Gemfibrozil
1. Drug Name
Generic Name: Gemfibrozil
Brand Names: Lopid
2. Drug Classification
Class: Fibrates
Subclass: Antilipemic agent
3. Mechanism of Action
Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α) Agonist: Gemfibrozil primarily exerts its effects by activating PPAR-α, a nuclear receptor that regulates lipid metabolism. The activation of PPAR-α leads to the transcription of several genes involved in lipid metabolism, including those responsible for increasing lipoprotein lipase (LPL) activity and reducing the production of very low-density lipoproteins (VLDL).
Lipoprotein Lipase Activation: Gemfibrozil increases the activity of LPL, an enzyme responsible for the hydrolysis of triglycerides (TG) in chylomicrons and VLDL particles, leading to a reduction in circulating triglyceride levels.
Reduction of VLDL Production: By decreasing hepatic production of VLDL, the drug reduces overall triglyceride levels.
Increase in HDL Levels: Gemfibrozil also increases high-density lipoprotein (HDL) cholesterol levels by promoting the synthesis of apolipoprotein A1 (apoA1), which is a major component of HDL.
Lipid Modulation: The primary benefit of gemfibrozil is the reduction of triglycerides and the modest increase in HDL cholesterol, which is beneficial for patients with hypertriglyceridemia or mixed dyslipidemia.
4. Pharmacokinetics
Absorption:
Gemfibrozil is well absorbed from the gastrointestinal tract, with peak plasma concentrations reached within 1-2 hours after oral administration.
Its bioavailability is about 60%, and food intake can affect its absorption, slightly increasing plasma levels.
Distribution:
It is extensively protein-bound (approximately 99%) to plasma proteins, predominantly albumin.
Gemfibrozil has a moderate volume of distribution (Vd) and is widely distributed in the body.
Metabolism:
Gemfibrozil is extensively metabolized in the liver via the cytochrome P450 3A4 enzyme system (CYP3A4), producing active metabolites that contribute to its lipid-lowering effects.
Excretion:
Half-life (t½): The elimination half-life of gemfibrozil is approximately 1-2 hours, with its active metabolites having a longer half-life of around 10-20 hours.
Excretion: The drug and its metabolites are primarily excreted in the urine, with a minor fraction eliminated in feces.
Special Considerations:
Renal Impairment: The drug should be used with caution in patients with renal dysfunction, as clearance may be reduced.
Hepatic Impairment: Caution is also advised in patients with liver disease, as gemfibrozil is primarily metabolized in the liver.
5. Indications
Primary Indications:
Hypertriglyceridemia: Gemfibrozil is indicated for the treatment of hypertriglyceridemia (serum triglycerides ≥500 mg/dL) to reduce the risk of pancreatitis.
Mixed Dyslipidemia: It is used for treating mixed dyslipidemia, where there is both elevated triglycerides and low HDL cholesterol.
Off-label Uses:
Hypercholesterolemia: Gemfibrozil may be used in some patients with high cholesterol levels, but fibrates are generally not the first-line agents for this indication.
Cardiovascular Risk: It is occasionally used to reduce the risk of cardiovascular events in patients with a high level of triglycerides, though this use is not widely supported by major clinical guidelines.
6. Dosage and Administration
Adult Dosing:
Hypertriglyceridemia: The typical adult dose is 600 mg taken twice daily, 30 minutes before meals.
Mixed Dyslipidemia: Same dosing regimen as for hypertriglyceridemia.
Pediatric Dosing:
The safety and efficacy of gemfibrozil in children have not been well established, and its use in pediatric patients is generally not recommended.
Renal Adjustments:
Dose adjustments may be needed for patients with moderate renal impairment (creatinine clearance <50 mL/min). The drug is contraindicated in severe renal impairment.
Hepatic Adjustments:
Gemfibrozil should be used with caution in patients with hepatic dysfunction, as the liver is the primary site of metabolism.
7. Contraindications
Absolute Contraindications:
Severe Renal Impairment: Gemfibrozil is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min).
Active Liver Disease: Contraindicated in patients with active liver disease, including cirrhosis or unexplained persistent liver enzyme elevations.
Gallbladder Disease: Gemfibrozil should not be used in patients with a history of gallstones or gallbladder disease.
Relative Contraindications:
Hypersensitivity: Contraindicated in patients with known hypersensitivity to gemfibrozil or any of its components.
Pregnancy: Category C for pregnancy; it should only be used if the potential benefit justifies the potential risk to the fetus.
Breastfeeding: It is not recommended during breastfeeding due to potential risks to the infant.
8. Warnings and Precautions
Rhabdomyolysis: There is an increased risk of myopathy and rhabdomyolysis, particularly when gemfibrozil is combined with statins. Myopathy symptoms such as muscle pain, tenderness, or weakness should be reported immediately.
Liver Function Monitoring: Liver function tests should be conducted before initiating treatment and periodically thereafter to monitor for liver enzyme elevations.
Gallstones: Gemfibrozil can increase the risk of gallstone formation, and patients with a history of gallstones should be monitored.
Renal Impairment: In patients with mild to moderate renal impairment, dose adjustments may be necessary.
Hypersensitivity Reactions: Rare allergic reactions such as rash, urticaria, or anaphylaxis have been reported.
9. Adverse Effects
Common Adverse Effects:
Gastrointestinal: Dyspepsia, nausea, abdominal pain, diarrhea, and constipation.
Less Common but Clinically Significant:
Liver Enzyme Elevations: Mild elevations in liver transaminases can occur, requiring periodic monitoring.
Myopathy: Muscle pain, weakness, and tenderness, which can progress to rhabdomyolysis, especially when used in combination with statins.
Fatigue: Some patients report general feelings of fatigue and malaise.
Rare/Serious Adverse Effects:
Rhabdomyolysis: Severe muscle breakdown that can lead to kidney damage, characterized by muscle pain, weakness, and dark-colored urine.
Pancreatitis: Though rare, gemfibrozil can cause pancreatitis, particularly in patients with predisposing factors.
10. Drug Interactions
Statins: The combination of gemfibrozil with statins significantly increases the risk of muscle toxicity (myopathy and rhabdomyolysis). The use of gemfibrozil with certain statins, such as simvastatin, is contraindicated.
Warfarin: Gemfibrozil may enhance the effects of warfarin, increasing the risk of bleeding. Close monitoring of prothrombin time (PT) and INR is recommended when used concomitantly.
Cyclosporine: The use of gemfibrozil with cyclosporine may increase cyclosporine levels, necessitating close monitoring and dose adjustments.
Oral Antidiabetic Agents: Caution should be exercised when gemfibrozil is used with oral hypoglycemic agents, as it may alter glucose metabolism.
Bile Acid Sequestrants: Gemfibrozil may reduce the absorption of bile acid sequestrants, and they should be taken at different times of the day.
11. Clinical Pharmacology
Pharmacodynamics: Gemfibrozil reduces triglycerides, increases HDL cholesterol, and lowers LDL cholesterol. It exerts its effects by increasing the activity of lipoprotein lipase and reducing hepatic VLDL production.
Additional Effects: Gemfibrozil also has some antioxidant and anti-inflammatory effects, which may contribute to its cardiovascular benefits.
12. Special Populations
Pregnancy: Category C; should only be used if the potential benefit justifies the potential risk.
Lactation: Contraindicated; gemfibrozil is excreted in breast milk.
Geriatrics: Older adults may have an increased risk of adverse effects, particularly myopathy and liver dysfunction.
Renal Impairment: Use with caution in renal impairment. Dose adjustments are necessary for moderate renal dysfunction.
Hepatic Impairment: Use with caution in hepatic dysfunction.
13. Therapeutic Uses
Primary Hypertriglyceridemia: Gemfibrozil is primarily used for reducing elevated triglycerides, especially when levels are over 500 mg/dL.
Mixed Dyslipidemia: Useful in patients with elevated triglycerides and low HDL cholesterol, typically in combination with other lipid-lowering therapies.
Cardiovascular Risk Reduction: Gemfibrozil may help reduce the risk of cardiovascular events, particularly in patients with high triglycerides.
14. Monitoring and Follow-Up
Liver Enzymes: Monitor for liver dysfunction before treatment and periodically during treatment.
Kidney Function: Monitor renal function, particularly in those with pre-existing renal disease.
Muscle Symptoms: Monitor for signs of muscle toxicity, particularly when used with statins.
15. Overdose Management
Symptoms of Overdose: Symptoms include gastrointestinal distress, liver dysfunction, and muscle pain.
Management: There is no specific antidote for gemfibrozil overdose. Treatment is symptomatic and supportive, focusing on monitoring liver and renal function.
16. Patient Counseling Information
Administration: Take gemfibrozil 30 minutes before meals.
Side Effects: Inform patients to report any unexplained muscle pain or tenderness, as it may indicate serious side effects such as rhabdomyolysis.
Liver Health: Advise patients to seek medical attention if they experience symptoms of liver problems, such as jaundice or dark urine.
Gallstone Risk: Gemfibrozil may increase the risk of gallstones, so notify the healthcare provider if new abdominal symptoms occur.