PARASITIC INFECTIONS  Parasitic diseases are prevalent under conditions of crowding, poverty and poor sanitation and constitute one of the major health problems of man.

PARASITIC INFECTIONS  Found throughout the world. With increasing travel, immigration and the use of immunosuppressive drugs and the spread of AIDS, health care workers anywhere may see infections caused by previously unfamiliar parasites.

PARASITIC INFECTIONS  They are often chronic in nature. They generally don’t produce sudden, severe life-threatening infections.

PARASITIC INFECTIONS  Successful control is dependent on a variety of public health measures including vector control, improvement of sanitation, health education and drug administration.

MALARIA  A world-wide common cause of mortality and morbidity.  The decrease in spraying and the increase in resistance have resulted in a resurgence of this disease.

MALARIA  An estimated 500 million people are infected with malaria annually and at least 2.5 million die mostly in Africa.  In endemic areas young children are at greatest risk because their natural immunity to the disease is weakest.

MALARIA CONTROL

MALARIA  In the near future the major mechanism for combating the disease will be a combination of vector control and drugs.

TREATMENT OF MALARIA  Differs greatly from one region to another depending upon the type of Plasmodium species and the degree of drug resistance.

MALARIA  Characterized clinically by spasms of severe chills, fever and profuse sweating.  These episodes sometimes occur at reasonably well-defined intervals determined by the life cycle of the invading Plasmodium.

MALARIA  Other frequent symptoms of a malarial attack include malaise, headache, delirium, aching muscles, abdominal discomfort, vomiting and diarrhea.  In some cases the disease can become chronic with repeated relapses.  It results from infection with protozoa of the genus Plasmodium.

MALARIA  Usually transmitted by mosquito bite but also by transfusion of infected blood and by sharing needles.

PLASMODIA SPP. AFFECTING MAN  More than 100 species, those infecting man include:  P. vivax  P.falciparum  P.malaria  P.ovale

MALARIA  P.Falciparum malaria causes a majority (80 %) of the cases of malaria and nearly all the deaths. (Malaria caused by other species is rarely fatal but is more difficult to cure completely).  This is called malignant tertian malaria (fever spikes occur irregularly).

MALARIA  The next most common type is the tertian variety caused by P.vivax (fever spikes occurring every other day).  P.ovale similar to vivax.  Quartan malaria is caused by P.malariae.

MALARIA  The lapse between invasion time and onset of clinical symptoms varies with the Plasmodium species as does the frequency of the fever spikes.

Plasmodia in RBC’s

ANTIMALARIAL DRUGS  Antimalarials can be classified on the basis of their action at different stages in the life cycle of the parasite in the human.  None of the antimalarials are true prophylactics.

Artemesinin, atovaquone

BLOOD SCHIZONTICIDES  Drugs in this class act rapidly on the erythrocytic stage to relieve clinical attacks (most sensitive to antimalarial drugs).

BLOOD SCHIZONTICIDES  Treatment of the erythrocytic stage makes the patient asymptomatic but often does not completely get rid of the parasite.  When therapy is stopped symptoms will resume.

BLOOD SCHIZONTICIDES  If a person stays in the area, continual reinvasion will occur and it is not reasonable to attempt complete eradication of the parasite.

TISSUE SCHIZONTOCIDES  Used prophylactically to prevent the erythrocytic stage of malaria.  Prevent relapse as they act on primary tissue forms.  Primaquine.

P.falciparum  Upon rupture of the hepatic schizont there is no reinvasion of the liver. Thus successful treatment of the initial attack results in complete eradication of the organism from the patient.  Resistance occurs more readily with P.falciparum than with the other species.

P.falciparum  Upon rupture of the hepatic schizont there is no reinvasion of the liver.  Resistance occurs more readily with P.falciparum.

Gametocytocides and Sporontocides

CHLOROQUINE CL NH CH CH 3 (CH 2 ) 3 N (C 2 H 5 ) 2 N A 4-aminoquinoline

ANTIMALARIAL ACTIVITY  Highly effective vs. erythrocytic forms of P.vivax, P.ovale, P.malariae and sensitive forms of P.falciparum.  No activity vs. latent tissue forms of P.vivax and P.ovale.

MECHANISM OF ACTION  Multiple effects.

MECHANISM OF ACTION  Intercalation into parasitic DNA.  Inactivation of hemoglobin proteases vital to the organism by direct binding or raising the intravacuolar pH.

MECHANISM OF ACTION  Interferes with Hb digestion in the blood stages of the parasite life cycle.  The parasite degrades Hb in an acidic food vacuole producing free heme and reactive oxygen spp. as toxic by-products.

MECHANISM OF ACTION  Heme is neutralized by polymerization while the free radicals are also detoxified.

MECHANISM OF ACTION  Chloroquine accumulates several thousand-fold in the food vacuole of the parasite.  Interferes with heme polymerization and/or detoxification of the free radicals effectively killing the parasite with its own metabolic waste.

Hb Chloroquine Mechanism of action of Chloroquine RBC Food Vacuole Heme Polymerization Parasite Globin digestion

Heme-Fe(II) 2+ Heme-Fe(III) 3+ e-e- O2O2 O2-O2- H2O2H2O2 SOD Catalase Peroxidase Inhibition of Free Radical Peroxidation 2H + H 2 O +1/2 O 2 R ox + H 2 O Chloroquine X

RESISTANCE  Probably involves multiple mechanisms under complex multigenic control.  Decreased drug accumulation.

ADVICE FOR TRAVELERS  Up to date automated information for travelers is available from the CDC at or on the internet at  Malaria branch of the CDC at

PHARMACOKINETICS  Rapid and complete absorption after oral administration (also IM and SC).  Accumulates in many tissues especially RBC’s (especially infected ones) and liver.

PHARMACOKINETICS  Undergoes appreciable metabolism.  Excreted in the urine.

CLINICAL USES  Used for acute malarial attacks as it is rapidly acting- cures Plasmodium falciparum malaria.  Chemoprophylactic agent (areas without resistant falciparum malaria).

CLINICAL USES  Rheumatoid arthritis and lupus.  Hepatic amebiasis.

TOXICITY  Adverse effects are usually mild and reversible especially when used for the short-term treatment of malaria.  Acute toxicity occurs when therapeutic or high doses are administered too rapidly by parenteral routes (primarily cardiovascular and CNS).

TOXICITY  Oral chloroquine-GI upset, headache, urticaria, pruritis and visual disturbances.  High doses and prolonged treatment can produce severe visual and cardiac reactions.  Little or no toxicity when used prophylactically.

PRECAUTIONS AND CONTRAINDICATIONS  Liver disease, GI, neurological or blood disorders.  Glucose-6-phosphate dehydrogenase deficient patients.  Considered safe in pregnancy and in young children.

DRUG INTERACTIONS  Mefloquine  Anticonvulsants  Inhibits CYP2D6

QUININE AND QUINIDINE  Natural alkaloids isolated from the cinchona tree bark.  Quinidine is an optical isomer of quinine.  Quinidine is more potent and more toxic than quinine.

MECHANISM OF ACTION  Blood schizonticide.  Similar to chloroquine.  Not as extensively concentrated in the food vacuole as chloroquine and may have some alternative targets in the parasite.

RESISTANCE  May result from increased efflux.

PHARMACOKINETICS  Readily absorbed when given orally or IM(also given IV).  Rapidly acting with a short t 1/2.  Extensively metabolized (CYP3A4).

THERAPEUTIC USES  Drug of choice for chloroquine-resistant and MDR falciparum malaria (with a sulfonamide, clindamycin or doxycycline).  For severe malaria it is used parenterally (quinidine in the U.S.).

ADVERSE EFFECTS  Bitter taste.  Quinine is an irritant to the GI mucosa and often causes nausea, vomiting or pain.

QUININE- TRIAD OF DOSE- RELATED TOXICITIES  Cinchonism (tinnitis, headache and disturbed vision, may progress to C.V. and dermal). GI symptoms are prominent in Cinchonism.

ADVERSE EFFECTS  Hyperinsulinemia and severe hypoglycemia.  Severe hypotension when given too rapidly IV.

ADVERSE EFFECTS  EKG abnormalities with IV quinidine.  Hypersensitivity reactions.  Severe toxicity is rare but may include fever, skin eruptions, GI effects, deafness, visual abnormalities and CNS effects.

PRECAUTIONS AND CONTRAINDICATIONS  Pregnancy (teratogenic).  Hemolysis in patients with G-6-P DH deficiency.  Patients with a history of episodes of hemolysis, hypersensitivity and cardiac arrhythmias, tinnitus and optic neuritis.

DRUG INTERACTIONS  Mefloquine

FANSIDAR  Sulfadoxine plus pyrimethamine

NH 2 CL N N CH3CH2 PYRIMETHAMINE

PHARMACOKINETICS  Pyrimethamine-slow but complete absorption when given orally.  Binds to plasma proteins and accumulates in certain organs.  Pyrimethamine-t 1/ h  Sulfadoxine-t ½ 7-9 days

CLINICAL USES  Chloroquine-resistant falciparum malaria in a one dose presumptive self- treatment when medical care is not immediately available (within 24h) for a presumed malaria illness.

CLINICAL USES  Prophylaxis and treatment of MDR falciparum malaria (with mefloquine).

TOXICITY  Pyrimethamine alone- little toxicity except occasional skin rashes and decreased hematopoiesis.  High doses - folic acid deficiency (megaloblastic anemia).  Combination- severe and even fatal cutaneous reactions.

P.falciparum, P.vivax, P.ovale

ANTIMALARIAL ACTIVITY  Active against the late hepatic stages of P.vivax and P.ovale.  Highly active against the primary exoerythrocytic stages of P.falciparum.  Gametocidal

MECHANISM OF ACTION  Converted in the liver to active quinone metabolites (active electrophiles). These may generate active oxygen species or

Primaquine

PHARMACOKINETICS  Completely and promptly absorbed when given orally.  Rapidly and extensively metabolized.  Excreted as metabolites.

CLINICAL USES  To prevent relapses (radical cure) of P.vivax and P.ovale infections (used with a blood schizonticide,usually chloroquine).  Terminal prophylaxis after completion of travel to an endemic area to diminish likelihood of a relapse.

ADVERSE EFFECTS  Large doses may cause abdominal distress, nausea and headache.  Hemolytic anemia, cyanosis (methemoglobinemia) and leukocytosis - less common.

ADVERSE EFFECTS  Produces hemolytic anemia in people with glucose-6-phosphate dehydrogenase deficiency.

PRECAUTIONS AND CONTRAINDICATIONS  Glucose-6-phosphate DHase deficiency.  Patients with a tendency towards granulocytopenia or methemoglobinemia.  Other potentially hemolytic or bone marrow depressing drugs.  Pregnancy.

MECHANISM OF ACTION  4-aminoquinoline methanol.  It is a blood schizonticide similar to chloroquine and quinine in many aspects.  May inhibit heme polymerization and may form toxic complexes with free heme that damages membranes.

RESISTANCE  Sporadic resistance in many areas has been reported.

PHARMACOKINETICS  Given orally (parenterally it can cause severe local reactions).  Slowly eliminated (t ½ around 20 days)

CLINICAL USES  Used for the treatment and prophylaxis of chloroquine-resistant and multidrug - resistant P.falciparum malaria.  It is the drug of choice for chemoprophylaxis for most travelers.

ADVERSE EFFECTS  GI upset (common).  CNS toxicity is seen in about half of the people who take the drug (dizziness, ataxia, headache etc).  Severe neuropsychiatric disturbances ( rare).

CONTRAINDICATIONS  Pregnancy.  Children less than 2 years old.  Patients with a history of seizures or neuropsychiatric disturbances.  Patients who have had adverse reactions to quinoline antimalarials.

ATOVAQUONE/ PROGUANIL  A fixed dose combination of atovaquone and proguanil hydrochloride.  Prevents rapid development of resistance to atovaquone.

ATOVAQUONE

ANTIMALARIAL ACTIVITY  Both drugs are active vs the erythrocytic forms of P.falciparum including strains resistant to chloroquine, mefloquine and pyrimethamine/sulfadoxine (not active vs hepatic stages).

ATOVAQUONE

Cycloguanil Proguanil

PHARMACOKINETICS  Atovaquone is poorly absorbed from the GI tract.  Proguanil is rapidly absorbed.

CLINICAL USES  Prevention and treatment of chloroquine- resistant P.falciparum malaria.

ADVERSE EFFECTS  Abdominal pain, nausea, vomiting, diarrhea, headache and rash have occurred and are more common with high doses.  Dose-related maculopapular rashes.  Mild elevations in liver aminotransferase activity.

ARTEMISININ  Extract from a Chinese herb.  Artemisinin is insoluble and can only be used orally.  Analogs have been synthesized to improve solubility and improve antimalarial efficacy (artesunate and artemether).

ANTIMALARIAL ACTIVITY  Active against all malarial species (especially useful for P.falciparum resistance).  Rapidly acting blood schizonticide.

MECHANISM OF ACTION  Free radical production that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge.  These covalently modify and damage specific malarial proteins.

PHARMACOKINETICS  Active form is dihydroartemesinin.  Short t ½ (45 mins)-precludes prophylactic use.

CLINICAL USES  Treatment of multidrug-resistant P.falciparum ( in conjunction with another agent such as fansidar or doxycycline).

ADVERSE EFFECTS  Nausea, vomiting and diarrhea.  Irreversible neurotoxicity has been seen with very high doses or long term therapy in animal studies.  Prolongation of the QT interval.

PRECAUTIONS AND CONTRAINDICATIONS.  Avoid in pregnancy.

DOXYCYCLINE  Used for treatment and prophylaxis in regions where multi-drug resistance is common.  Used alone for short term prophylaxis.  For treatment they are used in combination with other antimalarials (work slowly).

ANTIMALARIAL CHEMOTHERAPY  For acute attacks chloroquine is the treatment of choice.  For resistant strains use quinine plus fansidar or plus doxycycline or mefloquine (or atovaquone/proguanil).

ANTIMALARIAL CHEMOTHERAPY  For a radical cure of P.vivax or P.ovale use primaquine after departure from the endemic area.  For severe attacks use quinine or quinidine parenterally.

CHEMOPROPHYLAXIS OF MALARIA  Chloroquine for sensitive strains.  If symptoms of malaria occur while taking chloroquine a therapeutic dose of fansidar should be administered and medical care sought immediately.  Mefloquine and atovaquone/proguanil for chloroquine- resistant strains.  Doxycycline for multi-drug resistance.

AMEBIASIS  Asymptomatic cyst passers- organisms found in the intestinal lumen but patients show no symptoms.  Mild to moderate intestinal amebiasis.  Severe intestinal infection (dysentery).  Amebic liver abscesses.

PAROMOMYCIN (Humatin)  Direct amebicide with antibacterial activity (an aminoglycoside) (luminal amebicide).  Insignificant absorption.  May be useful in other protozoal infections and some worm infections.

ADVERSE EFFECTS  Diarrhea and abdominal pain are the main side effects.  Ototoxicity and renal toxicity associated with the systemic aminoglycosides are not seen.  GI superinfections are possible.

IODOQUINOL (Yodoxin)  Exact mechanism of action is not known.  Variable but significant absorption.  Luminal amebicide for asymptomatic cyst passers.  Toxicity-myelooptic neuropathy (rare).

METRONIDAZOLE  Metronidazole is the prototypical mixed amebicide.

METRONIDAZOLE -  Drug of choice for all symptomatic cases although a luminal amebicide must also be given.  Intestinal amebiasis with or without liver involvement.

OTHER DRUGS USED IN THE TREATMENT OF AMEBIASIS  Tinidazole  Chloroquine  Emetine and dihydroemetine

Metronidazole

HELMINTHIASIS  Prevalence is greatest in tropical regions.  Simultaneous infestation with more than one type of worm is common.  Due to travel and immigration worms can spread to locations that previously had been free of a particular organism.

ANTHELMINTICS  Many of these parasites have complex life cycles, parts of which occur in other animal hosts besides man.  In man most worms have some stage of their development within the GI tract and it is here that they are easiest to attack.  The adult form of the worm is the form usually attacked chemotherapeutically.

ANTHELMINTICS  Common target sites for anthelmintics Ion channels Microtubules Bioenergetics

BENZIMIDAZOLES  Mebendazole, Thiabendazole and Albendazole.  Versatile antihelminthic agents.

MEBENDAZOLE- PHARMACOKINETICS  Given orally but absorption is poor and erratic.  Undergoes rapid 1 st. pass metabolism.

THERAPEUTIC USES  Broad spectrum anthelminthic. Highly effective against GI nematode infections including roundworms, hookworm, whipworm and pinworm.  Particularly valuable for mixed infections.

ADVERSE EFFECTS  Little systemic toxicity due to poor absorption.  There is some transient abdominal pain such as cramping.  Teratogenic so it is contraindicated in pregnant women.

THIABENDAZOLE- PHARMACOKINETICS  Rapidly absorbed after oral administration.  Metabolized and excreted in the urine as the glucuronide and sulfate conjugates.

THERAPEUTIC USES  Drug of choice for treatment of “cutaneous larval migrans” caused by the larva of the dog hookworm.

THERAPEUTIC USES  Alternative drug for the treatment of threadworm (Strongyloides stercoralis) infections.

ADVERSE EFFECTS  GI- anorexia, nausea, vomiting and diarrhea (frequent).  CNS- (less frequent)dizziness, weariness, drowsiness, giddiness and headache.

ALBENDAZOLE- PHARMACOKINETICS  Variably and erratically absorbed from the gut.  Undergoes 1 st.pass metabolism in the liver.  Well distributed into various tissues.

THERAPEUTIC USES  Broad range of activity vs. many nematodes and cestodes including mixed infections of A. lumbricoides (intestinal roundworm),hookworm (Necator americanus) and whipworm (Trichuris)

THERAPEUTIC USES  Cystic hydatid disease (larval form of the dog tapeworm)(Echinococosis).  Cutaneous larval migrans.  Neurocysticercosis (larval form of the pork tapeworm).

NEUROCYSTICERCOSIS  Develops when humans or pigs ingest food contaminated with taenia (Taenia solium) eggs, which cross the digestive tract, enter the circulation and lodge in the tissues (usually brain or muscles).  A frequent cause of seizures often resistant to anticonvulsant therapy.

NEUROCYSTICERCOSIS  Adequate therapy with 1 week course of albendazole or a 1 day treatment with praziquantel (albendazole has better and more effective penetration into the brain tissue).  Corticosteroids to prevent inflammation.

ADVERSE EFFECTS  Transient abdominal pain, diarrhea, nausea and vomiting, headache, dizziness and allergic reactions.  At higher doses and prolonged use the most common effect is elevated serum aminotransferase (ATase).

N N O C PRAZIQUANTEL O

MECHANISM OF ACTION  Increases cell membrane permeability to calcium resulting in vacuolization, marked contractions, paralysis, dislodgement and death.  At low doses it causes increased muscular activity, followed by contraction and spastic paralysis (worms detach from host).

MECHANISM OF ACTION  At higher therapeutic concentrations it causes damage to the worms integument. This seems to activate host defense mechanisms and results in destruction and elimination of the worms.

PHARMACOKINETICS  Rapid absorption after oral administration.  Undergoes extensive metabolism.  Rapidly excreted in the urine mainly as metabolites.

Tapeworm life cycle

Taenia infections

THERAPEUTIC USES  Neurocysticercosis (cysts from larva of pork tapeworm in the brain).  Hydatid disease (cysts from larva of dog tapeworm, usually in the liver).

ADVERSE EFFECTS  Abdominal discomfort (pain and nausea).  Headache, dizziness and drowsiness.  Indirect effects such as fever, pruritus, urticaria, rashes, arthralgia and myalgia.

CONTRAINDICATIONS  Pregnancy

PYRANTEL PAMOATE (Antiminth)

MECHANISM OF ACTION  Effective vs susceptible worms in the intestinal tract (not other forms).  Depolarizing neuromuscular blocking agent.  Opens nonselective cation channels and induces marked persistent activation of nicotinic ACH receptors,which results in spastic paralysis of worms.  Inhibits cholinesterase.

PHARMACOKINETICS  Poorly absorbed from the GI tract.

THERAPEUTIC USES  Broad spectrum anthelmintic.  Highly effective for the treatment of pinworm (Enterobius).

PINWORM  Most common helminthic infection in the U.S.(more than 40 million schoolchildren affected).  More prevalent in temperate than tropical climates.  Rarely causes serious complications-pruritus in the perianal and perineal areas.

PINWORM  Easily distributed throughout members of a family, a school, or an institution.

THERAPEUTIC USES  DOC-Roundworm

ADVERSE EFFECTS  Nausea, vomiting, diarrhea and abdominal cramps.  Dizziness, drowsiness, headache, insomnia, rash, fever and weakness.

PRECAUTIONS AND CONTRAINDICATIONS  Not recommended in pregnancy and in children under 2.

IVERMECTIN (Stromectol)  Macrocyclic lactone which belongs to a class of natural compounds known as avermectins.

MECHANISM OF ACTION  Potentiation, direct activation or both of glutamate gated chloride channels found only in invertebrates.  It causes an influx of negatively charged ions and this hyperpolarization of the affected cells results in muscle paralysis.

PHARMACOKINETICS  Well absorbed when given orally.  Extensively metabolized.

THERAPEUTIC USES  Onchocerciasis (river blindness).  Lymphatic filariasis.

THERAPEUTIC USES  Intestinal nematode infections: Strongyloides (threadworm), cutaneous larval migrans, ascariasis (roundworm).

TOXICITY  Almost all the reactions are as a result of an immunological reaction to dead microfilariae (Mazotti reaction) fever,itching, dizziness, edema.

TOXICITY  In patients being treated for nematode infections diarrhea, nausea, dizziness and pruritus are common.  Some patients develop corneal opacities and other eye lesions.

PRECAUTIONS AND CONTRAINDICATIONS  Children under 5  Pregnancy