Anti-amoebic Drugs

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Anti-amoebic Drugs Powered By Docstoc
					Meha Varma

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Entamoeba histolytica (protozoan) Most people (~90%) are asymptomatic However, WHO reports 70,000 people who die from this illness every year Most famous outbreak in United States
 Chicago World Fair outbreak in 1933 ▪ 1000 cases were diagnosed ▪ 58 deaths were reported

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Tissue amoebicides
 For both intestinal and extraintestinal amoebiasis ▪ Nitroimidazoles – Metronidazole, Tinidazole, Secnidazole, Ornidazole, Satranidazole ▪ Alkaloids – Emetine, Dehydroemetine
 For extraintestinal amoebiasis only ▪ Chloroquine

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Luminal amoebicides
 Amide – Diloxanide furoate
 8-Hydroxyquinolines – Quiniodochlor

(Iodochlorohydroxyquin, Clioquinol), Diiodohydroxyquin (Iodoquinol)  Antibiotics - Tetracyclines

Metronidazole, Tinidazole, Secnidazole, Ornidazole, Satranidazole

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Prototype nitroimidazole 1959 as treatment for Trichomoniasis Broad spectrum cidal activity including against Giardia lamblia and some anaerobic bacteriae such as B. fragilis, Cl. perfringes, Cl. difficile etc No affect on Aerobic bacteria

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Mechanism of Action
 Nitro group is chemically reduced in anaerobic

bacteria and sensitive protozoans  Reactive reduction products appear to be responsible for antimicrobial activity by damaging DNA
▪ DNA helix destabilization and strand breakage

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Aerobic environment – not suitable for reductive activation required

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Pharmacokinetics
 Completely absorbed in intestines
 Widely distributed throughout the body  Therapeutic conc. in vaginal secretions, semen,

saliva, CSF  Metabolized in liver (by oxidation and glucoronide conjugation)  Excreted by urine  Plasma t ½- 8h

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Adverse Effects
 Anorexia, nausea, metallic taste, cramps
 Less frequent A/E – headache, glossitis, dryness

of mouth, dizziness, rashes  Prolonged admin – peripheral neuropathy, seizures  Thromboflebitis of injected vein occurs if solution is not well diluted

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C/I – neurological diseases, blood dyscrasias, 1st trimester of pregnancy, chronic alcoholism Interactions
 Disulfiram like intolerance to alcohol occurs

 Enzyme inducers (phenobarbitone, rifampin)

reduces its therapeutic effect  Cimetidine reduces its metabolism  Metronidazole has been found to decrease renal elimination of lithium

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Preps – Flagyl, Metrogyl, Metron, Aristogyl, Aldezol Amoebiasis – first line

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Giardiasis – 200mg TDS for 7d T. vaginitis – DOC, 400mg TDS for 7d (-100% cure) Anaerobic bacterial infections – combination with gentamicin or cephalosporins
 15mg/kg infused over 1h followed by 7.5 mg/kg every

 For invasive dysentry – 800mg TDS for 5-10 d  Mild disease – 400mg TDS for 5-7 d

6h till oral therapy of 400-800mg TDS

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P. colitis – 800mg TDS Ulcerative gingivitis, trench mouth – 200400mg TDS; combine with PenG or tetracycline H. pylori gastritis/peptic ulcer – Guinea worm infestation – not so effective

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Equally efficacious congener Similar for most part except
 Metabolism is slower, t ½- 12h, duration of action

is longer, more suited for single dose or once daily  Higher curative rates  Better tolerated, incidence of A/E lower, less metallic taste
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Recommended dosage
 Amoebiasis – 2g OD for 3d or 0.6g BD for 5-10d

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Congener with same spectrum of activity and potency
 Oral absorption is rapid and complete  Metabolism is slower plasma t ½ - 17-29h

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After 48h, single dose of 2g of Secnidazole remains w/n range of MIC values Single dose of 2g has been reported to yield cure rates equal to multiple doses of previous 2 drugs A/E similar to metronidazole

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Similar in action to metronidazole Slowly metabolized  t ½- 12-14h Similar dose to tinidazole A/E is similar to tinidazole

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Longer t ½ - 14h Advantages
 Better tolerability – no nausea, vomiting, metallic

taste, absence of neurological symptoms and disulfiram like reactions  Does not produce “acetamide” – carcinogen
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Dosage - 300mg tablet (Satrogyl)

Emetine, Dehydroemetine

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Derived from Cephaelis ipecacauanha Potent and directly acting amoebicide – kills trophozoites but has no effect on cysts MOA – inhibits protein synthesis by arresting intraribosomal translocation of tRNA-amino acid complex Stool in acute dysentery is rapidly cleared of the trophozoites Symptomatic relief occurs in 1-3d (faster than metronidazole) Not curative (pt continues to pass cysts in stool) Highly efficacious in amoebic liver abscess as well

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Pharmacokinetics
 Not given orally (will be vomited out)
 S.C. or IM injection – 60mg OD  Should be given only till acute symptoms subside,

not more than 10d  Concentrated in liver, kidney, spleen, lungs  Slowly excreted in urine (taking 1-2mos)
▪ 2nd dose should not be repeated w/n 6 wks

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A/E
 Highly toxic
 Local – irritant, pain, stiffness, eczematous lesions

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at the site of injection Nausea, vomiting (stimulation of CTZ) Cramps, diarrhea Weakness and stiffness of muscles Hypotension, tachycardia, ECG changes, myocarditis

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C/I – presence of cardiac or renal disease, pregnancy Use:
 B/c of A/E – used as reserve drug in severe

intestinal or extraintestinal amoebiasis or for pts not responding to metronidazole  Luminal amoebicide must follow emetine to eradicate cyst forming trophozoites  Liver fluke infestation

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Semisynthetic derivative Equally effective but less cumulative and less toxic to heart Preferred over emetine Dose – 30mg/ml inj

Extraintestinal amoebiasis ONLY

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Kills trophozoites, highly concentrated in liver
 Used in hepatic amoebiasis

Pharmacokinetics
 Completely absorbed from upper intestine and not so

highly concentrated in intestinal wall – neither effective in invasive dysentery nor in controlling the luminal cycle
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Efficacy similar to emetine but duration of treatment is longer and relapses are more frequent
 No development of resistance

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Safe to be admin, maybe given concurrently or immediately after a course of metronidazole  ensures complete eradication of trophozoites in liver A luminal amoebicide must always be given with or after chloroquine to abolish the luminal cycle Dose – 600mg for 2d followed by 300mg daily for 2-3 wks
 Only used if metronidazole is not effective

Diloxanide furoate

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Highly effective luminal amoebicide
 Directly kills trophozoites

Furoate ester is hydrolyzed in intestine> released diloxanide is absorbed Diloxanide is a weaker amoebicide than furoate ester Primarily metabolized by glucoronidation, excreted in urine No antibacterial effect Less effective in invasive amoebic dysentery b/c of poor tissue amoebicial action
 Produced high cure rates in mild intestinal amoebiasis and

in asymptomatic cyst passers

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Dose – 500mg TDS fr 5-10d Well tolerated A/E:
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Flatulence, occasional nausea, itching, urticaria

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Uses:
 Mild intestinal/asymptomatic amoebiasis  Given after any tissue amoebicide to eradicate

cysts  Usually combined w/ metronidazole or tinidazole

Quiniodochlor (Iodochlorohydroxyquin, Clioquinol), Diiodohydroxyquin (Iodoquinol)

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Iodoquinol – halogenated hydroxyquinoline Effective luminal amoebicide, commonly used with metronidazole Pharmacokinetics
 Poorly understood
 90% of the drug is retained in intestines ▪ Excreted in feces

 Remainder enters circulation, t ½- 11-14 h ▪ Excreted in urine as glucuronides

MOA – unknown  Effective against organisms in the bowel lumen but not against trophozoites in intestinal wall or extraintestinal tissues  A/E
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 Diarrhea, anorexia, nausea, vomiting, cramps, headache, rash, pruritis  Increases protein-bound serum iodine decrease in measured 131I

uptake  Normally no A/E at recommended dosage

Should be taken with meals to limit GI toxicity  Should be used with caution in pts with optic neuropathy, renal or thyroid disease, or nonamoebic hepatic disease  C/I – pts with intolerance to iodine
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Luminal amoebicide

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Aminoglycoside antibiotic, not absorbed from GIT Used only as luminal amoebicide, no effect on extraintestinal infections
 Effective, similar efficacy but less toxicity than other

luminal agents  Superior to Diloxanide furoate in clearing asymptomatic infections

Small amt absorbed in excreted unchanged, by glomerular filtration  Drug may accumulate in renal insufficiency contribute to renal toxicity
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A/E - occasional abdominal distress, diarrhea C/I – pts with significant renal disease, used with caution in pts with GI ulcerations

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Asymptomatic intestinal infection
 Luminal agent – Diloxanide furoate

(500mg, x3daily for 10d), or  Iodoquinol (650mg x3 daily for 21 d), or  Paromomycin sulfate (10mg/kg x3 daily for 7d)
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Mild to moderate intestinal infection
 Metronidazole (750mg x3 daily for 10d OR 500mg

IV every 6h for 10d), or  Tinidazole (2g daily for 3 d), PLUS  Luminal agent

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Severe intestinal infection
 Metronidazole (750mg x3 daily for 10d OR 500mg IV every 6h

for 10d), or  Tinidazole (2g daily for 3 d), PLUS  Luminal agent
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Hepatic abscess, amoeboma, other extraintestinal disease
 Metronidazole (750mg x3 daily for 10d OR 500mg IV every 6h

for 10d), or  Tinidazole (2g daily for 5 d), PLUS  Luminal agent

Katzung, Tripathi And Nilam Patel for moral support


				
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