Ion trapping
Encyclopedia
The term ion trapping is used to describe the build-up of a higher concentration of a chemical across a cell membrane
due to the pKa
value of the chemical and difference of pH
across the cell membrane. Generally speaking, this results in basic chemicals accumulating in acidic bodily fluids such as the cytosol
, and acidic chemicals accumulating in basic fluids such as mastitic milk.
Many cells
have other mechanisms to pump a molecule
inside or outside the cell against the concentration gradient, but these processes are active ones, meaning that they require enzymes and consume cellular energy
. In contrast, ion trapping does not require any enzyme or energy. It is similar to osmosis
in that they both involve the semipermeable nature of the cell membrane.
Cells have a more acidic pH inside the cell than outside (gastric mucosa
l cells being an exception). Therefore basic drugs (like bupivacaine
, pyrimethamine
) are more charged inside the cell than outside. The cell membrane is permeable to non-ionized (fat-soluble) molecules; ionized (water-soluble) molecules cannot cross it easily. Once a non-charged molecule of a basic chemical crosses the cell membrane to enter the cell, it becomes charged due to gaining a hydrogen ion because of the lower pH inside the cell, and thus becomes unable to cross back. Because transmembrane equilibrium must be maintained, another unionized molecule must diffuse into the cell to repeat the process. Thus its concentration inside the cell increases many times that of the outside. The non-charged molecules of the drug remain in equal concentration on either side of the cell membrane.
The charge of a molecule depends upon the pH of its solution. In an acidic medium, basic drugs are more charged and acidic drugs are less charged. The converse is true in a basic medium. For example, Naproxen
is a non-steroidal anti-inflammatory drug
that is a weak acid (its pKa
value is 5.0). The gastric juice has a pH of 2.0. It is a three-fold difference (due to log scale) between its pH and its pKa; therefore there is a 1000× difference between the charged and uncharged concentrations. So, in this case, for every one molecule of charged Naproxen, there are 1000 molecules of uncharged Naproxen at a pH of 2. This is why weak acids are better absorbed from the stomach and weak bases from intestine where the pH is alkaline. When pH of a solution is equal to pKa of dissolved drug, then 50% of the drug is ionized, another 50% is unionized.
Ion trapping is the reason why basic (alkaline) drugs are secreted into the stomach (for example morphine
) where pH is acidic, and acidic drugs are excreted in urine when it is alkaline. Similarly, ingesting sodium bicarbonate
with amphetamine
, a weak base, causes better absorption of amphetamine (in stomach) and its lesser excretion (in urine), thus prolonging its actions. Ion trapping can cause partial failure of certain anti-cancer chemotherapies.
Ion trapping is also important outside of pharmacology
. For example it causes weakly acidic hormones to accumulate in the cytosol of cells. This is important in keeping the external concentration of the hormone low in the extracellular environment where many hormones are sensed. Examples of plant hormones that are subjected to ion trapping are abscisic acid
, gibberellic acid
and retinoic acid
. Examples of animal hormones subjected to ion trapping include Prostacyclin
and Leukotrienes.
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
due to the pKa
PKA
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...
value of the chemical and difference of pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
across the cell membrane. Generally speaking, this results in basic chemicals accumulating in acidic bodily fluids such as the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
, and acidic chemicals accumulating in basic fluids such as mastitic milk.
Many cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
have other mechanisms to pump a molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
inside or outside the cell against the concentration gradient, but these processes are active ones, meaning that they require enzymes and consume cellular energy
Energy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
. In contrast, ion trapping does not require any enzyme or energy. It is similar to osmosis
Osmosis
Osmosis is the movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration, aiming to equalize the solute concentrations on the two sides...
in that they both involve the semipermeable nature of the cell membrane.
Cells have a more acidic pH inside the cell than outside (gastric mucosa
Gastric mucosa
The gastric mucosa is the mucous membrane layer of the stomach which contains the glands and the gastric pits. In men it is about 1 mm thick and its surface is smooth, soft, and velvety...
l cells being an exception). Therefore basic drugs (like bupivacaine
Bupivacaine
Bupivacaine is a local anaesthetic drug belonging to the amino amide group. AstraZeneca commonly markets it under various trade names, including Marcain, Marcaine, Sensorcaine and Vivacaine.-Indications:...
, pyrimethamine
Pyrimethamine
Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with...
) are more charged inside the cell than outside. The cell membrane is permeable to non-ionized (fat-soluble) molecules; ionized (water-soluble) molecules cannot cross it easily. Once a non-charged molecule of a basic chemical crosses the cell membrane to enter the cell, it becomes charged due to gaining a hydrogen ion because of the lower pH inside the cell, and thus becomes unable to cross back. Because transmembrane equilibrium must be maintained, another unionized molecule must diffuse into the cell to repeat the process. Thus its concentration inside the cell increases many times that of the outside. The non-charged molecules of the drug remain in equal concentration on either side of the cell membrane.
The charge of a molecule depends upon the pH of its solution. In an acidic medium, basic drugs are more charged and acidic drugs are less charged. The converse is true in a basic medium. For example, Naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
is a non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
that is a weak acid (its pKa
PKA
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...
value is 5.0). The gastric juice has a pH of 2.0. It is a three-fold difference (due to log scale) between its pH and its pKa; therefore there is a 1000× difference between the charged and uncharged concentrations. So, in this case, for every one molecule of charged Naproxen, there are 1000 molecules of uncharged Naproxen at a pH of 2. This is why weak acids are better absorbed from the stomach and weak bases from intestine where the pH is alkaline. When pH of a solution is equal to pKa of dissolved drug, then 50% of the drug is ionized, another 50% is unionized.
Ion trapping is the reason why basic (alkaline) drugs are secreted into the stomach (for example morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
) where pH is acidic, and acidic drugs are excreted in urine when it is alkaline. Similarly, ingesting sodium bicarbonate
Sodium bicarbonate
Sodium bicarbonate or sodium hydrogen carbonate is the chemical compound with the formula Na HCO3. Sodium bicarbonate is a white solid that is crystalline but often appears as a fine powder. It has a slightly salty, alkaline taste resembling that of washing soda . The natural mineral form is...
with amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
, a weak base, causes better absorption of amphetamine (in stomach) and its lesser excretion (in urine), thus prolonging its actions. Ion trapping can cause partial failure of certain anti-cancer chemotherapies.
Ion trapping is also important outside of pharmacology
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
. For example it causes weakly acidic hormones to accumulate in the cytosol of cells. This is important in keeping the external concentration of the hormone low in the extracellular environment where many hormones are sensed. Examples of plant hormones that are subjected to ion trapping are abscisic acid
Abscisic acid
Abscisic acid , also known as abscisin II and dormin, is a plant hormone. ABA functions in many plant developmental processes, including bud dormancy. It is degraded by the enzyme -abscisic acid 8'-hydroxylase.-Function:...
, gibberellic acid
Gibberellic acid
Gibberellic acid Gibberellic acid Gibberellic acid (also called Gibberellin A3, GA, and (GA3) is a hormone found in plants. Its chemical formula is C19H22O6. When purified, it is a white-to-pale-yellow solid....
and retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
. Examples of animal hormones subjected to ion trapping include Prostacyclin
Prostacyclin
Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
and Leukotrienes.