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Review ArticleOpen Access

Knowledge and Perception of Triple Whammy Among Pharmacists in the Kingdom of Saudi Arabia Volume 46- Issue 1

Fahad Abdullah Alharbi1* and Mohammed Salah2

  • 1Deanship of Postgraduate Studies, Riyadh Elm University, Saudi Arabia
  • 2Pharmacy Department, Riyadh Elm University, Saudi Arabia

Received: August 29, 2022;   Published: September 09, 2022

*Corresponding author: Fahad Abdullah Alharbi, Deanship of Postgraduate Studies, Riyadh Elm University, Riyadh, Saudi Arabia

DOI: 10.26717/BJSTR.2022.46.007297

Abstract PDF

ABSTRACT

Introduction: Renin-angiotensin system inhibitors (ACEI/ARB-II), diuretics, and NSAIDs, a combination known as “Triple Whammy”, can result in decreased glomerular filtration rate (GFR) and acute kidney injury (AKI).

Objectives: To measure the Knowledge and awareness of Saudi pharmacists about the risk of triple whammy.

Methods: Cross-sectional survey study was conducted from September 2020 to October 2020 in the Kingdom of Saudi Arabia, in different regions and it included hospitals and community Saudi pharmacists.

Results: Males more common to participate in this study, the percentage was 65% and females about 35%. Non-Saudi pharmacists are participating in this study about 4.3% but the Saudi participating about 95.7 %. Most of the pharmacists are working in the field of pharmacy in KSA had a bachelor’s degree in the pharmacy 65.3 % master’s degree 15.3 % and PhD. only 1.7%, most our participating not know about Triple Whammy in about 62.7% and who know about this is 37%.

Conclusion: Treatment with ACEI, ARB-II, diuretics, and/or NSAIDs shows a high incidence of hospitalization episodes due to AKI (Rosa Maria Garcia Camin et al ,2015, Spain), the percentage of pharmacists do not know anything about Triple Whammy in KSA is large 62.7% there is highly needed to make continuous medical education to increase the knowledge of pharmacists about the problem of the combination of these drugs.

Abbreviations:: GFR: Glomerular Filtration Rate; ACEIs: Angiotensin-Converting Enzyme Inhibitors; ARBs: Angiotensin Receptor Blockers; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; ADR: Adverse Drug Reactions; RAAS: Renin– Angiotensin–Aldosterone System; CKD: Chronic Kidney Disease; AKI: Acute Kidney Injury

Introduction and Literature Review

NSAIDs are associated with an increased risk of AKI, due to blockade of the COX-2 enzyme preventing prostacyclin synthesis, which causes afferent arteriolar vasoconstriction [1]. Inhibition is maximal when steady state plasma concentrations are reached, usually after three to seven days of treatment. The risk of AKI is highest in the first month of NSAID ACE inhibitors or ARBs generally preserve renal function. However, these medicines can also treatment. Pre-renal acute kidney injury (AKI) results from glomerular hemodynamic alterations leading to reduced glomerular filtration rate (GFR) with no parenchymal compromise. Reninangiotensin system inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), non-steroidal anti-inflammatory drugs (NSAIDs) and diuretics, are highly prescribed drugs that are frequently administered together. Double and triple associations have been correlated with increased pre-renal AKI incidence, termed “double whammy” and “triple whammy”, respectively (Prieto-García L, et al. [1]).

In the early 2000s, pharmacovigilance reports coined the “triple whammy” expression to illustrate the risk of renal injury associated with combinations of three of the following drugs, NSAIDs, ACEIs or ARBs and diuretics. More recently, Lapi, et al. [2]. confirmed this risk of “triple whammy” in the general population, using the UK Clinical Research Practice Datalink. In their cohort of 487,372 antihypertensive-treated patients, followed-up during 5.9 ± 3.4 years, triple therapy was associated with a 31% increased AKI, compared to patients treated with diuretic and ACEI or ARB only Increased AKI risk was maximal in the first 30 days of the associations. In addition, the use of long half-lives NSAIDs (more than 12 hours) tended to be associated with a higher increased risk of AKI, although there was no significant interaction between NSAIDs half-lives and the triple association. In 2012, published an observational study investigating drug interactions between NSAIDs and antihypertensive drugs in the French Pharmacovigilance Database found that around 25% of associations between NSAIDs and antihypertensive were associated with a “serious” Adverse Drug Reactions (ADR). Most of them were AKIs (92.8%). Thus, performed a secondary analysis of this study, using a case/non-case approach, aiming to investigate whether the number of drugs associated between NSAIDs, ACEIs, ARBs and diuretics was associated to disproportionate reporting of AKI [3]. Concurrent use of NSAIDs, renin–angiotensin–aldosterone system (RAAS) blockers, and diuretics is strongly related to the occurrence of AKI; this combination of drugs is called the “triple-whammy”. AKI induced by the triple-whammy is caused by a combination of pharmacological activities:

(1) NSAIDs lead to renal afferent arteriolar constriction;

(2) RAAS blockers cause hemodynamic reduction in the glomerular-filtration rate due to efferent arteriolar dilation, and

(3) diuretics lead to hypovolemia [1,3].

Thus, Japanese guidelines recommend that particular attention be paid to prescription of triple-whammy to patients with chronic kidney disease (CKD) because these combinations are likely to induce disease progression. In clinical-pharmacy-practice experience, triple-whammy prescriptions often occur when the three drug types are prescribed by different clinical departments. For example, NSAIDs may be prescribed by an orthopaedic surgery department, whereas RAAS blockers and diuretics may be prescribed by an internal medicine department. However, no reports have assessed the extent to which this occurs [4].

Literature Review

Taking two or more of the identified drugs was associated with significant renal impairment but did not correlate with heart failure or other diseases for which the drugs might have been prescribed. Care is necessary to balance the demonstrated advantages of these medications against the risk of inducing renal failure (Katarzyna K, et al. [5]). Triple whammy induces an overt AKI and NSAID including double whammies cause a subclinical AK Shows AKI associated with NSAID users of any combination of RASI and/or diuretics. The intervention improved the prescription and reduced the number of patients on TW combination. Treatment with ACEI, ARB-II, diuretics and/or NSAIDs shows a high incidence of hospitalization episodes due to AKI (Rosa Maria Garcia Camin, et al. [6]). The results indicate a degree of acute kidney injury prior (AKI) at-risk prescribing. There are opportunities to empower people to self-manage at-risk medicines during periods of acute illness (Dianne Vicary, et al. [7]).

Diuretics in monotherapy, dual and triple combination therapy (Triple Whammy) have an elevated incidence of AKI. Dual therapies including diuretics show the same incidence of AKI as the Triple Whammy. The profile of the at-risk patient is an elderly patient with an underlying renal or cardiac disease. The problem does not seem to be the drug itself but the onset of a concurrent diseasecausing hypovolemia. Monitoring renal function and potassium levels is recommended when these therapies are initiated and in situations of concurrent disease (Garcia Camin, et al. [8]). Taking two or more of the identified drugs was associated with significant renal impairment but did not correlate with heart failure or other diseases for which the drugs might have been prescribed. Care is necessary to balance the demonstrated advantages of these medications against the risk of inducing renal failure.

Rational

ARBs or ACEIs, NSAIDs and diuretics, are highly prescribed together, therefore prescribers should remember that using these medicines can increase the risk of AKI.

Aims

• To measure knowledge and awareness of pharmacists in Saudi Arabia about the risk of triple whammy.

• To regular medicine reviews to avoid inadvertent concurrent prescribing of an ACEIs /ARBs, diuretics and NSAIDs.

• To drug interaction checkers built into patient management system.

• To avoid oral NSAIDs when managing long-term pain conditions in patients taking ACEIs or ARBs and diuretics, mainly hypertension patients.

• Patients taking an ACEI or ARB and a diuretic should be warned of the risks of using NSAIDs and should be advised to avoid purchasing OTC NSAIDs.

Methodology

Design and Setting

cross-sectional survey study conducted from September 2020 to October 2020 in the Kingdom of Saudi Arabia, in different regions and it include hospital and community pharmacists and pharmacy technicians.

Data Collection

The data collected via online survey which be sent to targeted population via email or other online approaches.

Sample Size and Statistical Analysis

The sample size is estimated to be 300 Pharmacist and pharmacy technician in Saudi Arabia.

Results

According to the age of our participating it was fount high percentage of them between 30- 39 years old 61.7% but the age between 50 – 60 years old about 1% this reflecting that the middle age group between 30 – 39 years old are the most pharmacists working in KSA. (Tables 1 & 2). According to the gender, it was found that males more common to participate in this study near double fold, the percentage was 65% comparing to females about 35%. Non-Saudi pharmacists are participating in this study are too small comparing to Saudi pharmacists about 4.3% but the Saudi participating about 95.7 %. (Tables 3 & 4 and Figures 1-5). Most of the pharmacists are working in the field of pharmacy in KSA with had bachelor’s degree in the pharmacy 65.3 % master’s degrees 15.3 % and Ph.D. only 1.7% of this is reflecting there are needs to encourage the young pharmacists to get a higher education degree. Near half of our participating had pharmacists in the current position about 49.7 % and the clinical pharmacists still low in percentage about 12 %. Most of our participating are working in the field of the pharmacy from 1 year to 10 years about 59.7. (Figures 6-9). Many of our participating are working in Public Hospital Pharmacy about 70.7 % and Primary Healthcare Centre about 16.7 % the private hospital only 3.3 % (Tables 5-6). this is reflecting that most of Saudi pharmacists like to work MOH hospitals rather than private hospitals. Most of our participating from Najran and Jeddah and Riyadh and there is many participating all over KSA areas.

Figure 1: Bar chart showing timestamp.

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Figure 2: Bar chart showing gender.

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Figure 3: Bar chart showing qualification.

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Figure 4: Bar chart showing qualification.

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Figure 5: Bar chart showing experience.

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Figure 6: Bar chart showing place of work.

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Figure 7: Bar chart showing knowledge about triple whammy.

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Figure 8: Bar chart showing source of triple whammy information.

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Table 1: Demographics information.

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Table 2: Nationality.

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Table 3: Organization of work.

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Table 4: Triple whammy prescription.

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Table 5: Number of triple whammy prescription.

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Table 6: Action for triple whammy.

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Conclusion

Treatment with ACEI, ARB-II, diuretics and/or NSAIDs shows a high incidence of hospitalization episodes due to AKI (Rosa Maria Garcia Camin, et al. [ 6]), males more common to participate in this study, the percentage was 65% and females about 35%. Non- Saudi pharmacists are participating in this study about 4.3% but the Saudi participating about 95.7 %. Most of the pharmacists are working in the field of pharmacy in KSA had a bachelor’s degree in the pharmacy 65.3 % master’s degree 15.3 % and Ph.D. only 1.7%, most our participating don`t know about Triple Whammy in about 62.7% and who know about this is 37%. Internet and medical journal still had the best option to KSA to get the clinical information for any drugs and diseases the percentage of about 34.3 % comparing to friends the percentage 23.3% but the university about 14.3% this is indicating the need to increase the clinical education in regarding to triple whammy. the percentage of pharmacists do not know anything about Triple Whammy in KSA is large 37% there is highly needed to make continuous medical education to increase the knowledge of pharmacists about the problem of combination of these drugs, some solution Was given by the pharmacists need to be more investigated.

Acknowledgement

First and foremost, I thank ALLAH, who has blessed me with uncountable blessings, guided me throughout my life and continues making the impossible always possible. I would like to express my heartfelt thanks, appreciation, and unlimited gratitude to my family for providing the excellent encouraging family environment which enabled me to achieve more and for their great help, support, and advices throughout the years. It is my honor and great pleasure to thank my great role model and mentor the Chairman, Board of Trustees Prof. Abdullah Al-Shammery for his valuable advices, guidance, and continuous support. I am very grateful to my mentor the president of Riyadh Elm University Dr. Saleh Al-Shamrani for his unlimited help, great support, and guidance. Thanks a million, to the great Vice president of Riyadh Elm University Dr. Mansour Assery for his unforgettable advices, great efforts, ultimate guidance and giving me the chance to join the MSc Pharmacy program. I am also grateful to Dr. Hana Al-Khabbas, Dean of College of Pharmacy for her valuable advice and guidance.

This thesis would not have been possible without the help, great support, and patience of my supervisor Dr. Mohamed Salah Ali all his efforts and time are highly appreciated to have my thesis produced in a good shape.

I would like to express my special thanks and appreciation to my mentor and Program Director Dr. Tahani Alrahbeni for her great support and encouragement throughout the past three years. Last, but not least, I extend my thanks to my colleagues the residents of the different levels in the Master degree programs in Riyadh Elm University for their great help, support and encouragement throughout the last three years. It is my honor and great pleasure to thank my second home Riyadh Elm University for providing me with the opportunity to study the specialty of my dreams and for enhancing the academic environment with all facilities to excel and succeed. Heartfelt thanks and appreciation for all the efforts and guidance of the faculty members who taught us the professional knowledge and skills I will never forget all the great support. Thanks, and gratitude goes to all the administrative staff and all the great people of the auxiliary services working day and night at the university for their continuous efforts to facilitate our needs and making the academic environment as comfortable as ever possible.

References

  1. Prieto-García L, Pericacho M, Sancho-Martínez SM, Sánchez A, Sánchez CM, et al. (2016) Mechanisms of triple whammy acute kidney injury. Pharmacol There 167: 132-145.
  2. Lapi Francesco, Azoulay Laurent, Yin Hui, Nessim Sharon J, Suissa Samy (2013) Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control Study. BMJ 346: e8525.
  3. Pyry Jämsä, Esa Jämsen, Leo-Pekka Lyytikäinen, Jarkko Kalliovalkama, Antti Eskelinen, et al. (2017) Risk factors associated with acute kidney injury in a cohort of 20,575 arthroplasty patients. Acta Orthopaedica 88: 370-376.
  4. Shun go Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, et al. (2020) A cross-sectional exploratory survey on occurrence of triple-whammy prescription pattern in Japan. International Journal of Clinical Pharmacy 42(5): 1369-1373.
  5. Loboz Katarzyna K, Gillian M Shenfield (2005) Drug combinations and impaired renal function -- the 'triple whammy'. British journal of clinical pharmacology 59(2): 239-243.
  6. Rosa Maria Garcia Camin, Montse Cols, Julio Leonel Chevarria, Rosa García Osuna, Marc Carreras, et al. (2015) Renal agudo secundario a combinación de inhibidores del sistema renina-angiotensina, diuréticos y AINES. “La Triple Whammy”1 Nefrología 35: 197-206.
  7. Vicary D, Hutchison C, Aspden T (2020) Preventing acute kidney injury: assessing awareness to temporarily discontinue 'at-risk' medicines during acute illness in a New Zealand cohort. N Z Med J 133(1519): 12-23.
  8. Garcia Camin RM, Cols M, Chevarria JL, García Osuna R, Carreras M, et al. (2015) Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors, diuretics and NSAIDS: “The Triple Whammy.” Nefrología (English Edition) 35(2): 197–206.