Amlodipine and Pedal Edema

Amlodipine is a calcium channel blocker (CCB) of the third generation dihydropyridine CCB group, used as monotherapy or in combination, for treatment of hypertension, angina and certain other cardiac disorders.

The most frequently occurring adverse effect with amlodipine therapy includes palpitation, flushing, ankle/pedal edema, hypotension, headache and nausea.

Dihydropyridine  CCBs actually  appear  to  have  some  inherent  diuretic  actions,  yet  can  still  cause  edema  as  an  adverse reaction.Peripheral edema, particularly of the lower limbs, is a common adverse effect of dihydropyridine CCB. This might lead to dose reduction or drug withdrawal, adversely affecting the antihypertensive efficacy.

The degree of peripheral edema that occurs with CCB treatment is dependent on the dose and the drug used.Ankle edema is a common,often troublesome adverse effect for patients who are receiving CCB therapy, and may affect compliance. It is usually refractory to diuretic treatment as it is due to changes in capillary pressure leading to leakage into interstitial areas, rather thandue to water retention¹.

 

How does amlodipine cause pedal edema(swollen ankle)?

  • Calcium enters muscle cell through special voltage sensitive calcium channel.Normally, L-type of channels admit Ca+ and causes depolarization causing contraction of vascular smooth muscle and elevation of BP. Amlodipine exert its effect by antagonist blocking for inward movement of calcium by binding to the L-type channels in the heart and peripheral vasculature.

 

Amlodipine causes vasodilatation of the arterioles and not venules causing increased capillary hydrostatic pressures leading to edema.⁶

The pathophysiology of edema with CCB therapy has no relationship to salt and water retention.

The schematic diagram showing mechanism of amlodipine induced edema is attached along.

Any patients who present with ankle edema should first be assessed to rule out other causes.

How should ankle edema caused by calcium channel blockers be treated?

Treatment of ankle oedema will depend on the severity and otherpatient factors, with mild edema not requiring specific treatment provided it is not troublesome to the patient. Whilst ankle edema associated with calcium channel blockers is rarely clinically serious, it may significantly reduce adherence to these potentially useful agents⁵.Listed are the possible managements of amlodipine associated pedal edema:

  1. Non-Pharmacological methods : Elevation of legs when in a prone position, or graduated compression stockings, may be an option in some patientswith mild oedema. However, there is little evidence to suggest these methods may be effective in reducing oedema.⁵
  2. Dose adjustments :As ankle edema is dose related(although not necessarily in a dose-proportional manner), reducing the dosage of a CCB may lead to ankle edema reducing in severity.⁷
  3. CCB switching :Switching to another CCB class may reduce ankle edema, although current evidence on the success rates of this strategy are conflicting. If a patient on a DHP agent reports oedema, a switch to a non-dihydropyridine such as verapamil, if clinically suitable, may lead to resolving ofankle edema.Similary , shifting to fourth generation dual CCB ,like Cilnidpine may also be suitable , as Cilnidpine blocks both L-type and N type calcium channel, thus reducing the incidene of pedal edema.⁸
  4. Diuretics: Unlike other types of edema, diuretics appear to have little effect on CCB-induced edema, even where there is large natriuresis and a subsequent decrease in plasma volume². This applies to both thiazide and loop diuretics, and isdue to the fact that diuretics act by reducing water retention only, and do not affect vasodilatory induced fluid pooling². In fact, CCBs are thought to have natriuretic properties which are thought to contribute to their blood pressure lowering effects, but do not appear to preclude the formation of ankle edema³.
  5. Angiotensin Converting Enzyme Inhibitors (ACEIs): It has been demonstrated in several trials that adding an ACEI to a CCB reduces the incidence of ankle edema, although the mechanism by which this occurs is not currently known²ʼ³, but may be due to the dilation of venous capacitance vessels, which may then lead to a reduction in capillaryhypertensionand therefore leakage of fluidinto the surrounding tissues¹ʼ². It is currently unknown whether any ACEIs are superior in treating ankle edema, but any ACEI initiated should be dosed according to blood pressure lowering effect.
  6. Angiotensin II Receptor Blockers (ARBs): The mechanisms by which ARBs reduce incidence of CCB induced ankle edema remains unknown, but arelikely to be similar to that involved when ACEIs are added to CCB therapy².
  7. Nitrates : Nitrates, due to theirvenodilating action, may be offer some useful effects in treating CCB induced ankle edema, but their use are limited by the practical considerations of having a stop-start regimen so tolerance does not develop³.
  8. Discontinuation : If other treatment options fail, discontinuing the CCB, and switching to an antihypertensive from another class of drugs, may be required⁴

 

References:

  1. Messerli FH, and Grossman E. Pedal edema-not all dihydropyridine calcium antagonists are created equal. American Journal of Hypertension 2002; 15: 1019-1020
  2. Fogari R, Zoppi A, Derosa G et al. Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients. Journal of Human Hypertension 2007; 21: 220-224
  3. Sica DA. Calcium channel blocker-related peripheral edema: Can it be resolved? The Journal of Clinical Hypertension 2003; 5(4): 291-297
  4. Sirker A, Missouris CG and Macgregor GA. Dihydropyridine calcium channel blockers and peripheral side effects. Journal of Human Hypertension 2001; 15: 745-746
  5. Epstein BJ and Roberts ME. Managing peripheral edema in patients with arterial hypertension. Americal Journal of Therapeutics 2009; 16(6): 543-553
  6. Kiran K Shetty, RanjanShetty K., Naveenchandra G.S., Rohit Reddy P, VidhyaNayak .Calcium channel blockers induced pedal edema; mechanism and treatment options:  Review .International Journal of Sciences & Applied Research 2(12), 2015; 27-33
  7. Andresdottir MB, van Hamersvelt HW, venHelden MJ et al. Ankle edema formation during treatment with the calcium channel blockers lacidipine and amlodipine: a single-centre study. Journal of cardiovascular pharmacology 2000: 35 S25-S30.
  8. Prabhakar Adake, H.S. Somashekar, P. K. Mohammed Rafeeq, Dilshad Umar, Bahija Basheer and Kusai Baroudi. Comparison of amlodipine with cilnidipine on antihypertensive efficacy and incidence of pedal edema in mild to moderate hypertensive individuals: A prospective study. Journal of Advanced Pharmaceutical Technology & Research 2015 Apr-Jun; 6(2): 81–85. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397623/#__ffn_sectitle accessed on feb 7,2020.