A Power point presentation on "Antiamoebic and antiprotozoal drugs" suitable for UG MBBS level students

1. Antiamoebic and
Antiprotozoal Drugs
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. Section – 1
Antiamoebic Drugs
Drugs useful in infection caused by the protozoa Entamoeba
histolytica (E. histolytica)

3. Amoebiasis - Epidemiology
• Poor environmental sanitation, low socio-economic status
• Approximately 48 million individuals suffer from amoebiasis
throughout the world
• Endemic in most parts of India
• At least 40 thousand deaths are attributable to amoebiasis
• Ranks third among parasitic causes of deaths, behind only malaria
and schistosomiasis

4. 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 body
2. Trophozoite or the dividing form - Non-infective and do not persists outside the body
but invasive
• Two stages of development:
Ingested cyst reaches colon transforms to trophozoites
May 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)

5. 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 Amoebic liver abscesses
• Remember - In tissues, only
trophozoites are present

6. 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

7. 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,
Fusobacterium, H.pylori, Cl. Difficile, Campylobacter,
Anaerobic streptococci
• Helminths – Dracunculus medinensis
• Resistance – no significant resistance for E. histolytica till
now, but developed for T. vaginalis
G. lamblia T. vaginalis

8. 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 highly reactive nitro
group --- nitro radicals act as an electron sink --- competes with Biological
acceptor sites of anaerobic organisms for the electrons generated by 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
• Aerobic environment ??

9. 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

10. 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
– MOA: Disulfiram irreversibly inhibits the oxidation of acetaldehyde by
competing with the cofactor nicotinamide adenine dinucleotide (NAD)
for binding sites on ALDH
– Enzyme inducers like Phenobarbitone and Rifampicin (reduced
therapeutic effect)

11. Metronidazole - uses
1. Ameobiasis – 1st
line of drug - Kills E. histolytic trophozoites but less cysts.
Treatment of all tissue infections with E histolytica – diff doses – mild
intestinal, invasive dysentery and liver abscess
• Less effects against luminal parasites and so must be used with a luminal
amoebicide – for eradication - dosage
1. Giardiasis
2. Trichomonas vaginitis – DOC - additional intravaginal treatment and both
partners !!
3. Anaerobic bacterial infections
4. Pseudo-membranous enterocolitis: Cl difficile
5. Ulcerative gingivitis, trench mouth – DOC – ulcerative gingivitis
6. Helicobacter pylori

12. 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

13. Emetine and Dehydroemetine
• Emetine, alkaloid derived from Cephaelis ipecacuanha and dehydroemetine, a
synthetic analog – kills trophozoites of E histolytica
• MOA: Inhibiting intra-ribosomal translocation of tRNA-amino acid complex →
inhibition of protein synthesis
• Action: Effects on trophozoites but not on cysts. Potent and rapid action –
symptomatic relief in 1-3 days, but not curative - asymptomatic cyst passing
• Administered SC (preferred) or i.m. (but never i.v. or oral) because oral
preparations are absorbed erratically and vomiting – very slow excretion in urine1
-2 months
• Uses: Seldom used. Reserve drug for severe intestinal and extraintestinal
amoebiasis or for patients not responding to metronidazole. Luminal amoebicide
needed to be added

14. Emetine - ADRs
• Local stimulation: pain and tenderness in the area of injection
• Gastrointestinal tract discomfort: nausea, vomiting– CTZ (oral and
IV)
• Diarrhoea and abdominal cramps
• Neuromuscular blockade: muscle weakness and discomfort
• Cardiac toxicity: arrhythmias, congestive heart failure,
hypotension, ECG changes – bed rest
• Contraindication: Not be used in patients with cardiac or renal
disease, in young children, or in pregnancy

15. 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 & 300 mg for 2-3 days

16. Diloxanide furoate (DF)
Highly effective luminal amoebicide
Kills trophozoites responsible for production of cyst – however no
antibacterial action
MOA: Oral DF F hydrolyzed (exerts effects) and D is freed
90% D is absorbed remaining 10% reaches Large intestine and
exerts effects (weaker than F)
Absorbed D – low serum level – no therapeutic effects
Uses: Mild tissue amoebiasis/asymptomatic cyst passers, Tissue
amoebiasis and liver abscess with Metronidazole – no antibacterial
action
ADRs: Well tolerated, only flatulence, nausea, itching and rarely
urticaria

17. 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

18. 8-Hydroxyquinolines
 Drugs – Iodoquinol, Clioquinol, Quinodochlor 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
Trichomonas and fungal and bacterial infections. 250 to 500 mg tds

19. Choices of Drugs
Asymptomatic cysts carriers Diloxanide furoate or
Metronidazole/Tinidazole or Iodoquinol -
Repeated course
Diarrhoea / Dysentery Metronidazole/Tinidazole or Emetine -
Metronidazole + Diloxanide
Amebic liver abscess Chloroquine - Metronidazole + DF (or
Dehydroemetine)
Giardiasis (Giardia labmlia) Metronidazole or Nitazoxamide or
Quinodochlor or Furazolidone

20. 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, Clotrimazole,
Natamycin, Povidone Iodine etc.

21. •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

22. Available Drugs
• Antimonial – Sodium stibogluconate (SSG)
• Antifungal – Amphotericin B (AMB), Ketoconazole (KTZ)
• Others – Miltefosine, Mifepristone, Paromomycin and Allopurinol

23. 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
 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 in poor health patients

24. 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

25. Amphotericin B (AMB)
• Antifungal effective against Leishmania
• 2 forms – Liposomal AMB and AMB Deoxycholate
• MOA: Ergosterol (Ion channel)
• 99% cure rate
• ADR: Nephrotoxicity
• 1st
line of drug by WHO – but costly

26. Miltefosine – Latest Drug
 Alkyl phosphocholine derivative
 1st
orally effective anti-leishmaniasis drug
 1st
line agent now by NVBDCP – only available
 MOA: Not clear –
 interferes with lipid metabolism – or,
 Prevents synthesis of cell surface molecules - or,
 alter signal transduction
 Used as combination therapy with L- AMB or Paramomycin
 Kinetics: Absorbed orally – Distributed widely - Biphasic elimination
 7 days early half-life and total half-live 4 weeks
 ADRs: Hepatotoxicity, skin allergy and nephrotoxicity – also teratogenic (3 months)

27. Thank you