Sulfonamides and Sulfones

• Overview: sulfonamides and sulfones

  •  Blood schizonticidal activity against P. falciparum (some strains)

    • Mechanism: dihydrofolic acid synthesis inhibition

  •  Weak effects against blood schizonts of P vivax

  •  Inactive against immunocytes or liver stages of P falciparum or P vivax.

  •  Synergistic blockade of folic acid synthesis following combination of sulfones or sulfonamide with an antifols

    •  For management of chloroquine (Aralen)-resistant P falciparum

      • Pyrimethamine-sulfadoxine (Fansidar) or

      • Pyrimethamine (Daraprim)-dapsone

  •  Major disadvantage: sulfonamides and sulfones exhibit slow onset blood schizonticidal activity as well as significant adverse effects.

• Pyrimethamine-sulfadoxine (Fansidar)

  • Pharmacokinetics:

    •  Fansidar-well absorbed

    •  Renal route of excretion

  • Antimalarial Activity/Resistance:

    • Effective against falciparum malaria (some strains)

    • For serious cases, quinine (Quinamm) is given concurrently since Fansidar activity develops slowly

    • Ineffective:  against vivax malaria

• Quinine (Quinamm) and Quinidine

  • Overview:  quinine (Quinamm)

    •  Quinine (Quinamm)-alkaloid from the bark of the cinchona tree

    •  Quinine (Quinamm) is now unimportant antimalarial is a result of resistance development to other antimalarials

  • Pharmacokinetics:quinine (Quinamm)

    •  Rapid absorption; wide tissue distribution

    •  Elimination halftime: normal individuals -- 7-12 hours; 8-21 hours in malaria infected patients

    •  Hepatic metabolism (80%)

    •  Urine excretion

    •  Effective concentration range:

      • ineffective < 2 μg/mL

      • > 7 μg/mL-associated with "cinchonism"

      •  Narrow therapeutic range: frequent side effects associate with falciparum malaria management with quinine (Quinamm)

  • Antimalarial activity:quinine (Quinamm)

    • Rapid onset; highly effective blood schizonticide against the four malarial parasites: P vivax, P ovale, P falciparum, P. malariae.

    • Gametocidal for P vivax and P ovale; not very effective as a gametocidal agent for P falciparum gametocytes

    •  No effect on sporozoites or liver stages of any parasite.

  • Pharmacological effects: quinine (Quinamm)

    •  Oral use: gastric irritation

    •  Myocardial effects similar to quinidine, but quinine's effect less intense

    •  Skeletal muscle: curare-like effect; lengthened skeletal muscle membrane refractory.

      • May be used to reduce contracture of myotonia congenita.

    •  Slight oxytocic effect (especially third trimester time frame)

    •  With therapeutic doses: occasional hypoglycemia {secondary to pancreatic B-cell insulin release}-especially prominent in patients who are pregnant or with severe infections.

  • Resistance: quinine (Quinamm)

    • Resistance for monotherapy increasing; therapeutic failure due to resistance of quinine (Quinamm) + second-drug has not been confirmed.

  • Clinical Uses: quinine (Quinamm)

    • Parenteral treatment: severe falciparum malaria

      •  Slow, intravenous administration of quinine dihydrochloride (not available in the United States)-quinidine gluconate (Quinaglute, Quinalan) is used instead

      •  Alternative: dilute intramuscular injection acceptable

    • Oral treatment of falciparum malaria (chloroquine (Aralen)-resistant)

      •  Management (with other drugs) for acute P falciparum-chloroquine (Aralen) resistant malarial attacks

      •  Quinine (Quinamm) alone will not eliminate the infection {will reduce parasitemia, however}

      •  Quinine (Quinamm)-less effective than chloroquine (Aralen); quinine (Quinamm) not used to manage acute attacks of P ovale, P vivax, P. malariae or chloroquine (Aralen)-sensitive P falciparum malaria

    • Prophylaxis: quinine (Quinamm) generally not used

      •  Exceptions:

        •  P falciparum chloroquine (Aralen) resistance and:

          •  Mefloquine (Lariam)-unavailable

          •  Doxycycline (Vibramycin, Doryx)-unavailable

    • Other Uses:(quinine (Quinamm)

      •  Nighttime leg cramps

      •  Quinine (Quinamm) + clindamycin (Cleocin): for management in cases of severe  babesiosis (Babesia microti)

        • The Medical Letter recommends clindamycin (Cleocin) plus quinine as the drug regimen of choice.  It also notes that exchange transfusion has been used in severely ill patients with high parasitemias, and that combinations including other drugs (such as atovaquone (Mepron), azithromycin (Zythromax), pentamidine (Pentam), and trimethoprim-sulfamethoxazole (Bactrim)) may also be effective.-CDC reference http://www.dpd.cdc.gov/DPDx/HTML/Babesiosis.htm

    •  Adverse Effects--quinine (Quinamm)

      •  Gastrointestinal Effects:

        •  Nausea, epigastric pain, vomiting

      •  Cinchonism:

        •  Occurs if plasma levels > 7-10 μg/mL

        •  Symptoms:-if symptoms do not abate, discontinue quinine (Quinamm) and obtain blood level.

          • Slight visual disturbances

          • Mild tinnitus

          • Dizziness

          • Headache

          • Nausea

      •  Hematologic effects:

        •  Rare: (0.05%): hemolysis; they also occur in patients with glucose-6-phosphate dehydrogenase deficiency

        •  Rare: leukopenia, thrombocytopenic purpura, hypoprothrombinemia, agranulocytosis, Schonlein-Henoch purpura

      •  Hypoglycemia:

        •  May occur therapeutic doses; glucose administration may result and further insulin release and hypoglycemia exacerbation.

      •  Other Toxicities:

        •  IV quinine (Quinamm)-rare thrombophlebitis

        •  Rapid IV infusion: hypotension, seizures, ventricular fibrillation, death

        •  Congenital malformation if large-doesquinine (Quinamm) given in failed abortion

        •  Severe toxicity: rare {may include -- fever, deafness, visual abnormalities, CNS effects including syncope and confusion, quinidine-like effects}

• Quinidine gluconate (Quinaglute, Quinalan)

  • Summary

    • Dextrorotatory diasteriomer of quinine (Quinamm)

    • Quinidine gluconate (Quinaglute, Quinalan)-typically used for management of cardiac arrhythmias

      • Also used for parenteral treatment of severe malaria, when parenteral quinine (Quinamm) form is unavailable {note: in the United States, parenteral form of quinine (Quinamm), quinine (Quinamm) hydrochloride is unavailable}

    •  IV quinidine gluconate: adverse effects, cautions, contraindications

      • Rare: thrombophlebitis

      • Potentially cardiotoxic-consider risk vs. benefit ratio if administration to a patient with cardiac conduction hepatic or renal abnormalities

      • Generally contraindications/caution or quinidine gluconate (Quinaglute, Quinalan) similar to that for quinine (Quinamm)

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

Primary Reference: McLellan, S.L.F and Kozarsky, P.E., Malaria and Babesiosis in Medicine for the Practicing Physician (Hurst, J. W., ed) Appleton-Lange, 1996, pp. 465-469