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Nursing Pharmacology:  Antiparasitic Agents


  • Pyrimethamine-proguanil (Chloroguanide)

    • Overview:  pyrimethamine-proguanil (Chloroguanide)

      •  Pyrimethamine (Daraprim) & proguanil (Paludrine): dihydrofolate reductase inhibitors {folic acid antagonists: antifols}

      •  Pyrimethamine (Daraprim): related to trimethoprim (generic)

      •  Proguanil (Paludrine) -- biguanide primitive

    • Pharmacokinetics: pyrimethamine-proguanil (Chloroguanide)

      •  Slow, but complete absorption from the gastrointestinal tract

      •  Differences in elimination kinetics require that proguanil (Paludrine) be administered daily, although pyrimethamine (Daraprim) can be given once per week

      •  Pyrimethamine (Daraprim): extensively metabolize prior to excretion

      •  Proguanil (Paludrine): prodrug-triazine metabolite cycloguanil is the active form

    • Antimalarial-Characteristics:  pyrimethamine-proguanil (Chloroguanide)

      • Antimalarial activity:

        •  Slow-acting blood schizonticides

        •  Active against all four malarial species affecting humans (assuming susceptible strains)

        •  Proguanil (Paludrine): significant effect on primary tissue stage of P falciparum {possible prophylactic action; possibly effective even when blood schizonts are resistant}

        •  Neither proguanil (Paludrine) or pyrimethamine (Daraprim) are sufficiently gametocidal or effective against liver stages of P vivax or P ovale

        •  Pyrimethamine (Daraprim) & cycloguanil {active form of proguanil (Paludrine)} and are more effective inhibitors of plasmodial dihydrofolate reductase-compared to the human form.

      • Resistance:pyrimethamine-proguanil (Chloroguanide)

        •  Widespread pyrimethamine (Daraprim) & proguanil (Paludrine) resistance for P falciparum {less common resistance for P vivax}

          •  Prophylaxis against P falciparum is not recommended using these drugs alone.

      • Clinical Uses: (Chloroguanide), pyrimethamine (Daraprim)

        • Chemoprophylaxis:

          •  The combination pyrimethamine-proguanil (Chloroguanide) is used as an alternative to mefloquine (Lariam) in areas of the world without widespread chloroquine (Aralen) resistance

            • Note: proguanil (Paludrine) is not available in United States

        • Treatment of Chloroquine (Aralen)-resistant falciparum malaria

          •  Pyrimethamine-sulfadoxine (Fansidar)

        • Toxoplasmosis Treatment:pyrimethamine (Daraprim)

          • "Toxoplasma gondii is a protozoan parasite that infects most species of warm blooded animals, including humans, causing the disease toxoplasmosis."-CDC

          •  Treatment of choice: pyrimethamine (Daraprim) + either trisulfapyrimidines or sulfadiazine

            • Leucovorin calcium (folinic acid) is used avoid hematological consequences of pyrimethamine (Daraprim)-caused folate deficiency.

          •  For management of toxoplasmal encephalitis (associated with AIDS): higher doses are required

          •  With ocular Toxoplasmosis, systemic corticosteroids are administered to reduce increased intracranial pressure.

      • Adverse Effects:  pyrimethamine-proguanil (Chloroguanide)

        • For malarial treatment: pyrimethamine (Daraprim) & proguanil (Paludrine) are generally well tolerated

          •  Rare: skin rashes, itching, gastrointestinal disturbances

          •  Rare: mouth ulcers & alopecia (proguanil)

        • For management of Toxoplasmosis, higher dosages are required:

          •  Side effects related to folic acid deficiency-common (unless leucovorin calcium is concurrently used), including:

            •  Megaloblastic anemia

            •  Agranulocytosis

            •  Thrombocytopenia

            •  Atrophic glossitis

          •  Gastrointestinal irritation

          •  Neurological symptoms:

            •  Headache

            • Tremors

            •  Respiratory depression

            •  Seizures

            •  Ataxia

      •  Contraindications/Cautions:pyrimethamine (Daraprim)

        • cautious use in the presence of renal/hepatic dysfunction

        • pyrimethamine (Daraprim) avoidance during first trimester pregnancy-consider risk vs. benefit

        • When high doses are required for Toxoplasmosis treatment:

          • white blood cell/platelet counts-2 Times/week

          • Discontinuation if:

            • sore throat

            • purpura

            • glossitis

            • rash

        • Proguanil (Paludrine)-considered safe and pregnancy; leucovorin should be administered.

Primary Reference: Goldsmith, R. S., Antiprotozoal Drugs in Basic and Clinical Pharmacology (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 838-861.

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