Common side effects of the injectable form include low blood sugar, pain at the site of injection, nausea, vomiting, low blood pressure, and kidney problems.[1] Common side effects of the inhaled form include wheezing, 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 early pregnancy but may be used in later pregnancy.[1] Its safety during breastfeeding 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]
Pentamidine is classified as an orphan drug by the U.S. Food and Drug Administration[12]
Other uses
Use as an antitumor drug has also been proposed.[13]
Pentamidine is also identified as a potential small molecule antagonist that disrupts this interaction between S100P and RAGE receptor.[14]
Special Populations
Pregnancy
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]
Breastfeeding
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]
Children
Pentamidine can be used in the prevention of PCP in children with HIV who cannot tolerate Trimethoprim/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]
Elderly
There is no data for the use of pentamidine in this specific population.[15]
Contraindications
Patients with a history of anaphylaxis or hypersensitivity to pentamidine isethionate[8]
Side effects
Common
Burning pain, dryness, or sensation of lump in throat
Blood: Pentamidine frequently causes leukopenia and less often thrombopenia, which may cause symptomatic bleeding. Some cases of anemia, possibly related to folic acid deficiency, have been described.[17]
Kidney: 25 percent develop signs of nephrotoxicity ranging from mild, asymptomatic azotemia (increased serum creatinine and urea) to irreversible renal failure. Ample fluids or intravenous hydration may prevent some nephrotoxicity.[8]
Liver: Elevated liver enzymes are associated with intravenous use of pentamidine. Hepatomegaly and hepatitis 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 rarely Stevens–Johnson syndrome or Lyell 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 to adenine-thymine-rich regions of the Trypanosoma parasite DNA, forming a cross-link between two adenines four to five base pairs apart. The drug also inhibits topoisomerase enzymes in the mitochondria of Pneumocystis jirovecii. Similarly, pentamidine inhibits type II topoisomerase in the mitochondria of the Trypanosoma parasite, resulting in a broken and unreadable mitochondrial genome.[18]
Resistance
Strains of the Trypanosoma 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]
Pharmacokinetics
Absorption: Pentamidine is completely absorbed when given intravenously or intramuscularly. When inhaled through a nebulizer, pentamidine accumulates in the bronchoalveolar fluid of the lungs at a higher concentration compared to injections. The inhaled form is minimally absorbed in the blood.[9] Absorption is unreliable when given orally.[10]
Distribution: 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 the cerebrospinal fluid.[10] It has a volume of distribution of 286-1356 liters when given intravenously and 1658-3790 liters when given intramuscularly.[20] Inhaled pentamidine is mainly deposited into the bronchoalveolar lavage fluid of the lungs.[19]
Metabolism: Pentamidine is primarily metabolized by Cytochrome P450 enzymes in the liver.[20][21] Up to 12% of pentamidine is eliminated in the urine unchanged.[8]
Elimination: Pentamidine has an average half-life of 5–8 hours when given intravenously and 7–11 hours when given intramuscularly. However, these may increase with severe kidney problems.[19] Pentamidine can remain in the system for as long as 8 months after the first injection.[18]
Chemistry
Pentamidine isethionate for injection is commercially available as a lyophilized, 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 like zidovidine and intravenous heart medications like diltiazem. However, intravenous solutions of antiviral foscarnet and antifungal fluconazole are incompatible with pentamidine.[8] To avoid side-effects associated with intravenous administration, the solution should be slowly infused to minimize the release of histamine.[18]
History
Pentamidine was first used to treat African trypanosomiasis in 1937 and leishmaniasis 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 treating Pneumocystis jirovecii in young male patients was key in identifying the emergence of the HIV/AIDS epidemic at that time. [22]
Its efficacy against Pneumocystis 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.
