High Technology Letters ISSN NO : 1006-6748

Adverse Drug Reactions of Antihypertensive Drugs: A Review Sandhoshini Meena S 1, Praveen D 2, Ranadheer Chowdary P 2, M. Vijey Aanandhi 3*

1School of Pharmaceutical Sciences, Vels Institute of Science Technology and Advanced Studies (VISTAS), Chennai, India. 2Research Scholar, School of Pharmaceutical Sciences, Vels Institute of Science Technology and Advanced Studies (VISTAS), Chennai, India. 3Department of Pharmaceutical Chemistry and Analysis, School of Pharmaceutical Sciences, Vels Institute of Science Technology and Advanced Studies (VISTAS), Chennai, India.

Corresponding Author Dr. M. Vijey Aanandhi Professor and Head, Department of Pharmaceutical Chemistry and Analysis, School of Pharmaceutical Sciences, Vels Institute of Science Technology and Advanced Studies (VISTAS), Pallavaram, Chennai – 600117, India.

Abstract Adverse drug reaction (ADR) is defined by the World Health Organization (WHO) as “any response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function”. The recent epidemiological studies say that the adverse drug reactions (ADRs) are fourth to sixth leading cause of death. Adverse drug reactions (ADRs) are the major reason behind the cause of morbidity and mortality, and also the leading cause of hospital admissions. ADRs negatively affect the patient’s quality of life and confidence in medications, which consequently leads to worse treatment outcomes. Monitoring of ADRs should be an ongoing, continuing and ceaseless process. The most ADRs would subside once the causative agent is discontinued or dose is being reduced; however, many ADRs results in permanent damage to the patients. Monitoring of ADRs is even more important in case of chronic conditions such as hypertension. Hypertension is an asymptomatic disorder and requires long term treatment predisposing to adverse drug reactions. Most of the adverse drug reactions are predictable and preventable. Therefore continuous monitoring and reporting of ADRs can have a positive impact on the medication use, improving the patient’s quality of life and in reducing the incidence of devastating ADRs. The active surveillance of a clinical pharmacist in detecting the Adverse Drug Reactions and giving the awareness regarding the need of monitoring and reporting of adverse drug reactions among healthcare professionals would improve the scenario in under-reported hospitals.

Keywords: Adverse Drug Reactions (ADRs), Antihypertensive Drugs, Hypertension, Clinical Pharmacist, ADRs reporting.

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I. INTRODUCTION Adverse drug reaction (ADR) has been defined by the World Health Organization (WHO) as “any response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function”. The recent epidemiological studies say that the adverse drug reactions (ADRs) are fourth to sixth leading cause of death [1] . Adverse drug reactions are seen in day to day clinical practice. Estimation of the incidence rate of adverse drug reactions is very difficult and highly variable among countries all over the world. Prevalence of adverse drug reactions is 14.7% in United Kingdom and 16.2% in India [2,3] . The incidence of hospital admissions due to adverse drug reactions ranges from 2.4 to 12% while incidence of ADRs during hospital stay ranges from 0.05 to 0.19 % [4,5] . Fatality due to ADRs was found to be 0.3% [6]. Adverse drug reactions (ADRs) are the major reason behind the cause of morbidity and mortality, and also the leading cause of hospital admissions. ADRs negatively affect the patient’s quality of life and confidence in medications, which consequently leads to worse treatment outcomes [7]. Lack of reliable data on the true prevalence and incidence of ADRs is the major limitation in adverse drug reaction research. The incidence rate of adverse drug reactions is captured through voluntary reporting systems. Due to under- reporting the true incidence of adverse drug reaction is not known, which results in lack of information about the number of patients at risk and making assessment of the relative frequencies of different adverse drug reactions are impossible. Singapore stands the highest rate in spontaneous ADR reporting in the world. Even though under-reporting, incomplete information of the data and reporting bias causes inability to calculate the true prevalence of ADRs [8,9].

Monitoring of ADRs should be an ongoing, continuing and ceaseless process. Adverse drug reaction monitoring and reporting is still infancy in India, this must likely to change and expand in future years. As the newer medications are striking the Indian market, the need for ADR monitoring is important more than ever before. Therefore, monitoring of the adverse drug reactions particularly those of serious nature is obligatory. The most ADRs would subside once the causative agent is discontinued or dose is being reduced; however, many ADRs results in permanent damage to the patients. Therefore, it is important to motivate the healthcare providers to know their role and responsibility within the detection, treatment, documentation, and reporting of adverse drug reactions. Since most of the clinical trials exclude the geriatric, pediatric, pregnant women, patients with multiple diseases or metabolic disorder, and those on medication suspected of interactions with the study drug or investigational drug, thus the study population may not be the true representative of the real world where the medications are eventually used. Hence, there is a need to monitor the adverse drug reactions of all the medications on continuous basis. Monitoring of ADRs is even more important in case of chronic conditions such as hypertension. Hypertension is an asymptomatic disorder and requires long term treatment predisposing to adverse drug reactions. A study by Fowad Khurshid et al . carried out to monitor the adverse drug reactions (ADRs) caused by antihypertensive medicines prescribed in a university teaching hospital, New Delhi, India were a total of 21 adverse drug reactions were seen in 192 hypertensive patients. Combination therapy showed higher number of adverse drug reactions (66.7%) when compared to monotherapy (33.3%). Calcium channel blockers were found to be the most frequently associated drugs with the occurence of adverse drug reactions (n = 7), followed by diuretics (n = 5), and β-blockers (n = 4). Among individual medications, amlodipine was found to be associated with maximum number of adverse drug reactions (n = 7), followed by

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torasemide (n = 3). Pain in abdomen, ankle oedema, sedation, pedal oedema, and back pain were the adverse drug reaction observed with the use of amlodipine. Adverse drug reactions associated with central nervous system were found to be the most frequent (42.8%) followed by musculo-skeletal complaints (23.8%) and gastro-intestinal disorders (14.3%) [10,11]. Adverse drug reactions profile of antihypertensive medications will be useful in selecting the appropriate medicines for hypertension patients, improving patient adherence with the medications by selecting the medicines of fewer adverse drug reactions profile, reducing unnecessary financial burden to the patients due to the unintended effects of the medications. II. ADVERSE DRUG REACTIONS OF BETA- BLOCKERS 2.1. Raynaud’s phenomenon and Peripheral vasoconstriction: β-adrenoceptor blockers-induced Raynaud’s phenomenon (RP) is well known adverse drug reactions caused by beta blockers but its true incidence was not known. Beta-adrenoceptor blocker is the most common cause of secondary RP which was estimated by analysis of the Framingham Heart study data (34.2% of secondary RP). A meta-analysis was conducted in 2012 which includes 13 studies were 1012 patients are involved and this analysis observed a prevalence of 14.7% in patients receiving Beta blockers [12] . Transient ischaemia of the extremities is the characterization of Raynaud’s phenomenon (RP). Its clinical manifestation includes: changes to the fingers associated with pallor (vasospasm and decreased blood flow), cyanosis (deoxygenation of the static venous blood) and rubor (reperfusion), often accompanied by pain. RP is of two types: primary (i.e. idiopathic) and secondary. In both the type abnormality in the cutaneous microcirculation are mainly involved in the pathophysiology of RP. RP is aggravated or induced by several drugs which have peripheral vascular effects causing decreased microvascular perfusion. Due to limited information of this adverse drug reaction drug-induced RP probably goes unrecognized in clinical settings. A network meta-analysis of prospective randomized controlled trials was conducted which showed a prevalence of peripheral vasoconstriction among patients treated with Beta blockers of 7%. 4.6% and 1.7% of patients treated with placebo or active control experienced this adverse drug reaction [13,14,15] . Peripheral vasoconstriction is a known vascular adverse drug reactions of beta blockers. Beta-adrenoceptor blockers are known to induce peripheral vasoconstriction, probably according to their pharmacological properties (e.g. preferential binding to Beta 1‐adrenoreceptors, intrinsic sympathomimetic activity or vasodilator effect). However, this has never been confirmed in experimental studies. Charles Khouri et al conducted a network meta ‐analysis in order to assess the comparative risk of peripheral vasoconstriction of different Beta adrenoceptor blockers . All Randomized control trials reporting peripheral vasoconstriction as an adverse drug reaction of beta adrenoceptor blockers says that overall peripheral vasoconstriction was reported in 7% of patients with Beta adrenoceptor blockers and 4.6% in the control groups. Atenolol and propranolol had a significantly higher incidence than placebo. Pindolol, acebutolol and oxprenolol had no significant risk. The study result says that Beta adrenoceptor blockers have variable propensity to cause peripheral vasoconstriction and that it is not related to preferential binding to β1 adrenoceptors. These findings challenge FDA and European recommendations regarding precautions and contra indications of use of Beta adrenoceptor blockers and suggest that Beta adrenoceptor blockers with intrinsic sympathomimetic activity could be safely used in patients with peripheral vascular disease [16] . 2.2. Breast Pain and Swelling: A case of Atenolol-induced breast pain and swelling was reported were a 54-year-old woman was diagnosed with hypertension and Atenolol 25 mg daily was initiated. She reported symptoms of insomnia 9 days after starting the medication. During a follow-up visit 5 weeks

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later, the patient reported continued insomnia, as well as a 6 day history of breast pain, swelling, and tenderness. Atenolol was quickly titrated to discontinuation, and a thiazide diuretic was prescribed. Subsequently, the pain and swelling gradually resolved. Assessment using the Naranjo probability scale revealed that the adverse reaction was probably associated with atenolol. If a patient develops breast pain after initiation of atenolol, or possibly other β- blockers, it may warrant some investigation to rule out the β-blocker as the causative agent. Given the lack of published data, the only time frame to onset of symptoms that can be established is from this case. While additional cases and/or studies are required to document more thoroughly the causal relationship between atenolol and breast pain and swelling, clinicians should be aware that atenolol may cause nonorganic breast pain, tenderness, and enlargement [17] . 2.3. Hepatic Dysfunction/ Hepatotoxicity: Yusuf SW et al reported a case of hepatic dysfunction associated with atenolol were a 78- year-old man’s blood tests revealed abnormal liver function with markedly raised alanine aminotransferase (ALT) and moderately raised bilirubin and alkaline phosphatase (ALP), suggesting hepatocellular damage and some cholestasis. Atenolol was stopped on admission and subsequently there was an improvement in liver function which was almost normal after 2 weeks. In view of the improvement in liver function after stopping atenolol and absence of other causes, the author think that liver dysfunction in this case might have been induced by atenolol. Other beta blockers such as labetalol and practolol have been reported to cause liver dysfunction but hepatic dysfunction is not a well-established side-effect of atenolol [18] . Dumortier J et al reported a case represents hepatotoxicity due to atenolol with a significant increase in aminotransferase levels, which returned to normal levels within 3 months after the discontinuation of the medication. According to the Naranjo probability scale, the atenolol- related adverse drug event was considered probable [19] . 2.4. Pseudoakathisia: Patterson JF reported a case of pseudoakathisia with atenolol were a 54 years old man was admitted to the hospital following administration for 1 Month of Atenolol, 100 mg daily for Hypertension. He presented in the hospital with an inability to sit still, restlessness, and constant pacing. His initial mental status revealed only some anxiety over his incapacity to carry out his work because of pacing about. There were no other abnormalities of the mental status present. The atenolol was dicontinued at a rate of 50 mg/day, and within 24 hours after its discontinuation the restlessness, need to move about, and associated anxiety had disappeared. The patient's mental status had not changed. With the patient's informed consent, the atenolol was re started at a dosage of 50 mg/day, 6 days after the disappearance of the akathisia-like syndrome. Within 24 hours after the first dose, the patient became restless and had the need to move. He developed anxiety, which he felt was "alien" to himself and not inherent to his personality. The agitation became much worse within 48 hours, and the need to move about kept the patient in a constant pacing state. The atenolol was discontinued, and within 24 hours the akathisia-like syndrome lessened and within 48 hours disappeared. The patient's blood pressure when he was off atenolol was 140/85 mm Hg, standing, with a pulse of 76. It was recommended to him and to his future physicians that his hypertension be treated with a thiazide diuretic. Atenolol has been shown to cross the blood- brain barrier in small amounts compared to propranolol. This failure to cross the blood-brain barrier by atenolol, since it is hydrophilic, has been shown to produce a significant improvement in the CNS side effects. The small amount of atenolol which crossed the blood- brain barrier is hard to indict in this instance as producing the akathisia. Rather, it would seem that the peripheral blockade of the ß-adrenergic receptors in some manner produced a pseudoakathisia [20] .

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2.5. Erythroderma: Doyon JB et al reported a case of Metoprolol induced total body erythroderma were a 66- year-old female with psoriasis presented with a rash that appeared 2 months after starting metoprolol for new onset atrial fibrillation. Skin examination revealed total body erythroderma with generalized scaling. Thick, micaceous scale covering the entire scalp, with sparse eyebrows and eyelashes was noted. A punch biopsy revealed psoriasiform dermatitis with abundant eosinophils, consistent with a drug-induced hypersensitivity reaction superimposed on a psoriatic diathesis. Medications like beta-blockers, can directly trigger a psoriasis flare. Alternatively, drugs that cause a hypersensitivity reaction may have a chance to trigger a psoriasis flare through the Koebner phenomenon. The author suspected that metoprolol was the offending agent. Therefore, metoprolol was discontinued, and the patient was treated with oral cyclosporine which results in significant improvement of the patient’s skin findings. This case highlights how beta-blockers, can cause a dramatic flare of a patient’s psoriasis. Hence, medications should be discontinued if possible when there is a concern for a drug induced psoriasis flare [21] . 2.6. Gingival Hyperplasia: Raheel SA et al reported a case of Propranolol-induced gingival hyperplasia were a 32-year- old female patient was reported with chief complaints of growth in her upper and lower gums. The patient revealed that the swelling associated with the gums has been present for 2 years, and has been gradually increased to the present size. The patient is a known case of hypertension for past 6 years. The patient’s medication history includes tablet inderal 40mg (propranolol hydrochloride). Oropharyngeal (velopharyngeal) insufficiency with limited movement of the soft palate was also noted. Moreover, marked gingival hyperplasia of anterior gingiva was observed. The gingiva was pale in color, firm in consistency, and with a limited bleeding tendency on probing. Gingival hyperplasia usually shows its clinical evidence within 3-6 months of the use of the drug therapy. Most commonly associated antihypertensive drugs with gingival hyperplasia include nifedipine, diltiazem, verapramil, and amlodipine. Patients taking the drugs for a long period of time as in maintenance phase of drug therapy or as a substitute drug therapy for the immune system and other systemic diseases are prone to get either localized or generalized gingival swellings. These gingival enlargements or hyperplasia with drug therapies can be minimized by either discontinuing the offending agents or changing the mechanism of action. Drug-induced gingival hyperplasia was noted in this case with a patient taking oral propranolol for a long duration. A propranolol-induced gingival hyperplasia is a very rare oral drug reaction [22] . The role of propranolol has been proven to cause gingival enlargement but until now there is no scientific research evidence regarding its frequency of occurrence. The research facts about propranolol give us a fair description about the drug pharmacology and terms it as a safe drug used for the cardiovascular treatment and chronic migraine. Hence, propranolol stands safe as it has got a very low prevalence rate to cause the gingival enlargement but not as a serious threat. 2.7. Bradycardia: Moore BM et al conducted a study on efficacy and adverse effects of sotalol in adults with congenital heart disease were a significant symptomatic bradycardia occurred in 13% (11 patients (n = 11, with permanent pacing implemented in 4)) [23] . 2.8. Toxic Epidermal Necrolysis: Vlahovic-Palcevski V et al reported a case of fatal toxic epidermal necrolysis associated with carvedilol treatment. Two days after the initiation of carvedilol, a 70-year old woman presented with skin eruptions in the form of maculous rash with blisters that rapidly progressed to epidermal necrolysis. Carvedilol is not a drug commonly associated with toxic

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epidermal necrolysis. The study concludes, because of the close temporal relationship between the initiation of carvedilol treatment and the appearance of skin eruptions, and because carvedilol was the only new medication the patient had taken, the etiology of toxic epidermal necrolysis was most likely a reaction to this drug. Physicians should be aware of this extremely rare but serious ADR [24] . 2.9. Psoriatic Nail Disease: Gin A et al reported a case of Metoprolol-induced psoriatic nail disease were a 58-year-old Caucasian woman presented with a 6-month history of red, swollen and painful nails. On examination all five digits of the left hand and two digits on the right hand were affected. The changes seen were psoriasiform with onycholysis, pitting, salmon spots, leukonychia, splinter haemorrhages, a prominent brown onychodermal band, distal lamellar onychoschizia and elkonyxis. No bullae were seen. No photosensitivity was noted. Multiple nail clippings for mycology failed to yield any causative organisms or dermatophytes. The condition was unresponsive to topical treatments including betamethasone dipropionate 0.05% under occlusion, and mupirocin ointment. A number of oral treatment options including cephalexin, acitretin and methotrexate were trialled, with little effect. During a dermatology review it was noted that her nail symptoms had improved significantly. Systematic history taking showed the patient had ceased taking metoprolol (25 mg twice daily.) after receiving cardiac radiofrequency ablation therapy. The nail symptoms had resolved within weeks of drug withdrawal. Further questioning revealed that 1 month before the nail condition first began the patient had been commenced on metoprolol for supraventricular tachycardia. The patient’s cardiac condition deteriorated. Metoprolol (25 mg daily) was recommenced to treat this and the nail condition reappeared over a number of weeks. After identifying metoprolol as a possible trigger for the nail disorder, ivabradine was substituted for metoprolol. On subsequent dermatology review, 3 months after switching medications, the disease of the nails had resolved almost completely with only mild onycholysis remaining on one of the thumb nails. Changes seen in this case show typical features of psoriatic nail disease. Pitting, onycholysis, splinter haemorrhages, the salmon spot sign and leuconychia are characteristic. It is thought that the impairment of distal digital perfusion caused by beta blockers may damage the nail by ischaemic changes. However, the selective beta 1-adrenoreceptor blockade as seen in metoprolol is thought to prevent deleterious effects on the peripheral circulation. The exact mechanism of nail dystrophy in this case remains unclear. However, nail dystrophy due to beta blockers is rare. The identification of metoprolol as the causative agent and its subsequent cessation lead to a complete resolution of symptoms. There has been no recurrence subsequently [25] . 2.10. Acute Generalized Exanthematous Pustulosis: Gómez Torrijos E et al reported a case of Acute Generalized Exanthematous Pustulosis Due to Labetalol were a 31-year-old patient with a history of hypertension in the third trimester of pregnancy was treated with labetalol for 18 days and hydralazine, α-methyldopa and metamizole during the 3 days immediately preceding admission.. About 8 hours before cesarean delivery of twins, erythematous micropapular lesions appeared on the face and neck. These reactions became generalized in 4-5 days, affecting flexures, the intermammary cleft, chest, back, and palms and soles, with multiple micropustules accompanied by mild dermal itching and discomfort when swallowing. Physical examination of this patient revealed pharyngeal enanthem, no lymphadenopathy or organ enlargement, and low-grade fever (38.7°C). Despite withdrawing α-methyldopa, metamizole, and hydralazine on the second day of the eruption, new lesions continued to appear. On the fifth day after discontinuing labetalol, no new skin lesions had appeared. Patch tests performed 1 month after the onset of symptoms with labetalol, metamizole, hydralazine, and α-methyldopa (5% in water and petrolatum) were positive only for labetalol (water and petrolatum), and pustules were

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observed on the area tested. The results of challenge testing with metamizole, α-methyldopa, and hydralazine were all negative, with good tolerance. In order to offer an alternative to labetalol, patch tests were performed with 10% atenolol in water and petrolatum, and the results were negative. The result of the subsequent tolerance test with atenolol, however, was positive, and 1 hour after taking 25 mg, the patient complained of generalized itching and micropapules on back and palms, which lasted for up to 48 hours despite treated with 60 mg of 6-methylprednisolone. The dose was reduced to 16 mg every 8 hours for 2 days. A skin biopsy of the pustules revealed slightly acanthotic skin with subcorneal pustules marking the surface, underlying spongiosis, and spongiosis elsewhere in the epidermis. Polymorphonuclear exocytosis was also observed. A mild lymphohistiocytic inflammation with some interstitial neutrophils was observed in the superficial dermis. Consequently, the patient was diagnosed with acute generalized exanthematous pustulosis (AGEP) due to labetalol with cross-reactivity to atenolol. AGEP is an acute follicular rash that manifests with very small pustules on an erythematous edematous base that appear on the face, neck, and flexures 1-2 days after exposure to the offending drug, before rapidly becoming generalized. It is associated with fever and, sometimes, systemic symptoms, which resolve spontaneously in about 2 weeks. The condition is characterized by intradermal spongiform pustules, edema of the papillary dermis, and predominantly perivascular inflammatory infiltrate, which is occasionally associated with leukocytoclastic vasculitis. The interest of the present case lies in the fact that, even though the patient was treated with several drugs, the allergy workup and the skin biopsy provided abundant detail. Therefore, biopsy confirmed the diagnosis, the patch tests identified labetalol as the causative drug (but failed to detect cross-reactivity with other β-blockers), and an oral tolerance test with atenolol was positive [26] . III. ADVERSE DRUG REACTIONS OF ACE INHIBITORS Bullous Pemphigoid Ballout RA et al reported a case of Lisinopril-induced Bullous Pemphigoid in a 87-year-old woman with past history of hypertension, hypothyroidism and diabetes mellitus who presented with scaly and pruritic vesicles of erythematous base associated with crusted surface for a period of two month. This was first appeared on the abdomen and gradually spread to the lower back, thighs, before spreading to the upper and lower limbs. Lesions were non-painful but aggravated by sun exposure and sparing mucous membranes was noted. Nikolsky sign was found to be positive and there were no discernible fluid-filled bullae. History was remarkable only for a doubling of Lisinopril dosage 2 months prior to the appearance of the lesions, with no other potential environmental and/or drug triggers recognizable on history taking. In light of the appearance of the lesions after Lisinopril dose escalation, in the absence of any other discernible triggers, an adverse drug reaction (ADR) was entertained, yielding a corresponding Naranjo ADR probability score of 7. Also, skin biopsy revealed the diagnosis to drug-induced bullous pemphigoid (BP) [27] . 3.1. Toxic Epidermal Necrolysis (TEN): Alkurtass DA et al reported a case of toxic epidermal necrolysis (TEN) possibly induced by captopril in a 1-week-old boy who referred to the hospital for tetrology of fallot surgical repair, performed on admission day 2. On third day, the patient developed third-degree heart block, necessitating pacemaker connection and oral theophylline 3 mg/kg 3 times daily. Oral captopril 1 mg twice daily, furosemide intravenously 7 mg every 12 hours, and oral aldactone 7 mg twice daily was started. On day 5, the patient developed scaling erythematous skin lesions. On day 7, the temperature was raised to 37.8 degrees C, and pus discharge from the pacing wire site was noticed. Intravenous vancomycin 80 mg 3 times daily and intravenous ceftazidime 200 mg 3 times daily were initiated. On the same day, captopril was discontinued

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because the author suspected that it had induced the skin reaction. On day 15, the infant's skin problem progressed. The dermatologist diagnosed partial TEN. On that day, theophylline and furosemide were also discontinued. On day 16, the patient still had some blisters, but the skin started to show signs of healing, until complete healing occurred on day 22. The infant was discharged with oral medications which includes furosemide 7 mg twice daily, aldactone 7 mg twice daily, and enalapril 0.1 mg twice daily. Three weeks later, he was followed up. No recurrences were observed. The probability of captopril being the cause of TEN in this case was rated possible on the Naranjo probability scale. Based on the observations in this case, the author concludes that captopril was the most likely cause for the adverse reaction, which was aggravated by the other sulfa medications and the presence of infection. Although the incidence of captopril-induced TEN is very low, and even lower in the pediatric population, underreporting might mask its true incidence. Healthcare professionals, particularly clinical pharmacists, should be encouraged to report adverse drug reactions [28] . 3.2. Penile Angioedema: Miller DG et al reported a case of Penile Angioedema after 3 years of ACE inhbitors therapy in a 71-year-old man who presented with painless, non-pruritic genital swelling of four hour duration. The patient was a known case of peptic ulcer disease, hypertension, and benign prostatic hypertrophy. Medications history of past 3 years includes pantoprazole, hydrochlorothiazide, and lisinopril, without any recent change in dosing. The physical examination revealed diffuse, soft, nonpitting edema isolated to the scrotum and uncircumcised penis. The foreskin was only partially retractable. Urinalysis was found to be normal. All symptoms resolved within 48 hour of discontinuing lisinopril. There is no recurrence found at follow-up after 4 months. Angiotensin-converting enzyme inhibitor related angioedema (ACEI-RA) can present as isolated swelling of the genitals and is a potential cause of genital swelling. In this case management of the adverse drug reactions was discontinuing the offending agent [29] . 3.3. Isolated Unilateral Tongue Oedema: Edmund Leung et al reported a case of Isolated Unilateral Tongue Oedema induced by Angiotensin Converting Enzyme Inhibitors in a 64-year-old Caucasian woman with a history of liver transplant on Mammalian Target Of Rapamycin (mTOR) inhibitor, who attended Emergency department with angio-oedema only on the left side of the tongue. The airway was patent and the patient was haemodynamically stable. Trauma was denied. Two days earlier the patient was prescribed with lisinopril for newly diagnosed benign hypertension. Intravenous steroids and antihistamine were administered immediately. The oedema subsidence was noted. Precipitating factors is often difficult to pre-determine and to avoid. Early detection of risk factors and diagnosis of angio-oedema induced by drugs is necessary for further management of the conditions. Angio-oedema presents in 0.1% of patients treated with ACE Inhibitors. Unilateral tongue swelling induced by ACE Inhibitors occurs rarely. Inhibition of angiotensin converting enzyme blocks conversion of angiotensin I to II, thereby reduces catabolism of bradykinin and increases its activity. These vasodilatory and hyperpermeable effects is considered has the mechanisms responsible for angio-oedema [30] . 3.4. Angioedema of the small bowel: Mark Terence P Mujer et al reported a case of Angioedema of the small bowel caused by lisinopril in a 42-year-old man with a history of chronic kidney disease (stage III) and hypertension who presented with acute onset of left lower quadrant abdominal pain that results in disturbance of sleep. The patient described the pain as 8/10 in severity, cramping in nature and worsened on eating or drinking. Pain was associated with nausea, intractable vomiting, dyspnoea and dizziness. He had tenderness over the suprapubic and left lower quadrant. Initial CT scan of the abdomen pelvis with contrast revealed thick-walled small

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bowel loops of the proximal ileum and jejunum with surrounding haziness producing luminal narrowing. Evidence of mild free fluid in abdominal and pelvic cavities was also found. At this stage, inflammatory bowel disease or colitis was suspected, and the patient was started with empirical ciprofloxacin and metronidazole. The patient was kept on bowel rest. CT enterography (CTE) revealed diffuse thickening of the wall and fluid surrounding the distal small bowel; proximal ileum involvement was greater than jejunum. Moderate volume of free intra-abdominal fluid was also found. A detailed review of the patient’s history revealed that the patient was recently started on lisinopril approximately 2 weeks prior to the onset of symptoms. ACE inhibitors have been known to cause angioedema. Lisinopril was discontinued immediately. Patient had improvement of the symptoms in 24 hours and was subsequently discharged with no further recurrence [31]. 3.5. Linear immunoglobulin A (IgA) bullous dermatosis: Ilyse S. Friedman et al reported a case of Captopril-triggered linear IgA bullous dermatosis in a 57-year-old African–American woman with past history of asthma, hypertension, and congestive heart failure who presented with intensely pruritic, blistering eruption which was presented for a period of two months. The blistering began two weeks after the initiation of captopril for essential hypertension. It was localized and found to be predominant on the thighs and legs. Also, it was found recently that it spreaded to the upper extremities. Previously, the patient had been treated with albuterol and furosemide. She had been admitted to the hospital with a diagnosis of acute varicella, which was ruled out by a negative Tzanck preparation. Clarithromycin was prescribed upon discharge. Physical examination revealed multiple healed and crusted erosions ranging in size from 1 to 7 cm on the anteromedial aspect of the thighs and legs. Discrete and confluent tense vesicles, some forming arciform or rosette-like patterns, were noted. Multiple hypopigmented macules and patches were seen. On the flexural aspect of the forearms, there were multiple small erosions, some of which appeared excoriated. There were no urticarial lesions found and the oral mucosa and scalp were spared. Direct immunofluorescence (DIF) staining revealed linear deposition of immunoglobulin A (IgA) at the dermal–epidermal junction. Drug-induced Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is characterized by the spontaneous remission of the blisters after the removal of the offending drug. In this case, the patient continued to blister for 1 year despite the cessation of the implicated drug. In addition, she required treatment with dapsone and corticosteroids for complete control of the blistering process. This suggests that the drug may have induced the expression of a pre-existing bullous dermatosis [32] . 3.6. Cutaneous Vasculitis: Gupta S et al reported a case of Ramipril-induced cutaneous vasculitis in a 61-year-old patient who had been treated with ramipril for left ventricular dysfunction. The patient developed a painful symmetrical purpuric eruption over both feet after three days. A full vasculitis screen was found to be negative. Ramipril was stopped and the patient was treated with a course of steroids after which the rash improved slowly. The ACE inhibitors can cause various skin adverse drug reactions; however, it rarely causes cutaneous vasculitis [33] . 3.7. Generalized Pustular Psoriasis: Thakor P et al reported a case of Ramipril-Induced Generalized Pustular Psoriasis in a 67- year-old African American woman with a history of rheumatoid arthritis and psoriatic arthritis who presented to the emergency department with chief complaint of new-onset rash, chills, and fatigue after started taking ramipril (5 mg orally every day) for hypertension. The rash was found in the entire upper chest, both arms, palms, and soles and was characterized as exfoliating associated with scattered small pustules of 1-2 mm in size. Patient was admitted with a differential diagnosis of exfoliative dermatitis versus adverse drug reaction

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for which ramipril was stopped. After admission, the patient’s temperature was raised to 102° F associated with chills. Blood cultures, chest x-ray, and urine analysis were found to be normal. With the help of clinical characteristics, the patient was presumed to have generalized pustular psoriasis (GPP), which was later confirmed by the skin biopsy results. She was treated with methylprednisolone to which the patient responded dramatically with satisfied improvement in rash and fever was subsided. The GPP was considered to be secondary to ramipril. Health care providers should be aware of this potentially serious complication of psoriasis when ramipril is prescribed to the patients with psoriasis [34] . 3.8. Severe Hypoglycemia: Elorriaga-Sánchez F et al reported a case of severe hypoglycemia in a woman of 66-years- old, non-diabetic who received captopril for six years, and recently ramipril. Six months ago, the patient was presented with disorientation, sweating and confusing words frequently. Glucose tolerance test one hour after administration of glucose was found to be 53 mg/dl. Test of insulin and C peptide were found to be normal. Glucagon was found with moderate elevation. The Blood Pressure (BP) was found to be increased and the medication was changed to ramipril, which improved the blood pressure but the hypoglycemia persisted. A recent change was made to the patient where Losartan and Hydrochlorothiazide was given. After 72 hours the patient was improved. A new glucose tolerance test one hour after administration of glucose was found to be normal. General condition of the patient was observed for a period of three months and was found to be asymptomatic. The Blood Pressure was also found to be normal [35] . 3.9. Oral Bullous Eruption: Bari čevi ć M et al reported a case of Oral bullous eruption after taking lisinopril in a female patient who was under treatment with an angiotensin-converting enzyme inhibitor (ACE inhibitor), lisinopril for hypertension. The patient developed blisters and ulcerations on oral mucosa 3 weeks after lisinopril intake. Based on clinical finding drug-induced pemphigus was predicted. But direct and indirect immunofluorescence analysis revealed no autoantibodies which are commonly present in pemphigus. Histological study revealed allergic reaction. Lisinopril was discontinued immediately and after a month the patient has complete remission of the symptoms [36] . 3.10. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare, life-threatening, non- dose related and unpredictable adverse drug reaction manifesting with exanthema, eosinophilia, lymph node enlargement, hepatitis, interstitial pneumonia, myocarditis and interstitial nephritis. Pileri A et al reported a case of Ramipril-induced drug reaction with eosinophilia and systemic symptoms (DRESS) in a 69-year-old man with chief complaints of the abrupt onset of erythematous macules and plaques on the thorax, flanks and extremities associated with facial edema and fever (38°C). Physical examination revealed hepatosplenomegaly and bilateral axillary and cervical lymph-node enlargement. Ramipril (5 mg/day) was started five weeks before for arterial hypertension. The patient denied the intake of other drugs and the past medical history was unremarkable. Histopathological examination of a skin biopsy revealed a superficial perivascular lymphohistiocytic infiltrate with eosinophils, compatible with the diagnosis of drug reaction. Both direct and indirect immunofluorescence tests on the skin biopsy excluded bullous auto-immune disorders. Ramipril was discontinued, topical and systemic steroids (prednisone for 7 days, tapering within 3 weeks) were started. Skin lesions resolved within 2 weeks after the discontinuation of the drug; eosinophilia and hepatitis resolved completely after one month. The causality between DRESS and ramipril in this case can be described only as probable. DRESS develops in 1 week to 3 months after the consumption of a new drug. Clinically DRESS starts as a maculo-papular exanthema that can evolve into erythroderma. Face, trunk and upper

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limbs are firstly involved and facial oedema, especially in the periorbital area, is characteristic. Systemic symptoms as well as fever and malaise can be present. Regarding other ACE inhibitors, captopril also appears to be a possible trigger of DRESS. DRESS patients require prompt diagnosis and drug withdrawal, close monitoring, appropriate therapy and absolute avoidance of the trigger drug in the future [37] . 3.11. Interstitial Granulomatous Drug Reaction (IGDR): IGDR is a recently proposed drug-associated entity. The most common clinical manifestation is asymptomatic infiltrative erythematous to violaceous plaques, mainly involving the intertriginous areas, medial thighs and inner aspects of the arms. IGDR usually occurs after a prolonged incubation period ranging from 4 weeks to 25 years (mean 5 years), and resolves within 1–40 weeks (mean 8 weeks) after discontinuation of the implicated drug. Chen YC et al reported a case of Interstitial granulomatous drug reaction presenting as erythroderma due to enalapril maleate in a 66-year-old man presented with a mildly pruritic skin rash. He had a history of medically controlled hypertension and benign prostate hyperplasia. He denied any previous skin disorder. Medications included enalapril maleate, tamsulosin HCl and terazosin HCl. Under the suspicion of drug-induced skin eruption, tamsulosin HCl and terazosin HCl were discontinued sequentially. However, the eruption persisted and progressed from the abdomen and upper chest to erythroderma within 3 months. He was referred to the clinic for further evaluation. Physical examination showed diffuse erythematous changes over the whole body with redundant skin folds on the axillae and bilateral palpable inguinal lymph nodes. A full blood count revealed eosinophilia and atypical lymphocytes. Skin biopsies from the left axilla and upper left arm showed diffuse interstitial granulomatous infiltrates in the dermis. The infiltrate was composed of mainly small histiocytes and lymphocytes with palisading around partially degenerated collagen. There were numerous eosinophils and scattered multinucleated giant cells. Focal vacuolar interface dermatitis was also observed. Neither dermal mucin nor neutrophilia was prominent. No vasculitis was observed, nor was there subcutaneous tissue involvement. Most infiltrating cells were CD3+ and partially CD8+. Sparse CD56+ cells were also identified. The CD20 staining revealed scattered reactive B cells. No medication was prescribed and the cutaneous lesions resolved within 2 months after discontinuation of enalapril maleate. The blood tests showed no more atypical lymphocytes after discontinuation of the implicated drug for 9 months [38] . 3.12. Psoriatic Erythroderma: Antonov D et al reported a case of Psoriatic Erythroderma in a 59-year-old man with a 35- year personal and positive family history of psoriasis who admitted for treatment of psoriatic erythroderma. The patient was treated with enalapril 10 mg twice a day for hypertension approximately six weeks before admission to the hospital. Five weeks after the initiation of enalapril, the patient’s psoriasis began to flare, and for duration of about 1 week it was reached to the extent of erythroderma. Diffuse erythema and pronounced desquamation covering the entire trunk, scalp, and extremities was found in the patient. 100% of the total body surface area was affected. The palms and soles were also affected, which was characterized as erythema, hyperkeratosis, and painful fissures. The nails were characterized as pits, oil spots, and subungual hyperkeratosis. The patient also had psoriatic arthritis affecting the interphalangeal joints of the fingers. Laboratory investigations showed an elevated erythrocyte sedimentation rate, an elevated creatinine level, a blood urea nitrogen level, and a uric acid level. Urinalysis showed proteinuria. The patient's renal condition was revealed as chronic tubulointerstitial nephritis, most probably due to the dermatologic disease. Allopurinol and dietary measures was recommended to the patient. On treatment with methotrexate and replacement of enalapril , the erythema and scaling gradually subsided [39] .

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3.13. Dry Persistent Cough: A dry persistent cough is a known adverse drug reaction of the angiotensin- converting enzyme (ACE) inhibitor medications. The mechanism behind the ACE inhibitor- induced cough is due to the protussive mediators called bradykinin and substance P. These are the agents that are degraded by ACE and lead to accumulation in the upper respiratory tract when the ACE is inhibited, and prostaglandins, the production may be stimulated by bradykinin. The incidence rate of ACE inhibitor-induced cough has been estimated to be in the range of 5 to 35% in patients treated with the ACE inhibitors. Eventhough, incidence rate of patients presenting for the evaluation of chronic cough is lower. The onset of ACE inhibitor-induced cough occurs within hours of the first dose or months after the initiation of these agents. Resolution from this adverse drug reactions typically needs 1 to 4 weeks after the cessation of the offending agents (ie ACE inhibitors), but cough may linger for up to 3 months. The only effective treatment for ACE inhibitor-induced cough is the cessation of the offending agent. The incidence rate of cough due to angiotensin-receptor blockers appears to be similar to that of the control drug. In a small group of patients, cough will not recur after the reintroduction of ACE inhibitors. ACE inhibitors should be considered as wholly or partially causative agent in patients with chronic cough regardless of the temporal relation between the initiation of ACE inhibitors and the onset of cough. Even though the cessation of the ACE inhibitors is the only effective treatment for ACE inhibitor-induced cough, some pharmacologic agents have shown to attenuate the cough [40] .

IV. ADVERSE DRUG REACTIONS OF CALCIUM- CHANNEL BLOCKERS 4.1. Small Intestine Angioedema: Turcu AF et al reported a case of small intestine angioedema caused by calcium channel blockers (CCBs) in a 56-year-old African American woman presented with eight episodes of diffuse, intermittent abdominal pain, nausea, vomiting, and diarrhea, over the period of 2 years. Abdominal computed tomographic scans revealed prominent mural thickening of different intestinal segments, always involving the ileum. An esophagogastroduodenoscopy revealed patchy edematous, violaceous folds in the second portion of the duodenum. Colonoscopy showed a markedly edematous and erythematous distal ileum. The recurrences subsided after CCBs was discontinued in this patient and reoccurred when they were incidentally restarted. The case demonstrates that CCBs can cause isolated intestinal angioedema. The discontinuation of the suspected drug is the key for both diagnosis and management of the adverse drug recations [41] . 4.2. Hepatitis: Nifedipine-induced hepatitis is a rare drug induced liver injury (DILI). Dimas Yusuf et al reported a case of Nifedipine-induced hepatitis with Jaundice in a 78-year-old Caucasian female presented with jaundice, scleral icterus, and mild epigastric discomfort. The patient complaints a four day history of progressive fatigue with intermittent nausea and vomiting, diminished appetite, loose, lightly coloured, and foul-smelling stools. The past medical history included essential hypertension. The medications history was nifedipine 10 mg daily which was started 14 days prior to admission. Initial laboratory investigations showed elevations in all liver enzymes, bilirubin, and LDH, which is the indication of significant hepatocellular injury. A computed tomography (CT) scan of abdomen showed hepatic parenchyma was unremarkable, with no evidence of hepatic obstruction, biliary duct dilatation, thrombosis, or malignancy. A follow-up abdominal ultrasound showed that the patient’s liver had a heterogeneous echotexture. The gallbladder was markedly thickened and

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edematous but decompressed. Nifedipine was held on admission. The patient’s liver enzymes started to steadily improve during the admission. The reason behind nifedipine-induced hepatitis is not much known due to its rare occurrence. Therefore the prevalence is not known. The management of drug induced liver injury includes immediate discontinuation of the offending agent with supportive care. Eventhough, this condition can take months to resolve [42] . 4.3. Dysuria: Nifedipine XL is an extended-release calcium channel blocker that is widely used as antihypertensive medication. Patil K et al reported a case of a 40-year-old man who presented with 6 months of a burning sensation in his penis that was most noticeable during urination and worse after intercourse. He denied fevers, chills, night sweats, polyuria, hematuria, and abdominal pain. His medical history included hypertension, hypertriglyceridemia, and degenerative disk disease. Medications included nifedipine XL, hydrochlorothiazide, gemfibrozil, naproxen, cyclobenzaprine, and oxycodone. Physical examination results were unremarkable. Urinalysis, urine culture, chlamydia and gonococcus gene probes, comprehensive metabolic panel, complete blood count, human immunodeficiency virus antibody, and rapid plasma reagin syphilis screening test results were negative. Drug-reaction was suspected; all medications except gemfibrozil and nifedipine XL were discontinued, but dysuria persisted. Tamsulosin was started for possible benign prostatic hyperplasia, and ciprofloxacin was subsequently given for possible chronic prostatitis; neither yielded relief. Because of his high daily caffeine intake, discontinuation of caffeine was tried, but also with no improvement. The patient self-discontinued the gemfibrozil and nifedipine XL, and within several days the symptoms completely resolved. Symptoms recurred when nifedipine XL, but not gemfibrozil, was restarted. Discontinuation of nifedipine XL again resulted in resolution of dysuria. The Naranjo score was 7, making this case a probable adverse drug reaction. The pathophysiology behind this adverse drug reaction is unclear. Paradoxically, studies have shown nifedipine to be effective in treating interstitial cystitis, including cases where dysuria was a presenting symptom. Nifedipine also has been used to reduce the frequency and amplitude of bladder contractions. Given these findings, this patient may ostensibly be a slow metabolizer of a long-acting formulation, thereby having excess bladder smooth muscle relaxation secondary to elevated serum drug concentrations and thus experiencing discomfort from bladder distention. However, this does not seem likely given the absence of systemic hypotension or any symptoms of overflow incontinence [43] .

4.4. Acute generalized exanthematous pustulosis (AGEP):

Sáenz de Santa María García M et al reported a case of Acute generalized exanthematous pustulosis due to diltiazem in a 79-year-old women with hypertension, treated for 3 months with amlodipine. She was then switched to diltiazem by her primary care physician because of poor blood pressure control. She developed a micropapular rash on the thorax and face after taking the diltiazem for 6 days. The rash then spread to the rest of the trunk, folds, and thighs, eventually affecting about 30% of her total body surface area. The rash evolved to confluent surface pustules. She had crusted erosions in labial and gingival mucosa and labia edema. She also developed fever. The episode resolved in 10 days after the patient stopped diltiazem and treatment with methylprednisolone for 10 days. A skin biopsy was done at admission; the pathology described subcorneal spongiform pustules and spongiosis in the epidermis. There were perivascular infiltrates, interstitial inflammation, and polymorphonuclear eosinophils noted in the underlying dermis. The EuroSCAR score for AGEP was 10 (definitive). Patch testing (PT) was performed (4 weeks after resolution of AGEP) with diltiazem (in 10% petrolatum), verapamil (in 30% petrolatum), and nifedipine

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(in 2% petrolatum). Readings were taken at 48 hours (Day 2) and 96 hours (Day 4). The patient had positive results on Day 2 and Day 4 with diltiazem and verapamil (induration and erythema of 4 and 5 mm, respectively) and negative test results with nifedipine. Treatment is based on withdrawal of the offending agent, use of systemic steroids, and symptomatic treatment with antihistamines and emollients [44] .

4.5. Gynecomastia:

Komine N et al reported a case of Amlodipine induced Gynecomastia in a 42-year-old man. His past medication history includes 10mg of amlodipine. He began complaining of a painful right subareolar nodule. Physical examination revealed a right subareolar nodule measuring 2.5 × 1.0cm. It was suggested that the use of amlodipine had resulted in the right gynecomastia. Losartan was substituted for amlodipine. Symptoms of gynecomastia were seen to subside over the following two weeks. One month later, however, the patient wished to take amlodipine again because of worsening hypertension. Amlodipine was readministered. The patient then noticed mild left gynecomastia 3 weeks later, and consequently stopped taking amlodipine. In the present report, withdrawing amlodipine was associated with the disappearance of subareolar tissue. Furthermore readministration of the drug resulted in the recurrence of the disorder. During the last 2 decades, gynecomastia associated with calcium channel blockers (CCBs) has been reported. Verapamil, nifedipine, and diltiazem have been implicated as causing gynecomastia [45] .

4.6. Gingival Hypertrophy: Murat Sucu et al reported a case of Amlodipine induced massive Gingival Hypertrophy in a 14-year-old boy who presented with gingival swelling. Renal transplant for focal segmental glomerulosclerosis was done for the patient. Medical history showed that the patient was a known case of hypertension. His medication history includes oral amlodipine (10 mg twice daily) for the past 3 years. The patient had been suffering from increasing gum swelling since 2 years. Examination of the oral cavity showed substantial diffuse gingival hypertrophy of both the upper and lower gums. The hypertrophic gingiva was painless, and there was no sign of inflammation or ulceration. The patient’s oral hygiene was normal. After excluding other potential causes, the author considered the diagnosis of amlodipine-induced massive gingival hypertrophy. The author substituted an angiotensin receptor blocker for the amlodipine, and within 6 months the gingival hypertrophy had regressed completely. Amlodipine can cause gingival hypertrophy [46] . The prevalence of amlodipine-induced gingival hypertrophy has been estimated to be between 1.7% and 3.3% [47,48] . The incidence rate of gingival hypertrophy with nifedipine therapy has been reported to be as high as 20% [49] , and a 2002 study reported that the prevalence with the use of CCBs might be as high as 38%. Gingival hypertrophy is 3.3 times more common in men than in women. Untreated gingival hypertrophy might lead to bleeding, infection, abscess, ulceration, cosmetic deficiency, and functional difficulty (e.g.: chewing, talking) [50] . Treatment of drug-induced gingival hypertrophy includes cessation of the drug and decreasing other risk factors with meticulous mechanical and chemical plaque control. Replacing the affecting drug with another agent is also recommended when possible. Gingivectomy (excision of excessive gingival tissue) should be reserved for severe cases that affect oral hygiene or functionality, or can be performed for cosmetic reasons.

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V. ADVERSE DRUG REACTIONS OF VASODILATORS 5.1. Acute Cholestatic Liver Injury: Hadi Harati et al reported a case of hydralazine induced hepatotoxicity in the form of subacute hepatic necrosis in a 75-year-old African American woman presented with jaundice of 7-day duration. The patient was started on hydralazine 100 mg 3 times a day 10 weeks before presentation. Physical examination showed scleral icterus. Lab investigations showed elevated liver transaminases, alkaline phosphatase, and conjugated bilirubin. The patient was not a known case of liver disease. Liver function test was found to be normal before starting hydralazine. Abdominal imaging studies did not show any evidence of intrahepatic or extrahepatic biliary ductal dilatation, and no pathologies were seen in the liver and pancreas. The patient’s liver biopsy showed extensive lobular hepatitis, significant necrosis, mixed inflammatory infiltrate, and no significant fibrosis, supporting a diagnosis of drug-induced liver injury. Hydralazine was discontinued immediately. Improvement in clinical and laboratory findings was seen within 5 days after discontinuation of hydralazine. To rule out the diagnosis of hydralazine-induced liver injury, the author used assessment tool outlined by the Council for International Organization of Medical Sciences (CIOMS) scale that led to “high probable” relationship. Use of hydralazine can result in clinically significant, and potentially life-threatening liver injury. Both clinical and histological presentations in this patient suggest acute liver injury. The hydralazine-induced hepatitis seems to be reversible as discontinuation of the drug improves clinical outcomes. Hence, monitoring of the liver function during hydralazine treatment is recommended [51]. 5.2. Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis: Roman Zuckerman et al reported a case of drug-induced anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (DIV) in a 57-year-old Caucasian man with past medical history of hypertension and mild osteoarthritis, presented with complaints of hematuria and acute renal failure. Four days prior to the presentation, the patient was seen by the primary care for possible sinusitis, dysuria, and mild hematuria. Amoxicillin was prescribed for three days for a presumed urinary tract infection. The patient reported some fatigue, denied smoking or the use of alcohol and illicit drugs. Current medications included amlodipine 10 mg/day and hydralazine 50 mg twice a day, which was started six weeks before for better blood pressure control. There was no significant finding on the physical examination. The urinalysis revealed hematuria and low-grade proteinuria. Microscopic examination of the urine sediment showed numerous dysmorphic red blood cells, several red blood cell casts, and occasional white blood cells. Renal ultrasound was found to be normal. A diagnosis of hydralazine-induced DIV was considered and the medication was discontinued. Serology was positive for AHA, cANCA by immunofluorescence and PR3 by ELISA. The patient was treated with high-dose pulse steroid therapy (500 mg/day for three days). However, the renal failure continued to progress and the patient required dialysis therapy due to hyperkalemia and acidosis. Kidney biopsy revealed pauci-immune necrotizing glomerulonephritis with increase in 20% of glomeruli. The diagnosis of hydralazine-induced DIV was made. The patient was treated with pulse steroid and rituximab. Renal function stabilized and dialysis was discontinued after four sessions. He was discharged on day twelve with normal electrolytes and serum creatinine. PR3 and ANA were undetectable. Two years later, the patient remained stable but with an advanced CKD stage III. His blood pressure remained around 130-140/85-90 mmHg with amlodipine 10 mg/dL, chlorthalidone 12.5 mg/day, and ramipril 10 mg/day. The clinical presentation of hydralazine-induced DIV is usually more severe. It usually involves the skin, with involvement of kidneys and lungs also. Patients can present with rapidly progressing necrotizing and crescentic glomerulonephritis

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along with arthralgia, upper airway involvement, pulmonary disease, and cutaneous vasculitic findings [52] . 5.3. Amenorrhea: Kwadwo A. Yeboah et al reported a case of Hydralazine-Associated Amenorrhea in a 31- year-old premenopausal patient with CKD who developed amenorrhea after the initiation of hydralazine. When the patient reported amenorrhea as an adverse effect, her medications were fully reviewed to identify potential causes of the adverse effect. Hydralazine was determined to be the suspected drug by virtue of its initiation date in connection with the onset of the adverse effect. As a result, hydralazine was tapered and discontinued to see if the adverse effect would subside. Use of the Naranjo adverse drug reaction probability scale generated a score of 6. This suggests a probable relationship between the development of amenorrhea and hydralazine therapy [53] . 5.4. Lupus Pneumonitis: Hydralazine-induced lupus (HIL) is an adverse drug reaction of hydralazine which showed an incidence of 5–8% per year. Clinical features of HIL include arthralgias, myalgias, pleuritic chest pain, fever, and lymphadenopathy; however, symptoms are non-specific making certain diagnosis difficult. HIL often has a mild presentation with reversible symptoms after discontinuation of the offending agent. Pulmonary involvement of HIL is rare. Diagnosis of hydralazine-induced lupus is more difficult and challenging process as it requires temporal relationship between hydralazine administration and symptom onset, lack of alternative etiologies, and symptom improvement with drug withdrawal [54,55,56] . Borchers and colleagues established a list of diagnostic criteria to support the diagnosis of drug-induced lupus erythematosus. These criteria include (1) sufficient and continuing exposure to a specific drug, (2) at least one symptom being compatible with lupus, (3) having no history of SLE before using the drug, and (4) recovered and resolution of symptoms within weeks to months after discontinuation. These authors note that while a positive ANA is often considered to be required for the diagnosis, a negative ANA does not necessarily eliminate a diagnosis if the patient has other positive autoantibodies [57] . Sarah K. Holman et al reported a case of Acute Low-Dose Hydralazine-Induced Lupus Pneumonitis in a 35-year-old female who started on hydralazine 10 mg orally three times a day for treatment of postpartum hypertension. After multiple unsuccessful courses of prednisone and antibiotics for presumed pneumonia and asthma exacerbations, the patient’s respiratory symptoms progressed in severity and the patient developed resting hypoxia three months latter. Previous investigations included spirometry which showed restrictive pattern, chest CT revealed bilateral basilar consolidation, negative BAL, and nonspecific findings on lung biopsy of mild inflammatory cells. Review of systems was positive for arthralgia, lymphadenopathy, paresthesia, and fatigue that began four weeks after starting hydralazine. A clinical diagnosis of hydralazine- induced lupus (HIL) with pneumonitis was made. Antihistone antibodies were positive which supports the diagnosis of HIL. Management included cessation of hydralazine and a prolonged steroid therapy. Within days, patient began to improve symptomatically. Six weeks later, CT chest revealed complete resolution of infiltrates. Genetic testing revealed that the patient was heterozygous for N-acetyltransferase 2 (intermediate acetylator). In patients with lupus-like symptoms taking medications with a known association should be considered as drug induced lupus. While the majority of HIL cases occur with high doses and prolonged treatment, cases of low-dose HIL have been reported in patients who are slow acetylators.. When the Naranjo adverse drug reaction probability scale is used, this case showed a total score of seven making the causality probable [58] .

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VI. ADVERSE DRUG REACTIONS OF DIURETICS 6.1. Acute generalised exanthematous pustulosis (AGEP): Acute generalised exanthematous pustulosis (AGEP) is defined as a severe cutaneous adverse drug reaction which is characterised by erythematous plaques and papules with overlying non-follicular pinpoint pustules. Approximately 90% cases of AGEP are caused due to drugs. Leo E Reap et al reported a case of Hydrochlorothizide-induced acute generalised exanthematous pustulosis in 80-year-old woman who presented with the development of bilateral eye swelling that started three days prior to admission. The patient described 1-year history of a diffuse, erythematous rash localised to trunk, upper extremities and face which was extremely pruritic in nature. Skin examination showed a diffuse maculopapular rash on the chest, upper extremities, face and trunk with convalescent non-follicular pustules throughout. The rash was especially prominent in the skin folds with desquamation present on the dorsal hands and near the axillae. Periorbitally, there was erythema with epicanthal drainage and a yellow crust. Medication history revealed that a year before, the patient’s antihypertensive regimen was changed from atenolol monotherapy to combination Hydrochlorothizide (HCTZ)/losartan. Treatment in this case includes Cessation of combination HCTZ/losartan therapy, Administration of topical mupurocin periorbitally, Topical betamethasone administration and Initiation and titration of metoprolol succinate. After two weeks the patient had complete resolution of all symptoms. Only minimal residual desquamation apparent on the dorsal fingers bilaterally was seen in the patient. Healthy new skin growing in the previously affected areas was seen in the patients [59] . VII. ADVERSE DRUG REACTIONS OF ANGIOTENSIN II RECEPTOR ANTAGONISTS 7.1. Pustular Psoriasis: Pustular psoriasis is defined as the abrupt onset of macroscopic pustules associated with erythema, burning pain and constitutional symptoms. Subramaniam Keerthi et al reported a case of Telmisartan aggravates pustular psoriasis in a 50-year-old male patient who is a known case of pustular psoriasis, which was controlled on oral methotrexate. The patient presented with sudden exacerbation with fresh crops of pustules. The patient’s medical history includes hypertension. Medication history includes 10mg Amlodipine per day since 4 years for hypertension. Due to persistently high blood pressure of 160/100 mm Hg the patient was prescribed with telmisartan. One week later, the patient reported with chief complaints of severe burning sensation and several new groups of lesions occurring over the arms and legs. On examination, multiple, well-defined, discrete, pin-point pustules was observed over the bilateral arms, forearms, thighs and lower legs, with involvement of the bilateral axillae. The patient was treated symptomatically and telmisartan was discontinued. A gradual regression of new lesions and healing of existing lesions was seen within few days of treatment. The patient was discharged after complete resolution of the symptoms and prescribed with oral prazosin 2.5 mg. The patient was asymptomatic for period of 6 months. Pustular psoriasis aggravated due to telmisartan is considered as drug-induced reactions. Hence, discontinuation of the offending agent immediately is the first line step in management of the adverse drug reactions which results in stopping the progression of disease. This case indicates that the healthcare providers should be aware of drugs that exacerbate the skin conditions especially while starting a new drug in patients with pustular psoriasis [60] .

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7.2. Palmoplantar Hyperkeratosis: Losartan acts in the renin angiotensin system (RAS) by blocking the angiotensin II receptor. Several reports on cutaneous adverse drug reactions due to angiotensin II receptor antagonists results from their effect on the local cutaneous RAS. Calvo M et al reported a case of palmoplantar lesions that developed in a patient taking losartan and the subsequent remission was observed after treatment withdrawal. Incidence of cutaneous adverse drug reactions due to angiotensin II receptor antagonists was highly reported. This indicates that these agents may mimic a broad variety of classical skin disorders. Cause of sudden, inexplicable skin eruptions in patients taking angiotensin receptor antagonists should be considered and further management of the condition can decrease progression of the condition [61] . 7.3. Angioedema: Chiu AG et al conducted a retrospective chart review were three patients taking the Angiotensin II receptor blocker (ie, losartan) were presented with mucosal swelling in the head and neck which was clinically consistent with angioedema. A prior episodes of angioedema was observed in all the three patients who were on treatment with losartan. Involvement of the anterior tongue and face was observed in two patients which was resolved within 12 hours of discontinuation of the losartan. Intravenous steroids was administrated to those two patients. Recurring episodes of angioedema was observed in the third patient. Tracheotomy for airway compromise was required for the third patient. Discontinuing the losartan and administrating a course of intravenous steroids results in resolution of angioedema in 5 days. After the onset of symptoms the patient was decannulated for 10 days. The true incidence of Angiotensin II receptor blocker-induced angioedema was unknown and also the pathogenesis behind this adverse drug reaction was unclear [62]. VIII. ADVERSE DRUG REACTIONS OF ALPHA BLOCKERS 8.1. Acute generalized exanthematous pustulosis (AGEP): Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous eruption mostly aggravated by the drugs. Speck LM et al reported a case of AGEP in a 74-year-old male that was attributed to the ingestion of terazosin hydrochloride [63] . 8.2. Hepatotoxicity: Fernández Salazar L et al reported a case of hepatotoxicity induced by terazosin, which resolved after withdrawal of the drug [64] .

IX. CONCLUSION Adverse Drug Reactions to Antihypertensive drugs are common and some of them resulted in increased healthcare cost due to the need of some interventions and increased length of hospital stay. The health system should promote the spontaneous reporting of Adverse Drug Reactions to antihypertensive drugs, proper documentation and periodic reporting to regional pharmacovigilance centers to ensure drug safety. Most of the adverse drug reactions are predictable and preventable. Therefore continuous monitoring and reporting of ADRs can have a positive impact on the medication use, improving the patient’s quality of life and in reducing the incidence of devastating ADRs. The active surveillance of a clinical pharmacist in detecting the Adverse Drug Reactions and giving the awareness regarding the need of monitoring and reporting of adverse drug reactions among healthcare professionals would improve the scenario in under-reported hospitals.

CONFLICTS OF INTEREST The author declares no conflicts of interest.

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References

1. Tarun Wadhwa, Samar Gamal El Sheikh, Padma G.M. Rao. Monitoring and Reporting of Adverse Drug Reactions Due to Cardiovascular Drugs in Patients Admitted to a Secondary Care Hospital in Northern Emirate- a Prospective Surveillance Study. Indian Journal of Pharmacy Practice. 2018; 11(2):71-78. 2. Davies EC, Green CF, Taylor S, Williamson PR, Mottram DR, and Pirmohamed M et al. Adverse drug reactions in hospital in-patients: A prospective analysis of 3695 patient-episodes. PLoS One. 2009; 4(2):e4439. 3. Haile DB, Ayen WY, and Tiwari P et al . Prevalence and assessment of factors contributing to adverse drug reactions in wards of a tertiary care hospital, India. Ethiop J Health Sci.2013; 23(1):39-48. 4. Schneeweiss S, Hasford J, Gottler M, Hoffmann A, Riethling AK, and Avorn J et al . Admissions caused by adverse drug events to internal medicine and emergency departments in hospitals: A longitudinal population-based study. Eur J ClinPharmacol. 2002; 58: 285-291. 5. Wadhwa T, Patil PA, and Suresh VP et al . Monitoring Adverse Drug Reactions in Coronary Thrombosis Patients Admitted to Intensive Cardiac Care Unit in a Tertiary Care Hospital. Indian Journal of Pharmacy Practice. 2013; 6(1):6-12. 6. Bates DW, Cullen DJ, Laird N, Petersen LA, Small SD, and Servi D et al . Incidence of Adverse Drug Events and Potential Adverse Drug Events: Implications for Prevention. Journal of American Medical Association JAMA. 1995; 274(1):29-34. 7. Sze Ling Chan, Xiaohui Ang, Levana L. Sani, Hong Yen Ng, Michael D. Winther, Jian Jun Liu, Liam R. Brunham and Alexandre Chan. Prevalence and characteristics of adverse drug reactions at admission to hospital: a prospective observational study. Br J Clin Pharmacol. 2016 Dec; 82(6): 1636–1646. 8. Wise L, Parkinson J, Raine J, Breckenridge A. New approaches to drug safety: a pharmacovigilance tool kit. Nat Rev Drug Discov. 2009; 8: 779–82. 9. Viklund A, Biriell C. VigiBase scales new heights. Uppsala Reports. 2015; 70: 5. 10. Fowad Khurshid, Mohammed Aqil, Mohammad Shamshir Alam, Prem Kapur, and Krishna K Pillai. Monitoring of adverse drug reactions associated with antihypertensive medicines at a university teaching hospital in New Delhi. Daru. 2012; 20(1): 34. 11. Ahmad SR. Adverse drug event monitoring at the food and drug administration. J Gen Intern Med. 2003; 18:57-60. 12. De Angelis R, Salaffi F, Grassi W. Raynaud’s phenomenon: prevalence in an Italian population sample. Clin Rheumatol. 2006; 25: 506–10. 13. Herrick AL. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat Rev Rheumatol. 2012; 8: 469–79. 14. Herrick AL. Pathogenesis of Raynaud’s phenomenon. Rheumatol Oxf 2005; 44: 587- 96. 15. Khouri C, Blaise S, Carpentier P, Villier C, Cracowski JL, Roustit M. Drug-induced Raynaud's phenomenon: beyond β- adrenoceptor blockers. Br J Clin Pharmacol. 2016 Jul; 82(1):6-16. 16. Charles Khouri, Thomas Jouve, Sophie Blaise, Patrick Carpentier, Jean ‐Luc Cracowski, and Matthieu Roustit. Peripheral vasoconstriction induced by β- adrenoceptor blockers: a systematic review and a network meta- analysis. Br J Clin Pharmacol. 2016 Aug; 82(2): 549–560. 17. Kelleher JA. Atenolol-induced breast pain in a woman with hypertension. Ann Pharmacother. 2006 May; 40(5): 990-2.

Volume 27, Issue 3, 2021 32 http://www.gjstx-e.cn/ High Technology Letters ISSN NO : 1006-6748

18. Yusuf SW, Mishra RM. Hepatic dysfunction associated with atenolol. Lancet. 1995 Jul 15; 346(8968):192. 19. Dumortier J, Guillaud O, Gouraud A, Pittau G, Vial T, Boillot O, Scoazec JY. Atenolol hepatotoxicity: report of a complicated case. Ann Pharmacother. 2009 Oct; 43(10):1719-23. 20. Patterson JF. Pseudoakathisia associated with atenolol. J Clin Psychopharmacol. 1986 Dec; 6(6):390. 21. Doyon JB, Liu KJ, Berman RA. Metoprolol induced Total body Erythroderma. J Gen Intern Med. 2017 Feb; 32(2):221-222. 22. Raheel SA, Kujan OB, Tarakji B, Umar D, Ibrahim S. Propranolol-induced gingival hyperplasia with Nager syndrome: A rare adverse drug reaction. J Adv Pharm Technol Res. 2016 Apr-Jun; 7(2):64-8. 23. Moore BM, Cordina RL, McGuire MA, Celermajer DS. Efficacy and adverse effects of sotalol in adults with congenital heart disease. Int J Cardiol. 2019 Jan 1; 274:74-79. 24. Vlahovic-Palcevski V, Milic S, Hauser G, Protic A, Zupan Z, Reljic M, Stimac D. Toxic epidermal necrolysis associated with carvedilol treatment. Int J Clin Pharmacol Ther. 2010 Aug; 48(8):549-51. 25. Gin A, Gin D, Sinclair R. Metoprolol-induced psoriatic nail disease. Australas J Dermatol. 2013 Feb; 54(1):59-60. 26. Gómez Torrijos E, García Rodríguez C, Sánchez Caminero MP, Castro Jiménez A, García Rodríguez R, Feo-Brito F. First Case Report of Acute Generalized Exanthematous Pustulosis Due to Labetalol. J Investig Allergol Clin Immunol. 2015; 25(2):148-9. 27. Ballout RA, Musharrafieh U, Khattar J. Lisinopril- associated bullous pemphigoid in an elderly woman: a case report of a rare adverse drug reaction. Br J Clin Pharmacol. 2018 Nov; 84(11):2678-2682. 28. Alkurtass DA, Al-Jazairi AS. Possible Captopril-Induced Toxic Epidermal Necrolysis. Ann Pharmacother. 2003 Mar; 7(3):380-3. 29. Miller DG, Sweis RT, Toerne TS. Penile Angioedema developing after 3 years of ACEI therapy. J Emerg Med. 2012 Aug; 43(2):273-5. 30. Leung E, Hanna MY, Tehami N, Francombe J. Isolated Unilateral Tongue Oedema: The Adverse Effect of Angiotensin Converting Enzyme Inhibitors. Curr Drug Saf. 2012 Nov 1; 7(5):382-3. 31. Mark Terence P Mujer, Manoj P Rai, Divyesh Reddy Nemakayala, Julie L Yam. Angioedema of the small bowel caused by lisinopril. Drug Ther Bull. 2019 Jan; 57(1):14-15. 32. Friedman IS, Rudikoff D, Phelps RG, Sapadin AN. Captopril-triggered linear IgA bullous dermatosis. Int J Dermatol. 1998 Aug; 37(8):608-12. 33. Gupta S, Gandhi NM, Ferguson J. Cutaneous Vasculitis secondary to ramipril. J Drugs Dermatol. 2004 Jan-Feb; 3(1):81-2. 34. Thakor P, Padmanabhan M, Johnson A, Pararajasingam T, Thakor S, Jorgensen W. mipril-Induced Generalized Pustular Psoriasis: Case Report and Literature Review. Am J Ther. 2010 Jan-Feb; 17(1):92-5. 35. Elorriaga-Sánchez F, Corrales-Bobadilla H, Sosa-Trinidad E, Domínguez-Quezada B. Severe hypoglycemia secondary to angiotensin-converting-enzyme inhibitors in the absence of diabetes mellitus. Report of a case. Gac Med Mex. 2001 May-Jun; 137(3):249-52. 36. Bari čevi ć M, Mravak Stipeti ć M, Situm M, Marinovi ć B, Seiwerth S, Bari čevi ć D, Lon čar B. Oral bullous eruption after taking lisinopril—case report and literature review. Wien Klin Wochenschr. 2013 Jul; 125(13-14):408-11.

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37. Pileri A, Brunasso AM, Tilz H, Wolf P, Massone C. Ramipril-induced drug reaction with eosinophilia and systemic symptoms (DRESS). Eur J Dermatol. 2011 Jul-Aug; 21(4):624-5. 38. Chen YC, Hsiao CH, Tsai TF. Interstitial granulomatous drug reaction presenting as erythroderma: remission after discontinuation of enalapril maleate. Br J Dermatol. 2008 May; 158(5):1143-5. 39. Antonov D, Grozdev I, Pehlivanov G, Tsankov N. Psoriatic erythroderma associated with enalapril. Skinmed. 2006 Mar-Apr; 5(2):90-2. 40. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence - based clinical practice guidelines. Chest. 2006 Jan; 129(1 Suppl):169S- 173S. 41. Turcu AF, White JA, Kulaga ME, Skluth M, Gruss CB. calcium channel blocker- associated small bowel angioedema. J Clin Gastroenterol. 2009 Apr; 43(4):338-41. 42. Yusuf D, Christy J, Owen D, Ho M, Li D, Fishman MJ. A case report of nifedipine- induced hepatitis with jaundice. BMC Res Notes. 2018 Apr 3; 11(1):228. 43. Patil K, Tabibian JH, Lake M, Sisson S. Nifedipine XL- induced dysuria. Am J Med. 2012 Sep; 125(9):e3-4. 44. Sáenz de Santa María García M, Noguerado-Mellado B, Rojas Pérez-Ezquerra P, Hernandez-Aragües I, De Barrio Fernández M. Acute generalized exanthematous pustulosis due to diltiazem: Investigation of cross-reactivity with other calcium channel blockers. J Allergy Clin Immunol Pract. 2016 Jul-Aug; 4(4):765-6. 45. Komine N, Takeda Y, Nakamata T. Amlodipine-induced gynecomastia in two patients on long-term hemodialysis therapy. Clin Exp Nephrol. 2003 Mar; 7(1):85-6. 46. Sucu M, Yuce M, Davutoglu V. Amlodipine- induced massive gingival hypertrophy. Can Fam Physician. 2011 Apr; 57(4):436-7. 47. Jorgensen MG. Prevalence of amlodipine-related gingival hyperplasia. J Periodontol. 1997; 68(7):676–8. 48. Ellis JS, Seymour RA, Steele JG, Robertson P, Butler TJ, Thomason JM. Prevalence of gingival overgrowth induced by calcium channel blockers: a community based study. J Periodontol. 1999; 70(1):63–7. 49. Nery EB, Edson RG, Lee KK, Pruthi VK, Watson J. Prevalence of nifedipine-induced gingival hyperplasia. J Periodontol. 1995; 66(7):572–8. 50. Prisant LM, Herman W. Calcium channel blocker induced gingival over-growth. J Clin Hypertens (Greenwich) 2002; 4(4):310–1. 51. Harati H, Rahmani M, Taghizadeh S. Acute Cholestatic Liver Injury From Hydralazine Intake. Am J Ther. 2016 Sep-Oct; 23(5):e1211-4. 52. Zuckerman R, Patel M, Costanzo EJ, Dounis H, Haj RA, Seyedali S, Asif A. Hydralazine-associated adverse events: a report of two cases of hydralazine-induced ANCA vasculitis. J Bras Nefrol. 2018 Apr-Jun; 40(2):193-197. 53. Yeboah KA, Allspaw A, Al-Makki A, Shepler BM. Hydralazine-Associated Amenorrhea in a Premenopausal Patient With Chronic Kidney Disease: A Case Report and Review of Literature. Clin Ther. 2018 Sep; 40(9):1592-1595. 54. Xiao X and Chang C. Diagnosis and classification of druginduced autoimmunity (DIA). J Autoimmun. 2014 Feb-Mar; 48-49:66-72. 55. Handler J. Hydralazine-induced lupus erythematosis. J Clin Hypertens (Greenwich). 2012 Feb; 14(2):133-6. 56. Singh S. Hydralazine-induced lupus. South Med J. 2006 Jan; 99(1):6-7. 57. Borchers AT, Keen CL, and Gershwin ME. Drug-induced lupus. Ann N Y Acad Sci. 2007 Jun; 1108:166-82.

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58. Sarah K. Holman, Donique Parris, Sarah Meyers, and Jason Ramirez. Acute Low- Dose Hydralazine-Induced Lupus Pneumonitis. Case Rep Pulmonol. 2017; 2017:2650142. 59. Leo E Reap, Cassandra Rodd, Jose Larios, Michael Marshall. Hydrochlorothizide- induced acute generalised exanthematous pustulosis presenting with bilateral periorbital impetigo. BMJ Case Rep. 2019 Feb 11; 12(2). 60. Keerthi S, Rangaraj M, Karthikeyan K. Telmisartan aggravates pustular psoriasis. J Pharmacol Pharmacother. 2015 Apr-Jun; 6(2):107-9. 61. Calvo M, Fernández-Guarino M, Martín-Saez E, Carrillo R, Garate M. Palmoplantar hyperkeratosis associated with losartan. Actas Dermosifiliogr. 2006 Sep; 97(7):463-6. 62. Chiu AG, Krowiak EJ, Deeb ZE. Angioedema Associated With Angiotensin II Receptor Antagonists: Challenging Our Knowledge of Angioedema and Its Etiology. Laryngoscope. 2001 Oct; 111(10):1729-31. 63. Speck LM, Wilkerson MG, Perri AJ, Kelly BC. Acute generalized exanthematous pustulosis caused by terazosin hydrochloride. J Drugs Dermatol. 2008 Apr; 7(4):395- 7. 64. Fernández Salazar L, Palencia García A. Hepatotoxicity induced by terazosin. Med Clin (Barc). 2003 Feb 1.

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