Antihelminthic Drugs

Helminthies are commonly known as worms, which infect humans and animals. They are common in villages and areas of poor sanitary conditions. Children are mainly affected, as they have the habit of taking everything into mouth.

Those infecting humans are known as metazoa, which are of two groups:

1. Round worm -nematodes
2. Flat worm –cystodes, tramatodes

Worms are motile. Motility is essential for developmental cycle, which is a complicated process, involving one or more intermediate hosts.

Clinically worms are divided into two groups:

1. Those infecting intestines –intestinal helminthes
2. Those infecting tissue/viscera –visceral helminthes

Nematodes

• Ascaris lumbricoides
• Ancylostoma duodenale
• Enterobius vermicularis
• Dracunculus medinensis
• Strongyloides stercoralis
• Trichuris trichura
• Wuchereria bancrofti

Cestodes (Tape worms)

• Taenia saginata
• Taenia solium
• Diphyllobothrium latum
• Hymenolepis nana

Echinococcus granulosus

Trematodes (Flukes)

• Blood fluke
• Intestinal fluke
• Lung fluke
• Liver fluke

Intestinal Helminths

• Ascaris lumbricoids
• Ancylostoma duodenale
• Enterobius vermicularis
• Strongyloides stercoralis
• Trichuris trichura
• Taenia saginata
• Taenia solium

Tissue/visceral Helminths

• Echinococcus granulosus
• Wuchereria bancrofti
• Blood fluke

HELMINTH NEMATODES Ascaris lumbricoides Ancylostoma  duodenale Enterobius  vermicularis Strongyloides  stercoralis	OTHER NAME  Round worm Hook worm Pin worm Thread worm	DISEASE  Ascariasis Ancylostomiasis Enterobiasis (pin worm infection) Strongyloidiasis
Trichuris  trichuraDracunculus medinensis Wuchereria bancrofti	Whip wormGuinea worm              —-	TrichuriasisDracunculiasis Flariasis
CESTODESTaenia saginata Taenia solium Diphyllobothri-um latum Hymenolepis nana Echinococcus granulosus	TAPE WORMSBeef tapeworm Pork tapeworm Fish tapeworm      Dwarf tapeworm            —-	Taeniasis Cysticercosis Diphylobothri-asis Hymenolepiasis Hydatid disease
TREMATODESSchistosoma Heterophyes heterophyes Paragonimus westermani Clonorchis sinensis	FLUKESBlood fluke Intestinal fluke Lung fluke Liver fluke	Schistosomiasis              —- Paragonimiasis Clonorchiasis

Classification

Drugs Acting Against Nematodes

—  Ascariasis (round worm infection)

Albendazole

Mebendazole

Pyrantel pamoate

Ivermectin

—  Ancylostomiasis (Hook worm infection)

Albendazole

Mebendazole

Pyrantel pamoate

—  Dracunculiasis (Guinea worm infection)

Metronidazole

—  Enterobiasis (Pin worm infection)

Albendazole

Mebendazole

Pyrantel pamoate

Ivermectin

—  Filariasis (Wuchereria bancrofti)

Diethylcarbamazine

  Stongyloidosis (thread worm)

Ivermectin

Thiabendazole

Drugs Acting Against Cestodes

—  Taeniasis

Niclosamide

Praziquantel

Albendazole

Mebendazole

—  Hymenolepiasis

Niclosamide

Praziquantel

Diphylobothriasis (Diphyllobothrium Latum)

Niclosamide

Praziquantel

—  Hydatid disease (Echinococcus) –surgery is required for ultimate treatment

Albendazole

Mebendazole

Niclosamide

Drugs Acting Against Trematodes

—  Schistosomiasis (blood flukes)

Praziquantel

Metrifonate

oxamniquine

—  Intestinal Flukes

Praziquantel

—  Liver flukes

Praziquantel

—  Lung flukes

Praziquantel

Mebendazole

• Synthetic benzimidazole
• Wide spectrum antihelminthic  activity
• Low incidence of side effects

Pharmacokinetics

• Poorly  absorbed (< 10%)

• Absorption increased with fatty meal
• Highly protein bound -PPB >90%
• Half life 2-6 hrs.
• Rapidly metabolized in liver & mostly renaly  excreted

Mechanism of action

Primary Action

Binds with β tubulin of microtubules  & inhibit its synthesis à worm becomes immobile & dies slowly

Other Actions

• Blocks glucose uptake
• Uncoupling of oxidative phosphorylation

Results in loss of ATPs

Resistance

Point mutation in β tubulin results in decreased binding affinity to Mabendazole

Therapeutic Uses

Tablet should be chewed before swallowing.

Drug of choice for:

1. Pinworm Infections (enterobiasis) (single dose of 100 mg once, repeated after 2 weeks)
2. Round worm infection (Ascariasis)
3. Whip worm infection(Trichuriasis)
4. Hookworm infections
5. Intestinal capillariasis -200 mg twice daily for 21 days

Also used as alternative drug for:

1. Hydatid disease –surgery ultimate treatment
2. Taeniasis
3. Trichinosis

Adverse Effects

On short term therapy like intestinal nematodes

1. Mild nausea,
2. vomiting,
3. diarrhea, and
4. abdominal pain

On prolong duration therapy like hydatid cyst

1. hypersensitivity reactions (rash, urticaria),
2. agranulocytosis,
3. alopecia, and
4. elevation of liver enzymes

Drug Interactions

Enzyme inhibitors (Cimetidine) increase drug levels

Enzyme inducers (phenytoin) decrease drug levels

Contraindications

1. Pregnancy
2. children < 2 yrs age

Albendazole

• —  Benzimidazole
• —  Broad spectrum

Pharmacokinetics

• —  Erratically absorbed, rapidly metabolized in liver
• —  Absorption increases with fatty meal
• —  Active metabolite is albendazole sulfoxide
• —  Half life 8-12 hrs. (longer than mebendazole)
• —  Mostly protein-bound

• —  Distributes well to tissues, enters bile, cerebrospinal fluid, and hydatid cysts.
• —  Metabolites are excreted in the urine.

Mechanism of Action

—  Same as mabendazole (binds beta tubulin, resulting in immobility)

Larvicidal effects in hydatid disease, cysticercosis, ascariasis, and hookworm infection

Ovicidal effects in ascariasis, ancylostomiasis, and trichuriasis

Because of these two effects, albendazole is superior than mebendazole.

Uses

Taken on empty stomach when used for intestinal infections (ascariasis, enterobiasis)

Taken with fatty meal when used for tissue infections for increased absorption.

1. Drug of choice for Hydatid Disease (surgery)

Dose is 400 mg twice daily for one month.

2. Drug of choice for Ascariasis
3. Hookworm infection
4. Pinworm infections
5. Trichuriasis -400 mg OD for 3 days
6. Neurocysticercosis (pretreatment with glucocorticoid because dying worms produce inflammation, leading to allergic reaction)

Alternative drug for:

1. Gnathostomiasis

2. Cutaneous & visceral larva migrans
3. Intestinal capillariasis
4. Clonorchiasis

Adverse Effects

1.      On short term therapy like intestinal nematodes

1. Mild nausea,
2. vomiting,
3. diarrhea, and
4. abdominal pain

2.      On prolong duration therapy like hydated cyst

1. hypersensitivity reactions (rash, urticaria),
2. agranulocytosis,
3. alopecia, and
4. elevation of liver enzymes

Contraindications

• Pregnancy
• Children < 2 yrs age

Thiabendazole

• Benzimidazole compound
• Chelating agent forming stable complexes with a number of metals including iron, but does not combined with calcium.

Pharmacokinetics

• Rapidly absorbed when given orally
• half-life is 1.2 hours
• Metabolized in liver
• Excreted in urine
• Also absorbed from skin

Mechanism of Action

Same as other benzimidazoles

1. Binds beta tubulin inhibiting motility, worms die slowly
2. Decrease uptake of glucose
3. Uncoupling of oxidative phosphorylation

Uses: both oral and tropical

Thiabendazole is an alternative to Ivermectin for the treatment of:

1. strongyloidiasis and
2. cutaneous larva migrans.

Adverse effects

Much more toxic than other benzimidazoles, thus not preferred.

1. Common adverse effects include:

• dizziness,
• anorexia,
• nausea, and
• vomiting.

2. Less frequent problems are:

• epigastric pain,
• abdominal cramps,
• diarrhea,
• pruritus,
• headache,
• drowsiness, and

• neuropsychiatric symptoms.

3. Irreversible liver failure and fatal Stevens-Johnson syndrome
4. Crystaluria and hematuria
5. Urine has characteristic odor  due to metabolite

Contraindications

• Pregnancy
• Children < 2 yrs age
• Renal and hepatic disease

Pyrantel Pamoate

• Tetrahydropyrimidine derivative having broad spectrum
• Poorly  absorbed and excreted in feces
• First introduced in veterinary medicine, but due to effectiveness and lack of ADRs, tests were conducted for human trials.

Pharmacokinetics

1. Poorly absorbed from GIT
2. Highly active against luminal helminthic infection
3. Over half of administered dose is removed from body by feces.

Mechanism of Action

• Depolarizing neuromuscular blocking agent. It blocks NM transmission.
• Increases Acetyl choline release and inhibits Acetyl choline esterase
• Both effects result in increased acetylcholine at NMJ.
• Spastic paralysis
• Worm becomes immobile & expelled out

Uses

a.      Pinworm,
b.      Ascariasis,
c.       Hookworm,
d.      Trichostrongylus orientalis

Dose: 11 mg/kg. For Ascaris and hookworm, single dose is effective, while for pinworm infection, dose is repeated after 2 weeks.

Not effective against trichoriasis but one analog, oxantal palmoate has been successively used for this condition.

Adverse effects

Adverse effects are infrequent, mild, and transient.

1. nausea,
2. vomiting,
3. diarrhea,
4. abdominal cramps,
5. dizziness,
6. drowsiness,
7. headache,
8. insomnia,
9. rash,
10. fever, and
11. weakness

Contraindications

• Pregnancy
• Children < 2 yrs age

Ivermectin

Semisynthetic macrocyclic lactone, mixture of avermectin B_1a and avermectin B_1b

Mechanism of action

Potentiate release and binding of GABA, resulting in increased influx of calcium chloride and hyperpolarization, leading to flaccid paralysis. Worm becomes immobile and is expelled out.

Pharmacokinetics

• —  Rapidly absorbed from GIT
• —  wide tissue distribution and a volume of distribution of about 50 L
• —  half-life is about 16 hours
• —  Excreted in the feces.

Uses

Drug of choice for:

1. Onchocerciasis –does not kill adult worm, only microfilariae. 150 mcg/kg taken on empty stomach, singly dose, rapidly reduces count of microfilariae which remains low for many months, then starts growing again. Dose is repeated every year, complete removal may take 10 years or longer.

2. Strongyloidiasis –200 mcg/kg for two days

Alternative for:

1. Ascariasis
2. Cutanous larva migrans

3. Trichuriasis
4. Brugia malayi
5. Lice
6. Loasis
7. Scabies

Adverse effects

In treatment of Strongyloidiasis, side effects are infrequent and mild:

1. fatigue,
2. dizziness,
3. nausea,
4. vomiting,
5. abdominal pain, and
6. rashes

In Onchocerciasis principally because of dying microfilariae:

Mazotti reaction occurs due to killing of microfilariae

Includes:

1. fever,
2. headache,
3. dizziness,
4. somnolence,
5. weakness,
6. rash,
7. increased pruritis,
8. diarrhea,
9. joint and muscle pains,
10. hypotension,
11. tachycardia,
12. lymphadenitis,
13. lymphangitis, and
14. peripheral edema

This reaction starts on the first day and peaks on the second day after treatment

In 5-30% cases mild reaction occurs, in 1-3% of cases moderate to severe reaction occurs and in 0.1% cases very severe reaction with very high fever, hypotension, bronchospasm occurs.

To avoid, pretreatment with glucocorticoids is recommended.

Contraindications

• Pregnancy
•  < 5 yrs age

Niclosamide

• Salicylamide derivative
• —  Minimally absorbed when taken orally
• —  Rapidly kills adult worms (but not ova)

Mechanism of Action

• Inhibition of oxidative phosphorylation or stimulation of ATPase activity.
• Both result in decreased ATP, leading to death of worm.

Uses

2^nd line drug for tape worm infection, chewed properly before swallowing.

• —  T. Saginata                  
• —  T. Solium
• —  Diphylobothrium latum
• —  Hymenolepis nana – 2g for 7 days
• —  Hymenolepis diminuta
• —  Dipylidium caninum
• —  Intestinal fluke infections –alternate drugs, dose 2g on alternate days for 3 days

Adverse effects

Infrequent, mild, and transitory adverse events include:

1. nausea,
2. vomiting,
3. diarrhea, and
4. abdominal discomfort.

Contraindications

• —  Pregnancy
• —  Children > 2 years

Praziquantel

Chemistry-isoquinoline pyrazine

Pharmacokinetics

• —  Rapidly absorbed
• —  Absorption increase with a high carbohydrate meal
• —  Bioavailability of about 80%
• —  PPB 80%
• —  Rapidly metabolized to inactive mono- and polyhydroxylated products
• —  Half-life is 0.8–1.5 hours
• —  Excretion via kidneys (60–80%) and bile (15–35%).

Mechanism of Action

Increase the permeability of calciumà spastic  paralysis àdislodgement  à death

Uses

Should be taken with liquid after a meal & should be swallowed without chewing because its bitter taste can induce retching and vomiting.

Drug of choice in:

1. Tape worm infections –single dose, 2-10 mg/kg sufficient
2. Trematodes or flukes -200 mg/kg, 2doses after 4-6 hours

Alternative drug for:

1. Neurocysticercosis
2. Hydatid disease

Adverse effects

Mild and transient, begin within several hours after treatment, may persist for one day. Include:

1. Headache,
2. dizziness,
3. drowsiness, and
4. lassitude;
5. nausea,
6. vomiting,
7. abdominal pain,
8. loose stools,
9. pruritus,
10. urticaria,
11. arthralgia,
12. myalgia, and
13. low-grade fever

Contraindications

• Pregnancy
•  < 4 yrs age

Drug Interactions

• Enzyme inhibitors (Cimetidine) increase drug levels
• Enzyme inducers (phenytoin) decrease drug levels