Consider pharmacodynamic and kinetic aspects

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs for the treatment of pain, although there are certain differences between the various preparations in terms of pharmacodynamics and kinetics. Due to age-correlated changes, this is an important criterion when selecting therapy, especially for patients over 65 years of age. A European research team has summarized practical facts in an overview article published in the journal Biomedicine & Pharmacotherapy.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is recommended in international guidelines for the treatment of mild, moderate and severe pain [1]. A meta-analysis published in 2020 showed that the various oral NSAIDs do not differ significantly in terms of analgesic effects [2]. Particularly in older people, the main focus when selecting the respective preparation should therefore be on the safety profile, which is known to be related to the pharmacokinetic and pharmacodynamic properties [2,3]. Against this background, Ribeiro et al. conducted a secondary analysis in which they identified relevant publications published in the period 2011-2021 in scientific databases (Pubmed, Cochrane, NICE) according to predefined search criteria [1].

Ageing processes influence the metabolization of drugs

Ageing leads to certain changes in the body that influence the pharmacodynamics and kinetics of drugs [4,5]. Table 1 summarizes the most common changes in the absorption, distribution, metabolism and excretion of drugs [1]. Drug absorption is less affected by ageing per se than by the addition of several factors that interact with each other in old age. These include changes in dietary habits, consumption of over-the-counter medicines (e.g. antacids, laxatives), reduced gastric and intestinal motility, reduced gastric emptying and increased pH, reduced enzyme secretion and increasing mucosal atrophy. This has various implications with regard to the choice of therapy, according to a key statement by Ribeiro et al. [1].

• Maximum tolerated dose: Since older people show a decrease in body water compared to young adults, caution is required when analyzing drug distribution, as water-soluble drugs can easily reach critical toxicity concentrations. In other words, the maximum tolerated doses are lower in geriatric patients [4]. In contrast, fat-soluble drugs have a longer duration of action, as the body produces more fatty tissue, especially abdominal fat, with increasing age [4].
• Titration: Care should be taken when titrating fat-soluble drugs, both in terms of the recommended/administered doses and the time intervals between doses. The latter should be extended to ensure better safety [4].
• Hepatic metabolism: ageing leads to a decrease in hepatic blood flow and a reduction in enzyme activity involved in oxidation, reduction and hydrolysis (phase 1 of biotransformation, which includes cytochrome P450 activity) [3,5]. The activity of the enzymes involved in glucuronidation, acetylation and sulfation (phase 2 of hepatic biotransformation) remains practically unchanged [3]. Therefore, drugs that undergo phase 1 hepatic metabolism have a longer duration of action, a higher toxicity potential and a greater potential for drug-drug interactions [5].
• Renal elimination: Renal elimination is a pharmacokinetic characteristic that very frequently shows age-correlated changes. After the age of 40, the glomerular filtration rate decreases by around 0.75 ml/min/year, so that a reduction in kidney function of around 50% can be expected at the age of 70 [4].

The age-correlated decrease in serum albumin and the increase in α1-acid glycoprotein must also be taken into account. These aspects affect both the pharmacokinetics of cationic/acidic drugs (e.g. NSAIDs), which bind more strongly to albumin, and the reduction in their volume of distribution, as well as that of anionic/basic drugs (e.g. opioids), which tend to increase their volume of distribution [3].

Adverse drug reactions occur in around 20-40% of older people each year [1]. The main factors contributing to this high incidence of adverse drug reactions in this subpopulation are polymedication (including self-medication) and a high number of comorbidities with disease-related changes in drug availability/effectiveness. These factors lead to greater systemic effects, increased sensitivity to drug effects and altered pharmacokinetics. In view of this, it is important not to ignore drug interactions and side effects in older people (Box) . Ribeiro et al. also point out that it is important to observe certain rules when prescribing medicines in order to increase adherence to treatment and avoid adverse drug reactions:

• Start with reduced doses and titrate to the lowest effective dose;
• Wait for three age-adjusted half-lives before increasing the dose;
• If there is no therapeutic response, measure the plasma levels or switch to another drug.

When selecting a specific substance class or a preparation within this group, efficacy, safety data, costs and usability of the drug should be the main criteria [1].

Mechanisms of action and safety profile of various NSAIDs

NSAIDs inhibit the enzymes cyclooxygenase-1 and -2 (COX-1 and COX-2), both of which are involved in arachidonic acid metabolism, which leads to the production of prostaglandins and thromboxane [1,6]. However, there are differences between the various NSAIDs in terms of affinity for the COX enzyme, which results in a different potential for adverse effects. All NSAIDs have a direct and indirect effect on the gastrointestinal mucosa [10]. However, the preferential inhibition of COX-1 carries a higher risk of undesirable gastrointestinal side effects due to the constitutive presence of this enzyme in the gastrointestinal musculature. On the other hand, preferential inhibition of COX-2 carries a greater risk of adverse cardiovascular events, mainly due to the higher concentration of this enzyme in the vascular endothelium of the kidney, which leads to inhibition of prostaglandin production, particularly at the tubular or glomerular level, thus affecting GFR and contributing to greater sodium retention and edema, which may result in cardiac and renal failure [7–9].

In terms of distribution, fat-soluble NSAIDs such as ibuprofen, acemethacin and naproxen have a longer half-life in patients with more fatty tissue, such as the overweight and elderly. With water-soluble NSAIDs (diclofenac, etodolac and etoricoxib), the toxicity potential may be greater in patients with less body water [4]. In terms of metabolism, acemethacin is the only NSAID mentioned in Table 2 that has a phase 2 metabolism [11].

In terms of excretion, the drugs with lower renal elimination (percentage of the active substance excreted via the urinary tract) are, in ascending order: acemethacin, diclofenac, etodolac, etoricoxib, ibuprofen, naproxen [11].

A randomized controlled clinical trial of 24081 patients showed that naproxen and ibuprofen did not have a better cardiovascular safety profile than COX-2-selective NSAIDs, suggesting that non-selective NSAIDs do not have a better cardiovascular safety profile compared to COX-2-selective NSAIDs [12]. The study participants were randomized to celecoxib vs. naproxen vs. ibuprofen. The mean duration of treatment was 20.3±16.0 months and the average follow-up period was 34.1±13.4 months.

Literature:

1. Ribeiro H, et al: Non-steroidal anti-inflammatory drugs (NSAIDs), pain and aging: Adjusting prescription to patient features. Biomed Pharmacother 2022; 150: 112958.
2. Li M, Yu C, Zeng X: Comparative efficacy of traditional non-selective NSAIDs and selective cyclo-oxygenase-2 inhibitors in patients with acute gout: a systematic review and meta-analysis. BMJ Open 2020 Sep 10; 10(9): e036748.
3. Petrovic M, et al: Adverse drug reactions in older people: detection and prevention. Drugs Aging 2012; 29(6): 453-462.
4. Fialová D, et al: Medication use in older patients and age-blind approach: narrative literature review (insufficient evidence on the efficacy and safety of drugs in older age, frequent use of PIMs and polypharmacy, and underuse of highly beneficial nonpharmacological strategies). Eur J Clin Pharmacol 2019; 75(4): 451-466.
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6. Rao P, Knaus EE: Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci 2008; 11(2): 81; 10.18433/J3T886.
7. Arfè A, et al: Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ 2016; p. i4857.
8. Gunter BR, et al: Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis. J Clin Pharm Ther 2017; 42(1): pp. 27-38.
9. Sondergaard KB, et al: Non-steroidal anti-inflammatory drug use is associated with increased risk of out-of-hospital cardiac arrest: a nationwide case-time-control study. Eur Heart J Cardiovasc Pharmacother 2016: p. pvw041, 10.1093/ehjcvp/pvw041.
10. Tai FWD, McAlindon ME: NSAIDs and the small bowel. Curr Opin Gastroenterol 2018; 34(3): 175-182.
11. Drugbank 2021, https://go.drugbank.com,(last accessed 04.04.2024)
12. Nissen SE; PRECISION Trial Investigators. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med 2016; 375(26): 2519-2529.
13. O’Mahony D, et al: STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Ageing. 2015; 44(2): 213-218.
14. Katzung GB: Basic and Clinical Pharmacology. Endocrine Drugs. 2004. ^9th Edition, McGraw-Hill: Philadelphia.

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