[Histology] Basic Four Types of Tissues – Epithelia Tissues

May 18, 2016 Histology No comments , , , , , , , , , , , , , , , , , ,

Cells and ECM

Tissues have two interacting components: cells and extracellular matrix (ECM). The ECM consists of many kinds of macromolecules, most of which form complex structures, such as collagen fibrils and basement membranes. The ECM supports the cells and the fluid that transports nutrients to the cells, and carries away their catabolites and secretory products. The cells produce the ECM and are also influenced and sometimes controlled by matrix molecules. Cells and matrix interact entensively, with many components of the matrix recognized by and attaching to cell surface receptors. Many of these protein receptors span the cell membranes and connect to structural components inside the cells. Thus, cells and ECM form a continuum that functions together and reacts to stimuli and inhibitors together.

Types of Tissues

The fundamental tissues of the body are each formed by several types of cell-specific associations between cells and ECM. Organs are formed by an orderly combination of several tissues, and the precise combination of these tissues allows the functioning of each organ and of the organism as a whole. Despite its complexity, the human body is composed of only four basic types of tissue, including: epithelia, connective tissue, nervous tissue, and muscle. These tissue, which all contain cells and molecules of the extracellular matrix (ECM), exist in association with one another and in variable proportions and morphologies, forming the different organs of the body. Main characteristics of the four basic types of tissue are list in Table 4-1 below.

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Epithelial Tissue

Epithelial tissues are composed of closely aggregated polyhedral cells with strong adhesion to one another and attached to a thin layer of ECM. Epithelia are cellular sheets that line the cavities of organ and cover the body surface. The principal functions of epithelial tissues include (but not limited to) the following: 1.covering, lining, and protecting surfaces; 2.absorption; 3.secretion.


The shapes and dimensions of epithelial cells are quite variable, ranging from tall columnar to cuboidal to low squamous cells, which are generally dictated by their function. Most epithelial rest on connective tissue that contains the microvasculature bringing nutrients and O2 to both tissues. The area of contact between the epithelium and connective tissue may be increased by irregularities at the interface in the form of small evaginations called papillae which occur most frequently in epithelial tissues subject to friction.

Epithelial cells generally show polarity, with organelles and membrane protein distributed unevenly within the cell. The region of the cell contacting the connective tissue is called the basal pole and the opposite end, usually facing a space, is the apical pole. The two poles of epithelial cells differ in both structure and function. Regions of cuboidal or columnar cells that adjoin the neighboring cells are the lateral surfaces; cell membranes here often have numerous infoldings to increase the area of that surface, increasing its functional capacity.

ECM (basement membranes)

The primary ECM of epithelial tissue is the basement membranes. All epithelial cells in contact with subjacent connective tissue have at their basal surfaces a specialized, feltlike sheet of extracellular material referred to as the basement membrane. The basement membrane may be resolved into two structures. Nearest the epithelial basal poles is an electron-dense layer, 20-100 nm thick, consisting of a network of fine fibrils that comprise the basal lamina. Beneath this layer is often a more diffuse and fibrous reticular lamina. The macromolecules (laminin, type IV collagen, adhesive glycoprotein [entactin/nidogen, and perlecan]) of the basal lamina are secreted at the basal poles of the epithelial cells and form three-dimensional arrays.

Other cells besides those of epithelia (muscle cells, adipocytes, cells supporting peripheral neurons) also produce components of basal laminae but which are called external lamina. Surrounding these cells, this external lamina binds factors important for interactions with other cells and serves as semipermeable barrier further regulating macromolecular exchange between the enclosed cells and connective tissue.

PS: The term "basement membrane" and "basal lamina" are often used indiscriminately, causing confusion. Most authors use "basal lamina" to denote the extracellular epithelial layer seen ultrastructurally and "basement membrane" for the entire structure below an epithelium visible with the light microscope.

Specializations of The Apical Cell Surface

The apical ends of many tall or cuboidal epithelial cells face an organ's lumen and often have specialized projecting structures. These function either to increase the apical surface area for absorption or to move substances along the epithelial.


In epithelial cells specialized for absorption, the apical surfaces present an array of projections called microvilli. The average microvillus is about 1 um long and 0.1 um wide, but with hundreds or thousands present on the end of each absorptive cell, the total surface area can be increased by 20- or 30-fold. Glycocalyx covering intestinal microvilli is thick and includes enzymes for digestion of certain macromolecules.


Stereocilia are a much less common type of apical process, restricted to absorptive epithelial cells lining the epididymis and the proximal part of ductus deferens in the male reproductive system. Stereocilia increase the cell's surface area, facilitating absorption. More specialized stereocilia with a motion-detecting function are important components of inner ear sensory cells.


Cillia are long projecting structures, larger than microvilli, which contain internal arrays of microtubules. Most (if not all) cell types have at least one cilium of variable length, usually called a primary cilium, which is not motile but is enriched with receptors and signal transduction complexes for detection of light, odors, motion, and flow of liquid past the cells. Primary cilia are also important in the early embryo.

Motile cilia are found only in epithelia, where they are abundant on the apical domains of many cuboidal or columnar cells. Typical cilia are 5-10 um long and 0.2 um in diameter. Epithelial cilia exhibit rapid beating patterns of movement that propel a current of fluid and suspended matter in one direction over the epithelium.

Two Tyoes of Epithelia

Epithelia can be divided into two main groups: covering/lining epithelia and secretroy/glandular epithelia. This is an arbitrary division, for there are lining epithelia in which all the cells also secrete or in which glandular cells are distributed among the lining cells (mucous cells in the small intestine or trachea).

Epithelial cells that function mainly to produce and secrete various macromolecules may occur in epithelia with other major functions or comprise specialized organs called glands. Products to be secreted are generally stored in the cells within small membrane-bound vesicles called secretory granules. Structures of glandular epithelia are shown in Table 4-4. Epithelial cells in multicellular glands have three basic mechanisms for releasing their product, and cells involved in each type of secretion are easily recognized histologically:

  • Merocrine secretion: This is the most common method of protein secretion and involves typical exocytosis of proteins or glycoproteins from membrane-bound vesicles.
  • Holocrine secretion: In this process cells accumulate product as they mature and undergo terminal cell differentiation, culminating in complete cell disrutpion with release of the product and cell debris into the gland's lumen. This is best seen in the sebaceous glands of skin.
  • Apocrine secretion: Here product accumulates at the cells' apical ends, portions of which are then extruded to release the product together with a bit of cytoplasm and plasma membrane.  This is the mechanism by which droplets of lipid are secreted in the mammary gland.

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Renewal of Epithelial Cells

Epithelial tissues are relatively labile structures whose cells are renewed continuously by mitotic activity and stem cell populations.

Drug Absorption in the Gastrointestinal Tract

April 7, 2016 Biopharmaceutics, Pharmacokinetics No comments , , , , , , , , , , , ,

Rate-Limiting Steps in Drug Absorption

  • Disintegration of the drug product and subsequent release of the drug (rate-limiting step)
  • Dissolution of the drug in an aqueous environment (rate-limiting step)
  • Absorption across the cell membranes into the systemic circulation (rate-limiting step)

Physiochemical Factors that Affect Drug Absorption

  • Drug disintegration (rate-limiting step)
  • Drug dissolution (rate-limiting step)
  • Drug across the cell membrane (rate-limiting step)
  • Drug stability (loss of drug due to decomposition)
  • Drug particle size (drug particle surface area, affecting dissolution)
  • Drug polymorphism (affecting dissolution)

Passive Diffusion

Drugs may be absorbed by passive diffusion from all parts of the alimentary canal (oral cavity, esophagus, stomach, duodenum, jejunum, ileum, colon, and rectum). For most drugs, the optimum site for drug absorption after oral administration is the upper portion of the small intestine or duodenum region (remember factors determining the diffusion rate, including P = permeability, D = diffusion coefficient, K = lipid-water partition coefficient of drug in the biologic membrane that controls drug permeation, A = surface area of membrane, h = membrane thickness, and CGI – CP = difference between the concentrations of drug in the gastrointestinal tract and in the plasma; in addition the abundant capillary distribution in this region helps maintain a concentration gradient from the intestinal lumen and plasma circulation).

P = DAK/h

dQ/dt = P(CGICP) ≈ P(CGI)

Key factors must be considered in drug absorption include gastrointestinal motility, gastric emptying time, intestinal motility, perfusion of the gastrointestinal tract, drug-drug and food-drug interactions (GI CYP3A4 and P-gp), and finally effect of food on gastrointestinal drug absorption.

Physicochemical Nature of The Drug and Absorption

Solubility, pH, and Drug Absorption

The solubility-pH profile is a plot of the solubility of the drug at various physiologic pH values. In designing oral dosage forms, the formulator must consider that the natural pH environment of the gastrointestinal tract varies from acidic in the stomach to slightly alkaline in the small intestine. A basic drug is more soluble in an acidic medium, forming a soluble salt. Conversely, and acid drug is more soluble in the intestine, forming a soluble salt at the more alkaline pH. The solubility-pH profile gives a rough estimation of the completeness of dissolution for a dose of a drug in the stomach or in the small intestine. Solubility may be improved with the addition of an acidic or basic excipient. Solubilization of aspirin, for example, may be increased by the addition of an alkaline buffer.

In the formulation of controlled-release drugs, buffering agents may be added to slow or modify the release rate of a fast-dissolving drug. To be effective, however, the controlled-release drug product must be a nondisintegrating dosage form. The buffering agent is released slowly rather than rapidly, so that the drug does not dissolve immediately in the surrounding gastrointestinal fluid.

Stability, pH, and Drug Absorption

The stability-pH profile is a plot of the reaction rate constant for drug degradation versus pH. If drug decomposition occurs by acid or base catalysis, some prediction of degradation of the drug in the gastrointestinal tract may be made. For example, erythromycin has a pH-dependent stability profile. In acidic medium, as in the stomach, erythromycin decomposition occurs rapidly, whereas in neutral or alkaline pH, the drug is relatively stable. Consequently, erythromycin tablets are enteric coated to protect against acid degradation in the stomach. This information also led subsequently to the preparation of a less water-solube erythromycin salt that is more stable in the stomach.

Particle Size and Drug Absorption

The effective surface area of a drug is increased enormously by a reduction in the particle size. Because dissolution takes place at the surface of the solute (drug), the greater the surface area, the more rapid the rate of drug dissolution. The geometric shape of the particle also affects the surface area, and, during dissolution, the surface is constantly changing.

Smaller particle size results in an increase in the total surface area of the particles, enhances water penetration into the particles, and increases the dissolution rate.

Polymorphism, Solvates, and Drug Absorption

Polymorphism refers to the arrangement of a drug substance in varioius crystal forms or polymorphs. Polymorphs have the same chemical structure but different physical properties, such as solubility, density, hardness, and compression characteristics. Some polymorphic crystals have much lower aqueous solubility than the amorphous forms, causing a product to be incompletely absorbed.

Excipients and Drub Absorption

Excipients are added to a formulation to provide certain functional properties to the drug and dosage form; excipients also affect drug product performance, in vivo. Some of these functional properties of the excipients are used to improve the compressibility of the active drug, stabilize the drug against degration, decrease gastric irritation, control the rate of drug absorption from the absorption site, increase drug bioavailability, etc.

Eexicipents in the drug product may also affect the dissolution kinetics of the drug, either by altering the medium in which the drug is dissolving or by reacting with the drug itself. Other excipients include suspending agents that increase the viscosity of the drug vehicle and thereby diminish the rate of drug dissolution from suspensions. Tablet lubricants, such as magnesium stearate, may repel water and reduce dissolution when used in large quantities. Coatings, particularly shellac, will crosslink upon aging and decrease the dissolution rate. Surfactants may affect drug dissolution in an unpredictable fashion. Low concentrations of surfactants decrease the surface tension and increase the rate of drug dissolution, whereas higher surfactants concentrations tend to form micelles with the drug and thus decrease the dissolution rate. Poor disintegration of a compressed tablet may be due to high compression of tablets without sufficient disintegrant.

Some excipients may change the pH of the medium surrounding the active drug substance. Aspirin, a weak acid when formulated with sodium bicarbonate, will form a water-soluble salt in an alkaline medium, in which the drug rapidly dissolves. This process is called dissolution in a reactive medium. The solid drug dissolves rapidly in the reative solvent surrounding the solid particle. However, as the dissolved drug molecules diffuse outward into the bulk solvent, the drug may precipitate out of solution with a very fine particle size. These small particles have enormous collective surfacea area, dispersing and redissolving readily for more rapid absorption upon contact with the mucosal surface.

Excipients in a formulation may interact directly with the drug to form a water-soluble or water-insoluble complex. For example, if tetracycline is formulated with calcium carbonate, an insoluble complex of calcium tetracycline is formed that has a slow rate of dissolution and poor absorption.

PS: Rules for Drug Molecules That Would Improve the Chance for Oral Absorption

  • Molecular weight =<500 Da
  • Not more than five H-bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
  • Not more than 10 H-bond acceptors (nitrogen or oxygen atoms)
  • An octanol-water partition coefficient, log P =<5.0

Factors that Affect Bioavailability of Oral Route

Drug given by the enteral route for systemic absorption may be affected by the anatomy, physiologic functions, and contents of the alimentary tract. Moreover, the physical, chemical, and pharmacologic properties of the drug and the formulation of the drug product will also affect systemic drug absorption from the alimentary canal.

  • Site of absorption (absorption window)
  • pH
  • Fluid volume in the lumen
  • Enzymes
  • Stomach emptying (delayed by meals high in fat, cold beverages, and anticholinergic drugs [liquids and small particles less than 1 mm are generally not retained in the stomach])
  • Gastrointestinal motility/transit time
  • Coabsorption factors
  • Bile
  • villi and microvilli
  • GI perfusion/blood flow and lymph circulation
  • Microorganism/stability
  • First pass effect/prodrug
  • Hepatoenteral circulation
  • Gastrointestinal contents (e.g., food, beverage) and their effect on stomach empty, GI's pH, drugs' solubility, bile secretion, splanchnic blood flow, stability of drugs, and physical or chemical interaction with drugs

Anatomy – Site of Absorption, and Factors That Should Be Considered

Oral cavity: pH 7; fluid volume; ptyalin; mucin.

Esophagus: pH 5-6; fluid volume; ptyalin; mucin.

Stomach: pH (ANS; fasting or fed status; drugs; etc.); emptying (ANS; fasting or fed status; food type; osmolality; drugs; etc.); fluid volume; enzymes (pepsin, ptyalin); mucin; mixing; coabsorption factor (like VB12).

Duodenum: major site for passive drug absorption; pH 6-6.5; enzymes (pancreatic trypsin, pancreatic chymotrypsin, pancreatic carboxypeptidase, pancreatic amylase, pancreatic lipase, stomachic pepsin [inactive due to high pH of 5 above], ptyalin); fluid volume; mucin; bile;

Jejunum: same as above.

Ileum: same as above except for pH of 7-8.

Colon: limited drug absorption due to lack of villi, blood flow, and viscous and semisolid nature of the lumen contents. pH 5.5-7. Aerobic and anaerobic microorganisms that metabolize some drugs.

Rectum: lack of fluid (approximately 2 mL). pH of about 7.

Gastrointestinal motility

Once a drug is given orally, the exact location and/or environment of the drug product within the GI tract is difficult to discern. GI motility tends to move the drug through the alimentary canal, so the drug may not stay at the absorption site. For drugs given orally, an anatomic absorption window may exist within the GI tract in which the drug is efficiently absorbed. The transit time of the drug in the GI tract depends on the physicochemical and pharmacologic properties of the drug, the type of dosage form, and various physiologic factors. Movement of the drug within the GI tract depends on whether the alimentary canal contains recently ingested food or is in the fasted or interdigestive state.

Gastric Emptying Time

Anatomically, a swallowed drug rapidly reaches the stomach. Eventually, the stomach empties its contents into the small intestine. Because the duodenum has the greatest capacity for the absorption of drugs from the GI tract, a delay in the gastric emptying time for the drug to reach the duodenum will slow the rate and possibly the extent of drug absorption, thereby prolonging the onset time for the drug.

A number of factors affect gastric emptying time. Some factors that tend to delay gastric emptying include consumption of meals high in fat, cold beverages, and anticholinergic drugs. Liquids and small particles less than 1 mm are generally not retained in the stomach. These small particles are believed to be emptied due to a slightly higher basal pressure in the stomach over the duodenum (i.e., fine granules smaller than 1 to 2 mm in size and tablets that disintegrate are not significantly delayed from emptying from the stomach in the presence of food).Different constituents of a meal empty from the stomach at different rates. Large particles, including tablets and capsules, are delayed from emptying for 3 to 6 hours by the presence of food in the stomach. Indigestible solids empty very slowly, probably during the interdigestive phase, a phase in which food is not present and the stomach is less motile but periodically empties its content.

Intestinal Motility

Normal peristaltic movements mix the contents of the duodenum, bringing the drug particles into intimate contact with the intestinal mucosal cells. The drug must have a sufficient time (residence time) at the absorption site for optimum absorption. In the case of high motility in the intestinal tract, as in diarrhea, the drug has very brief residence time and less opportunity for adequate absorption.

The average normal small intestine transit time (SITT) was about 7 hours as measured in early studies while newwer studies have shown SITT to be about 3 to 4 hours. Thus a drug may take about 4 to 8 hours to pass through the stomach and small intestine during the fasting state. For modified-release or controlled-dosage forms, which slowly release the drug over an extended period of time, the dosage form must stay within a certain segment of the intestinal tract (anatomic absorption window) so that the drug contents are released and absorbed before loss of the dosage form in the feces.

Perfusion of the Gastrointestinal Tract (blood and lymph)

The blood flow to the GI tract is important in carrying abosrbed drug to the systemic circulation. A large network of capillaries and lymphatic vessels perfuse the duodenal region and peritoneum. Any decrease in mesenteric blood flow will decrease the rate of drug removal from the intestinal tract, thereby reducing the rate of drug bioavailability.

Absorption of drugs through the lymphatic system bypasses the first-pass effect due to liver metabolism.

Effect of Food on Gastrointestinal Drug Absorption

  • Delay in gastric emptying (especially fatty foods)
  • Stimulation of bile flow
  • A change in the pH of the GI tract
  • An increase in splanchnic blood flow
  • A change in luminal metabolism of the drug substance
  • Physical or chemical interaction of the meal with the drug product or drug substance
  • Dosage form failures (food affect the integrity of the dosage form)

Timing of drug administration in relation to meals is often important. Pharmacists regularly advise patients to take a medication either 1 hour before or 2 hours after meals to avoid any delay in drug absorption. But since fatty foods may delay stomach emptying time beyond 2 hours, patients who have just eaten a heavy, fatty meal should take related drugs 3 hours or more after the meal, whenever possible.

The presence of food in the GI tract can affect the bioavailability of the drug rom an oral drug product. Digested foods contain amino acids, fatty acids, and many nutrients that may affect intestinal pH and solubility of drugs. The effect of food are not always predictable and can have clinically significant consequences.

Food effects on bioavailability are generally greatest when the drug product is administered shortly after a meal is ingested. The nutrient and caloric contents of the meal, the meal volume, and the meal temperature can cause physiologic changes in the GI tract in a way that affects drug product transit time, luminal dissolution, drug permeability, and systemic availability. In general, meals that are high in total calories and fat content are more likely to affect GI physiology and thereby result in a larger effect on the bioavailability of a drug substance or drug product.

Check Point: anatomic absorption window, residence time, mesenteric blood flow, lymphatic system