Doxorubicin

Doxorubicin is an antineoplastic drug that belongs to the anthracycline class. 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 lies in its ability to bind to DNA, which prevents the proliferation of cancer cells. It is integrated into the DNA of cancer cells, blocking the process of RNA and DNA synthesis, which leads to disruption of the process of cell division and their death.

Doxorubicin is used both in 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.

Due to the potential for cardiac toxicity, close medical monitoring is required when using doxorubicin, including regular monitoring of cardiac function 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 recurrence.
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 may be used to treat stomach cancer, especially when combined with other anticancer drugs.
6. Sarcomas: Including osteosarcoma and Kaposi's sarcoma, doxorubicin may be part of the treatment regimen.
7. Lymphomas: Doxorubicin is active against both Hodgkin and non-Hodgkin 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 decision of the oncologist.

Release form

1. Solution for infusion: This is the most common form of doxorubicin. The solution is intended for intravenous administration and is often used to treat diseases 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 infusion solution: Liposomal doxorubicin is intended to reduce cardiotoxicity and improve drug distribution in the body. This helps reduce side effects and improve the effectiveness of treatment for certain types of cancer.

Pharmacodynamics

Main mechanisms of action of doxorubicin:

1. DNA intercalation: Doxorubicin is inserted between base pairs in the DNA double helix, which leads to disruption of DNA replication and transcription processes.
2. Inhibition of Topoisomerase II: Topoisomerase II is important for unwinding and recoiling DNA during replication processes. Doxorubicin inhibits this enzyme, causing the formation of stable enzyme-DNA complexes, which leads 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: Thanks to the mechanisms described above, 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 heart cells and the formation of free radicals.

Pharmacokinetics

1. Absorption: Doxorubicin is usually administered intravenously. After administration, it is quickly distributed in the tissues of the body.
2. Distribution: Doxorubicin is widely distributed throughout the body, penetrating various tissues and organs, including the heart, liver, lungs, spleen and kidneys. It also crosses the placental barrier and is excreted into 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, which leads to a decrease in toxic effects on the heart muscle (Legha et al., 1982).
2. Modification of the dosing schedule: Animal studies have shown that modification of the doxorubicin dosing schedule, including administration of smaller doses more frequently, can also reduce cardiotoxicity while maintaining the antitumor activity of the drug (Yeung et al., 2002).
3. Liposome Form: Administration of doxorubicin in liposomes may also reduce cardiotoxicity by releasing the drug more slowly and reducing its effects on the heart.

It is important to note that doxorubicin is usually administered 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

The use of doxorubicin during pregnancy requires caution due to its potential toxicity and the possibility of negative effects on the fetus. Important aspects:

1. Transplacental transfer: Studies have shown that doxorubicin can cross the placenta. In one case, after the use of doxorubicin, one child 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 found that the volume of distribution of doxorubicin increases during pregnancy, which may influence 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 showed 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 only possible in cases where the expected benefit to the mother outweighs the potential risk to the fetus. Consultation with a doctor 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 breastfeeding 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 liver dysfunction.
• General 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 lining of the mouth), food intolerance may occur.
4. Hair system: Hair loss is possible.
5. Allergic reactions: May manifest themselves in the form of allergic rashes, itching, urticaria.
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: Bone marrow suppression, leading to low levels of white blood cells, platelets and red blood cells, which increases the risk of infections, bleeding and anemia.
2. Cardiotoxicity: Development of acute heart failure, possibly including symptoms such as shortness of breath, swelling and fatigue.
3. Gastrointestinal disturbances: 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 levels of liver enzymes, indicating liver stress or damage.

Measures in case of overdose:

• Seek immediate medical attention: If you suspect an overdose, you should immediately seek qualified medical help.
• Symptomatic treatment: Includes maintaining fluid and electrolyte balance, treating nausea and vomiting with antiemetics, and maintaining adequate hemodynamics.
• Medicines to reduce cardiotoxicity: Use of drugs such as dexrazoxane, which may help reduce the cardiotoxicity of anthracyclines.
• Maintenance therapy: Including the possible use of growth factors (eg, G-CSF) to stimulate bone marrow recovery.
• Vital functions monitoring and support: Monitor cardiac status, renal and liver function, and monitor electrolytes and metabolic status.

Interactions with other drugs

1. Drugs that cause cardiotoxicity: Doxorubicin may increase 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 excretion 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. Drugs that affect the central nervous system: Doxorubicin may interact with drugs that affect the central nervous system, 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 2°C to 8°C. This ensures the stability of the drug and prevents its decomposition under the influence of high temperatures.
2. Protect 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. Keeping 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. Compliance with 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.