• Chloroquine (Aralen)

  • Overview/pharmacokinetics:

    •  4-aminoquinoline derivative

    •  Phosphate salt-oral use; hydrochloride-parenteral use

    •  Rapid, complete GI absorption; very large apparent volume of distribution (13,000 L = significant tissue binding)

    •  Crosses the placenta

    •  Renal excretion (half-life 3-5 days; real excretion enhanced by urinary acidification

  • Dosing considerations:

    •  Large volume of distribution requires a loading dose if schizonticidal chloroquine plasma levels are rapidly needed for management of acute attack

    •  Parenteral administration should proceed by slow infusion or by a series of small intramuscular doses to avoid life-threatening chloroquine toxicity

  • Antimalarial activity:

    • Highly effective; most widely used 4-aminoquinoline for chemoprophylaxis

    • Used to treat attacks of P vivax, P ovale, P. malariae, and sensitive strains of P falciparum malaria

    • Somewhat effective against gametocytes of P vivax, P ovale and P. malariae but not against those of P falciparum

    • Not active against preerythrocytic plasmodium

    • Does not provide radical cures of P vivax or P ovale {does not eliminate persistent liver parasitic stages}

  • Selective toxicity:Adverse Effects

    • Generally well tolerated during chronic administration (prophylaxis/treatment);

    • Uncommon Side-effects include:

      •  Gastrointestinal symptoms, headache, pruritus (particularly in black individuals), anorexia, blurred vision,

    • Possible long-term effects (> 100 g accumulated)

      •  Opthalmological/neuromuscular effects

      •  Recommendations: periodic evaluations relative to baseline levels

      •  Retinal/visual fields changes or muscular weakness: discontinue medication

    • Cardiovascular ECG changes-T-wave alterations; QRS complex widening

    •  Intramuscular injections (large dose, 10 mg/kg) and intravenous infusion: severe hypotension, respiratory and cardiac arrest

  •  Contraindications/cautions:

    •  Contraindicated in patients with:

      •  Chloroquine (Aralen) psoriasis-may cause acute attacks

        • Chloroquine (Aralen) should not be used in combination with other agents which may cause dermatitis

      •  Porphyria-chloroquine (Aralen) may cause acute attacks

      •  Retinal/visual fields abnormalities {consider risk-benefit in prescribing decision}

    •  Cautious Use in patients with:

      •  Hepatic damage, alcoholism, neurologic or hematologic disorders

    •  Drug-drug pharmacokinetic effects:

      •  Antacids +antidiarrheal drugs: (kaolin, magnesium trisilicate, calcium carbonate)-decision should not be taken within about four hours before or after chloroquine (Aralen)

    •  During pregnancy:

      •  No reports of teratogenic effects

      •  Considering risk vs. benefit: chloroquine (Aralen) benefits appear to outweigh possible fetal risks

      •  Oral chloroquine (Aralen): safe for children

  • Chloroquine-Resistance:

    •  Unknown mechanism

    •  Probably similar to resistance described for multidrug-resistant cancer cells (membrane P-glycoprotein pump)

      •  in vitro resistance reversible by verapamil (Isoptin, Calan) and desipramine (Norpramin)

  • Clinical Uses: Chloroquine (Aralen)

    • Acute malarial attacks by P vivax, P ovale, P. malariae and P. falciparum (not chloroquine (Aralen)-resistant)

      •  Termination by chloroquine (Aralen) of:

        •  Fever -- 24-48 hours

        •   Parasitemia-48-72 hours

      •  Indications for parenteral chloroquine (Aralen):

        1.  Vomiting precludes oral route

        2.  Peripheral asexual parasitemia > 5%

        3.  Presence of cerebral malaria

      • Cure for P. vivax and P ovale malaria requires primaquine concurrent administration to eliminate persistent liver stages.

      •  Alternative to chloroquine (Aralen):-hydroxycholoroquine

    • Chemoprophylaxis:

      • Chloroquine (Aralen)-preferred agent for prophylaxis against all forms of malaria {except where P. falciparum exhibits resistance to 4-aminoquinolines

    • Amebiasis:

      • Chloroquine (Aralen) + emetine (generic): alternative for amebic hepatic abscess

    • Autoimmune Disease:

      • Long-term chloroquine (Aralen) (or hydroxycholoroquine): reported useful for management of autoimmune disorders

• Mefloquine (Lariam)

  • Overview:  mefloquine (Lariam)

    • Synthetic, 4-quinoline methanol derivative (related to quinine (Quinamm))

    • Oral Route of Administration only (local irritation upon injection)

    • Highly plasma protein-bound

    • Hepatic clearance; very slow elimination; half-life= 13-33 days

  • Antimalarial Properties:mefloquine (Lariam)

    •  Blood schizonticidal activity against: P. falciparum and P vivax

    •  Inactive against P falciparum gametocytes or hepatic stages of P vivax

    •  Mechanism of action: unknown

    • Resistance has been reported

    • Quinidine-like cardiac effects

  • Clinical Uses: Mefloquine (Lariam)

    • Prophylaxis of chloroquine (Aralen)-resistant P. falciparum strains

      •  Effective against most chloroquine (Aralen)-resistant and pyrimethamine (Daraprim)-sulfadoxine resistant P falciparum species

      •  Curative protocol: four weeks after leaving an endemic region; used in this way-prophylaxis provided against P vivax and probably against P ovale and P. malariae

      •  Curative protocol for P vivax and P ovale necessitates the addition of primaquine (against hepatic stages)

      •  Mefloquine (Lariam) should be only used in malarious regions where chloroquine (Aralen) is not effective.

    • Treatment of chloroquine (Aralen)-resistant P falciparum

      •  Oral treatment of mild-moderate mefloquine-susceptible P falciparum infection

      •  Less rapid onset of action compared to quinine (Quinamm) or quinidine-suggesting that these drugs should be used in treating severe illness.

  •  Adverse Reactions:mefloquine (Lariam)

    •  Minor/transient adverse reaction, including gastrointestinal disturbances, syncope, extrasystoles.

    •  Transient thrombocytopenia, leukocytosis, and aminotransferase elevation

    •  Transient neurological reactions (convulsions, depression, psychoses)

    •  Symptoms are more likely to occur at doses > 1000 mg -frequency = as high as 1%

  •  Contraindications:  mefloquine (Lariam)

    •  Contraindicated in patients with a history of:

      •  Epilepsy

      •  Psychiatric disturbance

      •  Cardiac conduction anomalies

      •  Quinidine (and related compound) sensitivities

    •  Not appropriate for use in children under 15 kg or under two years of age {poorly tolerated/unsubstantiated efficacy in this group}

    •  Probably should not be used during first trimester of pregnancy

    •  Women of child-bearing age: use precautions against pregnancy for at least three months following last dosage of mefloquine.

    •  Neuropsychiatric disturbance development during mefloquine treatment: indication for cessation of mefloquine.

    •  Mefloquine (Lariam) may induce seizures in patients taking anticonvulsant medications (e.g. valproic acid (Depakene, Depakote) and divalproex sodium).

• Primaquine (generic)

  •  Overview: primaquine

    • Synthetic, 8-aminoquinoline derivative

    • Well absorbed orally

    • Completely metabolized and excreted in the urine

    • Major metabolite (carboxyprimaquine) accumulates with daily dosing--

      • Primaquine and/or one of its metabolites: responsible for clinical activity

  • Antimalarial Properties: primaquine

    • Activity profile:primaquine

      •  Active against late hepatic stages (hypnozoites and schizonts of P ovale and P vivax)-provides radical cure in these cases

      •  Highly active against primary exoerythrocytic P. falciparum stages

      •  Prophylaxis (with chloroquine (Aralen)): protective against P ovale and P vivax

      •  Highly gametocidal against P vivax, P ovale, P. malariae and P falciparum

  • Mechanism of action:  primaquine

    • Antimalarial activity may be secondary to quinoline-quinone oxidants

    • Other pharmacological effects:primaquine

      • Myeloid suppression (high doses)

      • May affect erythrocytes (standard doses but in genetically susceptible individuals)

  • Resistance:  primaquine

    • Primaquine relative resistance in some P vivax strains

  • Clinical Uses:   primaquine

    • Terminal P vivax and P ovale Malaria Prophylaxis

      •  Primaquine + a blood schizonticide (typically chloroquine (Aralen)) may allow a radical cure (terminal prophylaxis), due to effects on persistent hepatic stages

    • Radical cure of acute P vivax and P ovale malaria:

      •  Primaquine + chloroquine (Aralen): used to treat these infections (2 week primaquine duration typical)

    • Gametocidal Action:

      •  Single primaquine dose causes P falciparum gametocides to become noninfective

    • Pneumocystis carinii Pneumonia:

      • Clinical Features

        • "The symptoms of P. carinii pneumonia (PCP) include dyspnea, non-productive cough, and fever.  Chest radiography demonstrates bilateral infiltrates.  Extrapulmonary lesions occur in a minority (<3%) of patients, involving most frequently the lymph nodes, spleen, liver and bone marrow.  Typically, in untreated PCP increasing pulmonary involvement leads to death"-CDC

      • Laboratory Diagnosis:

        • "The specific diagnosis is based on identification of P. carinii in bronchopulmonary secretions obtained as induced sputum or broncho-alveolar lavage (BAL) material. 

          • In situations where these two techniques cannot be used, transbronchial biopsy or open lung biopsy may prove necessary. 

          • Microscopic identification of P.carinii trophozoites and cysts is performed with stains that demonstrate either the nuclei of trophozoites and intracystic stages (such as Giemsa) or the cyst walls (such as the silver stains).  

          • In addition, immunofluorescence microscopy using monoclonal antibodies can identify the organisms with higher sensitivity than conventional microscopy."-CDC

        •  

          Pneumocystis carinii trophozoites in broncho-alveolar lavage (BAL) material

          Pneumocystis carinii (jiroveci) trophozoites in broncho-alveolar lavage (BAL) material.  Giemsa stain.  The trophozoites are small (size: 1 to 5 µm), and only their nuclei, stained purple, are visible (arrows).  AIDS patient seen in Atlanta, Georgia. Courtesy of the CDC, used with permission

        •  

          Pneumocystis carinii cysts:B: 3 cysts in bronchoalveolar material, Giemsa stain

          Pneumocystis carinii (jiroveci) cysts:B: 3 cysts in bronchoalveolar material, Giemsa stain Courtesy of the CDC, used with permission

        •  

          Cysts in lung tissue, silver stain

          "Cysts in lung tissue, silver stain; the walls of the cysts are stained black; the intracystic bodies are not visible with this stain; baby who died with pneumonia in California." Courtesy of the CDC, used with permission

        •  

          Pneumocystis carinii cysts in broncho-alveolar lavage material; silver stain

          "Pneumocystis carinii (jiroveci) cysts in broncho-alveolar lavage material; silver stain; this greater magnification shows the irregular, saucer shape of the cysts." Courtesy of the CDC, used with permission

  • Adverse Effects: primaquine

    •  Few major side effects

      • Some gastrointestinal disturbances, headache

    •  More serious side effects include (rare):

      • Leukopenia/agranulocytosis

    •  Normal Doses:

      • Limited hemolysis(noted by urinary darkening/reddening) and the, significant hemolysis, methemoglobinemia (cyanosis evident) in patients with variance of glucose-6 phosphate dehydrogenase or certain other erythrocyte pentose phosphate pathway abnormalities.

  •   Contraindications/cautions:

    •  Primaquine should not be used in patients:

      • Currently taking quinidine

      • Having connective tissue abnormalities

      • Who have history of methemoglobinemia or granulocytopenia

      • Who are pregnant (definitely not during first trimester)

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