The ps in Therapeutics

In late 2011, a student provided my first look at the t-shirt logo, P H Ar Md, in which four atomic elements form an ironic basic science play on that implicitly clinical degree abbreviation. Similarly, the ps in "therapeutics" can represent the four original pharmaceutical sciences of pharmaceutical chemistry, pharmaceutics, pharmacognosy, and pharmacology.

From having taught 14 years in two 5-year BS in Pharmacy programs and 21 years in two 6-year PharmD degree programs, I summarize that the BS emphasized drug and product ps facts; whereas the PharmD emphasizes drug therapy and disease clinical facts. In general, the final BS to PharmD transition reduced ps credits to add (e.g., experiential training, patient assessment, and social and behavioral sciences [see Sidebar 1]).

A prime example of ps applications likely to be "dissed" or missed in patient-focused PharmD education and practice is the absence of causative explanation (e.g., acid-base or cation-anion reaction, from intravenous drug-drug compatibility-incompatibility observations and reports). The following more detailed and also clinically relevant ps in therapeutics examples demonstrate why our unique-in-pharmacy ps expertise, which was first formalized with national curricular guidelines and accreditation standards in 1906 and 1932, respectively,^1-3 should be preserved and treasured.

Example 1. Pharmaceutical Chemistry of Maillard Reactions
The nonenzymatic, heat-catalyzed covalent Maillard (my-ARE) Reaction (MX), also known as the browning or N-glycation reaction, occurs between (1) an aldehyde (RCHO) including the trace reducing forms dextrose and lactose; and (2) a primary (RNH₂) or secondary (R₂NH) amine. Unlike its well-known product hemoglobin A_1c, which was discovered in 1967, the "MX" per se is little known in pharmacy, as are the colored complex oxidation products from initial dextrose and amino acids adducts in parenteral nutrition (PN) solutions. Those and the browning of foods during cooking are termed advanced glycation end products (AGEs). In vivo MXs of aldehydes from diet and metabolism with tissue proteins produce AGEs associated with conditions ranging from harmless skin aging spots to atherosclerosis, cancer, inflammation, microvasculature necrosis, nephropathy, neuropathy, osteoarthritis, retinopathy, and yet to be elucidated pathologies.⁴

A readily observed MX is the yellow-amber discoloration in PN solutions, which appears sooner and more intensely in direct proportion to increasing temperature and concentrations of amino acids and dextrose, and progressively darkens over time as AGEs accumulate. Dextrose losses in PN are clinically insignificant because the reactive aldose form comprises less than 0.1% of total dextrose strength. Under refrigeration, there is less than a 5% loss of amino acids within 14 days, but at room temperatures losses up to12% can occur within 1 to 28 days.

The following amino drugs have been reported to form inactive MX adducts with the trace aldose forms of dextrose and lactose:

• Amphetamine
• Ampicillin
• Daptomycin
• Fluoxetine
• Oseltamivir
• Procainamide
• Sulfamethoxazole

Therefore, ps knowledge is required to identify amino groups on drugs and added substances or inactive ingredients when deciding their dilution in 5% dextrose versus 0.9% sodium chloride injection⁵ or compounding in syrups known or suspected to contain a reducing sugar. For example, daptomycin contains multiple amino groups, which explains the Cubicin labeling statement, "CUBICIN is not compatible with dextrose-containing diluents." Likewise, the MX accounts for the 3 to 10 times faster loss of ampicillin, ertapenem, and meropenem in dextrose than in sodium chloride injection.^4,6

Example 2. Pharmacology of Viagra
In 2009, a major television network's evening newscast reported that pharmacists at a university medical center declined or refused to compound Viagra (sildenafil) tablets in fluid form to treat a neonate or child with pulmonary hypertension (PH). Their reason was not stated. At the time, Viagra was approved only to treat male erectile dysfunction (ED), but the labeling states, "The inhibition of PDE5...may be the basis for...peripheral arterial-venous dilatation in vivo." The product package insert or Full Prescribing Information of a drug does not prohibit prescribing and dispensing for nonindicated, unlabeled, or "off label" uses, and PH has a high mortality rate with standard therapy. It seems in this PharmD era that hospital pharmacists would know or quickly learn that (a) the vasodilatation action of phosphodiesterase inhibitor ED drugs is pharmacologically logical ps to treat PH, and (b) the physicians were prescribing in the best interest of patients based on available reports.⁷ The other "PS" (postscript) to this episode is that "off label" treatment with Viagra of PH in children was a feature presentation on October 25, 2011 at the American College of Chest Physicians annual meeting.⁸

Example 3. Pharmaceutics of Pradaxa
Pradaxa (dabigatran etexilate mesylate) capsule shells are comprised of the carbohydrates, hypromellose (H) and carrageenan (C).⁹ This combination is a rare deviation from animal-derived gelatin capsule shells, which dissolve rapidly in gastrointestinal (GI) contents after which the gelatin is digested by proteolytic enzymes. H and C shells form viscous gels, which accounts for two important facts in the Pradaxa package insert deducible from ps knowledge. The first is "Keep the bottle tightly closed. Store in the original package to protect from moisture." This alludes to the desiccant being placed in the bottle cap. Chronic exposure of the H and C shells to high humidity could result in Pradaxa capsules sticking or fusing together, which could risk capsule rupture when removing them for administration. The second is "Oral bioavailability of dabigatran etexilate increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation." The deduced ps reason is that the viscous H and C gel formed after Pradaxa capsules are swallowed intact limits drug dissolution in and diffusion from that gel. Faster dissolution and diffusion in the absence of the H and C gel in GI contents explains the nearly doubled absorption extent. Ignoring the latter ps phenomena when, despite clinical justification, administering the drug pellets via enteral or nasogastric tube could cause acute harm or death to a patient.

Example 4. Pharmaceutical Chemistry of Injectable Drug Salts Not Labeled As Salts
Some drug injections and drugs for injection (sterile powders to become sterile solutions) name their drugs according to the pharmacologically active nonionized acid or base moiety, despite that they are salts (i.e., anions or cations). This is explained in United States Pharmacopeia (USP) Chapter <1121>.¹⁰ For example, Gentamicin Injection "…contains…Gentamicin Sulfate equivalent to not less than 90.0 percent and not more than 125.0 percent of the labeled amount of gentamicin,"¹⁰ (i.e., gentamicin is a cation). Lacking such explicit description, the determination of the drug being a salt is decided by either of the following sources:

1. The full chemical name (e.g., ceftobiprole medocaril) is actually a sodium salt (i.e., ceftobiprole medocaril is an anion).
2. The ps interpretation of drug structure in relation to the drug solution pH (e.g., the daptomycin for injection product) insert states "The only inactive ingredient is sodium hydroxide…for pH adjustment," and the USP Furosemide Injection monograph states it "…is a sterile solution of Furosemide…prepared with the aid of sodium hydroxide…."¹⁰ The furosemide structure contains a carboxylic acid group, -COOH,⁹ which has a pK_a value of 4 to 5¹¹; making furosemide greater than 99.9% ionized (i.e., anionic, at the injection pH range of 8.0 to 9.3).^10,12

In their constituted and manufactured solutions, respectively, daptomycin and furosemide are sodium salts, which cannot be officially named such because they are formed in situ. To preclude such confusion, I wrote some simple guidelines based on the last three letters in the names of the nondrug ions in salts of organic drugs, which enable rapid and reliable identification of drugs as anions or cations to avoid acid-base incompatibility or precipitation reactions.^12-13

Conclusion
The decline of ps content and emphasis, especially pharmaceutics, in pharmacy education has been followed by pharmacy practice journals since the final BS to PharmD degree transition of 1990-2000 (see Sidebar 1). The particular deficit of drug compatibility, compounding, packaging, reactivity, solubility, stability, and storage instruction and information was a major impetus for the 1997 premier of the International Journal of Pharmaceutical Compounding and the 2011 introduction of the Science and Technology for the Hospital Pharmacist (STHP) electronic newsletter. The preceding four ps examples corroborate the Introduction to STHP (Vol. 1 No. 2), which featured Dr. Richard Penna's (see Sidebar 2) prudent reflection that biological, chemical, and physical ps facts and knowledge are vital to patient care.¹⁴

References

1. Brady ES. The great debate: Which entry-level degree for pharmacists? Pharmaguide to Hospital Medicine 1990; 3(6): 1-6.
2. Buerki RA, Penna RP, Higby GJ. In search of excellence: The first century of the American Association of Colleges of Pharmacy. Am J Pharm Educ 1999; 63(Fall Suppl): 17-194.
3. Buerki RA. American pharmaceutical education, 1952-2002. J Am Pharm Assoc 2002; 42(4): 542-544.
4. Newton DW. Maillard reactions in pharmaceutical formulations and human health. IJPC 2011; 15(1): 32-40.
5. Newton DW. Drug compatibility and stability in dextrose vs saline. IJPC 2011; 15(3): 190-192.
6. Trissel LA. Handbook on Injectable Drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2011: 132, 604, 1012-1013.
7. Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. [National Institutes of Health Website.] Available at: http://www.nichd.nih.gov/cochrane/shah10/shah10.htm, Accessed September 22, 2011.
8. Kulik T. Viagra-like Drug May Help Children with Rare Disorder. Presentation at the American College of Chest Physicians Annual Meeting, Honolulu, HI, October 25, 2011. [HealthDay Website.] Available at: http://consumer.healthday.com/Article.asp?AID=658187. Accessed October 26, 2011.
9. Rowe RC, Sheskey PJ, Quinn ME, eds. Handbook of Pharmaceutical Excipients. 6th ed. London, UK: Pharmaceutical Press, and Washington, DC: American Pharmacists Association; 2009: 122-123, 326-327.
10. United States Pharmacopeial Convention, Inc. United States Pharmacopeia 34-National Formulary 29. Revised ed. Rockville, MD: US Pharmacopeial Convention, Inc.; 2011: 659-662, 2926-2927, 2961, 3564.
11. Lemke TL. Review of Organic Functional Groups. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2012: 174.
12. Newton DW. Drug incompatibility chemistry. Am J Health Syst Pharm 2009; 66(4): 348-357; correction: 66(16): 1431.
13. Newton DW. Crux of drug compatibility and incompatibility. Am J Health Syst Pharm 2010; 67(2): 108,112.
14. Penna RP. What makes pharmacists different? Am J Pharm Educ 1997; 61(Spring): 103.