Factors influencing drug absorption

Lecture (2) Pharmacology Dr. Dalia A. Muhsin

Factors influencing drug absorption:
1- Effect of pH on drug absorption:
Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a proton (H), causing a charged anion (A–) to form:

Weak bases (BH+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B).

A drug passes through membranes more readily if it is uncharged. Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A– cannot. For a weak base, the uncharged form, B, penetrates through the cell membrane, but BH+ the protonated form, does not. Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms.
The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa . [Note: The pKa is a measure of the strength of the interaction of a compound with a proton. The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug.]


2. Blood flow to the absorption site: e.g. absorption from the intestine is favored over that from the stomach because blood flow to the intestine is much greater than the flow to the stomach,. [Note: Shock severely reduces blood flow to cutaneous tissues, thereby minimizing the absorption from SC administration.]
3. Total surface area available for absorption: the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient.
4. Contact time at the absorption surface: If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug.
[Note: Parasympathetic input increases the rate of gastric emptying, whereas Sympathetic input (prompted, for example, by exercise or stressful emotions) as well as anticholinergics (for example, dicyclomine), delays gastric emptying.
Also, the presence of food in the stomach both dilutes the drug and slows gastric
emptying. Therefore, a drug taken with a meal is generally absorbed more slowly.]
Bioavailability
Bioavailability is the fraction of administered drug that reaches the systemic circulation. For example, if 100 mg of a drug are administered orally, and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7, or 70 percent.
Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration.

The route by which drug is administered, as well as the chemical and physical properties of the agent, affects its bioavailability.

Factors that influence bioavailability:
a. First-pass hepatic metabolism: When a drug is absorbed across the GI tract, it first enters the portal circulation before entering the systemic circulation . If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug that gains access to the systemic circulation is decreased. [Note: First-pass metabolism by the intestine or liver limits the efficacy of many drugs when taken orally. For example, more than 90 percent of nitro glycerin is cleared during a single passage through the liver, which is the primary reason why this agent is administered via the sublingual route]. Drugs that exhibit high first-pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target concentration.

b. Solubility of the drug:
Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions.
c. Chemical instability: Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes.
d. Nature of the drug formulation: For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption.
Bioequivalence
Two related drug preparations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations.
[Note: Clinical effectiveness of a drug often depends on both the maximum serum drug concentrations and on the time required (after administration) to reach peak concentration.]
DRUG DISTRIBUTION
Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and then the cells of the tissues.
The delivery of a drug from the plasma to the interstitium primarily depends on 1- cardiac output
2- regional blood flow
3- capillary permeability, the tissue volume
4- the degree of binding of the drug to plasma and tissue proteins
5- relative hydrophobicity (lipophilicity) of the drug.
A. Blood flow
The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs. Blood flow to the brain, liver, and kidney is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow.
B. Capillary permeability
Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies widely in terms of the fraction of the basement membrane that is exposed by slit junctions between endothelial cells. In the liver and spleen, a large part of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass .
This is in contrast to the brain, where the capillary structure is continuous, and there are no slit junctions . To enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported.. By contrast, lipid-soluble drugs readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells. Ionized, or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS, which have no slit junctions.These tightly juxtaposed cells form tight junctions that constitute the so-called blood-brain barrier.

C. Binding of drugs to plasma proteins and tissues
1. Binding to plasma proteins: Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment. Plasma albumin is the major drug-binding protein and may act as a drug reservoir (that is, as the concentration of the free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein).
2. Binding to tissue proteins: Numerous drugs accumulate in tissues, leading to higher concentrations of the drug in tissues than in the extracellular fluids and blood. Drugs may accumulate as a result of binding to lipids, proteins or nucleic acids. These tissue reservoirs may serve as a major source of the drug and prolong its actions or, on the other hand, can cause local drug toxicity.
3. Hydrophobicity:
The chemical nature of a drug strongly influences its ability to cross cell membranes. Hydrophobic drugs readily move across most biologic membranes. These drugs can dissolve in the lipid membranes and, therefore, permeate the entire cell’s surface.
By contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through the slit junctions.