Prof. Hanan HagarProf. Hanan HagarDr Ishfaq BukhariDr Ishfaq Bukhari

Pharmacology DepartmentPharmacology DepartmentMedical CollegeMedical College

Treatment of dysentery and Treatment of dysentery and amebiasisamebiasis

ObjectivesObjectives

To understand different causes of dysentery. To describe different classes of drugs used in treatment of

both bacillary dysentery and amebic dysentery. To be able to describe actions, side effects of drugs for

treating bacillary dysentery. To understand the pharmacokinetics, actions, clinical

applications and side effects of antiamebic drugs. To be able to differentiate between types of antiamebic drugs;

luminal amebicides, and tissue amebicide.

DysenteryDysentery

Dysentery:Dysentery: is an inflammatory disorder of the is an inflammatory disorder of the

intestine, especially of the colon, that results inintestine, especially of the colon, that results in

severe diarrheasevere diarrhea containing containing mucusmucus and/or and/or bloodblood

in the in the fecesfeces with with feverfever and and abdominal painabdominal pain

caused by any kind of infection.caused by any kind of infection.

Causes of DysenteryCauses of Dysentery

Dysentery results from Dysentery results from viral viral infections, infections, bacterialbacterial

infections, or infections, or parasiticparasitic infestations. infestations.

The two most common causes are:The two most common causes are: Amebic dysentery Amebic dysentery (protozoal infection (protozoal infection

mainly by Entameba Histolytica).mainly by Entameba Histolytica).

Bacillary dysentery Bacillary dysentery (bacterial infection (bacterial infection mainly by shigella).mainly by shigella).

Treatment of DysenteryTreatment of Dysentery

Maintain Maintain fluid intakefluid intake using oral rehydration using oral rehydration therapy or intravenous fluid therapy.therapy or intravenous fluid therapy.

Antimicrobial agentsAntimicrobial agents should not be given should not be given until stool analysis is done to specify the until stool analysis is done to specify the etiological agentetiological agent..

AMOEBIASISAMOEBIASIS

AmebiasisAmebiasis

Amebiasis is a Amebiasis is a protozoal infection protozoal infection of the of the intestinal tract that occurs due to ingestion of intestinal tract that occurs due to ingestion of foods or water contaminated with foods or water contaminated with cysts ofcysts of Entameba HistolyticaEntameba Histolytica..

The patients show varying degree of illness The patients show varying degree of illness from no symptoms to mild diarrhea to severe from no symptoms to mild diarrhea to severe dysentery.dysentery.

Clinical presentationsClinical presentations

Asymptomatic intestinal infectionAsymptomatic intestinal infection

(Carriers, passing cysts in stool)(Carriers, passing cysts in stool) Mild to moderate intestinal disease Mild to moderate intestinal disease (colitis)(colitis) Severe intestinal infection Severe intestinal infection (amoebic dysentery)(amoebic dysentery) Ameboma Ameboma (localized granulomatous lesion of (localized granulomatous lesion of

colon).colon). Hepatic abscess, and other extra-intestinal Hepatic abscess, and other extra-intestinal

diseases.diseases.

Life CycleLife Cycle

1. Cysts ingestion in contaminated food or water.

2. Liberation of trophozoites in the colon.

3. Invasion of intestinal wall.

4. Multiplication of trophozoites within colon wall.

5. Systemic invasion to other organs (liver, lungs, brain).

6. Cyst formation in rectum and excretion in feces.

LIFE CYCLELIFE CYCLE

ANTIAMEBIC DRUGSANTIAMEBIC DRUGS

▪▪ Luminal Amebicides Luminal Amebicides

▪ ▪ Tissue or systemic amebicidesTissue or systemic amebicides

Luminal amebicidesLuminal amebicides

Acts on the parasites in the lumen of the Acts on the parasites in the lumen of the bowel.bowel.

used for treatment of asymptomatic amebiasis used for treatment of asymptomatic amebiasis (carriers).(carriers).

IncludeInclude Diloxanide furoateDiloxanide furoate IodoquinolIodoquinol ParomomycinParomomycin

Tissue or systemic amebicidesTissue or systemic amebicides

Act on ameba in tissues (e.g. the intestinal wall Act on ameba in tissues (e.g. the intestinal wall and or other extra-intestinal tissues as liver, and or other extra-intestinal tissues as liver, brain and lung).brain and lung).

Used for treatment of systemic form of the Used for treatment of systemic form of the disease (invasive amebiasis) e.g. intestinal wall disease (invasive amebiasis) e.g. intestinal wall infection or liver abscesses.infection or liver abscesses.

IncludeInclude MetronidazoleMetronidazole Emetine Emetine DehydroemetineDehydroemetine Chloroquine (Chloroquine (liver onlyliver only))

METRONIDAZOLEMETRONIDAZOLE

Tissue amoebicide.Tissue amoebicide. Acts on trophozoites.Acts on trophozoites. Metronidazole inhibits DNA replication.Metronidazole inhibits DNA replication. Does not eradicate cysts from intestinesDoes not eradicate cysts from intestines Drug of choice Drug of choice for treating for treating

invasive amebic infections (intestinal & extra-invasive amebic infections (intestinal & extra-intestinal).intestinal).

PharmacokineticsPharmacokinetics Given orally or IV.Given orally or IV. Absorption is rapid and complete.Absorption is rapid and complete. Wide distribution to all tissues and body fluids Wide distribution to all tissues and body fluids

(CSF, saliva, milk).(CSF, saliva, milk). Plasma half life is Plasma half life is (8 h)(8 h) Metabolized in liver by mixed function oxidase Metabolized in liver by mixed function oxidase

followed by glucuronidation followed by glucuronidation (consider drug (consider drug interactions).interactions).

Excreted in urine.Excreted in urine. Clearance is decreased in liver impairmentClearance is decreased in liver impairment

Clinical UsesClinical Uses

Extra-luminal amoebiasis: is the drug of choice in Extra-luminal amoebiasis: is the drug of choice in all tissue amebiasis all tissue amebiasis

N.B. N.B. should be followed by luminal amebicidesshould be followed by luminal amebicides .. Giardiasis Giardiasis TrichomoniasisTrichomoniasis Broad spectrum of anaerobic bacterial infections Broad spectrum of anaerobic bacterial infections

e.g.e.g. Peptic ulcer Peptic ulcer (Helicobacter pylori)(Helicobacter pylori) Pseudo-membranous colitis Pseudo-membranous colitis (Clostridium (Clostridium

difficile).difficile).

Adverse effectsAdverse effectsGIT:GIT:

Dry mouth, metallic taste Dry mouth, metallic taste Nausea, vomiting, diarrhea (Nausea, vomiting, diarrhea (NVDNVD))Oral Thrush (Moniliasis, yeast infection).Oral Thrush (Moniliasis, yeast infection).

CNS: Neurotoxicological effectCNS: Neurotoxicological effectInsomnia, dizzinessInsomnia, dizzinessPeripheral neuropathy, paresthesiaPeripheral neuropathy, paresthesiaEncephalopathy, convulsion (Encephalopathy, convulsion (IV infusion, IV infusion,

rarerare).).Dysuria,Dysuria, dark urine. dark urine.NeutropeniaNeutropeniaDisulfiram-like effectDisulfiram-like effect if taken with alcohol. if taken with alcohol.

Disulfiram like-effect of metronidazoleDisulfiram like-effect of metronidazole

Combining metronidazole and alcohol causes Combining metronidazole and alcohol causes nausea, vomiting, abdominal distress, flushing, nausea, vomiting, abdominal distress, flushing, or headache, tachycardia, hyperventilationor headache, tachycardia, hyperventilation

Alcohol Alcohol dehydrogenasedehydrogenase

AldehydeAldehydedehydrogenasedehydrogenase

EthanolEthanol AcetaldehydeAcetaldehyde AcetateAcetate

Drug interactions:Drug interactions: Enzyme inhibitors Enzyme inhibitors (cimetidine, ketoconazole)(cimetidine, ketoconazole)

increase duration of action of metronidazoleincrease duration of action of metronidazole Inducers Inducers (phenytoin and phenobarbitone).(phenytoin and phenobarbitone).

decrease duration of action of metronidazoledecrease duration of action of metronidazole

Metronidazole inhibits CYP-450 ( 2C9 & 3A4) Metronidazole inhibits CYP-450 ( 2C9 & 3A4) so so increases anticoagulant effect of warfarin.increases anticoagulant effect of warfarin. Increases lithium toxicity.Increases lithium toxicity.

CONTRAINDICATIONS / PRECAUTIONS:CONTRAINDICATIONS / PRECAUTIONS:

▪ ▪ Pregnancy and breast feeding women.Pregnancy and breast feeding women.

▪ ▪ Alcohol intakeAlcohol intake

▪ ▪ CNS diseasesCNS diseases

▪ ▪ Severe renal diseaseSevere renal disease

Severe hepatic disease Severe hepatic disease

TinidazoleTinidazole

Tinidazole Tinidazole has similar activity to metronidazole

but better potency

Advantages of tinidazole has longer duration of action (12-14h) a simpler dosing regimen a better toxicity profile than

metronidazole.

EmetineEmetine and dehydroemetineand dehydroemetine

Emetine Emetine is is an alkaloid derived from ipeca while an alkaloid derived from ipeca while

dehydroemetinedehydroemetine is a synthetic analog. is a synthetic analog.

Both are effective against tissue trophozoites of Both are effective against tissue trophozoites of

E. histolytica causing irreversible block of E. histolytica causing irreversible block of

protein synthesis.protein synthesis.

Because of major toxicity concerns Because of major toxicity concerns they have they have

been almost completely replaced by been almost completely replaced by

metronidazolemetronidazole

Have erratic oral absorption.Have erratic oral absorption.

Given preferably subcutaneously but could be Given preferably subcutaneously but could be given by IM, given by IM, NEVER I.V.NEVER I.V.

Has long plasma half life about 5 days. Has long plasma half life about 5 days.

Metabolized & excreted slowly via kidney so Metabolized & excreted slowly via kidney so they have a they have a cumulative effect.cumulative effect.

Should not be used for more than 10 days Should not be used for more than 10 days (usually 3-5 days).(usually 3-5 days).

EmetineEmetine and dehydroemetineand dehydroemetine

Clinical UsesClinical Uses

Amoebic liver abscess.Amoebic liver abscess.

Intestinal wall infections.Intestinal wall infections.

Severe forms of amebiasis Severe forms of amebiasis acute amoebic acute amoebic

dysenterydysentery dehydroemetine is preferable due to dehydroemetine is preferable due to

less toxicity (3-5 days).less toxicity (3-5 days).

Adverse EffectsAdverse Effects

Dehydroemetine is less toxic than emetineDehydroemetine is less toxic than emetine GIT:GIT: nausea, vomiting, diarrhea. nausea, vomiting, diarrhea. Serious toxicities: cardiotoxicitySerious toxicities: cardiotoxicity

Hypotension, cardiac arrhythmias, heart Hypotension, cardiac arrhythmias, heart failure failure

Caution: the drug should not be used in the drug should not be used in patients with patients with cardiac or renalcardiac or renal disease, in disease, in young children,or in pregnancyyoung children,or in pregnancy..

ChloroquineChloroquine

Anti-malarial drugAnti-malarial drug Used in combination with metronidazole or Used in combination with metronidazole or

dehydroemetine for dehydroemetine for amebic liver diseasesamebic liver diseases..

Adverse effectsAdverse effects pruritus is common Nausea, vomiting, abdominal pain, anorexia. Blurring of vision. Hemolysis in G6PD deficient patients

Luminal amoebicidesLuminal amoebicides

IncludeInclude Diloxanide furoateDiloxanide furoate IodoquinolIodoquinol AntibioticsAntibiotics

- Paromomycin- Paromomycin

- Tetracycline- Tetracycline

used to eradicate cysts of used to eradicate cysts of E histolyticaE histolytica after  after

treatment of invasive disease.treatment of invasive disease.

Diloxanide furoateDiloxanide furoate Ester of diloxanide + furoic acid . Ester of diloxanide + furoic acid . Given orally.Given orally. It splits in the intestine, diloxanide is absorbed, It splits in the intestine, diloxanide is absorbed,

conjugated to form a glucoronide which is conjugated to form a glucoronide which is excreted in urine .excreted in urine .

The The unabsorbedunabsorbed diloxanide is the diloxanide is the amoebicidal amoebicidal agent .agent .

Diloxanide furoateDiloxanide furoate

Mechanism of action is unknownMechanism of action is unknown

Direct amoebicidal action against luminal Direct amoebicidal action against luminal formsforms

Not active against trophozoites in intestinal wall Not active against trophozoites in intestinal wall or extra-intestinal tissuesor extra-intestinal tissues..

Therapeutic UsesTherapeutic Uses

Drug of choice for Drug of choice for asymptomatic intestinal asymptomatic intestinal infection (cysts passers). infection (cysts passers).

to eradicate cysts of E histolytica after to eradicate cysts of E histolytica after treatment of invasive disease with systemic treatment of invasive disease with systemic amebicides.amebicides.

Adverse EffectsAdverse Effects FlatulenceFlatulence Nausea, vomiting, abdominal cramps.Nausea, vomiting, abdominal cramps.Contraindications:Contraindications:

- Pregnancy- Pregnancy - Children (less than 2 years).- Children (less than 2 years).

Iodoquinol Iodoquinol Is given orallyIs given orally

Poorly absorbed, excreted in feces.Poorly absorbed, excreted in feces. Mechanism of action is unknownMechanism of action is unknown

effective against the luminal forms of amebiasiseffective against the luminal forms of amebiasis

UsesUses luminal amoebicide for luminal amoebicide for

asymptomatic amebiasis.asymptomatic amebiasis.

Adverse EffectsAdverse Effects GIT:GIT: Nausea, vomiting, diarrhea. Nausea, vomiting, diarrhea. Peripheral neuropathyPeripheral neuropathy including optic neuritis including optic neuritis Enlargement of the thyroid gland.Enlargement of the thyroid gland. Iodine sensitivity Iodine sensitivity interference with thyroid function tests interference with thyroid function tests

(increase protein-bound serum iodine, (increase protein-bound serum iodine,

decrease in measureddecrease in measured ((131131I uptakeI uptake).).

Iodoquinol should be used with caution in Iodoquinol should be used with caution in patients with optic neuropathy, renal or patients with optic neuropathy, renal or thyroid disease.thyroid disease.

discontinueddiscontinued if it produces persistent if it produces persistent diarrhea or signs of iodine toxicity diarrhea or signs of iodine toxicity (dermatitis, urticaria, pruritus, fever).(dermatitis, urticaria, pruritus, fever).

Paromomycin SulphateParomomycin Sulphate

Aminoglycoside antibiotic.Aminoglycoside antibiotic. Given orallyGiven orally Not significantly absorbed from GITNot significantly absorbed from GIT Effective only against luminal forms of amebaEffective only against luminal forms of ameba Has Has direct direct amebicidal action amebicidal action (causes leakage by its (causes leakage by its

action on cell membrane of parasite).action on cell membrane of parasite). IndirectIndirect killing of bacterial flora essential for killing of bacterial flora essential for

proliferation of pathogenic amoebae.proliferation of pathogenic amoebae. Small amount absorbed is excreted unchanged in Small amount absorbed is excreted unchanged in

urine urine (may accumulate with renal insufficiency).(may accumulate with renal insufficiency).

Paromomycin SulphateParomomycin Sulphate

Use in chronic amebiasis to eliminate cysts (in Use in chronic amebiasis to eliminate cysts (in cysts passers).cysts passers).

Adverse effectsAdverse effects Gastrointestinal distress and diarrhea.Gastrointestinal distress and diarrhea.

PrecautionsPrecautions Severe renal diseaseSevere renal disease patients with GIT ulcerationpatients with GIT ulceration

Summary for treatment of amebiasis

Asymptomatic dysentery

(cyst carriers)

Luminal amebicides

Diloxanide or iodoquinol or Paromomycin

Amebic colitis and dysentery

ameboma,

and extra-intestinal disease

Metronidazole or tinidazole followed by luminal amebicides

Hepatic abscessMetronidazole or tinidazole or choroquine or dehydroemetine

Bacillary dysenteryBacillary dysentery

Treated by: Treated by:

• Fluoroquinolones such as ciprofloxacin • Cotrimoxazole (trimethoprim- sulfamethoxazole)• Children or patient allergic to sulpha drugs

parenetral ceftriaxone or oral cefixime (3dr gen cephalosporin) are safe and effective.

• Cotrimoxazole is commonly used in traveler’s diarrhea.

Ceftriaxone Third-generation cephalosporin with broad-spectrum, gram-negative activity. It acts by inhibiting cell wall synthesis 

Cefixime Third-generation oral cephalosporin with broad activity against gram-negative bacteria.

Ciprofloxacin active against a variety of gram-positive and

gram-negative bacteria. block bacterial DNA synthesis. Used in treatment of 1. Bacterial diarrhea (caused by shigella,

salmonella, and E coli). 2. Urinary tract infections 3. Respiratory tract infections 4. Soft tissues, bones, and joint infections

Adverse effects

Arthropathy (damage of growing cartilage). GIT disorders (nausea, vomiting, diarrhea). CNS disorders (headache, dizziness). CVS disorder (prolonged QT interval ) Phototoxicity. Liver toxicity.

Contraindications

Contraindicated: Children, pregnancy, nursing mother Epilepsy Arrhythmias. Should not be combined with antacids,

divalent cations

SUMMARYSUMMARY Maintain Maintain fluid fluid intakeintake (oral rehydration therapy or (oral rehydration therapy or

Intravenous fluid therapy).Intravenous fluid therapy). asymptomatic luminal amebiasis is treated by luminal asymptomatic luminal amebiasis is treated by luminal

amebicides amebicides (diloxanide, or iodoquinol or paromomycin )(diloxanide, or iodoquinol or paromomycin ).. MetronidazoleMetronidazole is the mainstay of therapy for invasive is the mainstay of therapy for invasive

amebiasisamebiasis (followed by luminal amebicides to prevent followed by luminal amebicides to prevent relapse). relapse).

Chloroquine has also been used for patients with hepatic Chloroquine has also been used for patients with hepatic amebiasis. amebiasis.

Dehydroemetine is useful but not preferable due to CVS Dehydroemetine is useful but not preferable due to CVS toxicitytoxicity

Ciprofloxacin is the drug of choice in bacillary dysentery. In children and pregnancy, ceftriaxone or cefixime is the choice.

Thank youThank you

Questions ?Questions ?