Helminthiasis worm infestation, Roundworm, hookworm, pinworm, and whipworm infestations and their treatment. Chemistry and SAR of anthelmintic agents

1. ANTHELMINTICS
DR. SHILPA SUDHAKAR HARAK
ASST. PROF., PHARM. CHEM.,
GES SIR DR. M. S. GOSAVI COLLEGE OF PHARMACEUTICAL
EDUCATION AND RESEARCH, NASHIK

2. HELMINTH INFECTIONS
 Helminthiasis also widely known as worm infestation
 Most prevalent diseases
 Parasitic worms cause serious complications.
 Number of infected – millions
 Rough estimation – 1/4th world population
 Unique Characteristics
 Multiply outside the definitive host
 Evade host immune defenses
 Can be chronic

3. HELMINTH INFECTIONS
 Two categories for human Helminthiasis:
Platyhelminthes (flatworms)
• Classes Cestode (tapeworms) and
• Trematode (flukes or schistosomes)
Aschelminthes or nematodes (roundworms).
• Roundworm, hookworm, pinworm, and whipworm.
o Structure : cylindrical in shape, with significant variations in
size, proportion, and structure

4. NEMATODE INFECTIONS
 Ancylostomiasis or Hookworm Infection
 Types of hookworm
 Necator americanus - American hookworm
 Ancylostoma duodenale - “Old World” hookworm
 The life cycles of both are similar.

5. LIFE CYCLE OF
HOOKWORM

6. ENTEROBIASIS OR PINWORM INFECTION
 Causative agent: Enterobius vermicularis
 Widespread in temperate zones
 It lives in the lumen of the GI tract, attaching itself by the mouth to the mucosa
of the cecum.
 Mature worms reach 10 mm in size.
 The female migrates to the rectum, usually at night, to deposit her eggs.
 Eggs resist drying and can be inhaled with household dust to continue the life
cycle.
 The worms are visible with the naked eye.
 The eggs can be collected in a similar manner but can only be seen under a
microscope.

7. ASCARIASIS OR ROUNDWORM INFECTIONS
 Ascaris lumbricoides
 Common in developing countries
 Size of an adult - 25 to 30 cm in length, Lodging in the small intestine.
 Either Asymptomatic or with symptoms
 Symptoms: abdominal discomfort and pain

8. ASCARIASIS OR ROUNDWORM INFECTIONS
 Lifecycle: Release eggs into the soil, incubate and remain viable for up to 6 years.
 When the egg is ingested, the larvae are released in the small intestine, penetrate
the intestinal walls, and are carried via the blood to the lungs.
 The pulmonary phase of the disease lasts approxi- mately 10 days, with the
larvae passing through the bron- chioles, bronchi, and trachea before being
swallowed and returning to the small intestine.
 Some patients have reported adult worms exiting the esophagus through the oral
cavity, and it is not unusual for live ascaris to be expelled with a bowel
movement.
 Poor or lacking sanitary facilities expose the population to infestation through
contaminated foods and beverages.

9. TRICHURIASIS ORWHIPWORM INFECTIONS
 Trichuris trichiura
 Infections by this parasite are caused by swallowing eggs from contaminated
foods and beverages.
 The eggs are passed with the feces from an infected individual.
 These eggs can live in the soil for many years.
 The ingested eggs hatch in the small intestine, and the larvae embed in the
intestinal wall.
 The worms then migrate to the large intestine, where they mature.
 Adult worms, which reach approximately 5 cm in length, thread their bodies
into the epithelium of the colon.
 They feed on tissue fluids and blood.

10. ANTHELMINTIC DRUGS CLASSIFICATION
 Based on chemical structure
 Piperazines: Diethylcarbamazine citrate (DEC), Piperazine citrate.
 Benzimidazoles:Albendazole, Mebendazole,Thiabendazole.
 Heterocyclics: Oxamniquine, Praziquantel
 Natural products: Ivermectin,Avermectin
 Vinyl pyrimidines: Pyrantel, Oxantel
 Amide: Niclosamide
 Nitro derivative: Niridazole
 Imidazothiazole: Levamisole

11. PIPERAZINES

12. PIPERAZINE
 Hexahydropyrazine or diethylenediamine (Arthriticine, Dispermin)
 Diethylcarbamazine (DEC) was found as a result of search for treatment for
the American troops during World War II as many were affected because of
filariasis
 The once-popular piperazine was discovered as anthelmintic after the
discovery of diethylcarbamazine
 Although chemically similar, they have activity against different helminths
 Piperazine is active against nematodes, whereas DEC is active against falaria
and microfalaria.

13. PIPERAZINE
 Hexahydropyrazine or diethylenediamine (Arthriticine, Dispermin)
 Treatment of pinworm (Enterobius [Oxyuris] vermicularis) & roundworm (Ascaris
lumbricoides) infestations.
 It is available in various salt forms (citrate) in syrup and tablet forms.
 Piperazine is active against nematodes
 MOA:
Blocks Ascaris
response to
Acetylcholine
Flaccid
paralysis in
the worm
dislodged
from the
intestinal wall
Expelled
outside host
body

14. DIETHYLCARBAMAZINE CITRATE
 DEC is active against falaria and microfalaria (64).
 MOA: unknown.
 DEC is inactive in vitro
 In vivo the drug has a very rapid onset of action suggesting that activation
of a cellular component is essential to the filaricidal action.
 Three mechanisms have been suggested.

15. DIETHYLCARBAMAZINE MOA
 Three mechanisms have been suggested.
 1. The first is involvement of blood platelets triggered by the action
of filarial excretory antigens.
 A drug – antigen reaction takes place
 Results in the loss of the cellular sheath, exposing antigenic
determinants to immune defense mechanisms.
 Severe damage then occurred to microfalaria organelles, leading to
death.

16. DIETHYLCARBAMAZINE MOA
2. The second is inhibition of microtubule polymerization &
disruption of preformed microtubules
3. The third is interference with arachidonic acid metabolism
 DEC is known to have anti-inflammatory action, which appears to
involve blockage at cyclooxygenase and leukotriene A4 synthase
(leukotriene synthesis).
 This action alters vascular and cellular adhesiveness and cell
activation.

17. DIETHYLCARBAMAZINE METABOLISM
 Also trace amounts of methylpiperazine and piperazine.
 All metabolites appear in the urine.
 10% to 20% of the drug is excreted unchanged.
 None of the metabolites are active

18. THERAPEUTIC APPLICATION
 Effective against microfilariae
 Not effective against adult worm
 Mild adverse effects, but under some conditions, it can produce severe adverse
reactions, including anaphylactic reactions, intense pruritus, and ocular
complications.
 The severe anaphylactic reaction is known as the Mazzotti reaction, and it appears to
be an immune response related to the presence of dead microfilariae
 This reaction is more common in individuals who have a high-load microfi larial
infection, and it can preclude the use of DEC in some patient populations

19. BENZIMIDAZOLES

20. BENZIMIDAZOLES
 Broad-spectrum group of drugs discovered in the 1960s as antihelminths.
 Several thousand benzimidazoles have been synthesized and screened for
anthelmintic activity
 Albendazole
 Mebendazole
 Thiabendazole

21. BENZIMIDAZOLE ANTHELMINTICS
Drugs R1 R2 R3
Thiabendazole H H
Mebendazole H
Albendazole H
Triclabendazole Cl
Fenbendazole H
Flubendazole H
N
H
N
R1
R2
R3
N
S
H
N OCH3
O
O
Cl Cl
-S-CH3
H
N OCH3
O
H
N OCH3
O
H
N OCH3
O
-S-CH2-CH2CH3
F
O
S
O

22. BENZIMIDAZOLES
 Broad-spectrum group of drugs discovered in the 1960s as antihelminths.
 Several thousand benzimidazoles have been synthesized and screened for
anthelmintic activity, with albendazole, mebendazole, and thiabenda- zole
representing the benzimidazoles marketed today.
MECHANISM OF ACTION
 1. Inhibition fumarate reductase: Fumarate reductase is an important
enzyme in helminths that appears to be involved in oxidation of NADH to NAD.
 It ultimately uncouples oxidative phosphorylation stopping ATP production.

23. 2. INHIBITION OFTUBULIN POLYMERIZATION
 Tubulin is a dimeric protein
 Binding to the tubulin prevents the self-association of subunits and creates a
“capping” of the microtubule at the associating end of the microtubule.
 The microtubulin continues to dissociate from the opposite end, with a net
loss of microtubule length.
 Selectivity
 Also bind to mammalian tubulin
 As anthelmintics destroy helminth
 Difference in binding to the two different tubulin proteins.

24. INHIBITION OF
TUBULIN
POLYMERIZATION
ANTHELMINTIC
BENZIMIDAZOLES

25. SAR OF ANTHELMINTIC BENZIMIDAZOLES

26. ALBENDAZOLE
 5-thioether increases the likelihood of sulfur oxidation.
 Metabolite, albendazole sulfoxide, is a potent anthelmintic.
 Oxidation is catalyzed (70%) by CYP3A4 and CYP1A2 and (30%) by flavin-
containing monooxygenase & is bound to plasma protein.
 This is active against the hydatid cyst found in echinococciasis, a tapeworm
disease
 Further oxidation by cytochrome P450 leads to the inactive sulfone.
 Additional metabolites :
• carbamate hydrolysis to the amine and
• oxidation of the 5-propyl side chain.

27. FLUBENDAZOLE
 It is the only benzimidazole approved in the European Union for the
control of endoparasitic infections in poultry
 Flubendazole’s use may generate residues of the parent drug and its
metabolites in foods.
 the presence of residues of flubendazole and its metabolites in the eggs
of laying hens receiving flubendazole for 7 and 21 day
 Fenbendazole was approved for the control of nematodes in turkeys in
the US

28. METABOLISM OF
FLUBENDAZOLE

29. THIABENDAZOLE
 2-(4-Thiazolyl)benzimidazole (Mintezol)
 Thiabendazole is a basic compound with a pKa of 4.7 that forms complexes with metal
ions.
 Thiabendazole inhibits the helminth-specific enzyme fumarate reductase.
 Action of metal ions in inhibition of the enzyme unknown
 Arrest nematode cell division in metaphase by interfering with microtubule assembly.
 They exhibit a high affinity for tubulin, the precursor protein for microtubule synthesis.
 Broad-spectrum anthelmintic activity

30. THIABENDAZOLE
 Broad-spectrum anthelmintic activity
 Treat enterobiasis
 Strongyloidiasis (threadworm infection),
 Ascariasis,
 Uncinariasis (hookworm infection), and
 Trichuriasis (whipworm infection).
 It has also been used to relieve symptoms associated with cutaneous larva
migrans (creeping eruption) and the invasive phase of trichinosis.
 Widely used in veterinary practice to control intestinal helminths in livestock.

31. HETEROCYCLICS

32. PRAZIQUANTEL (PZQ)
 2-(Cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4Hpyrazino[2,1-
a]isoquinolin-4-one
 An isoquinoline derivative
 Levo enantiomer most biologically activity
 Ineffective against nematodes
 Highly effective against cestodes and trematodes
 PZQ is rapidly absorbed and undergoes hepatic first-pass metabolism.
 The metabolites are either less active or inactive and consist of
hydroxylated compounds.

33. METABOLISM
• Less active or inactive
• Most hydroxylated compounds.
• Hydroxylation are catalyzed by CYP2B6 &
CYP3A4.
• Major 4-hydroxycyclohexyl carboxylate
• Secondary: dehydroxylated 50% to 60%
(urine)
• Excreted as conjugated form in the urine.

34. PRAZIQUANTEL (PZQ) MOA
Differs in different parasites
It affects Ca2+ redistribution either directly or indirectly
Praziquantel increases cell membrane permeability of susceptible
worms, resulting in the loss of extracellular calcium.
Massive contractions and ultimate paralysis of the fluke
musculature occurs, followed by phagocytosis of the parasite.
In the lumen in cestode infection it causes muscle contraction and
paralysis, leading in turn to worm expulsion.
PZQ inhibits phosphoinositide metabolism, which by an
undetermined mechanism leads to the worm paralysis

35. PRAZIQUANTEL (PZQ) MOA
In intravascular-dwelling schistosomes, it causes
damage of the tegument of the worm.
Resulting in attack by immune antibodies of the host on
the antigens in the helminth.
An antigen–antibody immunologic reaction leads to
the death of the parasite.
PZQ affects glycogen and energy metabolism

36. INDICATIONS FOR PRAZIQUANTEL
 Schistosomiasis and liver flukes (trematode and cestode
infections)
 The drug is stage specific
 Acts on the invasive stages:
 the cercariae, young schistosomula and the mature
worms, but not against the liver stages.
 Investigational drug in the treatment of schistosomiasis
and liver flukes.

37. SIDE EFFECTS OF PRAZIQUANTEL
 Bitter taste
 Not severe and consist of abdominal discomfort
(pain & diarrhea)
 Resistance Development

38. OXAMNIQUINE
 1,2,3,4-Tetrahydro-2-[(isopropylamino)methyl]-7-nitro-6-
quinolinemethanol
 Found in 1960s having limited antiprotozoal activity
 It is an antischistosomal agent
 Active against Schistosoma mansoni
 But inactive against other two schistosomal organisms
 Good Oral bioavailability
 The plasma half-life is 1 to 2.5 hours

39. OXAMNIQUINE MOA
 It has been shown to inhibit DNA, RNA, and protein synthesis in
schistosomes.
 The 6-hydroxymethyl group is critical for activity;
 Metabolic activation of precursor 6-methyl derivatives is critical
 The drug is stage specific
 Active against cercariae and very young schistosomula and adult
worms
 The drug is more effective against adult male worms than against
female worms
 Structural similarity to hycanthone (has severe toxicity and
teratogenic effects)

40. OXAMNIQUINE
 MECHANISM OF ACTION
 Oxamniquine organism Biologic ester dissociates electrophile
alkylates the helminth DNA
Irreversible inhibition of nucleic acid metabolism
In Resistant helminths do not esterify oxamniquine

41. OXAMNIQUINE METABOLISM
Metabolic
inactivation
The drug is extensively metabolized to inactive metabolites, of which the principal one is the 6-carboxy derivative.

42. THERAPEUTIC APPLICATION
 Orally bioavailable but short half-life
 Highly effective against Schistosoma mansoni (Brazil)
 West African S. mansoni
 Side effects are minimal, with transient dizziness being reported.
 Severe reactions, such as epileptiform convulsions, are rare.
 The major drawback is its high cost.
 Encouraging outcomes have been reported with the combination
of oxamniquine and PZQ.

43. NATURAL PRODUCTS

44. IVERMECTIN
 Antibiotics produced by fermentation of
products from Streptomyces avermitilis
 A mixture of 22,23-dihydro derivatives of
avermectins B1a and B1b
 Preparation: catalytic hydrogenation
 Contain pentacyclic 16-membered–ring
aglycones glycosidically linked at the 3-
position to a disaccharide that comprises
two ole and rose sugar residues.

45. IVERMECTIN
 25-position side chain of the
aglycone varies
 Avermectin B1a : sec-butyl
 Avermectin B1b : Isopropyl
 Contains 80% of 22,23-
dihydroavermectin B1a & NMT
20% 22,23-dihydroavermectin
B1b.

46. IVERMECTIN
 Veterinary application for control of endoparasites and ectoparasites in domestic
animals
 Effective for the treatment of onchocerciasis (“river blindness”) in humans
(roundworm Oncocerca volvulus)
 Ivermectin destroys microfilariae responsible for skin and tissue nodules that are
characteristic of the infestation and can lead to blindness
 It also inhibits the release of microfilariae by the adult worms living in the host.
 MOA: It blocks interneuron–motor neuron transmission in nematodes by stimulating
the release of the inhibitory neurotransmitter GABA.

47. IVERMECTIN MOA
Two mechanisms of action are thought to be involved in the action of IVM
1. Decreased motility of filariae:
 It blocks interneuron–motor neuron transmission in nematodes
 It stimulates gamma-aminobutyric acid (GABA) release or
 Is an inducer of chloride ion influx, leading to hyperpolarization and muscle paralysis.
 The chloride ion influx appears to be the more plausible mechanism
 Thus motility of microfalaria is reduced
 This allows cytotoxic cells of the host to adhere to the parasite resulting in elimination
from the host.

48. IVERMECTIN MOA
 It binds irreversibly to the glutamate-gated chloride channel of the nematode
Haemonchus contortus, whereas the channel is in an open conformation.
 The binding then remains locked in the open conformation, allowing ions to cross
the membrane, leading to the paralytic action of IVM.
 The result of this action is a rapid decrease in microfilarial concentrations.
 A second action of IVM leads to the degeneration of microfilariae in utero.
 This action would result in fewer microfilariae being released from the female
worms, and it occurs over a longer period of time.
 The presence of degenerated microfilariae in utero prevents further fertilization
and production of microfilariae.

49. VINYL PYRIMIDINES

50. PYRANTEL
 Trans-1,4,5,6,-Tetrahydro-1-methyl-2-[2-(2-thienyl)ethenyl] pyrimidine pamoate
 It is a depolarizing neuromuscular blocking agent that activates nicotinic receptors and inhibits
cholinesterase causing spastic paralysis in susceptible helminths.
 It is used in the treatment of infestations caused by pinworms and roundworms (ascariasis).
 Because its action opposes that of piperazine, the two anthelmintics should not be used together.
 More than half of the oral dose is excreted in the feces unchanged.
 Adverse effects associated with its use are primarily gastrointestinal.
 Although it has activity against most intestinal roundworm infections, it has not been approved by
the FDA for treatment of these infestations.

51. PYRANTEL
 It is considered to be the drug of choice in the treatment of
pinworms.
 Quite insoluble is not readily absorbed
 Insolublility is useful for drug for treatment of intestinal
helminths
 Used to treat enterobiasis
 Effective for hookworm and roundworm (ascariasis) infections

52. AMIDE

53. NICLOSAMIDE
 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide or 2,5'-dichloro-4'-nitrosalicylanilide
 It is a potent taeniacide that causes rapid disintegration of worm segments and the scolex.
 Penetration of the drug into cestodes is facilitated by the digestive juices of the host, in that very little
of the drug is absorbed by the worms in vitro.
 Niclosamide is well tolerated following oral administration, and little or no systemic absorption
 Used for treatment of tapeworm infections
 Niclosamide, once marketed in the US under the brand name Niclocide, was voluntarily withdrawn
from market by Bayer in 1996.

54. NITRO DERIVATIVE: NIRIDAZOLE

55. NIRIDAZOLE
 This compound belongs to the class of organic compounds known as nitrothiazoles.
 These are compounds containing a thiazole ring which bears a nitro group.
 It had serious neuropsychiatric side-effects in some patients who were treated with
niridazole in adults with Schistosoma mansoni infections, caution in the use of this
drug is advocated until the contraindications have been further elucidated.
 Nevertheless, niridazole is a very valuable and well-tolerated drug for the
ambulatory treatment of children with urinary schistosomiasis.

56. IMIDAZOTHIAZOLE: LEVAMISOLE

57. LEVAMISOLE
 Also known as ketrax or lepuron, belongs to the class of organic compounds known as imidazothiazoles.
 Organic polycyclic compounds with an imidazole ring fused to a thiazole ring
 Imidazole is 5-membered ring consisting of three carbon atoms, and two nitrogen centers at the 1- and 3-
positions
 Thiazole is a 6-membered ring that contains both sulfur and nitrogen.
 Levamisole is a drug which is used for adjuvant treatment in combination with fluorouracil after surgical
resection in patients with dukes' stage c colon cancer
 It is also used to treat malignant melanoma and head/neck cancer.
 Levamisole exists as a solid, slightly soluble (in water), & a very strong basic compound (based on its pKa).
 Levamisole has been detected in multiple biofluids, such as urine and blood.

58. ANTHELMINTIC
DRUGS