amifostine

Action and Spectrum

Actions and Spectrum: 

Mechanism of Action: 

• Free Radical Scavenging: amifostine’s active metabolite, WR-1065, can scavenge free radicals, such as reactive oxygen species (ROS), generated during cancer treatments like chemotherapy and radiation therapy. By neutralizing these free radicals, amifostine helps protect healthy cells from their damaging effects. 
• DNA Repair: amifostine also aids in the repair of DNA damage caused by chemotherapy and radiation therapy. It stimulates the DNA repair enzyme, DNA phosphatase, which helps restore damaged DNA strands. 
• Cellular Protection: The drug increases certain cellular antioxidants, such as glutathione, which protect cells from the harmful effects of chemotherapy drugs and radiation. 

Spectrum of Activity: amifostine has a relatively broad spectrum of activity and can protect various chemotherapy drugs and radiation therapy in specific organs or tissues. Its primary applications include: 

• Protection against Platinum-based Chemotherapy: amifostine has been extensively studied and used as a protective agent against platinum-based chemotherapy drugs like cisplatin, carboplatin, and oxaliplatin. It helps minimize the toxic effects of these drugs on healthy tissues, particularly the kidneys and the peripheral nervous system. 
• Radiation Therapy Protection: amifostine is used to reduce the toxicity of radiation therapy in certain situations. It is commonly employed in head and neck cancer treatments, where it helps protect the salivary glands from radiation-induced damage, decreasing the risk of xerostomia (dry mouth) and improving the quality of life for patients. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Hypotension (61%)  

Nausea/vomiting (96%)  

1-10% 

Stevens-Johnson syndrome (1%) 

Hypocalcemia (1%)  

Frequency not defined 

Flushing/feeling of warmth 

Fever 

Rash 

Hiccups 

Chills/feeling of coldness 

Dizziness 

Somnolence 

Malaise 

Sneezing 

Post-marketing reports 

Urticaria 

Anaphylactic reactions 

Myocardial infarction 

Cardiac arrest 

Bradycardia 

Supraventricular tachycardia 

Apnea 

Hypoxia 

Pruritus 

Laryngeal edema 

Myocardial ischemia 

Tachycardia 

Atrial fibrillation/flutter 

Extrasystoles 

Dyspnea 

Respiratory arrest 

Black Box Warning

Black box warning: 

None 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

• Hypersensitivity: Individuals with known hypersensitivity or allergic reactions to amifostine or its components should not use the drug. Allergic reactions can range from mild skin rashes to more severe symptoms like difficulty breathing and anaphylaxis. 
• Bleeding Disorders: amifostine can increase the risk of bleeding due to its potential effects on platelet function. Therefore, it is contraindicated in individuals with pre-existing bleeding disorders or those taking medications that affect blood clotting, such as anticoagulants (e.g., warfarin). 
• Uncontrolled Hypotension: amifostine has been associated with a drop in blood pressure as a side effect. Therefore, it should be used cautiously in individuals with uncontrolled hypotension (low blood pressure) or those already taking antihypertensive medications. 
• Pre-existing Kidney Disease: amifostine is primarily metabolized and excreted by the kidneys. It should be used cautiously or avoided in individuals with pre-existing kidney disease or impaired renal function, as it may further exacerbate kidney problems. 
• Pre-existing Hypocalcemia: amifostine can cause reductions in serum calcium levels. It should be used cautiously or avoided in individuals with pre-existing hypocalcemia (low blood calcium levels). 
• Pregnancy and Lactation: The safety of amifostine during pregnancy and lactation has not been established. It is generally not recommended in pregnant or breastfeeding women unless the potential benefits outweigh the risks. 

Caution: 

• Cardiovascular Conditions: amifostine can cause decreases in blood pressure, which may be of concern in individuals with pre-existing cardiovascular conditions, such as a history of heart disease, unstable angina, or a recent heart attack. Close monitoring of blood pressure is recommended during amifostine administration in such cases. 
• Diabetes: amifostine has been reported to affect glucose metabolism and insulin sensitivity, which may require adjustments in the management of diabetes. Diabetic patients should be closely monitored for changes in blood glucose levels, and appropriate adjustments in antidiabetic medications may be necessary during amifostine treatment. 
• Asthma or Chronic Obstructive Pulmonary Disease (COPD): amifostine can cause bronchoconstriction or exacerbate existing respiratory conditions. Caution should be exercised in individuals with a history of asthma or COPD, and appropriate respiratory support should be readily available during treatment. 
• Alcohol Use: amifostine may enhance the effects of alcohol, including drowsiness and dizziness. It is advisable to limit alcohol consumption during treatment with amifostine. 
• Concurrent Medications: amifostine may interact with certain medications, including antihypertensives, anticoagulants, and drugs that affect renal function. It is essential to inform the healthcare professional about all medications, including over-the-counter drugs and herbal supplements, being taken concurrently to avoid potential drug interactions. 
• Pediatric and Geriatric Use: The safety and efficacy of amifostine in pediatric and geriatric populations have yet to be extensively studied. Caution should be exercised when using amifostine in these age groups, and the dosages may need to be adjusted based on individual patient factors. 
• Renal impairment: amifostine is primarily eliminated through the kidneys. Patients with pre-existing renal impairment or compromised renal function may require dosage adjustments or careful monitoring during treatment to prevent the accumulation of the drug or its metabolites. 

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

Lactation: Excretion of the drug in human breast milk is unknown 

It is generally not recommended in pregnant or breastfeeding women unless the potential benefits outweigh the risks. 

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: 

amifostine is a cytoprotective agent used in medical settings to reduce the toxic effects of certain chemotherapy drugs and radiation therapy. Here is a detailed explanation of the pharmacology of amifostine: 

amifostine exerts its pharmacological effects through its active metabolite, WR-1065. The exact mechanism of action of WR-1065 is not fully understood but is believed to involve multiple pathways: 

• Free Radical Scavenging: WR-1065 acts as a potent free radical scavenger, particularly against reactive oxygen species (ROS) generated during cancer treatments like chemotherapy and radiation therapy. It reacts with and neutralizes free radicals, reducing their harmful effects on cells and tissues. 
• Antioxidant Activity: WR-1065 has antioxidant properties, which help protect cells from oxidative stress and damage caused by chemotherapy drugs and radiation. It helps balance reactive oxygen species and cellular antioxidants, reducing cellular injury. 
• DNA Protection and Repair: WR-1065 has been shown to protect DNA from the damaging effects of chemotherapy drugs and radiation. It can scavenge and reduce DNA-reactive species, preventing DNA strand breaks and minimizing genetic damage. It also stimulates DNA repair enzymes, such as DNA phosphatase, which aids in the restoration of damaged DNA strands. 

Pharmacodynamics: 

The primary pharmacodynamic actions of amifostine are attributed to its active metabolite, WR-1065. Here is an overview of the pharmacodynamics of amifostine: 

• Free Radical Scavenging: WR-1065 acts as a free radical scavenger, mainly targeting reactive oxygen species (ROS) generated during chemotherapy and radiation therapy. ROS can cause oxidative stress, leading to cellular damage and toxicity. WR-1065 interacts with and neutralizes ROS, reducing their harmful effects on cells. 
• Antioxidant Activity: WR-1065 exhibits antioxidant properties, helping to maintain the balance between oxidants and antioxidants in cells. It reduces oxidative stress by scavenging free radicals and preventing their detrimental effects on cellular structures and biomolecules, such as lipids, proteins, and DNA. 
• DNA Protection and Repair: WR-1065 plays a role in protecting and repairing DNA. It helps prevent DNA damage induced by chemotherapy drugs and radiation by scavenging DNA-reactive species. Additionally, WR-1065 stimulates DNA repair enzymes, such as DNA phosphatase, facilitating the repair of DNA strand breaks and reducing the risk of genetic mutations. 
• Cellular Protection: WR-1065’s actions on various cellular components mediate the cytoprotective effects of amifostine. By scavenging free radicals and enhancing antioxidant defense mechanisms, WR-1065 helps protect cells from chemotherapy and radiation-induced damage, preserving their structural and functional integrity. 

Pharmacokinetics: 

Absorption 

amifostine can be administered intravenously (IV) or as an oral prodrug called Ethyol. When given intravenously, the drug is rapidly and completely absorbed. The oral prodrug is converted to the active form, amifostine, in the body. The absolute oral bioavailability of amifostine is relatively low, ranging from 34% to 66% due to variable first-pass metabolism. 

Distribution 

amifostine is distributed widely in the body. It has a moderate volume of distribution, suggesting that it penetrates well into tissues. The drug crosses the blood-brain barrier and can reach therapeutic concentrations in the central nervous system. 

Metabolism 

amifostine undergoes metabolism primarily in the liver. The main metabolic pathway involves the conversion of amifostine to its active free thiol metabolite, WR-1065, by alkaline phosphatases. WR-1065 is responsible for the cytoprotective effects of amifostine. The metabolite undergoes further detoxification through conjugation with glutathione and other processes. 

Elimination and Excretion 

The elimination of amifostine and its metabolites occurs primarily via renal excretion. Approximately 40% to 50% of the administered dose is excreted unchanged in the urine within 24 hours. The elimination half-life of amifostine is relatively short, averaging about 3 minutes. The half-life of the active metabolite, WR-1065, is approximately 50 minutes. 

Adminstartion

Administration: 

amifostine can be administered via intravenous (IV) infusion or as an oral prodrug called Ethyol.  

Intravenous (IV) Administration: 

amifostine is typically administered as an IV infusion over 15 minutes. 

• The infusion can be given before chemotherapy or radiation therapy to provide cytoprotection to normal cells. 
• The recommended IV dose of amifostine varies depending on the indication and the chemotherapy regimen used. The dose may also be adjusted based on the patient’s body surface area or weight. 
• The healthcare provider will calculate the appropriate dose and schedule based on individual patient factors. 

Oral Administration (Ethyol): 

• Ethyol is an oral prodrug of amifostine that gets converted to an active form in the body. 
• It is usually administered as a daily dose 3 hours before chemotherapy or radiation therapy. 
• The recommended oral dose of Ethyol is typically lower than the IV dose due to differences in bioavailability and metabolism. 
• Ethyol tablets should be swallowed whole with a glass of water and not crushed, chewed, or dissolved. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: amifostine 

Why do we use amifostine? 

amifostine is a cytoprotective agent primarily used in cancer treatment to reduce the toxic effects of certain chemotherapy drugs and radiation therapy on normal tissues. Here are the primary uses of amifostine: 

• Chemotherapy-induced nausea and vomiting (CINV): amifostine can prevent or reduce the severity of nausea and vomiting caused by chemotherapy. It is particularly effective in reducing delayed nausea and vomiting that can occur 24 hours or more after chemotherapy administration. 
• Radiation therapy: amifostine is commonly used as a radioprotectant to minimize the side effects of radiation therapy. It helps protect healthy tissues and organs from damage caused by radiation, allowing for higher radiation doses to be delivered to the tumor while minimizing harm to surrounding healthy tissues. It is often used in head and neck cancer treatments. 
• Cytoprotection during chemotherapy: Certain chemotherapy drugs can cause significant damage to normal tissues, such as the kidneys, bladder, and salivary glands. amifostine can be used to provide protection to these tissues and reduce the risk of long-term complications.