Doxorubicin

Doxorubicin is an antineoplastic drug that belongs to the class of anthracyclines. It is a powerful chemotherapy agent widely used to treat various types of cancer, including breast cancer, leukemia, lymphoma, soft tissue sarcoma, and other cancers.

The action of doxorubicin is its ability to bind to DNA, which prevents the proliferation of cancer cells. It is embedded in the DNA of cancer cells, blocking the process of RNA and DNA synthesis, which leads to disruption of the cell division process and their death.

Doxorubicin is used both as a monotherapy and in combination with other drugs in chemotherapy regimens. However, despite its effectiveness, doxorubicin can cause serious side effects, including cardiotoxicity (heart damage), myelosuppression (bone marrow suppression), nausea and vomiting, alopecia (hair loss), and others.

Because of potential cardiac toxicity when using doxorubicin, careful medical supervision, including regular monitoring of cardiac function, is necessary during treatment.

Indications Doxorubicin

1. Breast Cancer: Doxorubicin is often used as part of combination chemotherapy to treat certain stages of breast cancer.
2. Acute lymphoblastic leukemia: The drug is used to treat this type of leukemia, especially when there is a high risk of relapse.
3. Ovarian cancer: Doxorubicin may be included in the treatment protocol for some forms of ovarian cancer.
4. Thyroid cancer: Used as part of combination therapy for some types of thyroid cancer.
5. Stomach cancer: The drug can be used to treat stomach cancer, especially in combination with other anticancer agents.
6. Sarcomas: Including osteosarcoma and Kaposi's sarcoma, doxorubicin may be part of the treatment regimen.
7. Lymphomas: Doxorubicin is active against both Hodgkin's and non-Hodgkin's lymphomas.
8. Bladder cancer: The drug may also be used to treat bladder cancer in certain cases.
9. Other types of cancer: Doxorubicin may be used to treat other types of cancer depending on the clinical situation and the oncologist's decision.

Release form

1. Infusion solution: This is the most common form of doxorubicin. The solution is intended for intravenous administration and is often used to treat conditions such as breast cancer, ovarian cancer, lung cancer, thyroid cancer, various forms of leukemia, and other types of cancer.
2. Lyophilized powder for solution for infusion: This form of doxorubicin comes as a powder that must be reconstituted before use. This provides additional stability and shelf life before use.
3. Liposomal solution for infusion: Liposomal forms of doxorubicin are designed to reduce cardiotoxicity and improve the distribution of the drug in the body. This helps reduce side effects and improve the effectiveness of treatment for certain types of cancer.

Pharmacodynamics

The main mechanisms of action of doxorubicin:

1. DNA intercalation: Doxorubicin intercalates between base pairs in the DNA double helix, resulting in disruption of DNA replication and transcription processes.
2. Topoisomerase II Inhibition: Topoisomerase II is important for the unwinding and rewinding of DNA during replication. Doxorubicin inhibits this enzyme, causing the formation of stable enzyme-DNA complexes, which lead to DNA strand breaks and cell death.
3. Free Radical Formation: Doxorubicin can catalyze the formation of free radicals that damage cell membranes, DNA, and other molecules, which also contributes to cell death.

Clinical effects:

• Antitumor effect: Due to the above-described mechanisms, doxorubicin effectively destroys cancer cells.
• Cardiotoxicity: One of the serious side effects of doxorubicin is its cardiotoxicity, which can lead to the development of cardiomyopathy and heart failure. This effect is associated with damage to the mitochondria of cardiac cells and the formation of free radicals.

Pharmacokinetics

1. Absorption: Doxorubicin is usually administered intravenously. After administration, it is rapidly distributed throughout the body's tissues.
2. Distribution: Doxorubicin is widely distributed throughout the body, penetrating into various tissues and organs, including the heart, liver, lungs, spleen, and kidneys. It also crosses the placental barrier and is excreted in breast milk.
3. Metabolism: Doxorubicin is metabolized in the liver by oxidation and deamination. Metabolites formed as a result of metabolism may also have anticarcinogenic properties.
4. Elimination: Doxorubicin is eliminated from the body primarily through bile and urine. Its half-life is approximately 20-48 hours.
5. Protein binding: Doxorubicin has a high affinity for plasma proteins.

Dosing and administration

1. Continuous intravenous administration: Studies have shown that continuous intravenous administration of doxorubicin significantly reduces the risk of cardiotoxicity. This is achieved by reducing peak plasma levels of doxorubicin, resulting in reduced toxic effects on the cardiac muscle (Legha et al., 1982).
2. Modification of the dosing schedule: Animal studies have shown that modification of the dosing schedule of doxorubicin, including administering smaller doses more frequently, can also reduce cardiotoxicity while maintaining the antitumor activity of the drug (Yeung et al., 2002).
3. Liposomal Formulation: Administration of doxorubicin in liposomes may also reduce cardiotoxicity by releasing the drug more slowly and reducing its effect on the heart.

It is important to note that doxorubicin is usually given intravenously, and the dosage may vary depending on the type and stage of cancer, as well as the combination chemotherapy regimen.

Use Doxorubicin during pregnancy

Use of doxorubicin during pregnancy requires caution due to its potential toxicity and potential for adverse effects on the fetus. Important considerations:

1. Transplacental transfer: Studies have shown that doxorubicin can cross the placenta. In one case, after doxorubicin administration, one baby was born healthy and the other was stillborn, highlighting the risks of its use during pregnancy (Karpukhin et al., 1983).
2. Pharmacokinetics: Changes in the pharmacokinetics of doxorubicin during pregnancy may require dosage adjustments. A study showed that the volume of distribution of doxorubicin increases during pregnancy, which may affect its efficacy and toxicity (Hasselt et al., 2014).
3. Cardiotoxicity: Doxorubicin is known to have cardiotoxic effects, which may be exacerbated during pregnancy. A study has shown cases of cardiomyopathy occurring during pregnancy in women previously treated with doxorubicin (Pan & Moore, 2002).

Based on the available data, the use of doxorubicin during pregnancy should be strictly limited and possible only in cases where the expected benefit to the mother outweighs the potential risk to the fetus. Consultation with a physician is always necessary to assess all risks and develop a safe treatment strategy.

Contraindications

1. Severe cardiomyopathy and heart failure. Doxorubicin may cause cardiotoxicity, which may be acute or delayed and may lead to heart failure. Patients with existing heart disease or those who have received high doses of doxorubicin or other anthracyclines may be particularly at risk.
2. Hypersensitivity to doxorubicin or other anthracyclines. A history of allergic reactions to these drugs may be a reason to avoid their use.
3. Severe myelosuppression: Because doxorubicin can cause bone marrow suppression, which results in low blood cell levels, its use in patients with pre-existing bone marrow suppression may be dangerous.
4. Pregnancy and lactation. Doxorubicin is teratogenic and can cause harm to the fetus, as well as penetrate into breast milk, which makes its use during pregnancy and lactation unacceptable.

In addition, the use of doxorubicin requires special caution in patients with:

• Liver failure, since doxorubicin is metabolized in the liver and its activity or toxicity may be altered by impaired liver function.
• A generally weakened state where the risks of drug toxicity may outweigh the potential benefits.

Side effects Doxorubicin

1. Cardiac toxicity: This is one of the most serious side effects of Doxorubicin. It can lead to cardiomyopathy, which increases the risk of heart failure. This is facilitated by the cumulative dose of the drug.
2. Bone marrow toxicity: Doxorubicin can suppress the bone marrow, which can lead to leukopenia (decreased white blood cell count), thrombocytopenia (decreased platelet count), and anemia (decreased red blood cell count).
3. Gastrointestinal toxicity: Nausea, vomiting, diarrhea, stomatitis (inflammation of the oral mucosa), and food intolerance may occur.
4. Hair system: Hair loss may occur.
5. Allergic reactions: May manifest as allergic rashes, itching, hives.
6. Specific side effects: Possible development of severe acute inflammatory process at the injection site (phlebitis), skin reactions at the injection site, etc.
7. Other side effects: Possible fatigue, weakness, muscle and joint pain, changes in skin and nail pigmentation, digestive disorders, etc.

Overdose

1. Myelosuppression: Suppression of the bone marrow, resulting in low levels of white blood cells, platelets, and red blood cells, increasing the risk of infections, bleeding, and anemia.
2. Cardiotoxicity: Development of acute heart failure, possibly including symptoms such as shortness of breath, oedema, and fatigue.
3. Gastrointestinal disorders: Nausea, vomiting and diarrhea, which may be particularly severe and further aggravate dehydration and electrolyte disturbances.
4. Damage to the mucous membrane: Stomatitis or mouth ulcers can make it difficult to eat and drink.
5. Liver Damage: Elevated liver enzyme levels, indicating liver stress or damage.

Measures in case of overdose:

• Immediate medical attention: If you suspect an overdose, seek qualified medical attention immediately.
• Symptomatic treatment: Includes maintenance of fluid and electrolyte balance, treatment of nausea and vomiting with antiemetics, and maintenance of adequate hemodynamics.
• Drugs to reduce cardiotoxicity: Use of drugs such as dexrazoxane, which may help reduce the cardiotoxicity of anthracyclines.
• Supportive care: Including possible use of growth factors (eg, G-CSF) to stimulate bone marrow regeneration.
• Monitoring and supporting vital functions: Monitoring cardiac status, renal and hepatic function, and monitoring electrolytes and metabolic status.

Interactions with other drugs

1. Drugs that have cardiotoxic effects: Doxorubicin may enhance the cardiotoxic effects of other drugs, such as antiarrhythmics or drugs that affect cardiac function. This may lead to an increased risk of cardiac arrhythmias or heart failure.
2. Drugs that affect liver function: Doxorubicin is metabolized in the liver, so drugs that affect liver function may affect its metabolism and elimination from the body.
3. Drugs that increase hematological side effects: Doxorubicin may increase the hematological side effects of other drugs, such as cytostatics or drugs that affect hematopoiesis. This may lead to an increased risk of anemia, thrombocytopenia or leukopenia.
4. Drugs that affect the immune system: Doxorubicin may interact with drugs that affect the immune system, which may worsen the risk of infections or allergic reactions.
5. Drugs that affect bone marrow: Doxorubicin may interact with drugs that affect bone marrow, such as granulocyte colony-stimulating factor (G-CSF), which may increase the risk of neutropenia.
6. CNS (central nervous system) acting drugs: Doxorubicin may interact with CNS acting drugs such as benzodiazepines, antidepressants, or antiepileptic drugs, which may increase the risk of neurological side effects.

Storage conditions

1. Storage Temperature: Doxorubicin is usually stored at a temperature of 2°C to 8°C. This ensures the stability of the drug and prevents its degradation under the influence of high temperatures.
2. Protection from light: Doxorubicin should be stored in a container or package protected from light. Light can destroy the active components of the drug, so its exposure should be minimized.
3. Special storage conditions: Some forms of doxorubicin, such as injection solutions, may require special storage conditions, such as refrigeration or protection from freezing.
4. Keep out of reach of children: As with other medications, it is important to keep doxorubicin out of the reach of children to avoid accidental poisoning.
5. Observing expiration dates: It is also important to monitor the expiration dates of the drug and use it before the expiration date. After this, the drug may lose its effectiveness and become unsuitable for use.