Drugs Used in the Treatment of Malaria Jean F. Regal, Ph.D. March 23, 2009 Regal/Froberg

Learning Objectives  Know the names, mechanisms and basis for selectivity  Know the major toxicities of the drugs  Understand the rationale for prophylactic treatment and the ‘radical cure’ Useful website for malaria drugs:

Best Plan  Don’t get bit  Use of netting and insect repellents  Avoid mosquito areas and exposure during periods of high insect activity

Plan B  Take advantage of drugs used for prophylaxis  If you are planning a trip to a malaria area, take the prophylactic drugs  Treat active malaria with the appropriate drug, depending on resistance, etc  Use the ‘radical cure’ if indicated

Considerations in Treatment  Which Area is visited? Resistance or not?  With or without Chloroquine resistant P. falciparum or Chloroquine resistant P. vivax  What is the probability of persistent hepatic forms of the organism  P. vivax and P. ovale  You need the ‘radical’ cure  Can the patient take medication orally?  Severity of the disease and necessity to achieve therapeutic levels quickly.

Epidemiology

Considerations in Treatment  Which Area is visited? Resistance or not?  With or without Chloroquine resistant P. falciparum or Chloroquine resistant P. vivax  What is the probability of persistent hepatic forms of the organism  P. vivax and P. ovale  You need the ‘radical’ cure  Can the patient take medication orally

 P. vivax and P. ovale infection results in latent forms in the liver

Website for malaria drugs ( 'Information for travelers' section which succinctly describes possible disease sources and precautions (insects, water, etc.) for different countries around the world. Indicates if chloroquine resistant malaria is in a certain geographic area. Indicates if prophylactic treatment is indicated for travel to a certain geographical region. Lists current drug treatments and side effects.

Drugs to Know

Mosquito Liver Stages Sporozoite HUMAN RBC Stages  P. vivax and P. ovale infection results in latent forms in the liver

Chloroquine  Basis for selectivity:  The parasitized RBC concentrates Chloroquine at least 25 fold more than unparasitized RBC. Chloroquine accumulates in the acid pH of the food vacuole.  Old mechanism of action  Intercalates between base pairs in DNA, thus inhibiting nucleic acid synthesis.

Chloroquine Mechanism  Interferes with heme handling:  The parasite digests host hemoglobin within the acidic food vacuole of plasmodia. This results in the production of large amounts of ferriprotoporphyrin IX (FPIX) inside the food vacuole. FPIX is toxic to the parasite so the parasite uses the enzyme heme polymerase to convert it to hemozoin which accumulates in the vacuole. Chloroquine binds to FPIX and prevents its conversion to hemozoin. Either free FPIX or chloroquine bound to FPIX is toxic to the plasmodium. FPIX (toxic) Host hemoglobin CQ - FPIX (toxic) Hemozoin (non-toxic) chloroquine Parasite heme polymerase

Adverse Effects of Chloroquine  Low dose suppressive therapy used in prophylaxis  no significant toxicity  Acute attack doses  dizziness, headache, itching, vomiting, skin rashes  difficulty in visual accommodation  large doses for prolonged periods can cause severe eye damage and even blindness

Quinine and Quinidine  More toxic than chloroquine but resistance has not readily developed  Used in chloroquine resistant P. falciparum  Mechanism probably the same as chloroquine  Adverse effects  Acute attack doses – Cinchonism tinnitus, blurred vision, nausea, headache, decreased hearing acuity permanent damage to vision, balance and hearing can result

Sulfadoxine Pyrimethamine Not effective against hepatic forms of P. vivax and P. ovale Slow onset and unclear effectiveness against exo- erythrocytic forms

Mefloquine  Mechanism  Probably acts like chloroquine  Sometimes nausea, vomiting, dizziness, visual or auditory disturbances  May cause disorientation, hallucinations and depression  Indicated only for the treatment and prevention of Chloroquine resistant P. falciparum  Because of the possibility of neuropsychiatric reactions, chloroquine is preferred if resistance is not a problem.

Atovaquone - Proguanil  Atovaquone  Mechanism of action - unique Depolarizes parasitic mitochondria and inhibits their electron transport  Drug interactions  Proguanil  Mechanism of Action metabolite of proguanil inhibits dihydrofolate reductase selective for the plasmodial enzyme Potentiates the activity of atovaquone Not active against hepatic stages of P. vivax and P. ovale Concentrated in erythrocytes

Atovaquone - Proguanil  Slow onset  Unclear effectiveness against exo- erythrocytic forms  Not effective against hepatic forms of P. vivax and P. ovale  Expensive and needs to be taken daily.  Replacing mefloquine for prophylaxis  GI disturbances can be a problem

Artemisinins (Artesunate)  Mechanism  Heme iron in the malarial pigment acts on the drug to produce free radicals that damage parasite proteins  Inhibits a calcium ion ATPase in P. falciparum  Rapid and potent activity against even multi-drug resistant organisms (not hepatic forms)  Do not use alone to avoid selection of resistant organisms  In the USA, only available from CDC

Primaquine ‘Radical Cure’  Drug of choice to eliminate hepatic forms of P. vivax and P. ovale  Eradicates hypnozoite forms dormant in liver  Mechanism of action – Unknown  Possibly by generation of reactive oxygen species or by interfering with electron transport in the parasite  Untoward effects  occasional GI distress, nausea, headache, pruritis, leukopenia  Hemolytic anemia in people with a glucose-6- phosphate dehydrogenase deficiency

Other drugs that may cause hemolysis in people with G6PD deficiency  Chloroquine, Primaquine, Quinine  Sulfonamides  Trimethoprim/Sulfamethoxazole  Chloramphenicol (only in patients of Mediterranean origin)  Para-aminosalicylic acid - TB  Probenecid - Uricosuric, prolongs Pen G  Dapsone - Leprosy  Isoniazid - TB  Nalidixic acid - Urinary tract antiseptic  Nitrofurantoin - Urinary tract antiseptic

ANTIMALARIAL AGENTS DrugMechanism of ActionBasis for Selectivity Chloroquine Quinine Quinidine Binds to ferriprotoporyphrin IX and prevents conversion to hemozoin. FPIX is toxic to the plasmodium Old hypothesis: Intercalated between base pairs in DNA - thus inhibiting nucleic acid synthesis Selective accumulation by the parasite in erythrocytes MefloquineUnknown: May act like chloroquineUnknown Primaquine Unknown: Possibly by generation of reactive oxygen species or by interfering with electron transport in the parasite Unknown Pyrimethamine Proguanil Inhibits folic acid reductaseSpecies difference in enzyme sensitivity AtovaquoneDepolarizes mitochondria and inhibits electron transportSpecies difference in electron transport Artesunate Heme iron in the malarial pigment acts on the drug to produce free radicals that damage parasite proteins. Inhibit a calcium ion ATPase in P. falciparum. Doxycycline Sulfadoxine