INTRODUCTION:

Both food consumption and biosynthesis contribute to the body's cholesterol concentrations. The liver, which generates roughly 70% of the daily need, produces most cholesterol healthy humans use, and the dietary intake accounts for the remaining 30%.¹ According to the National Centre for Chronic Disease Prevention and Health Promotion of the United States of America, Plaque accumulation in the coronary arteries, which carry blood to the heart, causes coronary artery disease because of the hyperlipidemia condition.The condition known as hyperlipidemia can be treated with a variety of medications.² Atherosclerosis is a complex illness that is influenced by the interaction of the environment and genotype.³ Statins have as pleotropic effects and have on impact on immune response.^4,5 Statins are effective in lessening COVID-19 symptoms.⁶However, statins significantly lower high cholesterol and offer effective therapeutic results that lower the mortality rate. Statins dramatically reduced low-density lipoproteins (LDL) levels compared to previously employed methods. By modifying the lipid profile and the inflammatory cell signaling pathways that regulate proliferation, vascular cell migration and chronic kidney disorders can be slowed down in their progression.⁷ A meta-analysis of statin clinical trials indicated similar risk reductions for vascular or coronary events.⁸ This was true regardless of age, sex, cholesterol levels, diabetes, hypertension, myocardial infarction, or other cardiac problems.⁹ In addition to diet and exercise, doctors have historically prescribed statin drugs to treat hypercholesterolemia, hyperlipoproteinemia, and hypertriglyceridemia as a primary objective is to prevent coronary artery disease.¹⁰But the major concern in prescribing the Pharmacological agents is an occurrence of untoward reactions in the patients. To recede the drug induced side effects, effective public health intervention is warranted.¹¹

A known side effect of statins is myalgia, which affects 1 to 10% of people taking them. Less frequently occurring myositis typically manifests as elevation in creatine kinase (CK). The most severe ill effect of statin is rhabdomyolysis, an uncommon (0.1% of people experience it). Still, it is associated with markedly elevated CK (10 times than the Reference range), decreased renal function by myoglobin in urine, Imbalance in electrolytes, and hemodynamic instability.¹² Statin was classified as Lipohilic and hydrophilic depends on its characteristics. Out of theses drugs, lipophilic statins are more prone to cause rhabdomyolysis.¹³Rhabdomyolysis is a horrible medical condition that can be fatal or leave a person permanently debilitated. Rhabdomyolysis is the process through which electrolytes and proteins from injured muscle tissue are released into circulation. These substances can kill an individual or permanently disable the heart and kidneys.

Case report:

A 63-year-old man presented with left-sided chest pain spreading to the left arm, trouble breathing, vomiting, and elevated perspiration at Lalpet Health care center, Lalpet, Tamil Nadu, India. The patient's vitals were Blood Pressure-160/100mm/Hg and pulse rate - 120 beats/min. Hematological parameters at the time of admission were white blood count - 12400/µl, hemoglobin - 13.7g/dl, Mean corpuscular volume - 94fl, Mean corpuscular hemoglobin - 32.8pg, Mean corpuscular hemoglobin concentration - 34.9g/dl, Platelet - 2.46/µl, Urea - 30mg/dl, Serum creatinine (SCr) - 0.8mg/dl, Total Bilirubin - 0.9mg/dl, Direct bilirubin 0.2mg/dl, Total Protein - 7.1g/dl, Albumin 4.2g/dl, sodium 136.4mEq/L, potassium - 7mEq/L, Troponin - 0.7ng/ml. The Electrocardiogram shows ST elevation in the anterior leads at the J point. From the above parameters, the patient is diagnosed with Acute Myocardial Infarction.

On the day of admission, the patient was treated with Inj. Streptokinase 1.5million IU in 100NS over 1hr followed by Inj. Heparin 5000IU QID after 6 hrs and T.ASA 300mg, T. Clopidogrel 75mg, Inj. Ranitidine 50mg/2ml, T. Enalapril 2.5mg, T. Simvastatin 40mg, and treatment were continued for three days. On the 3^rd day, the patient experienced severe body pain, especially in the thigh region, and complained of brown-colored urine.

The case reached the clinical pharmacist to assess the reason for the patient's following reaction. The patient was suggested for a complete blood count to evaluate the reason for the occurred response. The blood parameters showed increased liver enzymes level. Total bilirubin was 2.9mg/dl. Direct bilirubin was 3mg/dl, creatinine Kinase enzyme level was found to be 1100U/l, Blood urea nitrogen (BUN) was 40mg/dl, SCr was found to be 7mg/dl, and Urea 76mg/dl which show the condition of rhabdomyolysis. Statins are more prone to cause rhabdomyolysis; hence statin drug was stopped, and another class of dyslipidemia drugs, T. Ezetimibe, was prescribed instead of statin and rhabdomyolysis were treated with Anti-inflammatory medications like antihistamines and intravenous fluids to maintain rehydration to prevent muscle breakdown. Increased creatinine kinase, creatinine, urea, and BUN in a patient indicate Acute Kidney Injury (AKI). The primary treatment for AKI is severe hydration, which includes the administration of 500mL/h of saline solution, 500mL/h of 5% glucose solution, and 50mmol of sodium bicarbonate for each extra 2-3L of solution per hour. A urine output of 200mL/h, a urine pH target of >6.5, and a plasma pH target of 7.5 must all be met.

From day 6, the patient elevated CK, BUN, Urea, and Creatinine declined slowly, preventing Renal Replacement Therapy (RRT). As a follow-up, the patient's CK level has to be monitored every day till the CK level reaches normal. Levels of Creatinine, BUN, Urea, and CK on each day were displayed in the discussion (Table 1 and Table 2).

DISCUSSION:

Vitamin D and hormones are essential for the body's normal functioning, produced by a fatty substance known as cholesterol. A specialized category of particles called lipoproteins transports cholesterol through the blood. High-density lipoproteins (HDLs) carry extra cholesterol from various tissues back to the liver for removal, while LDL delivers liver cholesterol to the cells.¹⁴ Statins are Food and Drug Administration Authority of USA-approved to treat dyslipidemia worldwide to reduce excess cholesterol in the blood. A desirable activity of statins is gained by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the pathway of cholesterol biosynthesis.¹⁵

Table 1: Day-by-day Creatinine Kinase levels

Day	CK IU/L
3	1100
4	1250
5	1280
6	1026
7	998
8	842
9	771
10	601
11	547
12	432
13	389
14	380

Figure 1: Represents Creatinine Kinase (CK).

The above depicted figure (figure 1) indicates the creatinine Kinase level. A significant complication of increased creatinine kinase is Acute Kidney Injury, and severe body pain leads to a life-threatening condition. On day 3, elevated creatinine kinase indicates rhabdomyolysis, a known adverse drug reaction (ADR) of simvastatin, so simvastatin was stopped abruptly. Even though the drug was stopped, CK enzyme level increases warranted the patient on Renal Replacement Therapy (RRT) for the next three days. But from Day 6, CK level starts to decline gradually after withdrawal of RRT and shows positive effects on the drug administered.

Table 2: Levels of Urea, SCr, and BUN on different Days

Day	Urea (mg/dl)	SCr (mg/dl)	BUN (mg/dl)
3	76	7	40
4	80	8	42
5	83	7.2	40
6	77	6.6	38
7	75	5	34
8	73	4.8	33
9	69	3.8	30
10	67	2.8	32
11	61	2.6	28
12	57	2	28
13	50	1.8	30
14	44	1.6	24

Figure 2: Represents levels of BUN, SCr, Urea

The above depicted figure (figure 2) indicates BUN, SCr, and Urea levels. A sudden elevation of BUN, SCr, and Urea levels indicates Acute Kidney Injury leads to life-threatening conditions. On day 3, Elevated BUN, SCr, and Urea showed rhabdomyolysis-induced AKI, a known Adverse effect of simvastatin, so simvastatin was stopped abruptly. Even though the drug was stopped, BUN, SCr, and Urea levels increased, warranting the patient on Renal replacement therapy (RRT) for the next three days. But from Day 6, levels started to decline gradually, and RRT showed positive effects on Rehydration therapy. This Adverse reaction was reported by filling out the suspected ADR reporting form, and causality assessment was carried out by using the WHO-Uppsala monitoring center scale, and the grade was found to be probable.

Skeletal muscle damage leads to rhabdomyolysis, which releases myoglobin and other cellular components into the bloodstream. There may be more incidences and danger from acute exertional rhabdomyolysis than previously believed; recent reports show it is a mild to moderate condition that causes increased potassium, sodium, phosphorus, and Lactic acid.¹⁶ When statin and other substances that inhibit cytochrome p450-3A4 (CYP3A4) are co-administered, it leads to an increased concentration of statin medication in the blood, causing elevated CK and Muscle toxicity.¹⁷ First, statins blocking cytochrome P450 enzyme among pharmacokinetic variables increase systemic statin concentrations and increases oxidative stress.¹⁸ Second, cell membrane uptake transporters impact the amounts of statins inside myocytes. Thirdly, HMG-CoA reductase inhibitors alter gene expression and lower the downstream metabolites inside cells.¹⁹

When the enzyme CK is below 20000U/L, it indicates a reduced risk of acute renal failure in rhabdomyolysis.²⁰ Clinicians should concentrate on preventing acute renal injury as a therapy goal regardless of the underlying cause of the suspected rhabdomyolysis. The main therapeutic objective is to prevent the causes that lead to AKI, such as tubular blockage, volume depletion, free radical release, and aciduria. Depending on the underlying etiology of rhabdomyolysis, appropriate and adequate fluid resuscitation with normal isotonic saline should be administered. The offending agent should be removed at diagnosis, and IV fluids should be titrated to maintain a urine output of 200 to 300mL/h. CK levels are serially monitored daily to document decline levels. As previously stated, CK levels greater than 5,000 IU/L have been linked to an elevated risk of AKI development. Extensive volume fluid resuscitation is discouraged in patients with CK levels less than 5,000 IU/L because they are less prone to develop AKI.²¹ In severe situations where the CK is greater than 30,000 IU/L, rigorous alkaline diuresis may be considered. Loop diuretics can potentially treat volume excess caused by intensive fluid resuscitation.²²

Fluid management is crucial to preventing prerenal illness due to the potential accumulation of fluid in the muscle cavity and ensuing hypovolemia. Traditionally, urine is alkalinized by adding 50mEq of sodium bicarbonate to half-normal saline. Alkalinization with a bicarbonate infusion is related to hypocalcemia precipitation, which can cause tetany and seizures. The goal of alkaline fluid infusion is to keep the serum pH below 7.5 and the urine pH above 6.5. When serum pH reaches 7.5, discontinue bicarbonate in IV fluids immediately and autogenic inhibition can helps in reducing elevated CK level.^23,24 An aggressive intravenous fluid supply is necessary to prevent hypovolemia, which can cause water sequestration by muscles. Ten litres (or more) of fluid per day may be required to maintain volume equilibrium. Extracorporeal blood purification is the only efficient therapeutic option once an overt renal failure has manifested.²⁵ When taken twice weekly for six months, Mircera was found to be beneficial in maintaining haemoglobin levels in CKD patients who were not on dialysis.²⁶

CONCLUSION:

Muscle toxicity is the common ADR of increased doses of statin therapy worldwide; in that case, statin therapy should be stopped immediately, and patients need to receive symptomatic care if they experience significant muscle complaints or rhabdomyolysis. This treatment comprises administering sufficient fluid resuscitation, keeping track of urine output, and treating electrolyte abnormalities, particularly hyperkalemia. For statin overdose, there is no known remedy. Patients need to start retaking low-dose statins after recovering from an overdose. This instance emphasizes the significance of understanding complicated drug therapy interactions in an era of growing multi-drug practices and the discouragement that can occur when these interactions are disregarded. Reporting this study is more significant because rhabdomyolysis is a severe and fatal condition caused by the statins drugs used to treat and prevent coronary artery disease.

ABBREVIATIONS:

HMG-CoA:3-hydroxy-3-methylglutaryl coenzyme A; SCr: Serum creatinine; BUN: Blood Urea Nitrogen; CK: Creatinine kinase; WHO: World health organization; RRT: Renal Replacement Therapy; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; AKI: Acute kidney injury; ADR: Adverse drug reaction.

ETHICS STATEMENTS:

The patient has provided their informed consent for the publication of this case report.

CONTRIBUTORS:

All the authors have contributed with written passages and with proof reading of the article and have made significant contributions.

ACKNOWLEDGEMENT:

The authors would like to express their sincere gratitude to the patient and their family members for granting consent to utilize their valuable medical records for the purpose of case reporting.

CONFLICT OF INTEREST:

The Authors declared no conflicts of Interest.

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Received on 11.09.2023 Modified on 04.12.2023

Research J. Pharm. and Tech 2024; 17(7):3241-3245.

DOI: 10.52711/0974-360X.2024.00507