ANTIAMOEBIC AND ANTIPROTOZOAL DRUGSDr. D. K. BrahmaAssociate Professor Department of PharmacologyNEIGRIHMS, Shillong

Section – 1

Antiamoebic DrugsDrugs useful in infections caused by the protozoa Entamoeba histolytica (E. histolytica)

AMOEBIASIS - EPIDEMIOLOGY

E. histolytica, a protozoa parasite is the causative agent of amoebiasis

Approximately 48 million individuals suffer from amoebiasis throughout the world

At least 40 thousand deaths are attributable to amoebiasis

Ranks third among parasitic causes of deaths, behind only malaria and schistosomiasis

E. HISTOLYTICA – PATHOGENESIS

• It is a water-borne pathogen transmitted by the fecal-oral route

• Exists in 2 (two) forms:1. Cyst or the dormant form – can survive outside the

body2. Trophozoite or the dividing form - Non-infective and do

not persists outside the body but invasive

• Two stages of development: Ingested cyst reaches colon transform

to trophozoitesMay live as commensals

Form cysts that pass on to stool

1. Form amoebic ulcers (acute dysentery) - galactose/N- acetyl-galactosamine (Gal/GalNAc) lectin

2. Chronic amoebic dysentery (vague symptoms, amoeboma)

PATHOGENESIS OF E. HISTOLYTICA – CONTD.

• Trophozoites can also enter the blood stream and travel to other parts— commonly the liver, but sometimes the lungs or brain and can cause abscesses. • Remember - In tissues, only trophozoites are present

AVAILABLE DRUGS

1. Tissue amoebicides:a) Intestinal and extra-intestinal: Nitroimidazoles

– Metronidazole, Tinidazole, Secnidazole, Ornidazole, Satranidazole and Alkaloides – Emetine and Dihydroemetine

b) Extra-intestinal – Only Chloroquine

2. Luminal amoebicides: Amides – Diloxonide furoate, Nitazoxamide; 8-Hydroxyquinolines – Quinodochlor, Diiodohydroxyquin; Antibiotics - Tetracycline

METRONIDAZOLE – PROTOTYPE

Originally discovered and used for Trichomoniasis in 1959

Broad spectrum cidal activity against --- Protozoa – E. histolytica, T. vaginalis, G. lamblia

Anaerobic bacteria – B.fragilis, C.perfringes, H.pylori, Cl. difficile

Resistance – no significant resistance for E. histolytica till now, but developed for T. vaginalis

G. lamblia T. vaginalis

METRONIDAZOLE – MOA

• Selective Toxicity to anerobic microorganisms• A system unique to anaerobics - Pyruvate:ferredoxin

oxidoreductase pathway (PFOR) normally generates ATP via oxidative decarboxylation of pyruvate

• Metronidazole: Entry into the microorganism by diffusion (LMW) ---- Reduced to nitro radical by certain redox proteins in the mitochondria to nitro group --- nitro radicals act as an electron sink --- competes with Biological acceptor sites of anaerobic organisms for the electrons generated PFOR pathway of pyruvate reduction– Reduction of metronidazole creates a concentration

gradient that drives uptake of more drug, and promotes formation of intermediate compounds and free radicals

– Cytotoxic intermediate particles interact with host cell DNA, resulting in DNA strand breakage and fatal destabilization of the DNA helix

METRONIDAZOLE – CONTD.

Pharmacokinetics: Well absorbed from the small intestine Widely distributed in the body secretions – vaginal

secretions, semen, saliva and CSF Metabolized in liver by oxidation and

glucoronidation Half life – 8 Hrs

ADRs: Most common - Nausea, Vomiting, abdominal

cramps and metallic taste Less frequent – headache, glossitis, rashes and

dryness of mouth Prolonged administration – Peripheral neuropathy

and CNS effects Seizures at high dose

METRONIDAZOLE – CONTD.

• Contraindications:– First trimester of pregnancy– Neurological diseases and Blood

dyscrasias– Chronic alcoholism

• Interactions:– Disulfiram-like intolerance: Symptoms:

flushing, burning sensation, throbbing headache, perspiration, dizziness, vomiting, visual disturbance, mental confusion, fainting and circulatory collapse

– Enzyme inducers like Phenobarbitone and Rifampicin (reduced therapeutic effect)

METRONIDAZOLE - USES

1. Ameobiasis – Kills E. histolytic trophozoites but not cysts. Treatment of all tissue infections with E histolytic. No effects against luminal parasites and so must be used with a luminal amebicide – for eradication

2. Giardiasis3. Trichomonas vaginalis – additional

intravaginal treatment and both partners !!4. Anaerobic infections5. Pseudo-membranous enterocolitis6. Ulcerative gingivitis7. Helicobacter pylori

OTHER NITROIMIDAZOLES

• Tinidazole, Secnidazole, Ornidazole, Satranidazole• Tinidazole:

– Slower metabolism, duration of action longer (t1/2 12 hrs) – single dose

– Higher cure rates (!)– Better tolerated – lesser incidence of side effects

• Secnidazole: Rapid absorption, but slower metabolism – half life 17-29 hrs

• Ornidazole: 12 -24 • Satranidazole: 14 hrs half life – better tolerated

plus no nausea, vomiting and metallic taste - no disulfiram like reaction and neurological symptoms

EMETINE AND DEHYDROEMETINE Emetine, alkaloid derived from Cephaelis ipecacuanha

and dehydroemetine, a synthetic analog, are effective against tissue trophozoites of E histolytica

• MOA: Inhibiting intraribosomal translocation of tRNA-amono acid complex → inhibiting elongation of peptide chain → inhibiting protein synthesis

• Action: Effects on trophozoites but not on cysts. Potent and rapid action – symptomatic relief in 1-3 days, but not curative

Administered subcutaneously (preferred) or i.m. (but never i.v.) because oral preparations are absorbed erratically and vomiting

Uses: Seldom used now. Reserve drug for severe intestinal and extraintestinal amoebiasis or for patients not responding to metronidazole. Luminal amoebicide needed to be added

EMETINE - ADRS Local stimulation: pain and tenderness in

the area of injection Gastrointestinal tract discomfort: nausea,

vomiting, diarrhoea and abdominal cramps Neuromuscular blockade: muscle weakness

and discomfort Cardiac toxicity: arrhythmias, congestive

heart failure, hypotension, ECG changes Not be used in patients with cardiac or

renal disease, in young children, or in pregnancy

CHLOROQUINE

Kills trophozoites of E. histolytica Concentrates in liver – used in hepatic

amoebiasis Completely absorbed from upper intestine

– not effective in invasive or luminal dysentery

Efficacy in amoebic liver is equal to emetine, but longer treatment and relapse

Used after a course of Metronidazole – but a luminal amoebicide must be added

Dose - 600mg stat and next day &300mg for 2-3 days

DILOXANIDE FUROATE (DF) Highly effective luminal amoebicide Kills trophozoites responsible for production

of cyst – however no antibacterial action MOA: Oral DF F hydrolyzed and D is freed

90% D is absorbed remaining 10% reaches Large intestine and exerts effects Absorbed D – low serum level – no therapeutic

effects Uses: Mild tissue amoebiasis/asymptomatic

cyst passers, Tissue amoebiasis and liver abscess with Metronidazole

ADRs: Well tolerated, only falatulence, nausea, itching and rarely urticaria

NITAZOXANIDE

Newer Drug for Giardiasis Also effective in E. Histolytica, T. Vaginalis, H.

Pylori etc. Converted to Tizoxanide after absorption MOA: Inhibition of PFOR Uses: Giardiasis, aboebiasis as luminal

amebicide Dose: 500 mg BD for 3 days

8-HYDROXYQUINOLINES Drugs – Iodoquinol, Clioquinol and Iodochlorohydroxyquin Act against Entamoeba, Giardia, Trichomanas, some fungi and

Bacteria Luminal amoebicidal but no tissue action – not effective in acute

dysentery but in chronic intestinal amebiasis (but lesser than DF)

Absorbed very less amount (10-30%) - therapeutic conc. Is not attained conjugated and excreted in urine

Once a popular drug – but less now because of ADRs ADRs – well tolerated – only nausea, green stools pruritus etc.

plus Iodism But Subacute myelo-optic neuropathy (SMON) - the

inflammation of the optic nerve causing a complete or partial loss of vision and also peripheral neuropathy

Uses: Alternative to DF in amoebiasis, Giardia, local treatment of vaginal Trichomous and fungal and bacterial infections. 250 to 500 mg tds

CHOICES OF DRUGS

Asymptomatic cysts carriers

Iodoquinol or ParomomycinOr Diloxanide furoate

Diarrhea / Dysentery Metronidazole + Iodoquinol or Diloxanide or Paramomycin

Amebic liver abscess Chloroquine + Metronidazole + DF

Giardiasis (Giardia labmlia)

Metronidazole or Nitazoxamide or Iodoquinol or Furazolidone

TRICHOMONAS VAGINITIS TREATMENT

Metronidazole – 400 mg tds for 7 days or 2 gm single dose, or

Tinidazole 600 mg BD for 7 days or 2 gm single dose

Repeat after 6 weeks Additional intravaginal treatment for

refractory cases Resistance have been reported Both partners should be treated Local application drugs: Quinodochlor,

ClotrimazoleNatamycin, Povidone Iodine etc.

• Section – 2

• Drugs for Leishmaniasis

• Visceral leishmaniasis or kala-azar caused by Leishmania donovani

• Transmitted by bite of female sand fly of genus phlebotomus

• Amastigote and Promastigote

AVAILABLE DRUGS

Antimonial – Sodium stibogluconate (SSG) Diamide – Pentamidine Antifungal – Amphotericin B (AMB),

Ketoconazole (KTZ) Others – Mifepristone, Paromomycin and

Allopurinol

SODIUM STIBOGLUCONATE (SSG) The drug of choice in Leishmaniasis – some resistance Water soluble pentavalent antimonial compound –

1/3rd antimony by weight MOA: Not clear

-SH dependent enzymes are inhibited – bioenergetics of the parasite

Blocks glycolytic and fatty acid oxidation pathways Enzyme in leishmania converts SSG to trivalent

compound – causes efflux of glutathione and thiols – oxidative damage

Not metabolized – excreted unchanged in urine after IM injection

Dose: 20-30 mg/kg deep IM daily in buttock for 20-30 days or more – depends on response – also IV Response in Bone marrow and splenic aspirates

Should be give on alternate days I poor health patients

SSG - ADRS

All antimonials are toxic Pentavalent compounds are less toxic and

better tolerated Nausea, vomiting, metallic taste, cough and

pain abdomen Stiffness and abscess in injected muscles Pancreatitis, liver and kidney damage etc. Rarely shock and death

PENTAMIDINE

• MOA: Not clear, inhibits Topoisomerase II or interferes with aerobic glycolysis

• Dose: 4 mg/kg IM or slow IV for 1 Hr on alternate days for 5-15 weeks

• Not metabolized but stored in kidneys and liver – slowly released

• Toxicity: Histamine release – acute reactions– Sharp fall in BP, dyspnoea, palpitation, fainting,

vomiting and rigor etc. – supine position– Other reactions - rashes, mental confusion, kidney

and liver damage– Cytolysis of pancreatioc beta cells – initially insulin

release – hypoglycaemia, but later IDDM

PENTAMIDINE – USES

SSG failure cases as salvage therapy - AMB is preferred now

Leishmaniasis with Tuberculosis Pneumocystis jiroveci pneumonia in AIDS

patients

Other drugs AMB and Paromomycin etc. – shall be discussed elsewhere!

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