perhexiline

Action and Spectrum

Actions and Spectrum: 

perhexiline is a medication initially used to treat angina (chest pain) and was later found beneficial in some cases of heart failure. It belongs to a class of drugs known as anti-anginal agents and works by altering how the body utilizes energy from fats.  

Action: 

• Inhibition of Carnitine Palmitoyltransferase (CPT): perhexiline inhibits an enzyme called carnitine palmitoyltransferase, which is involved in the transport of the long-chain fatty acids into the mitochondria, where they are used as a source of energy. By inhibiting this enzyme, perhexiline reduces the oxidation of fatty acids, which leads to an increase in glucose utilization as an energy source. 
• Increase in Glucose Utilization: By reducing the oxidation of fatty acids, perhexiline forces the body to rely more on glucose for energy production.  

Spectrum: 

• Angina Pectoris: perhexiline was initially used to treat angina, a condition characterized by chest pain/discomfort caused by the diminished blood flow to heart muscle. By shifting the heart’s energy utilization from fatty acids to glucose, perhexiline helps improve the efficiency of the heart muscle and reduces angina episodes. 
• Heart Failure: perhexiline has also been investigated for its potential benefits in certain types of heart failure. Heart failure is when the heart cannot pump blood effectively, leading to symptoms like shortness of breath and fatigue. By improving the heart’s energy utilization, perhexiline may help in some instances of heart failure. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Rash 

Weight loss 

Tingling 

Numbness 

Tremors 

Loss of appetite 

Muscle weakness 

Difficulty in walking 

Impaired vision 

Dizziness or a drunken feeling 

Black Box Warning

Black Box Warning: 

None 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Hypersensitivity: perhexiline is contraindicated in individuals with known hypersensitivity/allergy to the drug or its components. Allergic reactions can vary from mild skin rashes to severe reactions, including anaphylaxis. 
• Liver Dysfunction: perhexiline is primarily metabolized in the liver. Therefore, individuals with severe liver dysfunction or impaired liver function should not use this medication. Using perhexiline in such cases can further compromise liver function and lead to severe complications. 
• Pregnancy and Breastfeeding: perhexiline should not be used during pregnancy condition unless the potential benefits outweigh the risks. There is limited information available on its safety during pregnancy. It is also not recommended for use while breastfeeding. 
• Concurrent Use of CYP2D6 Inhibitors: perhexiline is metabolized by the enzyme CYP2D6 in the liver. Concurrent use of drugs that inhibit CYP2D6 can lead to increased levels of perhexiline in the body, potentially causing toxicity. Therefore, potent CYP2D6 inhibitors should be avoided while taking perhexiline. 
• Heart Failure with Pulmonary Congestion: perhexiline should not be used in patients with heart failure associated with significant pulmonary congestion (fluid in the lungs) or significant left ventricular dysfunction, as it may exacerbate these conditions. 
• Cardiogenic Shock: perhexiline is contraindicated in cases of cardiogenic shock. It can worsen the already compromised cardiac function. 
• Children: perhexiline is not recommended for children, as its safety and efficacy in pediatric populations have not been adequately studied. 

Caution 

• Liver Function: perhexiline is primarily metabolized in the liver, so monitoring liver function regularly while using this medication is essential. Suppose there is any pre-existing liver disease or impairment. In that case, the drug should be used cautiously, and liver function tests should be performed regularly to detect any signs of liver dysfunction. 
• Cardiac Function: perhexiline affects the heart’s energy utilization and can lead to cardiac side effects, including arrhythmias or changes in heart rate. It should be used cautiously in patients with pre-existing heart conditions, and cardiac function should be closely monitored during treatment. 
• Hypoglycemia: Shifting the heart’s energy source from fatty acids to glucose can potentially lead to hypoglycemia (low blood sugar) in some individuals, especially those with diabetes/other conditions that affect blood sugar levels. Patients taking perhexiline should be monitored for signs of low blood sugar, and adjustments to diabetes medications may be necessary. 
• Vision Changes: perhexiline has been associated with optic neuropathy, which affects the optic nerve and can lead to visual disturbances or vision loss. Patients taking perhexiline should be aware of any changes in vision and report them promptly to their healthcare provider. 
• Peripheral Neuropathy: Some patients may experience peripheral neuropathy, a condition characterized by numbness, tingling, or pain in the hands and feet while taking perhexiline. This side effect should be monitored, and the drug may need to be discontinued if neuropathy develops. 
• Elderly Patients: Elderly patients might be more susceptible to the adverse effects of perhexiline, including liver and cardiac issues. Careful monitoring and dose adjustments may be necessary in this population. 
• Drug Interactions: perhexiline is metabolized by the enzyme CYP2D6 in the liver and can interact with other drugs that affect this enzyme. Concurrent use of potent CYP2D6 inhibitors or inducers should be avoided or closely monitored to prevent adverse effects or reduced efficacy of perhexiline. 
• Dosage and Monitoring: perhexiline requires individualized dosing and careful monitoring by a healthcare professional. The drug’s dose should be adjusted based on the patient’s response and side effects. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: Not assigned 

Lactation:   

Excreted into human milk: Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

perhexiline is a medication with unique pharmacological properties used in treating angina pectoris and some instances of heart failure. It acts by inhibiting carnitine palmitoyltransferase (CPT), an enzyme transporting fatty acids into the mitochondria for energy production. By inhibiting CPT, perhexiline reduces the oxidation of fatty acids, prompting the heart to rely more on glucose as an energy source. This shift in energy metabolism enhances myocardial efficiency, leading to improved cardiac function and reduced angina episodes.

However, perhexiline’s pharmacokinetics are highly variable, requiring careful monitoring and individualized dosing to avoid toxicity and potential side effects, particularly regarding liver function and optic neuropathy. Drug interactions should also be considered, as perhexiline is metabolized by CYP2D6, which can be affected by concomitant medications. As such, perhexiline’s therapeutic benefits must be balanced with its risks in specific patient populations, necessitating close supervision by healthcare professionals. 

Pharmacodynamics: 

Mechanism of action: The action of perhexiline involves its inhibition of an enzyme called carnitine palmitoyltransferase (CPT), which is a crucial component of the fatty acid oxidation pathway in cells, especially in cardiac muscle cells.  

• Fatty Acid Metabolism: Fatty acids serve as a vital energy source for muscle contraction within the heart. Fatty acids are broken down in mitochondria through beta-oxidation to produce adenosine triphosphate (ATP), the primary energy currency of cells. 
• Role of Carnitine Palmitoyltransferase (CPT): Before fatty acids can enter the mitochondria for beta-oxidation, they must be transported across the inner mitochondrial membrane. This process is facilitated by CPT, an enzyme that transfers the fatty acids from coenzyme A (CoA) to carnitine, forming acylcarnitine. The acylcarnitine can then cross the inner mitochondrial membrane. 
• Inhibition of CPT: perhexiline inhibits the activity of CPT, reducing the transport of fatty acids into the mitochondria for beta-oxidation. This leads to decreased oxidation of fatty acids and, consequently, decreased ATP production from fatty acid metabolism. 
• Shift to Glucose Metabolism: With the inhibition of CPT and reduced fatty acid oxidation, the heart shifts its energy source preference to glucose metabolism. Glucose utilization becomes more significant in producing ATP, allowing the heart to maintain its energy needs even when fatty acid utilization is impaired. 
• Improved Efficiency in Heart Muscle: By shifting the heart’s energy metabolism from fatty acids to glucose, perhexiline helps improve the efficiency of the heart muscle. 

Pharmacokinetics: 

Absorption 

perhexiline is well absorbed after oral administration. The absorption process takes place primarily in the small intestine. However, its absorption is highly variable among individuals, and factors such as food intake and other medications may affect its bioavailability. Taking perhexiline with food can enhance its absorption. 

Distribution 

perhexiline is extensively distributed throughout the body, including various tissues and organs. It has a relatively high volume of distribution, indicating that it can reach different compartments beyond the bloodstream. The drug readily crosses the BBB (blood-brain barrier) and can enter the central nervous system. 

Metabolism 

perhexiline is extensively metabolized in the liver. The main metabolic pathway involves N-dealkylation by the enzyme CYP2D6, leading to the formation of its active metabolite, desmethylperhexiline. This metabolite is responsible for most of the drug’s pharmacological effects. CYP2D6 is a genetically polymorphic enzyme, leading to individual variations in perhexiline metabolism. Some individuals are extensive metabolizers, while others may be poor metabolizers of the drug. 

Elimination and Excretion 

perhexiline and its metabolites are primarily excreted in the urine. Only a tiny fraction of the administered dose is eliminated unchanged. The majority of the drug and its metabolites are eliminated through the kidneys. As perhexiline undergoes extensive metabolism in the liver, impaired liver function can lead to reduced drug clearance, potentially increasing the risk of toxicity. 

Adminstartion

Administration: 

Oral administration 

perhexiline is usually administered orally in the form of tablets. A qualified healthcare professional should determine the dosing and administration of perhexiline based on the patient’s condition and medical history.  

• Dosage: The typical starting dose of perhexiline is usually low and gradually increased over time to achieve the desired therapeutic effect while decreasing side effects. The dosing regimen may vary depending on the treated condition and the patient’s response to the medication. 
• Timing: perhexiline is usually taken once daily, and the timing of administration may vary. Taking the medication with food is typically recommended to enhance absorption and reduce gastrointestinal side effects. 
• Swallowing: perhexiline tablets should be swallowed whole with a glass of water and not be crushed, chewed, or broken before consumption. 
• Duration of Treatment: The duration of therapy with perhexiline will be determined by the treating healthcare professional. It’s essential to continue taking the medication as prescribed, even if symptoms improve unless instructed otherwise by the healthcare provider. 
• Monitoring: During treatment with perhexiline, the patient will need regular monitoring of liver function, cardiac function, blood glucose levels (if applicable), and any potential side effects. The healthcare provider will schedule follow-up visits to assess the patient’s response to the medication and adjust the dosage if necessary. 
• Adherence: It’s crucial to take perhexiline consistently as prescribed. Skipping doses or taking the medication inconsistently can reduce effectiveness and may not provide the desired benefits. 
• Drug Interactions: Inform the healthcare provider about all other medications, supplements, or herbal products you are taking before starting perhexiline. Certain drugs, especially those affecting the CYP2D6 enzyme, can interact with perhexiline and may require dosage adjustments or careful monitoring to avoid adverse effects. 
• Discontinuation: Avoid taking perhexiline abruptly without consulting your healthcare provider. If there is a need to discontinue the medication, your healthcare provider will guide how to taper the dose gradually. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: perhexiline 

Why do we use perhexiline? 

perhexiline is a medication with various uses in treating certain cardiovascular conditions.  

• Angina Pectoris: perhexiline is used to manage stable angina, a chest pain caused by decreased blood flow to the heart muscle. By altering the heart’s energy utilization, perhexiline helps improve the heart’s efficiency and reduces angina episodes. 
• Heart Failure: In some cases of heart failure, especially when the heart muscle is inefficiently using fatty acids for energy, perhexiline may be prescribed to shift the heart’s energy source to glucose. This can potentially improve the heart’s function and symptoms of heart failure.