Antiparasitic Agents

Ma. Victoria M. Villarica RN, MD, FPSECP

Differentiate protozoal and helminthic infections Discuss conditions that promote parasitic infections Discuss the kinetics and dynamics of antiparasitic agents Enumerate the drug of choice for the different parasitic infections Learn to manage parasitic infections

Objective

Principles of Treatment: 1. Protozoal infections are always treated. 2. Helminthic infection therapy depends on: a. number and life span of worms harbored by the patient b. likelihood and seriousness of persons and public health complications c. availability and efficacy of therapeutic agents 3. Individualized treatment 4. Ff-up clinical and laboratory assessment is needed 5. Patient education is a must.

Conditions promoting parasitic infections:

1. Poor sanitation, personal hygiene and health education 2. Debilitation and compromised resistance of the host

3. High population density

4. Inadequate control of parasite vectors and reservoirs of infection 5. Increase population migration 6. Military operations

7. Resistance

3 Major types of potential targets for chemotherapy of parasitic disease: - rational approach is to target metabolic pathway that represents points of vulnerability 1. Unique enzymes found only in the parasite - limited use because of development of resistance 2. Enzymes indispensable only in the parasite - essential for

survival of the parasite

3. Common indispensable biochemical functions with different pharmacologic properties - found both on the

human host and the parasite but would target only the
parasite

 Unique enzymes found only in the parasite - pyruvate phosphate dikinase main source of energy of entamoebas (glycolysis) Indispensable enzymes - lanosterol demethylase is required for ergosterol synthesis in leishmanias Common indispensable biochemical functions - microtubules in ascaris and human host

Targets of antiparasitic chemotherapy

Parasitic infections:
a. protozoa
1. Sarcodina - amoebas 2. Sporozoans plasmodium, toxoplasma,

cryptosporidium
3. Flagellates trichomonas, giardia, trypanosoma, leishmania, pneumocystosis 4. Ciliates Balantidium coli b. metazoa 1. Cestoda - tapeworms 2. Trematoda - flukes 3. Nematoda roundworms, pinworms, etc

Antiprotozoal Agents

Sporozoans Malaria:
4 species of plasmodium cause human malaria (P. falcifarum, P. vivax, P. malariae, P. ovale; P. knowlesi) life cycle: liver/tissue phase and blood phase radical cure - eliminate both hepatic and erythrocytic stages; no such drug suppressive cure - complete elimination of parasite from the body by continued therapy clinical cure - terminate clinical attack

 Direct microscopy less expensive but skilled staff is needed RDT (rapid diagnostic test) - expensive

Diagnosis of malaria

1. Tissue schizonticide - eliminate developing or dormant

liver forms a. Primaquine 2. Blood schizonticide - act on erythrocytic parasite a. Chloroquine b. Quinine c. Mefloquine d. Inhibitors of folate synthesis e. Tetracycline, Doxycycline, Clindamycin f. Halofantine

3. Gameticide - kill sexual stages

a. Quinine b. Primaquine 4. Causal prophylactic drugs - capable of preventing erythrocytic infection a. Chloroquine b. Mefloquine c. Inhibitors of folate synthesis d. Doxycycline, Azithromycin

Antimalarial Agents:
I. Chloroquine - drug of choice for both treatment and
chemoprophylaxis of sensitive P. falcifarum and other species

act by concentrating in parasite food vacoules, preventing the polymerization of the hgb breakdown product, heme, into hemozoin and thus eliciting parasite toxicity due to build-up of free heme. Resistance is due to mutations in a putative transporter/decreased carrier-mediated transport

Safe in pregnancy and young children

Chloroquine
Adverse effect: GI upset, mild headache, visual disturbances, urticaria
- 5 gm. Fatal Availability: Aralen 250mg tablet (150mg base) Not given IV: cardiotoxicity Dose: adult: 1 gm ffed by 500mg at 6hrs., 24 hrs. and 48hrs. Or 1 gm at 0 , 24hrs then 500mg at 48hrs.

child: 10mg/kg initially then 5mg/kg at 6hrs. , 24 hrs. and 48 hrs.

(for P. vivax: ffed by: Primaquine 0.3mg/kg once a day x 14days)

II. Amodiaquine
- same mechanism of action as Chloroquine (not available in the Phils)
low cost; limited toxicity; effective against chloroquine-resistant strains in certain areas Tx for chloroquine resistant strains of P. falcifarum Not for chemoprophylaxis AE: agranulocytosis

III. Quinine
Used for treatment of severe Falcifarum malaria and chloroquine resistant strains MOA: inhibits plasmodium hgb polymerase AE: cinchonism, hemolytic anemia, blackwater fever
Preparation: 300mg (350mg base) tablet 300mg/l ampule Dose: child: 25 mg (8.33mg base)/kg/day in 3 doses x 3-7 days adult: 600 mg TID x 3-7 days IV: 20mg/kg loading dose over 4 hrs. ffed by 10mg/kg IV over 2-4hrs. every 8hrs. until oral therapy can be started

CNS or complicated malaria

Quinidine 10mg/kg IV for 1-2hrs ffed by 0.02mg/kg or
15mg/kg IV in 4 hrs. ffed by 7.5mg/kg in 4 hrs. every 8hrs.

OR Artesunate 2.4mg/kg IV or IM then 1.2mg/kg every 12hrs. for 1

day, then everyday

OR Artemether 3.2mg/kg IM then 1.6mg/kg/day everyday IM

IV. Melfloquine - chemically related to Quinine

- chemoprophylaxis and blood schizonticide for chloroquine-resistant strains of P. falcifarum - given only orally; severe local irritations - MOA: swelling of parasitic food vacuoles - considered safe for young children; safe in pregnancy but limited experience in 1st trimester - AE: confusion, psychosis (lessened by splitting the dose) - Availability: Lariam 250 mg tab - Dose: (treatment) adult: 750 mg then 500mg in 6-8hrs. child: 15mg/kg single dose (prophylaxis):250 mg weekly (1 week before and 4 weeks after)

 2002 reported murders and suicides among US soldiers at Fort Bragg, N.C., given Lariam while stationed in war zones March 5, 2009 Jeff Schogol, Arlington, Va - C/I in patients with depression, traumatic brain injury, convulsions

Mefloquine

V. Primaquine
- drug of choice for the eradication of dormant liver forms of P. vivax and ovale - MOA: : - unknown mechanism of action - swelling of parasitic food vacuoles - gametocidal (4 strains) - check G6PD status - not used as standard treatment; oral - C/I: pregnancy - Other uses: pneumocystis carinii infection - AE: hemolytic anemia - Dose: 26.3mg (15mg base)/kg once a day x 14 days - preparation: Primaquine 15mg tab (US)

VI. Inhibitors of folate synthesis

- selectively inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for the synthesis of folate - resistance is due to mutations in dihydrofolate

reductase and dihydropterase synthase

1. Pyrimethamine (Fansidar)- safe in pregnancy, chemoprophylaxis; toxoplasmosis, pneumocystosis

2. Proguanil (Chloroguanide)- safe in pregnancy; for

treatment and prophylaxis (safe alternative to mefloquine; (+) chloroquine 500mg weekly and proguanil 200mg daily

1. Pyrimethamine (Fansidar)
- safe in pregnancy, chemoprophylaxis; - toxoplasmosis, pneumocystosis - MOA: inhibit dihydropteroate synthase (failure of nuclear division) - synergism (sulfonamides) - not recommended for chemoprophylaxis because of toxicity (once weekly) - Dose: adult: 2 tabs. Single dose child: 1.25mg pyrimethamine/kg and 25mg sulfa/kg 0R sulfadoxine-pyrimethamine 4 yrs. tab ; 4-8yrs. 1 tab; 9-14yrs. 2 tabs; > 14yrs. 2-3 tabs. - Preparation: 500mg sulfadoxine + 25mg pyrimethamine tablet

2. Proguanil
- safe in pregnancy; for treatment and prophylaxis (safe alternative to mefloquine); - (+) chloroquine 500mg weekly and proguanil 200mg daily - Ineffective against resistant strains

VII. Antibiotics - Unclear mechanism of action (inhibits cell wall synthesis)

- Tetracycline (for malaria, intestinal amoebiasis), 20mg/kg/day in 4 doses (max. 250mg QID) x 7days (treatment) preparation: 250mg and 500mg caps. - Doxycycline (chemoprophylaxis in SE Asia; for tx: (+quinidine or quinine) 100mg BID x 7days prophylaxis: 100mg daily 2 days before and 1 week after departure from endemic area - Clindamycin (malaria, toxoplasmosis, pneumocystosis, babesiosis) (treatment): 600 mg BID x 7days - Azithromycin

VIII. Halofantrine
- limited use because of irregular absorption and cardiac toxicity - C/I: pregnancy - dose: (treatment) >40kg: 2 250mg at 6-hrs interval (6 tabs) or <40kg. 24mg/kg divided in 3doses at 6 hrs. interval - preparation: (not available in the Phils)

IX. Artemisinin and derivatives

- only drug reliably effective against quinine-resistant strains - production of free radicals; best given with doxycycline or Fansidar - C/I: pregnancy - Quinghaosu- insoluble and can only be used orally - preparation: 20mg artemether + 120mg lumefantrin tab.

Artemisinin and derivatives

Artemether + Lumefantrine (AL) BID X 3days Artesunate + Amodiaquine (AS+AQ) OD X 3 days Artesunate + mefloquine (AS + MQ) OD X 3 days Artesunate + Sulfadoxine-Pyrimethamine (AS + SP) OD X 3 days Dihydroartemisinin + Piperaquine (DHA + PPQ) - OD X 3 days

X. Malarone
Atovaquone + proguanil Alternative therapy to P. carinii (750mg TID with meals X 21 days) Dose: 4 tabs. Daily x 3 days (treatment) 250 mg tab (prophylaxis) Preparation: 250mg/100mg tab

 Tx for uncomplicated malaria: Dihydroartemisinin + Piperaquine (DHA + PPQ) - OD X 3 days first line; strong recommendation; high quality of evidence Artemether + Lumefantrine (AL) BID X 3days Artesunate + Amodiaquine (AS+AQ) OD X 3 days Artesunate + mefloquine (AS + MQ) OD X 3 days Artesunate + Sulfadoxine-Pyrimethamine (AS + SP) OD X 3 days

WHO 2010 Guidelines for the Treatment of Malaria

 Choloroquine + Primaquine ACT (except AS + SP) + Primaquine

Treatment for uncomplicated P. vivax malaria

 1st trimester - Quinine + Clindamycin X 7 days - Artesunate + Clindamycin X 7 days ACT X 3 days 2nd trimester - ACTSP X 3 days - AS + Clindamycin X 7 days - Quinine + Clindamycin X 7 days

Treatment of Malaria during Pregnancy

 Artesunate (OD) + Tetracycline (QID) or Doxycycline (OD) or Clindamycin (BID) X 7 days Quinine + Tetracycline (QID) or Doxycycline (OD) or Clindamycin (BID) X 7 days

nd 2 line antimalarial

agents

Pneumocystis pneumonia Trimethoprim + Sulfamethoxazole

Use: Pneumocystis jirovecii (carinii) pneumonia chemoprophylaxis: 1 (160 mg) tab OD or 3x/week treatment: 2 (160mg) tabs every 8 hrs. x 21 days Preparation: - 40mg/80mg trimetoprim + 200mg/400mg sulfamethoxazole susp. - 80mg/160mg trimetoprim tab. + 400mg/800mg sulfamethoxazole tab.

Amoeba Life Cycle:

Drugs used for Amoebiasis Classification:

I. Tissue amoebicide a. Dehydroemetine, Emetine b. Chloroquine II. Luminal amoebicide a. Halogenated hydroxyquinolines 1. Diiodohydroxyquin 2. Iodochlorhydroxyquin 3. Dibromohydroxyquinoline

b. Dichloroacetamide 1. Diloxanide furoate 2. Clefamide 3. Teclozan 4. Etofamide

c. Antibiotic 1. Paramomycin

III. Tissue and Luminal amoebic a. Nitroimidazole 1. Metronidazole 2. Tinidazole 3. Ornidazole 4. Secnidazole

b. Niridazole

Amebicidal Agents:
I. Metronidazole - drug of choice for the treatment of
extraluminal amebiasis - kills trophozoites but not cysts - nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoas - DOC: tissue amoebiasis, giardiasis, trichomoniasis (2 g. SD) - AE: nausea, headache, dry mouth, metallic taste, disulfiram-effect - Drug interaction: anticoagulants, phenytoin, phenobarbital

II. Iodoquinol - effective luminal amoebicide - unknown mechanism of action III. Diloxanide furoate - drug of choice for asymptomatic luminal infections - unknown mechanism of action

IV. Paramomycin sulfate - an aminoglycoside used only as a luminal amebicide Availability: 250 mg caps. (US)

V. Emetine and Dihydroemetine - has limited use, given

SC or IM, not IV x 3-5 days - analog derived from ipecac

AE: pain and tenderness; diarrhea, nausea and

vomiting C/I: patients with cardiac or renal disease; children and pregnancy

Other Protozoal Agents:

I. Pentamidine - only administered parenterally (IV and
aerosol) - used in Pneumocystosis (aerosol): once a month (prophylaxis) IV or IM: OD x 21 days (treatment) African Trypanosomiasis, Leishmaniasis - unknown mechanism of action (interferes with nucleic acid metabolism of protozoas)

cutaneous leishmaniasis

visceral leishmaniasis
anemia enlarged liver and spleen fever weaker inflammatory response (due to the loss of phagocytes) weight loss.

II. Sodium Stibogluconate

- 1st line agents against cutaneous and visceral Leishmaniasis - unknown mechanism of action - dose: 20mg/kg/day IV or IM x 20 days - AE: GI upsets, sterile abscess

III. Drugs for Trypanosomiasis

a. Suramin - for African trypanosomiasis,but do not enter the CNS - unknown mechanism of action - dose: 200mg IM test dose; 1g on days 1,3,7,14,21 b. Melarsoprol - 1st line therapy for advanced CNS African Trypanosomiasis - dose: 3.6mg/kg/day x 3-4days c. Eflornithine - an inhibitor of ornithine decarboxylase

- a 2nd therapy for advanced CNS African trypanosomiasis

- dose: 100mg/kg IV every 6hrs. X 14 days ffed by oral therapy for 3-4weeks

d. Nifurtimox - most common drug used for American

Trypanosomiasis (Chagas disease) dose: 8-10mg/kg orally x 3-4months

e. Benznidazole - for the treatment of acute Chagas disease

toxicities: peripheral neuropathy, rash, GI symptoms, myelosupression

Antihelminthic Agents

Ascaris lumbricoides

Enterobius vermicularis

Rectal prolapse in Trichuris trichiuria

pinworm/treadworm/seatworm

Antihelminthic Drugs:
I. Albendazole - drug of choice for the treatment of hydatid disease, neurocysticercosis and cutaneous larva migrans MOA: act by inhibiting microtubule synthesis in nematodes, thus irreversibly impairing glucose uptake; also has larvicidal effects in hydatid disease, cysticercosis, ascariasis and hookworm infection and ovicidal effects in ascariasis, ancylostomiasis and trichuriasis

Availability: Zentel 400mg tab and 200mg/5ml

Roundworms, pinworm, hookworm: 400mg SD may repeat in 3wks Strongyloidiasis, taeniasis: 400mg daily x 3 days (may rpt) Larval taeniasis: 800mg in 2 divided doses x 14-30days Neurocysticercosis: 15mg/kg OD x 8-30days

Albendazole

whipworm

II. Mebendazole - same MOA as Albendazole

- used in ascariasis, trichuriasis and hookworm and pinworm infection

- MOA: act by inhibiting microtubule synthesis in

nematodes, thus irreversibly impairing glucose uptake; also has larvicidal effects in hydatid disease, cysticercosis, ascariasis and hookworm infection and ovicidal effects in ascariasis, ancylostomiasis and trichuriasis

Availability: Antiox 100mg, 500mg tab 50mg/ml and 100mg/ml Ascariasis, Trichuriasis, Hookworm: 1-day treatment (500mg SD) 3-day treatment (100mg/day or 100mg BIDx 3days) Enterobiasis: 100mg SD, repeated after 2 weeks

Mebendazole

III. Thiabendazole
- alternative drug for the treatment of strongyloidiasis and cutaneous larva migrans - same MOA as Albendazole - a chelating agent - has anti-inflammatory properties, has immunomodulating effects on T cell function Cream: 2-3x a day x 5 days Trichinosis: 25mg/kg BID x 7 days Strongyloidiasis: 25mg/kg in 3 divided doses x 2 days

IV. Bithionol
- drug of choice for the treatment of fascioliasis - dose: 30-50mg/kg in 2-3divided doses, orally, after meals on alternate days x 10-15days - AE: abdominal cramps; caution in children - an alternative drug in the treatment of pulmonary paragonimiasis

V. Diethylcarbamazine Citrate
- drug of choice for the treatment of filariasis, Loiasis and tropial eosinophilia - MOA: immobilizes the microfilariae and alters their surface structure, making them more susceptible to destruction by host defense mechanism - mazzoti reaction (give antihistamines) - Mass treatment: 6mg/kg weekly every 6-12 mos. - Treatment: 2mg/kg 3x a day x 7 days (lymphatic filariasis) repeated after 3-4 weeks - Prophylaxis: 50mg monthly (lymphatic filariasis) - Treatment: 1mg/kg daily x 3 days then 8-10mg/kg x 2-3weeks (loa-loa) - Prophylaxis: 300mg weekly (loa-loa)

VI. Emetine Hydrochloride

- are alternative drugs for the treatment of Fasciola hepatica infection.

VII. Ivermectin
- drug of choice in strongyloidiasis and onchocercosis - an alternative drug for scabies and filariasis - no known pharmacologic or toxic effects in humans because it does not cross the blood brain barrier - MOA: modulates GABA-mediated neurotransmission - AE: mazzoti reaction - Dose: onchocercosis: 150ug/kg with water, 3 mos. interval x 12 mos. strongyloidiasis: 200ug/kg SD Bancroftian filariasis: 400ug/kg + diethylcarbamazine 6mg/kg scabies - C/I: children younger than 5 years of age or to those weighing less than 15 kg; to pregnant women; or to nursing mothers in the infant's first week of life.

VIII. Levamisole
- highly effective in eradicating ascaris and trichostrongylus and moderately effective against both species of hookworm (repeat tx once in 3-7days) - dose: 150mg SD - used as an immunomodulating agent as adjunct therapy with fluoroucil after surgical resection in patients with Duke stage C colon cancer.

IX. Metrifonate - a safe, low cost alternative drug for the

treatment of Schistosoma haematobium infections - MOA: cholinesterase inhibition - dose: 7.5-10mg/kg orally TID SD at 14days interval

X. Niclosamide - drug of choice for most tapeworm

infections, but not available in the US - MOA: inhibition of oxidative phosphorylation or to its ATPasestimulating property. - dose: 2 g. (4tabs) SD chewed then swallowed with

water

XII. Oxantel Pamoate/Pyrantel Pamoate

- MOA: depolarizing muscular blocking (Ach) agents (pyrantel: ascaris and hookworm oxantel: trichuriasis - dose: roundworm, pinworm, trichostrongyliasis: 11mg/kg SD hookworm: 11mg/kg/day OD x 3 days

XIII. Piperazine citrate - alternative drug in the treatment

of ascariasis - almost free of pharmacologic action in the host - MOA: causes paralysis of ascaris by blocking acetylcholine at the myoneural junction - dose: ascariasis: 75mg/kg/day OD x 2days enterobiasis: 65mg/kg/day OD x 7days - preparation: 500mg/5 ml and 1 g/5ml - AE: seizures

XIV. Praziquantel
- effective in the treatment of schistosome infection of all species and most other trematode and cestode infections, including cysticercosis - MOA: drug increases cell membrane permeability to calcium, resulting vacuolization, marked contraction, paralysis, dislodgement, and death

 Dose: schistosomiasis: 40mg/kg/dose BID x 1 day at 4-6hrs. interval flukes: 25mg/kg/dose every 8hrs. X 1-2days tapeworms: 5-10mg/kg SD cysticercosis: 15.5mg/kg/dose every 8hrs. X 15days Preparation: 600mg tab

Praziquantel

 Deworming 12-59 months old: Mebendazole 500 mg single dose OR Albendazole 400 mg single dose

Integrated Management of Childhood Illness (2008)

Differentiate protozoal and helminthic infections Discuss conditions that promote parasitic infections Discuss the kinetics and dynamics of antiparasitic agents Enumerate the drug of choice for the different parasitic infections Able to manage parasitic infections

In summary ..

(Boracay!!) Thanks dami