Antiprotozoal agents

Protozoal diseases
 highly prevalent in tropical Third World countries, where they infect both human and animal population

Protozoal diseases that are found in the United States

 malaria, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and, as a direct consequence of the AIDS
epidemic, P. carinii pneumonia (PCP)

AMEBCIDES EFFECTIVE IN INTESTINAL & EXTRAINTESTINAL

 Emetine
 Dehydroemetine
 Metroimidazole
 Chloroquine

EFFECTIVE IN INTESTINAL
 Paromomycin
 Iodoquinol
 Carbarsone
 Diloxanide

Other protozoal species that colonize the intestinal tract and cause enteritis and diarrhea
 Balantidium coli and the flagellates, G. lamblia and Cryptosporidium spp.

 Balantidiasis responds best to tetracycline. Metronidazole and iodoquinol may also be effective.
 Giardiasis may be treated effectively with furazolidone, metronidazole, or theantimalarial drug quinacrine.
 Cryptosporidiosis is normally self-limiting in immunocompetent patients and is not normally treated.
 Trichomoniasis, a venereal disease caused by the flagellated protozoan T. vaginalis. Oral metronidazole
provides effective treatment against all forms of the disease.
 P. carinii is an opportunistic pathogen that may colonize the lungs of humans and other animals and, under
the right conditions, can cause pneumonia. The combination of the antifolate trimethoprim and the
sulfonamide sulfamethoxazole constitutes the treatment of choice for PCP.
 Toxoplasma gondii is an obligate intracellular protozoan that is best known for causing blindness in neonates.
A combinationof the antifolate pyrimethamine and the sulfa drug sulfadiazineconstitutes the most effective
therapy for toxoplasmosis.
 Trypanosomiasis & Leishmianisis. Heavy metal compounds, such as the arsenicals and antimonials,
are sometimes effective but frequently toxic. The old standby suramin appears to be of some value in long-
and short-term prophylaxis. The nitrofuran derivative nifurtimox may be a major asset in the control of these
diseases, but its potential toxicity remains to be fully determined.

METRONIDAZOLE
2-Methyl-5-nitroimidazole-1-ethanol (Flagyl, Protostat, Metro IV)
• Most useful antiprotozoal nitroimidazole derivative
TREATMENT/USE:
 topical tx of T. vaginalis vaginitis
 tx for serious infections caused by anaerobic bacteria

MOA: Reactive intermediate formed in the microbial reduction of the 5-nitro group of metronidazole covalently
bind to DNA of the microorganism, triggering lethal effect.

 Pale yellow crystalline; Sparingly soluble in water; Weak base with a pKa of 2.5

DILOXANIDE
Furamide, or eutamide
TREATMENT/USE:
 Tx asymptomatic carriers of E. hystolytica

METABOLISM: Hydrolysis of amide (for amebicidal effect)

 Nonpolar ester –more potent; White crystalline powder

8-HYDROXYQUINOLONE
TREATMENT/USE:
 topical antiseptic

Parent compound: Oxine, quionophenol, oxyquinolone

MOA: Antibacterial & antifungal properties of oxine result from the ability to chelate metal ions

SAR: Substitution of iodine atom at 7-position yields broad spectrum amebicidal properties

IODIQUINOL
5,7-Diiodo-8-quinolinol, 5,7-diiodo-8-hydroxyquinoline, or diiodohydroxyquin (Yodoxin, Diodoquin, Diquinol)
TREATMENT/USE:
 For acute & chronic intestinal amebiasis
 Not used routinely for traveler’s diarrhea

Side effect: topic neuropathy

 Yellowish to tan microcrystalline, insoluble in water

EMETINE & DEHYDROEMETINE

• from ipecac extracts

TREATMENT/USE:
 amebicidal action on E. hystolytica
 for balantidial dysentery & fluke infestations like fascioliasis, paragonimiasis

MOA: Protoplasmic poisons that inhibit protein synthesis in protozoal & mammalian cells by preventing protein
elongation

 Levorotatory, white powders; insoluble in water

PENTAMIDINE ISETHIONATE
4,4_-(Pentamethylenedioxy)dibenzamidine diisethionate (NebuPent, Pentam 300)
TREATMENT/USE:
 tx of pneumonia caused by P. carinii
 inhalation as prevention for HIV patients
 for the prophylaxis & african trypanosomiasis, visceral leishmaniasis

ADR: cough, bronchospasm, hypertension and hypoglycemia.

 Water soluble crystalline salt

ATOVAQUONE
3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naphthoquinone (Mepron)
TREATMENT/USE:
 Recommended as alternative to trimethoprim-sulfamethoxazole (TMP-SMX) for tx & prophylaxis of PCP
resistant to this combination.
 Eradicate T. gondii

MOA: Structural similarity between atovaquone and ubiquinone, and it acts as an antimetabolite and thereby
interfere with the funtion of electron trsansport enzymes.

 Highly lipophilic, water-insoluble analog of ubiquinone 6, an essential component of mitochondrial

electron transport chain in microorganisms

EFLORNITHINE
TREATMENT/USE:
 Treatment if West African sleeping sickness caused by Trypanosoma brucei gambiense.
 Meningoencephalitic stage of the disease
 Myelosuppresive drug

ADR: anemia, leukopenia and thrombicytopenia

NIFURTIMOX
4-[(5-nitrofurfurylidene) amino]-3-methylthiomorpholine-1,1-dioxide, or Bayer 2502 (Lampit)
TREATMENT/USE:
 Effectiveness against T. cruzi
ADR: high incidence of nausea, vomiting, abdominal pain and anorexia.

BENZNIDAZOLE
N-Benzyl-2-nitroimidazole-1-acetamide (Radanil, Rochagan)
TREATMENT/USE:
 Treatment of Chagas disease.
ADR: peripheral neuropathy, bone marrow depression and allergic-type reactions.

MELARSOPROL
2-p-(4,6-Diamin-s-triazin-2-yl-amino)phenyl-4-hydroxymethyl-1,3,2-dithiarsoline (Mel B, Arsobal)
TREATMENT/USE:
 Treatment of the later stages of both forms of African trypanosomiasis.
 Effective against meningoencephalitic forms of T. gambiense and T. rhodesiense.

MOA: prepared by reduction of corresponding pentvalent arsanilate to the trivalent arsenoxide followed by
reaction of the latter with2,3-dimercapto-1-propanol (British anti-Lewisite [BAL]).

SODIUM STIBOGLUCONATE
Sodium antimony gluconate (Pentostam)
TREATMENT/USE:
 Treatment of various form leishmaniasis
  Organic antimonial compounds are used primarily for the treatment of schistosomiasis and other flukes.

MOA: Requires its reduction to the trivalent form, which is believed to inhibit phosphofructokinase in the parasite.

ADR: heavy metal poisoning

DIMERCAPROL
2,3-Dimercapto-1-propanol, BAL or dithioglycerol
TREATMENT/USE:
 Antidote for “Lewisite”
 Effective antidote for poisoning caused by arsenic, antimony, mercury, gold and lead.
 Treat arsenic and antimony toxicity associated with overdose or accidental ingestion of organoarsenicals
or organoantimonials.

SURAMIN SODIUM
TREATMENT/USE:
 Treatment of early cases of trypanosomiasis.
 Prophylaxis of onchocerciasis.

Anthelmintics

Anthelmintics
 Are drugs that the capability of ridding the body of parasitic worms or helminths.
 Derived from 2 phyle: Platyhelminthes and Nemathelminthes.
 Several classes of chemicals ar used as anthelmintics and include phenols and derivatives, piperazine and
related compounds, antimalarial compounds, various heterocyclic compounds, and natural products.

PIPERAZINE
Hexahydropyrazibe or diethylenediamine
TREATMENT/USE:
 Treatment of pinworm. (Enterobius [Oxyuris] vermicularis) and round worm (Ascaris lumbricoides)
infestations.

MOA: blocks the response of the ascaris muscle to acetylcholine, causing flaccid paralysis in the worm, which is
dislodged from the intestinal wall and expelled in the feces.

DIETHYLCARBAMAZEPINE CITRATE
N,N-Diethyl-4-methyl-1-piperazinecarboxamide citrate or 1-diethylcarbamyl1-4-methylpiperazine dihydrogen
citrate (Hetrazan)

TREATMENT/USE:
 Effective in various forms of filariasis, including Bancroft, onchocerciasis, and laviasis. It is also active
against ascariasis.

PYRANTEL PAMOATE
Trans-1,4,5,6,-Tetrahydro-1-methyl-2-[2-(2’-thienyl)ethenyl] pyrimidine pamoate (Antiminth)
TREATMENT/USE:
 Treatment of infestations caused by pinworms and roundworms (ascariasis)

ADR: Gastrointestinal

THIABENDAZOLE
2-(4-Thiazolyl)benzimidazole (Mintezol)
TREATMENT/USE:
 Treatment of eneterobiasis, strongyloidiasis (threadworm infection), ascariasis, uncinariasis (hookworm
infection), and trichuriasis (whipworm infection)
 Relieve symptoms associated with cutaneous larva migrans (creeping eruption) and the invasive phase of
trichinosis.
 Used in veterinary practice to control intestinal helminths in livestock.

MOA: Thiabendazole inhibits the helminth-specific enzyme fumarate reductase.

MEBENDAZOLE
Methyl 5-benzoyl-2-benzimidazolecarbamate (Vermox)
TREATMENT/USE:
 Effective against nematode infections, including whipworm, pinworm, roundworm and hookworm.

MOA: Mebendazole irreversible blocks glucose uptake in susceptible helminths, thereby depleting glycogen stored
in the parasite. It apparently does not affect glucose metabolism in the host.

ADR: abdominal discomfort.

ALBENDAZOLE
Methyl 5-(propylthio)-2-benzimidazolecarbamate (Eskazole, Zentel)
TREATMENT/USE:
 Treatment of intestinal nematode infection
 Effective as a single-dose treatment for ascariasis, new and old world hookworm infections, and
trichuriasis
 Multiple-dose therapy with albendazole can eradicate pinworm, threadworm, capillariasis, clonorchiasis,
and hydatid disease.
MOA: the drug undergoes rapid and extensive first-pass metabolism to the sulfoxide, which is the active form in
plasma.

ADR: bone marrow depression, elevation of hepatic enzymes, and alopecia

 Occurs as a white crystalline powder that is virtually insoluble in water.

 Oral absorption is enhanced by a fatty meal.

NICLOSAMIDE
5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide or 2,5’-dichloro-4’-nitrosalicylanilide (Cestocide,
Mansonil, Yomesan)
  A yellowish white, water-insoluble powder
 Potent taeniacide that causes rapid disintegration of worm segments and the scolex
 Saline purge 1-2 hours after ingestion of the taeniacide is recommended to remove the damaged scolex
and worm segments

TREATMENT/USE:
 Treatment of pork tapeworm infestation to prevent possible cysticercosis resulting from release of live
ova from worm segments damaged by the drug.

BITHIONOL
2,2’-Thiobis(4,6-dichlorophenol), or bis(2-hydoxy-3,5-dichlorophenyl)sulfide (Lorothidol, Bithin)
 A chlorinated bisphenol, was formerly used in soaps and cosmetics for its antimicrobial properties but was
removed from the market for topical use because of reports of contact photodermatitis

TREATMENT/USE:
 has useful anthelmintic properties
 agent of choice for the treatment of infestations caused by the liver fluke Fasciola hepatica and the lung
fluke Paragonimus westermani
 treatment of tapeworm infestations

OXAMNIQUINE
1,2,3,4-Tetrahydro-2-[(isopropylamino)methyl]-7-nitro-6-quinolinemethanol (Vansil)

TREATMENT/USE:
 antischistosomal agent that is indicated for the treatment of Schistosoma mansoni (intestinal
schistosomiasis) infection
MOA: inhibit DNA, RNA, and protein synthesis in schistosomes

 free base occurs as a yellow crystalline solid that is slightly soluble in water but soluble in dilute aqueous
mineral acids and soluble in most organic solvents

Side Effects:
 common but transitory- Dizziness and Drowsiness
 serious reactions- epileptiform convulsions (rare)

PRAZIQUANTEL
2-(Cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one (Biltricide)

TREATMENT/USE:
 a broad spectrum agent that is effective against various tramtodes (flukes)
 treatment of infections caused by schistosomes (blood flukes)
 effective treatment for fasciolopsiasis (intestinal fluke), clonorchiasis (Chinese liver fluke), and fascioliasis
(sheep liver fluke), opisthorchosis (liver fluke), and paragonimiasis (lung fluke)
 massive contractions and ultimate paralysis of the fluke musculature occurs, followed by phagocytosis of
the parasite
MOA: increases cell membrane permeability of susceptible worms, resulting in the loss of extracellular calcium

 a white crystalline solid that is insoluble in water, rapidly metabolized in the liver in the first-pass,
available as 600-mg film coated tablets

IVERMECTIN
(Cardomecm Eqvalan, Ivomec)
 is a mixture of 22,23-dihydro derivatives of avermectins B1a and B1b prepared by catalytic hydrogenation
 members of a family of structurally complex antibiotics produced by fermentation with a strain of
Streptomyces avermitilis
TREATMENT/USE:
 active in low dosage against a wide variety of nematodes and arthropods that parasitize animals
 effective for the treatment of onchocerciasis (“river blindness”) in humans, an important disease caused
by the roundworm Oncocerca volvulus
 destroys the microfilariae, immature forms of the nematode, which create the skin and tissues nodules
that are characteristic of the infestation and can lead to blindness
 inhibits the release of microfilariae by the adult worms living in the host

MOA: blocks interneuron-motor neuron transmission in nematodes by stimulating the relase of the inhibitory
neurotransmitter GABA

Antiscabious and Antipedicular agents

Antiscabious agents/Scabicides
 are compounds used to control the mite Sarcoptes scabiei, an organism that thrives under the conditions
of poor personal hygiene

Antipedicular agents/Pediculicides
 are used to eliminate head, body, and crab lice.

*Ideal scabicides and pediculicides- must kill the adult parasites and destroy their eggs

BENZYL BENZOATE
 is naturally occurring ester obtained from Peru balsam and other resins
 prepared synthetically from benzyl alcohol and benzoyl chloride
 clear colorless liquid with a faint aromatic odor
 insoluble in water but soluble in organic solvent

TREATMENT/USE:
 is an effective scabicide when applied topically
 immediate relief from itching probably results from a local anesthetic effect
 applied topically as a lotion over the entire dampened body, except the face

Advantage: odorless, non-staining, and nonirritating to the skin

LINDANE
1,2,3,4,5,6-hexachlorocyclohexane, γ-benzene hexachloride, or benzene hexachloride (Kwell, Scabene, Kwildane,
G-Well)
 halogenated hydrocarbon is prepared by the chlorination of benzene
 a light bluff to tan powder with a persistent musty odor and it is bitter
 insoluble in water but soluble in most organic solvents
 stable under acidic or neutral conditions but undergoes elimination reactions under alkaline conditions

TREATMENT/USE:
 action of lindane against insects is threefold: it is a direct contact poison, it has a fumigant effect, and it
acts as a stomach poison
 effect of lindane on insects is similar to that of DDT
 used locally as a cream, lotion, or shampoo for the treatment of scabies and pediculosis

SAR: the γ-isomer, present to 10% to 13% in the mixture, is responsible for the insecticidal activity

CROTAMITON
N-Ethyl-N-(2-methylphenyl)-2-butenamide or N-ethyl-o-crotonototuidide (Eurax)
 is a colorless, odorless oily liquid
 virtually insoluble in water but soluble in most organic solvents.

TREATMENT/USE:
 available in 10% concentration in a lotion and a cream intended for the topical treatment of scabies
 antipruritic effect is probably because of a local anesthetic action

PERMETHRIN
3-(2,2-Dichloroethenyl)-2,2-dimethyl-cyclopropanecarboxylic acid (3-phenoxyphenyl)methyl ester or 3-
(phenoxyphenyl)methyl (±)-cis, trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (Nix)
 synthetic pyrethrinoid compound is more stable chemically than most natural pyrethrins and is at least as
active as an insecticide
 colorless to pale yellow low-melting crystals or as a pale yellow liquid and is insoluble in water but soluble
in most organic solvents

TREATMENT/USE:
 exerts a lethal action against lice, ticks, mites, and fleas
 acts on the nerve cell membranes of the parasites to disrupt sodium channel conductance
 used as a pediculicide for the treatment of head lice

SAR: the 1(R), trans and 1(R),cis-isomers are primarily responsible for the insecticidal activity

Side effects: pruritus, which occurred in about 6% of the patients tested.