Pentamidine Isethionate

Summary

Synopsis

Pentamidine isethionate,¹ an aromatic diamidine, is an antiprotozoal agent proven to decrease mortality from Pneumocystis carinii pneumonia in debilitated infants and immunodeficient adults and children. Like the combination antimicrobial agent co-trimoxazole, pentamidine has been shown in retrospective studies to resolve episodes of pneumonia in approximately 41 to 87% of patients, including those with the acquired immunodeficiency syndrome (AIDS), when used alone or as sequential therapy.

Although about 45% of all patients given pentamidine experience side effects — which may include nephrotoxicity, hypotension, hypoglycaemia or local reactions — in patients with AIDS the incidence of side effects is less with pentamidine than with co-trimoxazole. Thus, despite its profile of potentially severe side effects, pentamidine isethionate is a proven antimicrobial agent with a distinct place in the treatment of Pneumocystis carinii pneumonia in the growing population of AIDS patients.

Antiprotozoal Activity

Quantitative analyses of the activity of pentamidine against P. carinii are lacking. However, in concentrations of 0.3 to 9 mg/L pentamidine decreases the viability of the organism in vitro. Doses of 10 or 20 mg/kg subcutaneously or 4 mg/kg intramuscularly daily or thrice weekly for 2 weeks prolonged the survival of rats with experimentally induced P. carinii pneumonia. Pentamidine inhibits P. carinii by a ‘cidal’ mechanism, thought to involve inhibition of one or more of the following: oxidative phosphorylation, nucleic acid and protein synthesis, glucose metabolism, or dihydrofolate reductase activity.

In vitro toxicity studies reveal that nephrotoxicity seen with pentamidine may result from the formation of nucleotide precipitates or from nucleic acid binding with subsequent depletion of adenosine triphosphate. Similarly, a direct cytotoxic effect of pentamidine on pancreatic β-islet cells is thought to precipitate hypoglycaemia (by initial insulin release) which may be followed by hyperglycaemia (via cytolysis and insulin depletion).

Pharmacokinetic Properties

Following an intramuscular dose of pentamidine 4 mg/kg to patients with malignant diseases, peak plasma concentrations of about 0.5 mg/L are attained in 1 hour. These concentrations are sustained for 24 hours, and the drug has been detected in the plasma of patients 6 to 8 weeks after administration. This is likely a reflection of the extensive tissue binding that occurs with pentamidine.

Studies in animals reveal that pentamidine is found in the kidney in double the quantities seen in the liver and 5 to 10 times those seen in the lung. In humans, the volume of distribution of pentamidine is estimated to be 3 L/kg.

Studies both in animals and in humans show that pentamidine does not undergo hepatic biotransformation. Thus, elimination is achieved by renal routes. Slow release of the drug from tissue compartments is probably responsible for its prolonged rate of elimination; in the presence of renal disease this may be further increased and thus dosage adjustment may be necessary.

Therapeutic Trials

Very few prospective trials have investigated the use of pentamidine in the treatment of P. carinii pneumonia; rather, the literature consists mostly of retrospective analyses of case reports. Several retrospective studies in patients with AIDS or other immunodeficiencies have assessed the efficacy rate of pentamidine 4 mg/kg administered once daily intravenously or intramuscularly for at least 10 days as the initial and only antimicrobial therapy of P. carinii pneumonia, or as replacement therapy in patients unresponsive to or who experienced adverse effects with co-trimoxazole. The results of studies which evaluated more than 15 patients of this type indicate an efficacy rate for pentamidine which ranges from 41 to 87%. In comparison, the efficacy rate observed with co-trimoxazole (trimethoprim 20 mg/kg plus sulphamethoxazole 100 mg/kg daily in divided doses orally or intravenously) as initial and only antimicrobial therapy in the same studies was 41 to 78%.

Patients with AIDS who are switched to pentamidine therapy because of adverse reactions to co-trimoxazole respond much better than those who receive the drug because of treatment failure with co-trimoxazole. However, concomitant therapy with both pentamidine and co-trimoxazole has not improved survival rates further than those achieved with either antimicrobial drug alone. A longer duration of therapy with pentamidine may be required in patients with AIDS than in those without AIDS, and relapse is more common.

Higher efficacy rates for both pentamidine and co-trimoxazole have been achieved in the small number of prospective, randomised trials which compared responses to either drug in a few AIDS and non-AIDS patients, than in retrospective studies. This may be a result of such factors as better methodology or improved patient care in the prospective trials.

Side Effects

About 45% of all patients receiving pentamidine experience adverse reactions, which can be severe. Nephrotoxicity, hypotension and paradoxical hypoglycaemic-hyperglycaemic reactions are seen most frequently; leucopenia, abnormal liver function, hypocalcaemia and local irritation at the site of intramuscular injection can also occur.

Nevertheless, in patients with AIDS, pentamidine causes a lower incidence of adverse reactions than does co-trimoxazole (45% versus 65%, respectively).

Dosage and Administration

For adults and children, the dose of pentamidine given as the isethionate salt is 4 mg/kg once daily for at least 14 days, preferably by slow intravenous infusion over 60 minutes. If the drug is administered by deep intramuscular injection, splitting the dose may minimise the possibility of local reactions.

Patients should remain supine during administration of the drug, and careful clinical and laboratory monitoring of patient status during and after treatment is essential. In the presence of impaired renal function, pentamidine should be administered over a longer infusion time or on alternate days.