Anti-protozoal drug

1
Anti-protozoal drug
2
INTRODUCTION

• Humans host a wide variety of protozoal parasites
  that can be transmitted by insect vectors,
  directly from other mammalian reservoirs or from
  one person to another.
• Because protozoa multiply rapidly in their hosts
  and effective vaccines are unavailable,
  chemotherapy has been the only practical way to
  both treat infected individuals and reduce
  transmission.

3
Protozoa

• Basic Properties of Protozoa
• Eukaryotic microorganisms
• No cell walls
• Most have heterotrophic metabolisms
• A few protozoa (eg Euglena) are photosynthetic.
• Many are free-living in soil or aquatic
  environments a few are parasitic.
• Single-celled or simple colonial organization
• Classification based predominately on the
  mechanism of motility

4
Basic properties of protozoa
Cont..

• Trophozoite and Cyst
• Some protozoa go through different stages in
  their life cycle.
• This is especially true of certain parasitic
  protozoa.
• Trophozoite Actively growing and reproducing
  stage
• Cyst A dormant stage, enclosed in a resistant
  cyst coat

5
Classification of protozoa

• 1)Class- Sarcodina
• Motile by pseudopodia amoeboid movement
• Examples
• Amoeba
• Entamoeba histolytica
• Naegleria fowleri
• 3)Class - Ciliophora
• Motile by cilia
• Examples
• Paramecium
• Balantidium coli

• 2) Class- Mastigophora
• Motile by flagella
• Examples
• Euglena
• Giardia lamblia
• 4)Class -Sporozoa
• Most have complex life cycles with both sexual
   asexual stages
• Adult forms are nonmotile
• Examples
• Plasmodium
• Toxoplasma gondii

6
Protozoan Diseases

1. Amebiasis
2. Giardiasis
3. Leishmeniasis
4. Primary Amoebic Meningoencephalitis
5. Trichomoniasis
6. Balantidiasis
7. Malaria
8. Pneumocystosis
9. Toxoplasmosis

7
Amoebiasis

• Two morphologically identical but genetically
  distinct species of Entamoeba (i.e., E.
  histolytica and E. dispar) have been isolated
  from infected persons.
• At the present time ,Entamoeba histolytica, is
  the causative agent of amebic dysentery and
  amebic liver abscess.
• Entamoeba dispar morphologically similar to E.
  histolytica is considered non-pathogenic at this
  time.

8
Entamoeba Life Cycle

• Entamoeba species exist in only two forms.
• The non-infective trophozoite stage and the
  ineffective cyst stage.
• Ineffective cysts are ingested by man.
• Some time after passing through the stomach and
  small bowel they excyst to form motile
  trophozoites.
• these trophozoites of E. histolytica that can
  penetrate, invade and colonize intestinal mucosa.
• As the trophozoite travels down the large bowel
  at some point when conditions are right , it
  encysts into the ineffective cyst stage and is
  excreted with the feces.

• www.practicalscience.com/introentamoeba.html

9
PATHOLOGY

• E. histolytica invades mucosal cells of colonic
  epithelium, producing the classic flask-shaped
  ulcer in the submucosa.
• If the trophozoite gets into the portal
  circulation, it will be carried to the liver,
  where it produces abscess and periportal
  fibrosis.
• Amoebic ulcerations can affect the perineum and
  genitalia, and abscess may occur in the lung and
  brain.

Flask-shaped ulcers
10
Manifestations

• Intestinal Disease
• Abdominal discomfort, severe abdominal cramps,
  flatulence, bloody diarrhea with mucus.
• Amoebic Liver Abscess
• High fever, significant leukocytosis with left
  shift, elevated alkaline phosphatase.
• Hepatomegaly, and liver tenderness, with referred
  pain to the left or right shoulder
• Erosion of liver abscesses also present as
  peritonitis.

11
Antiamebic drugs

• Tissue amoebicides
• FOR BOTH INTESTINAL AND EXTRA INTESTINAL
  AMEBIASIS
• Nitroimidzoles Metronidazole, Tinidazole,
  Secnidazole,Ornidazole, Satranadazole
• Alkaloids Emetine, Dehydroemetine
• FOR EXTRAINTESTINAL AMOEBIASIS ONLY
• Chloroquine
• Luminal amoebicides
• AMIDE Diloxanide furote
• 8-HYDROXYQUINOLINESQuiniodochlor
  (Iodochlorohydroxyquin,Clioquine),
  Diiodohydroxyquin (Idoquinol)
• ANTIBIOTICS Tetracyclines, paromomycine
  sulfate.

12
Mechanisms

• Inhibiting peptidyl-tRNA transposition ?
  inhibiting elongation of peptide chain ?
  inhibiting protein synthesis ? interfering
  cleavage and breeding of trophozoites

13
Treatment of Specific Forms of Amebiasis

• A. ASYMPTOMATIC INTESTINAL INFECTION
• Asymptomatic carriers generally are not treated
  in endemic areas but in nonendemic areas they are
  treated with a luminal amebicide.
• A tissue amebicidal drug is unnecessary.
• Standard luminal amebicides are diloxanide
  furoate, iodoquinol, and paromomycin.
• Each drug eradicates carriage in about 80-90 of
  patients with a single course of treatment.
• Therapy with a luminal amebicide is also required
  in the treatment of all other forms of amebiasis.

14
B. AMOEBIC COLITIS
Cont..

• Metronidazole luminal amebicide is the
  treatment of choice for colitis and dysentery.
• Tetracyclines and erythromycin are alternative
  drugs for moderate colitis but are not effective
  against extraintestinal disease.
• Dehydroemetine or emetine can also be used, but
  are best avoided because of toxicity.

15
C. EXTRAINTESTINAL INFECTIONS
Cont..

• The treatment of choice is metronidazole plus a
  luminal amebicide.
• A 10-day course of metronidazole cures over 95
  of uncomplicated liver abscesses.
• For unusual cases in which initial therapy with
  metronidazole has failed, aspiration of the
  abscess and the addition of chloroquine to a
  repeat course of metronidazole should be
  considered.
• Dehydroemetine and emetine are toxic alternative
  drugs.

16
Metronidazole

• Metronidazole is selectively toxic to anaerobic
  microorganisms.
• Mechanism of action
• Metronidazole is a prodrug it requires reductive
  activation of the nitro group by susceptible
  organisms.
• These anaerobic organisms contain electron
  transport components such as ferredoxins, small
  Fe-S proteins that have a sufficiently negative
  redox potential to donate electrons to
  metronidazole.
• The single electron transfer forms a highly
  reactive nitro radical anion that kills
  susceptible organisms by radical-mediated
  mechanisms that target DNA and possibly other
  vital biomolecules.

17
Pharmacokinetics
Cont..

• Metronidazole is almost completely absorbed from
  the small intestine little unabsorbed drug
  reaches the colon.
• It is metabolized in liver primarily by oxidation
  and glucuronide conjugation and excreted in
  urine.
• Plasma t1/2 is 8 hrs.

18

Unwanted effects contraindication

• GI-anorexia, diahorrea , headache ,abdominal
  cramp, unpleasant metallic taste , furry tongue.
• Hematological leucopenia
• Renal-darkened urin,dysuria,cystitis
• Cardiac-t-wave flattening
• Hypersensitivity reaction- urticaria,
  erythematous rash, dry mouth
• Contraindicated in pregnancy
• Disulfiram like effect with alcohol
• Increase the action of warfarin

19
USES
Cont.

• Amoebiasis
• Metronidazole is first line drug for all forms of
  amoebic infection.
• It is less effective than many luminal amebiasis
  in eradicating amoebic cysts from the colon.
• Giardiasis
• It is highly effective.
• Trichomonas vaginitis
• It is the drug of choice 400mg TDS for 7 days
  achives nearly 100 cure.
• Additional intravaginal treatment has been given
  but only in refractory cases.
• Anaerobic bacterial infection
• Metronidazole is generally used with gentamicin
  and cephalosporins.
• Pseudomembranous enterocolitis
• Ulcerative gingivitis
• H. pylori gastritis

20
Tinidazole

• It is similar to metronidazole in its mechanism
  of action and unwanted effects, but is eliminated
  more slowly, having a half-life of 12-14 hours.

21
Emetine

• It is an alkaloid from cephalis ipecacunha.
• Emetine is a potent and directly acting
  amoebicide-kills tropozoites but has no effects
  on cysts.
• It acts by inhibiting protein synthesis in
  amoebae by arresting intra-rebosomal
  translocation of tRNA amino acid complex.

22
Toxicity
Cont

• Pain and tenderness in the area of injection are
  frequent, and sterile abscesses may develop.
• Diarrhea is common.
• Other adverse effects are
• Nausea, vomiting, muscle weakness and discomfort,
  and minor electrocardiographic changes
• Serious toxicities include
• cardiac arrhythmias, heart failure, and
  hypotension.
• The drugs should not be used in patients with
  cardiac or renal disease, in young children, or
  in pregnancy unless absolutely necessary.

23
Use
Cont

• Because of toxicity, emetine is now seldom used
  as a reserve drug in severe intestinal or extra
  intestinal amoebiasis.
• It is also used for patients not responding to or
  not tolerating metronidazole.

24
Dehydroemetine

• Semisynthetic derivative of emetine.
• Equally effective but less cumulative and less
  toxic to heart.
• Thus, it is preferred over emetine.

25
Chloroquine

• Chloroquine reaches high liver concentrations ?
  treatment of amoebic liver abscess.
• Amoebae do not develop resistance to chloroquine.
• Not effective in the treatment of intestinal or
  other extrahepatic amoebiasis.

26
DILOXANIDE FUROATE

• It is an effective luminal amebicide but is not
  active against tissue trophozoites.
• The mechanism of action of diloxanide furoate is
  unknown.
• Diloxanide furoate does not produce serious
  adverse effects.
• Flatulence is common, but nausea and abdominal
  cramps are infrequent and rashes are rare.
• The drug is not recommended in pregnancy.
• It is the drug of choice for mild intestinal/
  asymptomatic amoebiasis.

27
8-HYDROXYQUINOLINES

• They are active against Entamoeba, Giardia,
  Trichomonas.
• They kill the cyst forming tropozoites in the
  intestine, but do not have tissue amoebicidal
  action.
• They are not very effective in acute amoebic
  desentry but afford relief in chronic intestinal
  amoebiasis.
• They are totally valueless in extraintestnal
  Amoebiasis.
• They are widely used for the prophylaxis and
  treatment of nonspecific diarrheas, traveler's
  diarrheas.

28
PAROMOMYCIN SULFATE

• Paromomycin sulfate is an amino glycoside
  antibiotic.
• Paromomycin is an effective luminal amebic idée
  that appears to have similar efficacy and
  probably less toxicity than other agents in a
  recent study, it was superior to diloxanide
  furcated in clearing asymptomatic infections.
• Paromomycin shares the same mechanism of action
  as neomycin and kanamycin (binding to the 30S
  ribosomal subunit) and has the same spectrum of
  antibacterial activity.
• Paromomycin has become the drug of choice for
  treating intestinal colonization with E.
  histolytic.
• It is used in combination with metronidazole to
  treat amebic colitis and amebic liver abscess and
  can be used as a single agent for asymptomatic
  individuals found to have E. histolytica
  intestinal colonization.

29
References

• Tripathi K D., Essential of medical pharmacology,
  2003 5 749-758
• Rang H P., Dale M M., Ritter JM., flower RJ.,
  Pharmacology, 2007 6 698-711
• Brunton L L., Lazo J S., Parker K L., Goodman
  Gilman's the pharmacological basis of
  therapeutics, 2006 11 1097-1120
• Katzung B G., Basic and clinical pharmacology,
  2007 9 1207-1237
• Seth S D.,Seth Vimlesh.,pharmacology,20093xi.20-
  xi32

30

• Thank
• you