Pentamidine

Pentamidine
Names
Trade namesNebupent, Pentam, others[1]
Other namespentamidine diisethionate, pentamidine dimesilate
IUPAC name
  • 4,4'-[pentane-1,5-diylbis(oxy)]dibenzenecarboximidamide
Clinical data
Drug classAromatic diamidine[2]
Main usesPneumocystis pneumonia, African trypanosomiasis, leishmaniasis, babesiosis[3][1]
Side effectsLow blood sugar, pain at the site of injection, nausea, vomiting, low blood pressure, kidney problems[1]
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Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    use    		IV, IM, inhalation
    Defined daily dose280 mg[4]
    External links
    AHFS/Drugs.comMonograph
    Legal
    Legal status
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Protein binding69%
    Elimination half-life6.4-9.4 hours
    Chemical and physical data
    FormulaC19H24N4O2
    Molar mass340.427 g·mol−1
    3D model (JSmol)
    Melting point186 °C (367 °F) (dec.)
    SMILES
    • O(c1ccc(cc1)C(=[N@H])N)CCCCCOc2ccc(C(=[N@H])N)cc2
    InChI
    • InChI=1S/C19H24N4O2/c20-18(21)14-4-8-16(9-5-14)24-12-2-1-3-13-25-17-10-6-15(7-11-17)19(22)23/h4-11H,1-3,12-13H2,(H3,20,21)(H3,22,23) checkY
    • Key:XDRYMKDFEDOLFX-UHFFFAOYSA-N checkY

    Pentamidine is a medication used to treat African trypanosomiasis, leishmaniasis, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function.[1] In African trypanosomiasis it is used for early disease before central nervous system involvement, as a second line option to suramin.[1] It is an option for both visceral leishmaniasis and cutaneous leishmaniasis.[1] Pentamidine can be given by injection into a vein or muscle or by inhalation.[1]

    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.[5] Pentamidine is in the aromatic diamidine family of medications.[2] 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 came into medical use in 1937.[6] It is on the World Health Organization's List of Essential Medicines.[7] It is available as a generic medication.[1] In regions of the world where the disease is common pentamidine is provided for free by the World Health Organization (WHO).[8] In the United States as of 2016 the inhalation powder costs US$122.84 and a vial for injection costs US$45.31 a dose.[9] Since it was found useful for PCP pneumonia the price has been increased greater than ten times.[6]

    Medical uses

    East African trypanosomiasis-Numerous ecchymoses in infected individual, that would be successfully treated with Pentamidine[10]
    • Treatment of PCP caused by Pneumocystis jirovecii[11]
    • Prevention of PCP in adults with HIV who have one or both of the following:
      • History of PCP
      • CD4+ count ≤ 200mm³[12]
    • Treatment of leishmaniasis[13]
    • Treatment of African trypanosomiasis caused by Trypanosoma brucei gambiense[13]
    • Pentamidine is classified as an orphan drug by the U.S. Food and Drug Administration[14]

    Other uses

    • Use as an antitumor drug has also been proposed.[15]
    • Pentamidine is also identified as a potential small molecule antagonist that disrupts this interaction between S100P and RAGE receptor.[16]

    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.[17]

    Dosage

    The defined daily dose is 280 mg by injection.[4] It is typically given as 4 mg/kg once a day by injection into a muscle or into a vein over an hour.[3] Treatment is generally for 14 to 21 days.[3]

    Contraindications

    • Patients with a history of anaphylaxis or hypersensitivity to pentamidine isethionate[11]

    Side effects

    Common

    • Burning pain, dryness, or sensation of lump in throat
    • Chest pain
    • Coughing
    • difficulty in breathing
    • difficulty in swallowing
    • skin rash
    • wheezing[18]

    Rare

    • Nausea and vomiting
    • Pain in upper abdomen, possibly radiating to the back
    • Severe pain in side of chest
    • Shortness of breath[18]

    Others

    Pregnancy and breastfeeding

    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.[19]

    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.[19]

    Interactions

    The additional or sequential use of other nephrotoxic drugs like aminoglycosides, amphotericin B, capreomycin, colistin, polymyxin B, vancomycin, foscarnet, or cisplatin should be closely monitored, or whenever possible completely avoided.[11]

    Mechanism of action

    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.[11][20] 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 breaks and unraveling its circular mitochondrial DNA.[20]

    Resistance

    Strains of the Trypanosoma brucei parasite that are resistant to pentamidine have been discovered. Pentamidine is brought into the mitochondria through carriers, and the absence of these carriers prevents the drug from reaching its site of action.[20]

    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.[12] Absorption is unreliable when given orally.[13]

    Distribution: When injected, pentamidine binds to tissues and proteins in the plasma. It accumulates in the kidney, liver, lungs, pancreas, spleen, and adrenal glands.[21] Additionally, pentamidine does not reach curative levels in the cerebrospinal fluid.[13] It has a volume of distribution of 286-1356 liters when given intravenously and 1658-3790 liters when given intramuscularly.[22] Inhaled pentamidine is mainly deposited into the bronchoalveolar lavage fluid of the lungs.[21]

    Metabolism: Pentamidine is primarily metabolized by Cytochrome P450 enzymes in the liver.[22][23] Up to 12% of pentamidine is eliminated in the urine unchanged.[11]

    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.[21] Pentamidine can remain in the system for as long as 8 months after the first injection.[20]

    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.[11] To avoid side-effects associated with intravenous administration, the solution should be slowly infused to minimize the release of histamine.[20]

    History

    Pentamidine was first used to treat African trypanosomiasis in 1937 and leishmaniasis in 1940 before it was registered as pentamidine mesylate in 1950. Its efficacy against Pneumocystis jirovecii was demonstrated in 1987, following its re-emergence on the drug market in 1984 in the current isethionate form.[13]

    Names

    For oral inhalation and for nebulizer use:[9]

    • NebuPent Nebulizer (APP Pharmaceuticals LLC - US)

    For intravenous and intramuscular use:[9]

    • US and Canada:
      • Pentacarinat 300 injection powder 300 mg vial (Avantis Pharma Inc - Canada)
      • Pentam 300 (APP Pharmaceuticals LLC - US)
      • Pentamidine isethionate 300 mg for injection (David Bull Laboratories LTD - Canada, Hospira Healthcare Corporation - Canada)
    • International Brands:[9]
      • Pentamidine isethionate (Abbott)
      • Pentacarinat (Sanofi-Aventis)
      • Pentacrinat (Abbott)
      • Pentam (Abbott)
      • Pneumopent

    See also

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Pentamidine Isethionate". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 3 December 2016.
    2. 1 2 Cohen, Jonathan; Powderly, William G.; Opal, Steven M. (2016). Infectious Diseases. Elsevier Health Sciences. p. 1368. ISBN 9780702063381. Archived from the original on 2017-03-08.
    3. 1 2 3 "PENTAMIDINE injectable - Essential drugs". medicalguidelines.msf.org. Archived from the original on 28 August 2021. Retrieved 4 September 2020.
    4. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 1 December 2020. Retrieved 4 September 2020.
    5. ↑ "Pentamidine Use During Pregnancy". www.drugs.com. Archived from the original on 9 November 2016. Retrieved 3 December 2016.
    6. 1 2 Magill, Alan J.; Strickland, G. Thomas; Maguire, James H.; Ryan, Edward T.; Solomon, Tom (2012). Hunter's Tropical Medicine and Emerging Infectious Disease (9 ed.). Elsevier Health Sciences. p. 723. ISBN 1455740438. Archived from the original on 2016-12-20.
    7. ↑ 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.
    8. ↑ "Trypanosomiasis, human African (sleeping sickness)". World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December 2016.
    9. 1 2 3 4 DrugBank, ed. (2016-08-17). "Pentamidine". DrugBank. Archived from the original on 2016-11-04.
    10. ↑ Paul, Małgorzata; Stefaniak, Jerzy; Smuszkiewicz, Piotr; Van Esbroeck, Marjan; Geysen, Dirk; Clerinx, Jan (27 February 2014). "Outcome of acute East African trypanosomiasis in a Polish traveller treated with pentamidine". BMC Infectious Diseases. 14: 111. doi:10.1186/1471-2334-14-111. ISSN 1471-2334. Archived from the original on 19 May 2014. Retrieved 20 October 2021.
    11. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "DailyMed - PENTAM 300- pentamidine isethionate injection, powder, lyophilized, for solution". dailymed.nlm.nih.gov. Archived from the original on 2016-11-04. Retrieved 2016-11-07.
    12. 1 2 "DailyMed - NEBUPENT- pentamidine isethionate inhalant". dailymed.nlm.nih.gov. Archived from the original on 2016-11-04. Retrieved 2016-11-07.
    13. 1 2 3 4 5 "Drugs". World Health Organization. Archived from the original on 2016-08-19. Retrieved 2016-11-04.
    14. ↑ "Drugs@FDA: FDA Approved Drug Products". www.accessdata.fda.gov. Archived from the original on 2014-08-13. Retrieved 2016-11-07.
    15. ↑ Lee MS, Johansen L, Zhang Y, Wilson A, Keegan M, Avery W, Elliott P, Borisy AA, Keith CT (December 2007). "The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action". Cancer Research. 67 (23): 11359–67. doi:10.1158/0008-5472.CAN-07-2235. PMID 18056463. Archived from the original on 2013-02-23. Retrieved 2008-12-14.
    16. ↑ Penumutchu SR, Chou RH, Yu C (2014). "Structural insights into calcium-bound S100P and the V domain of the RAGE complex". PLOS One. 9 (8): e103947. doi:10.1371/journal.pone.0103947. PMC 4118983. PMID 25084534.
    17. ↑ "Pneumocystis jirovecii Pneumonia | Pediatric OI Prevention and Treatment Guidelines | AIDSinfo". AIDSinfo. Archived from the original on 2016-11-07. Retrieved 2016-11-07.
    18. 1 2 3 "Pentamidine Side Effects in Detail - Drugs.com". www.drugs.com. Archived from the original on 2016-11-04. Retrieved 2016-11-04.
    19. 1 2 "Pentamidine Use During Pregnancy | Drugs.com". www.drugs.com. Archived from the original on 2016-11-09. Retrieved 2016-11-10.
    20. 1 2 3 4 5 Lemke TL, Williams DA, eds. (2013). Foye's Principles of Medicinal Chemistry (Seventh ed.). Philadelphia, PA: Lippincott Williams & Wilkins. ISBN 9781609133450.
    21. 1 2 3 "Pentamidine (Oral Inhalation) (Professional Patient Advice) - Drugs.com". www.drugs.com. Archived from the original on 2016-11-04. Retrieved 2016-11-04.
    22. 1 2 "NebuPent, Pentam (pentamidine) dosing, indications, interactions, adverse effects, and more". reference.medscape.com. Archived from the original on 2016-11-06. Retrieved 2016-11-06.
    23. ↑ Pubchem. "pentamidine | C19H24N4O2 - PubChem". pubchem.ncbi.nlm.nih.gov. Archived from the original on 2016-11-07. Retrieved 2016-11-06.
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