antiparasitic agents

1. ANTIPARASITIC
DRUGS:
ANTIHELMINTHICS
BY
DR BAKUT JOHN MAIGANGA
DEPARTMENT OF CLINICAL PHARMACOLOGY AND THERAPEUTICS
FACULTY OF BASIC CLINICAL SCIENCES
ABUTH, ZARIA.
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2. Introduction
• Over 1 billion people world wide infested with Nematodes
(round worms), Flukes (Trematodes), Tape worms
(Cestode)
• In many cases the goal of chemotherapy is control of
infestation, elimination of parasites and decreasing
transmission
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3. Drugs of choice
• Round worms (Nematodes): Albendazole, Mebendazole,
Pyrantel Pamoate, Ivermectin, Diethylcarbamazine
• Flukes (Trematodes): Praziquantel, Bithionol,
Triclabendazole, Niclosamide
• Tapeworms (Cestodes): Praziquantel, Niclosamide,
Albendazole
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4. Albendazole
• A broad spectrum oral helminthic for treatment of pin
worm, hookworm, ascariasis, trachuriasis, and
strongyloides
• A benzimidazole carbamate, absorbed erratically (more
with fatty meals)
• Rapidly undergoes first pass effect in the liver and
converted to active metabolite Albendazole sulfoxide
• Maximum plasma concentration is reached in 3 hours
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5. Albendazole
• Plasma half life is between 8-12 hours usually protien
bound but widely distributed in tissues reaching the CSF
and bile
• Excreted in urine
• Mechanism of action
Nematode: Inhibit microtubule synthesis
Larvicidal effects in Cysticercosis, Hydatid disease,
Ascariasis, Hookworm infestation
Ovicidal effects on Ascariasis, Ancylostomiasis and
Trachuriasis
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6. Albendazole
• Dosage
Given Tabs 400mg single dose
400mg daily for 2-3 days in heavy infestation
For children: Suspension of 100mg/5ml is available
400mg bids for 21 days for Neurocysticercosis
400mg daily for one-six months for Hydatid disease plus
surgical resection of cyst
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7. Albendazole
• Adverse effect include mild transient epigastric pain,
diarrhea, headache, nausea, vomiting, dizziness,
lassitude, insomnia
• Following long term use: Abd pain, headache, fever,
fatigue, alopacia, pancytopenia and elevation of Liver
enzymes
• Contraindicated in hypersensitivity, cirrhosis, Safety profile
not established in pregnancy, children less than 2 years
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8. Mebendazole
• A synthetic benzimidazole that has wide spectrum of
antihelminthic activity with low incidence of adverse effect
• Less than 10% orally administered drug is absorbed
• Greater than 90% is bound to plasma protein
• Converted to inactive metabolite by the liver
• Plasma half life is 2-6 hours
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9. Mebendazole
• Excreted in urine mainly as decarboxylated derivatives
• Also excreted in bile
• Acts by inhibiting microtubules synthesis in
parasites. It kills hookworm, ascaris, and trichuris
eggs
• Dosage is 100mg once and the repeated after 2 weeks
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10. Mebendazole
• For Ascaris, Trichuriasis, Hookworm and Trichostrongylus
infestation, a dosage of 100mg twice daily for 3 days can
be administered
• For intestinal capillariasis; 200mg twice daily for 21 days
• For intestinal and tissue larvae 200-400mg per dose for 3
days and may be extended to 400-500mg once daily for
10 days, co-administerd with Corticosteriod
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11. Bithionol
• An atternative to triclabendazole for the treatment of
Fascioliasis (Sheep fluke) and Paragonimiasis
• Peak blood level is reached within 4-8 hours of oral
administration
• Excretion is via the kidneys
• Oral 30-50 mg/kg in 2 or 3 divided doses after meal in
alternate days for 10-15 doses is recommended
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12. Bithionol
• Cure rate:
Pulmonary paragonimiasis is 90%
Cerebral paragonimiasis requires repeat courses of
treatment
• Adverse effects occur in 40% of patients
• These include diarrhea, abd cramps, anorexia, nausea,
vomiting, headaches, skin rashes, due to antigenic
reactions from dead worms
• Should be used with caution in children less than 8 years
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13. Diethylcarbamazine Citrate
• A synthetic Piperazine derivative
• It immobilizes microfilariae and alters their surface
structure, displacing them from tissues and making them
susceptible to destruction by host defense mechanisms.
Actions on adult worms not clear
• Drug of choice in treatment of filariasis, loiasis and tropical
eosinophilia. May be used in treatment of Onchocerciasis
• Rapidly absorbed in the GIT and should be taken after meals
• Reaches peak plasma levels within 1-2 hours
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14. Diethylcarbamazine Citrate
• Plasma half life is 2-3 hours, well distributed in tissues
except in fat
• Excreted in urine as an unchanged drug and the N-oxide
metabolite
• Reactions are generally mild and transient and may include
headache, malaise, anorexia, weakness, vomiting and
dizziness
• Release of protein from dying microfilariae or adult worms,
particularly severe in onchocercaisis (Ivermectin is used
instead)
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15. Ivermectin
• A semi-synthetic macrocyclic lactone, it is derived from
the soil actinomycete Streptomyces avermitilis
• Appears to paralyze nematodes and arthropods by
intensifying Ү-aminobutyric acid (GABA)-mediated
transmission of signals in peripherial nerves
• Drug of choice in treatment of Strongiloidiasis and
Onchocerciasis
• It is also an alternative to drug for a number of other
helminthic infections
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16. Ivermectin
• Used only orally in humans and is rapidly absorbed,
reaching maximum plasma concentration after 4 hours
• Has a wide tissue ditribution and a volume of distribution
of 50L
• Plasma half life is 16 hours
• Excreted exclusively via feaces
• After a single standard dose diminishes microfilariae
rapidly and remains for months
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17. Ivermectin
• Infrequent adverse effects include fatigue, dizziness,
nausea, vomiting, abdominal pain and rashes
• Microfilariae death could lead to fever, headache,
somnolence, weakness, rash, pruritus, diarrhea, joint and
muscle pain, hypotension, tachycardia, lymphagiatis,
peripherial oedema
• 0.1% of individuals will have severe reaction which
includes high fever, hypotension and bronchospasm,
corticosteriod are indicated
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18. Ivermectin
• Drugs that enhances GABA activity should not be used
with Ivermectin (Barbiturates, Benzodiazepines,
Valproate)
• Safety in children less than 5 years is not established
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19. Metrifonate (Trichlorofon)
• A safe, low-cost organophosphate compound
alternative drug for the treatment of Schistosoma spp
• It is rapidly absorbed after a standard oral dose reaching
peak blood levels in 1-2 hours
• The half life is 1.5 hours
• Clearance appears to be through nonenzymatic
transformation to dichlorvos, its active metabolite
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20. Metrifonate (Trichlorofon)
• Metrifonate and dichlorvos are well distributed in tissues
and are completely eliminated in 24-48 hours
• The mode of action is thought to be related to
cholinesterase inhibition. The inhibition temporarily
paralyses the adult worms resulting in their shift from
bladder veins to small arterioles in lungs where they
are trapped and immune system encase them and
destroy them
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21. Metrifonate (Trichlorofon)
• The drug has no effect on S. heamatobium eggs, the eggs will
continue to be excreted in urine months after treatment
• S. heamatobium oral treatment is done with 7.5–10mg/kg 3
times within 2 weeks with cure rate of 44-93% and marked
reduction in egg count
• Reactions are usually mild and transient cholinergic symptoms
including nausea, vomiting, diarrhea, bronchospasms, vertigo
• Contraindicated in pregnancy and recent exposure to drugs
that may potentiate cholinesterase inhibition
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22. Niclosamide
• Niclosamide is a second line drug for the treatment of
most tapeworm infestation
• A salicylimide derivative which act by inhibiting
oxidative phosphorylation or ATPase activity thereby
rapidly killing adult worms but not their ova
• Adult dose is 2g once on empty stomach, chewed
thoroughly and swallowed with water
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23. Niclosamide
• Clinically use in treatment of Taenia spp, Diphyllobothrium
latum (fish tape worm)
• Cure rate is between 85%-95% for Taenia spp and
Diphyllobothrium spp
• Praziquantel is more effective for treatment of dwarf worm
• Niclosamide is not effective in treatment of cysticercosis
and hydatid disease
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24. Niclosamide
• Treatment of intestinal flukes Fasciolopsis buski,
Heterophyes heterophyes and Metagonimus yokogawai is
done by giving standard doses every other day for 3 days
• Infrequent mild and transitory adverse events including
nausea, vomiting, diarrhea, abd pain,
•
• Consumption of alcohol should be avoided on the day of
treatment and 1 day afterwards
• Safety profile in pregnancy and children less than 2 years
is not established
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25. Oxamniquine
• Is an alternative to Praziquantel for the treatment Schistosoma
mansoni
• A semi-synthetic tetrahydroquinoline
• Rapidly absorbed orally and should be taken with foods
• Plasma half life is 2.5 hours and extensively metabolized to
inactive form and excreated in urine upto 75% within 24 hours
• Mode of action is unknown but it causes contraction and
paralysis of the worms resulting in detachment from
venules in mesentery leading to the liver where many die
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26. Oxamniquine
• Is effective in instances of praziquantel resistance
• Clinically use in treatment of all stages of S. mansoni and
advanced hepatosplenomegarly
• Adult dose is from 12-15 mg/kg with cure rate of 70-95%
with marked reduction in egg concentrtion
• Adverse reactions include dizziness, headaches and
drowsiness, nausea, vomiting, diarrhea, colics, pruritus
urticaria, orange-coloured urine, protienuria, microscopic
heamaturia, seizure, decreased leukocytes
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27. Piperazine
• An alternative for the treatment of ascaris with cure rate of
90% when taken for 2 days but not recommended for
other helminths
• Is a Hexahydrate and has a variety of salts
• Readily absorbed orally reaching maximum plasma
concentration in 2-4 hours
•
• Excreted unchanged in urine in 2-6 hours and completely
in 24 hours
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28. Piperazine
• Acts by causing paralysis of ascaris by blocking
acetylcholine at a myoneural junction; unable to
maintain their position in the host, live worms are
expelled by normal peristalsis
• Dose is 75mg/kg per day for 2 days (max dosage is 3.5g)
• Adverse effects include nausea, vomiting, abd pain,
dizziness, headache, neurotoxicity and allergy are rear
• Contraindicated in pregnancy, hepatic and renal
impairement
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29. Praziquantel
• Is effective in treatment schistosome, trematode, cestode and
cysticercosis
• A synthetic isoquinoline-pyrazine derivative
• Rapidly absorbed with bioavailability of 80% after oral
administration (CSF Conc 14-20%)
• Peak plasma concentration is reached at 1-3 hours and 80% is
bound to plasma protein
• Rapidly metabolized to inactive mono and polyhydroxylated
products after a first pass in the liver
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30. Praziquantel
• Plasma half life is 0.8-1.5 hours
• Excretion via kidneys (60-80%), bile (15-35%)
• Drug absorption and bioavailability are increased by
taking it with cimetidine and high carbohydrate diet and
reduced by corticosteroids, phenytoin, carbamazipine
• Act by increasing permeability of trematode and cestode
cell membranes to calcium, resulting in paralysis,
dislodgement and death
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31. Praziquantel
• Adverse effects are mild and transient, most common are
headaches, dizziness, drowsiness, lassitude, nausea,
vomiting and diarrhea, abd pain, pruritus, urticaria,
arthralgia, myalgia
• Severe meningismus, mental changes, intracranial
hypertension,
•
• Contraindicated in ocular cysticercosis because parasite
destruction can lead to irreparable eye damage
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32. Praziquantel
• Safety in children less than 4 years is not established
• Should be avoided in pregnancy because it causes
abortion in rats
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33. Pyrantel Pamoate
• A broad-spectrum antihelminthic highly effective for
treatment of pinworm, ascaris, hookworm
• Is a tetra-hydropyrimidine derivative
• It is poorly absorbed from GIT
• Peak plasma levels are reached in 1-3 hours
• About 50% is excreted in feaces unchanged
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34. Pyrantel Pamoate
• Acts as a neuromuscular blocking agent that causes
release of acetylcholine and inhibit cholinesterase
and leads to paralysis of worms and that leads to
expulsion of the worms
• Standard dose is 11mg/kg (max 1g) given orally once with
or without food may be repeated when treating pinworm
• Cure rate range between 85-100%
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35. Pyrantel Pamoate
• Adverse effects are infrequent, mild and transient,
includes: nausea, vomiting, diarrhea, abd cramps,
dizziness, drowsiness, headache, insomnia, rash, fever,
weakness,liver dysfunction
• Safety profile in pregnancy and children less than 2 years
is not well establish
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36. Thiabendazole
• Alternative to Ivermectin and albendazole in the treatment
of strongyloides and cutaneous larva migrans
• A benzimidazole that chelates iron however it does not
bind calcium
• Absobed rapidly after ingestion of standard dose reaching
peak plasma concentration in 1-2 hours
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37. Thiabendazole
• Almost completely metabolized in the liver to 5-hydroxy
form
• About 90% is excreted in urine in 48 hours as glucuronide
or sulfonate conjugate
• Standard dosage is 25 mg/kg (max 1.5 g) twice daily
given after meals for 2-7 days depending on type and
density of worms
• Cure rate is 93%
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38. Thiabendazole
• Adverse effects include dizziness, anorexia, nausea,
vomiting, epigastric pain, diarrhea, pruritus, headaches
• Severe effects include neuropsychiatric symptoms,
irreversible liver failure, fatal Steven johnsons syndrome
• Contraindicated in children less than 15kg and pregnancy
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39. Reference
1. Bertram G K, Masters S B, Trevor J A, Basic and clinical
Pharmacology twelfth Edition 2012; Pg 937-47
2. Charles C, Robert E, Modern pharmacology with clinical
applications
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