Antiprotozoal Drugs and Malaria

• Antiprotozoal drugs are used for the management and chemoprophylaxis of malaria

Aim of Therapy

• Treat an acute episode of malaria
• Eradicate the parasite from the patient's body
• Reduce the parasite's reservoir to prevent transmission

Antimalarials

• Erythrocytic schizontocides target erythrocytic schizogony
• Tissue schizontocides target pre-erythrocytic and exoerythrocytic stages like P. vivax in the liver
• Gametocides kill gametocytes in the blood

Malaria Prevention

• Chemoprophylaxis is a method of preventing malaria
• Non-chemo prophylactically is a method of preventing malaria

Chemoprophylaxis of Malaria

• Prophylactic drugs target the pre-erythrocytic phase of the parasite in the liver
• Schizontocides are a type of drug used which suppresses the erythrocytic phase, thus attacking malarial fever

Chemoprophylaxis: Who Needs It?

• Travelers from low-risk malaria areas:
  • Malarone (Atovaquone 250mg and Proguanil 100mg): taken daily 2 days before travel and continued for 7 days after return
  • Doxycycline 100 mg: taken daily starting a day before travel and for 4 weeks after returning from areas endemic with chloroquine-resistant P. falciparum
  • Mefloquine: dose is taken weekly, starting 2 weeks before travel, continued in endemic country, conclude 4 weeks after leaving
• Sickle cell disease patients:
  • Pyrimethamine 12.5 mg and dapsone 100 mg (deltaprim/ maloprim) administered weekly
• Intermittent preventative treatment of malaria in pregnancy (IPTp):
  • Fansidar (sulfadoxine 500 mg and pyrimethamine 25) is given
  • Target a minimum of 3 doses with first dose given in the 2nd trimester
  • Intervals of 1 month apart
• Patients with splenectomy or those taking cytotoxic or immunosuppressive drugs due to malignancy

Management of Malaria Treatment

• Treatment is based on the parasitic life cycle
  • RBC stage/erythrocytic stage
  • Hepatic stage/exoerythrocytic stage
• Treatment classification
  • Asymptomatic malaria
  • Uncomplicated malaria
  • Severe malaria
  • Malaria in pregnancy and children
• Combination therapy is necessary for malaria treatment

Advantages of Combination Therapy

• Rapid clinical cure and parasite eradication
• High cure rates and less relapse
• Absence of resistance
• Increased ability to tolerate drugs

Drugs Targeting Life Stages of Malaria Parasite

• Tissue schizonticides in exorythrocytic stage:
  • Primaquine
  • Proguanil
• Gametocidal in the erythrocytic stage
  • Primaquine and artemisinin (all Plasmodium spp)
  • Chloroquine and Quinine (P. vivax)
• Prevent development of sporozoites:
  • Proguanil
  • Pyrimethamine

Therapeutic Classification

• Suppressive Prophylaxis
  • Tetracyclines
  • Mefloquine
  • Chloroquine
  • Proguanil
• Clinical Cure
  • Fast acting:
    • Chloroquine
    • Mefloquine
    • Artemisinin
    • Atovaquone
  • Slow acting:
    • Tetracyclines
    • Sulphonamides
    • Pyrimethamine
    • Proguanil

Mechanism of Action of Antimalarial Drugs

• Inhibitors of heme crystallization
• Antifolates
• Antibiotics
• Free radical producers
• Inhibition of protein synthesis of parasitic mitochondria
• Targeting essential parasitic apicoplast metabolism
• Dihydrofolate reductase (DHFR) inhibitors
• Dihydropteroate synthase (DHPS) inhibitors

Inhibitors of Heme Crystallization

• Detoxification of heme starts with the self-oxidation of Fe(II) in the heme group into Fe(III)
• This forms potentially toxic Hydroxyferriprotoporphyrin IX
• Detoxification ends with the formation of highly insoluble brown crystals known as hemozoin (β-hematin)

Mechanism of Action: Chloroquine/Lumefantrine/Quinine

• Free hemin is increased by Chloroquine
• Action promotes oxidative reactions and inhibits proteolysis
• This is mediated by three cysteine proteases: papain, ficin, and cathepsin B

Chloroquine

• It is a rapidly acting erythrocytic schizontocide against all species of plasmodia
• Drug resistance is associated with reduced drug accumulation
• This limits its use in Zambia where falciparum is endemic
• Given orally with bioavailability higher than 50% and may also be administered IM
• It is bound to plasma proteins and melanin
• Concentrated in the liver, spleen, and kidney and may accumulate in the retina with long-term use
• The drug is extensively distributed with a volume of distribution of 200 to 800 L/kg when calculated from plasma concentrations and 200 L/kg when estimated from whole blood data
• Concentrations are 5 to 10 times higher and cleared by the kidney and liver
• Rapidly dealkylated via cytochrome P450 enzymes (CYP) into the pharmacologically active desethylchloroquine and bisdesethylchloroquine with elimination half-lives of 20 to 60 days.
• Adverse effects: anorexia, uncontrollable itching, epigastric pain, prolongation of QT interval, difficulty in accommodation, and headache
• Clinical use: RA, extraintestinal amoebiasis, LE
• Prolonged high doses can cause loss of vision due to retinal damage and corneal deposits although corneal deposits are reversible on discontinuation
• Drug-drug interactions: prolongation of QT-interval with antiarrhythmic drugs

Quinine

• Levo-rotatory alkaloid obtained from cinchona bark, d-isomer is quinidine. Do not use with mefloquine
• Highly effective blood schizonticide against the four human malaria parasite species
• Gametocidal against P. vivax and P. ovale but not P. falciparum
• Not active against liver stage parasites
• Used in complicated malaria although artemisinin derivatives are now often preferred
• Rapidly and completely absorbed orally; 70% bound to plasma proteins
• Toxicity is high and dose-related; 8-10 g in a single dose may be fatal
• PK varies in different populations but is metabolized in the liver and excreted via urine
• Quinine toxicity can cause hematologic reactions, renal impairment, optic neuritis, tinnitus, black water fever, and QT prolongation
• Adverse effects include hypoglycemia, flushing of the skin, impaired hearing, night blindness

Lumefantrine

• Given orally alongside artemisinin derivatives (artemether in drug coartem) in uncomplicated malaria
• Drug absorption improves when given with food and has high lipophilicity. High Vd and distributes well into tissue.
• Metabolized to more active metabolites, with little overall effect on antimalarial activity through CYP3A4
• Excreted through bile
• Elimination half-life is 3-4 days
• Side effects associated with coartem: headache, dizziness, muscle and joint pains, anorexia

Artemisinins

• Free radical producers
• They produce free radicals (superoxides)
• Cause oxidative stress, leading to damage in critical cellular components such as proteins and lipids
• Fe 2+ interacts with the endoperoxide bridge, forming peroxides and other free radicals that are toxic to the parasite
• Causes lipid peroxidation and resulting membrane damage in the parasites which inhibits bioactivity, ultimately leading to death of the parasite
• Artemisinin-based drugs are rapid erythrocytic schizonticides

Artesunate

• It is given PO, IM, IV, and rectally
• Recommended for initial treatment of severe malaria, followed by an appropriate oral regimen
• Must be administered with antimalarials effective against hypnozoite liver stages in P. vivax or P. ovale cases
• May not prevent relapses due to limitations with its activity
• Commonly reported adverse effects include anemia, increased transaminase, thrombocytopenia, hyperbilirubinemia, leukocytosis, and hypersensitivity

Artemether

• Given orally and IM
• Used as the first line in the management of uncomplicated malaria in combination with lumefantrine
• Bioavailability is improved by meals
• 99% protein-bound
• Metabolized by CYP 3A4 to dihydroartemisinin (DHA), which is active

Atovaquone 250mg and Proguanil 100mg (Malarone)

• Atovaquone targets tissue schizonts and gametes for P. falciparum and other plasmodia
• MOA involves collapsing plasmodial mitochondrial membranes and interfering with ATP production, resulting in energy deprivation in the parasite
• Proguanil augments Atovaquone anti-malarial activity and prevents the emergence of resistance. It is a slow-acting erythrocytic schizontocide that also inhibits the pre-erythrocytic stage of falciparum
• MOA: selective DHFRase inhibitor via its active metabolite cycloguanil via CYP enzymes
• The drug is effective for both exoerythrocytic and erythrocytic parasites
• A fixed-dose oral combination is 4 tabs given for 3 days of treatment of uncomplicated chloroquine-resistant P. falciparum and P. vivax
• Bioavailability is improved with a fatty meal
• Half-life: Atovaquone is 2-3 days and Proguanil is 12-21 hours
• Atovaquone is excreted in feces, while proguanil is excreted in urine
• Atovaquone is also used for the management and prevention of Pneumocystis carinii pneumonia as an alternative to Septrine

Primaquine

• Given orally Mechanism of Action not understood
• Used for pre-erythrocytic schizonts, thus preventing relapse
• Sensitive towards P. vivax but not P. falciparum
• Completely lacks sensitivity to plasmodium in the erythrocytic phase
• Contraindicated in G6P deficiency and pregnancy
• Used as a radical cure alongside chloroquine
• Readily absorbed after oral ingestion and oxidized in the liver with a plasma t½ of 3-6 hrs
• Excreted in urine within 24 hours without accumulation
• Side effects: abdominal pain, weakness, uneasiness in the chest, and dose-related hemolysis

Pyrimethamine

• Directly acting inhibitor of plasmodial DHFRase and has very poor action on bacterial DHFRase
• MOR: Mutation on the DHFRase
• Targets the erythrocytic phase of malaria parasite and is a slowly acting erythrocytic schizonticide
• Does not eliminate the pre-erythrocytic phase of P. falciparum
• Used in malaria prophylaxis in pregnancy
• Absorbed well orally but slowly
• Concentrated in certain organs like the liver, spleen, kidney, and lungs
• Metabolized and excreted in urine with a t½ of 4 days and activity of up to 2 weeks
• Addition of sulfadoxine results in reduced resistance

Drugs Used to Manage Malaria in Pregnancy

• Uncomplicated malaria:
  • 1st trimester: oral quinine and clindamycin
  • 2nd and 3rd trimester: artemether/lumefantrine or Dihydroartemisinin-piperaquine
• Severe malaria:
  • Quinine may be used to manage the presenting symptoms accordingly

Drugs Used to Manage Malaria in Children

• Uncomplicated:
  • Artemether/lumefantrine dosages vary according to weight bands
  • Children less than 5 kg: may be given the same doses as those between 5-15 kg but must be monitored
• Severe:
  • Artesunate/artemether/quinine can be used parenterally until the patient tolerates oral medication

Trichomoniasis

• Caused by the parasitic protozoan Trichomonas vaginalis
• Symptoms: vaginal canal pain, vulvar itching with edema, tenderness, chafing, redness, yellow discharge, green foul smelling discharge, painful urination, punctate hemorrhages on the cervix known as colpitis macularis or strawberry cervix
• Transmission is through sexual contact

Chemotherapy of Trichomoniasis

• Single dose of Metronidazole 2 gm once, or Metronidazole PO 500 mg TDS for 7 days
• Treat the male sexual partner with Tinidazole
• Metronidazole and Tinidazole are nitroimidazoles active against amoebas and protozoa
• Other therapeutic applications: diarrhea, and erradication of H.pylori (Secnidazole)

PK of Metronidazole

• Good oral absorption, available as parenteral drugs
• Able to penetrate all tissues
• Intracellular concentrations rapidly approach extracellular levels
• Low protein binding (10-20%)
• A half-life of unchanged drug is 7.5 hrs for metronidazole and 12-14 hrs for tinidazole
• Metronidazole is metabolized in the liver via oxidation and glucuronidation. Hydroxy-metronidazole is an active metabolite
• Unchanged drug and metabolites are excreted in urine
• Plasma clearance is decreased in liver dysfunction
• ADRs: unpleasant, metallic taste. Disulfiram-like effect

Chemotherapy for Amebiasis

• Amebiasis, or amebic dysentery, is an infection of the intestinal tract caused by Entamoeba histolytica
• The disease can be acute or chronic with varying degrees of illness from no symptoms to mild diarrhea to fulminating dysentery, ameboma, liver abscess, and other extraintestinal infections
• Entamoeba histolytica exists in two forms: cysts and trophozoites
  • Cysts survive outside the body and are labile but invasive
  • Trophozoites do not persist outside the body
• Treatment is indicated for both acutely ill patients and asymptomatic carriers (Dormant E. histolytica may cause future infections and be a potential source of infection)

Paramomycin

• Aminoglycoside
• May also be used for the management of hepatic encephalopathy as adjuvant therapy
• Administered orally with meals, via parenteral routes, and topically
• Excreted via the kidneys unchanged
• ADRs: nausea, vomiting, epigastric pain, and heartburn; ototoxicity for the parenteral route is not uncommon