ANTI-PROTOZOAL DRUGS

ANTI-PROTOZOAL DRUGSDR.RAVIRAJ JAGDHANIJR-2, DEPT. OF PHARMACOLOGYSVNGMC, YAVATMAL

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CONTENTINTRODUCTIONANTIAMOEBIC DRUGSDRUGS FOR GIARDIASISDRUGS FOR TRICHOMONIASISDRUGS FOR LEISHMANIASISDRUGS FOR TRIPANOSOMIASISOTHER PROTOZOAL INFECTIONSSUMMARY REFERENCES

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INTRODUCTION

Human host a wide variety of protozoal parasites

Protozoa multiply rapidly in their host

Immune system

Opportunistic infections

PROTOZOAL INFECTIONS OF HUMANS

PROTOZOAL INFECTIONS OF HUMANS

ANTIAMOEBIC DRUGS

INTRODUCTION: AMOEBIASISAnaerobic protozoa Entamoeba histolytica

Worldwide distribution

Endemic in most part of India

In tissues: Trophozoites

In intestine: Trophozoites and cyst

In colonic lumen: symbiotic relationship

HISTORY: ANTI-AMOEBIC DRUGSBrazil root or Cephaelis ipecacuanha: 17th century

Emetine (pure alkaloid): 1912

Chloroquine: 1948

Diloxanide furoate: 1960

Metronidazole: early 1960

Tinidazole: 19708-hydroxyquinolines: banned in 1970 (Japan)

CLASSIFICATIONTISSUE AMOEBICIDES

A. For both intestinal and extraintestinal amoebiasis:Nitroimidazoles: Metronidazole, Tinidazole, Secnidazole, Ornidazole, Satranidazole, Nimorazole Alkaloids: Emetine, Dehydroemetine

B. For extraintesitinal amoebiasis only: Chloroquine

2. LUMINAL AMOEBICIDES:

Amide: Diloxanide furoate, Nitazoxanide8-Hydroxyquinolines: Quiniodochlor, DiiodohydroxyquinAntibiotics: Tetracyclines, Paromomycin

METRONIDAZOLE (1959)Amoebicide

Broad spectrum:

Selectively toxic to anaerobic and microaerophilic microorganisms

Enters cell by diffusion

Mechanism of ActionMetronidazole (nitro group) Nitro radical

PharmacokineticsSmall intestine

Widely distributed

Liver (oxidation and glucuronide conjugation)

Renal excretion

8 hr

Adverse effectsFrequent and unpleasant but non serious

Anorexia, nausea, metallic taste and abdominal crampsLooseness of stoolsHeadache, glossitis, dryness of mouth and dizzinessUrticaria, flushing, itching, rashes and fixed drug eruptionProlonged administration peripheral neuropathy and CNS effects, seizures (high dose),Repeated course - leucopeniaThrombophlebitis

ContraindicationsNeurological diseases

Blood dyscrasias

1st trimester of pregnancy

Cautious use in chronic alcoholics

InteractionsAlcohol

Enzyme inducers

Cimetidine

Warfarin

Lithium

UsesAmoebiasisGiardiasisTrichomonas vaginitisAnaerobic bacteria infectionsPseudomembranous enterocollitisAcute necrotizing ulcerative gingivitis (ANUG)H.pylori gastritis/peptic ulcerGuinea worm infestation

OTHER CONGENERS OF METRONIDAZOLEDRUGSPHARMACOKINETICSTINIDAZOLESlow metabolism, 12hr, better toleratedSECNIDAZOLERapid absorption, slow metabolism, 17-29hrORNIDAZOLE12-14hrSATRANIDAZOLE14hr, better tolerabilityNIMORAZOLE12-14hr

EMETINEIt is an alkaloid from Cephaelis ipecacuanha.

Emetine is a potent and directly acting amoebicide-kills trophozoites

It acts by inhibiting protein synthesis in amoebae by arresting intraribosomal translocation of tRNA-amino acid complex.

Symptomatic relief occurs in 1-3 days

It is administered by s.c. or i.m. : 60 mg 0D

It is an irritant; pain, stiffness and eczematous lesions occur at the site of injection.

High systemic toxicity

Nausea, vomiting (CTZ and gastric irritation)

Hypotension, ECG changes and myocarditis

C/I in presence of cardiac or renal disease and during pregnancy.

DEHYDROEMETINESimilar efficacy

Less cumulative and less toxic

Acute amoebic dysentry OR amoebic liver abscessLiver fluke infestation

Dose: 60-100mg s.c./i.m. OD (not more than 10days)

CHLOROQUINEKills trophozoites of E. histolytica

Highly concentrated in liver (hepatic amoebiasis only)

Completely absorbed from the upper intestine

Efficacy similar to emetine, but duration is longer

Dose: 600mg for 2 days, f/b 300mg daily * 2-3 weeks

DILOXANIDE FUROATEIt is a highly effective luminal amoebicide Directly kills trophozoites responsible for production of cysts. The furoate ester is hydrolysed in intestine and the released diloxanide is largely absorbed.Diloxanide is a weaker amoebicide than its furoate esterIt is primarily metabolized by glucuronidation and is excreted in urine.

Very well tolerated

S/E: flatulence, occasional nausea, itching and rarely urticaria.

It is the drug of choice for mild intestinal/ asymptomatic amoebiasis,

It is given after any tissue amoebicide to eradicate cysts. Some chronic cases require repeat courses for eradication.

Dose: 500mg TDS * 5-10daysChildren: 20mg/kg/day

NITAZOXANIDESalicylamide congener of the anthelmintic Niclosamide

Prodrug: Tizoxanide

Inhibitor of PFOR enzyme

Glucuronide conjugated

Urine and bile

Uses:Cryptosporidiosis (esp.in children and AIDS pt.)GiardiasisAmoebic dysentery

S/E: abdominal pain, vomiting and headache

Dose: 500mg BD* 3 days Children: 7.5 mg/kg BD* 3 days

8-HYDROXYQUINOLINESThey kill the cyst forming trophozoites in the intestine, but do not have tissue amoebicidal action.

Less efficacy

Absorption from intestine is variable.

The absorbed fraction is conjugated in liver with glucuronic acid and sulfate and excreted in urine;

12 hours

8-Hydroxyquinolines are well tolerated: produce few side effects-nausea, transient loose and green stools, pruritus, etc.

Goiter has been reported after prolonged medication.

Subacute myelo-optic neuropathy (SMON)

Neuropathy and visual impairment

Quiniodochlor: 250-300mg TDS* 14 daysDiiodohydroxyquin: 650mg TDS* 14 days

TETRACYCLINESDirect inhibitory action on Entamoeba

Incompletely absorbed in the small intestine, reach the colon in large amounts and inhibit the bacterial flora with which Entamoebae live symbiotically

Valuable in chronic, difficult to treat cases with only the luminal cycle and little mucosal invasion

Adjuvant role

PAROMOMYCINAminoglycoside antibiotic

Bind to 30S ribosome and interfere with protien synthesis

Orally administered neither absorbed nor degraded excreted unchanged in faeces

Efficacy as luminal amoebicide is similar to diloxanide furoate

Dose: 500mg TDS* 7 days

Treatment of different forms of amoebic infections

DRUGS FOR GIARDIASIS

METRONIDAZOLE/TINIDAZOLEMetronidazole: 400mg TDS (children 15mg/kg/day)* 5-7days or 2gm daily * 3 days

Tinidazole: 600mg daily * 7 days or 2gm single dose

Secnidazole: 2gm single dose

NITAZOXANIDE :Dose: 500mg BD * 3days (children 7.5 mg/kg)

QUINIODOCHLOR:250mg TDS * 7days

PAROMOMYCIN:500mg TDS* 5-7 daysCan be used during pregnancy

FURAZOLIDONENitrofuran compound

100mg TDS * 5-7 days

Partly absorbed from intenstine

Urine (orange)

Nausea, headache, dizziness

DRUGS FOR TRICHOMONIASIS

DRUGS USED ORALLYMetronidazole: 400mg TDS * 7 days or 2 gm single dose

Tinidazole: 600mg daily * 7 days or 2gm single dose

Secnidazole: 2gm single dose

Both partners should be treated concurrently

DRUGS USED INTRAVAGINALLYDiiodohydroxyquin 200 mg inserted intravaginally at bed time for 1-2 weeks (vaginal pessaries)

Quiniodochlor 200 mg inserted in the vagina every night for 1-3 weeks

Povidone-iodine 400 mg inserted in the vagina daily at night for 2 weeks

DRUGS FOR LEISHMANIASIS

DRUGS FOR LEISHMANIASIS

VISCERAL LEISHMANIASISVisceral Leishmaniasis Leishmania donovani

Female sandfly phlebotomus

Fly promastigote form (extracellular)Human amastigote form (intracellular)

Tropical and subtropical regions

India kala azar control programme in 1990

Upgraded in 2000 to aim at elimination (NVBDCP)

CURRENTLY USED DRUGSSodium stibogluconate (SSG)Amphotericin B (AMB)MiltefosineParomomycin

SODIUM STIBOGLUCONATE(SSG)(1945)Water soluble pentavalent antimonial

MOA: unclear

Specific reductase enzyme (pentavalent Sb to toxic trivalent), promotes efflux of glutathoine & reduced thiols oxidative damage

Rapidly absorbed

Urine (within 6-12 hours)

A small fraction enters tissues and remain stored for long

Repeated doses are cumulative

Accumulation of SSG within macrophages prolonged inhibitory effect on leishmania

Dose: 20 mg/kg (max. 850 mg) daily by i.m. (in buttocks) or i.v. injection for 20-30 days or more.

The duration of treatment is adjusted according to clinical response.

Patients are considered cured when no parasites are detected in splenic or bone marrow aspirates.

Adverse effects In general, antimonials are toxic drugs, but the pentavalent compounds (particularly SSG) are better tolerated.

Nausea, vomiting, metallic taste, cough, pain abdomen, pain and stiffness of injected muscle, sterile abscesses, and mental symptoms often occur.

Pancreatitis, liver and kidney damage, myelosuppression, ECG changes are possible, but are seldom severe.

Few cases shock and death are on record.

AMPHOTERICIN-BAMB-DOCL-AMB

Like fungi, leishmania has high percentage of ergosterol

Presently, AMB is the drug with highest cure rate in kalaazar: up to 99% clinical and parasitological cure has been reported in SSG-resistant cases.

High toxicity and need for prolonged hospitalization, monitoring and repeated slow i.v. infusions limit its application

DOC pregnant and breast feeding mothers

L-AMB: delivers drug inside RES in spleen & liver

15mg/kg administered over 3-5 days

MILTEFOSINEDerivative of alkyl phosphocholine

First oral antileishmania drug

1st line (NVBDCP)

MOA: unknownInterfere with lipid metabolism of parasite OR prevent synthesis of cell surface anchor molecules OR alter signal transduction

Rapidly absorbed

Widely distributed

7 days

Anorexia, vomiting & diarrhoea

Skin allergy, raised hepatic transaminase, rise in Sr.creatinine

C/I in pregnancy

100mg/OD* 4 weeks

PAROMOMYCINAminoglycoside antibiotic

AE: Ototoxicity, elevated Sr.transaminase and injected side pain

Effective, less expensive and easier to use

11mg/kg/day i.m. * 21days

COMBINATION THERAPYL-AMB (5mg/kg i.v. single dose) + Miltefosine (oral)daily * 7days (NVBDCP)L-AMB (5mg/kg i.v. single dose) + Paromomycin (i.m.)daily * 10 daysMiltefosine (oral)daily + Paromomycin (i.m.)daily * 10 days (NVBDCP)

Post Kala-azar Dermal Leishmaniasis (PKDL) patients are to be treated with

(i) Liposomal amphotericin B: 5mg/kg per day by infusion two times per week for 3 weeks for a total dose of 30mg/kg, or (ii) Miltefosine: 100mg orally per day for 12 weeks, or

(iii) Amphotericin B deoxycholate: 1mg/kg over 4 months 60-80 doses

Other alkylphospholipids such as edelfosine and ilmofosine, as well as perifosine, have proved to possess potent in vitro antiparasitic activity.

In 2008, Cabrera-Serra et al. tested edelfosine and perifosine orally in mice infected with Leishmania amazonensis.

This pre-clinical study showed that perifosine had higher activity in the in vivo assay and may be a possible alternative treatment against cutaneous leishmaniasis

Sitamaquine is a promising oral treatment for visceral leishmaniasis in Africa.

A 28-day course of treatment was efficacious and well tolerated in 61 Kenyan patients infected by L. donovani, with the tested dose of 2.0 mg/kg/day; however, further studies are required to define the optimal dose.

Some adverse effects included abdominal pain, headache, and a severe renal event.

The effects of sitamaquine on the kidney need further investigation

DERMAL LEISHMANIASIS (ORIENTAL SORE)Not life threatening

Treated by local application of drugs

Sodium stibogluconate: Infiltrate 2 ml of the solution (100 mg antimony I ml) round the sore. Paromomycin ointment: applied topically on the sore.

DRUGS FOR TRYPANOSOMIASIS

AFRICAN TRIPANOSOMIASISSLEEPING SICKNESS

Bite of tsetse fly

2 stages:1st stage haemolymphatic stage (LN enlargement, fever and headache)2nd stage meningo-enchephalopathic stage (mental disturbances and drowsiness)

SURAMINDOC early phaseDont cross BBB

Drug bind to host protein drug protein complex trypanosomeDrug is liberated by lysosomal proteases to exert detrimental action on trypanosomal enzymes

Slow i.v. Half life: 50 days

Sensitivity test: important

S/E:Immediate: nausea, vomiting, shock, loss of consciousness and even death

Abdominal pain, mouth ulcers, urticaria

Later: paraesthesia, hyperasthenia of palm and soles, fever, polyuria, polydipsia, lacrimation, proteinuria and heamaturia

PENTAMIDINEBinds protozoal DNA and inhibits DNA replication and function

i.m. or aerosol (i.v. is avoided)

12 days

Alternative to suramin

Pancreatic beta-cell toxicity is common

MELARSOPROLTrivalent arsenicalReserved later stageBind to SH group of protozoal enzyme and protein alter cellular structure inhibit functioni.v. infusion (2.2% solution in propylene glycol)Therapeutic significant conc. achieved in CSF S/E: Reactive encephalopathy Peripheral neuropathy, HTN, myocardial damage, albuminuria, fever, abdo pain, vomiting, hypersensitivityC/I: G6PD deficiency and leprosy pt.

EFLORNITHINEIrreversible inhibitor of trypanosomal ornithine decarboxylase inhibits biosynthesis of protozoal polyaminesPolyamines are required for cell division and differentiation

i.v.Good accumulation in CSFLess toxicS/E: vomiting, diarrhoea, anaemia, thrombocytopenia and seizures

AMERICAN TRYPANOSOMIASISCHAGAS DISEASE

T.cruzi is carried by infected triatomine bugs which feed on human blood.

Cardiomyopathy, mega-colon and mega-esophagus

NIFURTIMOXOral

Effective in acute > chronic

Fails to prevent GIT and cardiac manifestations

It udgergoes reduction nitroamine radical H2O2, hydroxyl and superoxide free radical

Toxic to trypanosome devoid of catalase

S/E:Immediate hypersensitivity reactions anaphylaxisDelayed hypersensitivity dermatitis, icterus and feverWeight loss (anorexia)Peripheral neuropathyPsychic problemHeadache, nausea, vomiting

BENZNIDAZOLEOral

Efficacy is similar to nifurtimox

12 hr

MOA: nitroimidazole

Better tolerated

OTHER PROTOZOAL INFECTIONS

PROTOZOAL INFECTIONSDRUGS OF CHOICEALTERNATIVE DRUGSCryptosporidiosisParomomycin 500mg TDS*10daysORNitazoxanide 500mg BD*3days(adults)100-200mg BD*3days(children)Azithromycin 500mg OD*3weeksPneumocystosisCotrimoxazolePentamidineTrimethoprimDapsoneClindamycinPrimaquineAtovaquoneToxoplasmosisPyrimethamine+Clindamycin+Folinic acid

Spiramycin (pregnancy)Pyrimethamine+Sulfadiazine+Folinic acid ORAzithromycin/Clarithromycin/Atorvaquone

SUMMARY

Most of these drugs have been in use for years despite major advances in bioscience relevant to parasite biology, host defences and mechanisms of disease.

Satisfactory agents for treating important protozoal infections are still lacking.

Development of drug resistance also poses a serious threat to better tolerated drugs in current use.

Unfortunately, many of these diseases afflicts the poor in developing countries.There is little economic incentive for pharmaceutical companies to develop new antiparasitic drugs.

Scientists and physicians working in this field must be creative and have turned to drugs developed originally for other indications (e.g., amphotericin and miltefosine for leishmaniasis), to investigational drugs made available directly from the Centers for Disease Control and Prevention (CDC), or

to agents developed for veterinary use to discover new antiparasitic therapies.

REFERENCES

Brunton L and et.al. Goodman and Gilmans The Pharmacological Basis of Therapeutics. 12th Ed. Chemotherapy of protozoal infections:1419-1441.Tripathi KD. Essentials of medical Pharmacology. 7th Ed. Antiamoebic and other antiprotozoal drugs:836-848.Sharma HL, Sharma KK. Principles of Pharmacology. 3rd Ed. Antiamoebic and other protozoal drugs:838-848.

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