Pentamidine
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| Systematic (IUPAC) name |
| 4,4'-[pentane- 1,5-diylbis(oxy)]dibenzenecarboximidamide |
| Clinical data |
| Trade names |
Nebupent |
| AHFS/Drugs.com |
monograph |
| Pregnancy cat. |
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| Legal status |
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| Routes |
IV, IM, inhalation |
| Pharmacokinetic data |
| Protein binding |
69% |
| Half-life |
6.4-9.4 hours |
| Identifiers |
| CAS number |
100-33-4 Y |
| ATC code |
P01CX01 QP51AF02 |
| PubChem |
CID 4735 |
| DrugBank |
DB00738 |
| ChemSpider |
4573 Y |
| UNII |
673LC5J4LQ Y |
| KEGG |
D08333 Y |
| ChEBI |
CHEBI:45081 Y |
| ChEMBL |
CHEMBL55 Y |
| Chemical data |
| Formula |
C19H24N4O2 |
| Mol. mass |
340.42 g/mol |
SMILES
- O(c1ccc(cc1)C(=[N@H])N)CCCCCOc2ccc(C(=[N@H])N)cc2
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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) Y
Key:XDRYMKDFEDOLFX-UHFFFAOYSA-N Y
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| Y (what is this?) (verify) |
Pentamidine (formulated as a salt, pentamidine diisethionate or dimesilate) is an antimicrobial medication given for prevention and treatment of Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a severe interstitial type of pneumonia often seen in patients with HIV infection. The drug is also the mainstay of treatment for stage I infection with Trypanosoma brucei gambiense (West African Trypanosomiasis).
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[1]
Contents
- 1 Medical uses
- 1.1 Acute PCP
- 1.2 Primary and secondary prophylaxis of PCP
- 1.3 Other
- 2 Contraindications
- 3 Side effects
- 4 Drug Interactions
- 5 Mechanism
- 6 Brand names and dose forms
- 7 See also
- 8 References
Medical uses
Pentamidine is also used as a prophylactic against PCP in patients receiving chemotherapy, as they also have a depressed immune system as a direct side-effect of the drugs used. The mortality of untreated PCP is very high. Additionally, pentamidine has good clinical activity in treating leishmaniasis, and yeast infections caused by the organism Candida albicans. Pentamidine is also used as a prophylactic antibiotic for children undergoing treatment for leukemia.
The exact mechanism of its anti-protozoal action is unknown (though it may involve reactions with ubiquitin[2]), despite the fact that it is a basic therapeutic modality (in concurrence with multiple antifungal medications) when treating Acanthamoeba infections in the immunocompromised patients. In the United States, pentamidine is currently designated an orphan drug by the U.S. Food and Drug Administration.
Pentamidine is taken up by purine receptors by Trypanosoma brucei gambiense.This parasite is unable to synthesise its own adenine and must uptake this nucleotide from the host. It thereby accumulates to micromolar concentrations within the parasite to kill it by inhibiting enzymes and interacting with DNA.[3]
Acute PCP
In the acute treatment of PCP, pentamidine is considered equally or slightly less active than co-trimoxazole (brand names Bactrim, Septrin, or Septra). Clinical evidence suggests that pentamidine is often better tolerated than co-trimoxazole because a high dose of co-trimoxazole is needed, which is associated with a high incidence and severity of side effects such as hepatitis, bone-marrow-damage, renal-damage, and life-threatening skin disease (Lyell-syndrome). Moreover, many patients are or become allergic to co-trimoxazole. For treatment of PCP, 4 milligrams of pentamidine per kilogram of body weight is given intravenously once daily for 14 to 21 days. Treatment exceeding 21 days may be necessary, but is associated with increased toxicity. Intramuscular injection is not recommended. The effect of pentamidine often becomes evident within the first 2 days of treatment, with reduction in fever and improvement of respiratory function. In any case, improvements of chest x-ray studies occur within 6 to 8 days, provided therapy is successful. Pentamidine therapy cures 50 to 70% of all patients treated.
Primary and secondary prophylaxis of PCP
Primary prophylaxis of severely immunocompromised patients can be indicated where PCP has not yet been diagnosed. Secondary prophylaxis aims to prevent recurrent infections by PCP. For both forms of prophylaxis, an aerosolized formulation of pentamidine given by nebulizer once monthly in a dose of 300 mg is used. In primary prophylaxis, this reduces the long term likelihood of PCP by 70% when compared to no prophylaxis. The aerosolized route of administration is particularly suited for pregnant women in their first trimester (when TMP-SMX is contraindicated). Aerosolized administration may lead to an atypical PCP infection involving the upper lobes.
Other
For other indications, such as leishmaniasis or sleeping sickness, special treatment schedules developed by the WHO or CDC exist.
Use as an antitumor drug has also been proposed.[4]
Contraindications
- Severe allergy; no others in PCP patients in whom a proper diagnosis has been made.
Side effects
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This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be removed. (November 2013) |
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Pentamidine can cause allergic and toxic side effects, most commonly having effects on the pancreas, which in part depend on the daily and/or cumulative dose:
- 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.
- Cardiovascular: Hypotension, which may be severe, severe or fatal arrhythmias and heart failure are quite frequent[citation needed]
- Gastrointestinal: Nausea, vomiting, gastrointestinal discomfort, diarrhea, unpleasant taste
- 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.
- 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.
- Neurological: Dizziness, drowsiness, neuralgia, confusion, hallucinations, seizures and other central side effects are reported.
- Pancreas: Hypoglycemia that requires symptomatic treatment is frequently seen. On the other hand, pentamidine may cause or worsen diabetes mellitus.[5]
- Respiratory: Cough and bronchospasm, most frequently seen with inhalation.
- 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.
- Others
- Eye discomfort, conjunctivitis, throat irritation, splenomegaly, Herxheimer reaction, electrolyte imbalances (e.g. hypocalcemia).
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.
Mechanism
The mechanism is not well characterized, but there is some evidence that it may involve mitochondrial function.[6]
Brand names and dose forms
- For oral inhalation and for nebulizer use: NebuPent Nebulizer
- For parenteral treatment: Pentacrinat, Pentam 300, and Pentamidine isethionate for injection (Abbot); all containing 300 mg of Pentamidine.
The concomitant use of Foscarnet( against CMV, or HSV) and I.V Pentamidine (against pneumocystis jiroveci) results in increased nephrotoxicities and hypocalcemia.
See also
- DNA-binding protein
- Hoechst 33258
- Netropsin
- Lexitropsin
- Nucleic acid simulations
References
- ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ Nguewa PA, Fuertes MA, Cepeda V, et al. (2005). "Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin". Chem. Biodivers. 2 (10): 1387–400. doi:10.1002/cbdv.200590111. PMID 17191940.
- ^ "WHO | Drugs". Who.int. 2011-12-28. Retrieved 2013-03-26.
- ^ Lee MS, Johansen L, Zhang Y, et al. (December 2007). "The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action". Cancer Res. 67 (23): 11359–67. doi:10.1158/0008-5472.CAN-07-2235. PMID 18056463.
- ^ C. P. Thakur, et al. (1991). "Comparison of regimes of treatment of antimony-resistant kala-azar patients: a randomized study". American Journal of Tropical Medicine and Hygiene 45 (4): 435–441. PMID 1659239.
- ^ Sun T, Zhang Y (March 2008). "Pentamidine binds to tRNA through non-specific hydrophobic interactions and inhibits aminoacylation and translation". Nucleic Acids Res. 36 (5): 1654–64. doi:10.1093/nar/gkm1180. PMC 2275129. PMID 18263620.
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Antiparasitics – antiprotozoal agents – Excavata antiparasitics (P01)
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| Discicristata |
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Trypanosomiasis
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- African trypanosomiasis: ornithine (Eflornithine#)
- arsenical (Melarsoprol#)
- benzamidine (Pentamidine#)
- naphthalenesulfonate (Suramin#)
Chagas disease: nitroimidazole (Benznidazole#)
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Leishmaniasis
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- macrolide (Amphotericin B#)
Pentavalent antimonials (Meglumine antimoniate#, Sodium stibogluconate)
- benzamidine (Pentamidine#)
- phosphorylcholine (Miltefosine)
- neomycin (Paromomycin)
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PAM
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- macrolide (Amphotericin B)
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| Trichozoa |
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Giardiasis
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- nitroimidazole (Metronidazole#, Tinidazole)
- benzimidazole (Albendazole)
- thiazole (Nitazoxanide)
- nitrofuran (Furazolidone)
- aminoacridine (Quinacrine)
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Trichomoniasis
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- nitroimidazole (Carnidazole, Metronidazole#, Tinidazole)
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Dientamoebiasis
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- nitroimidazole (Metronidazole
- Secnidazole)
- oxyquinoline (Iodoquinol)
- tetracycline (Doxycycline)
- neomycin (Paromomycin)
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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Antifungals (D01 and J02)
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Wall/
membrane |
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Ergosterol
inhibitors
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Azoles
(lanosterol 14
alpha-demethylase inhibitors) |
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Imidazoles
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- Topical: bifonazole
- butoconazole
- clomidazole
- clotrimazole#, croconazole
- econazole
- fenticonazole
- ketoconazole
- isoconazole
- miconazole#, neticonazole
- omoconazole
- oxiconazole
- sertaconazole
- sulconazole
- tioconazole
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Triazoles
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- Topical: (fluconazole#, fosfluconazole
- terconazole)
- Systemic: (fluconazole
- hexaconazole
- isavuconazole†, itraconazole
- posaconazole
- voriconazole)
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Thiazoles
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Topical: (abafungin)
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Polyene antimycotics
(ergosterol binding)
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- Topical: (hamycin
- natamycin
- nystatin#)
Systemic: (amphotericin B#, hamycin)
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Allylamines
(squalene monooxygenase
inhibitors) |
- Topical: (amorolfine
- butenafine
- naftifine
- terbinafine)
Systemic: terbinafine
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β-glucan synthase
inhibitors
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- echinocandins (anidulafungin
- caspofungin
- micafungin)
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| Intracellular |
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Pyrimidine analogues/
thymidylate synthase inhibitors
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Mitotic inhibitors
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Aminoacyl tRNA synthetase inhibitors
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| Others |
- bromochlorosalicylanilide
- methylrosaniline
- tribromometacresol
- undecylenic acid
- polynoxylin
- chlorophetanol
- chlorphenesin
- ticlatone
- sulbentine
- ethylparaben
- haloprogin
- salicylic acid
- selenium disulfide#
- ciclopirox
- amorolfine
- dimazole
- tolnaftate
- tolciclate
- sodium thiosulfate#
- Whitfield's ointment#
- potassium iodide#
- taurolidine
- tea tree oil
- citronella oil
- lemon grass
- orange oil
- patchouli
- lemon myrtle
- PCP: pentamidine
- dapsone
- atovaquone
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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