ANTIPROTOZOAL AGENTS

PROTOZOA (single celled, eukaryotes)

INTESTINAL ♦ E. histolytica [Amebiasis, liver

abscess]♦ G. lamblia [Giardiasis]♦ Cryptosporidium sp [Crytosporidiosis]♦ Balantidium coli [Dysentery]♦ Isospora belli [Isosporosis]

Urogenital tract (men and women) ♦ T. vaginalis [Trichomoniasis]

BLOOD AND TISSUE ♦ Plasmodium sp [Malaria] ♦ Trypanosoma sp [Trypanosomiasis]

T. cruzi [Chagas’ disease] T. gambiense [sleeping sickness] T. rhodensiense [sleeping sickness]

♦ Leishmania sp [Leishmaniasis]Visceral (Kala-azar) Cutaneous (old world)Cutaneous (new world)Mucocutaneous

♦ Toxoplasma gondii [Toxoplamosis]

♦ Naegleria sp [Meningoencephalitis]

♦ Acanthamoeba [Meningoencephalitis]

♦ Babesia microti [Babesiosis]

NB. ♦ Pneumocystis jirovecii Pneumonia

Not a protozoa but a fungi but some behaviors like that of protozoa e.g. response to treatment

AMOEBIASIS (E. HISTOLYTICA) ►Trophozoites and cysts► Trophozoites can

(i) Live in lumen(ii) Invade colon epithelium – ulceration (iii) Spread to other organs/tissues e.g. liver

Trophozoites can simply live on gut bacteria – addition of a broadspectrum antiobiotic, e.g. a Tetracycline can lead to rapid improvement as the parasites major food source is depleted

Range of illness/symptoms(i) Asymptomatic carrier(ii) Mild intestinal infection - diarrhea(iii) Severe intestinal infection - dysentery(iv) Amoebic liver hepatitis and abscess(V) Amoeboma & extraintestinal infection

ANTI-AMOEBIC AGENTS

Classification – based on global site of action

Luminal 1. The amides - Diloxanide furoate, Etofamide, teclozan2. Iodoquinol, clioquinol (Halogenated hydroxyquinolines)3. Antibacterials- Tetracyclines, Paramomycin, Erythromycin

Extra luminal /Tissue1. Chloroquine2. Emetine, dehydroemetine (Alkaloids)- restricted use ‘coz of

toxicity on almost all tissues

(Both) Luminal and TissueNitroimidazoles – Metronidazole, tinidazole, secnidazole

1. The AMIDES - diloxanide furoate, etofamide, teclozanMxn: not clear, amebicidal

-Split in the GIT to diloxanide and furoic acid, Adm; oralAbs: most of diloxanide is absorbed (90%) what is left is still

effectiveElimination: metabolized then renal excretion

S/e♦ Flatulence♦ Dry mouth♦ Nausea, abdominal cramps♦ Pruritus, urticaria♦ Avoid in pregnancy and young children (<2yrs)

UsesLuminal amoebiasis (rx asymptomatic or along w. Tissue

amebicide to eradicate infection)

2. PARAMOMYCIN Sulphate (an aminoglycoside)

Mxn: (i) directly amoebicidal: interferes w/ cell membrane to cause leakage (ii) antibacterial – reduces food source for trophozoites

Adm: oralAbs; insignificant

S/E ♦ GIT irritation, diarrhea

Caution♦ Persons with GIT ulcers♦ Persons with renal dysfxn (the little abs can accumulate)

Uses1. Mild to moderate intestinal (Luminal) amoebiasis2. Giardiasis3. Leishmaniasis4. Tapeworm infestation (not DOC)

3. Halogenated hydroxyquinolines - IODOQUINOL and clioquinol Mxn: unclear, Directly amoebicidal (trophozoite, cyst) in lumen

Adm: oral Abs: poor (10%)S/E♦ GIT distress - (take w/ meals)♦ Allergic rxn (skin)♦ Goitre♦ Neurotoxic e.g. optic atrophy (limits its use), peripheral neuropathyD/I♦ Increases protein binding of iodine, ↓ iodine uptake by thyroid C/I♦ In persons intolerant to iodine♦ Caution in renal impairment, optic neuropathy or thyroid disease, or

hepatic disease (non amoebic)

Uses (2nd line) :1. Luminal amebicide (add metronidazole for systemic infection)2. Superficial fungal infections e.g. Tinea pedis3. Trichomonal vaginitis (as inserts) 4. Balantidium coli

4. NITROIMIDAZOLES – Metronidazole, tinidazole, secnidazole, Ornidazole, nimorazole, etc

Mxn: reduced by the parasite/bacteria to metabolites that are toxic to DNA and proteins – cell death (trophozoites only)

Adm: oral, parenteralDistributn: widely into all tissues (including CNS, saliva, breast

milk)Elimination: Metabolized (NB.liver failure) then renal excretion

S/E♦ Metallic (unpleasant) taste in the mouth ♦ Monoliasis (furry tongue), glossitis, stomatitis♦ Sig. GIT irritation –take w/ food♦ Disulfiram-like rxn w/ alcohol♦ Neurotoxic - (esp w/ parenteral)♦ Mutagenic (in bacteria) and tumorigenic in mice – best

avoided in pregnancy

4. Nitroimidazoles – Metronidazole, tinidazole D/I

♦ Potentiates - oral anticoagulants (warfarin)♦ Enzyme inducers e.g. Phenytoin and phenobarb increase metronidazole elimination♦ Enzyme inhibitors e.g. Cimetidine decreases its elimination

Uses (Metronidazole and members)1. DOC for all extra-intestinal amoebiasis e.g. liver abscess and amoebic dysentery (w/ a luminal agent for eradication of infection)2. DOC for giardiasis3. DOC for trichomoniasis 4. Anaerobic bacteria (e.g. C. difficile, B. fragilis, Peptostreptococcus)5. Balantidium coli (alternative)6. Drucunculiasis

5. CHLOROQUINE Uses: 1. Extra-intestinal amebiasis (along w/ metronidazole and diloxanide)2. Sensitive malarial parasites

6. EMETINE (natural alkaloid) & DIHYDROEMETINE (synthetic analogue)

Mxn: Inhibits protein synthesisAdm: under observation- parenteral (SC or IM NEVER IV)

(erratic GIT abs)

Serious S/E ●Cardiotoxic - arrhythmias, hypotension, CHF

C/I● Heart disease ● Renal failure●Children ● Pregnancy

Uses: where no better alternatives 1. Extra–intestinal amebiasis 2. Fasciola hepatica (alternative)3. Paragonimus westermani

NITAZOXANIDEMxn: a prodrug converted to tizoxanide the active drug,

inhibits an oxidoreductase enzyme involved in anaerobic metabolism

Spectrum; G. Lamblia, Cryptosporidium parvum, E. Histolytica, H.pylori

P’kinetics: oral; rapidly hydrolyzed to tizoxanide

A/E: GIT abdominal pain, vomiting, headache, nausea and diarrhea.

Uses: Cryptosporidiosis

Others:Named antibacterials act only by decreasing lumen

bacterial population- food source for trophozoites

GIARDIASIS – ♦ Metronidazole / tinidazole ♦ Mepacrine/quinacrine♦ Paramomycin (pregnancy)

TRICHOMONIASIS - ♦ Tinidazole (DOC)♦ Metronidazole

Less common intestinal & tissue protozoa

CRYPTOSPORIDIOSIS (usually self limiting in the

immunocompetent)♦ Spiramycin, Azithromycin♦ Paramomycin ♦Nitazoxanide

BALANTIDIUM COLI♦ Tetracycline♦ Metronidazole♦ Iodoquinol

ISOSPORA BELLI♦ Co-trimoxazole♦ Pyrimethamine (supplement folic

acid)

TOXOPLASMOSIS♦ Cotrimoxazole♦ Pyrimethamine+Sulphadiazine♦ Pyrimethamine+clindamycin♦ Pyrimethamine+azithromycin♦ Pyrimethamine+atavaquone

BABESIOSISQuinine + clindamycin

Various ways of classifying

A) Based on chemical structure

i) Sesquiterpenes (endoperoxides) e.g. Artemisinin

ii) Quinoline methanols (Cinchona alkaloids) e.g. quinine

iii) Quinoline-methanols (synthetic) e.g. mefloquine

iv) Phenanthrene methanols e.g. halofantrine

v) 4-aminoquinolines e.g. amodiaquine, chloroquine (CQ)

vi) 8-aminoquinolinese.g. Primaquine

vii) Diaminopyrimidines e.g. pyrimethamine, trimethoprim

viii) Biguanides e.g. Proguanil

ix) Antibacterials e.g. Sulphonamides, tetracylines, lincomycins

x) Acridine dyes e.g. quinacrine

B) Based on stage of plasmodial parasite affected and rapidity of effect – provide clinical cure by eradicating erythrocytic stages

i) Rapid blood schizonticides e.g. Artemisinin, quinine, chloroquine, amodiaquine, mefloquine, halofantrine

ii) Slow blood shizonticides e.g. Pyrimethamine, Proguanil, the antibiotics

iii) Tissue schizonticides e.g. primaquine

iv) Gametocides e.g. Primaquine, artemisinin, chloroquine

C) Suppressive Prophylactic agents e.g. Mefloquine, proguanil, doxycycline, Atavaquone-proguanil, primaquine

True Causal prophylaxis – preventing the ‘cause’ from infecting any human cell – before 1° infection of the liver

Malaria1. ARTEMISININ and its derivatives

♦ Artemisinin – water insoluble, ltd to oral use♦ Artesunate – water soluble, oral, IV, IM, rectal ♦ Artemether – lipid soluble - oral, IM, rectal♦ Arteether, Artelinic acid

Uses: ♦ Increasingly the DOC for P. falciparum ♦ Quinine resistant P. falciparum

Mxn: Fast acting blood schizonticide on all species ♦ The endoperoxide ring is cleaved w/in parasite to release free radicals that damage the parasite

1. ARTEMISININ and its derivatives Abs; rapid

Elimination: metabolized to active drug - dihydroartemisinin ♦ Short t1/2 - (leads to high recrudescence rate, best co-adm with other drugs)

i.e. Artemisinin-based combination Therapy - ACT) e.g. lumefantrine, fansidar, doxycycline amodiaquine

S/E (fairly well tolerated) ♦ GIT disturbance (nausea, vomiting, diarrhea) ♦ Teratogenic in high doses (so far only in animals) ♦ Cardiac conduction defects

P/C: ♦ 1st trim Pregnancy, ♦ Lumefantrine: those on previous halofantrine ♦ Cardiac dse

2. QUININE, QUINIDINE Mxn: - Actual mxn not clear - rapid blood schizonticide against all 4 sp♦ NOT active against liver stages♦ Other P’cological effects

i) curare-like effect (use on leg cramps)ii) oxytoxic effect – esp with advanced pregnancyiii) local irritant action – site of admiv) mild analgesic and antipyretic effect

Adm: oral, parenteral Abs: rapid, impaired by Al3+ containing antacidsDistribution: wide, protein- bound, (give a loading dose to

achieve peak levels soonest)Elimination: Quinidine shorter t1/2 Metabolized, renal excretion

S/E1. Cinchonism –Tinnitus, impaired hearing, visual

disturbance, dizziness, headache, nausea, flushed skinSerious S/E2. Audio-visual disturbance3. GIT irritation – abdominal pain, vomiting, diarrhea4. Hypersensitivity rxns – e.g. urticaria, bronchocospasm,

angioedima, (some hematological, below)5. Hematological abnormalities –

● Thrombophlebitis at site of infusion6. Hypoglycemia (stimulates insulin release, most felt by

pregnant patients)7. GIT irritation –pain, vomiting, diarrhea8. Uterine contractions in pregnancy (esp 3rd trimester) –

still DOC for severe falciparum but observe patient 9. Hypotension – with rapid infusion10. ECG changes

2. Quinine: Precautions/ avoid:

♦ If severe cinchonism occurs (discontinue therapy)♦ Auditory or visual problems♦ Cardiac abnormalities♦ Patients who have recently received mefloquine♦ Hypersensitivity rxns - hemolysis

D/I♦ Mefloquine (increases its toxicity) – do not co-administer ♦ Warfarin and Digoxin – quinine raises their plasma conc.

Uses: 1. Severe falciparum malaria (DOC, parenteral)

often combined w/ another drug (fansidar, doxycycline) to shorten duration of Rx and limit toxicity.

2. Babesiosis (Babesia microti) DOC in combination w/ clindamycin

3. MEFLOQUINE Mxn: unclear

Blood schizonticide (NOT gametocytes or liver stages)Resistance: not common in E. Africa

●Associated w/ resistance to quinine and halofantrine but not CQ

Adm: oral only (severe local irritation with parenteral use)Abs: good, slowDistribution: extensively in tissuesElimination: t1/2- long

● Some metabolism, Biliary excretion mainlyS/E

● GIT irritation ● Sleep disorders● Neuropsychiatric disturbance, discontinue if serious● Hepatic damage (mild)● Cardiac (conduction) defects – arrhythmias, bradycardia

3. MEFLOQUINEC/I – presence or Hx of

1. Cardiac conduction defects, use of cardiotoxic drugs2. Epilepsy3. Neuropsychiatric disorders4. Hypersensitivity (to related drugs)5. Quinine, quinidine or halofantrine (do not co-adm)6. 1st trimester of pregnancy

(NB can use in pregnancy 2nd, 3rd trimester – as last option)

Uses:1.Chemoprophylaxis (all 4 sp) (CQ preferred in areas where it is still sensitive)2. Rx of falciparum malarial infection – not DOC, not recommended

4. HALOFANTRINEMxn: not clearRapid blood schizonticide against all 4 sp (NOT gametes or hepatic

stages)Resistance: cross resistance w/ mefloquineOral Abs: variable, enhanced with meals (esp fatty foods)- but take on

empty stomach to avoid high plasma conc. ass. w/ toxicities

S/E♦ GIT irritation ♦ Headache, cough♦ Pruritus, rash ♦ Mild hepatic damage (elevated liver enzymes)♦ Cardiac conduction defects – arrhythmias, deathdose – related, worsened by prior mefloquine therapy ♦ Embryotoxic in animals

C/I♦ Persons w/ cardiac conduction defects♦ Persons recently on mefloquine♦ Use of other drugs that prolong Q-T interval♦ Pregnancy & lactation

Uses:• Rx of falciparum malaria (NOT for chemoprophylaxis)

5. CHLOROQUINE (CQ) Synthetic, 4-aminoquinolineMxn: prevents polymerization of heme to hemozoin, heme

accumulates and is toxic to parasite♦ Rapid blood schizonticide (v. effective on sensitive strains)♦ Moderately effective on gametes of all except P. falciparum♦ Not effective against hepatic forms

Other p’cological effectsi) anti-inflammatory, ii)Anti-amoebiciii)Quinidine –like effect

Adm: oral, parenteralAbs: rapid, almost complete, Ca2+, Mg2+ antacids and Kaolin

interfere w/ abs.Distribution: wide, sequestration in tissues - loading dose,

5. CHLOROQUINE

S/E: fairly well tolerated (in small malarial doses) reduced by taking after food♦ Pruritus (esp in Africans), urticaria ♦ GIT irritation, anorexia♦ Malaise ♦ Blurred vision♦ Large or rapid parenteral adm – hypotension (severe), respiratory and cardiac arrest (always infuse slowly)

Rare S/E♦ Hemolysis (w/ G6PDH deficiency), agranulocytosis♦ CNS disturbance –♦ Impaired hearing♦ Allergic rxn –♦ Cardiac conduction defects

S/E -Long –term and high doses ♦ Irreversible ototoxicity, rethinopathy, myopathy, peripheral neuropathy, CNS disturbance

5. CHLOROQUINEC/I

• Psoriasis, porphyria – it precipitates these diseases• Visual& muscle disorders• Caution in persons w/ Liver, hematological or neurologic disorders

Uses: 1. Hepatic amebiasis (where Metronidazole has failed or is C/I) + a lumicide2. Anti-inflammatory – rheumatoid arthritis, SLE etc – alternative

3. Infection w/ Clonorchis sinensis, Fasciola hepatica, Paragonimus spp, giardia spp

4a. Rx of Acute P. vivax, ovale, malariae infection (+ primaquine for radical cure)4b. Rx of sensitive forms ONLY of acute falciparum malaria –•Advantages: Rapid clearance of parasitemia, cheap, convenient regimen, few S/E5.Suppressive Chemophrophylaxis –ONLY in areas w/out resistance, (+ primaquine for radical cure)

6. AMODIAQUINE (Similar to CQ in many ways)Adm: oralS/E •Agranulocytosis, hepatotoxicUses:

•Sensitive strains of malaria•(don’t use for prophylaxis due to S/E)

7. ATAVAQUONE + proguanil = malarone - Still under studyAtavaquoneAdm: oralAbs: erratic – improved by fatty foodDistribution: sig. protein bindingS/E• GIT effects- nausea, vomiting diarrhea• Fever, Headache, insomnia• RashUses • Uncomplicated malaria and prophylaxis – combined w/ proguanil • Alternative in P. jirovecii infection (not as efficacious as Co-

trimox)• Toxoplasmosis

8. PRIMAQUINEMxn: Molecular mxn not clearActive against all hepatic stages (the only drug against

hypnozoites) but too toxic for causal prophylaxis♦ Gametocytocidal to all 4 sp (prevents transmission - to mosquitoes)♦(schizonticidal power is too weak to be significant)

Adm: oral (NEVER give parenteral – severe hypotension)

S/E♦ GIT distress -improved if taken w/ food♦ Hemolysis and methemoglobinemia esp in G6PDH deficiency

Serious ♦ Hematological abnormalities – leucopenia,agranulocytosis ♦ Cardiac arrhythmias

8. PRIMAQUINEC/I

♦ Those at risk of granulocytopenia, methemoglobinemia, mylosuppression♦ In pregnancy (just in case fetus is G6PDH deficient)

Uses:1. Radical cure of P. vivax & P. ovale infections (add a

schizonticide too)2. Terminal prophylaxis (after end of travel) to eradicate any

liver forms3. May be used for causal prophylaxis of malaria (any sp)-

given before travel to endemic area (then it need not be continued for long after return from endemic area

4. Alternative for mild Pnuemocystis jirovecii infection (along w/ clindamycin)

9. Sulphonamide-pyrimethamine (SP)Pyrimethamine Mxn: plasmodial dihyrofolate reductase inhibitorActs slowly against erythrocytic stage of all 4 sp. Resistance: altered enzyme, increased enzyme synthesisAdm: oralElimination: Extensive metabolism, t1/2 allows once a week

dosing

S/E (few)♦ GIT irritation♦ Rashes, itching♦ Teratogenic in animals (but fansidar still used in pregnancy)

NB. Always supplement folic acid if antifolates are used in pregnancy)

9. Sulphonamide-pyrimethamine (SP)Pyrimethamine

Uses: 1. Acute attacks and suppression of Malaria (in combination)

(sensitive strains)2. Toxoplasmosis (1st line - combined w/ sulfadiazine or

clindamycin and folic acid tabs) congenital, acute infection, immunocompromized

FANSIDAR = SULPHADOXINE (500 mg) + PYRIMETHAMINE (25 mg)

METAKELFIN = SULFALENE (500 mg) + PYRIMETHAMINE (25 mg)

MALOPRIM = DAPSONE (100mg) + PYRIMETHAMINE (12.5mg)

NB. Sulfonamides and sulfones – weak blood schizonticide, must not be used alone but combined

10. PROGUANIL (a biguanide)Mxn: A dihydrofolate reductase inhibitor

♦ A prodrug – must be metabolized to cycloguanil♦ Its activity as a blood schizonticide is slow ♦ not gametocidal

Abs; oral, adequateElimination: t1/2 – once daily dosingS/E

♦ GIT irritation♦ Skin rash♦ Mouth ulcers♦ Alopecia♦ Headache, vertigo

Uses:1. Prophylaxis of malaria – (alternative to mefloquine) in combination

w/ choloroquine (sensitive strain areas), (not acute attack)NB it is safe in pregnancy

11. Antibacterial antimalarials – schizonticidesE.g.Tetracycline and Doxycycline

♦ Are SLOW – never use alone for Rx (e.g . used w/ quinine – to shorten course)

Uses:1. Rx of falciparum malaria in conjuction w/ other

drugs e.g. quinine2. Chemoprophylaxis of malaria (Doxy)

♦ Clindamycin – along w/ quinine (e.g. where tet is not indicated - children)

TRYPANOSOMIASIS

♦ Objective of Rx is to clear blood, tissue and CSF of parasite

♦ Available drugs are not that efficient and have serious S/E

1. SURAMIN Mxn: not established – may inhibit critical enzymes and

energy metabolismAdm: IV Distribution – does NOT enter CNSElimination: t1/2 - 50 days, Slow renal excretion

1. SURAMIN S/E; common severeImmediate

♦ Minor; urticaria, harmless albuminuria (cloudy urine) ♦ Fatigue, vomiting ♦ Seizures, hypotension, shock, death

Later rxns ♦ Neuropathy, paresthesias, photophobia ♦ Renal damage ♦ Hematologic effects – hemolysis, agranulocytosisAdrenal cortical damage

Uses: ♦ Early (hemolymphatic) stages of East African trypanosomiasis (eflornithine is preferred for West African) ♦ Onchocerciasis ♦ Has been tried in some cancers e.g. prostate

2. PENTAMIDINE (others – stilbamidine, propamidine) Mxn: not clearAdm: parenteralDistribution: sequestered and accumulates in tissues (high

affinity) but NOT CNS, slow release back into circulationElimination: t1/2 – long

S/E (highly toxic, and common- 50%)♦ CVS - Due to rapid IV – hypotension, arrhythmias, dizziness,

dyspnea - IM adm – local pain and abscess

♦ Pancreatic toxicity – hypoglycemia (inappropriate release of insulin, later hyperglycemia)

♦ Renal damage ♦ Liver damage ♦ Hematological disorders ♦ Neurological disorders♦ Metallic taste etc

2. PENTAMIDINED/I with other nephrotoxic drugs

Uses1. Alternative (to Suramin) in early (hemolymphatic stages) of T.

rhodesiense (not gambiense)2. Visceral leishmaniasis – Alternative to sodium stibogluconate3. P. carinii infection: Alternative to Co-trimox4. Acanthamoeba

3. MELARSOPROL, Tryparsanide – (arsenicals)

Mxn: binds sulfhydryl gps of proteins, selective uptake by parasiteAdm: slow IV (water soluble melarsoprol by IM), under hospital

supervisionDistribution: slow accumulation in the CNSElimination: rapid, fecal (but accumulates to effective conc. over days)

3. MELARSOPROL

S/E (v. toxic)♦ Fever, arthalgia, vomiting♦ Reactive encephalopathy (rxn to byproducts of trypanosome death) –♦ Renal damage♦ Myocarditis♦ Hypersensitivity♦ thrombophlebitis

Uses1. Advanced trypanosomiasis (CNS disease) - 1st line drug2. Early trypanosomiasis (as alternative for patients who can not stand

suramin or pentamidine, its toxicity precludes use as a 1st line agent)

3. Tryparsanide (pentavalent arsenical)- alternative for Gambiense (+ suramin) for those intolerant to melarsoprol

4. EFLORNITHINEMxn: inhibits ornithine decarboxylase and prevents nucleic acid

synthesis

Adm: oral, IVDistribution: effective CNS penetrationElimination: renal excretion

S/E (most reversible, less toxic than melarsoprol)♦ GIT disturbance – nausea, vomiting diarrhea♦ Hematologic abnormalities – anemia, leucopenia,

thrombocytopenia♦ Hair loss ♦ Seizures♦ Hearing loss (ototoxicity) ♦ Teratogenic risk

Uses:1. Advanced (CNS) & early West African trypanosomiasis

(scarce, expensive)

5. NIFURTIMOXMxn: formation of radicals by parasite enzymes

Adm: oralAbs: goodElimination: metabolized

S/E (often reversible but contribute to non-completion of dose) ♦ GIT irritation ♦ Fever, restlessness, insomnia ♦ hypersensitivity rxns ♦ Neuropathies including seizures

Uses:1. Acute Chaga’s disease (American trypanosomiasis) – early stages, decreases symptoms and but does not fully eradicate parasite, and does not prevent progression to GIT and heart disorders) (not effective in chronic disease)

6. BENZNIDAZOLE (a nitroimidazole)Use: Acute chaga’s disease

S/E GIT disturbance♦ Peripheral neuropathy♦ Mylesuppression♦ Rash (dermatitis)

LEISHMANIASIS1. SODIUM STIBOGLUCONATE and Meglumine

antimonate (Pentavalent antimonials)Mxn: is a prodrug, converted to the active trivalent antimonial - Actual mxn not clear – may inhibit glucose metabolism Adm: parenteral (not abs orally)Distribution: some sequestrationElimination: renal excretionS/E (toxicity increases w/ time on therapy)

♦ Pain at injection site♦ GIT disturbance ♦ Pancreatitis♦ Fever, headache, myalgias, arthralgias, rash♦ Cardiac conduction defects ♦ Hepatic and renal damage (monitor their fxn periodically) ♦ Hemolytic anemia

1. SODIUM STIBOGLUCONATE and Meglumine antimonate (Pentavalent antimonials)

C/I pancreatitis, hepatitis, mycocarditisUses:

1. Cutaneous leishmaniasis (1st line in areas w/ minimal resistance)2. Visceral leishmaniasis (1st line)

Other antileishmanial agents2. Amphotericin B3. Pentamidine4. Miltefosine5. Paramomycin6. Ketoconazole (L. mexicana not L. braziliensis) 7. Imiquimod cream - immune response modulator

MILTEFOSINEMxn; not clear probably via effects on cell-

signaling pathways and membrane synthesis

UsesVisceral leishmaniasisCutaneous metastases of breast cancer

C/I; Pregnancy

Intestinal nematodes• Roundworm• Hookworm• strongyloides• Pinworm• Whipworm• T.spiralisTissue nematodes

(filaria)• O. volvulus• W. bancrofti• B. malayi• Loa loa• D. medinensis (guinea

worm)

• Toxocara larva (Roundworm) (visceral larva migrans)

• Dog & cat hookworm – cutaneous larva migrans

• T. spiralis larva

Cestodes (tapeworms)• T. solium• T. saginata• D. latum• E. granulosus• H. nana (dwarf)

Trematodes (flukes)• S. mansoni• S. japonicum• S. hematobium• Fasciola hepatica (liver fluke)• Clonorchis sinensis (liver fluke)• Paragonimus westermani (lung

fluke)• Fasciolopsis buski (intestinal

fluke)

COMMOM HELMINTHS

ANTIHELMITICSMost are parasite specific thus one has to be fairly definite

about the parasite

1. BENZIMIDAZOLESAlbendazole, mebendazole, thiabendazole, triclabendazoleSpectrum: broad

Mxn: inhibit microtubule assembly and microtubule-dependent glucose uptake; - parasite immobilized

Adm: oral Abs: minimal for Meb and Alb (empty stomach, Fatty meals

increase), rapid for Thia. Triclabendazole -taken with food to enhance absorption

Distribution: plasma conc. of albendazole is x100 that of mebendazole

Elimination: rapid conjugation; Biliary & renal excretion

ANTIHELMITICS1. BENZIMIDAZOLES

S/E (Short & long term)-GIT irritation-Rash -Teratogenic and embryotoxic in animals (best avoided in pregnancy)-More toxic effects w/ Thia (CNS disturbance, hypotension, erythema multiforme, Steven Johnsons syndrome, dizziness, GIT)

Long term Albendazole-alopecia, leucopenia, eosinophilia, pruritus

Uses (nematodes, few cestodes)- Mebendazole: Hook, round, pin, whipworms- Thia – strongyloidiasis, cutaneous larva migrans- Triclabendazole — DOC for Fasciola hepatica

Uses of albendazole1. Intestinal Nematode infestation-Hookworm -Round worms -Pin/Threadworm-Whipworm-Threadworm - moderately effective NB. objective to cure to prevent autoinfection

2. Hydatid disease – DOC, Rx (long- 3 months) and pre & post surgery Rx; (+ praziquantel)

3. Neurocysticercosis – co-adm w/ a steroid, (steroids also increase abs of albendazole) (albendazole is C/I in the acute phase of cysticercotic encephalitis – where steroids should be used)

4. Cutaneous larva migrans

5. Others - TrichinosisToxocariasisLoiasis

2. LEVAMISOLEMxn: Nicotinic action - continuous stimulation of muscle leading to blockage and

paralysis and expulsion Adm: oralAbs: rapidDistribution: wide including CSFElimination: metabolized (to inactive cpds) renal eliminationS/E (Few w/ single doses)

♦ GIT irritation♦ High conc. – nicotinic effects on mammalian autonomic ganglia

Uses: Round worms

3. PYRANTEL PAMOATEMxn: Depolarizing NMJ blocker, immobilizes parasite Adm: oralAbs: poor (intestinally active)S/E♦ GIT irritation (nausea, vomiting, diarrhea)♦ Mild CNS –headache, insomnia, drowsiness

Uses:1. Hook, round, pin worms

4. PIPERAZINEMxn: inhibitor of neuromuscular transmission – Blocks Acetylcholine at

NMJ in nematode muscle- paralyzes parasiteAdm: oral Abs: moderateElimination: part metabolized, part renal excretionS/E

-GIT disturbance-Allergic rxns: Urticaria, fever, bronchospasm,-Mild neurotoxicity – dizziness, somnolence, paresthesia, vertigo, incoordination, visual disturbance

C/I-Persons with Hx of neurological disease esp epileptic seizures-Persons w/ impaired hepatic or renal fxn-Do not co-adminster w/ phenothiazines-Avoid in pregnancy

Uses: 1. Round (single dose) and pin worms (lower multiple doses)2. Rx of filariasis –(last option) often elicits rxn (skin, eye, systemic) to parasite particles, severity varying with drug & intensity of infection.

5. IVERMECTINMxn: binds and opens glutamate-gated chloride channels in invertebrate

nerve and muscle cells, increasing chloride conductance- then hyperpolarization of the nerve or muscle cell, paralysis & death ffed by elimination by reticuloendothelial system -Microfilaricidal, embryotoxic

Adm: oral (on empty stomach)Abs: rapidDistribution: wide, slowly into eyes (NOT meninges)Elimination: metabolism, biliary excretion

USES:1. Onchocerciasis - DOC (co-adm a steroid w/ 1st Rx for eye infestation)2. Strongyloidiasis - (aim always to cure)

- Repeat Rx in immunonusuppressed3. Elephantiasis (2nd line, or combined w/ diethlycarbazine)4. Others – not DOC

-B. malayi-Cutaneous larva migrans-Scabies and head liceNB: in loiasis it induces a severe rxn if there is heavy load of parasite (>3000/ml)

5. IVERMECTINS/E

-Rashes, fever, headache, dizziness-GIT irritation – nausea, vomiting, abdominal pain-Myalgia, arthralgia-Mazotti rxn (dying parasites – peaks on 2nd day, correlates w/ skin microfilaria load, more frequent in non-residents persons and children, lessen w/ antihistamines and anti-inflammatory (aspirin) or steroids, they lessen w/ subsequent dosing)Features of mazotti rxn –

○CVS/lymphatic – hypotension (advice lying down), tachycardia, lymphadenopathy, limb edema,

○ GIT effects, ○ CNS - headache, dizziness, somnolence, ○ Miscellaneous - rash, pruritus, myalgia, arthralgia ○ Bronchospasm, ○ Eye effects – ocular inflammation

Caution & C/I-Avoid simultaneous use w/ other GABA agonists e.g. barbiturates, benzodiazepines, valproic acid-Avoid in pregnancy, breastfeeding and children < 5 yrs-Avoid in those with impaired BBB – meningitis, African trypanosomiasis

6. DIETHYLCARBAMAZINE - micro and macrofilaricide Mxn: interferes with parasite surface structures making them more susceptible to

host immune mxns, immobilizes microfilaria, Adm: oralAbs: rapidDistribution: into all tissues except fatElimination: Mainly renal excretion, some metabolism, (increased in acidic urine),

adjust dose with renal impairment or alkaline urineS/E

-GIT irritation – nausea, vomiting, anorexia-Headache, dizziness, malaise, sleepiness- some s/e due to symbiotic parasite on the filarial worms (Wolbachia)

Uses1. DOC in Rx (may also be used for prophylaxis)-

-W. bancrofti (elephatiasis)-B. malayi-Loa loa (loiasis)

2. Onchocerciasis – (2nd line, microfilaricide) – adm under observation (Mazzoti rxn)3. Mass Rx for W. bancrofti to reduce transmission (once wkly or monthly for 1 yr)

Caution: persons w/ ♦ Hypertension, Renal disease

NB. Rx any malaria first (may exacerbate it)

7. NICLOSAMIDEMxn: Inhibits oxidative phosphorylation (ATP syn), leads to death of

scoleces and segments (but not eggs), digested or expelled; purge in T. solium

Adm: oral (chew, on empty stomach - best 2hrs before breakfast) Abs: minimalS/E

- GIT effects - Headache, vertigo- Rash, urticaria, pruritus ani (allergy to parasite parts

Caution:- Avoid alcohol (up to 1 day after Rx)- Avoid in pregnancy and children below 2 yrs (no drug tests done on these gps)

Uses:1. DOC in beef, pork (w/ purge) and fish tapeworms2. Dwarf tapeworm (alternative to praziquantel) (must be given for long (7 days) and effective only on intestinal lumen parasite and not those lodged in villi3. Alternative in intestinal flukes (e.g. Fasciolopsis buski)

8. PRAZIQUANTELMxn: increases cell membrane permeability to calcium leads to – vacuolization,

contraction, paralysis and dislodgment from host, death, immune defense is essential

Adm: Oral (don’t chew, vomiting – regurgitation of T. solium segment is dangerous)

Abs: rapid, increased with carbohydrate meal & cimetidineBioavailability reduced with some drugs – antiepileptics & corticosteroidsDistribution: wide including CSF, breast milk, NB. Protein binding, Elimination: first pass metabolism (NB. liver dysfxn), renal, biliary excretion S/E (due to drug - increase w/ dosage)

- Fever, headache, dizziness, drowsiness, lassitude - GIT effects- Rash, pruritus, urticaria- Mild liver damage- Effects of dying parasites - eosinophilia

rxn to dying parasite (antiemetics, analgesics, diuretics and anticoncvulsants) – e.g. hydatid Rx- Meningismus, mental changes, seizures, increased CSF fluid, intracranial HPTn, arachnoiditis, hyperthermia,

NB steroids reduce the plasma conc. of praziquantel (upto 50 %)

8. PRAZIQUANTELC/I

- Ocular cysticercosis –parasite degeneration → irreparable damage- Avoid in pregnancy- stop breastfeeding for 3 days after Rx

Uses: trematodes, cestodes (not active against F. hepatica)1.Schistosomiasis – DOC for all forms

Use in early infection may lead to severe hypersensitivity rxn and also young schistosomes (2-5 wks old) are not very insensitive to praziquantel

2. H. nana - DOC

3. Taeniasis (saginata and solium w/ purge) and D. latum infectionsNB. In cysticercosis endemic areas – best use a lower dose to minimize rxns from any existing/ unknown cysticercosis

4. Neurocysticercosis – alternative to albendazole, to be adm under supervision

5. Hydatid disease – added to albendazole (pre and post surgery – it increases albendazole sulfoxide conc. and kills protoscoleces)

9. METRIFONATE – active only on S. hematobiumMxn: an organophosphate, a prodrug – active metabolite - dichlorvos

-Inhibits cholinesterase – paralysis of the parasite, detach from the bladder, transported to lungs where they are trapped and killed by the immune system-Active against both mature and immature stages but not eggs

Adm: oralAbs: readyDistribution: well, wideElimination: metabolized to dichlorvos (active drug, forms only 1%)

S/E- cholinergic symptoms (inhibition of cholinesterase (plasma and erythrocyte) – e.g. bronchospasm, diarrhea, abdominal spasms - CNS- dizziness, vertigo- Sweating

C/I - Avoid use of muscle relaxants, or in persons recently exposed to organophosphates - Avoid in pregnancy

10. OXAMNIQUINE –acts only on S.mansoniMxn: unclear – causes detachment of parasites from venules (in the

mesentery) and relocation to liver, an unsuitable environment where they die.

Active against mature and immature stages, but not cercaricidalAdm: oral, take w/ foodAbs: readyDistribution:Elimination: t1/2 – 2.5 hrs. metabolized, renal excretionS/E -fairly safe

- CNS effects – fever, headache, dizziness, drowsiness- GIT effects –-Urticaria, pruritus-Orange discoloration of urine

(Uncommon)- CNS- seizures, insomnia, amnesia (avoid activities requiring attention), behavioral change, hallucinations- Microhematuria, proteinuria

10. OXAMNIQUINEEffects due to dying parasite

- Liver damage- Pulmonary infiltrates (cough)

Caution

- In patients w/ epilepsy (should be hospitalized)- C/I in pregnancy

Uses:1. S. mansoni infection – all stages (acute – katayama syndrome or

late – hepatosplenomegaly)

Other drugs (Schistosomes)Bithionol – DOC for liver fluke (Fasciola hepatica), paragonimiasis, Emetine and dehydroemetine – alternative for fascioliasis