Pentamidine

Pharmacokinetics

The pharmacokinetics of pentamidine are incompletely known. It is not absorbed after oral administration and needs to be given parenterally or by aerosol. After intramuscular injection peak concentrations are seen after about 1 hour, and the serum concentration stays about the same for 24 hours. A study of multiple dosing over 2 weeks showed progressive accumulation in the plasma during that time. After multiple intravenous doses the half-life was 12.5 days. After a course of treatment decreasing amounts of pentamidine can be found in the urine for as long as 8 weeks. It seems that pentamidine is stored or bound in the tissues and excreted slowly in the urine and the amount excreted changes only marginally with repeated doses. The highest tissue concentrations have been found in the kidney, followed by the liver and then other tissues, but pentamidine was not found in the brain. Serum concentrations after aerosol therapy are markedly lower than after intravenous therapy. Uptake via the lungs is limited, which explains the lack of serious systemic toxicity seen with aerosol treatment, but also explains the reported occurrence of extrapulmonary Pneumocystis infections.

These pharmacokinetic data merit attention, because they may be helpful in preventing toxicity, which seems to be dictated by tissue accumulation rather than serum concentrations; major toxic reactions usually occur only after the first week of parenteral treatment. The pharmacokinetics may also explain the varied response to treatment with aerosolized pentamidine and the more satisfactory results of prophylaxis with the aerosol after initial parenteral treatment [ ]. A retrospective study showed efficacy of intravenous pentamidine in AIDS patients with P. jirovecii pneumonia, the most frequent toxic effects being gastrointestinal, especially nausea [ ].

General adverse effects and adverse reactions

Pentamidine in therapeutic doses has a high rate of adverse reactions (over 50%). Toxicity seems to occur more often in patients with AIDS. Hypotension subsequent to injection or infusion, hypoglycemia, and nephrotoxicity are the major adverse effects. Hepatotoxicity and neutropenia are not uncommon. Compared with the general population there is a high incidence of pancreatitis in patients with AIDS, particularly during aerosol treatment. Hypoglycemia has also been seen after aerosol treatment. Intermittent prophylactic aerosol use causes few adverse effects, apart from cough and bronchial irritation after inhalation. There is a higher incidence of spontaneous pneumothorax with aerosol prophylaxis. There is also a higher incidence of extrapulmonary infections with P . jirovecii in patients treated with aerosolized pentamidine. Another disturbing finding was the higher incidence of other opportunistic infections with pentamidine aerosol versus placebo, while pentamidine aerosol was associated with a markedly lower recurrence rate of P . jirovecii pneumonitis in a placebo-controlled pentamidine aerosol study of prophylaxis after initial treatment [ ]. Intramuscular administration of pentamidine brings its own adverse effects: localized pain, erythema, and sterile abscesses are frequent and troublesome [ ]. The use of the Z-track technique for injection mitigates the local effects. Allergic reactions have been reported. There is no information about tumor-inducing effects.

Observational studies

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 [ ]. 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.

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 [ ]. 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.

Cardiovascular

Severe hypotension can occur after a single intramuscular injection of pentamidine or with rapid intravenous administration, but has been seen with slow infusion as well. Infusing the drug over 60 minutes or more may reduce this risk. Facial flushing, breathlessness, dizziness, and nausea and vomiting can occur at the same time.

Cardiac dysrhythmias, including ventricular tachycardia, have been reported during treatment [ , ]. Prolongation of the QT interval, which usually precedes the development of ventricular dysrhythmias with pentamidine, occurs in one-third of patients, usually within 2 weeks of starting therapy. Torsade de pointes has been described [ ]. Any dysrhythmia can recur many days after the pentamidine has been discontinued, which is not surprising, in view of the long half-life and tissue accumulation. Electrolyte abnormalities, including low serum magnesium concentrations, have been noticed at times of dysrhythmias [ , , ].

Local thrombophlebitis can occur after injection of pentamidine, but problems are more often seen at the injection site after intramuscular injection.

Respiratory

Inhalation of pentamidine can cause intolerable coughing. Bronchospasm can occur, especially in cases of asthma; tolerance of inhaled pentamidine is increased in nearly all patients by pretreatment with inhaled β ₂ -adrenoceptor agonists [ ].

In lung function tests, high-dose aerosolized pentamidine (600 mg/month) was associated with an increased pulmonary residual volume, reduced flow rates, and increased airway reactivity [ ].

There is an increased incidence of spontaneous pneumothorax after the administration of pentamidine by aerosol, which may be connected with the effect on airway resistance. In one study there was a particularly high frequency of spontaneous pneumothorax in people with hemophilia; the authors suggested that P . jirovecii infection and treatment resistance had played a role [ ]. Fatal cases have been reported [ ].

Acute eosinophilic pneumonia after one dose of inhaled pentamidine of 300 mg has been reported; the reaction subsided within 2 weeks but recurred on rechallenge [ ].

Dissemination of lung infection is a potentially serious matter, especially when using pentamidine by the aerosol route. While high alveolar drug concentrations can be reached in the most accessible parts of the lung, systemic absorption is minimal and the organism can spread through the lung and beyond, despite containment of the initial pulmonary infection; in some cases there has been extensive spread of P . jirovecii into major organs and the bone marrow [ ]. Patients who have been treated with parenteral pentamidine are at a lower risk of disseminated P . jirovecii infection than those given aerosol prophylaxis only [ , ].