All medicines are chemicals. The specific chemical structure of a medication is what determines its mechanism of action, physical properties, metabolism, and safety profile. Therefore, it is important to have a basic understanding of chemistry in order to use and administer these agents safely.

Salt form

Around half of all marketed drugs are supplied as a salt form. That is, the parent drug is paired with an appropriate counter-ion (or salt). Some of the salts most commonly used in medicine are hydrochloride, sodium, sulfate, and acetate.

A drug may be presented as a salt to improve its pharmacokinetic profile. Salt formation is often used to improve the solubility and dissolution rates of acidic and basic drugs. Salt forms may also be utilised to improve stability or taste, target delivery to a specific site in the gastrointestinal tract, or to reduce injection site reactions for parenteral products.

Inclusion of the salt of the active ingredient in prescriptions and labelling can be a source of confusion for patients. For example, one patient discontinued taking their prescribed potassium supplement after receiving a prescription for losartan potassium. In this instance, the patient assumed that the potassium salt of losartan replaced their potassium supplement. To avoid medication errors, the Australian Commission on Safety and Quality in Health Care recommend that the salt of the chemical is not included in orders unless it is clinically significant.

Another potential source of confusion is the different doses required of each salt form to achieve an equivalent dose of the active ingredient. This occurs because each individual salt contributes a different weight to the overall weight of the compound. For example, calcium supplements are commonly presented as the carbonate or citrate salts as shown in Table 1.

Table 1. Chemical differences in calcium salts

Salt form Molecular formula Molecular weight (g/mol) Approx. calcium content Dose ≈ 600mg elemental calcium
Calcium (elemental) Ca 40.078 100% 600mg
Calcium citrate C12H8Ca3O18 570.492 21% 2,850mg
Calcium carbonate CaCO3

 

100.086 40% 1,500mg

To achieve the commonly prescribed dose of 600mg of elemental calcium, approximately 1,500mg of calcium carbonate or 2,850mg of calcium citrate will be required. As this example shows, failure to appreciate the differences in salt forms could lead to significant under or overdoses.

Particular care is required while prescribing and administering medications available in multiple salt forms. Table 2 displays some examples of significant salt form differences that could cause confusion during medication administration.

Table 2. Different salt forms of medications

Parent drug Salt form Notes
Perindopril Perindopril arginine 2.5mg perindopril arginine = 2mg perindopril erbumine. Considered equivalent for the purposes of substitution on the PBS.
Perindopril erbumine
Mycophenolate Mycophenolate mofetil CellCept® strength expressed as mycophenolate mofetil.

1g mycophenolate mofetil = 720mg mycophenolic acid

Mycophenolate sodium Myfortic® strength expressed as mycophenolic acid.

Enteric coated tablets – improved gastrointestinal tolerability.

Diclofenac Diclofenac sodium Enteric coated tablets – delayed release
Diclofenac potassium Potassium salt more water soluble ∴ absorbed faster
Metoprolol Metoprolol tartrate Immediate-release tablet
Metoprolol succinate Extended-release tablet

As the above examples suggest, many salt forms of the same active ingredient have different dissolution and release characteristics. These differences may cause significant differences in bioavailability, rendering many of these agents non-interchangeable in clinical practice.

Stereochemistry

Stereochemistry is a field of chemistry concerned with the spatial arrangement of atoms in a molecule and the effects these positions have on the properties of a compound. Many drug molecules can exist as enantiomers; a pair of molecules with the same molecular structure that are non-superimposable mirror images of each other. While these enantiomers will have identical chemical formulae and molecular weight, the mirror images may have significantly different bioavailability, metabolism rate, potency and selectivity for target sites, and toxicity.

Naming conventions for enantiomers may use d (dextrorotatory) and l (levorotatory) to denote the direction in which each enantiomer rotates the plane of polarised light. Alternatively, R- (rectus [Latin: right]) and S- (sinister [Latin: left]) may be assigned to enantiomers with groups arranged in a clockwise or anticlockwise direction respectively, according to Cahn-Ingold Prelog Rules. There is no direct relationship between these two naming systems, i.e. a molecule could rotate the plane of polarised light to the right (dextrorotatory) while having its groups arranged in an anticlockwise (sinister) direction and vice versa.

A medication may be presented as a mixture of enantiomers in which case it is called a racemate or racemic mixture. An example of a racemate is the selective serotonin reuptake inhibitor (SSRI), citalopram. Citalopram is presented as a mixture of both the R- and the S- enantiomers. However, the S- enantiomer of citalopram is significantly more potent than the R- enantiomer in inhibiting serotonin uptake in vitro. This led to the development of escitalopram, which contains only the S- enantiomer of citalopram. Owing to its greater potency, the equivalent dose of escitalopram is half that of citalopram. Other examples of enantiomerically pure medications are shown in Table 3.

Table 3. Some single enantiomer preparations available

Parent drug Single enantiomer Benefit of single isomer
Bupivacaine Levobupivacaine (l-isomer) Reduced toxicity allows for larger doses, improved safety where risk of accidental intravascular injection high.
Cetirizine

 

Levocetirizine (l-isomer)

 

Greater affinity for H1 receptors.
Dopa Levodopa (l-isomer) d-isomer is clinically inactive and associated with adverse effects. Only pure l-isomer is used therapeutically.
Modafanil Armodafinil (R-isomer) 3x longer half-life
Omeprazole Esomeprazole (S- isomer)

 

Slower and more predictable metabolism gives higher and more sustained plasma levels.
Penicillamine D-penicillamine (D-isomer) L-penicillamine is toxic as it is a pyridoxine antagonist. Only pure D-penicillamine used therapeutically, also known as penicillamine.

Specific enantiomers can have significantly different properties to the racemic mixture and are, therefore, not interchangeable.

Interconversion between enantiomers can occur within the body. For example, ibuprofen is supplied as a racemic mix even though the R-isomer is inactive. However, as around 60% of the R-isomer is enzymatically converted to the active S-isomer after absorption, an enantiomerically pure ibuprofen product has not yet been marketed.

Possibly the most dramatic example of the potential difference between enantiomers is the case of thalidomide. Thalidomide is well-known as a highly teratogenic agent. However, it is only the S-isomer that is teratogenic owing to its antiangiogenic properties. However, thalidomide enantiomers interconvert rapidly in the body. Therefore, administration of only the R-isomer would not be an effective means of improving the safety profile of thalidomide, and it remains available as a racemic mix under a highly-regulated program.

Interestingly, the approved name for thyroxine has recently changed to levothyroxine as part of the Therapeutic Goods Administration’s harmonisation of ingredient names. This is to highlight that these products contain only the more potent levorotatory isomer of thyroxine; the primary secretion of the thyroid gland. However, the formulation of these medications has not changed. The new name is only intended to align with international naming conventions and remove any ambiguity.

Summary

The availability of multiple salt forms of the same active drug and the use of different isomers with similar-sounding names are common causes of confusion. An understanding of the basic chemical concepts behind these issues will reduce medication confusion. It is also vital that any unclear order is clarified before medication administration to reduce errors and subsequent patient harm.

References:

  1. Aronson JK. Meyler’s Side Effects of Analgesics and Anti-inflammatory Drugs. Oxford: Elsevier; 2010.
  2. Caldolor® (ibuprofen) Australian approved product information. Parkville: Seqirus. Approved September 2018.
  3. Chhabra N, Aseri ML, Padmanabhan D. A review of drug isomerism and its significance. Int J Appl Basic Med Res. 2013; 3(1): 16-8.
  4. McDougall DJ, Hoehns JD, Feller TT, Kriener S, Witry MJ. Inclusion of salt form on prescription medication labeling as a source of patient confusion: a pilot study. Pharm Pract (Granada). 2016; 14(1): 677.
  5. National Centre for Biotechnology Information. PubChem. Bethesda, United States of America.
  6. Nguyen LA, Pham-Huy C. Chiral drugs: an overview. Int J Biomed Sci. 2006; 2(2): 85-100.
  7. Rossi S (ed). Australian Medicines Handbook. Adelaide: AMH; 2018.

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