Transcript Antiparasitic

Korir
 Protozoans
Amoeba
Heamoflagellate
Flagellates
Cilliates
 Helminthes
Nematodes
Trematodes
Cestodes
 Faeco
oral route
 Poor environmental sanitation
 Low socio-economic status
 Water
 Arthropod vector
•
Luminal Phase
Cysts in Faeces – propagation of disease.
 • Tissue phase
-Ulcer /dysentery
-Abcess /Amoeboma
-Extra intestinal ,Lung, Spleen, Kidney, Brain
 There
can be three potential targets for
chemotherapy of parasitic diseases:
1. Unique essential enzymes only found in the
parasite
2. Similar enzymes found in the host and
parasite but indispensable only for the
parasite
3. Common biochemical functions found in
both the parasite and the host, but with
different pharmacological properties
 Enzymes
i.
ii.
iii.
with developed drugs
Trypanothione reductase – Kinetoplastida
Nifurtimox
Enzyme for dihydropteroate synthesisApicomplexa
Pyruvate-ferrodoxin oxireductase –
Nitroimidazole
pyruvate + CoA + 2 oxidized ferredoxin
ferredoxin + 2 H+
iv.
acetyl-CoA + CO2 + 2 reduced
Nucleoside phosphotransferase- allopurinol
riboside and formycin B
i.
ii.
iii.
Pyruvate phosphate Dikinase
Shikimate pathway
Glycoprotein synthesis - trypanasomes
 Lanosterol
C- 14α Demethylase – leish and
tryps. Azole
 Purine Phosphoribosyl Transferase –Protozoaallopurinol.
 Purine nucleoside kinase – T. vaginalis,
E.histolytic. None
 Ornithine decarboxylase- H.A.T, αDifluoromethylornithine
 Dihyrofolate
reductase-thymidylate synthesis
bifunction bifunctional enzymepyrimethamine
 Thiamine transporter – coccidia – Ampurolium
 Mitochondrial electron transporter –
apicomplexa – 4 hydroquinolines and 2hydroxy-naphthoquinones
 Microtubules – helminth – Benzimidazoles
 Nervous synaptic transission- helminths
levamisole.
•
Tissue Amoebiasis
*Both intestinal & extra intestinal
 Nitroimidazoles –Metronidazole
- Tinidazole
- Secnidazole
- Ornidazole
 Alkaloids - Emetine
-Hydroemetine
*
Extra intestinal amoebiasis only
-Chloroquine
 • Luminal amoebiasis
-Amide
–Diloxanide furoate-8-Hydroxy quinolones
–Quinidochlor
-Antibiotics
- Tetracycline
 Treatment
with tissue amoebicide
 SHOULD always be followed by
 Luminal amoebicide
 to eradicate source of infection
•
Prototype drug.
 A nitroimidazole
 Effective against
 Giardia lamblia, anaerobic bacteria,
Bacteroides fragilis, Fusobacterium,
Clostridium perfringes, Helicobacter
pylori, Anaerobic Streptococci
 Not
clearly understood
 • Enters micro-organism by diffusion
Nitro group reduced
DNA damaged
Cytotoxicity
Oral metronidazole and tinidazole are readily
absorbed by simple diffusion.
 Peak plasma concentrations are reached in 1-3
hours.
 Protein binding of both drugs is low (10-20%);
 The half-life of unchanged drug is 7.5 hours for
metronidazole and 12-14 hours for tinidazole.
 Metronidazole and its metabolites are excreted
mainly in the urine.
 Plasma clearance is decreased in patients with
impaired liver function.
 Dose adjustment for renal and liver diseases.

 Amebiasis
– tissue amoebiasis, for luminal
combine
 Giardiasis –treatment of choice and well
tolerated.
 Trichomoniasis – 2gm stat. Metronidazole
resistant organism can led to drug failures.
Frequent
Anorexia, nausea, METALLIC TASTE,
abdominal cramps
 Less frequent
Headache, glossitis, dry mouth,dizziness,
rashes, transient neutropenia
 On prolonged administration
Peripheral neuropathy, CNS effects
 Taking with food lessens G.I.T

 Caution
in patients with CNS disease.
 Anticoagulant effect of coumarin-type
anticoagulants.
 Phenytoin and phenobarbital may accelerate
elimination, while cimetidine may decrease
plasma clearance.
 Lithium toxicity may occur when the drug is
used with metronidazole.( reduced renal
clearance)
 Avoided in pregnant or nursing women.
 With Alcohol- disulfiram like effect.
 Is
a halogenated hydroxyquinoline.
 It is an effective luminal amebicide.
 90% of the drug is retained in the intestine
and excreted in the feces.
 The remainder enters the circulation, has a
half-life of 11-14 hours, and is excreted in
the urine as glucuronides.
 It is effective against organisms in the bowel
lumen but not against trophozoites in the
intestinal wall or extraintestinal tissues.
Infrequent adverse effects include
diarrhea, anorexia, nausea, vomiting

The drug may increase protein-bound serum
iodine, leading to a decrease.

Severe neurotoxicity with prolonged use at
greater than recommended doses.

Taken with meals to limit G.I.T toxicity.

Caution in- optic neuropathy, renal or thyroid
disease, or nonamebic hepatic disease.

The drug should be discontinued if it produces
persistent diarrhea or signs of iodine toxicity









Diloxanide furoate is a dichloroacetamide derivative.In the
gut, it is split into diloxanide and furoic acid; about 90% of
the diloxanide is rapidly absorbed and then conjugated to
form the glucuronide, which is promptly excreted in the
urine.
The unabsorbed diloxanide is the active antiamebic
substance.
Highly effective luminal amoebicide but not tissue trophs
Directly kills trophozoites
No systemic antiamoebic activity seen despite absorption
No anti bacterial action
It does not produce serious adverse effects. Flatulence is
common, but nausea and abdominal cramps are infrequent
and rashes are rare.
Not recommended in pregnancy
 Alkaloid
from Cephaelis ipecacuanha
 Potent directly acting amoebicide
(trophozoites) Does not kill cysts
 Cumulative toxicity high –Seldom used
 Reserve drug
 Luminal amoebicide follows emetine to
eradicate cysts
 Dihydroemetine =effective but less toxic
Preferred over emetine.
 Administered SC or IM but never I.V
mild when the drugs are used for 3-5 days.
 sterile abscesses may develop.
 Diarrhea is common. Others 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.






Pentamidine has activity against trypanosomatid
protozoans and against P jiroveci, but toxicity is
significant.
Chemistry & Pharmacokinetics
its an aromatic diamidine formulated as an isethionate
salt.
Pentamidine is only administered parenterally.
The drug leaves the circulation rapidly, with an initial
half-life of about 6 hours, but it is bound avidly by
tissues.
accumulates and is eliminated very slowly, with a
terminal elimination half-life of about 12 days.
Only trace amounts of pentamidine appear in the
central nervous system.







A. PNEUMOCYSTOSIS
prophylaxis against pneumocystosis in 10 and 20 -aerosol . The
drug is well-tolerated in this form.
Its efficacy is very good but clearly less than that of daily
trimethoprim-sulfamethoxazole.
HAT
Its used for early hemolymphatic stage
The drug can also be used with suramin.
Chemoprophylaxis against African trypanosomiasis, with dosing
of 4 mg/kg every 3-6 months.
LEISHMANIASIS
alternative to sodium stibogluconate in the treatment of visceral
leishmaniasis.
The dosage is 2-4 mg/kg intramuscularly daily or every other day
for up to 15 doses,.
highly toxic drug, with adverse effects noted in
about 50% of patients receiving 4 mg/kg/d.
 Rapid intravenous administration can lead to
severe hypotension, tachycardia, dizziness, and
dyspnea, so the drug should be administered
slowly (over 2 hours).
 Pancreatic toxicity. Hypoglycemia
 Reversible renal insufficiency is also common.
 Other adverse effects include rash, metallic
taste, fever .....

 Pentavalent
antimonials, including sodium
stibogluconate and meglumine antimonate,
are generally considered first-line agents for
cutaneous and visceral leishmaniasis.
 The drugs are rapidly absorbed after
intravenous or intramuscular administration
and eliminated in two phases.
 Few adverse effects occur initially, but the
toxicity of stibogluconate increases over the
course of therapy
Nitazoxanide is a nitrothiazolyl-salicylamide.
 It is rapidly absorbed and converted to
tizoxanide and tizoxanide conjugates,
 which are subsequently excreted in both urine
and feces.
 The active metabolite, tizoxanide, inhibits the
pyruvate:ferredoxin oxidoreductase pathway.
 activity against metronidazole-resistant
protozoal strains and is well tolerated..

The recommended adult dosage is 500 mg twice
daily for 3 days.










Suramin is a sulfated naphthylamine that was introduced in
the 1920s.
It is the first-line therapy for early hemolymphatic African
trypanosomiasis.
It does not enter the central nervous system,
The drug's mechanism of action is unknown.
It is administered intravenously and displays complex
pharmacokinetics with very tight protein binding.
It has a short initial half-life but a terminal elimination
half-life of about 50 days.
The drug is slowly cleared by renal excretion.
Combination therapy with pentamidine may improve
efficacy.
Suramin can also be used for chemoprophylaxis
Adverse effects are common. Immediate reactions and
Late reactions .
 It
is a trivalent arsenical.
 first-line therapy for advanced central
nervous system African trypanosomiasis.
 After intravenous administration it is
excreted rapidly, but clinically relevant
concentrations accumulate in the central
nervous system within 4 days.
 Melarsoprol is extremely toxic.
 The most important toxicity is a reactive
encephalopathy









Eflornithine (difluoromethylornithine),
an inhibitor of ornithine decarboxylase,
is the only new drug registered to treat African trypanosomiasis
in the last half-century.
It is a second therapy for advanced central nervous system
African trypanosomiasis
Is less toxic than melarsoprol but not as widely available.
Eflornithine is administered intravenously, and good central
nervous system drug levels are achieved.
Peak plasma levels are reached rapidly, and the elimination halflife is about 3 hours.
Toxicity from eflornithine is significant, but considerably less
than that from melarsoprol.
Adverse effects include diarrhea, vomiting, anemia,
thrombocytopenia, leukopenia, and seizures. These effects are
generally reversible.
A nitrofuran, is the most commonly used drug for
American trypanosomiasis .
 It is well absorbed after oral administration and
eliminated with a plasma half-life of about 3
hours.
 Nifurtimox decreases the severity of acute disease
and usually eliminates detectable parasites, but it
is often ineffective in fully eradicating infection.
 Adverse effects are reversible but often lead to
cessation of therapy before completion of a
standard course.

pregnant within 2 months of treatment) because of
its teratogenic effects.


BENZNIDAZOLE
Benznidazole is an orally administered nitroimidazole that
appears to have efficacy similar to that of nifurtimox.
Important toxicities include peripheral neuropathy, rash,
gastrointestinal symptoms, and myelosuppression.
AMPHOTERICIN
This important antifungal drug, is an alternative therapy
for visceral leishmaniasis, especially in parts of India with
high-level resistance to sodium stibogluconate,

MILTEFOSINE
Miltefosine is an alkylphosphocholine analog that has
recently shown efficacy in the treatment of visceral
leishmaniasis.
Transient elevations in liver enzymes and nephrotoxicity
are also seen. The drug should be avoided in pregnancy