Nitrogen mustards

Nitrogen mustards

Nitrogen mustards represent the largest group of alkylating drugs. They include:

• chlorambucil
• cyclophosphamide
• estramustine
• ifosfamide
• mechlorethamine hydrochloride
• melphalan.

First and fast

Mechlorethamine hydrochloride was the first nitrogen mustard introduced and is rapid-acting.

Pharmacokinetics (how drugs circulate)

The absorption and distribution of nitrogen mustards, as with most alkylating drugs, vary widely.

Metabolism and excretion

Nitrogen mustards are metabolized in the liver and excreted by the kidneys. Mechlorethamine undergoes metabolism so rapidly that no active drug remains after a few minutes. Most nitrogen mustards possess more intermediate half-lives than mechloreth-amine.

Pharmacodynamics (how drugs act)

Nitrogen mustards form covalent bonds with DNA molecules in a chemical reaction known as alkylation. Alkylated DNA can’t replicate properly, thereby resulting in cell death. Unfortunately, cells may develop resistance to the cytotoxic effects of nitrogen mustards. 

Now I get it!

How alkylating drugs work

Bifunctional alkylation

Some drugs become inserted between two base pairs in the DNA chain, forming an irreversible bond between them. This is called bifunctional alkylation; it causes cytotoxic effects capable of destroying or poisoning cells.

Monofunctional alkylation

Other drugs react with just one part of a pair, separating it from its partner and eventually causing it and its attached sugar to break away from the DNA molecule. This is called monofunctional alkylation; it eventually may cause permanent cell damage.

Pharmacotherapeutics (how drugs are used)

Because they produce leukopenia (reduced number of white blood cells [WBCs]), the nitrogen mustards are effective in treating malignant neoplasms, such as Hodgkin’s disease (cancer causing painless enlargement of the lymph nodes, spleen, and lymphoid tissues) and leukemia (cancer of the blood-forming tissues), that can have an associated elevated WBC count.

Nitrogen bomb

Nitrogen mustards also prove effective against malignant lymphoma (cancer of the lymphoid tissue), multiple myeloma (cancer of the marrow plasma cells), melanoma (malignancy that arises from melanocytes), and cancers of the breast, ovaries, uterus, lung, brain, testes, bladder, prostate, and stomach.

Drug interactions

Nitrogen mustards interact with a wide variety of other drugs:

• Calcium-containing drugs and foods, such as antacids and dairy products, reduce absorption of estramustine.
• Cyclophosphamide taken with cardiotoxic drugs produces additive cardiac effects.
• Cyclophosphamide may reduce serum digoxin levels.
• An increased risk of ifosfamide toxicity exists when the drug is taken with allopurinol, barbiturates, chloral hydrate, or phenytoin.
• Corticosteroids reduce the effects of ifosfamide.
• The lung toxicity threshold of carmustine may be reduced when taken with melphalan.
• Interferon alpha may reduce serum concentration of melphalan.