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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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