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Statins

Statins are competitive inhibitors of HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy. HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism is the rate-limiting step in cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism synthesis Synthesis Polymerase Chain Reaction (PCR). Inhibition results in lowered intrahepatocytic cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism formation, resulting in up-regulation Up-Regulation A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (gene expression regulation), mRNAs, and proteins. Pharmacokinetics and Pharmacodynamics of LDL receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors and, ultimately, lowering levels of serum LDL and triglycerides Triglycerides Fatty Acids and Lipids. Statins can lower LDL 20%–60% (depending on their intensity) and have benefits that are cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism-independent (e.g., reduced vascular inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and atherosclerotic plaque Plaque Primary Skin Lesions stabilization). Indications for prescribing statins include prevention of primary or secondary cardiovascular disease in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with dyslipidemia. The main adverse effects are transaminitis Transaminitis Tick-borne Encephalitis Virus and muscle toxicity Toxicity Dosage Calculation.

Last updated: 21 May, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Chemistry and Pharmacodynamics

Definition

Statins are competitive inhibitors of the enzyme HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism, which is the rate-limiting step in cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy.

Chemical structure

Statins are structural analogs of HMG-CoA.

  • Some statins are inactive prodrugs with a lactone ring Lactone Ring Polyenes → hydrolyzed in the body to the open, active form
  • Others statins are active, fluorine-containing molecules.
Chemical structure of statins

The similarities in chemical structure of statins to HMG-CoA:
Lovastatin and simvastatin contain an inactive lactone ring Lactone Ring Polyenes, which is hydrolyzed in the body to the active form.

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Mechanism of action

Normal physiology:

  • Most circulating cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism originates from internal manufacture, rather than diet.
  • HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism converts HMG-CoA to mevalonate Mevalonate Cholesterol Metabolism (a precursor to cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism) in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy.
  • This is a rate-limiting step in cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism synthesis Synthesis Polymerase Chain Reaction (PCR).

Statins:

  • Competitively inhibit the enzyme HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism in hepatic cells
  • Occupy a portion of the binding site of HMG CoA → block access of this substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes to the active site Active site Area of an enzyme that binds to specific substrate molecules in order to facilitate a reaction. Basics of Enzymes on the enzyme
  • Synthesis Synthesis Polymerase Chain Reaction (PCR) of cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism and isoprenoid intermediates (lipid compounds with downstream inflammatory pathways)
  • Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism levels in hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy up-regulation Up-Regulation A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (gene expression regulation), mRNAs, and proteins. Pharmacokinetics and Pharmacodynamics of LDL receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors→ ↑ uptake of LDL from the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment
  • Note: The medication effect is mostly due to ↑ LDL receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors expression (not necessarily the reduction of internal cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology).
Cholesterol synthesis

The cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism synthesis Synthesis Polymerase Chain Reaction (PCR) pathway:
Statins competitively inhibit HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism, which is a rate-limiting step in the pathway.
NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway: nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes

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Mechanism of action of statins

The mechanism of action of statins ( HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism inhibitors) in comparison to other lipid-lowering therapies:
Statins block intrahepatocyte synthesis Synthesis Polymerase Chain Reaction (PCR) of cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism, resulting in up-regulation Up-Regulation A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (gene expression regulation), mRNAs, and proteins. Pharmacokinetics and Pharmacodynamics of LDL receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors and a reduction in serum LDL.
CoA: coenzyme A

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Physiologic effects

  • ↓↓ LDL by 20%–60%
  • ↓ VLDL production
  • ↓ Triglyceride levels: 
  • ↑ HDL levels (modest)
  • Effects of ↓ isoprenoid generation:
    • Reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Nonalcoholic Fatty Liver Disease
    • Improve endothelial function by ↑ nitric oxide Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from arginine by nitric oxide synthase. Nitric oxide is one of the endothelium-dependent relaxing factors released by the vascular endothelium and mediates vasodilation. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic gmp. Pulmonary Hypertension Drugs bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics 
    • ↓ Vascular inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation 
    • Platelet aggregation Platelet aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Hemostasis (prevent clot formation)
    • Stabilize atherosclerotic plaques

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

  • All statins are administered orally.
  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption may be reduced when taken with food (exception: lovastatin).

Distribution

  • High plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products-protein–binding
  • Widely distributed through the body, including:
    • Blood–brain barrier Blood–Brain Barrier Meningitis in Children
    • Placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity
    • Breast milk
  • Solubility:
    • Most are lipophilic, allowing passive entry into hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy.
    • Hydrophilic Hydrophilic Aminoglycosides statins do not pass easily through membranes:
      • More likely to remain in the plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products
      • Organic anion transporter proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (OATPs) assist with entry into hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy.

Metabolism

  • Undergo 1st-pass extraction by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
  • Most are metabolized by members of the cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury superfamily of drug oxidizing enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
  • Exception: pravastatin (metabolized by sulfation and conjugation Conjugation A parasexual process in bacteria; algae; fungi; and ciliate eukaryota for achieving exchange of chromosome material during fusion of two cells. In bacteria, this is a unidirectional transfer of genetic material; in protozoa it is a bi-directional exchange. In algae and fungi, it is a form of sexual reproduction, with the union of male and female gametes. Bacteriology)

Excretion

  • Bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy (majority)
  • Urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat (5%–20%)

Classification

Statins are classified on the basis of their percent reduction of LDL and dosing:

  • High-intensity statins (lower LDL by ≥ 50% from baseline):
    • Atorvastatin: 40–80 mg
    • Rosuvastatin: 20–40 mg
  • Moderate-intensity statins (lower LDL by 30%–40% from baseline): 
    • Atorvastatin: 10–20 mg
    • Rosuvastatin: 5–10 mg
    • Simvastatin: 20–40 mg
    • Pravastatin: 40–80 mg
    • Lovastatin: 40 mg
    • Fluvastatin: 40 mg twice daily
    • Pitavastatin: 2–4 mg
  • Low-intensity statins (lower LDL by ≤ 30% from baseline):
    • Simvastatin: 10 mg
    • Pravastatin: 10–20 mg
    • Fluvastatin: 20–40 mg
    • Pitavastatin: 1 mg

Indications

Major adverse cardiovascular events

Statins are indicated to treat dyslipidemias Dyslipidemias Abnormalities in the serum levels of lipids, including overproduction or deficiency. Abnormal serum lipid profiles may include high total cholesterol, high triglycerides, low high density lipoprotein cholesterol, and elevated low density lipoprotein cholesterol. Lipid Disorders with the intent of reducing major adverse cardiovascular events:

  • Major adverse cardiovascular events are defined as 1 or a combination of the following: 
  • Primary prevention of major adverse cardiovascular events:
    • For a patient who has not previously experienced an atherosclerotic vascular event (cardiovascular disease):
      • LDL > 100 mg/dL
      • Based on calculated cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) risk (includes diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, tobacco use, and age)
    • Rationale is based on data documenting:
      • Continuous, positive, graded relationship Relationship A connection, association, or involvement between 2 or more parties. Clinician–Patient Relationship between LDL concentration and cardiovascular events and mortality Mortality All deaths reported in a given population. Measures of Health Status
      • Evidence that ↓ LDL in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with a broad range of LDL levels ↓ the risk of cardiovascular disease (clinical benefit)
    • MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction risk is the most ↓ of all cardiovascular events.
    • There is benefit for LDL lowering with statin therapy with virtually all levels of cardiovascular risk.
  • Secondary prevention of major adverse cardiovascular events:
    • For patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with preexisting cardiovascular disease with prior:
      • MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
      • Stroke
      • Stable or unstable angina Unstable angina Precordial pain at rest, which may precede a myocardial infarction. Stable and Unstable Angina
      • Aortic aneurysm Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Thoracic Aortic Aneurysms
      • Other arterial ischemic disease in the presence of atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis
    • Statin therapy produces an estimated:
    • Greater benefit with high-intensity statins

Familial hypercholesterolemia Hypercholesterolemia A condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population. Lipid Disorders (FH)

  • Genetic disorder that causes a loss of function Loss of Function Inflammation of the LDL receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Manifests in ↑ LDL levels from birth
  • LDL levels are generally > 190 mg/dL.
  • Can result in premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis atherosclerotic coronary heart disease Coronary heart disease Coronary heart disease (CHD), or ischemic heart disease, describes a situation in which an inadequate supply of blood to the myocardium exists due to a stenosis of the coronary arteries, typically from atherosclerosis. Coronary Heart Disease and death
  • Note: Statins may be less effective, especially for those with homozygous FH.

Adverse Effects and Contraindications

Adverse effects

  • Muscle effects:
    • Myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy
      • Most common side effect
      • Muscle pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, soreness, and tenderness
      • Normal CK level
    • Myopathy Myopathy Dermatomyositis:
      • Muscle weakness
      • No pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
      • CK may or may not be elevated.
    • Myositis:
      • Muscle inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
      • Muscle symptoms
      • ↑ CK
    • Myonecrosis Myonecrosis A severe condition resulting from bacteria invading healthy muscle from adjacent traumatized muscle or soft tissue. The infection originates in a wound contaminated with bacteria of the genus Clostridium. C. perfringens accounts for the majority of cases (over eighty percent), while C. novyi, C. septicum, and C. histolyticum cause most of the other cases. Clostridia and rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis (rare): 
      • Muscle symptoms
      • CK > 10 times the upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal
      • Myoglobinuria Myoglobinuria The presence of myoglobin in urine usually as a result of rhabdomyolysis. Rhabdomyolysis or acute renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
  • Transaminitis Transaminitis Tick-borne Encephalitis Virus
    • No need to routinely monitor transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids levels
    • Rise in levels is generally seen within the first 3 months of therapy.
    • Dose-dependent
    • Levels < 3 times the upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal are acceptable.
    • Severe liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy injury is rare.
  • ↑ Risk of developing type 2 Type 2 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus: 
    • Occurs in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with risk factors
    • Benefits still generally outweigh the risks.

Drug–drug interactions

  • Medications that inhibit CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) → ↑ blood concentrations of statins
    • Grapefruit, grapefruit juice, and bitter oranges
    • Cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants
    • Macrolide antibiotics (except azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides)
    • Nondihydropyridine calcium channel blockers Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)
    • HIV HIV Anti-HIV Drugs protease inhibitors Protease Inhibitors Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). Anti-HIV Drugs
    • Azole antifungals
    • Amiodarone Amiodarone An antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting potassium channels and voltage-gated sodium channels. There is a resulting decrease in heart rate and in vascular resistance. Pulmonary Fibrosis
    • Nefazodone Nefazodone Serotonin Reuptake Inhibitors and Similar Antidepressants
    • Rifampin Rifampin A semisynthetic antibiotic produced from streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits dna-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. Epiglottitis
  • OATP inhibitors → ↑ blood concentrations of statins
    • Cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants
    • Direct-acting antivirals for hepatitis C Antivirals for Hepatitis C Antivirals against hepatitis C include a wide range of drug classes. The previous treatment regimen included interferon alfa (IFN-α) and ribavirin, which target viral entry, immune modulation, and viral replication. New, direct-acting antiviral (DAV) agents target specific nonstructural (NS) proteins of hepatitis C virus (HCV), which are important for viral replication. Antivirals for Hepatitis C virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology
    • Rifampin Rifampin A semisynthetic antibiotic produced from streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits dna-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. Epiglottitis
  • Associated with ↑ muscle toxicity Toxicity Dosage Calculation:
    • Niacin Niacin A water-soluble vitamin of the B complex occurring in various animal and plant tissues. It is required by the body for the formation of coenzymes nad and NADP. It has pellagra-curative, vasodilating, and antilipemic properties. Lipid Control Drugs
    • Fenofibrates
    • Colchicine Colchicine A major alkaloid from colchicum autumnale l. And found also in other colchicum species. Its primary therapeutic use is in the treatment of gout. Gout Drugs
  • Other considerations:
    • Bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy acid sequestrants: ↓ statin absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption 
    • Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants: Fluvastatin raises warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants levels via CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants inhibition.
    • Dabigatran Dabigatran A thrombin inhibitor which acts by binding and blocking thrombogenic activity and the prevention of thrombus formation. It is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Anticoagulants: ↑ risk of major hemorrhage

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Active liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
  • Breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding

Comparison of Statin Medications

The following table compares and contrasts members of the statin drug class. The drugs are listed in descending order of potency.

Table: Members of the statin class in descending order of potency
Statin Solubility Metabolism Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics Optimal dosing time
Pitavastatin Lipophilic CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants 12 hours Anytime
Rosuvastatin Hydrophilic Hydrophilic Aminoglycosides CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants 19 hours Anytime
Atorvastatin Lipophilic CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) 14 hours Anytime
Lovastatin Lipophilic CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) 2‒3 hours Evening
Simvastatin Lipophilic CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) 2‒3 hours Evening
Pravastatin Hydrophilic Hydrophilic Aminoglycosides Sulfation 1‒3 hours Anytime
Fluvastatin Lipophilic CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants 1‒3 hours Evening

References

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