pharmacology 2nd year MBBS theory class

1. ANTI AMOEBIC DRUGS

2. Antiamoebic Drugs
Drugs useful in infections caused by the protozoa
Entamoeba histolytica (E. histolytica)
E. histolytica, a protozoal parasite causative agent of
amoebiasis

3. E. HISTOLYTICA –
PATHOGENESIS
• Water-borne pathogen transmitted by fecal-oral route
• Exists in 2 forms:
1. Cyst or dormant form INFECTIVE & can survive
outside the body
2. Trophozoite or dividing form Non-infective and
do not persists outside the body but invasive

4. E. HISTOLYTICA –
PATHOGENESIS
• Two stages of development 
Ingested cyst reaches colon transform to trophozoites
May live as
commensals
Form cysts that
pass on to stool
1. Multiply & invade to ulcerate the
mucosa of large intestine
2. Form amoebic ulcers (acute
dysentery
3. Chronic amoebic dysentery
(vague symptoms, amoeboma)

5. PATHOGENESIS OF E. HISTOLYTICA
• Late stage extra intestinal
• Trophozoites enter  blood stream and travel to other parts
most commonly liver, sometimes lungs or brain  abscesses.
• In tissues, only trophozoites are present

6. AVAILABLE DRUGS
1. Tissue amoebicides:
a) Intestinal and extra-intestinal:
Nitroimidazoles – Metronidazole, Tinidazole, Secnidazole,
Ornidazole, Satranidazole
Alkaloides – Emetine and Dihydroemetine
a) 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, H.pylori, Cl.
difficile
 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
• Anaerobic protozoan parasites ( including amoebae),possess an
enzyme, pyruvate –ferrodoxin oxido –reductase involved in energy
production and other metabolic functions through electron transfer
reactions.
• This enzyme is not found in mammalian cells.
• The nitro group in metronidazole serves as an electron
acceptor.
• Reduced metronidazole is cytotoxic to anaerobic
bacteria/protozoa and disrupts replication , transcription and
repair process of DNA  results in cell death.

9. METRONIDAZOLE
 Pharmacokinetics:
 Well absorbed from small intestine
 Widely distributed in body secretions – vaginal secretions, saliva and
CSF
 Metabolized in liver by oxidation and glucoronidation
 Half life – 8 Hrs
 ADRs:
 Most common - Nausea, Vomiting, abdominal cramps and metallic
taste , dark brown urine
 Less frequent – headache, glossitis, rashes and dryness of mouth
 Prolonged administration – Peripheral neuropathy and CNS effects
 Seizures at high dose

10. METRONIDAZOLE
• Contraindications:
– First trimester of pregnancy
– Neurological diseases and Blood dyscrasias
– Chronic alcoholism
• Interactions:
– Disulfiram-like intolerance
– Symptoms  flushing, burning sensation, throbbing
headache, dizziness, vomiting, visual disturbance, mental
confusion, fainting and circulatory collapse
– Enzyme inducers like Phenobarbitone and Rifampicin
(reduced therapeutic effect)

11. METRONIDAZOLE -DOSE
1. The recommended dose regimen :
2. For moderate intestinal amoebiasis 400 mg orally TDS for 7
days
3. For amoebic dysentry and liver abscess  800 mg TDS for 7
days
4. Giardiasis  200 mg TDS for 7 days
5. Trichomonas vaginitis  400 mg TDS orally for 7 days (male
partner also be treated )
6. Pseudomembraneous colitis  500 mg TDS
7. Anaerobic infections  15 mg/kg IV infusion over 1 hr
followed by 7.5 mg/kg IV infusion every 6 hrs till oral therapy
could be started . (400 mg TDS for another 7 days )

12. METRONIDAZOLE - USES
1. Ameobiasis – Kills E. histolytic trophozoites but not cysts.
2. Giardiasis
3. Trichomonas vaginalis – both partners
4. Anaerobic infections
5. Pseudo-membranous enterocolitis
6. Ulcerative gingivitis
7. Helicobacter pylori

13. OTHER NITROIMIDAZOLES
• Tinidazole, Secnidazole, Ornidazole, Satranidazole
• Tinidazole:
– Slower metabolism, duration of action (t 1/2 12 hrs) – single dose
– Higher cure rates (600 mg BD for 5-7 days )
– Better tolerated – lesser incidence of side effects
• Ornidazole: t ½ 12 -24 hrs
• Secnidazole: Rapid absorption, but slower metabolism – t ½ 17-29
hrs)
• Satranidazole: t ½ 14 hrs – better tolerated ; no nausea, vomiting
metallic taste . ( no disulfiram like reaction or neurological
symptoms )
• (300 mg BD for 5 days-amoebiasis ) (600 mg orally single dose for giardiasis
and trichomoniasis

14. EMETINE AND DEHYDROEMETINE
 Emetine, alkaloid derived from Cephaelis ipecacuanha
 Dehydroemetine , a synthetic analog, are effective against
tissue trophozoites of E histolytica
• MOA 
• Inhibiting intra ribosomal translocation of t RNA-amino acid
complex → inhibiting elongation of peptide chain → inhibiting
protein synthesis

15. EMETINE AND DEHYDROEMETINE
• Action Effects on trophozoites (but not on cysts)
• Potent and rapid action – symptomatic relief in 1-3 days, but
not curative
 Administered s/c (preferred) or i.m. (but never i.v.)
 Uses: Seldom used now. (Cardiac toxicity)
 Dehydroemetine is preferred over emetine.
 DOSE 60 mg IM once daily for 3-5 days .

16. EMETINE - ADRS
 Local stimulation pain and tenderness in the area of
injection
 GIT discomfort nausea, vomiting, diarrhoea and abdominal
cramps
 Neuromuscular blockade muscle weakness and discomfort
 Cardiac toxicityarrhythmias, congestive heart failure,
hypotension, ECG changes
 C/I  cardiac or renal disease, in young children & pregnancy

17. CHLOROQUINE
 Highly concentrated in liver & Kills trophozoites of E.
histolytica
 – used in hepatic amoebiasis
 Completely absorbed from upper intestine – not effective in
invasive or luminal dysentery
 Effective in amoebic liver abscess , extra intestinal amoebiasis
 Not effective against cyst form– so a luminal amoebicide must
be added after chloroquine to abolish luminal cycle
 Dose  600mg stat and next day & 300mg for 2-3 days

18. DILOXANIDE FUROATE (DF)
• Highly effective luminal amoebicide
• Kills trophozoites responsible for production of cyst
• 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

19. • Uses: Mild tissue amoebiasis/asymptomatic cyst passers,
Tissue amoebiasis and liver abscess with Metronidazole
• ADRs: Well tolerated, only flatulence, nausea, itching and
rarely urticaria
 DOSE500 mg TDS for 5–10 days
 children 20 mg/kg/day.

20. NITAZOXANIDE
• Newer Drug for Giardiasis
• Also effective in E. Histolytica, T. Vaginalis, H. Pylori etc.
• Converted to Tizoxanide after absorption
 MOA: inhibitor of PFOR (pyruvate ferrodoxin oxido reductase)
enzyme , an essential pathway of electron transport energy
metabolism in anaerobic organisms.
• Uses: Giardiasis, amoebiasis as luminal amoebicide
 Abdominal pain, vomiting and headache are mild and
infrequent side effects.
• Dose: 500 mg BD for 3 days

21. 8-HYDROXYQUINOLINES
• Drugs – Iodoquinol and Iodochlorohydroxyquin
• Act against Entamoeba, Giardia, Trichomanas, some fungi and
Bacteria
 kill the cyst forming amoebic trophozoites in the intestine, but
do not have tissue amoebicidal action.
• Absorbed very less amount (10-30%)
• conjugated and excreted in urine
• Once a popular drug – but less now because of ADRs

22. 8-HYDROXYQUINOLINES
• ADRs
• 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 , fungal and bacterial infections.
• 250 to 500 mg tds

23. TETRACYCLINES
• direct inhibitory action on Entamoeba.
• incompletely absorbed in the small intestine, reach the colon in
large amounts and inhibit the bacterial flora
• Added as the third drug along with a nitroimidazole +
• a luminal amoebicide in the treatment of amoebic dysentery

24. PAROMOMYCIN
• aminoglycoside antibiotic active against many protozoa like
Entamoeba, Giardia, Cryptosporidium, Trichomonas,
Leishmania
• mechanism of antiprotozoal action of paromomycin
• same as its antibacterial action  binding to 30S ribosome and
interference with protein synthesis.
• Orally administered paromomycin acts only in the gut lumen. It
is neither absorbed nor degraded in the intestines, and is
eliminated unchanged in the faeces.

25. PAROMOMYCIN
• Paromomycin is an efficacious luminal amoebicide.
• Given along with metronidazole in acute amoebic dysentery
and in hepatic amoebiasis to eradicate the luminal cycle.
• Paromomycin is an alternative drug for giardiasis, especially
during 1st trimester of pregnancy when metronidazole and
other drugs are contraindicated.
• Topically, it may used in trichomonas vaginitis and dermal
leishmaniasis

29. THANK U

30. OTHER ANTI-PROTOZOAL
DRUGS

31. GIARDIASIS
 Giardia lamblia – flagellate protozoan
 Intestinal commensal
 Invades mucosa – acute watery diarrhoea
 Faeco-oral transmission

32. TREATMENT
 Metronidazole – 400mg TDS 5-7 days
 Tinidazole – 0.6g daily 7 days
 Nitazoxanide – 500mg BD 3 days
 Quiniodochlor – 250mg TDS 7 days
 Furazolidone

33. TRICHOMONAS VAGINITIS
 Microaerophilic flagellate protozoan
 Vulvovaginitis
 Common STD

34. 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.

35. •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

36. AVAILABLE DRUGS
 Antimonial – Sodium stibogluconate (SSG)
 Diamide – Pentamidine
 Antifungal – Amphotericin B (AMB),
Ketoconazole (KTZ)
 Others – Mifepristone, Paromomycin and
Allopurinol

37. 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

38. 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

39. 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

40. 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!

41. DID YOU SLEEP DURING LAST 45
MIN. ?
If yes, no problem – just have to go
and read Metronidazole and SSG
If No, enjoy today - for knowing
Metronidazole and SSG

42. THANK YOU