Pentamidine

Last updated
Pentamidine
Pentamidine-skeletal.svg
Pentamidine 3D.png
Clinical data
Trade names Nebupent, Pentam, others [1]
Other namespentamidine diisethionate, pentamidine dimesilate
AHFS/Drugs.com Monograph
Routes of
administration 		IV, IM, inhalation
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding 69%
Elimination half-life 6.4-9.4 hours
Identifiers
  • 4,4'-[pentane-1,5-diylbis(oxy)]dibenzenecarboximidamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.002.583 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H24N4O2
Molar mass 340.427 g·mol−1
3D model (JSmol)
Melting point 186 °C (367 °F) (dec.)
  • O(c1ccc(cc1)C(=[N@H])N)CCCCCOc2ccc(C(=[N@H])N)cc2
  • 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) Yes check.svgY
  • Key:XDRYMKDFEDOLFX-UHFFFAOYSA-N Yes check.svgY
   (verify)

Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, Balamuthia infections, [2] 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]

Contents

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 came into medical use in 1937. [5] It is on the World Health Organization's List of Essential Medicines. [6] It is available as a generic medication. [1] In regions of the world where trypanosomiasis is common pentamidine is provided for free by the World Health Organization (WHO). [7]

Medical uses

Other uses

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

Side effects

Common

Rare

Others

Drug 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. [8]

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. [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. 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]

Trade names and dose form

For oral inhalation and for nebulizer use: [22]

For intravenous and intramuscular use: [22]

See also

Related Research Articles

<span class="mw-page-title-main">African trypanosomiasis</span> Parasitic disease

African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species Trypanosoma brucei. Humans are infected by two types, Trypanosoma brucei gambiense (TbG) and Trypanosoma brucei rhodesiense (TbR). TbG causes over 98% of reported cases. Both are usually transmitted by the bite of an infected tsetse fly and are most common in rural areas.

<span class="mw-page-title-main">Route of administration</span> Path by which a drug, fluid, poison, or other substance is taken into the body

A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.

<span class="mw-page-title-main">Trypanosomiasis</span> Medical condition

Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. In humans this includes African trypanosomiasis and Chagas disease. A number of other diseases occur in other animals.

<span class="mw-page-title-main">Aztreonam</span>

Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as Pseudomonas aeruginosa. This may include bone infections, endometritis, intra abdominal infections, pneumonia, urinary tract infections, and sepsis. It is given by intravenous or intramuscular injection or by inhalation.

<span class="mw-page-title-main">Suramin</span> Medical drug

Suramin is a medication used to treat African sleeping sickness and river blindness. It is the treatment of choice for sleeping sickness without central nervous system involvement. It is given by injection into a vein.

<span class="mw-page-title-main">Colistin</span> Antibiotic

Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as colistin. Resistance to colistin began to appear as of 2015.

<span class="mw-page-title-main">Melarsoprol</span>

Melarsoprol is an arsenic-containing medication used for the treatment of sleeping sickness. It is specifically used for second-stage disease caused by Trypanosoma brucei rhodesiense when the central nervous system is involved. For Trypanosoma brucei gambiense, eflornithine or fexinidazole is usually preferred. It is effective in about 95% of people. It is given by injection into a vein.

<span class="mw-page-title-main">Eflornithine</span>

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis and excessive hair growth on the face in women. Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is taken intravenously or topically. It has also been given orally on at least some rare occasions for the treatment of African trypanosomiasis.

<span class="mw-page-title-main">Paromomycin</span>

Paromomycin is an antimicrobial used to treat a number of parasitic infections including amebiasis, giardiasis, leishmaniasis, and tapeworm infection. It is a first-line treatment for amebiasis or giardiasis during pregnancy. Otherwise it is generally a second line treatment option. It is taken by mouth, applied to the skin, or by injection into a muscle.

<span class="mw-page-title-main">Imipenem/cilastatin</span> Pharmaceutical drug combination

Imipenem/cilastatin, sold under the brand name Primaxin among others, is an antibiotic useful for the treatment of a number of bacterial infections. It is made from a combination of imipenem and cilastatin. Specifically it is used for pneumonia, sepsis, endocarditis, joint infections, intra-abdominal infections, and urinary tract infections. It is given by injection into a vein or muscle.

<span class="mw-page-title-main">Cutaneous leishmaniasis</span> Medical condition

Cutaneous leishmaniasis is the most common form of leishmaniasis affecting humans. It is a skin infection caused by a single-celled parasite that is transmitted by the bite of a phlebotomine sand fly. There are about thirty species of Leishmania that may cause cutaneous leishmaniasis.

<span class="mw-page-title-main">Atovaquone</span> Antimicrobial and antiprotozoan drug

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<span class="mw-page-title-main">Amikacin</span> Antibiotic medication

Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.

<span class="mw-page-title-main">Sodium stibogluconate</span>

Sodium stibogluconate, sold under the brand name Pentostam among others, is a medication used to treat leishmaniasis. This includes leishmaniasis of the cutaneous, visceral, and mucosal types. Some combination of miltefosine, paramycin and liposomal amphotericin B, however, may be recommended due to issues with resistance. It is given by injection.

<span class="mw-page-title-main">Pegaspargase</span>

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<span class="mw-page-title-main">Miltefosine</span> Phospholipid drug

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<i>Pneumocystis</i> pneumonia Medical condition

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<span class="mw-page-title-main">Nifurtimox</span> Anti-parasitic medical drug

Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness. For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment. In Chagas disease it is a second-line option to benznidazole. It is given by mouth.

Synthalin was an oral anti-diabetic drug. Discovered in 1926 it was marketed in Europe by Schering AG of Berlin as a synthetic drug with insulin-like properties that could be taken orally. However, it was toxic to the liver and kidney and was withdrawn from the market in the early 1940s.

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References

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  2. ↑ "Treatment | Balamuthia | Parasites | CDC". 5 September 2019.
  3. ↑ "Pentamidine Use During Pregnancy". www.drugs.com. Archived from the original on 9 November 2016. Retrieved 3 December 2016.
  4. ↑ Cohen J, Powderly WG, Opal SM (2016). Infectious Diseases. Elsevier Health Sciences. p. 1368. ISBN   9780702063381. Archived from the original on 2017-03-08.
  5. ↑ Magill AJ, Strickland GT, Maguire JH, Ryan ET, Solomon T (2012). Hunter's Tropical Medicine and Emerging Infectious Disease (9 ed.). Elsevier Health Sciences. p. 723. ISBN   978-1455740437. Archived from the original on 2016-12-20.
  6. ↑ 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.
  7. ↑ "Trypanosomiasis, human African (sleeping sickness)". World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December 2016.
  8. 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.
  9. 1 2 "DailyMed - NEBUPENT- pentamidine isethionate inhalant". dailymed.nlm.nih.gov. Archived from the original on 2016-11-04. Retrieved 2016-11-07.
  10. 1 2 3 4 5 "Drugs". World Health Organization. Archived from the original on 2016-08-19. Retrieved 2016-11-04.
  11. ↑ "Treatment | Balamuthia | Parasites | CDC". 5 September 2019.
  12. ↑ "Drugs@FDA: FDA Approved Drug Products". www.accessdata.fda.gov. Archived from the original on 2014-08-13. Retrieved 2016-11-07.
  13. ↑ 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.
  14. ↑ 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. Bibcode:2014PLoSO...9j3947P. doi: 10.1371/journal.pone.0103947 . PMC   4118983 . PMID   25084534.
  15. 1 2 3 "Pentamidine Use During Pregnancy | Drugs.com". www.drugs.com. Archived from the original on 2016-11-09. Retrieved 2016-11-10.
  16. ↑ "Pneumocystis jirovecii Pneumonia | Pediatric OI Prevention and Treatment Guidelines | AIDSinfo". AIDSinfo. Archived from the original on 2016-11-07. Retrieved 2016-11-07.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. ↑ Pubchem. "pentamidine | C19H24N4O2 - PubChem". pubchem.ncbi.nlm.nih.gov. Archived from the original on 2016-11-07. Retrieved 2016-11-06.
  22. 1 2 3 DrugBank, ed. (2016-08-17). "Pentamidine". DrugBank. Archived from the original on 2016-11-04.
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