Pharmacology of antiprotozoal drugs

Presented by:
Rozaimah Zain-Hamid

Department of Pharmacology & Therapeutics

Faculty of Medicine
Universitas Sumatera Utara
 Antiprotozoal drugs
Amoebiasis Malaria Trypanosomiasis Toxoplasmosis

Chloroquine, Chloroquine, Melarsoprol, Pyrimethamine +

Dehydroemetine, Mefloquine, Nifurtimox, trisulfapyrimidines
Diloxanide furoate, Primaquine, Pentamidine,
Emetine, Pyrimethamine, Suramin.
Metronidazole, Quinine/
Paramomycin. Quinidine.
Giardiasis
Leishmaniasis

Quinacrine
Sodium stibogluconate
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 Anti-amoebiasis drugs

Department of Pharmacology & Therapeutics Faculty of Medicine, USU.

 Classification based on
localization of action of anti-amoebiasis drugs
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)

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 Amibicides : Location of action

Pharmacology, 4th ed.Lippincot’s illustrated review

Department of Pharmacology & Therapeutics Faculty of Medicine, USU.
 Notice ! ! !

Treatment with tissue amoebicide

SHOULD always be followed
by luminal amoebicide
to eradicate source of
infection

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 Drugs used in amoebiasis
► Amoebiasis:
is due to infection with Entamoeba histolytica,
→ causes dysentery associated
→ invasion of the
intestinal wall &, rarely, of the liver. The organism
may be present in motile, invasive
form, or as a cyst

► Metronidazole: given orally → active against

the invasive form in gut & liver but not the cyst.
Unwanted effects → are rare → GI upsets & CNS
symptoms
► Diloxanide: given orally → no serious unwanted effects,
active while unabsorbed against the non invasive
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Department of Pharmacology
 Anti-Amoeba
Anti-amoeba Indication MoA ADR
Chloroquine Amebic liver
abscess
Metronidazole Intestinal & Disruption of DNA Metallic taste,
extra-intestnal synthesis & nausea, vomiting,
nucleic acid diarrhea,
synthesis abdominal cramps

Iodoquinol Intestinal Directly kills the N/V, diarrhea,

protozoa anorexia,
agranulocytosis

Paramomycin Intestinal Inhibiting protein N/V, diarrhea,

synthesis stomach cramps,
ototoxic, tinnitus

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 Anti-Amoeba

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 Metronidazole

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 Metronidazole
• Prototype drug introduced in 1959
• Bactericidal against :
Giardia lamblia, anaerobic bacteria,
Bacteroides fragilis, Fusobacterium,
Clostridium perfringens, Helicobacter
pylori,
Anaerobic Streptococci

5-nitroimidazoles
♦ Metronidazole, tinidazole, ornidazole, nimorazole.
♦ Active on anaerobic bacteria & protozoa.
♦ Entamoeba (not invariably the cysts) , Trichomonas,
Giardia, Blastocystis, ...
♦ Disulfiram-like effects, mutagenic in bacteria.
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 Nitroimidazoles

The nitro group of metronidazole

is chemically reduced in anaerobic bacteria
& sensitive protozoans.
Reactive reduction products
appear to be responsible for antimicrobial
activity.

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 Metronidazole
Mechanism of action of metronidazole
✦Not clearly understood

✦ Enters micro-organism by diffusion

► Nitro group reduced  DNA damaged  cytotoxicity
► High selective anaerobic action
► Interference with electron transportation from NADPH
or other reduced substrates

✦ Also inhibits cell mediated immunity

✦ Induce mutagenesis

✦ Cause radio-sensitization
Department of Pharmacology & Therapeutics Faculty of Medicine, USU.
 Metronidazole
Pharmacokinetics
 Oral metronidazole is readily absorbed
& permeates all tissues by
simple diffusion
 Protein binding is low (<20%)
 Through blood brain barrier
 Metabolizing in liver
 Excreted
Contramainly in the urine.
indication
• Neurological diseases, blood dyscrasias,
• First trimester of pregnancy,
• Chronic alcoholism

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 Metronidazole

Drug interaction

 Disulfiram reaction: unpleasant condition with alcohol

 Enzyme inducers - Rifampicin -↓ therapeutic effect

 Cimetidine  ↓metronidazole metabolism  ↓ dose

 Metronidazole ↓renal elimination of lithium

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 Emetine

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 Emetine
• Alkaloid from Cephaelis ipecacuanha

• Potent directly acting amoebicide (trophozoites)

• Does not kill cysts

• Cumulative toxicity high – seldom used

- Because of major toxicity concerns → almost
completely replaced by metronidazole

Reserve drug – not responding / intolerant to metronidazole

• Luminal amoebicide follows emetine to eradicate cysts

Administered subcutaneously (preferred) or i.m. (but never i.v.) because oral

preparations → absorbed erratically & induce emesis
Dihydroemetine = effective but less toxic

• Preferred over emetine

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 Diloxanide

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 Diloxanide
✦ Diloxanide furoate is a dichoroacetamide derivative

✦ Effective luminal amebicide

but is not active against tissue trophozoites

✦ The unabsorbed diloxanide in the gut

is the active antiamebic substance

✦ Effective for asymptomatic luminal infections

✦ It is used with a tissue amebicide, usually metronidazole

✦ Adverse Effects:
flatulence, nausea, abdominal cramps, rashes, abortion.
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Anti-trypanosomiasis
drugs

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 Antitrypanosomiasis drugs

 The drug of choice for American trypanosomiasis:

nifurtimox

 The drug of choice for African trypanosomiasis:

suramin, pentamidine & melarsoprol

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 Pentamidine

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 Pentamidine
Pharmacokinetics
 Administered parenterally → not well absorbed from g.i.t
 Leaves the circulation rapidly & is bound avidly
by the tissues, especially the liver, spleen, &
kidney
 Excreted unchanged, mostly in the urine

 Does not cross blood-brain-barrier, but can cross placenta

 Appear in the CNS <<< → other trypanosomiacides
must be used to treat the CNS involvement
in late-stage of African trypanosomiasis

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 Pentamidine

Pharmacodynamics
 Cause mast cells to release histamine
→ peripheral sympathoplegia
is the probable cause of the marked
hypotensive reaction that follows i.v administration
 May cause severe hypotension (i.v route)

 Selectively toxic to ᵝ cells of pancreatic islets.

This initially produces an appropriate,
nonsuppressible insulin release → hypoglycemia,
up to several month later,
may be replaced by hyperglycemia & DM
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 Pentamidine

Clinical uses
 Provides an alternative to suramin treatment for the early
stages of Trypanosoma brucei gambiense
or Trypanosoma brucei rhodesiense infection
 Can not pass BBB → can not use in advanced disease
when CNS involved

Department of Pharmacology & Therapeutics Faculty of Medicine, USU.

 Pentamidine

Adverse drug reaction

 Pain at the injection site is common,
infrequently a sterile abcess develops & ulcerates
 Occasionally reactions include rash, neutropenia,
abnormal LFT, serum folate depression, hyperkalemia,
hypocalcemia & delayed nephrotoxicity with azotemia

 Because severe hypotension may develop

even after single dose of pentamidine,
the patients should be recumbent when the drug
is given. Blood
pressure should be followed closely
during administration & thereafter until stable
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 Pentamidine

Adverse drug reaction

 Emergency resuscitation equipment
should be immediately available

 Rare adverse reactions include: megaloblastic anemia,

acute pancreatitis, thrombocytopenia,
thrombocytopenic purpura, toxic epidermal necrolysis,
hyperkalemia, & renal toxicity

 Fatalities have occurred from hypotension,

hypoglycemia, or arrhytmias

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 Pentamidine

Contra indication & cautions

 Cautiously in the presence of hypotension, hypertension,
latent or clinical diabetes, malnutrition, thrombocytopenia,
or renal or hepatic dysfunction

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 Drugs for toxoplasmosis

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 Anti-toxoplasmosis drugs
Pyrimethamine + sulfonamides
is the treatment of choice in
toxoplasmosis & some
other protozoal infections
 Pyrimethamine: 2,4 diaminopyrimidine,
the
dihydrofolic acid reductase inhibitor
(folic acid antagonist / antifols)
of protozoa, which the enzymes
that convent dihydrofolic acid
to tetrahydrofolic acid,
a stage
leading toDepartment
synthesis of purines
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 Pyrimethamine

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 Pyrimethamine
Pharmacokinetics
 Slowly but adequately absorbed from g.i.t
& reaches peak plasma levels 4-6 hours after an oral
dose
 Bound to plasma proteins,
& has an elimination half-life about 3.5 days

Pharmacologic effects
 Higher doses used for toxoplasmosis, macrocytic anemia,
& other adverse effects may occur

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 Pyrimethamine
Toxoplasmosis treatment
 Drug of choice for toxoplasmosis treatment:
75 mg/day for 3 days, then 25 mg daily
plus trisulfapyrimidine (2-6g/day in four divided
dosis); continue with this treatment for 3 - 4 weeks

 Leucovorin calcium (folinic acid), 10 mg/day

in two or four divided dose, → avoid the hematologic
effects of pyrimethamine-induce folate deficiency

 Platelet & leucocytes counts

should be performed at least twice weekly
 Patients should be screened
for history of sulfonamide sensitivity

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 Pyrimethamine
Toxoplasma encephalitis in AIDS
 Primary therapy for 6 weeks or longer
if necessary is as follows:
pyrimethamine 200 mg as loading dose → two divided
dose, then 1- 1.5 mg/kg/day; & sulfadiazine or
trisulfapyrimidines, 4-6 g/day → four divided doses
 Maintenance therapy is as follows:
pyrimethamine 25-50 mg/day ; sulfadiazine
or trisulfapyrimidine, 2 g/day → two divided doses

 Leucovorin calcium (folinic acid), 5-20 g/day

→ two divided dose
 Corticosteroids, often added → ↓ intracranial pressure↑
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 Pyrimethamine

Adverse effects & cautions

• Gastrointestinal symptoms, skin rashes

• Interfering folic acid metabolism in human

→ megalocyte anemia, granulocytopenia
• Acute intoxication

• Teratogenesis
(not recommended in pregnancy)

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 Drugs for leishmaniasis

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 Drugs for leishmaniasis
Leishmaniasis treatment
 Treatment of leishmaniasis is not satisfactory,
because of drug toxicity, required long course,
treatment failure & frequent need hospitalization
 Drug of choice: sodium stibogluconate / Sb5
( sodium antimony gluconate), started
with 200 mg test dose, followed by 20 mg Sb5 /kg/day.
Route of administration i.m: locally
painful. i.v route is preferred
 The drug is given on consecutive days:
20 days for cutaneous form
& 30 days for visceral & mucocutaneous
leishmaniasis
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 Sodium stibogluconate

Adverse effects
 G.i.t symptom most common, fever & rash.
 Hemolytic anemia, liver, renal & heart damage are rare

 Drug of choice: sodium stibogluconate / Sb5

( sodium antimony gluconate), started
with 200 mg test dose, followed by 20 mg Sb5 /kg/day.
Route of administration i.m: locally
painful. i.v route is preferred
 The drug is given on consecutive days:
20 days for cutaneous form
& 30 days for visceral & mucocutaneous
leishmaniasis
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 Drugs for giardiasis

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 Drugs for giardiasis

Giardiasis treatment

 Drug of choice:
metronidazole, adult dose:
250 mg orally three times /day for 5 days,
children: 5 mg/kg bw 3 times/ day for 5 days

 Quinacrine is the alternative drug

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Thank You

Department of Pharmacology & Therapeutics Faculty of Medicine, USU.