Observational study on Chronic intake of amlodipine and its side effects as skin pigmentation on the legs near ankles

*Corresponding author: Newton Paul Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Observational study on Chronic intake of amlodipine and its side effects as skin pigmentation on the legs near ankles Newton Paul * Department of Zoology, Isabella Thoburn College, Lucknow-226007, Uttar Pradesh, India. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 176-182 Publication history: Received on 02 July 2025; revised on 10 August; accepted on 13 August 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.23.2.0750 Abstract High blood pressure (hypertension) is a chronic cardiovascular disorder characterized by sustained elevation of arterial pressure, leading to increased cardiac workload, vascular remodelling, and heightened risk of stroke, myocardial infarction, and heart failure. Persistent hypertension increases systemic vascular resistance, forcing the left ventricle to pump against higher afterload, which can result in left ventricular hypertrophy and impaired cardiac function over time. Amlodipine, a long-acting dihydropyridine calcium channel blocker, is widely prescribed for hypertension and angina due to its potent vasodilatory effects and favourable safety profile. Although generally well tolerated, rare cases of cutaneous hyperpigmentation have been reported with chronic use. The exact mechanism remains unclear but is hypothesized to involve drug-induced photosensitivity, increased melanin synthesis, or deposition of drug–melanin complexes in the dermis. In some cases, hemosiderin deposition from localized capillary leakage secondary to vasodilation has also been reported. Clinically, pigmentation often presents as diffuse or patchy brownish discoloration, typically in sun-exposed areas or the lower extremities, and may be reversible upon discontinuation of the drug. Keywords: Hypertension; Skin pigmentation; Amlodipine; Olmesartan Medoxomil 1. Introduction In today's lifestyle, the rush and stress have increased a lot, due to which people are facing many health problems. Compared to earlier, people are now paying less attention to their daily routine, diet, and exercise, due to which diseases like obesity, heart disease, and diabetes have become common. Heart disease is mainly caused by plaque or the deposition of fat in the arteries, which affects blood flow due to a narrow passage and can lead to a heart attack or stroke. Amlodipine, a dihydropyridine calcium channel blocker, is widely prescribed for the long-term management of hypertension and angina pectoris due to its potent vasodilatory action, once-daily dosing, and favourable safety profile. While common adverse effects include peripheral edema, reddening of the skin, particularly the face, and headache, cutaneous manifestations are rare and often underrecognized [1]. Chronic intake of amlodipine has been associated with progressive skin pigmentation, particularly in the lower extremities near the ankles. This pigmentation may arise from multiple mechanisms, including increased melanin synthesis, drug–melanin complex deposition, or hemosiderin accumulation secondary to chronic vasodilation-induced capillary leakage. Although usually asymptomatic, such discoloration can have cosmetic and psychological impacts on patients and may lead to unnecessary diagnostic investigations if not correctly attributed to the drug. Awareness of this potential adverse effect is essential for timely recognition, patient counselling, and consideration of therapeutic alternatives when indicated. Different drugs lower the blood pressure (BP) by targeting different points in the body’s blood pressure control system, such as the heart, blood vessels, kidneys, and the nervous system (Table 1). Calcium channel blockers (amlodipine), ACE World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 176-182 177 inhibitors (enalapril), ARBs (losartan), and Alpha-blockers (prazosin) cause relaxation in smooth muscle in the vessel walls or block signals that cause tightening or hardening and facilitate widening of arteries that allow more blood flow and decrease the pressure [20]. Diuretics (hydrochlorothiazide, furosemide) work via the organ system and target on kidneys. After receiving a chemical signal, the kidneys start to excrete more water and salt, due to low fluid in the blood vessels lower blood pressure. Medicines such as atenolol and propranolol block the beta receptor in the heart, known as a beta blocker, which decreases blood pressure by blocking the effects of hormones adrenaline and norepinephrine on the heart and blood vessels. They mainly act on beta-adrenergic receptors in the heart, and to a lesser extent in blood vessels and the kidneys. They target β₁-receptors in the heart. In normal conditions, adrenaline binds to β₁ receptors, causing the heart to beat faster and more forcefully to pump more blood and increasing blood pressure. If Blocks β₁ receptors that slow heart rate (negative chronotropic effect) and contraction force decreases (negative inotropic effect), due to this, less blood is pumped per minute and blood pressure decreases [12,20]. It also reduces blood pressure by affecting β₁receptors in the kidney’s juxtaglomerular cells. In a normal situation, on β₁ stimulation release more renin which activates the RAAS (renin–angiotensin–aldosterone system), causing vessel constriction and fluid retention, and finally, increasing blood pressure. But when Beta-receptor block less renin release, which converts less angiotensin II and aldosterone, causing relaxation in vessels and less fluid retention, blood pressure decreases [4, 25] (Table 1). Alpha-blockers such as prazosin lower blood pressure mainly by relaxing blood vessels, making it easier for blood to flow. Prazosin specifically targets α₁-adrenergic receptors located on the smooth muscle of arterioles and veins and blocks them [18]. Normally, these receptors respond to norepinephrine from sympathetic nerves, causing vasoconstriction. When prazosin blocks α₁ receptors, norepinephrine can’t trigger contraction of vascular smooth muscle, resulting in vasodilation (both arteriolar and venous). Arteriolar dilation will decrease systemic vascular resistance (afterload), which lowers blood pressure. Also, vasodilation increases venous capacity, reduces venous return (preload) further lowers blood pressure. This drug also improves blood flow in specific regions such as the skin and kidneys, and other organs [3] (Table 1). Drugs related to blocking hormonal blood pressure-raising signals selectively target another route to slow down blood pressure in the hormonal system. There are two Angiotensin-Converting Enzyme (ACE) inhibitors, and Angiotensin Receptor Blockers (ARBs), both are used to treat high blood pressure and other cardiovascular conditions. Both of them effectively work by affecting the RAS (renin-angiotensin system), a hormonal system that regulates blood pressure and fluid balance. ACE Inhibitors block the enzyme that converts angiotensin I to angiotensin II, a potent vasoconstrictor (a substance that narrows blood vessels). By inhibiting this enzyme, ACE inhibitors help relax blood vessels and lower blood pressure. Whereas ARBs drugs specifically block the receptor sites where angiotensin II acts to constrict blood vessels [24]. By blocking these receptors, ARBs prevent angiotensin II from exerting its vasoconstricting effects, leading to lower blood pressure [6]. Both ACE inhibitors and ARBs are effective in managing hypertension and protecting the kidneys by interrupt the renin–angiotensin–aldosterone system (RAAS), which normally increases BP by tightening vessels and retaining fluid, especially in people with diabetes or chronic kidney disease. They are often used as first-line treatments for such conditions. Some drugs target the central nervous system, such as clonidine, methyldopa (Central acting agents) act in the brain to reduce sympathetic nervous system activity, resulting in less vessel constriction result lower blood pressure (Table 1). Diuretic drugs such as hydrochlorothiazide (HCTZ) (thiazide) and furosemide (loop diuretic) lower blood pressure mainly by reducing the volume of fluid in the blood vessels and, over time, by relaxing blood vessels. Both medicines target different ion channels in the distal and convoluted tubules of the nephron for the common goal of decreasing blood pressure. Hydrochlorothiazide (Thiazide), also known as a water pill, works in the distal convoluted tubule where it blocks the Na⁺/Cl⁻ symporter. Whereas Furosemide (Loop diuretic) works in the thick ascending loop of Henle and blocks Na⁺/K⁺/2Cl⁻ cotransporter. Both medicinal components prevent sodium reabsorption into the blood [23]. After a long time (months), blood volume and cardiac output partly return toward normal. But blood pressure stays low because chronic sodium loss causes less sodium inside vascular smooth muscle cells. This reduces calcium entry into those cells. Less calcium causes vasodilation, which decreases systemic vascular resistance. Each medicine has a demerit that it can cause electrolyte imbalances (low K⁺, low Na⁺, dehydration) in the body (Table 1). World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 176-182 178 Table 1 Different Drugs commonly used in High Blood Pressure Treatment Medicinal Compound Action via Main Action Result on Blood Pressure Atenolol and Propranolol Beta-blockers Slow heart, reduce pumping force Decrease Blood Pressure Lisinopril and Valsartan Angiotensin-Converting Enzyme (ACE) inhibitors, and Angiotensin Receptor Blockers (ARBs), Block vesseltightening hormones Decrease Blood Pressure Hydrochlorothiazide (HCTZ) and Furosemide Diuretics Reduce blood volume Decrease Blood Pressure Prazosin Alpha-blockers Stop vessel constriction signals Decrease Blood Pressure Amlodipine Calcium channel blockers Relax blood vessel muscles Decrease Blood Pressure Amlodipine is a selective drug that blocks Calcium channels and is commonly known as a Calcium channel blocker (CCB). through alternation in calcium channels that block the flow of calcium ions, which lowers blood pressure mainly by relaxing and widening arteries so blood flows with less resistance [5,13]. Amlodipine blocks L-type calcium channels in the smooth muscle cells of arterial walls. In Normal conditions, Calcium enters smooth muscle cells through L-type channels and binds to calmodulin, activating myosin light chain kinase (MLCK). Once MLCK triggers actin–myosin interaction, muscles contract and arteries narrow (vasoconstriction), which raises blood pressure. In the presence of amlodipine, L-type calcium channels are blocked, due to which less calcium enters cells. MLCK remains inactive, and smooth muscle stays relaxed. Arteries widen (vasodilation), causing vascular resistance to drop and a decrease in Blood pressure. But almondine does not stop here, it also causes some extra consequences if taken for a long time on the cutaneous surface. Amlodipine can rarely cause pigmentation on the legs, and when it happens, it’s usually due to secondary effects, not direct effects. Amlodipine dilates small arteries (arterioles) much more than veins and causes an increase in hydrostatic pressure inside the capillaries of the legs [9]. Due to high pressure for a long time causes fluid and red blood cells (RBCs) leak out of tiny blood vessels into the surrounding skin tissue. The leaked RBCs are broken down by the body’s immune cells (macrophages). Haemoglobin from these RBCs is degraded into an iron-containing pigment called haemosiderin. Haemosiderin accumulates in the skin of the ankles and appears as brownish pigmentation around the lower legs [19] (Table 1). 2. Material and methods A study was conducted on a 42-year-old hypertensive patient in Lucknow city, Uttar Pradesh. He is a male person suffering from high blood pressure since 2011 and was previously prescribed earlier amlodipine-based medicines. His old history and new medical prescription by the doctor were considered in the study. All observations were recorded as per the prescription and medical report. 3. Results Amlodipine, a long-acting dihydropyridine calcium channel blocker, lowers blood pressure by inhibiting L-type calcium channels in vascular smooth muscle. This blockade reduces intracellular calcium concentration, causing relaxation of arteriolar smooth muscle and consequent vasodilation. The primary hemodynamic effect is a reduction in systemic vascular resistance, thereby decreasing afterload and improving oxygen supply-demand balance in the myocardium. Due to its gradual onset and prolonged duration of action, amlodipine provides effective 24-hour blood pressure control with a low incidence of reflex tachycardia, making it a preferred agent in the long-term management of hypertension. Amlovas-5, containing 5 mg of amlodipine, is a long-acting dihydropyridine calcium channel blocker widely used for the management of hypertension. By selectively inhibiting L-type calcium channels in vascular smooth muscle, it induces peripheral arterial vasodilation, thereby reducing systemic vascular resistance and lowering blood pressure. Although World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 176-182 179 amlodipine is generally well tolerated, chronic administration has been rarely associated with cutaneous adverse effects, including hyperpigmentation. This pigmentation often manifests as brownish discoloration over the lower legs, particularly near the ankles [15, 22]. Natrilam-5 is a fixed-dose combination antihypertensive medication containing amlodipine (a dihydropyridine calcium channel blocker) and indapamide (a thiazide-like diuretic). It is prescribed for the management of essential hypertension, particularly in patients requiring dual therapy to achieve blood pressure control. Amlodipine lowers blood pressure by inhibiting L-type calcium channels in vascular smooth muscle, resulting in arteriolar vasodilation and reduced systemic vascular resistance. Indapamide complements promoting sodium and water excretion, due to which blood volume decreases [8]. Although generally well tolerated, chronic use of Natrilam-5 has been rarely associated with skin pigmentation, especially in the lower legs and ankles. The pigmentation may present as diffuse or patchy brownish discoloration and is thought to result from mechanisms such as drug–melanin complex deposition, druginduced photosensitivity, or hemosiderin accumulation secondary to vasodilation-induced capillary leakage. Olmezest Beta 50 is a combination of two components: named antihypertensive medication containing Olmesartan Medoxomil (an angiotensin II receptor blocker, ARB) and metoprolol succinate (a selective β₁-adrenergic blocker) [7]. It is prescribed for the treatment of essential hypertension, particularly in patients requiring dual therapy to achieve optimal blood pressure control. Olmesartan lowers blood pressure by selectively blocking the binding of angiotensin II to AT₁ receptors in vascular smooth muscle, thereby preventing vasoconstriction and reducing systemic vascular resistance. Metoprolol complements this effect by decreasing heart rate, myocardial contractility, and cardiac output, which further contributes to blood pressure reduction. Unlike certain calcium channel blockers, such as amlodipine, which have been rarely associated with skin hyperpigmentation, Olmezest Beta 50 is associated with causing pigmentation of the skin on the lower legs. Its safety profile concerning dermatological effects is favourable, making it a suitable choice for long-term blood pressure management in patients who have previously experienced cutaneous adverse effects with other antihypertensive classes. A 42-year-old man was diagnosed with high blood pressure along with gout (elevated levels of uric acid and creatinine) in September 2023. As per patient history, he was previously observed to have had hypertension since 2011. Earlier, he was prescribed an amlodipine-based 5mg tablet once a day in the morning (Table 2). This medicine was very effective and properly controlled his high blood pressure. This medicine was continued till 2014, but the doctor discontinued it when the patient was observed with red or brown patches on the skin of his lower legs, especially near the ankle areas, along with swelling (Figure 1R1 and L1). Now he was prescribed another amlodipine-based 5mg medicine along with Febuxostat daily in the morning to decrease creatinine and uric acid, along with blood pressure (Table 2). Booth medicines were quite effective and also decreased uric acid and creatinine well. But the problem of brown -red patches or pigmentation continues on the skin of his lower legs, especially near the ankle areas. The patient was very disappointed and moved to homeopathic treatment. He was quite satisfied when he observed that pigmentation on the legs had decreased by 2023. In August 2023, the patient was observed to have dark and large brown patches on the same area of his legs. He was referred to a cardiologist who performed all pathological tests and confirmed these patches were due to the amlodipine compound present in the previous medicine. The patient was prescribed an amlodipinebased medicine from 2011 to 2023. From September 2023, he was advised to take Olmesartan Medoxomil for high blood pressure. The patient was treated with new medicine based on Metoprolol succinate extended release and Olmesartan Medoxomil daily in the morning that does not contain amlodipine (Table 2). In the next 7-9 months, intake of this medicine reduces brown patches on both legs. The darkness of previous brown patches also becomes light. After one year of treatment with Olmesartan Medoxomil was found to cause no pigmented leg skin (Figure 1R2 and L2). World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 176-182 180 Figure 1 Pigmentation on both legs specially around ankles due to Amlodipine; R1(Right leg) dark brown pigment on the skin due to amlodipine (arrow indicate); R2 (Right leg) previous pigmentation on the skin disappears with Olmesartan Medoxomil; L1(Left leg) dark brown pigment on the skin due to amlodipine; L2 (Left leg) previous pigmentation on the skin disappears with Olmesartan Medoxomil Table 2 Medicines prescribed by physician to patient Drugs components Medicine name Result Amlodipine besilate Amlovas-5 Decrease blood pressure Pigmentation on skin Indapamide Amlodipine besilate Natrilam-5 Decrease blood pressure Pigmentation on skin Febuxostat FBX 40 Decrease Uric acid and creatinine level Metoprolol succinate Olmesartan Medoxomil Olmezest Beta 50 Decrease blood pressure No Pigmentation on skin A case related to pigmentation due to prolonged administration of amlodipine. A patient with high blood pressure was prescribed amlodipine 10 mg once daily in combination with lisinopril 20 mg daily. As per the record, after 3 months, blood pressure was lowered. But the patient was observed to have purpuric skin eruptions around the ankle region with ankle oedema. The skin becomes darker in appearance and resulting in Schamberg-like irregular brown-coloured spots on the outer side of the tibia from the ankles to the knees [22]. A case report based on a 73-year-old woman, having an allergy to neomycin, was prescribed with medicine telmisartan and hydrochlorothiazide. After 4 to 5 months, patches of pigmentation were developed on her inner forearms, dorsal surface of feet, and left popliteal area [21]. Harper et al. [15] reported a case associated with hyperpigmentation due to the intake of Calcium channel blockers for the treatment of hypertension. Although such cases are rare, but reported due to chronic amlodipine use. A 62-yearold male had hypertension and prescribed medications were amlodipine, hydrochlorothiazide/lisinopril, metoprolol tartrate, simvastatin, and colchicine. After 2 years and 7 months, several small dark spots were observed on their lower leg skin; some of them were in clusters, forming a large patch [24]. 4. Discussion The occurrence of cutaneous hyperpigmentation associated with amlodipine remains rare. But reported. Amlodipineinduced pigmentation typically presents on the lower extremities, particularly the shins and legs, after prolonged therapy. The pigmentation often manifests as brownish, rust-coloured, or bluish-gray macules or patches. Histopathological studies from case reports have demonstrated variable findings, including increased epidermal World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 176-182 181 melanin deposition, dermal melanophages, and hemosiderin accumulation, suggesting a multifactorial pathogenesis [9,12,22]. Amlodipine-induced vasodilation leading to chronic capillary leakage, red blood cell extravasation, and subsequent hemosiderin deposition. Additionally, calcium channel blockade may alter melanocyte activity, promoting increased melanin synthesis [9,22]. In contrast, Olmesartan Medoxomil, an angiotensin II receptor blocker (ARB), has not been convincingly implicated in causing lower-leg hyperpigmentation. The lack of pigmentation with Olmesartan may be attributed to its different pharmacodynamic profile: ARBs do not cause peripheral vasodilation via calcium channel blockade and, therefore, are less likely to induce microvascular changes that predispose to hemosiderin deposition [8,13]. The absence of pigmentation with Olmesartan in this context supports its potential role as a safer alternative in patients requiring long-term antihypertensive therapy, but regular observation is required to check any further consequences. 5. Conclusion The present study highlights a clinically relevant distinction between two widely used antihypertensive agents with respect to dermatological side effects. Chronic administration of amlodipine, a dihydropyridine calcium channel blocker, has been associated with the development of hyperpigmentation on the lower legs, due to increased melanin production, or deposition of hemosiderin secondary to drug-induced alterations in microcirculation. In contrast, treatment with Olmesartan Medoxomil, an angiotensin II receptor blocker, did not demonstrate any such brown pigmentation on the legs. Both medicines are very effective in reducing blood pressure, but some patient develops skin pigmentation due to amlodipine. Compliance with ethical standards Acknowledgments The author is grateful to the Principal Dr. (Maj.) Neerja Masih, Isabella Thoburn College, Lucknow, Uttar Pradesh, India for her continuous encouragement and guidance. 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