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Pentamidine


Pentamidine

Article Author:
Sumaiya Hafiz
Article Editor:
Chris Kyriakopoulos
Updated:
5/21/2020 7:31:47 PM
For CME on this topic:
Pentamidine CME
PubMed Link:
Pentamidine

Indications

Pentamidine is a broad-spectrum anti-infective agent active against several parasitic worms, protozoa, and fungi. It has been used in the treatment of Pneumocystis jiroveci pneumonia in the immunocompromised, leishmaniasis (cutaneous and Visceral), and Human African trypanosomiasis (African Sleeping sickness). It is a relatively toxic drug and requires careful monitoring during therapy. 

FDA Indications:

Pentamidine isethionate is used in the treatment and prevention of  Pneumocystis jirovecii pneumonia in high-risk, HIV-infected patients who meet the following criteria :

  1. A history of one or more, previous episodes of Pneumocystis jiroveci pneumonia
  2. A CD4+ count of 200 cells/mm^3 or less

Due to its various toxicities, its use is only for severe Pneumocystis jirovecii pneumonia, which has failed to respond to other first-line agents.

Non-FDA approved indications :

Anti Protozoal and Anti Parasitic action: Pentamidine is a treatment for protozoal infections such as cutaneous and visceral leishmaniasis caused by the bite of phlebotomine sand flies.

It is also used in the treatment of a tropical disease like sleeping sickness, known as human African trypanosomiasis caused by the bite of an infected tsetse fly.[1][2] The causative parasites of this disease are Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. It is the drug of choice for stage 1 (hemolymphatic) of sleeping sickness caused by Trypanosoma brucei gambiense.

Mechanism of Action

Pentamidine is an aromatic diamidine drug consisting of pentane-1,5-diol, which interferes with polyamine synthesis, RNA polymerase activity,  enters the protozoal cell binding to transfer RNA, and prevents the synthesis of protein, nucleic acids, phospholipids, and folate. Additionally, it is known to be an anti-inflammatory agent, xenobiotic, and an antagonist of the NMDA receptor, histone acetyltransferase, and calmodulin.[3][4]

Administration

It used in various forms such as inhalational, intravenously, or intramuscularly. It is not available in oral form, as it is poorly absorbed orally.

It undergoes metabolism in the liver and has a half-life of 10 to 14 days.

Pneumocystis Pneumonia 

Treatment - the recommended regimen is 3 to 4 mg/kg once in a day intravenous or intramuscularly, for 2 to 3 weeks (14 to 21 days).

Prevention- the recommended regimen is 300 mg in a nebulized form every four weeks, or 4mg/kg intravenous/intramuscularly, once every month.   

Leishmaniasis 

Cutaneous leishmaniasis: 

Daily once or every alternate day 2 to 3 mg per kg doses for four to seven days Intramuscular or Intravenous is recommended by the CDC (Centre for disease control and prevention). 

Visceral leishmaniasis:

2 to 4 mg/kg intramuscular/intravenous, daily once or alternate days for fifteen days. Alternatively, 4mg per kg (IM/IV) can be given three times weekly, for five weeks or more, based on patient response to the medication. 

Trypanosomiasis (Trypanosoma brucei gambiense)

Used in the first stage of the disease as the drug of choice: 4 mg per kg per day Intramuscular/Intravenously for seven to ten days.[5]

Adverse Effects

Due to its mechanism of action, which includes inhibition of protein and RNA synthesis and antagonism of receptors, it affects multiple organs producing various adverse effects.

  • Endocrine - Most commonly, it causes hypoglycemia due to pancreatic islet cell damage, and very rarely hyperglycemia.
  • Cardiology - hypotension, arrhythmias including twisting of peaks (Torsades de Pointes), fast or abnormal heart rate and prolonged QT interval [6]
  • General - fatigue, dysgeusia (bad taste), anaphylaxis, night sweats, anorexia, nausea, vomiting, syncope, rash
  • Nephrological - nephrotoxicity, electrolyte imbalances such as hyperkalemia, hypocalcemia, hypomagnesemia
  • Hematological - most commonly leukopenia, thrombocytopenia, and less commonly anemia can occur
  • Gastroenterological and hepatological - hepatotoxicity (most commonly elevation of serum aminotransferase), pancreatitis
  • Neurological -  neuropathy such as tingling or numbness, headache, altered mental status [7][8]
  • Injection form - Local pain or abscess formation at the site of injection
  • Inhaled form - bronchospasm, wheezing, and cough [7]

Contraindications

  • Previous history of an anaphylactic reaction to pentamidine in inhaled or parenteral form
  • The use of pentamidine with other nephrotoxic drugs like cyclosporine, cisplatin, aminoglycoside antibiotics, beta-lactam antibiotics, amphotericin B, and indomethacin should be closely monitored or avoided.[9]
  • Prolong QT interval should be avoided by using drugs like antiarrhythmics, antihistamines, antipsychotics, antidepressants, neuroleptics, atypical antipsychotics, antibiotics (quinolone, macrolides), antimalarials, and antifungals, to prevent torsades de pointes. [10]
  • Pregnancy category C risk. Adequate data is currently not available to asses the risk of pentamidine use in pregnant women and nursing mothers. 
  • In nursing mothers, it is advisable to discontinue breastfeeding or to stop taking the drug if an alternative is available as the risk to the child is unknown.

Monitoring

The following investigations are necessary before initiating therapy, during the administration of the drug and after treatment to monitor the drug and its toxicity : 

  • Kidney function testing including serum creatinine and blood urea nitrogen
  • Blood glucose measurement - to check for hypoglycemia or hyperglycemia
  • Full blood count and platelet count
  • Liver function test 
  • Serum bilirubin, alkaline phosphatase
  • Electrolytes (potassium, calcium, sodium, magnesium) 
  • ECG - to check for arrhythmias

Toxicity

Pentamidine is known to cause an elevation in serum aminotransferase levels during therapy.

Other findings in pentamidine toxicity include - Hypotension, clinically apparent hepatic dysfunction, pancreatitis, renal impairment, which can cause a rise in serum creatinine, cardiopulmonary arrest, and leucopenia.

According to a previously published study, charcoal hemoperfusion has previously been employed as an antidote for overdose or toxicity.[11]

Due to the multi-organ toxicities caused by pentamidine, it is not a commonly chosen therapy except in conditions where other first or second-line agents have failed to respond.

Enhancing Healthcare Team Outcomes

Pentamidine is used in Pneumocystis pneumonia, leishmaniasis, and as a first-line agent for Stage 1 of trypanosomiasis caused by T. gambiense. The drug is available in nebulized (inhaled) and intramuscular or intravenous injection form. Healthcare workers such as doctors and nurses caring for patients who require the drug should closely monitor the patients for signs of adverse effects of the drug, which are quite common due to its multiple mechanisms of action, which cause multiorgan toxicities. Additionally, as there is currently no proven antidote for the drug, appropriate measures should be taken to counteract the effects of toxicity.

Studies show differences in efficacy related to the dose, hence making it essential to prescribe adequate doses and administer them accordingly for maximum benefit and prevention of harmful effects.

In the event of hepatotoxicity or renal impairment, specialists should be involved to monitor progress, and if a nephrotoxic drug is required, the patient requires close monitoring to prevent deterioration.

Injection site abscesses and infections should be cared for and treated accordingly.

Instructions for the inhaled form should be explained to the patient and administered efficiently to ensure maximum delivery of the drug.


References

[1] Brown KS,Reed MD,Dalal J,Makii MD, Tolerability of Aerosolized Versus Intravenous Pentamidine for Pneumocystis jirovecii Pneumonia Prophylaxis in Immunosuppressed Pediatric, Adolescent, and Young Adult Patients. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG. 2020;     [PubMed PMID: 32071585]
[2] Pentamidine 2012;     [PubMed PMID: 31644251]
[3] Block F,Schmitt T,Schwarz M, Pentamidine, an inhibitor of spinal flexor reflexes in rats, is a potent N-methyl-D-aspartate (NMDA) antagonist in vivo. Neuroscience letters. 1993 Jun 11;     [PubMed PMID: 7690919]
[4] Kitamura Y,Arima T,Imaizumi R,Sato T,Nomura Y, Inhibition of constitutive nitric oxide synthase in the brain by pentamidine, a calmodulin antagonist. European journal of pharmacology. 1995 Apr 28;     [PubMed PMID: 7542607]
[5] Dorlo TP,Kager PA, Pentamidine dosage: a base/salt confusion. PLoS neglected tropical diseases. 2008 May 28;     [PubMed PMID: 18509543]
[6] Wharton JM,Demopulos PA,Goldschlager N, Torsade de pointes during administration of pentamidine isethionate. The American journal of medicine. 1987 Sep;     [PubMed PMID: 3499072]
[7] Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy., Quinn M,Fannin JT,Sciasci J,Bragg A,Campbell PK,Carias D,Crews KR,Gregornik D,Jeha S,Maron G,Pauley JL,Swanson HD,Wolf J,Greene W,, Antimicrobial agents and chemotherapy, 2018 Aug     [PubMed PMID: 29866879]
[8] Pohlig G,Bernhard SC,Blum J,Burri C,Mpanya A,Lubaki JP,Mpoto AM,Munungu BF,N'tombe PM,Deo GK,Mutantu PN,Kuikumbi FM,Mintwo AF,Munungi AK,Dala A,Macharia S,Bilenge CM,Mesu VK,Franco JR,Dituvanga ND,Tidwell RR,Olson CA, Efficacy and Safety of Pafuramidine versus Pentamidine Maleate for Treatment of First Stage Sleeping Sickness in a Randomized, Comparator-Controlled, International Phase 3 Clinical Trial. PLoS neglected tropical diseases. 2016 Feb;     [PubMed PMID: 26882015]
[9] Mendoza SA, Nephrotoxic drugs. Pediatric nephrology (Berlin, Germany). 1988 Oct;     [PubMed PMID: 3153061]
[10] Nachimuthu S,Assar MD,Schussler JM, Drug-induced QT interval prolongation: mechanisms and clinical management. Therapeutic advances in drug safety. 2012 Oct;     [PubMed PMID: 25083239]
[11] Watts RG,Conte JE Jr,Zurlinden E,Waldo FB, Effect of charcoal hemoperfusion on clearance of pentamidine isethionate after accidental overdose. Journal of toxicology. Clinical toxicology. 1997;     [PubMed PMID: 9022658]