Pentamidine adverse effects

Amphotericin B Azoles Nephrotoxins (e.g, aminoglycosides, cidofovir, cyclosporine, foscarnet, pentamidine) See Chap. 125 in Pharmacotherapy A Pathophysiologic Approach, seventh edition, page 1998. Additive adverse effects Monitor renal function... 

It is used in the treatment of pneumocystosis (pulmonary and extrapulmonary disease caused by P. carinii), African trypanosomiasis (disease caused by Trypanosoma brucei) and leishmaniasis. Systemic pentamidine is highly toxic and can lead to severe hypotension, tachycardia, dyspnea, dizziness, hypoglycemia. Other adverse effects are skin rash, metallic taste, gastrointestinal symptoms, thrombocytopenia and cardiac arrhythmias. 

Pentamidine is a highly toxic drug, with adverse effects noted in about 50% of patients receiving 4 mg/kg/d. Rapid intravenous administration can lead to severe hypotension, tachycardia, dizziness, and dyspnea, so the drug should be administered slowly (over 2 hours), and patients should be recumbent and monitored closely during treatment. With intramuscular administration, pain at the injection site is common, and sterile abscesses may develop. 

Suramin is administered after a 200-mg intravenous test dose. Regimens that have been used include 1 g on days 1, 3, 7, 14, and 21 or 1 g each week for 5 weeks. Combination therapy with pentamidine may improve efficacy. Suramin can also be used for chemoprophylaxis against African trypanosomiasis. Adverse effects are common. Immediate reactions can include fatigue, nausea, vomiting, and, more rarely, seizures, shock, and death. Later reactions include fever, rash, headache, paresthesias, neuropathies, renal abnormalities including proteinuria, chronic diarrhea, hemolytic anemia, and agranulocytosis. 

Adverse Effects. The primary adverse effect of systemic pentamidine administration is renal toxicity. Renal function may be markedly impaired in some patients, but kidney function usually returns to normal when the drug is withdrawn. Other adverse effects include hypotension, hypoglycemia, gastrointestinal distress, blood dyscrasias (leukopenia, thrombocytopenia), and local pain and tenderness at the site of injection. Adverse effects are reduced substantially when the drug is given by inhalation, and this method of administration is desirable when pentamidine is used to prevent pneumocystis pneumonia in patients with human immunodeficiency virus (HIV) disease. 

The primary adverse effect of intravenous cidofovir is a dose-dependent nephrotoxicity. Concurrent administration of other potentially nephrotoxic agents (eg, amphotericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs, pentamidine, foscarnet) should be avoided. Prior administration of foscarnet may increase the risk of nephrotoxicity. Other potential side effects include uveitis, decreased intraocular pressure, and probenecid-related hypersensitivity reactions. Neutropenia and metabolic acidosis are rare. The drug caused mammary adenocarcinomas in rats and is embryotoxic. 

Pancreatic toxicity is common. Hypoglycemia due to inappropriate insulin release often appears 5-7 days after onset of treatment, can persist for days to several weeks, and may be followed by hyperglycemia. Reversible renal insufficiency is also common. Other adverse effects include rash, metallic taste, fever, gastrointestinal symptoms, abnormal liver function tests, acute pancreatitis, hypocalcemia, thrombocytopenia, hallucinations, and cardiac arrhythmias. Inhaled pentamidine is generally well-tolerated but may cause cough, dyspnea, and bronchospasm. 

PENTAMIDINE ISETIONATE NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS t adverse effects with didanosine, tenofbvir and zidovudine Additive toxicity Monitor FBC and renal function closely. Consider stopping didanosine while pentamidine is required for Pneumocystis jiroveci pneumonia... 

When atovaquone was compared with intravenous pentamidine in the treatment of mild and moderate Pneumocystis jiroveci pneumonia in an open trial, the success rates were similar. However, withdrawal of the original treatment was much more frequent with pentamidine (36%) than atovaquone (4%) (4). However, the authors conclusion that the two approaches have a similar success rate has been challenged, and their series was small (5,6). Treatment-limited adverse effects occurred in only 7% of patients given atovaquone, compared with 41 % given pentamidine. They included cases of rash and an increase in creatinine concentrations atovaquone (unlike pentamidine) produced no vomiting, nausea, hypotension, leukopenia, acute renal insufficiency, or electrocardiographic abnormalities, but it did cause one case of dementia (4). 

Pentamidine is the drug of choice for the treatment of cutaneous leishmaniasis in Surinam. Pentamidine mesylate in 235 patients and pentamidine isethionate in 80 patients have been compared in a retrospective study the cure rate (healing without relapse) was nearly 90% in both groups (2). Relapses occurred in about 10% of patients in both groups. Minor adverse effects, such as pain at the injection site, bitter taste, and nausea, occurred with both drugs in about 65% of patients. Respiratory tract problems occurred in under 10% of patients who took pentamidine isethionate but were uncommon in those who took pentamidine mesylate. 

Mild dizziness can occur with pentamidine, but nervous system adverse effects are uncommon. 

Table 1. Clinical studies reporting on adverse effects of pentamidine in patients with AIDS (1984-1997).

Pentamidine can cause bronchospasm and airway irritation in humans [9]. This appears to be caused by the pentamidine moiety itself, because similar irritation is seen in nonisethionate salts of pentamidine. Because P. carinii habitats the alveolus and because of the potential adverse effects of pentamidine on the airways, pentamidine ideally should be aerosolized in a small particle, between 1 and 2 pm. Studies that make in vitro comparisons of nebulizers cannot be valid unless the particle sizes are identical. The present state of knowledge cannot allow determination of the most effective device because not all the devices have been comparatively tested in humans [10,11]. The optimal particle size for alveolar deposition is between 1 and 3 pm, with 1 pm achieving more peripheral distribution and less airway distribution [12-14]. However, 19% of particles as small as 2 pm still impact in the tracheobronchial regions. The ideal device should have a particle size of 1 -2 pm with a high output. Particles between 0.5 and 1 pm have relatively less alveolar deposition than particles between 1 and 2 pm. Other features, such as reservoirs, flows, and external filters, may also be important [9]. However, any nebulizer with particle sizes, on average, greater than 8 pm would not deliver adequate dmg to the alveoli. 

Prior to the AIDS epidemic, the incidence of acute renal failure associated with intravenous pentamidine administration for the treatment of PCP was between 19 to 23% [123,125]. During the 1980 s the number of reported cases increased (Table 1). The average incidence of nephrotoxicity, the most frequent systemic adverse effect, was 41%, ranging from 20 to 94% as... 

Zidovudine is rapidly absorbed from the G1 tract with peak serum concentrations occurring within 30 to 90 minutes. It binds to plasma proteins to the extent of 35 to 40%. Zidovudine is rapidly metabolized in the liver to the inactive 3 -azido-3 -deoxy-5 -0-beta-D-glucopyranuronosylthymi-dine (GAZT), which has an apparent elimination half-life of 1 hour. Zidovudine undergoes glomerular filtration and active tubular secretion. Coadministration of zidovudine with agents such as dapsone, pentamidine, amphotericin B, flucytosine, vincristine, vinblastine, adriamycin, and interferon with potential to cause nephrotoxicity or cytotoxicity to hematopoietic elements, enhance its risk of adverse effects. Probenecid will inhibit the renal excretion of zidovudine. 

TOXICITY AND SIDE EFFECTS Approximately 50% of individuals given pentamidine at recommended doses will show some adverse effect. Intravenous administration may be associated with hypotension, tachycardia, and headache, probably secondary to the abihty of pentamidine to bind imidazoline receptors, which can be ameliorated by slowing the infusion rate. Hypoglycemia, which can be life threatening, may occur at any time during pentamidine treatment. Careful monitoring... 

Toxicity Severe adverse effects follow parenteral use including respiratory stimulation followed by depression, hypotension due to peripheral vasodilation, hypoglycemia, anemia, neutropenia, hepatitis, and pancreatitis. Systemic toxicity is minimal when pentamidine is used by inhalation. 

Clinical use and toxicity Atovaquone is approved for use in mild to moderate pneumo-cystis pneumonia. It is less effective than TMP-SMZ or pentamidine, but is better tolerated. Adverse effects include rash, cough, nausea, vomiting, diarrhea, fever, and abnormal Uver function tests. 

In an uncontrolled study in French Guiana, intramuscular pentamidine isethionate (two 4 mg/kg injections 48 hours apart) in 198 patients with cutaneous leishmaniasis produced a cure rate of 87% 80% of treatment failures responded to an identical second course (1). Compared with published studies, adverse events were relatively mild pain on injection (54%), gastrointestinal effects (53%), and hypotension (8%). There were no dysrhythmias or glucose abnormalities. This may reflect the brief course of pentamidine used. 

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