Antiparasitic Agents Revised

7/28/2019 Antiparasitic Agents Revised

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Antiparasitic AgentsMa. Victoria M. Villarica RN, MD, FPSECP



Objective

•

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 parasiticinfections

• Learn to manage parasitic infections



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 complicationsc. availability and efficacy of therapeutic agents

3. Individualized treatment

4. Ff-up clinical and laboratory assessment is

needed5. 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



Targets of antiparasitic

chemotherapy

• 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



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



Diagnosis of malaria

• Direct microscopy – less expensive but skilled staff is

needed

• RDT (rapid diagnostic test) - expensive



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 breakdownproduct, 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 chloroquineresistant 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 limitedexperience 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)



Mefloquine

• 2002 –

reported murders and suicides among US soldiersat 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



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. – ½ 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 21days)

• Dose: 4 tabs. Daily x 3 days (treatment)

250 mg tab (prophylaxis)

• Preparation: 250mg/100mg tab



WHO 2010 Guidelines for the

Treatment of Malaria

• 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



Treatment for uncomplicated

P. vivax malaria

• Choloroquine + Primaquine

• ACT (except AS + SP) + Primaquine



Treatment of Malariaduring Pregnancy

• 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



2nd line antimalarialagents

•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



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 amoebicidea. 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 actionIII. 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 acidmetabolism of protozoas)



anemia

enlarged liver and spleenfever

weaker inflammatory response (due to the

loss of phagocytes)

weight loss.

cutaneous leishmaniasis

visceral leishmaniasis



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



Enterobius vermicularisAscaris lumbricoides



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



Albendazole

Roundworms, pinworm, hookworm:

400mg SD may repeat in 3wksStrongyloidiasis, 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



“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 glucoseuptake; also has larvicidal effects in hydatid

disease, cysticercosis, ascariasis and

hookworm infection and ovicidal effects in

ascariasis, ancylostomiasis and trichuriasis



Mebendazole

Availability: Antiox 100mg, 500mg tab

50mg/ml and 100mg/mlAscariasis, Trichuriasis, Hookworm:

1-day treatment (500mg SD)

3-day treatment (100mg/day or

100mg BIDx 3days)Enterobiasis:

100mg SD, repeated after 2 weeks



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 immunomodulatingeffects 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 onalternate 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)



I. 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 doesnot 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 lessthan 15 kg; to pregnant women; or to nursing mothers in the infant'sfirst 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 withfluoroucil after surgical resection in patients with Duke stage

C colon cancer.

IX Metrifonate f l t lt ti d f th



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



II. 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 speciesand most other

trematode and cestode infections, including cysticercosis

- MOA: drug increases cell membrane permeability to calcium,resulting vacuolization, marked contraction,

paralysis, dislodgement, and death



Praziquantel

• Dose: schistosomiasis: 40mg/kg/dose BID x 1 day at

4-6hrs. intervalflukes: 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



Integrated Management of

Childhood Illness (2008)

• Deworming – 12-59 months old: Mebendazole 500 mg

single dose OR

Albendazole 400 mg single dose



In summary …..

• 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 parasiticinfections

• Able to manage parasitic infections



(Boracay!!)

Thanks dami

Antiparasitic Agents Revised

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