• PHL 418 (Part I) components:
- Antiparasitic drugs:
(Antiprotozoal drugs & Antihelminthic drugs
“Anthelmintic”) .
- Immunomodulators:
(Immunosupressants & immunostimulants)
PHL 418 (Part II)
Course outline
• Total Marks (50)
• Mid-term (30)
- Activity (up to 7)
- Quiz (5)
- Written exam (18)
• Final
- Written exam (20)
PHL 418 (Part II)
Start of class
1st week (25/3/1435 – 26/1/2014)
First Quiz
5th week; (23/4/1435 – 23/2/2014)
Mid-term exam
Start 6th week; ( 22/1/1433 – 17/12/2011)
Activity due
End of 8th week (19/5/1435 - 20/3/2014)
Final exam
TBA
PHL 418 Activity Presentations
• Students (individually) are asked to write a review
article that will deserve up to 7 marks on your
course about the onefollowing topics:
• Students (6-10): Write about Leishmaniasis
• Students (16-21)  : Write about Toxoplasmosis
• Students (1-5)  : Write about Fascioliasis
• Students (11-15)  : Write about Lymphatic filariasis
: Indicates to student’s serial number in class roster.
PHL 418 (Part II)
Antiparasitic Drugs
Course references:
- Rang & Dale’s Pharmacology 6th or 7th
editions. Chapter # 49 & 50
- Classroom materials and lectures.
Parasitic diseases
• Parasitic are a serious health
problem worldwide.
• Malaria 300-500 million infection
and one 1-3 million died annually.
• Most of parasitic infection are
common in underdeveloped areas
of the world (tropical-subtropical
countries) where much poverty is
existed and associated with
inadequate sanitary conditions,
and hygienic practice.
Parasitic diseases (cont’d)
• Parasitic diseases are infectious diseases caused
or transmitted by parasite.
• Parasitic diseases can affect practically all living
organisms, including plants and mammals.
• Some parasites can cause disease directly, or by
the toxins that they produce.
• Two main routes that used by parasites to invade
mammalian host body, the skin and mouth.
Parasitic diseases (cont’d)
• Four main mechanisms for parasitic
transfer:
– Ingestion of contaminated food or
water (egs or larval stages…etc)
• Ascaris
• Entamoeba
– The infective stage of the parasite
can burrow into the skin of the host
• Schistosoma cercaria
– The larva of the parasite can move from
person to person through bug bites
(insect vector)
• Trypanosomes
• Plasmodia
– Sexual transmission
• Trichomonas vaginalis
• Pubic lice
What are parasites?
• By definition parasites are organisms that are
obligated to live with host to survive.
• Parasites Include:
(1) protozoa:
• They are a diverse group of single cell eukaryotic
organisms, many of which are motile.
• Classified mainly according to mode of locomotion (They
move around with whip-like tails called flagella, hair-like
structures called cilia, or foot-like structures called
pseudopodia. Others do not move at all)
• Reproduce by binary fission at some point in life cycle.
What are parasites? (cont’d)
• Examples of human diseases caused by protozoal
infections:
- Amoebiasis (Entamoeba histolytica)
- Giardiasis (Giardia lamblia)
- Trichmoniasis (Trichomonas vaginalis)
- Trypanosomiasis “Sleeping sickness Africa; Chagas
Disease - South America” (Trypanosoma spp.)
- Toxoplasmosis (Toxoplasma gondii)
- Malaria (Plasmodium spp)
What are parasites? (cont’d)
(2) Helminths (worms)
• Multicellular parasites that, live inside their host.
They are worm-like organisms that live and feed off
living hosts, receiving nourishment and protection
while disrupting their hosts' nutrient absorption,
causing weakness and disease.
• They live in a large variety of tissues, though many
are specialized to single tissues such as muscle,
vein, brain, or intestine.
What are parasites? (cont’d)
• Helminthes are classified into:
(a) Cestodes (tapeworms)
Examples of tapeworms that infect humans
include:
1- Beef tapeworm (Taenia saginata) and Pork
tapeworm (Taenia solium) Taeniasis
2- Fish tapeworm (Diphyllobothrium latum)
 Diphyllobothriasis
What are parasites? (cont’d)
(b) Trematodes (flukes or flat worms)
Example of flukes that infect humans include:
1- Intestinal fluke (Fasciolopsis buski)
 Fasciolopsiasis
2- Blood fluke (Schistosoma japonicum, Schistosoma
mansoni, Schistosoma haematobium)
 Schistosomiasis
3- Liver fluke (Fasciola hepatica, Fasciola gigantica)
 Fascioliasis
What are parasites? (cont’d)
(c) Nematodes (roundworms)
- Examples of roundworms that infect humans
include:
1- Enterobius vermicularis (pinworm)  Enterobiasis
(oxiyoriasis)
2- Ascaris lumbricoides  Ascariasis
3- Ancylostoma duodenale (hookworm)
 Ancylostomiasis
4- Wuchereria bancrofti (flaria)  Flariasis
(elephentiasis)
What are parasites? (cont’d)
(3) Ectoparasites
Organisms that live on the outer surface of
another organism, its host, and which does not
contribute to the survival of the host
Examples of ectoparasites affect human:
1- Human fleas
2- Human lice ( body louse, Head louse, and Pubic
or crab louse )
3- Ticks
4- Mites (Dust mites , Itch mites (Sarcoptes scabiei)
that cause the condition known as scabies.
Anti protozoal drugs
Rang & Dale’s Pharmacology 6th edition
Chapter 49 (698- 711)
Antiprptozoal drugs
• Anti-Protozoal Drugs are medications used to treat
infections or diseases caused by Protozoa.
• These drugs aim to destroy protozoa or prevent their
growth and ability to reproduce.
• They are available in many pharmaceutical forms (liquid,
tablet, and injectable forms).
• The challenges associated with protozoal infections is that
protozoa are eukaryotic organisms which have metabolic
processes close to those of human host than procaryotic
bacterial pathogens.
• Thus parasitic diseases are less easily to be treated than
bacterial infections and antiprotozoal drugs are more toxic
Organism
Disease
Common drug treatment
Amoebas (pseudopodia)
Entamoeba histolytica
Amoebic dysentery
(amoebiasis)
Metronidazole, tinidazole diloxanide
Sleeping sickness
Suramin, pentamidine, melarpasol,
eflornithine, nifurtimox
Nifurtimox, benzindazole
Sodium stibogluconate, amphotericin,
pentamidine isethionate
Flagellates
Trypanosoma rhodesiense
Trypanosoma gambiense
Trypanosoma cruzi
Leishmania tropica
Leishmania donovani
Leishmania braziliensis
Leishmania mexicana
Trichomonas vaginalis
Giardia lamblia
Chagas' disease
Oriental sore
Kala-azar
Espundia
Chiclero's ulcer
Vaginitis
Diarrhoea, steatorrhoea
Metronidazole, tinidazole
Metronidazole, tinidazole, Nitazoxanide
Sporozoa
Plasmodium falciparum
Plasmodium vivax
Plasmodium ovale
Plasmodium malarariae
Malignant tertian malaria
Benign tertian malaria
Benign tertian malaria
Quartan malaria
Amodiaquine, artemisinin and
derivatives, atovaquone, chloroquine,
dapsone, doxycycline, halofantrine,
lumefantrine, mefloquine, primaquine,
proguanil, pyrimethamine, quinine,
tafenoquine and tetracycline
Toxoplasma gondii
Encephalitis, congenital
malformations, eye disease
Pyrimethamine, sulfadiazine
pentamidine isethionate
Pneumonia
Co-trimoxazole, atovaquone,
pentamidine isethionate
Ciliates and others
Pneumocystis carinii
Drugs Used in Treatment of
Amoebiasis
• Amoebiasis (entamoebiasis or amoebic dysentry) is a
gastrointestinal pathological condition caused by the
proatozoal pseudopodial parasite Entamoeba histolytica
(amoeba).
• This protozoan is distributed throughout the world and is
commonly acquired by ingestion of contaminated food or
water.
• It is estimated that about 40 to 50 million people infected
with E. histolytica worldwide annually. Up to 100,000
deaths per year may occur from the most sever forms of
amoebiasis. It is considered to be the second leading
cause of death from parasitic diseases worldwide
Anti-amoebic drugs
• Pathogenesis:
- Amoebiasis is usually transmitted by the fecal-oral
route through ingestion food or water contaminated
with the cyst (entamoeba infective stage) a semidormant and hardy structure form of the parasite,
found mainly in feces of infected individuals.
- A gastrointestinal infection that may or may not be
asymptomatic (in almost 80-90% of cases) and can
remain latent in an infected person for several years.
- When no symptoms are present, the infected
individual is still a carrier, able to spread the parasite
to others through poor hygienic practices.
Anti-amoebic drugs
• Pathogenesis (con’d):
- Symptoms can range from mild diarrhea to dysentery
(sever diarrhea with blood and mucus in the stool)in
association of abdominal cramps.
- Severe amoebiasis infections (known as invasive or
fulminant amoebiasis) occur in two major forms.
- Invasion of the intestinal lining causes amoebic
dysentery or amoebic colitis due to sloughing of
intestinal wall.
- If the parasite reaches the blood stream it can spread
through the body, most frequently ending up in the
liver where it causes amoebic liver abscesses.
- Liver abscesses can occur without previous
development of amoebic dysentery. Lung and brain
tissues may also be attached.
Anti-amoebic drugs
E. histolytica “Life cycle”
Invasive infection
Anti-amoebic drugs
•
Treatment of amoebiasis:
- The use of drugs to treat this condition depends
largely on the site and type of infection, as different
drugs are differentially effective in acute amoebic
dysentery, in chronic intestinal amoebiasis, in
extraintestinal infection and in the carrier state.
- The main drugs currently used are metronidazole,
tinidazole , diloxanide. iodoquinol, dehydroemetine
and paromomycin. These agents may be used either
as monotherapy in combination.
Anti-amoebic drugs
• Treatment of amoebiasis (cont’d)
• For example:
- Tissue amoebicides ides like Metronidazole (or a related
drug such as tinidazole) followed by luminal amobicides
like Iodoquinol or diloxanide for acute invasive intestinal
amoebiasis resulting in acute severe amoebic dysentery
- Iodoquinol, Paromomycin, or Diloxanide for chronic
intestinal amoebiasis (mild symptoms)
- Metronidazole (or tinidazole) followed by luminal
amobicides like paromomycin, Iodoquinol or diloxanide for
hepatic amoebiasis
- Diloxanide , or Iodoquinol, Paromomycin for the carrier
state (asymptomatic).
Anti-amoebic drugs
(1) Nitroimidazole drivatives
Metronidazole (Flagyl)
Tinidazole (Fasigyn)
Therapeutic Uses:
• Nitroimidazole derivatives are group of drugs used for treatment of
many parasitic infections like amoebiasis, trichomoniasis and
giardiasis in addition to their use for treatment of anaerobic bacterial
infections.
• Metronidazole, or a related drug such as Tinidazole, Secnidazole or
Ornidazole have amebicidal activity.
• Metronidazole and congors kill the trophozoites of E. histolytica but
has no effect on the cysts. It is the drug of choice for invasive
amoebiasis of the intestine or the liver, but it is less effective against
organisms in the lumen of the gut.
Anti-amoebic drugs
(1) Nitroimidazole drivatives (cont’d)
Mechanism of action
• Metronidazole is selectively absorbed by anaerobic bacteria and
sensitive protozoa by simple diffussion.
• Once taken up by such organisms, it is reduced by pyruvateferredoxin oxidoreductase system in the mitochondria to more toxic
metabolites.
• Reduced metabolites will interact with many intracellular targets
like DNA, leading to strand breakage , destabilization and lead to
parasite apoptosis.
• In addition many of its intermediate metabolites will interact with
cysteine-bearing enzymes and proteins and thereby inactivate
them.
• This reduction usually happens only in anaerobic cells, it has
relatively little effect upon human cells or aerobic bacteria.
• Tinidazole is chemically similar to metronidazole. It is used
treatment for a variety protozoal infections including of amoebiasis.
• Tinidazole may be a therapeutic alternative in the setting of
metronidazole tolerance.
Anti-amoebic drugs
(1) Nitroimidazole drivatives (cont’d)
Pharmacokinetics:
• Metronidazole and tinidazole are usually given orally
and are rapidly and completely absorbed, achieving
peak plasma concentration in 1-3 hours, with t1/2about
7 hrs (metronidazole) or 12-14 hrs (tinidazole).
• Rectal and intravenous preparations are also available.
• They are distributed rapidly throughout the tissues,
reaching high concentrations in the body fluids,
including the cerebrospinal fluid.
• Some is metabolized, but most are excreted
unchanged in urine (leading to dark urine).
Anti-amoebic drugs
(1) Nitroimidazole drivatives (cont’d)
Unwanted Effects:
- Drugs has a metallic, bitter taste in mouth.
- Common adverse drug reactions (≥1% of patients) including
GIT disturbances (nausea, vomiting and mild diarrhea).
- Some CNS symptoms may be experienced (dizziness,
headache, sensory neuropathies).
- Infrequent adverse effects include: hypersensitivity reactions
(rash, itch, flushing, fever and/or paraesthesia)
- The drug interferes with alcohol metabolism, and concurrent
use of the substance thought to be associated with toxicity
symptoms nausea, vomiting, flushing of the skin, tachycardia,
and shortness of breath. Simultaneous administration should
be strictly avoided.
- Drugs are contraindicated to be used during pregnancy.
Anti-amoebic drugs
(2) Dichloroacetate derivatives
Diloxanide Furoate (Furamet)
•
•
•
Both diloxanide and its insoluble ester, diloxanide furoate, are the drugs of choice for
treatment of asymptomatic and chronic amoebiasis, and are often given as a followup after the disease has been reversed using metronidazole.
Both drugs are effective luminal amebicide (parasites just before encystment.) but is
not active against tissue trophozoites. In the gut, diloxanide furoate 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 (90%).
Diloxanide furoate is given orally, the unabsorbed moiety being the amoebicidal agent
The mechanism of action of diloxanide furoate is unknown. It may inhibit protein
synthesis.
•
•
It is used with a tissue amebicide, usually metronidazole, to treat serious intestinal and
extraintestinal infections.
Diloxanide furoate has an excellent safety profile . Almost no ADRs , but fatulence loss
of appetite may be experienced . The drug is not recommended in pregnancy.
Anti-amoebic drugs
(3) Paromomycin
• Paromomycin is an aminoglycoside
antibiotic, first isolated from
Streptomyce krestomuceticus.
• It is designed to fight intestinal
parasitic
infections
including
amoebiasis and giardiasis.
• The route of administration IM and
Paromomycin (Humatin)
oral capsule.
• Paromomycin inhibits protein synthesis by binding to 16S rRNA.
• Side effects: ototoxicity and nephrotoxicity with systemic
administration. Drug is contraindicated in patients with impaired
kidney function
• Its activity is lower than nitroimidazole drs.; however, because it is
poorly absorbed by small intestine, a higher concentration of the drug
remains in the lumen to combat the organisms.
• The drug is recommended to treat E. histolytica in resistant infection
and during pregnancy.
Drugs Used in Treatment of
Giardiasis
• Giardiasis (beaver fever) is a is a gastrointestinal
pathological condition caused by the proatozoal
flagellate parasite called Giardia lamblia.
• Giardiasis occurs worldwide with a prevalence of 20–
30% in developing countries.
• Giardia has a wide range of mammalian hosts besides
humans, thus making it very difficult to eradicate.
• Giardiasis can be fatal for those patients with
immunodeficiency, such as children, elderly and AIDS
patients.
Anti-giardiasis drugs
Pathogenesis:
- Giardiasis is usually transmitted by the fecal-oral
route through ingestion food or water contaminated
with faecal matter containing the cysts (giardia
infective stage) that found mainly in feces of
infected individuals. As few as 10 cysts can cause
disease and up to 900,000,000 cysts can be released
by an infected individual in one day.
- Symptoms usually begin 1 to 2 weeks (average 7
days) after an individual becomes infected. In
otherwise healthy individuals, symptoms may last 2
to 6 weeks. Though symptoms may last longer,
medications can help decrease the duration of
symptoms.
- The trophozoite form of this parasite colonizes the
upper part of GIT, and the cysts pass out in the
faeces.
Anti-giardiasis drugs
G. lamblia“Life cycle”
Anti-giardiasis drugs
Pathogenesis (con’d):
• A range of clinical syndromes may occur, with
gastrointestinal syndromes being the most prevalent.
Gastrointestinal symptoms:
• A small number of infected individuals experience an
abrupt onset of abdominal cramps, frothy watery
diarrhea, vomiting, Flatulence , and fever which may last
for 3–4 days before proceeding into a more sub-acute
phase. The majority of infected persons may have recurrent
symptoms.
• In most cases, stools become greasy and malodorous but
do not contain blood or pus because giardiasis does not
involve dysenteric symptoms.
• Watery diarrhea may cycle with soft stools and
constipation. Upper GI symptoms including nausea, early
satiety, bloating, substernal burning, and acid indigestion
may be exacerbated by eating .
• Persistence of diarrhea may lead to chronic debilitation.
Anti-giardiasis drugs
Pathogenesis (con’d):
Constitutional symptoms:
• The most common constitutional symptoms are loss of
appetite, malaise, and fatigue. Weight loss affects more
than 50% of patients. Adults with long lasting
malabsorption syndrome and children with failure to
thrive may experience chronic illness.
• Additional syndromes may include lactose intolerance,
biliary tract disease and allergic manifestations such as
bronchospasm and urticaria.
Anti-giardiasis drugs
Treatment:
• Nitroimidazole derivatives (e.g. Metronidazole , Tinidazole,
Secnidazole or Ornidazole) are the drugs of choice in
treatment of giardiasis. In addition to many other drugs are
also used to treat giardiasis like Nitazoxanid, Quinacrine,
Furazolidone, Paramomycin, Albendazole, and Mebendazole.
• In some cases Giardia parasites may show resistance to the
common anti-giardial drugs, such as metronidazole, quinacrine,
and albendazole. Treatment for truly resistant strains consists of
three options:
- Treating with the original drug for a longer period of time or at higher
doses;
- Using a drug from a different class to treat the resistant infection. This
way considered the most efficacious approach.
- Using a combination of different antiprotozoal drugs like metronidazolequinacrine or metronidazole-albendazole .
Anti-giardiasis drugs
Nitazoxanid
Nitazoxanide (Nizonide)
• Nitazoxanide is a synthetic nitrothiazolyl derivative .
• Nitazoxanide is a first-line choice for the treatment of
infectious diarrhea caused by G. lamblia . It is also effective
in treatment of many other protozoal (e.g. C. parvum) and
helminthes (e.g. tapeworms) infections.
• It is used in patients 1 year of age and older.
Anti-giardiasis drugs
Mechanism of action
• The anti-protozoal activity of nitazoxanide is assumed to be due to
interference with the pyruvate-ferredoxin oxidoreductase (PFOR)
enzyme-dependent electron transfer reaction which is essential step
in protozoal energy production.
Pharmacokinetics
• Nitazoxanide is available in two oral dosage forms - tablet and oral
suspension. It is a prodrug ; following oral administration, it is rapidly
hydrolyzed to its active metabolite, tizoxanide which has the
antiprotozoal activity. Tizoxanide is 99% protein bound. Peak
concentrations are observed 1–4 hours after administration. It is
excreted in the urine, bile and feces.
Adverse effects
• Side effects are minimal (~3-6% of cases) and mostly
gastrointestinal (abdominal pain, dyspepsia , and constipation) ,
headache, dizziness, dry mouth, and yellow discoloration of urine .
• The drug should be taken with food to minimize adverse effects.
Furazolidone
Anti-giardiasis drugs
Furazolidone (Furoxone )
• Furazolidone is a nitrofuran drivative.
• It is used to treat diarrhoea and enteritis caused by some bacteria
(e.g. salmonellosis) or protozoan (e.g. giardiasis) infections.
• It is administered orally and has the ability to reach all body tissues
and fluids like saliva, breast milk, semen and vaginal fluid
Mechanism of action
• It is believed to work by crosslinking of DNA.
Side effects
• Mainly GI symptoms (nausea, vomiting, diarrhea) are observed in 10%
of patients. Other side effects include brown discoloration of urine, and
hemolysis in G6PDH-deficient patients
• Not recommended to treating pregnant patients
Quinacrine
Anti-giardiasis drugs
Quinacrine(Atabrine)
• Quinacrine is a drug with a number of different medical
applications. It is used as an antiprotozoal , anthelmintic
(especially tapeworm infections), and in management of
autoimmune disorders (like SLE) .
• Antiprotozoal use include targeting malaria and Giardiasis.
• Quinacrine is indicated as a primary antigiardiasis agent for
patients with metronidazole-resistant giardiasis and patients
who can not tolerate metronidazole. Giardiasis that is very
resistant may even require a combination of quinacrine and
metronidazol
Anti-giardiasis drugs
Quinacrine (cont’d)
Mechanism of action
• Its mechanism of action against protozoa is thought to
interference with the protozoan's cell membrane integrity.
Side effects
• Bitter taste (less accepted in children patients), nausea ,
vomiting and yellow/orange discoloration of the skin, sclera,
and urine are the most common side effects.
• Other side effects include headache, dizziness and fever.
• Qinacrine-induced psychosis has been observed in some
patients. Dermatitis and drug-induced retinopathy may also
observed (uncommon).
• Drug is contraindicated in pregnant patients that it can cross
placental barrier and cause fetal malformation (proven
teratogenic).