1. Pharmacology -3 Anti-protozoal drugs
Dr. Magdy M.Awny By

2. Amoebiasis
A protozoan infection of intestinal tract that occurs due to ingestion of food or water contaminated with mature cysts of
E. Histolytica which passes into colon, where they divide into trophozoites; that either enter the tissues or reform cysts.
This agent can cause a symptomatic intestinal infection, colitis, dysentery (severe intestinal infection), liver abscess and extra intestinal infection (liver, lung, or the brain) .
Histo=tissue lytica=distroying

3. Life cycle of E. Histolytica

4. 1-Bowel Lumen (luminal) Amebiasis: 90 % of cases
Is asymptomatic (subclinical) (carriers) , the motile trophozoites (non infective)
& cysts (infective) are passed in the feces→ transmission of infection
Drug of choice (luminal amebicide) is diloxanide furoate (furazole®);
iodoquinol or paromomycin as alternative drugs
2- Tissue Invading Amebiasis: 10% of cases
It causes dysentery, hepatic amebiasis and liver abscess.
Drug treatments include:
metronidazole, tinidazole (systemic amebicides; kill ameba in intestinal wall and liver),
these drugs are also available in parenteral form for pts who are too ill to
take drugs by mouth.
In severe cases of amoebic dysentery, tetracycline or emetine or dehydroemetine
can be used in addition to the systemic amebicide to avoid
perforation and peritonitis
Symptoms can range from mild diarrhea to severe dysentery with blood and mucus
Incubation period takes about 2- 4 weeks then pt develops symptoms

5. 1-Metronidazole (Flagyl®, Amrizole®)
kills trophozoites but not cysts of E histolytica.
Mechanism of action:
Nitro group of metronidazole is chemically reduced by ferridoxine oxidoreductase
(In protozoa & anaerobic bacteria) → FRs and cytotoxic compounds
Disrupt DNA, inhibit nucleic acid synthesis
Inhibition of enzymes important for energy production
These enzymes are located in bacterial cytoplasm but protected by mitochondria in mammalian cell
Clinical uses:
1-Antiprotozoal: Metronidazole is the first drug of choice in:
Amebiasis (intestinal (Amoebic dysentery) & hepatic)
Giardiasis (infection of small intestine by giardia lamblia “ flagellated protozoan”)
Metronidazole plus albendazole work synergistically for giardiasis
Trichomoniasis (vaginitis)
2- Antimicrobial:
- Colitis (inflammation of large intestine) & Brain abscess
- Peptic ulcer
- Dental infections
caused by Giardia lamblia parasites that infect the small bowel
Reduction of NO2…..NH2
Common symptoms of giardiasis include:
fatigue
nausea
diarrhea or greasy stools
loss of appetite
vomiting
bloating and abdominal cramps
weight loss
excessive gas
headaches
abdominal pain

6. Adverse effects of metronidazole:
Nausea, vomiting, (metallic taste) headache, dry mouth, insomnia, weakness, dizziness, rash, dark urine, vertigo, “neutropenia and ototoxicity (high dose, systemic treatment)”.
Metronidazole alone rarely causes Stevens–Johnson syndrome, but is reported to occur at high rates
when combined with mebendazole
Disulfiram-like effect [N, V, flushing, tachycardia] if taken with ethanol As Metronidazole inhibit dehydrogenase so inhibit metabolism of alcohol.
So alcohol consumption should be avoided during Metronidazole therapy or at
least 24 hrs after completion of treatment
It potentiates the effect of anticoagulant (coumarin)…..it decrease its breakdown
Phenytoin and phenobarbital increase metabolism of metronidazole, while cimetidine decreases its plasma clearance.
Toxic epidermal necrolysis, SJS

7. 2-Tinidazole (Fasigyn®) 3- Secnidazole (Fladazole®, Secinda-Misr®)
It is a long acting (half-life 14 hours) amoebicidal drug
It has less adverse effects than metronidazole
It is given as a single daily dose for only 3-5 days
It is more expensive than metronidazole.
NB: CONAZ®(norfolxacin400mg+ tinidazole 600mg) treat diarrhea, dysentery of bacterial, amoebic or mixed origin.
3- Secnidazole (Fladazole®, Secinda-Misr®)
A new second-generation 5-nitroimidazole derivative with a broad spectrum
of activity against anaerobic bacteria.
It is used for amoebiasis, trichomoniasis and giardiasis 
It has longer half-life (20 hrs) than metronidazole, making it suitable for
single-dose (2 gm) therapy, therefore potentially offers an advantage over
multiple-dose metronidazole regimens.
Side effects: Nausea, mouth ulcer and stomach pain. 
Bacteria e.g. salmonella, shigella, e coli …..cause dysentry

8. It is a synthetic analog of emetine used as a trophozoticidal agent
4-Diloxanide (Damizol®, Furamibe®)
It is highly effective luminal amoebicide directly kill trophozoites
It exerts no antibacterial action. Mech is Unkn may, it may inhibit protein synthesis.
It is less effective in invasive amoebic dysentery, probably because of
a poor tissue amoebicidal action
5- Dehydroemetine (Mebadin®)
It is a synthetic analog of emetine used as a trophozoticidal agent
I.M. Injection is the preferred route cause vomiting if taken orally.
It inhibits protein synthesis by blocking chain elongation
It is only used in severe intestinal amebiasis
It should not be taken for more than 5 days (cardiotoxicity).
It may induce HF or arrhythmia in susceptible pts

9. Metro…trophozoite only
6-Iodoquinol
a halogenated hydroxyquinoline, the drug of choice for treating asymptomatic
or moderate forms of amebiasis. Unkn mechanism
It is effective against the luminal trophozoite & cyst forms of E. histolytica
About 90% of the drug is retained in the intestine (as it is poorly absorbed from
GIT so its amoebicidal effect  produced at the site of infection) and excreted in
the feces.
The t1/2 is hrs and excreted in the urine as glucuronides.
It should be taken with meals to minimize GIT toxicity.
Side effects:
Stomach cramps, Anorexia, vomiting, abdominal pain, headache, rash,
thyroid enlargement. On long period treatment it may cause blindness
(optic neuritis).

10. 7- Paromomycin It is an aminoglycoside antibiotic,
only effective against the intestinal (luminal) forms of E. histolytica because it is not significantly absorbed from GIT.
It works by stopping the growth of parasites in the intestine.
via inhibition of protein synthesis by binding to 16 S ribosomal RNA.
Intestinal forms of E histolytica = trophozoite and cyst

11. Nifuroxazide (Antinal, Diax )
is an oral nitrofuran antibiotic
and used to treat colitis and diarrhoea  in humans and non-humans it control diarrhea with in 24 hrs of intake.
Broad spectrum intestinal anti-infective agent
which covers most enteropathogenic microbacterials, Shigella, E-coli,
salmonella, staphylococcus
Mechanism of action
It inhibit bacterial growth by acting on nucleic acid and energy metabolism of pathogen
Dose: duration of treatment 5-7 days
Adult …..200 mg 4 times daily
2-18 years…..200 mg 3 times daily
Less than 2 years it is not recommended, also in pregnancy & breastfeeding
Side effects: urticaria, anaphylactic shock
NB:-Not teratogenic in animals, there is no studies on human …but should not administered

12. Anthelmintic drugs

13. → Pain, itching in anal area → irritability and difficulty of sleep,
Up to 45 cm
Types of helminthes:-
Nematodes (Roundworms):
Intestinal e.g.
Ascaris lumbricoides→largest nematodes, causes abdominal pain, intestinal obstruction
Ankylostoma duodenale (Hookworms) → intestinal blood loss →Iron deficiency anemia.
Enterobius vermicularis (Pinworms) (also known as enterobiasis or oxyuriasis)
→ Pain, itching in anal area → irritability and difficulty of sleep,
these symptoms are caused by the female pinworm during laying its eggs.
Measures should be taken during treatment of enterobiasis:
1-simultaneously treat all family from E. Vermicularis
2-Prescribe drug at least 3 times at 2 weeks interval.
3-Personal & group hygiene must improve.
4-discourage children from sucking fingers.
Ankylostoma
pinworms
Ascaris

14. 2. Trematodes (Flukes or flat worms):
Blood-dwelling flukes e.g. Schistosoma haematobium,
S.mansoni & S. japonicum
3. Cestodes (Tapeworms):
Taenia saginata (Beef tapeworms),
Taenia solium (Pork tapeworms)
Dwelling=living
Taenia saginata= 4-10 meter length and may reach 22 meter
t. Solium 2-3 m and may reach 8 meter

15. Drugs for the treatment of nematodes
1-Albendazole (Bendax®, Vermizole®, Antizole®)
Broad spectrum oral anthelmintic
Its absorption is increased with fatty meal.
Mechanism of action
It selectively binds to nematode ß-tubulin, inhibiting its polymerization→ preventing the formation of microtubules → stopping cell division.
Impaired glucose uptake by the parasite→ depletion of glycogen stores and ↓ATP stores → immobilization and death of the parasite.
It is C.I. in pregnancy (category C.), liver cirrhosis and in children under the age of 2 in some countries.
Microtubules function in many essential cellular processes, including mitosis. Tubulin-binding drugs kill cancerous cells by inhibiting microtubule dynamics, which are required for DNA segregation and therefore cell division.

16. Clinical uses:
Ascariasis, hook worm and pinworms
adult or child > 2 years: 400 mg single dose repeated after 7 days.
Child up to 20 kilos: 200 mg, (10 ml of suspension) repeated after 7 days.
Side effects:
alopecia, elevation of liver enzymes, nausea, headache, diarrhea, dizziness,
insomnia, fever, fatigue.

17. 2. Mebendazole (Antiver®, Mebamox®, Vermox®)
Mechanism of action
It Inhibits microtubule synthesis and glucose uptake leading to depletion of ATP stores →immobilization and death of the parasite.
Absorption is increased with fatty meal
Therapeutic uses:
It is effective in Ascariasis, hookworm and pinworm infections
dose: adult, children > 2 years: 100 mg single oral dose, repeated after 2 wks if necessary).
It is C.I. in pregnancy (category C, fetotoxic in animal)
neither pyrantel pamoate nor mebendazole is recommended during either pregnancy or breastfeeding.  Breastfeeding mothers can take either medication if they “pump and dump” afterwards.  The good news is that pinworms can still be eradicated during pregnancy (or breastfeeding) using the strict hygiene approach to treatment (see below).  Some people also recommend enemas for flushing the pinworm eggs out of the rectum, although I have not found any research that supports this treatment.  The lack of research doesn’t mean this approach doesn’t work– a study to show effectiveness would be very hard to do.
Prevention– how to keep the pinworms out of your home: Strict hygiene measures can clear up pinworm infection without medication, and reduce the risk of reinfection. The worm has a lifespan of about six weeks, therefore the strict hygiene needs to last that long. Everyone in the household has to adhere to strict hygiene, which can be very hard if you have a nail-biter or thumb sucker.  But do the best you can and take advantage of the opportunity to motivate your children to improve their hygiene.
3. Flubendazole (Fluvermal®)
Fluoro-analogue of mebendazole
Inhibits glucose uptake & affects microtubule formation
Contraindicated in pregnancy

18. 4. Thiabendazole ( Mintezol®)
Mechanism of action:
It may inhibit mitochondrial enzyme fumarate reductase of worms thus
decreasing the formation of ATP
Uses: for the treatment of trichinosis (due to consumption of larvae of
Trichinella spiralis in undercooked meat, especially pork).
5. Pyrantel pamoate (Combantrin®)
Mechanism of action
- it is a depolarizing neuromuscular blockers, causing persistent activation of
parasite's nicotinic receptors
-It Increases release of acetylcholine & also inhibits acetylcholinesterase →
spastic paralysis of worm
Uses: it is the drug of choice in Ascariasis also highly effective against
Ancylostoma & Enterobius infections

19. 6. Levamisole (Ketrax®) 7- Diethylcarbamazine (Hetrazan®)
Depolarizing neuromuscular blocker & also has anticholinesterase effect
Used in roundworm infections & is also immunostimulant
Used now in colon cancer
7- Diethylcarbamazine (Hetrazan®)
Used in the treatment of filariasis because of its ability to immobilize worms and render them susceptible to host defense mechanisms
Filariasis (elephantiasis):
Arms, legs or genitals are filled with fluid due to Wuchereria bancrofti (round worms) that destroy the lymph channels so disrupt the flow of the lymph causing lymphoedema. 
NB: bite of infected mosquito release microflariae into human blood that migrate and mature into
adult worm in lymphatic system leading to its blockade → varices

20. B- Drugs for the treatment of trematodes (flat worms):
1- Praziquantel ( Distocide®, Biltricide®)
Mechanism of action
Increases cell permeability to Ca++ resulting in contraction & spastic
paralysis of worm
Therapeutic uses: Drug of choice in all species of schistosoma
Adverse effects: Abdominal pain, headache, dizziness, fever & rash
Contraindicated in first trimester of pregnancy
2. Oxamniquine (Vansil®)
• The drug is activated inside the parasite and binds to DNA
and inhibit synthesis of nucleic acid
• Effective only against S. mansoni
• Not used in pregnancy & epilepsy
The tegument coats the worm and acts as a physical barrier to host antibodies and complement

21. 3- Metrifonate ( Bilarcil®)
• Acts by inhibiting cholinesterase enzyme thus paralyzing the worm
• Effective only against S. haematobium
• Contraindicated in pregnancy
C- Drugs for the treatment of Cestodes (tape worms)
Niclosamide (Yomesan®)
• Blocks glucose uptake & damages the scolex (attachment end) of
tapeworms
• Purgatives can be used to expel the dead worm segments
• Drug of choice in T saginata & T solium

22. Case study
Mona is 7 years old girl who travelled to Alex with her mother to visit her grandmother. Upon getting there, her grandmother took her out to eat at a local restaurant. Two weeks later after returning home Mona began feeling ill with stomach cramping and loose stools. Her symptoms became worse and she developed a fever, bloody stools, felt weak, and she complained of severe stomach pain and perianal itching at night. Her mother took her to get examined by the family physician who ran several tests including a complete blood count which showed she was anemic and microscopic stool studies that revealed E. Histolytica trophozoites and some eggs of Enterobius vermicularis (pinworms). The family physician prescribed metronidazole 500mg TID for amoebiasis and mebendazole for enterobiasis.

23. 1-Does the treatment(s) afforded for Mona be used simultaneously to cure her infections? If NO, Justify?
2-Describe the mechanisms by which metronidazole and mebendazole act to cure Mona’s infections?
3- What measures would you recommend the patient to prevent reinfection with enterobiasis?
4-Mention the dose regimen of mebendazole that prescribed for Mona to treat her pinworm infection?