Absorption of drugs

(Highly relevant and laconic information)

Dr. Amit Gangwal AKA

Amit Ratn Gangwal Jain Smriti college of pharmaceutical

education, Indore

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Highly important taken as such from Wikipedia (Thanks to Wikipedia)

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.

Continue

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.

Continue Cells have a more acidic pH inside the cell than outside. 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 trans membrane 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.

Continue • 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.[3]

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 andLeukotrienes.

Mainly unionized drugs are absorbed from body at

physiological conditions.

Ionized chemicals /drugs are poorly absorbed from body.

They are charged, so it is difficult for body membranes to

make them pass through so easily.

Ionized drugs may pass through the cells, through pores but it will be in poor quantity, provided they are of low molecular weight.

If a drug is soluble in acidic milieu of stomach, then it will be absorbed from stomach, as in this environment , this drug will be unionized.

If a drug is soluble in basic milieu of intestine, then it will be

absorbed cardinally from intestine, as in this environment,

this drug will be unionized.

• An acid dissociation constant, Ka, (also known as acidity constant, or acid-ionization constant) is a quantitative measure of the strength of an acid in solution.

• It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions.

• The larger the Ka (not pKa)value, the more dissociation of the molecules in solution and thus the stronger the acid.

• The equilibrium of acid dissociation can be written symbolically as:

• where HA is a generic acid that dissociates by splitting into A−, known as the conjugate base of the acid, and the hydrogen ion or proton, H+, which, in the case of aqueous solutions, exists as the hydronium ion—in other words, a solvated proton.

In the example shown in the figure, HA represents acetic acid, and A− represents the acetate ion, the conjugate base. The chemical species HA, A− and H+ are said to be in equilibrium when their concentrations do not change with the passing of time. The dissociation constant is usually written as a quotient of the equilibrium concentrations (in mol/L), denoted by [HA], [A−] and [H+]:

Due to the many orders of magnitude spanned by Ka values,

a logarithmic measure of the acid dissociation constant is more

commonly used in practice. The logarithmic constant, pKa, which is

equal to −log10 Ka, is sometimes also (but incorrectly) referred to as

an acid dissociation constant:

In pharmacology, ionization of a compound alters its physical behavior and macro properties such as solubility and lipophilicity(log p).

For example ionization of any compound will increase the solubility in water, but decrease the lipophilicity.

This is exploited in drug development to increase the concentration of a compound in the blood by adjusting the pKa of an ionizable group.

pKa is that pH on which a drug is 50 % ionized and 50%

unionized.

E.g. if a drug has pKa 3.5, it means at pH 3.5 it is 50%

ionized and 50% unionized.

If pKa - pH > 1 then the solution is 99 -100% ionized or 99-100% unionized

If pKa - pH = 0.5,

then the solution is 75% ionized/ 25% unionized or

75% unionized/ 25% ionized

Putting it in another way

• If pKa - pH = 0, then 50% of drug is ionized and 50% is unionized

http://www.manuelsweb.com/pka.htm

An acid in an acid solution will not ionize.

An acid in a basic solution will ionize.

A base in a basic solution will not ionize.

A base in an acid solution will ionize.

• Ionized = water soluble = poor absorption through stomach, BBB, and placenta.

• Non-ionized = lipid soluble = absorbed well (because cell membranes are composed of lipids)

• For example, sodium (Na+) and chloride (Cl-) are both ionized.  Cells must provide a channel for these ions to enter an otherwise impenetrable lipid membrane.

The pH of the stomach is 2.5.  The pKa of sodium pentothal is 7.4 and it is acidic.  If a

patient is given sodium pentothal orally

instead of IV, will it put the patient to sleep? 

• None of the sodium pentothal is ionized in the stomach.  Therefore the patient would absorb 100% of this medication (from stomach) and it would put him to sleep.

Another beautiful example

A basic drug with a pKa of 7.8 is a known teratogen.  If given IV to a pregnant

woman whose blood pH is 7.4, will this drug cross the placenta and effect the

baby? 

• In this example, 72% of the drug is ionized which means 28% of the drug is unionized and will pass through the placenta to effect the baby.

The larger the value of pKa, the smaller the extent of

dissociation at any given pH i. e. the weaker the acid.

A weak acid has a pKa value in the approximate range

−2 to 12 in water.

Acids with a pKa value of less than about −2 are said to

be strong acids; a strong acid is almost completely dissociated in aqueous solution, to the extent that the concentration of the undissociated acid becomes undetectable.

pKavalues for strong acids can, however, be estimated by

theoretical means or by extrapolating from measurements in non-aqueous solvents in which the dissociation constant is smaller, such as acetonitrile and dimethylsulfoxide.

The quantitative behavior of acids and bases in solution can be understood only if their pKa values are known.

In particular, the pH of a solution can be predicted when the analytical concentration and pKa values of all acids and bases are known; conversely, it is possible to calculate the equilibrium concentration of the acids and bases in solution when the pH is known.

For example, many compounds used for medication are

weak acids or bases,

and a knowledge of the pKa values, together with the water-octanol partition coefficient, can be used for estimating the

extent to which the compound enters the blood stream. 

The buffer capacity of a simple buffer solution is largest when pH = pKa. 

pKa values are determined by potentiometric (pH) titration, but for pKa values less than about 2 or more than about 11, spectrophotometric or NMR measurements may be required due to practical difficulties with pH measurements.

http://n-pharmacology.blogspot.in/2013/06/absorption-of-drugs.html

Passive diffusion: 

• The driving force for passive absorption of a drug is the concentration gradient across a membrane separating two body compartments; that is, the drug moves from a region of high concentration to one of lower concentration. Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. The vast majority of drugs gain access to the body by this mechanism. Lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane bilayers. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores 

Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes allowing the passage of drugs or endogenous molecules into the interior of cells, moving them from an area of high concentration to an area of low concentration. This process is known as facilitated diffusion. This type of diffusion does not require energy, can be saturated, and may be inhibited.

• Active transport:This mode of drug entry also involves specific carrier proteins that span the membrane. A few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using these specific carrier proteins. Active transport is energy-dependent and is driven by the hydrolysis of adenosine triphosphate . It is capable of moving drugs against a concentration gradient that is, from a region of low drug concentration to one of higher drug concentration. The process shows saturation kinetics for the carrier, much in the same way that an enzyme-catalyzed reaction shows a maximal velocity at high substrate levels where all the active sites are filled with substrate.

• Most drugs are either weak acids or weak bases. • Acidic drugs (HA) release an H+ and weak bases (BH+) can also

release an H+ causing a charged anion (A-) to form. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base(B):

• Passage of an uncharged drug through a membrane: 

• A drug passes through membranes more readily if it is uncharged.

•  Fig.:A diffusion of non ionized form of a weak acid through a lipid membrane .Fig.:B diffusion of non ionized form of a weak base through a lipid membrane.

Thus, for a weak acid, the uncharged HA can permeate through membranes, and A cannot. For a weak base, the uncharged form, B, penetrates through the cell membrane, but BH+  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 pKa.

• (Figure: The distribution of a drug between its ionized and non-ionized forms depends on the ambient pH and pKa  of the drug. For illustrative purposes, the drug has been assigned a pKa of 6.5.).

• 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. Distribution equilibrium is achieved when the permeable form of a drug achieves an equal concentration in all body water spaces. Highly lipid-soluble drugs rapidly cross membranes and a often enter tissues at a rate determined by blood flow.

• Determination of how much drug will be found on either side of a membrane: The relationship of pKa and the ratio of acid-base concentrations to pH is expressed by the Henderson-Hasselbalch equation:

• This equation is useful in determining how much drug will be found on either side of a membrane that separates two compartments that differ in pH—for example, stomach (pH 1.0-1.5) and blood plasma (pH 7.4). [Note: The lipid solubility of the non-ionized drug directly determines its rate of equilibration.]

• Blood flow to the intestine is much greater than the flow to the stomach; thus, absorption from the intestine is favored over that from the stomach. [Note: Shock severely reduces blood flow to cutaneous tissues, thus minimizing the absorption from SC administration.

• Because the intestine has a surface rich in microvilli, it has a surface area about 1000-fold that of the stomach; thus, absorption of the drug across the intestine is more efficient.

• If a drug moves through the GI tract very quickly, as in 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.

• 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), prolongs 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.

http://www.pharmacology2000.com/General/Pharmacokinetics/kinobj1.htm

• Ionization state of the drug is an important factor: charged drugs diffuse-through lipid environments with difficulty.

• pH and the drug pKa, important in determining the ionization state, will influence significantly transport (ratios of lipid-to aqueous-soluble forms for weak acids and bases described by the Henderson-Hasselbalch equation.

•  uncharged form: lipid-soluble

• charged form: aqueous-soluble, relatively lipid-insoluble (does not pass biological membranes easily)

• Lipid diffusion depends on adequate lipid solubility– Drug ionization reduces a drug's ability to cross a lipid bilayer.

• The lower the pH relative to the pKa the greater fraction of protonated drug is found.  The protonated form of an acid is uncharged (neutral); however, protonated form of a base will be charged.

• As a result, a weak acid at acid pH will be more lipid-soluble because it is uncharged and uncharged molecules move more readily through a lipid (nonpolar) environment than charged molecules

• Similarly a weak base at alkaline pH will be more lipid-soluble because at alkaline pH a proton will dissociate from molecule leaving it uncharged and again free to move through lipid membrane structures

• Henderson-Hasselbalch equation

• General Form:  log (protonated)/(unprotonated) = pKa - pH

• For Acids: pKa = pH + log (concentration [HA] unionized)/concentration [A-]

•  – note that if [A-] = [HA] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH

• For Bases: pKa = pH + log (concentration [BH+] ionized)/concentration [B]

– note that if [B] = [BH+] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH

With inputs from my colleagues Mr. Avnish Jain and Ms. Payal Jain

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