Common side effects of the injectable form includelow blood sugar, pain at the site of injection, nausea, vomiting,low blood pressure, and kidney problems.[1] Common side effects of the inhaled form includewheezing, cough, and nausea.[1] It is unclear if doses should be changed in those with kidney or liver problems.[1] Pentamidine is not recommended in earlypregnancy but may be used in later pregnancy.[1] Its safety duringbreastfeeding is unclear.[3] Pentamidine is in the aromatic diamidine family of medications.[4] While the way the medication works is not entirely clear, it is believed to involve decreasing the production of DNA, RNA, and protein.[1]
It has not been shown to cause birth defects in animal studies when given intravenously. There are no controlled studies to show if pentamidine can harm the fetus in pregnant women. It is only recommended if the drug of choice trimethoprim-sulfamethoxazole is contraindicated.[15]
There is no information regarding the excretion of pentamidine in breast milk, but since the adverse effects on breastfed infants are unknown currently, it is recommended by the manufacturer for the infant to not be breastfed or for the mother to stop the drug. Risks versus benefits for the mother should be considered when making this decision.[15]
Pentamidine can be used in the prevention of PCP in children with HIV who cannot tolerateTrimethoprim/Sulfamethoxazole and can use a nebulizer. Intranvenous solutions of pentamidine should only be used in children with HIV older than 2 years old when other treatments are unavailable[16]
Blood: Pentamidine frequently causesleukopenia and less oftenthrombopenia, which may cause symptomatic bleeding. Some cases ofanemia, possibly related tofolic acid deficiency, have been described.[17]
Liver: Elevatedliver enzymes are associated with intravenous use of pentamidine.Hepatomegaly andhepatitis have been encountered with long term prophylactic use of pentamidine inhalation.[8]
Neurological: Dizziness, drowsiness,neuralgia, confusion, hallucinations,seizures and other central side effects are reported.[8]
Skin: Severe local reactions after extravasculation of intravenous solutions or following intramuscular injection treatment have been seen. Pentamidine itself may cause rash, or rarelyStevens–Johnson syndrome orLyell syndrome.[8]
The mechanism seems to vary with different organisms and is not well understood. However, pentamidine is suspected to work through various methods of interference of critical functions in DNA, RNA, phospholipid and protein synthesis.[8][18] Pentamidine binds toadenine-thymine-rich regions of theTrypanosoma parasite DNA, forming a cross-link between two adenines four to five base pairs apart. The drug also inhibitstopoisomerase enzymes in themitochondria ofPneumocystis jirovecii. Similarly, pentamidine inhibitstype II topoisomerase in the mitochondria of theTrypanosoma parasite, resulting in a broken and unreadable mitochondrial genome.[18]
Strains of theTrypanosoma brucei parasite that are resistant to pentamidine have been discovered. Pentamidine is brought into the mitochondria through carrier proteins, and the absence of these carriers prevents the drug from reaching its site of action.[18]
Pentamidine is completely absorbed when given intravenously or intramuscularly. When inhaled through a nebulizer, pentamidine accumulates in thebronchoalveolar fluid of the lungs at a higher concentration compared to injections. The inhaled form is minimally absorbed in the blood, but the effects of chronic inhaled administration on these levels are not known.[9] Absorption is unreliable when given orally.[10]
When injected, pentamidine binds to tissues and proteins in the plasma. It accumulates in the kidney, liver, lungs, pancreas, spleen, and adrenal glands.[19] Additionally, pentamidine does not reach curative levels in thecerebrospinal fluid.[10] It has avolume of distribution of 286–1356 liters when given intravenously and 1658–3790 liters when given intramuscularly.[20] Inhaled pentamidine is mainly recovered from thebronchoalveolar lavage fluid of the lungs.[9][19]
Pentamidine has an average half-life of five to eight hours when given intravenously and seven to eleven hours when given intramuscularly. However, these may increase with severe kidney problems.[19] Pentamidine can remain in the system for as long as eight months after the first injection.[18]
Pentamidine isethionate for injection is commercially available as alyophilized, white crystalline powder for reconstitution with sterile water or 5% dextrose. After reconstitution, the mixture should be free from discoloration and precipitation. Reconstitution with sodium chloride should be avoided due to formation of precipitates. Intravenous solutions of pentamidine can be mixed with intravenous HIV medications likezidovidine and intravenous heart medications likediltiazem. However, intravenous solutions of antiviralfoscarnet and antifungalfluconazole are incompatible with pentamidine.[8] To avoid side-effects associated with intravenous administration, the solution should be slowly infused to minimize the release ofhistamine.[18]
Pentamidine was first used to treatAfrican trypanosomiasis in 1937 andleishmaniasis in 1940 before it was registered as pentamidine mesylate in 1950.
The sudden increase in requests for use of pentamidine isethionate in then unlicensed form from the CDC in the early 1980s for treatingPneumocystis jirovecii in young male patients was key in identifying the emergence of the HIV/AIDS epidemic at that time.[22]
Its efficacy againstPneumocystis jirovecii was demonstrated in 1987, following its re-emergence on the drug market in 1984 in the current isethionate form.[10]
^World Health Organization (2019).World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Lee MS, Johansen L, Zhang Y, Wilson A, Keegan M, Avery W, et al. (December 2007). "The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action".Cancer Research.67 (23):11359–11367.doi:10.1158/0008-5472.CAN-07-2235.PMID18056463.
^abcdeLemke TL, Williams DA, eds. (2013).Foye's Principles of Medicinal Chemistry (Seventh ed.). Philadelphia, PA: Lippincott Williams & Wilkins.ISBN978-1-60913-345-0.
