Editing Pentamidine

{{Short description|Medical antimicrobial drug}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{drugbox
| Watchedfields = changed
| verifiedrevid = 464198089
| IUPAC_name = 4,4'-[pentane-1,5-diylbis(oxy)]dibenzenecarboximidamide
| image = Pentamidine-skeletal.svg
| image_class = skin-invert-image
| width = 280
| image2 = Pentamidine 3D.png
| image_class2 = bg-transparent
| tradename = Nebupent, Pentam, others<ref name=AHFS2016/>
| synonyms  = pentamidine diisethionate, pentamidine dimesilate
| Drugs.com = {{drugs.com|monograph|pentamidine-isethionate}}
| pregnancy_US = C
| legal_status = Rx-only
| routes_of_administration = [[Intravenous therapy|IV]], [[Intramuscular|IM]], inhalation
| bioavailability =
| protein_bound = 69%
| metabolism =
| elimination_half-life = 6.4-9.4 hours
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 100-33-4
| ATC_prefix = P01
| ATC_suffix = CX01
| ATC_supplemental = {{ATCvet|P51|DF02}}
| PubChem = 4735
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00738
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4573
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 673LC5J4LQ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08333
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 45081
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 55
| C=19 | H=24 | N=4 | O=2
| smiles = O(c1ccc(cc1)C(=[N@H])N)CCCCCOc2ccc(C(=[N@H])N)cc2
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = XDRYMKDFEDOLFX-UHFFFAOYSA-N
| melting_point = 186
| melting_notes = (dec.)
}}

'''Pentamidine''' is an [[antimicrobial]] [[medication]] used to treat [[African trypanosomiasis]], [[leishmaniasis]], ''[[Balamuthia]]'' infections,<ref>{{Cite web|url=https://www.cdc.gov/parasites/balamuthia/treatment.html|title = Treatment &#124; Balamuthia &#124; Parasites &#124; CDC|date = 5 September 2019}}</ref> [[babesiosis]], and to prevent and treat [[pneumocystis pneumonia]] (PCP) in people with [[immunosuppression|poor immune function]].<ref name=AHFS2016/> In African trypanosomiasis it is used for early disease before [[central nervous system]] involvement, as a second line option to [[suramin]].<ref name=AHFS2016/> It is an option for both [[visceral leishmaniasis]] and [[cutaneous leishmaniasis]].<ref name=AHFS2016/> Pentamidine can be given by injection into a vein or muscle or by [[inhalation]].<ref name=AHFS2016/>

Common side effects of the injectable form include [[hypoglycemia|low blood sugar]], pain at the site of injection, nausea, vomiting, [[hypotension|low blood pressure]], and kidney problems.<ref name=AHFS2016/> Common side effects of the inhaled form include [[wheezing]], cough, and nausea.<ref name=AHFS2016/> It is unclear if doses should be changed in those with kidney or liver problems.<ref name=AHFS2016/> Pentamidine is not recommended in early [[pregnancy]] but may be used in later pregnancy.<ref name=AHFS2016/> Its safety during [[breastfeeding]] is unclear.<ref>{{cite web|title=Pentamidine Use During Pregnancy|url=https://www.drugs.com/pregnancy/pentamidine.html|website=www.drugs.com|access-date=3 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161109153337/https://www.drugs.com/pregnancy/pentamidine.html|archive-date=9 November 2016}}</ref> Pentamidine is in the aromatic diamidine family of medications.<ref>{{cite book | vauthors = Cohen J, Powderly WG, Opal SM |title=Infectious Diseases|date=2016|publisher=Elsevier Health Sciences |isbn=9780702063381 |page=1368 |url= https://books.google.com/books?id=Dhq3DAAAQBAJ&pg=PA1368 |url-status=live|archive-url=https://web.archive.org/web/20170308050532/https://books.google.ca/books?id=Dhq3DAAAQBAJ&pg=PA1368|archive-date=2017-03-08}}</ref> While the way the medication works is not entirely clear, it is believed to involve decreasing the production of DNA, RNA, and protein.<ref name=AHFS2016/>

Pentamidine came into medical use in 1937.<ref name=Mag2012>{{cite book| vauthors = Magill AJ, Strickland GT, Maguire JH, Ryan ET, Solomon T |title=Hunter's Tropical Medicine and Emerging Infectious Disease|date=2012|publisher=Elsevier Health Sciences|isbn=978-1455740437|page=723|edition=9|url=https://books.google.com/books?id=x15umovaD08C&pg=PA723|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220031404/https://books.google.ca/books?id=x15umovaD08C&pg=PA723|archive-date=2016-12-20}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO }}</ref> It is available as a [[generic medication]].<ref name=AHFS2016>{{cite web|title=Pentamidine Isethionate|url=https://www.drugs.com/monograph/pentamidine-isethionate.html|publisher=The American Society of Health-System Pharmacists|access-date=3 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220053807/https://www.drugs.com/monograph/pentamidine-isethionate.html|archive-date=20 December 2016}}</ref> In regions of the world where trypanosomiasis is common pentamidine is provided for free by the [[World Health Organization]] (WHO).<ref name=WHO2016>{{cite web|title=Trypanosomiasis, human African (sleeping sickness)|url=https://www.who.int/mediacentre/factsheets/fs259/en/|website=World Health Organization|access-date=7 December 2016|date=February 2016|url-status=live|archive-url=https://web.archive.org/web/20161204153318/http://www.who.int/mediacentre/factsheets/fs259/en/|archive-date=4 December 2016}}</ref>

==Medical uses==
* Treatment of PCP caused by ''Pneumocystis jirovecii''<ref name=":10">{{Cite web|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8|title=DailyMed - PENTAM 300- pentamidine isethionate injection, powder, lyophilized, for solution|website=dailymed.nlm.nih.gov|access-date=2016-11-07|url-status=live|archive-url=https://web.archive.org/web/20161104141904/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8|archive-date=2016-11-04}}</ref>
* Prevention of PCP in adults with HIV who have one or both of the following:
** History of PCP
** CD4+ count ≤ 200mm³<ref name=":11">{{Cite web|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2ad9d3c-b6c3-4f70-87e0-722a8ff94ccb|title=DailyMed - NEBUPENT- pentamidine isethionate inhalant|website=dailymed.nlm.nih.gov|access-date=2016-11-07|url-status=live|archive-url=https://web.archive.org/web/20161104142253/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2ad9d3c-b6c3-4f70-87e0-722a8ff94ccb|archive-date=2016-11-04}}</ref>
* Treatment of [[leishmaniasis]]<ref name=":1" />
* Treatment of African trypanosomiasis caused by [[Trypanosoma brucei|''Trypanosoma brucei gambiense'']]<ref name=":1" />
* ''[[Balamuthia]]'' infections<ref>{{Cite web|url=https://www.cdc.gov/parasites/balamuthia/treatment.html|title = Treatment &#124; Balamuthia &#124; Parasites &#124; CDC|date = 5 September 2019}}</ref>
* Pentamidine is classified as an [[orphan drug]] by the U.S. Food and Drug Administration<ref>{{Cite web|url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|title=Drugs@FDA: FDA Approved Drug Products|website=www.accessdata.fda.gov|access-date=2016-11-07|url-status=live|archive-url=https://web.archive.org/web/20140813131107/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|archive-date=2014-08-13}}</ref>

===Other uses===
* Use as an [[antitumor]] drug has also been proposed.<ref name="pmid18056463">{{cite journal | vauthors = Lee MS, Johansen L, Zhang Y, Wilson A, Keegan M, Avery W, Elliott P, Borisy AA, Keith CT | title = The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action | journal = Cancer Research | volume = 67 | issue = 23 | pages = 11359–11367 | date = December 2007 | pmid = 18056463 | doi = 10.1158/0008-5472.CAN-07-2235 | doi-access =  }}</ref>
* Pentamidine is also identified as a potential small molecule antagonist that disrupts this interaction between S100P and RAGE receptor.<ref name="pmid25084534">{{cite journal | vauthors = Penumutchu SR, Chou RH, Yu C | title = Structural insights into calcium-bound S100P and the V domain of the RAGE complex | journal = PLOS ONE | volume = 9 | issue = 8 | pages = e103947 | date = 2014 | pmid = 25084534 | pmc = 4118983 | doi = 10.1371/journal.pone.0103947 | doi-access = free | bibcode = 2014PLoSO...9j3947P }}</ref>

=== 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.<ref name=":12">{{Cite web|url=https://www.drugs.com/pregnancy/pentamidine.html|title=Pentamidine Use During Pregnancy {{!}} Drugs.com|website=www.drugs.com|access-date=2016-11-10|url-status=live|archive-url=https://web.archive.org/web/20161109153337/https://www.drugs.com/pregnancy/pentamidine.html|archive-date=2016-11-09}}</ref>

==== 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.<ref name=":12" />

==== Children ====
Pentamidine can be used in the prevention of PCP in children with HIV who cannot tolerate [[Trimethoprim/sulfamethoxazole|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<ref name=":8">{{Cite web|url=https://aidsinfo.nih.gov/guidelines/html/5/pediatric-oi-prevention-and-treatment-guidelines/415/pneumocystis-jirovecii-pneumonia|title=Pneumocystis jirovecii Pneumonia {{!}} Pediatric OI Prevention and Treatment Guidelines {{!}} AIDSinfo|website=AIDSinfo|access-date=2016-11-07|url-status=live|archive-url=https://web.archive.org/web/20161107155510/https://aidsinfo.nih.gov/guidelines/html/5/pediatric-oi-prevention-and-treatment-guidelines/415/pneumocystis-jirovecii-pneumonia|archive-date=2016-11-07}}</ref>

==== Elderly ====
There is no data for the use of pentamidine in this specific population.<ref name=":12" />

==Contraindications==
* Patients with a history of anaphylaxis or hypersensitivity to pentamidine isethionate<ref name=":10" /><!--PLEASE RESPECT ALPHABETICAL ORDER-->

==Side effects==

=== Common ===
* Burning pain, dryness, or sensation of lump in throat
* Chest pain
* Coughing
* difficulty in breathing
* difficulty in swallowing
* skin rash
* wheezing<ref name=":4">{{Cite web|url=https://www.drugs.com/sfx/pentamidine-side-effects.html|title=Pentamidine Side Effects in Detail - Drugs.com|website=www.drugs.com|access-date=2016-11-04|url-status=live|archive-url=https://web.archive.org/web/20161104142210/https://www.drugs.com/sfx/pentamidine-side-effects.html|archive-date=2016-11-04}}</ref>

=== Rare ===
* Nausea and vomiting
* Pain in upper abdomen, possibly radiating to the back
* Severe pain in side of chest
* Shortness of breath<ref name=":4" />

=== Others ===
* [[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.<ref name=":4" />
* [[Cardiovascular system|Cardiovascular]]: [[Hypotension]], which may be severe. Severe or fatal [[Heart arrhythmia|arrhythmia]]s and [[heart failure]] are quite frequent.<ref name=":10" />
* [[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.<ref name=":10" />
* [[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.<ref name=":10" />
* [[Nervous system|Neurological]]:  Dizziness, drowsiness, [[neuralgia]], confusion, hallucinations, [[seizure]]s and other central side effects are reported.<ref name=":10" />
* [[Pancreas]]: [[Hypoglycemia]] that requires symptomatic treatment is frequently seen. On the other hand, pentamidine may cause or worsen [[diabetes mellitus]].<ref name=":10" />
* [[Respiratory system|Respiratory]]: Cough and [[bronchospasm]], most frequently seen with inhalation.<ref name=":10" />
* [[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 [[Toxic epidermal necrolysis|Lyell syndrome]].<ref name=":10" />
* Eye discomfort, [[conjunctivitis]], throat irritation, [[splenomegaly]], [[Herxheimer reaction]], [[electrolyte]] imbalances (e.g. [[hypocalcemia]]).<ref name=":10" />

==Drug interactions==
The additional or sequential use of other nephrotoxic drugs like [[aminoglycoside]]s, [[amphotericin B]], [[capreomycin]], [[colistin]], [[polymyxin B]], [[vancomycin]], [[foscarnet]], or [[cisplatin]] should be closely monitored, or whenever possible completely avoided.<ref name=":10" />

==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.<ref name=":10" /><ref name=":6" /> Pentamidine binds to [[adenine]]-[[thymine]]-rich regions of the ''[[Trypanosoma brucei|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 brucei|Trypanosoma]]'' parasite, resulting in a broken and unreadable mitochondrial genome.<ref name=":6">{{Cite book|title=Foye's Principles of Medicinal Chemistry | edition = Seventh | veditors = Lemke TL, Williams DA |publisher= Lippincott Williams & Wilkins |year=2013 |isbn=9781609133450 |location=Philadelphia, PA }}</ref>

=== 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.<ref name=":6" />

== 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, but the effects of chronic inhaled administration on these levels are not known.<ref name=":11" /> Absorption is unreliable when given orally.<ref name=":1" />

===Distribution===
When injected, pentamidine binds to tissues and proteins in the plasma. It accumulates in the kidney, liver, lungs, pancreas, spleen, and adrenal glands.<ref name=":2" /> Additionally, pentamidine does not reach curative levels in the [[cerebrospinal fluid]].<ref name=":1" /> It has a [[volume of distribution]] of 286–1356 liters when given intravenously and 1658–3790 liters when given intramuscularly.<ref name=":7">{{Cite web|url=http://reference.medscape.com/drug/nebupent-pentam-pentamidine-342568#10|title=NebuPent, Pentam (pentamidine) dosing, indications, interactions, adverse effects, and more|website=reference.medscape.com|access-date=2016-11-06|url-status=live|archive-url=https://web.archive.org/web/20161106185759/http://reference.medscape.com/drug/nebupent-pentam-pentamidine-342568#10|archive-date=2016-11-06}}</ref> Inhaled pentamidine is mainly recovered from the [[bronchoalveolar lavage fluid]] of the lungs.<ref name=":11" /><ref name=":2" />

===Metabolism===
Pentamidine is primarily metabolized by [[cytochrome P450]] enzymes in the liver.<ref name=":7" /><ref>{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/pentamidine#section=DrugBank-Interactions&fullscreen=true|title=pentamidine {{!}} C19H24N4O2 | work = PubChem | publisher = U.S. National Library of Medicine |access-date=2016-11-06|url-status=live|archive-url=https://web.archive.org/web/20161107011758/https://pubchem.ncbi.nlm.nih.gov/compound/pentamidine#section=DrugBank-Interactions&fullscreen=true|archive-date=2016-11-07}}</ref> Up to 12% of pentamidine is eliminated in the urine unchanged.<ref name=":10" />

===Elimination===
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.<ref name=":2">{{Cite web|url=https://www.drugs.com/ppa/pentamidine-oral-inhalation.html|title=Pentamidine (Oral Inhalation) (Professional Patient Advice) - Drugs.com|website=www.drugs.com|access-date=2016-11-04|url-status=live|archive-url=https://web.archive.org/web/20161104142839/https://www.drugs.com/ppa/pentamidine-oral-inhalation.html|archive-date=2016-11-04}}</ref> Pentamidine can remain in the system for as long as eight months after the first injection.<ref name=":6" />

== Chemistry ==
Pentamidine isethionate for injection is commercially available as a [[Freeze-drying|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 [[Zidovudine|zidovidine]] and intravenous heart medications like [[diltiazem]]. However, intravenous solutions of antiviral [[foscarnet]] and antifungal [[fluconazole]] are incompatible with pentamidine.<ref name=":10" /> To avoid side-effects associated with intravenous administration, the solution should be slowly infused to minimize the release of [[histamine]].<ref name=":6" />

==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. <ref>{{cite journal | vauthors = Schultz MG, Bloch AB | title = In Memoriam: Sandy Ford (1950–2015) | language = en-us | journal = Emerging Infectious Diseases | volume = 22 | issue = 4 | pages = 764–765 | date = April 2016 | pmid = 27358969 | doi = 10.3201/eid2204.151336 | pmc = 4806958 }}</ref>

Its efficacy against ''Pneumocystis jirovecii'' was demonstrated in 1987, following its re-emergence on the drug market in 1984 in the current isethionate form.<ref name=":1">{{Cite web|url=https://www.who.int/trypanosomiasis_african/drugs/en/|title=Drugs|website=World Health Organization|language=en-GB|access-date=2016-11-04|url-status=dead|archive-url=https://web.archive.org/web/20160819074511/http://www.who.int/trypanosomiasis_african/drugs/en/|archive-date=2016-08-19}}</ref>

==Trade names and dose form==
For oral inhalation and for nebulizer use:<ref name=Bank2016>{{Cite journal|date=2016-08-17 |title=Pentamidine|url=https://www.drugbank.ca/drugs/DB00738|journal=DrugBank|url-status=live|archive-url=https://web.archive.org/web/20161104141744/https://www.drugbank.ca/drugs/DB00738|archive-date=2016-11-04}}</ref>
* NebuPent Nebulizer (APP Pharmaceuticals LLC - US)
For intravenous and intramuscular use:<ref name=Bank2016/>
* US and Canada:
** Pentacarinat 300 injection powder 300&nbsp;mg vial (Avantis Pharma Inc - Canada)
** Pentam 300 (APP Pharmaceuticals LLC - US)
** Pentamidine isethionate 300&nbsp;mg for injection (David Bull Laboratories LTD - Canada, Hospira Healthcare Corporation - Canada)
* International Brands:<ref name=Bank2016/>
** Pentamidine isethionate (Abbott)
** Pentacarinat (Sanofi-Aventis)
** Pentacrinat (Abbott)
** Pentam (Abbott)
** Pneumopent

== See also ==
* [[Netropsin]]
* [[Lexitropsin]]

== References ==
{{reflist}}

== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/pentamidine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Pentamidine }}

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[[Category:Antifungals]]
[[Category:Antiprotozoal agents]]
[[Category:Amidines]]
[[Category:DNA-binding substances]]
[[Category:NMDA receptor antagonists]]
[[Category:Phenol ethers]]
[[Category:World Health Organization essential medicines]]
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