The elderly population is increasing worldwide, and the elderly patients are often on a long list of medications which include over the counter medications and prescribed medications for their multiple comorbidities. The over the counter medications (OTC) are often viewed as harmless and are often self-prescribed. Qato showed that the older adults are the most frequent consumers of the OTC, with an average older adult taking 4 medications from the OTC. (1) The range of drugs available over the counter is rapidly increasing, with over 300,000 FDA approved drugs, available to the consumers in the US market. (2) Drug related problems resulting in adverse reactions, poorly controlled chronic diseases, delirium, etc have caused increased hospital visits at the emergency department, ambulatory setting and hospital admissions, resulting in high healthcare costs. (3) The combination of OTC medications and prescribed medications has a potential to cause drug-drug interactions or interfere with the existing medical conditions resulting in adverse events, among the elderly with reduced physiological reserve.

Adverse drug reactions (ADR) refer to the harmful reactions unrelated to usage of drugs as FDA approved drugs, under normal usage and dosage, including side effects, allergic reactions, toxic reactions, drug dependence, mutation, distortion, carcinogenic effects, etc. (4) The possibility of an adverse drug event should always be borne in mind when prescribing to an older adult individual, as adverse events to common drugs can create serious consequences in elderly.

This paper gives an example of seemingly harmless OTC which are frequently self-prescribed for common ailments, without realising the potential adverse reactions which resulted in hospitalisations, prolonged hospitalisation and morbidity. A short review of the potentially harmful OTC medication related to this case is also summarised.

Madam A is an elderly lady with a past medical history of hypertension, dyslipidemia, hyperthyroidism, brain aneurysm, left eye glaucoma and osteoporosis. She was brought to the hospital for worsening insomnia and one week’s duration fluctuating behavioral changes (occasionally incoherent, paranoid with emotional outbursts). She has a background of insomnia for years and was on a combination of Hydroxyzine and hypnotics from her family physician. Her family reported worsening insomnia over the last 2 months prior to admission and low mood. She had trouble with her stock as they were losing their values and she had a recent fall out with her confidante. She was self-titrating her sleep medication at home.

Timeline of her medication changes: She was self-medicating on hydroxyzine and her family was uncertain how much hydroxyzine she was taking to induce sleep. She visited the emergency department after 2 weeks for insomnia where she was given Zolpidem, Bromazepam and Hydroxyzine. This combination cocktail failed too. She subsequently went to see a psychiatrist and was diagnosed with major depression, treatment with Mirtazapine and Lorazepam was given. A week later, she was noted to have outbursts of inappropriate behavior at home, for which she was aggressive and threatened her helper at home. Her family suspected she was still self-medicating with Hydroxyzine in addition to the new prescription. Her family took her to see another physician, where Mirtazapine was stopped and she was started with Zopiclone. She was brought to emergency department the following day for persistent insomnia and was noted to be incoherent.

Madam A has a baseline anxious personality and was the sole caregiver of her husband with dementia. Her pre-morbid function level was high as she was investing in shares and was still driving. Her physical examination showed an anxious and agitated thin elderly lady who was incoherent. She was intermittently screaming, answering questions incoherently, not eating and not sleeping.

There were no significant physical signs of note. Her parameters were all stable and she was afebrile. Her blood investigations showed acute kidney injury with low serum sodium and potassium levels, mild metabolic acidosis. All her other blood investigations were unremarkable. Septic work up were all negative. Electrocardiogram and chest Xray were unremarkable. CT brain and MRI brain with contrast showed no evidence of stroke or signs suggestive of leptomeningeal diseases. Working diagnosis:

• Delirium due to medications with anticholinergic properties and acute kidney injury.

• Acute kidney injury due to dehydration and poor oral intake.

She was seen by psychiatry and neurology multiple times with the consistent impression of delirium with visual hallucinations. Extensive workup for organic causes included Cerebrospinal fluid (CSF) examination for infective and autoimmune encephalitis were done and were all negative. CSF cytology and CSF NMDA were negative. CCSF cell count, glucose content and protein content were all unremarkable. CSF smear for TB and fungal were also negative. To exclude non-convulsive seizures, an electroencephalogram (EEG) was requested which showed mild diffuse encephalopathy with no evidence of seizure. Her abbreviated mental test score prior to admission was 8/10.

During her stay in the ward, she refused all food and drink for the first 2 weeks. After extensive discussion with family, a nasogastric tube (NGT) was inserted to allow for administration of nutrition, medication and fluids. The indications for NGT were to get nutrition and hydration into her since poor nutrition is a cause for delirium and the tube will be removed as soon as she can sustain her nutritional needs with oral feeding. Due to her agitation, she required mittens and intermittent arm restraints to stop her from pulling the NGT. In the first 3 weeks of her hospital stay, she refused to get out of bed and subsequently developed acute retention of urine with febrile episodes requiring antibiotics for urinary tract infection. She also had an episode of lower gastrointestinal bleeding, which was due to haemorrhoids and settled spontaneously.

At admission, all her hypnotics were discontinued. She required the use of haloperidol 0.5mg, up to a maximum of 1.5mg per day as needed for agitation. Her sleep was fragmented during the nights, scoring a max of 4 hours per night, but had intermittent naps during the day. She was started with Mirtazapine for her depression after 3rd week of hospital stay as she was frequently crying and depressed. She was gradually noted to show signs of improvement in her cognition after 6 weeks of hospital stay. She has also severely declined in her function compared to her pre morbid level. She stayed for a total of 10 weeks in the hospital for this episode which included 4 weeks of rehabilitation at a step down care facility.

Discussion:

Drug related problems are common in older adults, one of which is adverse drug effects. Adverse drug effects are effects that are unwanted, uncomfortable, or dangerous. Common examples are over sedation, confusion, hallucinations, falls, and bleeding. (5) Adverse drug effects can occur in any patient, especially among the older adults who have reduced physiological reserves. The pharmacokinetics and pharmacodynamics are also different among the elderly due to impaired organ function, body fat / lean muscle mass distribution and comorbidities. In addition, the long list of prescription drugs can potentially cause drug-drug interactions resulting in adverse events. The authors have reported 3 cases of adverse drug reactions from the commonly used drugs which are widely available from over the counter. In Singapore where the authors practise, the range of drugs available from the OTC are not as wide as the US. The commonly available drugs like antihistamines, cough syrups still require a doctor’s prescription.

One in ten hospital admissions in older patients are due to adverse drug reactions. Non steroidal anti-inflammtory drugs (NSAIDs) are the commonest class of medication causing hospital admissions. (6) One in eight elderly patients hospitalised for an adverse drug reaction had a repeat admission for an adverse drug reaction within 12 months of discharge. The commonest organ dysfunction related to adverse events from drug use is renal disorders (44.4%) and the most frequently implicated drug classes were diuretics (44.8%) and NSAIDS. (7)

One in ten hospital admissions in older patients are due to adverse drug reactions. Non steroidal anti-inflammtory drugs (NSAIDs) are the commonest class of medication causing hospital admissions.

H1 antihistamines down regulate allergic inflammation mainly through the H1-receptor which is widespread in smooth-muscle and neurons. H1 antihistamines are commonly classified according to function – of which, first-generation are sedating, as compared with second-

generation which are relatively non-sedating. These H1 antihistamines differ from each other by their ability to cross the blood-brain barrier, which determines the presence of

sedative central effects. The importance of sedation (reduction of daytime alertness, slight drowsiness or deep sleep) varies according to the degree of blood-brain barrier crossing and to the relative affinity of H1-antihistamines for peripheral and central receptors. (8) 

Hydroxyzine, an H1 antagonist, is commonly prescribed for the following conditions, as adjunct treatment of anxiety, perioperative adjunct and pruritus. Hydroxyzine has a long t½ and a large volume of distribution in the elderly. Studies have also suggested the possibility of enhanced H1‐receptor activity in old age. (8)

Its common side effects are drowsiness (transient), xerostomia, respiratory depression (high doses). It is identified in the Beers Criteria as a potentially inappropriate medication and to be avoided in patients 65 years and older (independent of diagnosis or condition) due to its potent anticholinergic properties resulting in increased risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity; its use should also be avoided due to reduced hepatic and renal functions with advanced age and tolerance associated with use as a hypnotic (Beers Criteria [AGS 2019]). (9)

In Madam A’s case, there is use of a combination of several hypnotic agents over the course of 2 months, namely benzodiazepine, hydroxyzine, zopiclone, zolpiderm (nonbenzodiazepine receptor agonists) and mirtazapine (noradrenergic and selective serotonergic antidepressant). Benzodiazepine, hydroxyzine and zopiclone are not recommended for routine use as hypnotics for the elderly due to concerns of common adverse effects such as cognitive impairment, fall risk and delirium (Beers Criteria [AGS 2019]) (9). The fact that Madam T still could not get a relief from her insomnia despite a combination of drugs is seemingly counterintuitive. All four drugs prescribed for Madam T have CNS depressant effects and their combination enhances the effects, which may explain the protracted delirium our patient is suffering from. However, it has been reported that all the involved drugs can cause paradoxical agitation in older patients. (10-12)

In addition, there is no advantage in combining hypnotic agents and the practice is not recommended, especially in geriatric population as there is increased fall risk. These agents, with their CNS suppressant effects, can increase the risk of fall possibly due to their delirium inducing effects, which reduce patients’ safety awareness, and their negative impact on patients’ psychomotor versatility. Chronic use can also result in addiction and withdrawal can lead to rebound insomnia. (11) Non-pharmacological therapy such as promoting sleep hygiene and cognitive behavioural therapy, has also been advocated as first line therapy for elderly suffering from insomnia. (13)

Conclusion

The use of sedating antihistamine for managing insomnia is not an uncommon practice among the general public. However, few patients are aware of the anticholinergic side effects which may potentially cause harm among the elderly. In this particular case, she required prolonged hospitalisation which further caused hospital associated complication due to delirium, which resulted in poor nutrition, weight loss, restraint use and eventually required rehabilitation to restore her back to her premorbid function. This further underlies the fact that no matter how well tolerated a drug is among the general population, using a drug always comes with a risk.

The use of sedating antihistamine for managing insomnia is not an uncommon practice among the general public. However, few patients are aware of the anticholinergic side effects which may potentially cause harm among the elderly.

Hence, pharmacotherapy should only be employed if non-pharmacological treatment is not available or inadequate. Older adults are often prescribed drugs for minor symptoms that may be better treated with nonpharmacological methods or by reviewing the current medication list to exclude usual drugs causing adverse effects.

References

1. Qato DM et al. Use of prescription and over-the-counter medications and dietary supplements among the older adults in the United States. The Journal of American Medical Association. 2008;300:2867-2878.

2. Jin Xiang-qiu and Min Lian-qiu. Analysis on 85 Case Reports of Adverse Drug Reactions, Afr J Tradit Complement Altern Med. 2013; 10(3): 508–512.

3. Fu A.Z et al. Potentially inappropriate medication use and healthcvare expenditures in US community-dwelling elderly. Medical Care. 2007;45:472-476.

4. J. Mark Ruscin and Sunny A. Linnabur, Drug-Related Problems in Older Adults, Merck Manual for Professionals

5. Oscanoa TJ, Lizaraso F, Carvajal A. Hospital admissions due to adverse drug reactions in the elderly. A meta-analysis., Eur J Clin Pharmacol. 2017 Jun;73(6):759-770

6. Parameswaran Nair N, Chalmers L, Bereznicki BJ, Curtain CM, Bereznicki LR. Repeat Adverse Drug Reaction-Related Hospital Admissions in Elderly Australians: A Retrospective Study at the Royal Hobart Hospital., Drugs Aging. 2017 Oct;34(10):777-783

7. Wongrakpanich S, Wongrakpanich A, Melhado K, Rangaswami J.A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly. Aging Dis. 2018 Feb 1;9(1):143-150.

8. Simons KJ1, Watson WT, Chen XY, Simons FE., Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly., Clin Pharmacol Ther. 1989 Jan;45(1):9-14.

9. Beers Criteria [AGS 2019]

10. Schieveld, J. N., Strik, J. J., & Bruining, H. (2018). On Benzodiazepines, Paradoxical Agitation, Hyperactive Delirium, and Chloride Homeostasis. Critical care medicine, 46(9), 1558-1559.

11. Simons, F. E. R. (2004). Advances in H1-antihistamines. New England Journal of Medicine, 351(21), 2203-2217.

12. Rattehali R. D., Deshpande S., Jayaram M. Paradoxical agitation and sexual disinhibition following zopiclone. Prog Neurol Psychiatry—Case Notes. 2009;1(1):1–4.

13. Charles M. Morin, PhD,1 Peter J. Hauri, PhD,2 Colin A.Espie, PhD,3 Arthur J. Spielman, PhD,4 Daniel J. Buysse, MD,5 and Richard R. Bootzin, PhD6, Nonpharmacologic treatment of Chronic Insomia, An American Academy of Sleep Medicine Review.

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