Drug Absorption –Zubeyda Faynus

DRUG ABSORPTION

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Drug absorption is just one of the many applications of equilibrium, particularly acid-base equilibrium. Drug absorption is defined as the movement of a drug from its site of administration into the bloodstream. Some of the most important factors that affect the absorption of a drug so that it can reach its desired site of action is the nature of the drug, in other words whether it is acidic or basic, the solubility of the drug, whether the drug is ionized or non ionized, the pH levels on either side of the cell membrane and the pKa of the drug.

Solubility of drugs

Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. Extremely hydrophobic drugs however are also poorly, 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. This is one reason why most drugs are weak acids or weak bases. There are some drugs that are highly lipid-soluble, and they are transported in the aqueous solutions of the body on carrier proteins such as albumin.

 Ionization of Drugs

Once in solution, drugs exist as a mixture of two interchangeable forms. This is water-soluble which the ionized or electrically charged form, it cannot cross the membrane, or the lipid-soluble non-ionized form which is uncharged and can readily cross the membrane. There is always an ongoing rapid equilibrium between the dissolved forms of the drug, between the ionized and nonionized forms. Once the non-ionized form of the drug leaves the compartment it is in, then the two forms are no longer in equilibrium. Immediately some of the ionized form will become non-ionized to re-establish the equilibrium. Then more non-ionized form is present and can be absorbed, thus putting the two forms out of equilibrium, so some more will become non-ionized and so on in a continual cycle. The trick is that the pKa and pH must be sufficiently close so that some fraction is non-ionized to start with. Usually 0.1% is sufficient. Since most drugs are either a weak acid or a weak base, when they are dissolved in body fluids, some or all of the drugs molecules become ionized/unionized. This is illustrated below in the standard equations for the ionization of a weak acid and weak base:

Weak acid ionization:                                         HA = H+ + A-  

Weak base ionization:                                        BH = H+ + B-

What percentage of the drug is ionized or unionized is determined by; whether the drug was an acid or base, whether it was dissolved in acid or base medium for example the stomach or intestines and also the pKa of the drug. As the pH increases, a weak base will become more and more unionized, lipid soluble and better absorbed. On the other hand, as the pH decreases, a weak base will become more and more ionized, lipid insoluble, and will not be absorbed. It will also become more water soluble and better excreted. In relation, as the pH increases, a weak acid will become more and more ionized lipid insoluble and will not be absorbed. It will also become more water soluble and better excreted. In contrast, as the pH decreases, a weak acid will become more and more unionized, lipid soluble and better absorbed. So in essence, acidic drugs are absorbed best in acidic environments and basic drugs are best absorbed in basic environments.

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pKa

The pKa of a drug is equivalent to the pH at which 50% drug is ionized and 50% is unionized. The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbalch equation. The Henderson-Hasselbalch equation relates the ratio of protonated to unprotonated weak acid or weak base to the molecule’s pKa and the pH of the medium as follows:

pH = pKa + log Unprotonated form /Protonated form

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  • For a weak acid, if the pH – pKa  is low it will be more non-ionized and better absorbed
  • For a weak base if pH – pKa value is high it will be more non-ionized and better absorbed

This video explains how equilibrium is kept between the ionized and unionized forms of a drug using the weak acid drug Aspirin as an example.

 

References

  1. http://www.rxpgonline.com/article900.html
  2. http://www.drug-dissolution-testing.com/?p=1816
  3. http://home.kku.ac.th/korawut/prin-phar/pdf/02-PK-absorption-eng.pdf
  4. http://www.pharmatutor.org/pharmacology/general-pharmacology/physical-properties-drugs.html
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3 Responses to Drug Absorption –Zubeyda Faynus

  1. nivethau says:

    How does a low or high PKA affect the degree to which the drug is absorbed to reach its disired site of action?

  2. seemas2013 says:

    what determines the equilibrium rate of the drug absorption of an intestine?

  3. nelvin1 says:

    This was well done. I have 2 questions about this:
    1. “pKa” was mentioned a few times in this article but where does pKa come from?
    2. What is the relationship between pH and pKa?

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