Pravastatin is a synthetic lipid-lowering agent. Pravastatin competitively inhibits hepatic hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. Pravastatin lowers plasma cholesterol and lipoprotein levels, and modulates immune responses by suppressing MHC II (major histocompatibility complex II) on interferon gamma-stimulated, antigen-presenting cells such as human vascular endothelial cells.
Pravastatin is a member of the drug class of statins, used in combination with diet, exercise, and weight loss for lowering cholesterol and preventing cardiovascular disease &cholesterol-lowering agent that belongs to a class of medications known as statins. It was derived from microbial transformation of mevastatin, the first statin discovered. It is a ring-opened dihydroxyacid with a 6’-hydroxyl group that does not require in vivo activation. Pravastatin is one of the lower potency statins; however, its increased hydrophilicity is thought to confer advantages such as minimal penetration through lipophilic membranes of peripheral cells, increased selectivity for hepatic tissues, and a reduction in side effects compared with lovastatin and simvastatin.
Mechanism of Action of Pravastatin
Pravastatin acts as a lipoprotein-lowering drug through two pathways. In the major pathway, pravastatin inhibits the function of hydroxymethylglutaryl-CoA (HMG-CoA) reductase. As a reversible competitive inhibitor, pravastatin sterically hinders the action of HMG-CoA reductase by occupying the active site of the enzyme. Taking place primarily in the liver, this enzyme is responsible for the conversion of HMG-CoA to mevalonate in the rate-limiting step of the biosynthetic pathway for cholesterol. Pravastatin also inhibits the synthesis of very-low-density lipoproteins, which are the precursor to low-density lipoproteins (LDL). These reductions increase the number of cellular LDL receptors, thus LDL uptake increases, removing it from the bloodstream.Overall, the result is a reduction in circulating cholesterol and LDL. A minor reduction in triglycerides and an increase in high-density lipoproteins (HDL) are common.Pravastatin sodium produces its lipid-lowering effect in two ways. First, as a consequence of its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in intracellular pools of cholesterol. This results in an increase in the number of LDL-receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic synthesis of VLDL, the LDL precursor.
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Statins are largely used in clinics in the treatment of patients with cardiovascular diseases for their effect on lowering circulating cholesterol. Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for ox-LDL, plays a central role in the pathogenesis of atherosclerosis and cardiovascular disorders. We have recently shown that chronic exposure of cells to lovastatin disrupts LOX-1 receptor cluster distribution in plasma membranes, leading to a marked loss of LOX-1 function. Here we investigated the molecular mechanism of statin-mediated LOX-1 inhibition and we demonstrate that all tested statins /including pravastatin/ are able to displace the binding of fluorescent ox-LDL to LOX-1 by a direct interaction with LOX-1 receptors in a cell-based binding assay. Molecular docking simulations confirm the interaction and indicate that statins completely fill the hydrophobic tunnel that crosses the C-type lectin-like (CTLD) recognition domain of LOX-1. Classical molecular dynamics simulation technique applied to the LOX-1 CTLD, considered in the entire receptor structure with or without a statin ligand inside the tunnel, indicates that the presence of a ligand largely increases the dimer stability. Electrophoretic separation and western blot confirm that different statins binding stabilize the dimer assembly of LOX-1 receptors in vivo. The simulative and experimental results allow us to propose a CTLD clamp motion, which enables the receptor-substrate coupling. These findings reveal a novel and significant functional effect of statins.
Indications of Pravastatin
- For the treatment of hypercholesterolemia and to reduce the risk of cardiovascular disease.
- High Cholesterol
- Hyperlipoproteinemia
- High Cholesterol, Familial Heterozygous
- Hyperlipoproteinemia Type III, Elevated beta-VLDL IDL
- Hyperlipoproteinemia Type IIa, Elevated LDL
- Hyperlipoproteinemia Type IIb, Elevated LDL VLDL
- Hyperlipoproteinemia Type IV, Elevated VLDL
- Ischemic Stroke, Prophylaxis
- Myocardial Infarction, Prophylaxis
- Revascularization Procedures, Prophylaxis
- Atherosclerotic Cardiovascular Diseases
- Hyperlipidemias
- Secondary prevention cardiovascular event
Therapeutic indications of Pravastatin
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In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), Pravachol (pravastatin sodium) is indicated to: reduce the risk of myocardial infarction, reduce the risk of undergoing myocardial revascularization procedures and reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes.
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In patients with clinically evident coronary heart disease (CHD), Pravachol is indicated to: reduce the risk of total mortality by reducing coronary death, reduce the risk of myocardial infarction (MI), reduce the risk of undergoing myocardial revascularization procedures, reduce the risk of stroke and stroke/transient ischemic attack (TIA) and slow the progression of coronary atherosclerosis.
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As an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and triglyceride (TG) levels and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Types IIa and IIb).
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Pravastatin has been shown to slow the progression and/or induce regression of atherosclerosis in a few patients without clinical evidence of coronary heart disease (CHD) who had mild to moderate elevations of low-density lipoprotein (LDL)-cholesterol. The drug also has reduced transient myocardial ischemia in male patients with clinical evidence of CHD or unstable angina pectoris.
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While some statins have been shown to reduce the rate of restenosis following coronary stent implantation, pravastatin has not been shown to reduce the incidence of restenosis in patients undergoing coronary balloon angioplasty.
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Pravastatin has reduced total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia), cardiac or liver transplantation, or nephrotic syndrome (nephrotic hyperlipidemia).
Contra-Indications of Pravastatin
- Alcoholism
- Uncontrolled epilepsy
- Hemorrhage in the brain
- Severely low blood pressure
- Liver problems
- Rhabdomyolysis
- Recent operation
- Loss of memory
- High blood sugar
- Abnormal liver function tests
- Trauma
- Pregnancy
- A mother who is producing milk and breastfeeding
- Muscle pain or tenderness with increase creatine kinase
- Metabolic syndrome X
- Muscle damage due to autoimmunity
Dosage of Pravastatin
Strengths: 10 mg; 20 mg; 40 mg; 80 mg
Hyperlipidemia
- Initial dose: 40 mg orally once a day
- Maintenance dose: 40 mg to 80 mg orally once a day
Hyperlipoproteinemia Type IIa (Elevated LDL)
- Initial dose: 40 mg orally once a day
- Maintenance dose: 40 mg to 80 mg orally once a day
Hyperlipoproteinemia Type IIb (Elevated LDL + VLDL)
- Initial dose: 40 mg orally once a day
- Maintenance dose: 40 mg to 80 mg orally once a day
Hypertriglyceridemia
- Initial dose: 40 mg orally once a day
- Maintenance dose: 40 mg to 80 mg orally once a day
Cardiovascular Disease
- Initial dose: 40 mg orally once a day
- Maintenance dose: 40 mg to 80 mg orally once a day
Side Effects of Pravastatin
The most common
- back pain
- constipation
- muscle aches
- Nausea and vomiting
- Severe stomach ache
- diarrhea,
- anorexia,
- flatulence,
- headache,
- dizziness,
- heartburn
- joint pain
Common
- Nausea and vomiting
- Severe stomach ache
- Severe diarrhea
- Mouth sores
- Vaginal thrush
- Skin rash
- Headache
Less common
- fever
- general feeling of discomfort or illness
- joint pain
- loss of appetite
- muscle aches and pain
- runny nose
- shivering
- sore throat
- sweating
- trouble sleeping
- unusual tiredness or weakness
- Bladder pain
- bloody or cloudy urine
- cough producing mucus
- dark-colored urine
- difficult, burning, or painful urination
- difficulty with breathing
Drug Interactions of Pravastatin
Pravastatin may interact with following drugs, supplements & may change the efficacy of drug
- colchicine,
- gemfibrozil.
- cyclosporine
- desipramine
- dexamethasone
haloperidol - loperamide
- macrolide antibiotics (e.g., azithromycin, erythromycin, clarithromycin)
- metronidazole
- midazolam
- mifepristone
- norfloxacin
- ondansetron
- paliperidone
- phenobarbital
- fluconazole
- niacin
- nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., diclofenac)
- omeprazole
- phenytoin
- ranitidine
- rifampin
- spironolactone
- warfarin
Pregnancy & Lactation of Pravastatin
FDA pregnancy category X
Pregnancy
This medication should not be taken during pregnancy, as it may cause harm to the developing baby. If you become pregnant while taking this medication, stop taking it immediately and contact your doctor.This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, stop taking it immediately and contact your doctor.
Lactation
This medication passes into breast milk. If you breastfeeding-feeding mother and are taking pravastatin, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.
References
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