Pentamidine

340.42

340.42

202-841-0

673LC5J4LQ

9921

DTXSID7023431

C731

Crystallizes as colorless plates from water

2925290090

118

2.41

Solid

1.29 g/cm³

186 °C (dec.)

238°C

103°C c.c.

1.6620 (estimate)

Solubility in water, g/100ml at 20°C: 0.035

-20°C Freezer, Under Inert Atmosphere

Vapour pressure, kPa at 20°C: 0.016

Relative vapour density (air = 1): 4.72

Henry's Law constant = 4.97X10-17 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 1.17X10-10 cu cm/molec-sec at 25 °C (est)|Fine needles from dil hydrochloric acid, mp 232-234 °C /Dihydrochloride/|Mol wt 532.64. White powder /Dimethanesulfonate/

III

6.1(b)

3249

23/24/25-33-51/53

(1/2)-28-37-45-61

CV6475000

T, N

Separated from food and feedstuffs. See Chemical Dangers. Well closed.

After reconstitution with sterile water, the Pentam solution is stable for 48 hours in the original vial at room temperature if protected from light.

P261, P264, P271, P272, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P333+P313, P337+P313, P362, P363, P403+P233, P405, P501

H315

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl pentamidine isethionate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Pentamidine Isethionate/

Local exhaust ventilation systems such as isolation booths, hoods, tents, or other enclosures should be used for aerosolized pentamidine (AP) administration at all facilities. The exhaust air from these units should pass through a HEPA filter before being released into the room or exhausted to the outside. These local exhaust ventilation systems capture the air contaminants at or near the source and remove them without exposing persons in the area. Local exhaust ventilation is preferable and more efficient than general ventilation, which involves the dilution and removal of contaminants in a much larger volume of air, such as a whole room. If local exhaust ventilation cannot be used, or during the interim period when controls are being implemented, efforts should be made to ensure that the pentamidine administration room is under negative pressure relative to adjacent areas and that a minimum of six air changes per hour are provided in accordance with guidelines for respiratory isolation rooms. Air should be exhausted directly to the outside, not recirculated to other areas within the facility. If this is not possible, room air must be passed through a HEPA filter before being recirculated back into the room or to other areas of the facility. Ideally, the pentamidine administration rooms should be set up to meet these guidelines even if local exhaust ventilation is used, to further reduce the potential for exposure to pentamidine and M. tuberculosis.|The doors and windows to the administration rooms should be kept closed during treatments to minimize the potential for contamination of the air in surrounding areas and to maintain negative pressure in the rooms. The use of window air conditioning units and personal cooling fans in place of mechanical ventilation systems is not appropriate. Additionally, the air pressure differential should be checked on a periodic basis (i.e., weekly) to ensure that air flows into the room from surrounding areas (i.e., from "clean" to potentially contaminated areas).|Surgical masks do not provide adequate respiratory protection against small aerosols such as pentamidine isethionate or M. tuberculosis due to inadequate filter efficiency and face seal leakage. NIOSH-approved respirators should be worn in situations requiring respiratory protection. The CDC recommends that respirators be worn by HCWs during cough inducing or aerosol-generating procedures on patients with known or suspected infectious tuberculosis. The Occupational Safety and Health Administration (OSHA) requires the use of respirators by health care workers when performing such procedures on patients with suspected or confirmed TB. High-efficiency particulate air respirators are the minimum acceptable level of respiratory protection required by OSHA, and which currently meet the performance criteria established by CDC.|Select a ventilated cabinet depending on the need for aseptic processing. Aseptic technique is important for protecting hazardous drugs from possible contamination. However, it is also important to consider worker protection and to assure that worker safety and health is not sacrificed. Therefore, when asepsis is required or recommended, use ventilated cabinets designed for both hazardous drug containment and aseptic processing. Aseptic requirements are generally regulated by individual State boards of pharmacy. When asepsis is not required, a Class I BSC or an isolator intended for containment applications (a containment isolator) may be sufficient. When aseptic technique is required, use one of the following ventilated cabinets: Class II BSC (Type B2 is preferred, but Types A2 and B1 are allowed under certain conditions); Class III BSC; Isolators intended for asepsis and containment (aseptic containment isolators). Air flow and exhaust: regardless of type, equip each ventilated cabinet with a continuous monitoring device to confirm adequate air flow before each use. Use a high-efficiency particulate air filter (HEPA filter) for the exhaust from these controls, and where feasible, exhaust 100% of the filtered air to the outside. Install the outside exhaust so that the exhausted air is not pulled back into the building by the heating, ventilating, and air conditioning (HVAC) systems or by the windows, doors, or other points of entry. Place fans downstream of the HEPA filter so that contaminated ducts are maintained under negative pressure. Do not use a ventilated cabinet that recirculates air inside the cabinet or exhausts air back into the room environment unless the hazardous drug(s) in use will not volatilize (evaporate) while they are being handled or after they are captured by the HEPA filter. Information about volatilization should be supplied by the drug manufacturer (possibly in the MSDS) or by air-sampling data. Seek additional information about placement of the cabinet, exhaust system, and stack design from NSF/ANSI 49-2002. Incorporate their recommendations regardless of the type of ventilated cabinet selected. /Hazardous drugs/|... Some clinicians suggest that use of gowns, gloves, goggles, and masks by health-care personnel be considered, although the level of protection provided is not known. ... Use of surgical masks by health-care personnel caring for pentamidine-treated patients probably is unlikely to provide an effective means for reducing environmental exposure to the drug; therefore, if a face mask is used, alternative, appropriately designed (e.g., for adequate particle-size filtration) and well-fitted face masks (e.g., 3M Company model 9970 or 9920) should be employed since they are more likely to substantially reduce respiratory exposure levels.

Spill Control. Manage hazardous drug spills according to the established, written policies and procedures for each workplace. Be aware that the size of the spill might determine who is authorized to conduct the cleanup and decontamination and how the cleanup is managed. Assure that the written policies and procedures address the protective equipment required for various spill sizes, the possible spreading of material, restricted access to hazardous drug spills, and signs to be posted. Assure that cleanup of a large spill is handled by workers who are trained in handling hazardous materials [29 CFR 1910.120]. Locate spill kits and other cleanup materials in the immediate area where exposures may occur. /Hazardous drugs/

Drug Preparation and Administration. Initial steps: ... evaluate and review the entire drug preparation and administration process to identify points at which drugs might be released into the work environment. Always consider the possibility of contamination on the outside of containers ... Limit access to areas where drugs are prepared to protect persons not involved in drug preparation. Coordinate tasks associated with preparing and administering hazardous drugs for most effective control of worker exposures. /Hazardous drugs/|Preparing hazardous drugs. Use a ventilated cabinet designed to reduce worker exposures while preparing hazardous drugs ... Train all staff who use ventilated cabinets to employ work practices established for their particular equipment. The safe use of any control depends on proper work. Practice proper technique and use of equipment. Include initial and periodic assessments of technique in the safety program, and verify technique during drug administration. Wear protective gloves and gowns if you are involved in preparation activities such as opening drug packaging, handling vials or finished products, labeling hazardous drug containers, or disposing of waste. /Hazardous drugs/|Administering hazardous drugs. Administer drugs safely by using protective medical devices (such as needleless and closed systems) and techniques ... Wear PPE (including double gloves, goggles, and protective gowns) for all activities associated with drug administration, opening the outer bag, assembling the delivery system, delivering the drug to the patient, and disposing of all equipment used to administer drugs. ... Consider double bagging all contaminated equipment. Wash hands with soap and water before leaving the drug administration site. /Hazardous drugs/|Ventilated Cabinets. Use of cabinets: Mix, prepare, and otherwise manipulate, count, crush, compound powders, or pour liquid hazardous drugs inside a ventilated cabinet designed to prevent hazardous drugs from being released into the work environment. Do not use supplemental engineering or process controls (such as needleless systems, glove bags, and closed-system drug transfer devices) as a substitution for ventilated cabinets, even though such controls may reduce the potential for exposure when preparing and administering hazardous drugs. /Hazardous drugs/|For more Preventive Measures (Complete) data for PENTAMIDINE (11 total), please visit the HSDB record page.

Adverse effects ... include eye irritation (e.g., conjunctivitis); perioral and perinasal paresthesia; ... burning sensation of the eyes, nose, and throat; sinus irritation; ... nasal stuffiness; ... shortness of breath; ... acute bronchospasm ...

Symptoms of overdose include pain, nausea, anorexia, hypotension, fever, rash, bad taste in mouth, confusion/hallucinations, dizziness, and diarrhea.

Pentamidine has been associated with serum aminotransferase elevations in 9% to 15% of patients receiving 2 to 3 weeks of therapy for pneumocystis pneumonia. Clinically apparent liver injury has also been reported with its use, but always in association with multiple other severe complications, such as respiratory or renal failure and pancreatitis. The onset of injury is within days of starting therapy and is characterized by acute hepatic necrosis, marked elevations in serum aminotransferase levels, rapid development of prolongation of prothrombin time and minimal or no jaundice. Recovery is typically rapid and usually complete.

Since nephrotoxic effects may be additive, the concurrent or sequential use of pentamidine isethionate and other drugs with similar toxic potentials such as aminoglycosides, amphotericin B, capreomycin, colistin, cisplatin, foscarnet, methoxyflurane, polymyxin B, or vancomycin should be closely monitored or avoided, if possible.|Concurrent use of other nephrotoxic medications with pentamidine may increase the potential for nephrotoxicity; renal function determinations, dosage reductions, and/or dosage interval adjustments may be required.|Renal side-effects are frequently observed after parenteral administration of pentamidine. In this study in a rat model, the nephrotoxicity was assessed by measuring urinary loss of tubular cells, malate dehydrogenase activity and creatinine clearance. In addition, we studied the influence of other nephrotoxins such as tobramycin, amphotericin B and cyclosporin on the pentamidine-associated nephrotoxicity and proved the possibilities of reducing this toxicity by coadministration with other drugs. The tubular toxicity of pentamidine (1, 10 or 20 mg/kg daily) is dose-related and reversible. The toxicity can be reduced by coadministration of fosfomycin (1 x 500 or 2 x 250 mg/kg daily) and D-glucaro-1,5-lactam (2 x 5 mg/kg daily) and enhanced by tobramycin (2 x 2.5 mg/kg daily), amphotericin B (1 mg/kg daily) and cyclosporin (10 mg/kg daily). Furthermore, an increase in the creatinine clearance in pentamidine-treated rats can be obtained with both verapamil (2 x 1.5 mg/kg daily) and enalapril (5 mg/kg daily).|Concurrent use /of foscarnet/ with pentamidine may result in severe, but reversible, hypocalcemia, hypomagnesemia, and nephrotoxicity.|For more Interactions (Complete) data for PENTAMIDINE (8 total), please visit the HSDB record page.

LD50 Mouse subcutaneous 120 mg/kg|LD50 Mouse intraperitoneal 63 mg/kg|LD50 Mouse IV 15 mg/kg

Pentamidine isethionate (PIT) is an aromatic diamidine which was synthesized originally for the therapy of trypanosomiasis. It has found increasing usefulness in the treatment of pneumocystosis. Pentamidine isethionate has been effective in treating AIDS patients for pneumocystis carinii pneumonia. It is for this reason that it was selected for immunotoxicity studies. The objective of this study was to determine if pentamidine isethionate, administered subcutaneously, altered the immune status. NTP Tier I & selected Tier II assays were performed. Female C57Bl/6 mice were treated with 10, 17 or 25 mg/kg pentamidine isethionate for 5 days a week for four weeks by the subcutaneous route. Since pentamidine isethionate accumulates in the tissues and appears in the urine for six to eight weeks after cessation of therapy, the lymphoid organs were most likely to be continuously exposed to the drug. Since the immune system is targeted by the HIV virus and because antiviral therapy is being used after detection of antibody to HIV, detecting and understanding potential actions on the immune system is important. The objective of this study was to determine the potential of pentamidine isethionate to compromise the immune system. Pentamidine isethionate was administered by the subcutaneous injection daily for 5 days per week for 4 weeks. The studies were divided into standard toxicology studies, which provided the base against which to compare the immunology studies, and the immunology studies, which provided data on specific cellular targets of the drug. Executive Summary Table 1 (ES-1) shows a summary of the standard toxicology studies. Treatment with pentamidine isethionate in doses as high as 25 mg/kg/day for 22 days over a 30 day period were tolerated by adult female C57Bl/6 mice. There was less than 1% mortality from exposure and no overt signs of toxicity. There were no histopathologic findings in the lung, mesenteric lymph node, spleen, thymus, liver or kidney that could be attributed to pentamidine isethionate treatment. Body weight changes associated with pentamidine isethionate treatment were minimal. As expected, the comparative control, azathioprine, produced a significant weight loss from exposure to 10 mg/kg/day for 30 days. Two organs were affected by exposure to the high dose (25 mg/kg) of pentamidine isethionate. These included a 13% decrease in thymus weight and a 9% increase in kidney weight. Pentamidine isethionate treatment was associated with a decrease in the erythroid elements as seen in decreases in erythrocytes, hemoglobin, and hematocrit. The leukocyte elements were not significantly affected by pentamidine isethionate treatment. Bone marrow cellularity, DNA synthetic ability, and the number of CFU-M and CFU-GM stem cells were unaffected by treatment with pentamidine isethionate. Azathioprine produced the expected decrease in cellularity and number of stem cells with a concomitant compensatory increase in DNA synthesis. The no effect level for the standard toxicological parameters was not reached. Pentamidine isethionate affected the erythrocyte number at the lowest dose (10 mg/kg) tested. Executive Summary Table 2 (ES-2) summarizes the immunology studies of mice treated with pentamidine isethionate. Treatment of mice with pentamidine isethionate produced no effects on indicators of humoral immunity, such as changes in B cell number, proliferative ability or ability to differentiate into antibody producing cells to a T-dependent antigen. T lymphocyte numbers were slightly decreased in pentamidine isethionate-treated mice but the decrease did not translate into functional changes. Spleen cell response to the T-dependent antigen was unaffected, indicating the regulatory T cells were similar to those from control mice. Proliferative capacity, as measured by response to T cell mitogens and to allogenic cells, was unaffected by pentamidine isethionate treatment. Differentiation and the killing mechanism of T cells were intact in mice treated with pentamidine isethionate as seen in a CTL response which did not differ from the control group. Macrophages, derived from the peritoneal cavity of mice treated with pentamidine isethionate, were more responsive to activation by gamma interferon than control mice which may be a response to the local granuloma produced at the injection site. Natural killer cell activity was unaffected by pentamidine isethionate treatment. The no effect level for these studies was below 10 mg/kg and the erythroid elements were one of the most sensitive parameters. The immune system is not a target for toxicity by pentamidine isethionate.

Pentamidine isethionate inhalation should be used with caution in patients with hypoglycemia, hyperglycemia or glucose intolerance, diabetes mellitus, thrombocytopenia, asthma, or hepatic, renal, or pulmonary dysfunction; some authorities state that the drug should not be used in patients with a history of hypoglycemia, pancreatitis, arrhythmia, or severe hypotension associated with administration of pentamidine by any route. Patients with severe asthma or a history of extensive smoking may not tolerate pentamidine inhalation therapy because of drug-induced bronchospasm or cough. /Pentamidine isethionate/|HIV-infected patients with Pneumocystis carinii pneumonia may worsen during the first 5 days of /pentamidine isethionate/ therapy, possibly from an inflammatory response to killed organisms. ... Treatment failures, relapses, and drug toxicity and intolerance are especially prevalent in patients with AIDS. These individuals are more likely to respond favorably to trimethoprim-sulfamethoxazole if that medication is tolerated. /Pentamidine isethionate/|Pentamidine isethionate should be used with caution in patients with hypertension, hypotension, ventricular tachycardia, hypoglycemia, hyperglycemia, hypocalcemia, pancreatitis, leukopenia, thrombocytopenia, anemia, hepatic or renal dysfunction and Stevens-Johnson syndrome. /Pentamidine isethionate/

69%

For the treatment of pneumonia due to Pneumocystis carinii.

Pentamidine is a potent, broad spectrum antiinfective agent with activity against several parasitic worms, protozoa and fungi that has been used mainly in the treatment and the prophylaxis of Pneumocystis jiroveci (formerly carinii) infection in immunocompromised persons. Pentamidine is relatively toxic and therapy requires careful monitoring. Pentamidine has been associated with transient serum aminotransferase elevations during therapy and with rare instances of clinically apparent liver injury.

Antifungal/Anthelmintic Agents

Pentamidine is indicated in the treatment of Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). Sulfamethoxazole and trimethoprim combination is considered to be the primary agent for PCP in patients who can tolerate it. /Included in US product labeling/|Pentamidine is used as a secondary agent in the treatment of visceral leishmaniasis (kala-azar) caused by Leishmania donovani. Stibogluconate sodium, a pentavalent antimony derivative, is considered to be the primary agent for visceral leishmaniasis. /NOT included in US product labeling/|Pentamidine is used as a secondary agent in the treatment of cutaneous leishmaniasis caused by Leishmania tropica, L. major, L. mexicana, L. aethiopica, L. peruviana, L. guyanensis, and L. braziliensis. Stibogluconate sodium, a pentavalent antimony derivative, is considered to be the primary agent for cutaneous leishmaniasis. /NOT included in US product labeling/|Aerosolized pentamidine is indicated in both secondary prophylaxis (patients who have already had at least one episode of Pneumocystis carinii pneumonia) and primary prophylaxis (HIV-infected patient with a CD4 lymphocyte count less than or equal to 200 cells per cubic millimeter) of Pneumocystis carinii pneumonia. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for PENTAMIDINE (12 total), please visit the HSDB record page.

Fatalities due to severe hypotension, hypoglycemia, acute pancreatitis and cardiac arrhythmias have been reported in patients treated with pentamidine isethionate, both by the IM and IV routes. Severe hypotension may result after a single IM or IV dose and is more likely with rapid IV administration. The administration of the drug should, therefore, be limited to the patients in whom Pneumocystis carinii has been demonstrated. Patients should be closely monitored for the development of serious adverse reactions.|Nephrotoxicity reportedly occurs in at least 25% of patients with pneumocystis pneumonia receiving parenteral pentamidine isethionate. Pentamidine-induced nephrotoxicity is manifested by an increase in serum creatinine concentration and/or BUN, usually developing gradually and appearing during the second week of therapy with the drug. Azotemia also has been reported. Renal insufficiency is usually mild to moderate in severity and reversible following discontinuance of pentamidine; however, acute renal failure (e.g., serum creatinine concentration greater than 6 mg/dL) or severe renal insufficiency requiring discontinuance of the drug may occur occasionally. Limited evidence suggests that nephrotoxicity and hyperkalemia both may occur more frequently in patients with AIDS than in other patients treated with parenteral pentamidine; hyperkalemia has been severe in some patients. Rarely, pentamidine-induced acute renal failure has been associated with myoglobinuria or gross hematuria. The risk and degree of pentamidine-induced renal impairment may be increased in the presence of dehydration or by concomitant use of other nephrotoxic drugs. Acute renal failure has been reported in at least 1 patient receiving pentamidine inhalation therapy; flank pain and nephritis also have been reported occasionally in patients receiving the aerosolized drug by oral inhalation via nebulizer.|Cardiorespiratory arrest (following rapid IV injection), ventricular tachycardia, atypical ventricular tachycardia (torsade de pointes), ECG abnormalities, and facial flushing have also been reported in patients receiving parenteral pentamidine. The risk of hypotensive reactions following IM or IV administration of pentamidine isethionate has not been directly compared, but some data suggest that there is no difference in the frequency of these reactions following either route of administration when IV infusions of the drug are administered over a period of at least 60 minutes. Hypotensive reactions may be particularly likely to occur following rapid IV injection or infusion. To minimize the risk of this adverse effect when pentamidine isethionate is administered IV, infusions of the drug should be given over a period of 60-120 minutes. However, hypotension, which was not ameliorated by adjustment of the infusion rate, persisted beyond completion of the infusion, and required volume expansion for correction, has been reported in some patients. Hypotension, hypertension, tachycardia, palpitations, syncope, dizziness, light-headedness, diaphoresis, cerebrovascular accident, vasodilatation, and vasculitis have been reported occasionally in patients receiving orally inhaled pentamidine.|Since pentamidine has become commercially available, there is renewed interest in using it as the initial treatment for Pneumocystis carinii pneumonia in AIDS patients. /The authors/ reviewed the use of pentamidine in 24 patients with Pneumocystis carinii pneumonia to gain information on the prevalence and severity of adverse effects from this drug. Twenty out of twenty-four patients (83 percent) experienced some kind of adverse effect. Hepatic abnormalities (58 percent), nausea and vomiting (46 percent), hypoglycemia (33 percent), azotemia (25 percent), and pain at the injection site (25 percent) were the most frequently seen effects.|For more Drug Warnings (Complete) data for PENTAMIDINE (25 total), please visit the HSDB record page.

The diamidines are concn via an energy-dependent, high-affinity uptake system that operates more effectively in drug-sensitive than in drug-resistant strains ... The diamidines utilize a transporter selective for adenine and adenosine, purines that must be imported to assure parasite survival ... Failure to concn diamidines is the usual cause of pentamidine resistance ...

Pentamidine is an antiprotozoal agent. It is an aromatic diamidine, and is known to have activity against Pneumocystis carinii. The exact nature of its antiprotozoal action is unknown. in vitro studies with mammalian tissues and the protozoan Crithidia oncopelti indicate that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids and proteins. Little is known about the drug's pharmacokinetics. The medication is also useful in Leishmaniasis and in prophylaxis against sleeping sickness caused by Trypanosoma brucei gambiense. Hydration before treatment lessens the incidence and severity of side effects, which include liver or kidney dysfunction, hypertension, hypotension, hypoglycemia, hypocalemia, leukopenia, thrombcytopenia, anemia, and allergic reaction. It is generally well-tolerated.

Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. (See all compounds classified as Antifungal Agents.)|Substances that are destructive to protozoans. (See all compounds classified as Antiprotozoal Agents.)|Agents destructive to the protozoal organisms belonging to the suborder TRYPANOSOMATINA. (See all compounds classified as Trypanocidal Agents.)

Absorbed poorly through the gastrointestinal tract and is usually administered parenterally.|Pentamidine isethionate is fairly well absorbed from parenteral sites of admin despite the formation of sterile abscesses that may occur after its used. Following a single intravenous dose, the drug disappears from plasma with an apparent half-life of several min to a few hours; this is followed by a slower distribution phase and a prolonged elimination phase lasting from weeks to months. Patients with African trypanosomiasis exhibit marked interindividual variations in pharmacokinetic parameters. Their mean system plasma clearance after a single dose is about 1120 mL/min, but the volume of distribution is about 25,000 L, a finding that accounts for the prolonged average elimination half-life of about 12 days ... The renal clearance of pentamidine averages only about 2% to 11% of its systemic clearance ... but whether the drug is metabolized or excreted in bile ... is unknown. In patients receiving multiple injections of the drug over a 13-day period for treatment of pneumocystosis, drug accumulation occurs such that no steady-state plasma concn is attained ... /Pentamidine isethionate/|... After multiple parenteral doses, the liver, kidney, adrenal, and spleen of patients with AIDS contain the highest concn of drug, whereas only traces are found in the brain ... Lungs of such patients contain intermediate but therapeutic concn after 5 daily doses of 4 mg of base/kg. Higher pulmonary concn should be achieved by inhalation of pentamidine aerosols for prophylaxis or as adjunctive treatment for mild to moderate Pneumocystis carinii pneumonia; delivery of drug by this route results in little systemic absorption and decreased toxicity compared with intravenous admin in both adults and children. The actual dose delivered to the lungs depends on both the size of particles generated by the nebulizer and the patient's ventilatory patterns. /Pentamidine isethionate/|Aerosolized pentamidine produces concentrations approximately 10 to 100 times higher in the lungs than would a comparable dose of IV pentamidine.|Systemic absorption of inhaled pentamidine is minimal, with serum pentamidine concentrations less than 20 nanograms per mL after a nebulized dose of 4 mg/kg in most cases (versus 612 nanogram per mL after a single IV dose of 4 mg/kg). Peak systemic absorption occurs at, or near, completion of inhalation therapy.|For more Absorption, Distribution and Excretion (Complete) data for PENTAMIDINE (14 total), please visit the HSDB record page.

Hepatic.|By using high-performance liquid chromatography, the in vitro conversion of pentamidine to the corresponding amidoximes (N-hydroxypentamidine and N,N'-dihydroxypentamidine) was studied in supernatants of rat liver homogenate centrifuged at 9,000 x g. The presence of the two amidoxime peaks in chromatograms was confirmed by liquid secondary ion mass spectrometry and by unequivocal synthesis of the suspected metabolites. The metabolic reactions were found to be catalyzed by the cytochrome P-450 system (mixed-function oxidases). The formation of the monohydroxylated product was found to have a Km of 0.48 mM and a Vmax of 29.50 pmol/min per mg of protein, while the dihydroxylated metabolite had a Km of 0.73 mM and a Vmax of 4.10 pmol/min per mg of protein. ...|The antiprotozoal/antifungal drug pentamidine [1,5-bis(4-amidinophenoxy)pentane] has been recently shown to be metabolized by rat liver fractions to at least six putative metabolites as detected by high-performance liquid chromatography. ... In this study, the two major microsomal metabolites have been identified as the 2-pentanol and 3-pentanol analogs of pentamidine [1,5-di(4-amidinophenoxy)-2-pentanol; and 1,5-bis(4-amidinophenoxy)-3-pentanol]. As well, a seventh putative metabolite has been discovered and identified as para-hydroxybenzamidine, a fragment of the original drug. ... the cytochromes P-450 have been demonstrated as the enzyme system responsible for pentamidine metabolism ... the mixed-function oxidases readily convert pentamidine to hydroxylated metabolites, but exactly which isozyme(s) of cytochrome P-450 is responsible is not clear.|The antiprotozoal drug pentamidine [1,5-bis(4'-amidinophenoxy)pentane] has been previously shown to be metabolized by rat liver microsomes, and five of the seven putative primary metabolites have been identified. With the synthesis and identification of 5-(4'-amidinophenoxy)pentanoic acid and 5-(4'-amidinophenoxy)-1-pentanol as the remaining two metabolites, the primary metabolism of pentamidine in rats appears fully characterized. ... Isolated, perfused rat livers were used with [14C]pentamidine to identify secondary metabolites. Only two novel radioactive peaks were detected by HPLC analysis of perfused liver samples. The treatment of liver samples with sulfatase or beta-glucuronidase resulted in the reduction or elimination of these peaks and gave rise to peaks identified as para-hydroxybenzamidine and 5-(4'-amidinophenoxy)pentanoic acid. It was concluded from these results that only these two primary metabolites were conjugated with sulfate or glucuronic acid.|Pentamidine /is a substrate for/ human liver microsomal P450 enzyme CYP2C19. /From table/

9.1-13.2 hours|Intramuscular: 9.1 to 13.2 hours. Intravenous: Approximately 6.5 hours. Terminal half-life: 2 to 4 weeks. Renal function impairment: Pentamidine half-life may be prolonged in patients with renal dysfunction ; however, no correlation between renal function and plasma clearance of pentamidine has been found.

The mode of action of pentamidine is not fully understood. It is thought that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids, and proteins.|... Up to now, it has been thought that therapeutic compounds causing QT prolongation are associated with direct block of the cardiac potassium channel human ether a-go-go-related gene (hERG), which encodes the alpha subunit of cardiac I(Kr) currents. /The authors/ show that pentamidine has no acute effects on currents produced by hERG, KvLQT1/mink, Kv4.3, or SCNA5. Cardiac calcium currents and the guinea pig cardiac action potential were also not affected. After overnight exposure, however, pentamidine reduced hERG currents and inhibited trafficking and maturation of hERG with IC(50) values of 5 to 8 uM similar to therapeutic concentrations. Surface expression determined in a chemiluminescence assay was reduced on exposure to 10, 30, and 100 uM pentamidine by about 30, 40, and 70%, respectively. These effects were specific for hERG since expression of hKv1.5, KvLQT1/minK, and Kv4.3 was not altered. In isolated guinea pig ventricular myocytes, 10 uM pentamidine prolonged action potential duration APD(90) from 374.3 or + or - 57.1 to 893.9 + or - 86.2 ms on overnight incubation. I(Kr) tail current density was reduced from 0.61 + or - 0.09 to 0.39 + or - 0.04 pA/pF. /The authors/ conclude that pentamidine prolongs the cardiac action potential by block of hERG trafficking and reduction of the number of functional hERG channels at the cell surface. /The authors/ propose that pentamidine, like arsenic trioxide, produces QT prolongation and torsades de pointes in patients by inhibition of hERG trafficking.|... Inhibition in vitro of trypanosomal mitochondrial topoisomerase II and plasma Ca+2, Mg+2-ATPase also has been reported ... Pentamidine promotes linearization of trypanosome kinetoplast DNA, consistent with its being a type II topoisomerase inhibitor ... The drug also inhibits ATP-dependent topoisomerases in extracts of Pneumocystis carinii ...|Not clearly defined; pentamidine may interfere with incorporation of nucleotides into RNA and DNA and inhibit oxidative phosphorylation and biosynthesis of DNA, RNA, protein, and phospholipid; may also interfere with folate transformation.|... The cytotoxic properties of pentamidine isethionate (2) towards the promastigotes of the protozoan parasite Leishmania infantum /was determined/. The leishmanicidal activity of 2 was 60 times higher after 72 hr of incubation than that of cisplatin. The pentamidine salt 2 induced a higher amount of programmed cell death (PCD) than cisplatin, which is associated with inhibition of DNA synthesis and cell-cycle arrest in the G2/M phase. Circular dichroism (CD) data indicate that binding of 2 to calf-thymus DNA (CT-DNA) induces conformational changes in the DNA double helix, consistent with a B-->A transition. Moreover, the interaction of 2 with ubiquitin led to a 6% increase in the beta-sheet content of the protein as observed by CD spectroscopy. Fluorescence-spectroscopy studies agreed with the CD data, showing that the pentamidine portion of 2 induces a significant decrease in the fluorescence of the Ub residues Phe4 and Phe45 located on the beta-cluster of the molecule, but not of Tyr59 on the alpha-cluster. These data indicate that pentamidine specifically modifies the beta-cluster, i.e., the 'basic face' of ubiquitin. ... /The/ results suggest that the biochemical mechanism of action of pentamidine may be a consequence of its dual binding to DNA and proteins.|In this work pentamidine is shown to exhibit characteristics of a cationic uncoupler of oxidative phosphorylation in isolated rat liver mitochondria: it released respiratory control, enhanced the latent ATPase activity, and released the inhibition of State 3 respiration by oligomycin. Maximal stimulation of respiration and ATPase activity was observed at a concentration of pentamidine of 200-300 microM. Higher concentrations had an inhibitory effect on mitochondrial respiration. As it happens with other cationic uncouplers, the uncoupling effect of pentamidine required inorganic phosphate. Pentamidine-induced uncoupling of oxidative phosphorylation was accompanied by an efflux of Ca2+ from the mitochondria and partial collapse of the mitochondrial membrane potential.

A patient received an accidental overdose (40 times the prescribed dose) of intravenous pentamidine due to a pharmacy mixing error. Charcoal hemoperfusion was utilized to attempt to lower the serum concentration of pentamidine and lessen toxicity. Measurement of pentamidine concentrations in the patient's blood demonstrates a beneficial effect of hemoperfusion. Charcoal hemoperfusion may represent a useful modality in the management of pentamidine isethionate overdosage. /Pentamidine isethionate IV/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ The incidence and severity of adverse drug reactions in human immunodeficiency virus-infected persons receiving intravenous pentamidine for Pneumocystis carinii pneumonia during a 5-year period were reviewed retrospectively. Predisposing risk factors for adverse drug reactions were identified. Adverse drug reactions were included if they occurred during or within 1 week following the discontinuation of pentamidine treatment. Nephrotoxicity, dysglycemia, hepatotoxicity, hyperkalemia, and hyperamylasemia accounted for 80% of adverse drug reactions (n = 174) that occurred in 76 (71.7%) of 106 patients during 84 treatment courses of pentamidine. A significant relationship between hypoglycemia and nephrotoxicity was observed (P = 0.002). Four factors were significantly associated with occurrence of an adverse drug reaction: number of concomitant medications (odds ratio (OR) = 1.36, P = 0.005), nonwhite ethnicity (OR = 5.00, P = 0.017), cumulative dosage of pentamidine (OR = 1.03, P = 0.030), and concurrent use of other nephrotoxic drugs (OR = 2.34, P = 0.047). Two factors, daily dosage and history of intravenous drug use, approached significance. Knowledge of and avoidance of potential risk factors might allow safer use of pentamidine and reduce the prevalence of adverse drug reactions.|/SIGNS AND SYMPTOMS/ ... Intravenously administered pentamidine frequently results in QTc prolongation with a subsequent risk of torsade de pointes in HIV-infected patients.|/SIGNS AND SYMPTOMS/ Adverse effects reported to date in health-care personnel and others exposed to aerosolized pentamidine include eye irritation (e.g., conjunctivitis); perioral and perinasal paresthesia; numbness of the mouth and nose; bitter metallic taste; burning sensation of the eyes, nose, and throat; sinus irritation; increased mucous discharge; nasal stuffiness; sneezing; shortness of breath; cough; tightness of the chest; acute bronchospasm; wheezing; hoarseness; fatigue; headache; and light-headedness.|/SIGNS AND SYMPTOMS/ At therapeutic doses (4 mg/kg/day), pentamidine causes toxicity in about 50% of patients treated, whether or not they have AIDS ... IV injection of pentamidine (and other diamidines) can be followed by alarming and sometimes dangerous reactions. These include breathlessness, tachycardia, dizziness or fainting, headache, and vomiting. These reactions probably relate to the sharp fall in blood pressure that follows too rapid iv admin of the drug, and they may be due in part to the release of histamine. If soln of pentamidine cannot be given slowly by the IV route, the drug is well tolerated after intramuscular injection. However, the latter route is associated with formation of sterile abscesses at the injection site. Pentamidine does not appear to cause late neuropathies. Pancreatitis and hypoglycemia and, paradoxically, hyperglycemia and insulin-dependent diabetes have been documented following its admin; the hypoglycemia may be life-threatening or even fatal if not recognized. Other adverse effects include skin rashes, thrombophlebitis, thrombocytopenia, anemia, neutropenia, elevation of liver enzymes, and nephrotoxicity. Impaired renal function has been seen in 24% of patients receiving the drug, but this is usually reversible.|For more Human Toxicity Excerpts (Complete) data for PENTAMIDINE (42 total), please visit the HSDB record page.

Diamidine

Pentam 300 (pentamidine isethionate for injection) 300 mg, lyophilized product in single-dose vials, packages of 10 (American Pharmaceutical Partners, Inc).|... Pentamidine isethionate is the preparation used clinically. It is marketed for injection (PENTAM 300) or for use as an aerosol (NEBUPENT). One milligram of pentamidine base is equivalent to 1.74 mg of the pentamidine isethionate ... /Pentamidine isethionate/

Analyte: pentamidine; matrix: ambient air, personal air, sediment; procedure: high-performance liquid chromatography|Analyte: pentamidine; matrix: air; procedure: high-performance liquid chromatography with fluorescence detection

Analyte: pentamidine; matrix: blood; procedure: ELISA-based immunoassay|Analyte: pentamidine; matrix: urine; procedure: liquid chromatography-tandem mass spectrometry|Analyte: pentamidine; matrix: serum, urine; procedure: micellar electrokinetic chromatography|Analyte: pentamidine; matrix: urine; procedure: high-performance liquid chromatography

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