Absorption of drugs: how drugs are absorbed in the body? ePharmacology
Today on ePharmacology we will discuss about how drugs are absorbed into the body? To answer that we need to know what is absorption.
Absorption is the process by which drug enters into the systemic circulation from the site of administration (except intravenous or intraarterial route) through biological barrier. In case of intravenous or intraarterial administration the drug is not absorbed as it enters into the circulation directly.
What we will learn today
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- Alimentary tract
- Parenteral sites
- Respiratory tract
- Alimentary tract
- Parenteral sites
- Respiratory tract
Sites of absorption of drugs
Drugs are absorbed from different sites of administration such as:
- Alimentary tract
- Parenteral sites except intravenous or intraarterial route
- Respiratory tract
Ancient people used to hunt animals by arrows with tubocurarine in its tip. Animals died due to paralysis of muscles caused by tubocurarine. But why the peoples were safe after eating those meat?
Every parts of the alimentary tract (the oral cavity, stomach, small intestine, and the rectum) are important while considering the absorption of drugs. The extent of absorption is greatest from the small intestine.
Oral cavity is lined with several layers of epithelial cells. It is highly vascular. The normal external environment of the epithelial cell is slightly acidic. Drugs are absorbed into the systemic circulation by simple diffusion. The area of absorptive surface is relatively small and the time during which absorption occurs is also short. Following absorption within the oral cavity, the drug gains access to the systemic circulation without first traversing the liver (i.e. it bypasses the first pass metabolism).
The inner mucosal layer of the stomach has three components: a superficial layer, lamina propria, and the innermost thin small muscle cell layer.
The superficial layer is composed of a single layer of epithelial cells. It is not a smooth surface but contains many folds. These folds increase the number of epithelial cells. Lamina propria contains connective tissue, blood vessels, and lymphatics.
Only a limited amount of drug is absorbed from the stomach. The extensive vascular supply to the stomach provides a good area for the absorption of drug. But the surface area of absorption is less and the drug remains within the stomach for a short time. However, a significant amount of aspirin and alcohol are absorbed from the stomach.
Small Intestine (in human) is about 280 cm long and 4 cm in diameter. The total absorbing surface area is about 200 m2. Thus the area of a simple cylinder is only 3,300 sq. cm. The area of Folds of Kerckring is about 10,000 sq. cm, i.e. three times increase in surface area. While considering the villi, its surface area will be increased to 100,000 sq. cm. Finally considering the surface area of microvilli it is about 2,000,000 sq. cm, i.e. 600-fold increase in surface area.
Another fun fact!
The pH of the intestinal lumen is changed somewhat along its length. In the duodenum it is acidic ranging from 4 to 5 due to the gastric contents that have been emptied into it.
The rest of the small intestine is slightly acidic to slightly alkaline. Alkaline secretion of the pancreas, bile and intestine are responsible for the change of the pH.
Like stomach, the inner epithelial lining of the mucosal layer of the small intestine is composed of a single layer of cells. The mucosal surface is heaped up into folds (folds of Kerckring). These folds contain more numerous and deeper projections called villi. These villous projections make an additional ten-fold relative increase in the luminal surface area. Individual villus is lined with the primary absorbing unit- epithelial cells- and with goblets, the mucous secreting cells. The central part of each villus contains the blood and lymph capillaries.
Blood flow to the intestine is much greater than that of the stomach. Most drugs in nonionized form are absorbed from the upper part of the small intestine by simple diffusion. Ionized drugs are incompletely and slowly absorbed by filtration.
Some drugs such as α-methyldopa, fluorouracil, levodopa are absorbed from the intestine by an active transport mechanism.
The absorption of drug from the lower two-thirds of the rectum bypasses the first-pass metabolism of the liver because middle and inferior rectal veins collect blood from these parts of rectum and then drain into the inferior vena cava via hypogastric vein. On the other hand, the drug absorbed from the upper part of the rectum passes through the liver as because the superior rectal vein drains into the mesenteric vein and then into the portal circulation.
The absorption of drug from the rectum is slow, incomplete, and unreliable. The absorption occurs by simple diffusion. However, the extent of absorption is not large. The absorption of drug from the rectal suppository is relatively inadequate. For example, less than 40% of an aspirin dose is absorbed from a rectal suppository. Some amounts of drugs undergo first-pass effect. Presence of stool in the rectum reduces the extent of absorption.
The capillary wall is the barrier of absorption of drug from the subcutaneous tissue and muscle. The permeability of the capillary in both the areas is same. The absorption of drug into systemic circulation from these sites occurs by simple diffusion. The absorption of drug from the intramuscular site is usually more rapid and uniform than from subcutaneous site because of the more extensive, vascular supply of the muscle compared with the subcutaneous fatty tissue.
The outermost layer, the stratum corneum, is made up of scaly, squamous plaques of dead cells that contain keratin. This horny layer is thick over areas of the body which are subjected to abrasion such as the palms of the hands, and thin over other more protected areas.
The absorption through the skin is also by simple diffusion but the rate of penetration is comparatively slow. The absorption occurs more easily through the cell lining, sweat and sebaceous glands, and hair follicles than through keratinized epidermis because of its multiple cell layers.
When we inhale air, it passes through the pharynx and trachea into the lungs. Within the lungs the bronchial tubes subdivide into the finer bronchioles. The bronchioles then communicate with the alveoli (a total of 300 to 400 million in human lungs).
The alveolus is the minute sac-like chamber that enables the lung to carry out its primary function of rapidly supplying oxygen to the body and removing carbon dioxide. Each alveolus is lined with a single layer of flat epithelial cells forming an extremely thin barrier (0.5 to 1.0 µm thick) between alveolar air and an interstitium richly supplied with capillaries. It provides a total surface area of about 200 m2.
Chemicals are also inhaled as aerosols, which are liquid droplets or solid particles so small that they remain suspended in air for some times instead of settling out quickly under gravitational pull.
Gases are small molecules of relatively high lipid/water partition coefficient. So, it can instantaneously cross the cellular membrane of the alveolus by diffusion. Thus, the movement of gas from the alveoli to blood and vice versa depends on the site of high concentration. This principle is applied for the anesthetic gas like nitrous oxide.
Factors modifying absorption of drug
When we consider the factors modifying absorption of drug, we usually mean the factors affecting the absorption of drug from the alimentary tract. But the factors which affect absorption of drug from the site of administration other than oral route should not be ignored.
So, there are some factors that modify the absorption from the alimentary tract, parenteral sites except intravenous administration, and skin.
There are several factors related to drug and related to patient that affect the absorption of drugs.
The factors related to drugs that affect absorption are:
- Molecular weight
- Lipid / water partition coefficient
- Interaction with other drugs
The factors related to patient that affect absorption are:
- PH of the gut
- Rate of gastric emptying
- Presence of food in gut
- Bowel transit time
- Mucosal surface area available for absorption
- Regional blood flow
- Gastrointestinal diseases
Molecular weight, size, lipid/water partition coefficient, pKa, formulation, disintegration and dissolution have already been described in previous articles.
The drugs may be inactivated or metabolized in the alimentary tract before they are absorbed. For example, orally administered oxytocin or insulin is inactivated by the enzyme chymotrypsin present within the alimentary tract. The drugs may be inactivated by biotransformation during their passage through the intestinal wall and by the gut bacteria. Diazepam is also metabolized in the intestinal mucosa immediately after absorption and before the drug can pass into the portal venous blood.
Interaction with other drugs
When two or more drugs are administered simultaneously, one drug may affect the absorption of other drug. Calcium, iron, aluminum, and magnesium reduce the absorption of tetracycline. Phenobarbitone reduces the absorption of griseofulvin. Alcohol weakens the barrier to the passage of iron salts and causes excessive absorption, which may cause disease due to iron-pigment accumulation in the tissues.
pH of the gut
The pH of the gut has important consequences for the absorption of drug because it can dramatically affect the degree of ionization of drug. An increase in pH of the gut leads to an increased fraction weak base being nonionized, and an increased fraction of weak acid being ionized in the gastric juice, and consequently the absorption of ionized form of drug from the stomach will be slow. On the other hand, weak acid paracetamol (pKa=9.5) will exist mainly in its nonionized form and can readily diffuse from the stomach into the circulation.
Rate of gastric emptying
The rate of gastric emptying markedly influences the drug absorption irrespective of their acidic, basic, and neural properties.
The greater the gastric emptying rate the greater the rate of drug absorption and vice versa. In general, factors that increase the gastric emptying rate will increase the absorption of drug unless it dissolves slowly.
There are some factors such as volume and constituent of gastric content, physical activity, position of the body and drugs that influence the gastric emptying rate. For example, small volume of diet decreases whereas large volume increases the gastric emptying rate. Patient lying on the left side decreases the rate of gastric emptying compared with lying on the right side.
Fatty diet decreases the rate of gastric emptying compared with the effect of carbohydrate foods. Muscarinic cholinoceptor antagonists such as atropine decrease the gastric emptying rate. Metoclopramide increases the gastric emptying rate.
The rate of gastric emptying may be unpredictable due to several factors. Thus, it is advisable to take a drug with water on a relatively empty stomach to conclude that it will reach small intestine rapidly.
Bowel transit time
Bowel transit time is the time required for a particular food stuff to pass through the bowel.
It may be classified into small and large bowel transit time.
Bowel transit, particularly small bowel transit, may influence the absorption of drug by altering the time during which a drug is in contact with small bowel mucosa. Bowel transit time is mainly dependent on its motility. It decreases in case of increased intestinal motility which tends to decrease the absorption, the opposite being the case for increased bowel transit time.
Mucosal surface area available for absorption
The greater the surface area of epithelial layers the greater will be the extent of absorption. Due to its many folds, villi and microvilli, the mucosal surface area of the small intestine is 600-fold greater than that of stomach. So, the extent of absorption is the greatest from the intestine.
Several gastrointestinal diseases can affect the absorption of drug. For example, coeliac disease and Crohn’s disease may change the pattern of absorption so that more drug is absorbed from the gastrointestinal tract.
Gut edema in patient with congestive cardiac failure may reduce the absorption of diuretic.
Generally the drugs with high lipid/water partition coefficient continue to be well absorbed despite extensive gastrointestinal disease, whereas absorption of water soluble drugs such as digoxin, tetracycline are more likely to be important.
Presence of food in the gut
Presence of food in the gut influences the extent of drug absorption. Most of the drugs are better absorbed in empty stomach. Food interferes with the absorption of water soluble drugs. Ampicillin, aspirin, doxycycline, isoniazid, levodopa, oxytetracycline are considered as examples. So, these drugs are best taken at least 1 hour before meal for better absorption.
However, drugs producing gastrointestinal irritation such as aspirin should be taken during or immediately after meal although food decreases its absorption.
The lipid/water partition coefficient of a drug also influences the extent of absorption. The drug with high lipid/water partition coefficient shows increased absorption in the presence of food. These are griseofulvin, hydralazine, mefloquine, nitrofurantoin, riboflavin, propranolol, and spironolactone. So, these drugs are best taken during meal.
Fun fact # 3
The blood flow through muscle varies greatly according to the muscle chosen for the injection (deltoid > quadriceps femoris > gluteus maximus). The blood flow may be low as 3 ml/100 gm/min at rest, and high as 30 ml/100 gm/min!
The extent of absorption from parenteral sites except intravenous or intraarterial administration depends on the:
- Site of injection
- Area of absorptive surface
- Blood flow
- The time of contact with absorptive surface
- The concentration gradient
- Dosage formulation
Absorption of drug from different parts of subcutaneous tissue is not same. For example, it is rapid from the subcutaneous tissue of abdominal wall, followed by the arm, buttock, and thigh.
Rubbing the site of injection increases the extent of absorption by increasing the surface area of drug as well as by increasing the vascularity of that area. For example, 1 ml of drug in a spherical form would have a surface area of 4.84 cm. If the same amount of drug produces a disk of 1 mm thick, it would have a surface area of 21.07 cm. Thereby, we can increase the surface area of drug several times simply by changing the shape of absorptive surface.
The rate of absorption of drug from subcutaneous tissue and muscle is same when the muscles are at rest. But during activity, the blood flow to the muscle tissue increases and thereby increases the rate of absorption.
The blood supply to the superficial area can be increased by applying heat, hot bath, local vasodilators, massage, or exercise. Increased blood supply causes an increase in absorption. In the upright posture, subcutaneous blood flow diminishes considerably in the legs, and to a lesser extend in the abdominal wall. On the other hand, use of tourniquet or cold decreases the blood supply to the superficial area and thus decreases the absorption of drug.
The dosage formulation affects the absorption of drug from the parenteral sites.
For example, drug in aqueous solution is usually absorbed more rapidly than the drug in suspension.
The degree of absorption from skin depends upon several factors such:
- As surface area
- Concentration gradient
- Lipid/water partition coefficient
The absorption of drug will be better if the sebum is washed off before the drug is applied.
The rate of absorption through skin is determined by the thickness and vascularity. For instance, hexachlorophene, an antiseptic, is quite safe when used in the skin of healthy adult and children. But sufficient amount of hexachlorophene will be absorbed and may cause damage to the nervous system if it is applied on the skin of premature infants or on burned skin. Inflammation significantly increases transdermal absorption.
What systemic effects develop after administering timolol eye drops for glaucoma?
Many drugs produce their responses after absorption through the epithelium of the conjunctival sac. In this case adequate lipid solubility of the drug is essential for adequate absorption.
The degree of penetration of drug into the respiratory tract depends upon the size of drug particles in solid and liquid aerosols. The rate of absorption is rapid due to high surface area of the alveoli and high vascular supply of the lung.
Solubility of the drug is also an important factor. The greater the rate of dissolution of the drug, the greater is the rate of absorption. Insoluble particles are dangerous only if they reach the alveoli.
Drug particles larger than 10 micron are trapped in the respiratory tract whereas the size of less than 2 micron can enter the alveoli.
The term bioavailability means the fraction of administered dose which reaches the systemic circulation from the particular form.
It can be calculated as the ratio of the area under the oral (or other route) and intravenous concentration-time curves.
Bioavailability is expressed in percentage. If drug A occupies an area of 70 smallest squares following oral administration and 175 smallest squares following intravenous administration, then the bioavailability of that drug is: 70/175 = 40%.
The bioavailability can vary among different dosage forms of a drug.
Extent of absorption and first-pass biotransformation are the important factors on which bioavailability largely depends. Extent of absorption is the total amount of drug that undergoes absorption and it is directly proportional to bioavailability. First-pass biotransformation is inversely proportional to the bioavailability.
The bioavailability of a drug given chronically may differ from that following a single dose as the bioavailability of the gut and liver enzymes to metabolize a drug at the first-pass can be saturated.
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Answer these following question yourself:
1. What are the factors that modify the absorption of drug from the alimentary tract?
2. Why is the extent of absorption from the small intestine greatest?
3. What are the factors that modify the absorption of drug from the site of parenteral administration?
4. Name the drugs which are more absorbed in the presence of food.
5. What is bioavailability?
6. How can we calculate the bioavailability of a drug?
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