Introduction
Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either paralyzing or killing them and without causing significant damage to the host.
Helminths are worms (round, hook, whip, pin and flat etc). Pathogenic helminths for humans are classified as:
- Nematodes (roundworms),
- Trematodes (Flukes) and
- Cestodes (tapeworm).
Children appear to be more susceptible to helminths infection and clinical morbidity than adults. Resistance to infection also seems to be proportional to the general state of well being and nutrition of the individual.
Helminths infections are not limited to the alimentary tract, migrating immature stages (larvae) or even the adult forms are also found in associated structures and in such organs as the liver, lungs, blood circulation, skeletal tissues and subcutaneous tissue. In some cases the adult form lives in the intestine while the immature forms live or migrate to other tissues.
Nematodes
Common nematodes include Enterobius vermicularis, Ascaris lumbricoides, Trichuris tricuria, Ancyclostoma duodenale, Necator americanus, Strongyloides sterccoralis, Trichostrongylus species, Trichinella spiralis, Dracunculus medinensis (guinea worm), Onchocerca volvolus, Wucheraria bancrofti, Brugia malayi, Loa loa etc.
Cestodes
Common cestodes or tapeworms are Taenia saginata (beef tapeworm), Taenia solium (pork tapeworm), Diphyllobothium latum (fish tapeworm), Hymenolepis nana and Echinococcus granulosus etc.
Trematodes
The trematodes or flukes include Fasciola hepatica, Clonorchis sinensis (liver flukes), Paragonimus westernmani (lung fluke) and the schistosomes e.g Schistosoma haematobium, Schistosoma mansoni and Schistosoma japonicum etc.
Antihelminthics are drugs that act either locally to expel worms from the gastrointestinal tract or systematically to eradicate adult helminths or developmental forms that invade organs and tissues.
General mechanism of action of antihelminthics
The chemotherapy of helminthiasis exploits some peculiarities in the physiology and biochemistry in order to selectively eliminate them. Many adult helminths reside in the gastrointestinal tract of their hosts. They can therefore be eliminated with drugs that are not readily absorbed from the gut. Antihelminthics appear to have three main mechanisms of action.
1. Paralysis
Some antihelminthics cause paralysis of the muscle of the worm, either by competitively antagonizing acetylcholine (e.g the effect of piperazine on Ascaris: flaccid paralysis comparable to the effect of d- tubocurarine on mammalian skeletal muscle), or prolonged depolarization and contracture of the worm (e.g the effect of pyrantel on Ascaris which is similar to the effect of succinylcholine on mammalian skeletal muscle). Parasites may also be paralyzed by potentiation of GABAergic transmission and increasing chloride transmission in the parasite (e.g the action of ivermectin against Wucheraria bancrofti.
2. Damage of helminths cuticle:
Some antihelminthics damage the helminths cuticle resulting in death and easy elimination of the parasite by the host immune system. Diethylcarbamazine has this effect on Loa loa and Wucheraria bancrofti, although it also has a hyperpolarizing effect like piperazine.
3. Interfering with helminths metabolism:
Niclosamide, for example inhibits anaerobic production of ATP by uncoupling oxidative phosphorylation in the tape worm. The benzimidazoles produce many changes in the biochemistry of nematodes, namely blockade of glucose uptake, depletion of glycogen stores, decreased in the formation of ATP in susceptible nematodes and interference with β – tubulins.
Types of antihelminthics
1. Benzimidazoles:
- Albendazole – effective against threadworms, roundworms, whipworms, tapeworms, hookworms
- Mebendazole – effective against various nematodes
- Thiabendazole – effective against various nematodes
- Fenbendazole – effective against various parasites
- Triclabendazole – effective against liver flukes
- Flubendazole – effective against most intestinal parasites
2. Abamectin (and by extension ivermectin)
Effective against most common intestinal worms, except tapeworms, for which praziquantel is commonly used in conjunction for mass dewormings.
3. Diethylcarbamazine
Effective against Wuchereria bancrofti, Brugia malayi, Brugia timori and Loa loa.
4. Pyrantel pamoate
Effective against most nematode infections residing within the intestines
5. Levamisole
6. Salicylanilide mitochondrial un-couplers (used only for flatworm infections)
- Niclosamide
- Oxyclozanide
7. Nitazoxanide
Readily kills Ascaris lumbricoides, and also possess antiprotozoal effects
8. Praziquantel
Effective against flatworms (e.g., tapeworms and schistosoma)
9. Octadepsipeptides (e.g.: Emodepside)
Effective against a variety of gastrointestinal helminths
10. Monepantel (aminoacetonitrile class)
Effective against a variety of nematodes including those resistant to other anthelmintic classes
11. Spiroindoles (e.g., derquantel)
Effective against a variety of nematodes including those resistant to other anthelmintic classes
12. Artemisinin
This shows anthelmintic activity.
Specific Anthelmintics
1. ALBENDAZOLE
Absorption
Albendazole is poorly absorbed from GIT. Its bioavailability is 5%.
Distribution
Albendazole concentrations are negligible or undetectable in the plasma.
Mechanism of Action
Albendazole causes degenerative alterations in the tegument and intestinal cells of the worm by diminishing its energy production, ultimately leading to immobilization and death of the parasite.
Metabolism
It is rapidily converted to the sulfoxide metabolite before reaching systemic circulation.
Excretion
No unchanged albendazole is excreted, as it is metabolized too quickly. In humans, the metabolites mostly excreted in the bile, with only a small amount being excreted in the urine (less than 1%) and feces.
Elimination half-life:
8-12 hours
Side Effects
Signs of an allergic reaction include
- hives
- difficult breathing
- swelling of face lips, tongue, or throat.
Common side effects may include:
- headache
- neck stiffness
- increased sensitivity to light,
- confusion
- fever
- nausea
- vomiting
- stomach pain
- abnormal liver function tests
- dizziness
- spinning sensation; or
- Temporary hair loss.
Dosages
- Hydatid Disease (infection of various organs with laval stage of tapeworms of genus Echinococcus): 60 kg or greater – 400 mg twice daily, with meals; Less than 60 kg – 15 mg/kg/day given in divided doses twice daily with meals (maximum total daily dose 800 mg) for 28-day cycle followed by a 14 day albendazole free interval, for a total of 3 cycles.
- Neurocysticercosis (Infection of brain and/or muscles with the eggs and lavae of pork tapeworm – Taenia solium): 60 kg or greater – 400 mg twice daily, with meals; Less than 60 kg – 15 mg/kg/day given in divided doses twice daily with meals (maximum total daily dose 800 mg) for 8 – 30 days.
2. MEBENDAZOLE
Mebendazole is used to treat infections caused by worms such as whipworm, pinworm, roundworm, and hookworm. It is also used to treat infections caused by more than one of these worms at the same time (mixed infection).
Route
Oral
Dosages
For common roundworms, hookworms, and whipworms:
- Adults and children 2 years of age and older — 100 mg two times a day, for 3 consecutive days. Treatment may need to be repeated in 3 weeks.
- Children younger than 2 years of age — Use and dose must be determined by a Pharmacist or a doctor.
For pinworms
- Adults and children 2 years of age and older — 100 mg once a day for 1 day. Treatment may need to be repeated in 3 weeks.
- Children younger than 2 years of age — Use and dose must be determined by a Pharmacist or a doctor.
Contraindications
Mebendazole is contraindicated if one is allergic to it, or if one also takes metronidazole, breast-feeding or is less than 2 years old.
Absorption
Poorly absorbed (approximately 5 to 10%) from gastrointestinal tract. Fatty food increases its absorption.
Distribution
90-95% of the drug bind to plasma Protein.
Metabolism
Mebendazole is metabolized primarily in the liver. All metabolites are devoid of anthelmintic activity.
Route of elimination
In man, approximately 2% of administered mebendazole is excreted in urine and the remainder in the feces as unchanged drug or a primary metabolite.
Half life
The half life ranges from 2.5 to 9 hours in patients with normal hepatic function and approximately 35 hours in patients with impaired hepatic function.
Mechanism of action
Mebendazole works by selectively inhibiting the synthesis of microtubules which leads to blocking the uptake of glucose and other nutrients, resulting in the gradual immobilization and eventual death of the helminthes.
Side Effects
Signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Common side effects may include: nausea, vomiting, loss of appetite, diarrhea; stomach pain, gas; or Rash.
Adverse Effects
Mebendazole sometimes causes elevated liver enzymes. In rare cases, it has been associated with a dangerously low white blood cell count, low platelet count, and hair loss, with a risk of agranulocytosis in rare cases.
Drug interactions
- Carbamazepine and phenytoin lower serum levels of mebendazole.
- Stevens–Johnson syndrome and the more severe toxic epidermal necrolysis can occur when mebendazole is combined with high doses of metronidazole.
3. TRICLABENDAZOLE
Uses of Triclabendazole
Treatment of liver flukes
Route of administration
oral
Dosage of Triclabendazole
one or two doses are required
Mechanism of actions
Triclabendazole works by inhibition of microtubule formation and inhibition of protein and enzyme synthesis thus immobilizing the worms.
Absorption
Triclabendazole is absorbed from the GIT following oral administration. The absorption is increased twofold to threefold when triclabendazole is taken after a fatty meal.
Distribution
Triclabendazole and its metabolites attain high concentrations in the biliary tract through which they are excreted back into the intestine over period of several days. Less than 1% is distributed into breast milk.
Metabolism
Its metabolism is by oxidation to sulfone and sulfoxide metabolite.
Excretion
It is mainly excreted through the feces (> 95%). Other routes of excretion include urine (2%) and milk (<1%). The elimination half life is 22 – 24 hrs.
Side Effects
- Abdominal pain
- Headaches
- Biliary colic (due to dying worms)
4. DIETHYLCARBAMAZINE
Uses
Treatment of filariasis
Route of administration
oral
Dosages for filarial disease:
- Day 1: 50 mg orally PC
- Day 2: 50 mg orally TID
- Day 3: 100 mg orally TID
- Day 4-14: 6 mg/kg/day orally TID
Absorption
Diethylcarbamazine is absorbed readily
Distribution
It is widely distributed throughout all body compartments except adipose tissue. Peak plasma time is 1-2 hrs.
Metabolism
DEC is an inhibitor of arachidonic acid metabolism in microfilariae. This makes the microfilariae more susceptible to innate immune attack, but does not kill the parasite outright. Its metabolite is diethylcarbamazine N-oxide.
Excretion
DEC is excreted through urine and feces. It has a half life of 8 hrs.
Side Effects
- Itching
- Facial swelling
- Headaches
- Vision loss and
- Dizziness
Contraindication
Previous history of heart problems, gastrointestinal problems and allergies
5. PYRANTEL PAMOATE
Uses
Treatment of pin worm, round worm, and hook worm
Route of administration
Oral with or without food
Dosage
This is based on body weight, type of infection and response to treatment but not more than a total of 1 g in a single dose.
Mechanism of action
It act as a depolarizing neuromuscular blocker thereby causing sudden contraction that is followed by paralysis of the helminthes.
Absorption
It is poorly absorbed
Distribution
Peak serum concentration occur 1 – 3 hrs after a single dose
Metabolism
Pyrantel pamoate is partly metabolized in the liver rapidly. Its half life is 1.75 hrs.
Excretion
7% or less is excreted in urine unchanged and as metabolite. More than 50% of each dose being excreted unchanged in the feces.
Side Effects
- Nausea
- Headache
- Sizziness
- Trouble sleeping and
- Rash
Contraindication
Children < 2 yrs
6. LEVAMISOLE
Uses
Specifically for the treatment of ascariasis and hook worm infections
Route
Oral
Absorption
Readily absorbed from the GIT
Distribution
After absorption, levamisole is widely distributed in the body and accumulates in the liver and kidney.
Metabolism
It is metabolized in the liver
Excretion
Mainly in the urine (70%); 5% is excreted unchanged. Elimination hale life is 3-4 hrs
Side Effects
Abdominal pain, vomiting, headache and dizziness
Adverse Effects
- Agranulocytosis
Contraindication
It is contraindicated during breast feeding and in the 3rd trimester of pregnancy.
7. NICLOSAMIDE
Uses
It is used to treat tapeworm infestation
Route
It is taken orally thoroughly chewded or crushed.
Dosages for beef tapeworm
- Adult: 2 g as a single dose (may be repeated 7 days if necessary)
- Children 11-34 kg: 1 g as a single dose (may be repeated 7 days if necessary),
- Children Over 34 kg: 1.5 g as a single dose (may be repeated 7 days if necessary)
Absorption
Only a small amount is absorbed fron the GIT. Alcohol enhances absorption and increases the risk of side effects.
Distribution
The little (2%) that is absorbed is metabolized quickly to glucuronide.
Mechanism of Action
It inhibits glucose uptake, oxidative phosphorylation and anaerobic metabolism in the tapeworm
Metabolism
The enzymes involved in niclosamide metabolism are CYP450 and UDP glucuronosyl transferase (UGTs). Main contributors are CYP1A2 and UGT1A1. These produce one hydroxylated metabolite and one mono-o-glucuronide respectively.
Excretion
Niclosamide is excreted through the feces.
Side Effects
- Nausea
- Vomiting
- Abdominal pain
- Itchiness
- Constipation
- Rarely dizziness
- Skin rash
- Drowsiness
Contraindication
- Alcohol
- The scorlex and the proximal segment of the worm are killed in contact with the drug and the worm may be digested in the gut.
Limitations to the use of niclosamide include:
- Purgative is recommended 1 – 2 hrs after administration
- Side effects
- Necessary duration of therapy
- Limited availability
8. NITAZOXANIDE
Uses
Antihelminthics (treatment of Ascaris lumbricoids)
Route
Oral
Absorption
It is moderately absorbed from the GIT with 33% of the drug eliminated in the urine and 67% in the feces.
Distribution
Nitazoxanide is highly protein bound with over 99% bound to plasma proteins. Its metabolite tizoxanind is > 99.9% plasma protein bound.
Mechanism of Action
Nitazoxanide interferes with pyruvate ferredoxin oxide reductase enzyme dependent electron transfer reaction which is essential to anaerobic energy metabolism.
Metabolism
It is rapidily hydrolyzed to tizoxanide which is in turn conjugated to tizoxanide glucuronide.
Excretion
2/3 of nitazoxanide is excreted through the feces and the remaining in urine. Its elimination half life is 3.5 hrs. Tizoxanide is excreted in urine, bile and feces. Tizoxanide glucuronide is excreted in urine and bile.
Side Effects
- Stomach pain
- Headache
- Stomach upset
- Vomiting
- Skin rash
- Itching
- Fever
- Flu syndrome.
Contraindication
It is contraindicated in individuals who have experience hypersensitivity reactions to nitazoxanide or the inactive ingredients of its formulation.
9. PRAZIQUANTEL
Uses
Treatment of schizotosomiasis, tapeworm and other flukes. It should be used for worm infection of the eye.
Route
Oral
Absorption
Rapidly absorbed with bioavailability of 80% – 100%. It undergoes extensive first pass hepatic metabolism to inactive metabolite. Consequently, most of the active drug does not reach the systemic circulation.
Distribution
At high temperature, the peak values reach significantly higher levels only in the liver. The peak values of 10.2 – 31.2 µg/g were reached in 4 – 16 hrs after administration of the drug.
Mechanism of Action
It induces contraction of the worms resulting in paralysis. It also causes focal disintegration and disturbances of oviposition. Recently, it was reported that praziquantel seems to interfere with adenosine uptake in cultured worms.
Metabolism
It is metabolized in the liver
Excretion
It is mainly excreted in the urine. Its elimination half life is 0.8 – 1.5 hrs and 4 – 5 hrs for its main metabolites.
Side Effects
Some of the side effects of praziquantel include:
- Poor coordination
- Abdominal pain
- Vomiting
- Headache
- Dizziness
- Malaise
- Drowsiness
- Fatigue
- Rash
- Urticaria
- Myalgia and
- Fever.
Interactions
- Rifampicin decreases plasma concentration of praziquantel.
- Carbamazepine and phynetoin reduces its bioavailability while cimetidine increases its bioavailability.
10. ARTEMISININ
Uses
Treatment of malaria and parasitic worms (helminthics)
Route
Oral
Absorption
Artemisinin and its derivatives are rapidly but incompletely absorbed when given orally; however, through IM route, absorption is slow and eratic.
Distribution
It is rapidly distributed after 1 hr and rapidly declined at 24 hrs in all tissues except spleen. It crosses BBB having concentration 2 folds more than that in the plasma.
Mechanism of Action
Artemisinin is actively cleaved at its endoperoxide ring. This produces free radicals that in turn damage susceptible proteins, resulting in death of the parasite.
Metabolism
In the liver, artemisinin is converted to different inactive metabolites such as deoxyartemisinin and deoxydihydroartemisinin. The enzymes involved in the metabolism are CYP2B6 and CYP3A4. All the metabolites undergo glucuronidation.
Excretion
Artemisinin is excreted in urine and feces
Side effects – nausea, vomiting, loss of appetite and dizziness; allergic reaction is rare but serious.
Artemisinin has advantages over other antihelminthics in that it has the ability to kill worms faster and it kills all the life cycle stages of the parasite.
Limitations
- It has low bioavailability
- Poor pharmacokinetic properties
- It is costly