the concentration gradient, area and the permeability coefficient and is inversely proportional to the thickness of the membrane.

2. Molecular/ Particle Size:

Molecular size is the size of a single molecule. The particle size is different for different preparations of the same drug. More the particle size, slow is the diffusion and absorption.

Therefore, if we want to have slower time of absorption, we can make the particle size larger.

3. Membrane Surface Area:

More is the surface area of the membrane, more is the absorption. Stomach and intestinal lining is the main area of absorption for the oral drugs. Thus the absorption is greater in the small intestine due to the large surface area.

4. Lipid Water Particle Coefficient:

Membranes have a thin water layer on them. Therefore, part of the drug must dissolve in the water film, while most of the remaining portion is lipid soluble. If the lipid water particle coefficient is large, more diffusion will occur due to greater lipid solubility. In cases of small lipid water particle coefficient, less diffusion will occur due to the less lipid solubility.

5. Ionization of Drugs:

Most of the drugs are either weak acids or weak bases. Therefore they are part ionized and part unionized. The ionized portion is charged, which attracts water molecules, thus forming large complexes. These complexes cannot cross the membranes because they are less lipid soluble. This is why the ionized part of the drugs cannot cross the membrane. Drugs are better absorbed in unionized form.

Decreasing pH by one unit, 91% of acid would become unionized and 91% of base would become ionized. Decreasing pH by two units, 99% of acid would become  unionized.

Acidic drugs

AH ↔ A- + H+      (eq 1)

Acidic drugs on dissociation give anion and proton.

Basic drugs

B + H+ ↔ BH+   (eq 2)

Basic drugs on combining with a proton become an anion.

The existence of drugs as neutral or charged particles depends on the pH.

Acidic Medium

In acidic medium, lots of protons are present. Therefore, greater amount of acidic drug is unionized (shift towards left of eq 1). Thus in acidic medium acidic drug is present more in unionized form, which increases its absorption. This is why acidic drugs are better absorbed from the stomach.

Basic drugs get ionized in acidic medium (right shift of eq 2), thus this form is poorly absorbed. Aspirin, an acidic drug is unionized in acidic medium of stomach, so is easily absorbed.

Basic Medium:

The opposite is true in case of basic medium. Acidic drugs are poorly absorbed while the basic drugs are well absorbed. Quinidine and pyrimethamine are antimalarials and basic, so are ionized in stomach and unionized in intestines, from where they are absorbed.

6. Protonated/Unprotonated form:

Protonated form of acidic drugs is well absorbed while the protonated form of basic drugs is poorly absorbed, due to the reasons given above.

7. Ionization Coefficient:

Ionization coefficient is the pH at which the drug is 50% ionized and 50 % unionized. For acidic drugs, pKa is lower, while that for basic drugs is higher.

8. Henderson Hasselbalch Equation:

This can be stated as:

pKa – pH = log [P/UP]

where P is the protonated form while UP is the unprotonated form

If pH is lower than pKa the value will be positive indicating that the protonated form is more than the unprotonated form.

For acidic drugs,

pKa – pH = log [AH/A-]

If pH is lower than pKa, AH will be more.

For basic drugs,

pKa – pH = log [BH+/B]

If pH is lower than pKa, BH+ will be more.

Drugs in Intestines:

For acidic drugs A- is more, so the drugs are present in ionized form in the intestines, thus are less absorbed. But as the surface area of the stomach is small while that of intestines is very large, even acidic drugs are more absorbed from the upper part of the intestine.

For basic drugs, B is more, thus are present in unionized form in the intestines and are absorbed in a much greater quantity.

In short we can say that acidic drugs are better absorbed in the acidic medium while basic drugs are better absorbed in the basic medium.

Ion trapping:

Most of the drugs are reabsorbed from the proximal tubules of kidneys. Acidic drugs are better reabsorbed from acidic urine. This is an important fact, which can be manipulated to get desired results, as is the case of poisoning with acidic drugs. If we make the urine alkaline (by administering sodium bicarbonate), decreased reabsorption of acidic drugs take place, a phenomenon known as ion trapping.

In case of poisoning with basic drug, urine can be made more acidic (by administering ammonium chloride), by virtue of which the basic drug becomes ionized and is not reabsorbed, with the result that more of it is excreted out.

Filtration:

Filtration involves the aqueous channels or pores through which hydrophilic drugs can pass. Filtration occurs in the jejunum and proximal tubules of kidneys. It is absent in the stomach and the lining of the urinary bladder.

Only certain ions like Na+ and drugs of low molecular weight, like ethanol and glycerol can undergo filtration.

Bulk Flow:

The drug in this process passes through the pores between capillary endothelial cells. The passage is independent of water and lipid solubility. Bulk flow is the phenomenon mostly seen with the intra muscular and subcutaneous injections. Drug is injected in bulk form into the muscle. Drug molecules along with the aqueous medium pass through the pores of endothelium, and diffuse into the blood. This type of transport is independent of pH and pKa. Bulk flow does not occur in brain because of absence of pores.

However, bulk flow is dependent on the blood flow, more the blood flow, more rapid is the absorption. This is why the area is rubbed after intra muscular injections to increase the blood flow.

Active Membrane Transport:

Active membrane transport is for the drugs which cannot cross the lipid membrane and require transport proteins. Their structure is similar to the endogenous substances undergoing active transport like amino acids, sugars, neurotransmitters, which have the transport proteins. Active transport is the carrier mediated transport.

The drug moves against the concentration gradient. Energy in the form of ATP is required for the process to occur. Different drugs bind different proteins, thus their absorption is selective from different areas, as well as their distribution.

Some drugs directly affect the brain like the Levo Dopa, which utilize amino acid transporting mechanism. Other examples include methyl dopa for hypertension and fluorouracil which is anticancer drug.

Active transport mechanism is saturable and can be inhibited by competing drugs.

Primary Active Transport:

When the substance moves against the concentration gradient by the expenditure of energy, the process is called primary active transport.

Secondary Active Transport:

When the substance moves against the concentration gradient by the energy stored by a substance moving down the concentration gradient, the process is called secondary active transport.

Phagocytosis:

Phagocytosis is also known as cell eating. This type of transport is utilized by large molecular weight drugs. This may be a two way process.

1. Endocytosis- e.g. uptake of vitamin B12 along with intrinsic factor
2. Exocytosis- e.g. anticancer drugs

 

Pinocytosis:

Pinocytosis, or cell drinking, requires expenditure of energy. Fat soluble vitamins, protein molecules and folic acid enter the cells by this process.

Facilitated Transport:

Facilitated transport involves the drug moving down the concentration gradient by the help of transport proteins. No energy expenditure is required. This type of transport is also specific and saturable. The main objective is that lipid insoluble drugs become lipid soluble by combining with the carrier. E.g. iron binds with apoferritin and certain catecholamines enter the nerve cells by this process.

Simple Diffusion	Facilitated Diffusion	Active Transport
Down concentration gradient	Down concentration gradient	Against concentration gradient
No energy required	No energy required	Energy required
No carrier protein involved	Carrier proteins involved	Carrier proteins involved
Non-specific	Specific	Specific
Non-saturable	Saturable	Saturable
Lipid soluble drugs	Non-diffusible drugs	Lipid insoluble drugs

Factors affecting Absorption of Drugs

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