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CALCIUM CHANNEL BLOCKERS INDUCED PERIPHERAL EDEMA

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Kamala Sangam
Kamala Sangam
Kamala Sangam
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Pragathi Devireddy
Pragathi Devireddy
Pragathi Devireddy
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Venkateswarlu Konuru at CMR College of Pharmacy, Hyderabad , India
Venkateswarlu Konuru
  • CMR College of Pharmacy, Hyderabad , India
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Abstract

Purpose: To evaluate the onset of Calcium channel blockers (CCBs) induced Peripheral edema (PE) by taking time gap (date of initiation of drug to date of withdrawal of the drug due to ADR) into consideration. Method: A Prospective and retrospective pilot study was conducted in tertiary care centers and patients on CCBs therapy who has experienced peripheral edema were enrolled. The information collected includes: Drug, Time gap, Drug management, ADR management, WHO's probability scale and severity of ADR. The information obtained was analyzed by calculating Mean, standard deviation and P value using Fishers exact test. Results: Total 700 ADR's were reported in them 46 (6.57%) were CCB's induced PE, among them 27 (58.70%) amlodipine and 19 (41.30%) nifedipine induced PE. The study shows patients with age (years) (64±11) amlodipine, (56±13) nifedipine and P=0.7330, within them males were 26 (56.52%).Based on time gap there is a significant difference between Amlodipine (27.29±15.98) and Nifedipine (52.15±28.69) and P=0.0005. Drug management in patients experiencing ADR due to amlodipine (n=20) drug withdrawn and Nifedipine (n=12) drug withdrawn. ADR management of patients taking amlodipine (n=11) specific, (n=10) symptomatic and Nifedipine (n=15) nil. WHO's probability scale in patients taking amlodipine possible (n=7) and nifedipine (n=19) probable. ADR severity due to amliodipine moderate (level3=10,level4=5) and nifedipine mild (level2=17). Conclusion: The incidence of PE due to CCBs is high, there is a significant difference in the time gap between amlodipine and nifedipine. Before initiating the therapy patient should be counselled regarding the risk of PE and immediate physician consultation.
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CALCIUM CHANNEL BLOCKERS
INDUCED PERIPHERAL EDEMA
Kamala Sangam, Pragathi Devireddy, Venkateswarlu Konuru*
Department of Clinical Pharmacy and PharrmD, St. Peter’s Institute of Pharmaceutical sciences,
Kakatiya University, Warangal, Rohini Super Specialty Hospital, Telangana, India
E-mail: venkipharmd@gmail.com
ABSTRACT
Purpose: To evaluate the onset of Calcium channel blockers (CCBs) induced Peripheral edema (PE) by taking
time gap (date of initiation of drug to date of withdrawal of the drug due to ADR) into consideration. Method:
A Prospective and retrospective pilot study was conducted in tertiary care centers and patients on CCBs therapy
who has experienced peripheral edema were enrolled. The information collected includes: Drug, Time gap,
Drug management, ADR management, WHO’s probability scale and severity of ADR. The information
obtained was analyzed by calculating Mean, standard deviation and P value using Fishers exact test. Results:
Total 700 ADR’s were reported in them 46 (6.57%) were CCB’s induced PE, among them 27 (58.70%)
amlodipine and 19 (41.30%) nifedipine induced PE. The study shows patients with age (years) (64±11)
amlodipine, (56±13) nifedipine and P=0.7330, within them males were 26 (56.52%).Based on time gap there is
a significant difference between Amlodipine (27.29±15.98) and Nifedipine (52.15±28.69) and P=0.0005. Drug
management in patients experiencing ADR due to amlodipine (n=20) drug withdrawn and Nifedipine (n=12)
drug withdrawn. ADR management of patients taking amlodipine (n=11) specific, (n=10) symptomatic and
Nifedipine (n=15) nil. WHO’s probability scale in patients taking amlodipine possible (n=7) and nifedipine
(n=19) probable. ADR severity due to amliodipine moderate (level3=10,level4=5) and nifedipine mild
(level2=17). Conclusion: The incidence of PE due to CCBs is high, there is a significant difference in the time
gap between amlodipine and nifedipine. Before initiating the therapy patient should be counselled regarding the
risk of PE and immediate physician consultation.
Key words: Calcium channel blockers, Adverse drug reaction, Peripheral edema.
INTRODUCTION
Calcium channel prevent calcium from entering cells of the heart and blood vessel walls, resulting in lower
blood pressure. CCB’S are also frequently used to alter heart rate, to prevent cerebral vasospasm, to manage
migraine, in Raynaud's disease and to reduce chest pain caused by angina pectoris. Various CCB’S include
Diltiazem, Felodipine, Amlodipine, Isradipine, Nifedipine, Nicardipine, Verapamil. Common ADR’S of
calcium channel blockers include:headache, constipation, rash, nausea, Hot flushes, edema (fluid accumulation
in tissues), drowsiness, low blood pressure and dizziness. [1]
The combination of a CCB and an angiotensin receptor blocker (ARB) are the best option in hypertension
management.[2][3] is effective in reducing BP in hypertensive patients.[4] When used as monotherapy, CCBs are
associated with a substantial risk of peripheral edema,[5] including ankle edema, is a recognised adverse effect of
the calcium channel blocking agents which may reduce usefulness, particularly in an aging population who have
co-morbidities. If Ankle edema is mild or severe it can affect quality of life of patients. Ankle edema is
developed mostly in women, elderly patients, those with heart failure, upright position, and those in humid
environments ankle edema is a class effect in all CCBs, there are differences in the incidence of ankle edema
between the different classes of CCB’S, with edema more likely with the dihydropyridine agents. The incidence
of ankle edema has been reported as ranging from 1-15% in patients treated with DHP agents. Within the DHP
group, those that are “membranophilic”, may have lower incidence of ankle edema. Ankle edema is mostly
dose related, and its incidence may exceed 80% in patients taking long term high doses of DHP agents.
CCB-induced edema is caused primarily by the increased capillary hydrostatic pressure that results from greater
vasodilation of pre-capillary than post-capillary vessels. This effect may be mediated, in part, by greater
sensitivity of resistance vessels may lead to CCB-induced reductions in myogenic vascular reactivity, may be
augmented by CCB-induced decrease in postural vasoconstriction. Because the edema is related to the
mechanism of action of dihydropyridine CCBs, it represents a class effect. Thus, although differences among
CCBs in edema incidence rates have been reported in a number of studies, it is evident that dose-dependent
peripheral edema remains a common side effect in patients receiving both established and newer CCBs.[6] CCBs
are used as antihypertensive drugs, Common ADR of them is Peripheral edema (Up to 10.8%), with amlodipine
Incidence is Up to 10.8% [7] and with nifedipine Incidence is 7% to 29%.
Kamala Sangam et al. / International Journal of Pharma Sciences and Research (IJPSR)
ISSN : 0975-9492
Vol. 7 No. 6 Jun 2016
290
MATERIALS AND METHODS
A Prospective and retrospective pilot study was conducted in tertiary care centers. The ADR’s in our study
were collected from the ADR’s which are documented in the department of pharmacy practice. The patients on
CCBs therapy and reporting peripheral edema were enrolled in our study. The information collected includes:
Drug, Time gap, Drug management, ADR management, WHO’s probability scale and severity of ADR. The
information obtained was analyzed by calculating Mean, standard deviation, P value using Fishers exact test.
RESULTS AND DISCUSSION
Total 700 ADR’s were documented in the department of pharmacy practice. Out of them 46 (6.57%) patients
were CCB’s induced PE, among them 27 (58.70%) amlodipine induced and 19 (41.30%) were nifedipine
induced PE. The patients were distributed according to their sex in both amlodipine and nifedipine and their
average age was calculated in both the groups.The details were shown in fig.1.
Figure-1: Based on age & gender distribution of ADRs
The above figure explains that there is no age difference between patients with PE taking amlodipine
(53.66±10.88), nifedipine (55.57±13.15)where P=0.7330 which is similar to Makani H[8] study where One
hundred and six studies with 99 469 participants, mean age of (56±6) years, has satisfied our inclusion criteria
and were included in their analysis.. Among 46 patients with PE, females were 20 (43.48%), males 26 (56.52%)
and P=0.7657 which is similar with Harikrishna Makani[9] study where 55% were men.There is no difference
between male and female. Estimation of time gap, i.e., the period between drug intake and onset of ADR. The
time gap is calculated in both the groups and details were shown in table.1.
Table-1: Distribution of data based on time gap
DRUG TIME GAP (DAYS) P value
Amlodipine 27.29 ±15.98
0.0005
Nifedipine 52.15± 28.69
The above table explains that there is a significant difference of time gap between amlodipine and nifedipine.
Amlodipine (27.29±15.98) and Nifedipine (52.15±28.69) and P=0.0005. WHO’s probability scale and ADR
severity wise distribution of patients of both the groups is seen in table.2.
Age:53.66±10.88 Age:55.57±13.15
AMLODIPINE NIFEDIPINE
Males 16 10
Females 11 9
0
5
10
15
20
25
30
Incidence of ADRs
AGE AND GENDER WISE DISTRIBUTION OF ADRS
Kamala Sangam et al. / International Journal of Pharma Sciences and Research (IJPSR)
ISSN : 0975-9492
Vol. 7 No. 6 Jun 2016
291
Table-2: Assessment of Peripheral edema by using WHOs &ADR scales
WHO’s probability scale in patients taking amlodipine probable(n=20), possible(n=7) and for nifedipine (n=19)
probable. ADR severity due to amliodipine mild (level1=2, level2=10), moderate (level3=10, level4=5) and due
to nifedipine mild (level 2=17) and moderate (level 3=2). Estimation of treatment strategies of suspected drug
and its ADR management, is shown in table.3.
Table-3: Management strategies for peripheral edema
Drug management of suspected drug in patients experiencing an ADR due to amlodipine (n=20) drug
withdrawn, (n=3) dose altered, (n=4) no change and in Nifedipine (n=12) drug withdrawn, (n=6) dose altered,
(n=1) no change which similar to Makani H [8] study where Both the incidence of edema and patient withdrawal
rate due to edema increases with the duration of therapy with CCBs reaching 24% and 5%, respectively, after 6
months. ADR management of patients taking amlodipine, (n=11) specific, (n=10) symptomatic, (n=06) nil and
Nifedipine (n=2)specific,(n=2)symptomatic,(n=15)nil, which is similar with two studies they were A de la
Sierra[10] study and Domenic A. Sica[11] study where dose reduction, interclass shifting of medication, ACE
Inhibitors or an ARB were added to reduce the incidence of edema and to improved efficacy of CCB
monotherapy. CONCLUSION
The incidence of PE due to CCBs is high; there is a difference of time gap between amlodipine and nifedipine.
Patients taking Amlodipine experience ADR approximately after one month and Nifedipine approximately after
two months. Among both the drugs nifedipine takes longer time to develop an ADR than compared to
amlodipine. Many of the patients were newly taking the drugs. Before initiating the therapy patient should be
counseled regarding the risk of PE and the time taken to experience ADR and if the patient experience ADR
immediate medical consultation is required. Management strategies to follow after ADR appears were Dose
adjustments, interclass shifting of medication, ACE inhibitors or ARB therapy, Diuretics, Nitrates and lifestyle
modifications include Na restricted diet and Elevation of the legs.
WHO’S Probability Scale AMLODIPINE (%) NIFEDIPINE(%)
Probable 20( 43.48) 19( 41.30)
Possible 7( 15.22) 0( 0.00)
ADR SEVERITY
LEVEL 1 2(4.35) 0(0.00)
LEVEL 2 10(21.74) 17(36.96)
LEVEL 3 10(21.74) 2(4.35)
LEVEL 4 5(10.87) 0(0.00)
FATE OF THE DRUG AMLODIPINE (%) NIFEDIPINE (%)
Drug Withdrawn 20( 43.48) 12( 26.09)
Dose Altered 3( 6.52) 6( 13.04)
No change 4( 8.70) 1( 2.17)
ADR MANAGEMENT
Specific 11(23.91) 2(4.35)
Symptomatic 10(21.74) 2(4.35)
Nil 6(13.04) 15(32.61)
Kamala Sangam et al. / International Journal of Pharma Sciences and Research (IJPSR)
ISSN : 0975-9492
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REFERENCES
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[2] Mancia G, De Backer G, Dominiczak A, Cifkova R,Fagard R, Germano G et al. 2007 Guidelines for the management of arterial
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[3] National Collaborating Centre for Chronic Conditions. Hypertension: Management in Adults in Primary Care: Pharmacological
Update 2006. Royal College of Physicians: London. ISBN-10: 1-86016-285-1
[4] Allemann Y, Fraile B, Lambert M, Barbier M, Ferber P,Izzo Jr JL. Efficacy of the combination of amlodipine and Valsartan in patients
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[5] Malacco E, Vari N, Capuano V, Spagnuolo V, Borgnino C, Palatini P. A randomized, double-blind, active controlled, parallel-group
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systolic hypertension in elderly patients: the Val-Syst study. Clin Ther 2003; 25 (11): 2765–2780.
[6] Messerli FH. Vasodilatory edema: a common side effect of antihypertensive therapy. Am J Hypertens 2001; 14 (9 Pt 1): 978–979.
[7] Micromedex. Version 2.0. Michigan: Thomson Reuters; 2012.
[8] Harikrishna Makani, Sripal Bangalore, Jorge Romero, Omar Wever-Pinzon, Franz H. Messerli et al. Effect of Renin-Angiotensin
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[9] Makani H , Bangalore S, Romero J, Htyte N, Berrios RS, Makwana H et al . Peripheral edema associated with calcium channel
blockers incidence and withdrawal rate a metaanalysis of randomized trials. Journal Hypertension. 2011 Jul;29 (7) : 1270-1280.
[10] A de la Sierra. Mitigation of calcium channel blocker related oedema in hypertension by antagonists of the renin–angiotensin system.
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[11] Domenic A. Sica, Calcium Channel Blocker-Related Peripheral Edema: Can It Be Resolved? The Journal Of Clinical Hypertension.
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... Peripheral edema is reported to occur mainly in the lower extremities within weeks of initiation of treatment and rises with increasing doses and duration of therapy. It is relatively more common among women, elderly, chronic kidney disease and patients with congestive heart failure [Sangam et al., 2016, Yale et al., 2001. The mechanism of edema formation is believed to be largely due to arteriolar and precapillary dilatation without commensurate dilation in the venous or post capillary circulation [Malacco et al., 2003]. ...
... Among the most frequently prescribed CCBs are Amlodipine and Nifedipine [Elliot et al., 2018, Shetty et al., 2017 which are known to be very effective in sustaining reduction in blood pressure [Dalal et al., 2015, Yavdav et al., 2015. The effect of BDF and Lisinopril on incidence and severity of ankle edema showed that the latter caused a nonsignificant reduction in incidence and severity of edema which is consistent with earlier studies [Fogari et al., 2003, Oparil et al., 2010, Chrysant et al., 2008, Sangam et al., 2016. The former [BDF] had no significant effect on drug induced edema which is comparable to monotherapies [Weir 2001]. ...
Prevalence of Calcium Channel Blocker Induced Ankle Edema and its Treatment in a Cohort of Newly Diagnosed Hypertensive Patients
Article
Full-text available
  • May 2022
Background: Calcium channel blockers are widely prescribed either as monotherapies or in combination therapies in the management of hypertension and other cardiovascular disorders. One of the major challenges with this class of drugs is their association with difficult to treat peripheral edema. There is limited literature evidence on the incidence and severity of CCB induced edema and the efficacy of management practices in developing countries. This study therefore aims to assess incidence and the common treatments. Methods: A total of 193 eligible subjects were enrolled into an eight week study and allocated into three treatment groups for each drug [Amlodipine 10mg or Nifedipine 20mg]. One group received no intervention, while the other two groups received either Bendrofluthiazide 5mg [BDF] or Lisinopril 5mg depending on blood pressure or other patient factors. Edema was monitored every two weeks throughout the study using standard tools. The data were analyzed using students t test, one way ANOVA and descriptive statistics as appropriate. P values ≤ 0.05 was considered statistically significant. Results/Discussion: The overall incidence of edema was about 29% at the end of the study period. Lisinopril addition to therapy resulted in significant reduction in incidence and severity of edema as opposed to other interventions. This suggests that ACEIs have a positive role in minimizing incidence of peripheral edema. Conclusion: Peripheral edema remains a complication factor in CCB therapy and ACEIs may be considered in management of edema induced by this class of drugs.
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... Peripheral edema development with CCB use increases with duration of treatment is dependent on the type of CCB used. The incidence of peripheral edema after 90 days of treatment is approximately 10% and increases to 24% as duration of treatment reaches 180 days (32,33). The estimated incidence of lymphedema also increases over time, with the vast majority of diagnoses occurring within 180 days of breast cancer treatment (7). ...
... Furthermore, CCBs can be divided into two classes, dihydropyridines and nondihydropyridines, with dihydropyridines being associated with higher incidences of peripheral edema compared with nondihydropyridines (32,33). However, our subgroup analysis revealed no significant difference between CCB subgroups and lymphedema development, suggesting the increased risk of lymphedema development may be a class-wide association. ...
Calcium Channel Blockers and Risk of Lymphedema among Breast Cancer Patients: Nested Case-Control Study
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  • Aug 2019
Background: To assess the risk of lymphedema associated with the use of calcium channel blockers (CCB) among breast cancer patients. Methods: A nested case-control study of adult female breast cancer patients receiving an antihypertensive agent was conducted using administrative claims data between 2007 and 2015. Cases were patients with lymphedema who were matched to 5 controls based on nest entry date (±180 days), age (±5 years), number of hypertensive drug classes, Charlson Comorbidity Index (CCI), thiazide exposure, and insurance type. Exposure to CCBs and covariates was identified in the 180-day period prior to event date. Conditional logistic regression was used to assess the impact of exposure among cases and controls. Results: A total of 717 cases and 1,681 matched controls were identified. After matching on baseline characteristics, mastectomy (7.8% vs. 4.8%; P = 0.0039), exposure to radiotherapy (27.1% vs. 21.7%; P = 0.0046), taxane-based chemotherapy (11.7% vs. 7.4%; P = 0.0007), anthracycline-based chemotherapy (6.0% vs. 3.6%; P = 0.0073), CCB use (28.3% vs. 23.3%; P = 0.0087), and CCI (19.8% vs. 12.7%; P < 0.0001; score of 4 or above) were all higher in cases during the 180 days prior to the event date. In the adjusted analysis, CCB exposure was significantly associated with increased risk of lymphedema (OR = 1.320; 95% confidence interval, 1.003-1.737). Conclusions: CCB use was significantly associated with the development of lymphedema in breast cancer patients. Impact: CCBs should be avoided or used with caution in breast cancer patients to reduce the risk for developing lymphedema.
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... Some studies done previously suggest combination therapy with ACEI/ARB and concurrent use of ARB or ACEI to be beneficial in reducing adverse effects including peripheral vascular edema in patients even to the level of half of the dose prescribed (especially with mild hypertension). 5,11,17,18 The underlying mechanism is suggestive to be related to the ability of ACEI/ARB to oppose the circulatory changes by CCBs causing edema. 17 But, in the present study, the concurrent use of ACEI/ARBs, type of amlodipine used (S isomer), age, and gender of the patient did not have association (P > .05) ...
... In contrast, previous studies have shown the association between the incidence of vasodilatory edema among elderly patients. 5 Pedal edema is found to be more common with CCB monotherapy; so it is advisable to use combination therapy with either ARB or ACEI. 1 This not only reduces pedal edema but also the combination therapy is more effective than monotherapy with CCB to maintain optimum blood pressure in hypertensive patients. 19 This study also showed an increased incidence of pedal edema in those who have been using amlodipine for more than 5 years in comparison to those who have been using it for a lesser period of time (P < .001). ...
Amlodipine-Induced Pedal Edema and Its Relation to Other Variables in Patients at a Tertiary Level Hospital of Kathmandu, Nepal
Article
Full-text available
  • Oct 2018
  • J Pharm Tech
Background: Vasodilatory edema is a frequently encountered side effect among hypertensive patients using antihypertensive drugs. This dose-dependent adverse effect is seen more commonly with amlodipine, so low-dose combination therapy is often used and preferred in practice. Pedal edema following use of amlodipine is scarcely studied in Nepalese population so far. Objectives: To find out the prevalence of amlodipine-associated pedal edema and its relation with other variables among patients presenting to a tertiary care center of Kathmandu, Nepal. Methods: A prospective cross-sectional study was conducted among hypertensive patients using amlodipine in combination with or without other antihypertensive medications under regular follow-up in an outpatient department of internal medicine of Shree Birendra Hospital, Kathmandu, Nepal, during the 7-month period from September 2017 to March 2018. The prevalence of pedal edema and its relation with amlodipine dose, duration, and other factors were studied using χ2 test and logistic regression using SPSS version 22. Results: A total of 505 patients were observed during the study period, with the mean age of the population being 61.5 ± 13.4 years. Among the cases studied, edema was present in 79 (15.6%) cases. Use of amlodipine longer than 5 years was 21.65 (confidence interval [CI] = 9.575-48.970, P ˂ .001) times more likely to exhibit pedal edema; similarly, there was 2.149 (CI = 1.209-3.820, P = .009) times higher risk of having pedal edema in hypertensive individuals with other comorbidities. Increasing the dose of amlodipine has increased the likelihood of having pedal edema, but it is not statistically significant (odds ratio = 2.804, CI = 0.423-18.584, P = .285). Conclusion and Relevance: Significant number of hypertensive patients using amlodipine developed pedal edema. Likelihood of vasodilatory edema increases with the presence of comorbidities, higher dose, along with longer duration of amlodipine use.
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... Several studies have suggested that combination therapy with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) can effectively reduce the incidence of peripheral edema associated with CCBs, even at reduced doses, particularly in patients with mild hypertension. 16,22,23 Given that pedal edema is more prevalent with CCB monotherapy, combining these agents with either an ACEI or ARB may not only mitigate edema but also enhance overall blood pressure control. 24,25 Despite similar reductions in blood pressure, the frequency of pedal edema varies among different CCBs, suggesting that the occurrence cannot solely be attributed to differences in their effects on peripheral arteries. ...
Comparative efficacy and safety of Cilnidipine and Amlodipine in the management of hypertension
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  • Apr 2025
Background & objective: Hypertensive patients with coronary artery disease and diabetes mellitus usually benefit from selective antihypertensive medications like calcium channel blockers (CCBs). Of the dihydropyridine (DHP) CCBs, amlodipine has an excellent pharmacokinetic and pharmacodynamic profile. The only drawback of amlodipine is that it causes pedal oedema leading to drug discontinuation in many cases. The new generation CCB, cilnidipine has demonstrated equal efficacy in controlling blood pressure, but its adverse effect as is observed in amlodipine has not been widely tested. The present study was, therefore, designed to make a comparative evaluation of cilnidipine and amlodipine in the management of blood pressure in hypertensive individuals. Patients & Methods: The present non-randomized clinical trial was conducted in the private practices of renowned cardiologists and specialists in internal medicine in Chittagong Metropolitan City over a period of four years, from January 2020 to December 2023. A total of 496 hypertensive patients of both sexes were consecutively enrolled in the study. Among them, 455 patients-246 in the Amlodipine group and 209 in the Clinidipine group completed the two scheduled follow-up visits within six months of the intervention (the study endpoint) and were subsequently included in the final analysis. The study drugs were considered effective if 80% of the subjects in the study experienced control of blood pressure (systolic blood pressure < 140 mmHg and/or diastolic blood pressure < 90 mmHg) after 6 months of intervention with the study drugs. The study drugs were termed safe if they did not cause impairment of renal, neuro, and cardiac functions significantly during the study period. Pedal oedema was assessed by clinical method over the medial malleolus of both legs. Result: The cilnidipine and amlodipine groups were comparable regarding age and sex. However, obesity and diabetes were more prevalent in the amlodipine group, while smokers were more frequent in the cilnidipine group. Mean systolic and diastolic blood pressures were slightly lower in the cilnidipine group. Fasting blood sugar levels were similar, and dyslipidemia was common in both groups. The comparative evaluation of cilnidipine and amlodipine in the management of systemic hypertension revealed significant differences in heir efficacy and safety profiles. Both medications effectively reduced blood pressure, with a greater mean reduction in systolic blood pressure being observed in the amlodipine group compared to the cilnidipine group (19.9% vs. 15.6%, p < 0.001). However, the incidence of adverse effects, particularly pedal edema, was notably higher in the amlodipine group (11% vs. 4.8%, p = 0.016), indicating a preference for cilnidipine among hypertensive patients concerned about tolerability. Despite these differences in side effects and blood pressure control, the overall efficacy in achieving target blood pressure levels (SBP < 140 mmHg and DBP < 90 mmHg) was comparable between the two groups, as evidenced by the high control rates of 87% in the amlodipine group and 88.5% in the cilnidipine group (p = 0.622). Conclusion: The study concluded that both cilnidipine and amlodipine are equally effective in reducing blood pressure in hypertensive individuals. However, cilnidipine is less likely to cause pedal oedema than amlodipine. This advantage of cilnidipine makes it a preferred antihypertensive drug over amlodipine. Ibrahim Card Med J 2024; 14(1): 19-27
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... CCBs reduce the lymphatic tone and phasic contraction, leading to decreased interstitial clearance and, thus, edema formation [89]. Interestingly, individuals with low baseline lymphatic contractility are more likely to develop edema when treated with CCBs [92]. Since kidney disease impairs the contractility of kidney-collecting vessels [43], CKD patients might be particularly susceptible to CCB-induced edema. ...
Moving toward a better understanding of renal lymphatics: challenges and opportunities
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  • PEDIATR NEPHROL
The development of lymphatic-specific markers has enabled detailed visualization of the lymphatic vascular network that has greatly enhanced our ability to explore this often-overlooked system. Lymphatics remove fluid, solutes, macromolecules, and cells from the interstitium and return them to circulation. The kidneys have lymphatics. As in other organs, the kidney lymphatic vessels are highly sensitive to changes in the local microenvironment. The sensitivity to its milieu may be especially relevant in kidneys because they are central in regulating fluid homeostasis and clearance of metabolites delivered into and eliminated from the renal interstitial compartment. Numerous physiologic conditions and diseases modify the renal interstitial volume, pressure, and composition that can, in turn, influence the growth and function of the renal lymphatics. The impact of the renal microenvironment is further heightened by the fact that kidneys are encapsulated. This review considers the development, structure, and function of the renal lymphatic vessels and explores how factors within the kidney interstitial compartment modify their structure and functionality. Moreover, although currently there are no pharmaceutical agents that specifically target the lymphatic network, we highlight several medications currently used in children with kidney disease and hypertension that have significant but underappreciated effects on lymphatics. Graphical abstract
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... 5 However, the incidence of peripheral edema with CCBs varies between studies, ranging from 7% to 33%, and can reach up to 80% in patients on high doses for extended periods. 5,6 A systematic review of 48 case reports involving risperidone, olanzapine, and quetiapine reported edema in 29.4% of cases. 7 In contrast, a larger observational study of 462,662 patients treated with psychotropic drugs found severe edema in only 231 patients (0.05%). ...
Advances in understanding medication-induced lower limb edema: Review for clinical practice
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Drug-induced lower limb edema is a common side effect of many medications, posing diagnostic challenges for clinicians. This review provides a comprehensive analysis of implicated medications, underlying mechanisms (including arteriolar vasodilation, sodium/water retention, increased capillary permeability, and lymphedema), and differential diagnoses. It emphasizes the importance of recognizing drug-induced edema in patients presenting with bilateral leg swelling and the need for careful medication review and potential dose adjustments. The review notes the limited efficacy of diuretics in this context and calls for further research to improve prevention, diagnosis, and treatment strategies. This review offers clinicians essential guidance for optimizing patient outcomes.
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... [19][20][21] However, it is worth noting that CCBs come with common adverse effects, including peripheral edema, particularly in the lower limbs, and headaches. [22][23][24] The incidence of peripheral edema caused by CCBs ranges from 5% to 60%, often leading to treatment discontinuation. 24 In Thailand's National List of Essential Medicines (NLEM), amlodipine besylate is the recommended first-line DHP-CCB medication to be added to RASBs. ...
Cost-effectiveness Analysis of Lercanidipine Compared to Amlodipine as an Addition to Renin-angiotensin System Blockers in Diabetic Hypertensive Patients with Albuminuria in Thailand
Article
Full-text available
  • Aug 2024
Objective: Dihydropyridine calcium channel blocker (DHP-CCBs) is an appropriate add-on antihypertensive option for uncontrolled blood pressure diabetic hypertensive patients with albuminuria who are already taking renin-angiotensin system blockers (RASBs). Among DHP-CCBs, amlodipine is the first-line medication in combination with RASBs. However, new-generation DHP-CCBs like lercanidipine has demonstrated superior effectiveness and fewer side effects, although at a higher cost than amlodipine. This study aims to assess the cost-effectiveness of lercanidipine versus amlodipine when added to RASBs in diabetic hypertensive patients with albuminuria. The objective is to provide robust evidence guiding the selection of the most suitable and worthwhile treatment option in Thailand. Materials and Methods: This study analyses the cost-effectiveness of lercanidipine versus amlodipine as an addition to RASBs in diabetic hypertensive patients with albuminuria. The analysis was conducted from a societal perspective using a Markov model. Results: The total costs of lercanidipine and amlodipine treatments were 370,392.83 baht and 384,221.85 baht, respectively. The life years gained for lercanidipine and amlodipine treatments were 11.33 years and 10.96 years respectively. Additionally, the quality-adjusted life years (QALYs) of lercanidipine and amlodipine treatments were 8.06 years and 7.51 years respectively. Conclusion: Due to lercanidipine's noticeable cost-effectiveness, lower costs, and longer QALYs. Adding lercanidipine has proven to be more cost-effective than amlodipine for diabetic hypertensive patients with albuminuria who have been unable to achieve their blood pressure goals with RASBs alone. Therefore, lercanidipine should be the preferred choice as an add-on to RASBs in Thailand. These results could significantly aid policymakers in making informed decisions.
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... In addition, they are associated with a considerable risk of peripheral edema which often leads to the discontinuation of treatment. [14,15] The National List of Essential Medicines of Thailand (NLED) described the indication of CCBs, including amlodipine, manidipine, and lercanidipine, for the treatment of hypertension. Amlodipine besilate is the firstrecommended DHP-CCB drug while manidipine hydrochloride and lercanidipine hydrochloride, and the new generation DHP-CCBs, are substitutes for patients who cannot tolerate the side effects of amlodipine, especially peripheral edema. ...
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... e tolerability and efficacy of the two CCBs were established over the years. More significant vasodilation of precapillary vessels as compared to postcapillary vessels is considered as the mechanism attributed to the CCB-induced edema [9]. e prevalence of pedal edema due to CCBs reported to be higher in the warm climate of tropical countries such as India and Brazil [10]. ...
A Retrospective, Observational, EMR-Based Real-World Evidence Study to Assess the Incidence of Pedal Edema in Essential Hypertensive Patients on Amlodipine or Cilnidipine
Article
Full-text available
  • Feb 2022
Introduction: Calcium channel blockers have pedal edema as one of the confining factors of treatment. A real-world study may help evident reality of the situation in regular Indian clinical practice. The aim of the study is to assess effectiveness and incidence of pedal edema in essential hypertensive patients treated with amlodipine or cilnidipine monotherapy. Methods: Retrospective EMR data of adult essential hypertensive patients, prescribed amlodipine (n = 800) or cilnidipine (n = 800) as monotherapy, were analyzed. Incidence of pedal edema from baseline visit was analyzed in terms of dose and duration of treatment. The changes in systolic (SBP) and diastolic blood pressure (DBP) from baseline and proportion of patients achieving target BP goals were assessed. Results: In amlodipine and cilnidipine groups, mean changes in SBP and DBP from baseline to end of the study period were 28.4 and 15.1 mmHg and 24.3 and 13.5 mmHg, respectively (p value <0.05). More than 50% of patients in both groups achieved BP goal at the end of the study (p value 0.266). In amlodipine group, total 23.9% reported pedal edema, while in cilnidipine, 27.6% (p value 0.0863). At the end of the study, 3.5% and 8.2% of patients remain with pedal edema, respectively, in both groups (pvalue <0.005). Conclusion: Amlodipine demonstrated greater BP reduction at a lower average dose, better efficacy, and tolerability in terms of pedal edema count as a lesser number of patients reported edema at the end of the study and a higher percentage of patients continued the prescribed baseline dosage regimen as compared to cilnidipine. Thus, the study established amlodipine as an effective and well-tolerated antihypertensive for Indians.
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Efficacy of the Combination of Amlodipine and Valsartan in Patients With Hypertension Uncontrolled With Previous Monotherapy: The Exforge in Failure After Single Therapy (EX-FAST) Study
Article
Full-text available
  • Apr 2008
In this randomized, double-blind, multicenter study, patients whose blood pressure (BP) was uncontrolled by monotherapy were switched directly to amlodipine/valsartan 5/160 mg (n=443) or 10/160 mg (n=451). After 16 weeks, BP control (levels <140/90 mm Hg or <130/80 mm Hg for diabetics) was achieved in 72.7% (95% confidence interval [CI], 68.6-76.9) of patients receiving amlodipine/valsartan 5/160 mg and in 74.8% (95% CI, 70.8-78.9) receiving amlodipine/valsartan 10/160 mg. Incremental reductions from baseline in mean sitting systolic and diastolic BP were significantly greater with the higher dose (20.0+/-0.7 vs 17.5+/-0.7 mm Hg; P=.0003 and 11.6+/-0.4 vs 10.4+/-0.4 mm Hg; P=.0046). Incremental BP reductions were also achieved with both regimens irrespective of previous monotherapy, hypertension severity, diabetic status, body mass index, and age. Peripheral edema was the most frequent adverse event. These results provide support for the BP-lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy.
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Peripheral edema associated with calcium channel blockers: Incidence and withdrawal rate - A meta-analysis of randomized trials
Article
  • Jul 2011
  • J Hypertens
Peripheral edema is considered to be a common and annoying adverse effect of calcium channel blockers (CCBs). It has been thought to occur secondary to arteriolar dilatation causing intracapillary hypertension and fluid extravasation. We aimed to evaluate the incidence and withdrawal rate of peripheral edema with CCBs. A systematic search was made in PubMed, EMBASE and CENTRAL from 1980 to January 2011 for randomized clinical trials reporting peripheral edema with CCBs in patients with hypertension. Trials enrolling at least 100 patients in the CCB arm and lasting at least 4 weeks were included in the analysis. Both the incidence and withdrawal rate due to edema were pooled by weighing each trial by the inverse of the variance. Head-to-head comparison was done to evaluate the risk of edema between newer lipophilic dihydropyridine (DHP) CCBs and older DHPs. One hundred and six studies with 99 469 participants, mean age 56 ± 6 years, satisfied our inclusion criteria and were included in this analysis. The weighted incidence of peripheral edema was significantly higher in the CCBs group when compared with controls/placebo (10.7 vs. 3.2%, P < 0.0001). Similarly, the withdrawal rate due to edema was higher in patients on CCBs compared with control/placebo (2.1 vs. 0.5%, P < 0.0001). Both the incidence of edema and patient withdrawal rate due to edema increased with the duration of therapy with CCBs reaching 24 and 5%, respectively, after 6 months. The risk of peripheral edema with lipophilic DHPs was 57% lower than with traditional DHPs (relative risk 0.43; 95% confidence interval 0.34-0.53; P < 0.0001). Incidence of peripheral edema in patients on DHPs was 12.3% compared with 3.1% with non-DHPs (P < 0.0001). Edema with high-dose CCBs (defined as more than half the usual maximal dose) was 2.8 times higher than that with low-dose CCBs (16.1 vs. 5.7%, P < 0.0001). The incidence of peripheral edema progressively increased with duration of CCB therapy up to 6 months. Over the long term, more than 5% of patients discontinued CCBs because of this adverse effect. Edema rates were lower with both non-DHPs and lipophilic DHPs.
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Effect of Renin-Angiotensin System Blockade on Calcium Channel Blocker-Associated Peripheral Edema
Article
  • Feb 2011
Peripheral edema is a common adverse effect of calcium channel blockers. The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way. We performed a MEDLINE/COCHRANE search for all prospective randomized controlled trials in patients with hypertension, comparing calcium channel blocker monotherapy with calcium channel blocker/renin-angiotensin system blocker combination from 1980 to the present. Trials reporting the incidence of peripheral edema or withdrawal of patients because of edema and total sample size more than 100 were included in this analysis. We analyzed 25 randomized controlled trials with 17,206 patients (mean age 56 years, 55% were men) and a mean duration of 9.2 weeks. The incidence of peripheral edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than that with calcium channel blocker monotherapy (P<.00001) (relative risk [RR] 0.62; 95% confidence interval [CI], 0.53-0.74). Similarly, the risk of withdrawal due to peripheral edema was 62% lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy (P=.002) (RR 0.38; 95% CI, 0.22-0.66). ACE inhibitors were significantly more efficacious than ARBs in reducing the incidence of peripheral edema (P<.0001) (ratio of RR 0.74; 95% CI, 0.64-0.84) (indirect comparison). In patients with hypertension, the calcium channel blocker/renin-angiotensin system blocker combination reduces the risk of calcium channel blocker-associated peripheral edema when compared with calcium channel blocker monotherapy. ACE inhibitor seems to be more efficacious than ARB in reducing calcium channel blocker-associated peripheral edema, but head-to-head comparison studies are needed to prove this.
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Mitigation of calcium channel blocker-related oedema in hypertension by antagonists of the renin–angiotensin system
Article
  • Feb 2009
This review is aimed at examining calcium channel blocker (CCB)-related oedema and how this can be attenuated through the use of agents that inhibit the renin-angiotensin system. CCBs are effective antihypertensive agents, but their propensity for causing oedema may reduce compliance. A review of the literature has indicated that the absolute incidence of this side effect is difficult to determine because reported rates vary widely, a factor that may stem from differences in the surveillance technique (active vs passive). In a recent trial incorporating active surveillance, 25% of patients who received amlodipine 10 mg per day experienced oedema. CCB-induced oedema is caused by increased capillary hydrostatic pressure that results from preferential dilation of pre-capillary vessels. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) cause post-capillary dilation and normalize hydrostatic pressure, and are thus ideally suited for prevention/reversal of CCB-induced oedema. The efficacy of this strategy was proven using both subjective and objective techniques. ARB/CCB and ACEI/CCB combination therapy is also more effective than CCB monotherapy in controlling blood pressure. These combinations represent an important advance in the management of hypertension.
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Calcium Channel Blocker-Related Peripheral Edema: Can It Be Resolved?
Article
  • Jul 2003
Calcium channel blocker (CCB)-related edema is quite common in clinical practice and can effectively deter a clinician from continued prescription of these drugs. Its etiology relates to a decrease in arteriolar resistance that goes unmatched in the venous circulation. This disproportionate change in resistance increases hydrostatic pressures in the precapillary circulation and permits fluid shifts into the interstitial compartment. CCB-related edema is more common in women and relates to upright posture, age, and the choice and dose of the CCB. Once present it can be slow to resolve without intervention. A number of strategies exist to treat CCB-related edema, including switching CCB classes, reducing the dosage, and/or adding a known venodilator such as a nitrate, an angiotensin-converting enzyme inhibitor, or an angiotensin-receptor blocker to the treatment regimen. Angiotensin-converting enzyme inhibitors have been best studied in this regard. Diuretics may alter the edema state somewhat, but at the expense of further reducing plasma volume. Traditional measures such as limiting the amount of time that a patient is upright and/or considering use of graduated compression stockings are useful adjunctive therapies. Discontinuing the CCB and switching to an alternative antihypertensive therapy will resolve the edema.
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A Randomized, Double-Blind, Active-Controlled, Parallel-Group Comparison of Valsartan and Amlodipine in the Treatment of Isolated Systolic Hypertension in Elderly Patients: The Val-Syst Study
Article
  • Dec 2003
  • CLIN THER
Some antihypertensive therapies are limited by dose-dependent adverse effects (AEs). The angiotensin II receptor blocker valsartan has been shown to reduce blood pressure (BP) in a dose-related manner with minimal dose-limiting AEs. Amlodipine besylate is a potent dihydropyridine calcium channel blocker also with dose-related antihypertensive efficacy, but with possible dose-limiting AEs, particularly peripheral edema. This study compared the risk/benefit profiles of valsartan and amlodipine in elderly patients who have isolated systolic hypertension (ISH). This 24-week, randomized, double-blind, active-controlled, titration-to-effect, parallel-group study was conducted at 35 outpatient centers in Italy. Elderly (aged 60-80 years) patients with ISH received oral treatment with valsartan 80-mg capsules or amlodipine 5-mg capsules once daily. After 8 weeks of treatment, the dose of the patients with poorly controlled systolic BP (SBP) was titrated to 160 mg (valsartan) or 10 mg (amlodipine) once daily. At week 16, if trough SBP was still not adequately controlled, a low-dose diuretic (hydrochlorothiazide [HCTZ] 12.5 mg) was added to the treatment regimen for an additional 8 weeks. Tolerability was assessed at all study visits using physical examination and patient interview. Of 421 randomized patients (231 women, 190 men; mean [SD] age, 69 [6] years), 208 were included in the valsartan group, and 213 in the amlodipine group. The efficacy of valsartan-based treatment. in reducing SBP was similar to that of amlodipine-based treatment. With doubled doses, efficacy (change in SBP) increased significantly from baseline (both P < 0.01). The frequency of AEs doubled with amlodipine 10 mg but was not clinically relevant with valsartan 160 mg. Overall, AEs were observed in 31.9% of those receiving amlodipine versus 20.2% of the patients receiving valsartan (P < 0.003), with peripheral edema rates of 26.8% and 4.8%, respectively (P < 0.001). In this study population of elderly patients with ISH, valsartan-given alone or in combination with HCTZ 12.5 mg-showed similar efficacy but better tolerability than amlodipine-based treatment.
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Version 2.0. Michigan: Thomson Reuters
  • Jan 2012
  • Micromedex
Micromedex. Version 2.0. Michigan: Thomson Reuters; 2012.