Pharmacology and mechanism of action
Pentamidine is a synthetic aromatic diamidine chemically related to the antidiabetic drug phenformin and was introduced into the treatment of trypanosomiasis and leishmaniasis in 1940. Pentamidine has also an established place in the treatment of Pneumocystis carinii pneumonia
[1].
The mechanism of action of pentamidine is not known. The drug concentrates in trypanosomes via an energy-dependent, high affinity uptake system, which operates more rapidly in drug sensitive strains. Inside the cell, pentamidine interacts with nucleic acids thus affecting DNA biosynthesis
[2]. It has also been shown that the drug inhibits the plasmamembrane Ca++-ATPase of the parasites
[3]. In vitro, the drug causes ultra-structural disruptions of the mitochondrial structures of Leishmania mexicana and tropica
[2, 4]. The drug has also been shown to inhibit trypanosomal S-adenosyl-L-methionine decarboxylase, thus reducing the synthesis of polyamines
[5].
Indications
Trypanosomiasis
In the treatment of early-stage Trypanosoma brucei gambiense.
Leishmaniasis
In the treatment of patients with visceral, diffuse cutaneous, or mucocutaneous leishmaniasis due to L. aethiopica and L. guyanensis who are unresponsive or intolerant to antimony preparations.
Pneumocystis carinii pneumonia
Pentamidine is also used in the prophylaxis and treatment of Pneumocystis carinii pneumonia as a second choice.
Side effects
Following parenteral administration of pentamidine, about 45% of the patients may experience side effects some of which can be fatal . Rapid i.v. injection may cause sudden hypotension followed by breathlessness, tachycardia, dizziness, headache, vomiting and fainting which are due to histamine release. Local pain and sterile abscess may be formed after intramuscular injection
[6]. Nephrotoxicity which is usually mild to moderate and reversible is the most common side effect. Hypoglycaemic reactions are also common. A few patients may develop hyperglycaemia and diabetes mellitus. This paradoxical effect is thought to be due to a cytolytic release of insulin followed by destruction of the beta-cells. Leucopenia, abnormal liver function, hypocalcaemia and Stevens-Johnson syndrome can also occur . There have been occasional reports of acute pancreatitis
[7].
In two smaller studies conducted in Côte d’Ivoire, the most common subjective side effect reported was abdominal pain. A few patients complained of hypersalivation
[8]. Pentamidine has been reported to possess anticholinesterase activity
[9] and the abdominal pain and the hypersalivation reported in the former study may be due to this effect.
Contraindications and precautions
Patients should remain supine during pentamidine administration and their blood pressure and blood glucose levels monitored. It is advisable to have adrenaline ready in case of a sudden collapse. Where possible, kidney and liver function tests should be assessed regularly during the treatment.
Pentamidine is not recommended for use in patients with late-stage trypanosomiasis.
Interactions
There have been no reports.
Preparations
Available as pentamidine isethionate (174 mg isethionate is equivalent to 100 mg base).
• Pentacarinat® (Rhône-Poulenc Rorer). Vials containing 300 mg pentamidine isethionate powder which is dissolved with 2–3 ml of sterile water.
• Pentam-300® (LyphoMed, USA). Vials containing 300 mg pentamidine isethionate
powder which is dissolved with 2–3 ml of sterile water.
References
1. Goa KL, Campoli-Richards D (1987). Pentamidine Isethionate. A review of its antiprotozoal activity, pharmacokinetic properties and therapeutic use in Pneumocystis carinii pneumonia. Drugs, 33, 242–258.
2. Sands M, Kron MA, Brown RB (1985). Pentamidine: A review. Rev Infect Dis, 7, 625–634.
3. Benaim G, Lopez-Estrano C, Docampo R, Moreno SNJ (1993). A calmodulin-stimulated Ca2+ pump in plasma-membrane vesicles from Trypanosoma brucei; selective inhibition by pentamidine. Biochem J, 296, 756–763.
4. Steck EA, Kinnamon KE, Rane DS, Hanson WL (1981). Leishmania donovani, Plasmodium berghei, Trypanosoma rhodesiense: antiprotozoal effects of some amidine types. Exp Parasitol, 52, 404–413.
5. Bitonti AJ, Dumont JA, McCann PP (1986). Characterisation of Trypanosoma brucei brucei SadenosylL-methionine decarboxylase and its inhibition by Berenil, pentamidine and methylglyoxal bis(quanylhydrazone). Biochem J, 237, 518–521.
6. Navin TR, Fontaine RE (1984). Intravenous versus intramuscular administration of pentamidine. N Engl J Med, 311, 1701–1702.
7. Murphey SA, Josephs AS (1981). Acute pancreatitis associated with pentamidine therapy. Arch Intern Med, 141, 56–58.
8. Bronner U, Gustafsson LL, Doua F, Ericsson Ö, Miézan T, Rais M, Rombo L (1995). Pharmacokinetics and adverse reactions of a single dose of pentamidine in patients with
9. Alston TA (1988). Inhibition of cholinesterase by pentamidine. Lancet, ii, 1423.
Description
Pentamidine is an aromatic diamine that is effective against protozoal diseases, such as amoebic dysentery, malaria, trypanosomiasis, and leishmaniasis. In clinical studies, it has also been shown to be an effective prophylaxis against pneumocystis pneumonia.
Chemical Properties
Crystalline Solid
Originator
Nebupent,Fujisawa Healthcare Inc ,USA
Uses
Has been widely used as a drug to treat protozoal diseases, such as malaria, amoebic dysentery and trypanosomiasis. It has also been shown to be effective for both prophylaxis of pneumocystic carinii pneumonia (PCC).
Uses
antiprotozoal, inhibits nucleic acid & protein synthesis
Indications
Pentamidine (Pentam 300) binds to DNA and may inhibit
kinetoplast DNA replication and function. It also
may act by inhibiting dihydrofolate reductase and interfering
with polyamine metabolism. An effect on organism
respiration, especially at high doses, also may play a
role.
Definition
ChEBI: Pentamidine is a diether consisting of pentane-1,5-diol in which both hydroxyl hydrogens have been replaced by 4-amidinophenyl groups. A trypanocidal drug that is used for treatment of cutaneous leishmaniasis and Chagas disease. It has a role as a trypanocidal drug, an antifungal agent, a NMDA receptor antagonist, an anti-inflammatory agent, a chemokine receptor 5 antagonist, an EC 2.3.1.48 (histone acetyltransferase) inhibitor, a calmodulin antagonist, a S100 calcium-binding protein B inhibitor and a xenobiotic. It is a carboxamidine, a diether and an aromatic ether. It is a conjugate base of a pentamidinium(2+).
Manufacturing Process
2.5 g of p,p'-dicyano-1,5-diphenoxy-pentane (obtained by the interaction of phydroxybenzonitrile and pentamethylene-dibromide in aqueous alkaline solution, melting point 114°C) are dissolved in 15 cc of nitrobenzene and 2.5 cc of absolute ethyl alcohol added. The solution is saturated with dry hydrochloric acid gas at 0°C and allowed to stand for 48 h. It is then diluted with dry ether and the precipitated 1,5-diphenoxypentane, 4,4'di(ethoxycarbonimidoyl) dihydrochlorid is filtered and washed with ether.
4 g of 1,5-diphenoxypentane, 4,4'-di(ethoxycarbonimidoyl) dihydrochloride are mixed with 30 cc. of 6 % ethyl alcoholic ammonia and heated in a closed vessel at 50°C for 5 h. The alcohol is removed and the residual 1,5diphenoxypentane, 4,4'-diamidino dihydrochloride is twice recrystallised fromdilute hydrochloric acid and finally purifled by dissolving in water and precipitating with acetone. Its melts at 236°C, dec.
Pentamidine isetionate salt may be produced by the reaction pentamidine base with isethionic acid.
brand name
Nebupent [as isethionate]
(Fujisawa); Pentacarinat [as isethionate] (Rhone-Poulenc
Rorer); Pentam 300 [as isethionate] (Fujisawa).
Therapeutic Function
Antiprotozoal
Antimicrobial activity
Pentamidine has broad activity in experimental models against
P. falciparum, Toxoplasma gondii, Leishmania spp., Trypanosoma
spp. and Babesia spp. It also has activity against Pn. jirovecii.
Acquired resistance
Relapse rates of 7–16% have been reported in the treatment
of human African trypanosomiasis in West Africa. Patients
usually respond to a subsequent course of treatment with
melarsoprol. A membrane transporter is involved in crossresistance
of arsenic-resistant T. brucei to diamidines, affecting
diminazene and stilbamidine more than pentamidine.
Pharmaceutical Applications
A synthetic diamidine, available as the isethionate
(2-hydroxymethane sulfonate) salt for parenteral use. It is also
administered by instillation of a nebulized solution directly
into the lungs.
Mechanism of action
Pentamidine is not well absorbed from the intestinal
tract after oral administration and generally is given by
intramuscular injection. The drug binds to tissues, particularly
the kidney, and is slowly excreted, mostly as the
unmodified drug. It does not enter the central nervous
system (CNS). Its sequestration in tissues accounts for
its prophylactic use in trypanosomiasis.
Pharmacokinetics
Oral absorption: Negligible
C
max 4 mg/kg intramuscular: c. 0.5 mg/L after 1 h
Plasma half-life: c. 6.5 h
Volume of distribution: 3 L/kg
Plasma protein binding: c. 70%
Pentamidine is rapidly and extensively metabolized by rat liver,
and high concentrations are retained in renal and hepatic tissue
for up to 6 months after administration. In humans distribution
is mainly in the liver, kidney, adrenal glands and spleen,
with lower accumulation in the lung. This tissue retention is
the basis for its prophylactic use. Although transport across
the blood–brain barrier has been demonstrated in experimental
models, it is probably unable to cross the blood–brain
barrier in sufficient quantity to be trypanocidal: <1% of the
plasma concentration has been measured in the CSF of sleeping
sickness patients. About 15–20% of the dose is excreted
in the urine but because of retention in tissues there is an
extremely long terminal half-life (>12 days).
Clinical Use
Pentamidine is active against Pneumocystis carinii,
trypanosomes, and leishmaniasis unresponsive to pentavalent
antimonials. It is an alternative agent for the
treatment of P. carinii pneumonia. Although it is more
toxic than trimethoprim–sulfamethoxazole, it has been
widely used in patients with acquired immunodeficiency
syndrome (AIDS), in whom P. carinii infection is
common.
Pentamidine is an alternative drug for visceral leishmaniasis,
especially when sodium stibogluconate has
failed or is contraindicated. Pentamidine is also a reserve
agent for the treatment of trypanosomiasis before
the CNS is invaded. This characteristic largely restricts
its use to Gambian trypanosomiasis.
Clinical Use
Human African trypanosomiasis (early stages before CNS involvement)
Prophylaxis and therapy of Pn. jirovecii pneumonia
Visceral leishmaniasis unresponsive to pentavalent antimonials and
cutaneous leishmaniasis caused by L. guyanensis
There is limited evidence for its use in the treatment of
babesiosis.
Side effects
Side effects range from local irritation and sterile abscess at
the site of injection to transient effects (vomiting, abdominal
discomfort) and serious systemic effects (hypotension, effects
on the heart, hypoglycemia and hyperglycemia, leukopenia,
thrombocytopenia). In a study of the treatment of South
American cutaneous leishmaniasis, 17% of patients prematurely
terminated treatment due to toxicity and another 30%
reported side effects.
Side effects
Adverse reactions occur frequently. Rapid drug infusion
may produce tachycardia, vomiting, shortness of
breath, headache, and a fall in blood pressure. Changes
in blood sugar (hypoglycemia or hyperglycemia) necessitate
caution in its use, particularly in patients with diabetes
mellitus. Renal function should be monitored
and blood counts checked for dyscrasias.
Synthesis
Pentamidine, 4-4??-(pentamethylendioxy)dibenzamidine (37.4.2), is made by
reacting 4-hydroxybenzonitrile with 1,5-dibromopentane in the presence of sodium hydroxide to make 1,5-bis-(4-cyanophenoxy)pentane (37.4.1). Subsequent reaction of this with an
ethanol solution of hydrogen chloride with the intermediate formation of an iminoester, and
then with an ethanol solution of ammonia gives the desired pentamidine.
