Antiprotozoal agents

PHARMACOLOGY
Group III

Beguas, Beltran, Bejawada, Bingari,

Cabrera, Cadawas, Caliwag

S
Plasmodium species that infect humans
S Plasmodium falciparum

S Plasmodium malariae

S Plasmodium ovale

S Plasmodium vivax
 DRUGS FOR MALARIA

A. Chloroquine
a.Classification and pharmacokinetics
S 4-aminoquinoline derivative
S rapidly absorbed orally
S Antacids may decrease oral absorption of the drug
S excretion:urine
 B. Mechanism of action (Chloroquine)
S accumulates in the food vacuole of plasmodia

S prevents polymerization of the hemoglobin breakdown product heme

into hemozoin

(mechanism of resistance:Decreased intracellular accumulation via

increased activity of membrane transporters)

**pfcrt (P falciparum chloroquine-resistance transporter)

C. Clinical use (Chloroquine)
S solely a blood schizonticide

S DOC: acute attacks of non-falciparum and sensitive

falciparum malaria

S also used in : autoimmune disorders

D. Toxicity
Low doses Gastrointestinal
Skin rash
Headaches

High doses Severe skin lesions

Peripheral neuropathies
Myocardial depression
Retinal damage
Auditory impairment
Toxic psychosis

Also precipitate Porhyria attacks

Other Quinolones

S
 Artesunate, Arthemeter,
Dihydroartemisinin

S Metabolized in the food vacuole of the parasite

S Artemisinins  P falciparum

S Shorf half-lives of 1-3 hours

S First choice for Chloroquine-resistant malaria

S Artemisinins – ONLY drugs reliable for Quinine-resistant strains

S AE: Nausea, Vomiting, Diarrhea

 Quinine

S Classification
S Rapidly absorbed orally and metabolized before renal
excretion
S IV administration is intended for severe infections

S Mechanism of Action:
S Complexes with double-stranded DNA to prevent strand
separation = blocking DNA replication and RNA
transcription
S Solely a blood schizonticide
 Quinine

S Clinical use
S P falciparum infections resistant to chloroquine
S Used with doxycycline or clindamycin
S Quinidine – used intravenously for treatment of severe malaria

S Toxicity
S Causes cinchonism (GI distress, headache, vertigo, blurred vision,
tinnitus)
S Disturbed cardiac conduction
S Hemolysis in G6PD patients
S Blackwater fever
 Mefloquine

S Classification and Pharmacokinetics

S Synthetic 4-quinolone derivative
S Given orally

S Clinical use
S First-line drug given for prophylaxis in all areas with
chloroquine resistance
S Alternative drug to quinine in acute attacks resulting
from P falciparum
 Mefloquine

S Toxicity
S AE: GI distress, skin rash, headache, dizziness
S High doses: Cardiac conduction defects, psychiatric
disorders, neurologic effects (seizures)
 Primaquine

S Classification and Pharmacokinetics

S Synthetic 8-aminoquinoline
S Oral administration

S Mechanism of action
S Forms quinolone-quinone metabolites, which are electron-
transferring redox compounds that act as cellular oxidants.
S Tissue schizonticide
S Limits malaria transmission by acting as a gametocide
 Primaquine

S CLINICAL USE
S Eradicates liver stage of P vivax and P ovale
S Should be used with blood schizonticide
S 14-day course of Primaquine is standard after treatment with
Chloroquine

S TOXICITY
S Well tolerated buy mat cause GI distress, pruritus, headaches
and methemoglobinemia
S Serious toxicity = hemolysis in G6PD deficient patients
S Contraindicated in pregnancy
 Atovaquone

S Initially developed as an antimalarial

agent (component of Malarone)
S Used for mild to moderate P jiroveci
pneumonia
 Atovaquone

Pharmcokinetics:
S Oral
S Low bioavailability
S Fatty food increases absorption
S Half-life: 2 to 3 days
S Elimination: unchanged in feces
 Atovaquone

S Acts against plasmodia

S Disrupts mitochondrial electron transport

S Active against tissue and erythrocytic schizonts

S Discontinued 1 week after the end of exposure

 Atovaquone

Malarone

S Atovaquone initially: selection of resistant parasites during therapy

S A fixed combination of atovaquone (250mg) and proguanil (100mg)

S Treatment and chemoprophylaxis of falciparum malaria

S Shorter periods of treatment

S Taken with food

S Well tolerated
 Atovaquone

S Alternative therapy for P jiroveci infection

S Lower efficacy than trimethroprim-sulfamethoxazole

S 750mg with food, daily for 21 days

 Atovaquone

Adverse effects

S Fever

S Rash

S Nausea

S Vomiting

S Diarrhea

S Headache

S Insomnia
 INHIBITORS OF
FOLATE SYNTHESIS

S
 Inhibitors of Folate Synthesis

Pyrimethamine and Proguanil

S Slowly but adequately absorbed from the GIT

S Pyrimethamine: peak plasma levels after 2 to 6

hours, half-life of 3.5 days (once a week)
S Proguanil: Peak plasma levels after 5 hours, half-life
of 16 hours (daily)
 Inhibitors of Folate Synthesis

Fansidar

S Fixed combination of sulfadoxine (500mg) and pyrimethamine

(25mg)

S Well absorbed

S Peak plasma levels after 2 to 8 hours

S Renal excretion

S Half-life: 170 hours

 Antimalarial Action &
Resistance

Pyrimethamine and proguanil

S Act slowly against erythrocytic forms of susceptible strains of all

four human malaria species

S Proguanil: some activity against hepatic forms

S Neither is effective against liver stages of P vivax and P ovale

S Mechanism of action: selective inhibition of plasmodial

hydrofolate reductase
 Antimalarial Action &
Resistance

Sulfonamides and sulfones

S Active against erythrocytic schizonts but not against
liver stages or gametocytes
S Not used alone as antimalarials; used in
combination with other agents
S Mechanism of action: inhibit dihydropteroate
synthase
 Antimalarial Action &
Resistance

S Resistance is common in P falciparum and P

vivax
S Mutations in dihydrofolate reductase and
dihydropteroate synthase
S Resistance limits the efficacy of sulfadoxine-
pyrimethamine for the treatment of malaria
 Clinical Uses

1. Chemoprophylaxis

S Single folate antagonists are no longer recommended

S Combination of chloroquine (500mg weekly) and proguanil

(200mg) daily, but with increasing resistance

S Fansidar and Maloprim: both effective against sensitive

parasites; resistance and toxicity

S Trimethoprim-sulfamethoxazole: more active against bacteria

parasites; HIV-infected patients
 Clinical Uses

2. Intermittent preventive therapy

S High-risk patients receive intermittent
treatment, regardless of infection status
S Most accepted in pregnancy
 Clinical Uses

3. Treatment of chloroquine-resistant falcilparum malaria

S Fansidar should not be used in severe malaria and

vivax malaria

S Artesunate + sulfadozine-pyrimethamine: falciparum

malaria
 Clinical Uses

4. Toxoplasmosis
S Pyrimethamine + sulfadiazine: first-line
therapy in toxoplasmosis
S Including acute infection, congenital
infection, and disease in
immunocompromised patients
S Replace sulfadiazine with clindamycin if
toxicity occurs
 Clinical Uses

5. Pneumocystosis
S Trimethoprim + sulfamethoxazole: first-line
therapy
S High-dose intravenous or oral therapy for 21 days

S P jiroveci in mmunocompromised patients

S Toxicity
 Adverse Effects & Cautions

S Pyrimethamine and proguanil: well-tolerated

S GI symptoms, skin rashes, and itching (rare)
S Mouth ulcers and alopecia (proguanil)
S Proguanil: pregnancy

S Fansidar
S Severe cutaneous reactions (erythema multiforme, Stevens-Johnson syndrome, toxic
epidermal necrolysis)
S Safe in pregnancy

S Maloprim
S Agranulocytosis

S Used cautiously in renal or hepatic dysfunction

S Pregnant women receiving Fansidar preventive therapy: high-dose folate

supplementation should be replaced by standard recommended dosage to avoid potential
loss of protective efficacy
 ANTIBIOTICS

S Bacterial protein synthesis inhibitors

S Should not be used as single agents in malaria (slow action)

S Tetracycline and doxycycline: eryhthrocytic schizonts of all human

malaria parasites; not active in liver stages

S Doxycycline: falciparum malaria (with quinine)

S Complete treatment courses
S Standard chemoprophylactic drug
S AE: GI symptoms, candidal vaginitis, photosensitivity
 ANTIBIOTICS

S Clindamycin: slowly active against eryhthrocytic schizonts

S Used after treatment courses of quinine, quinidine, or
artesunate for those now allowed to use doxycycline
S (with other agents): toxoplasmosis, pneumocystosis,
babesiosis

S Tetracycline and erythromycin: intestinal amebiasis

S Spiramycin: primary toxoplasmosis acquired during pregnancy

HALOFANTRINE
AND
LUMEFANTRINE

S
 Halofantrine

S Effective against erythrocytic stages of all four

human malaria species
S Oral absorption: variable; enhanced by food

S Plasma levels peak after 16 hours

S Half-life: 4 days

S Excretion: feces
 Halofantrine

S Mechanism of action: Unknown

S Rapidly effective against P falciparum

S Limited use due to cardiac toxicity

S Should not be used for chemoprophylaxis

S Well tolerated

S Contraindicated in pregnancy
 Halofantrine

S Adverse effects
S Abdominal pain S Headache
S Diarrhea S Pruritus
S Vomiting S Elevated liver
S Cough enzymes
S Rash S Arrhythmia
S Contraindicated in
patients with
cardiac conduction
defects and in
pregnancy
 Lumefantrine

S First-line therapy for uncomplicated falciparum

malaria
S Half-life (when used in combination): 3 to 4 days
S Drug interaction
S Administered with fatty food to maximize efficacy
S Administered twice daily for 3 days
S Well tolerated
 Lumefantrine

S Adverse effects
S GI disturbances
S Headache
S Dizziness
S Rash
S Pruritus
S Toxicities
Amebiasis

S
 METRONIDAZOLE
&TINIDAZOLE
Metronidazole

S A nitroimidazole

S Is the drug of choice in the treatment of extraluminal amebiasis.

S It kills trophozoites but not cysts of E histolytica.

S Effectively eradicates intestinal and extraintestinal tissue infection.

Tinidazole

S A related nitroimidazole

S Appears to have similar activity and a better toxicity profile

 Pharmacokinetics

S Oral imidazole and tinidazole are readily absorbed and permeate all
tissues by simple diffusion.

S Peak plasma conc. Are reached in 1-3 hours.

S Protein binding of both drugs is low (10-20%)

S Half life of unchanged drug is 7.5 hours (metronidazole) and 12-14

hours (tinidazole).

S Metronidazole and its metabolite are excreted mainly in the urine.

S Plasma clearance of metronidazole is decreased in patients with

impaired liver function.
 Mechanism of Action

S The nitro group of metronidazole is chemically

reduced in anaerobic bacteria and sensitive
protozoans.
S Reactive reduction products appear to be responsible
for antimicrobial activity.
S The mechanism of tinidazole is assumed to be the
same.
 Clinical uses

A. Amebiasis
B. Giardiasis
C. Trichomoniasis
A. Amebiasis
S Metronidazole or tinidazole is the drug
of choice in the treatment of all tissue
infections with E histolytica.
B. Giardiasis

S Metronidazole is the treatment of choice for giardiasis.

S Dosage for giardiasis is much lower

S Drug thus better tolerated than that for amebiasis.

C. Trichomoniasis
S Metronidazole is the treatment of choice.

S A single dose of 2 g is effective.

S Metronidazole-resistant organisms can lead to treatment

failures.
S Tinidazole may be effective against some of these resistant
organisms.
 Adverse effect

S Nausea, headache, dry mouth, or a metallic taste in the

mouth occurs commonly.

S Metronidazole has a disulfiram-like effect.

S The drug should be used with caution in patients with

central nervous system disease.

S The dosade should be adjusted for patients with severe liver

or renal disease.
 Adverse effect

S Metronidazole has been reported to potentiate the

anticoagulant effect of coumarin-type clearance.

S Phenytoin and phenobarbital may accelerate elimination of

the drug.

S Cimetidine may decrease plasma clearance

S Lithium toxicity may occur when the drug is used with

metronidazole.
 IODOQUINOL
(diiodohydroxyquin)

S Is a halogenated hydroxyquinoline

S It is an effective luminal amebicide.

S 90% of the drug retained in the intestine and excreted in the
feces.

S The remainder enters the circulation

S Half life: 11-14 hours

S Excreted in the urine as glucoronides.

S Mechanism of action is unknown.

S Effective against organism in the bowel lumen but not against

trophozoites in the intestinal wall and extraintestinal tissues.
 Adverse effect

S Diarrhea ( infrequent AE which usually stops after several days)

S Anorexia, nausea, vomiting, abdominal pain, headache, rash and

pruritus.

S Increase protein bound serum iodine.

S Iodoquinol should be taken with meals to limit GI toxicity.

S Used with caution in patients w/ optic neuropathy, renal or thyroid

dse. Or nonamebic hepatic disease.

S Contraindicated in patients with intolerance to iodine.

 DILOXANIDE FUROATE

S Is a dichloroacetamide derivative.

S It is an effective luminal amebicide

S In the gut (diloxanide furoate is split into diloxanide and furoic acid)

S 90% is rapidly absorbed and conjugated to form the glucoronide.

S Unabsorbed diloxanide is the active antiamebic substance.

S Does not produce serious adverse effect.

S Flatulence is common, nausea and abdominal cramps are infrequent and

rashes are rare.
 PAROMOMYCIN SULFATE

S An aminoglycoside antibiotic that is not significantly absorbed

from the GIT.
S Used as luminal amebicide and has no effect against
extraintestinal organisms.
S The small amount absorbed is slowly excreted unchanged, mainly
by GFR.
S Antiamebic luminal agent of choice in the USA.

S AE: distress and diarrhea

S Parenteral Paromomycin is used to treat leishmaniasis.

 EMETINE AND
DEHYDROEMETINE

EMETINE - An alkaloid derivative from ipecac

Dehydroemetine – synthetic analog

S Effective against tissue trophozoites of E. histolytica,

S Dehydroemetine is preferred because of its somewhat better

toxicity profile.

S The drug should be used for the the minimum period needed to
relieve severe symptoms (usually 3-5 days)

S Should administered subq (preferred) or IM.

 Adverse effect

S Generally mild with the use for 3-5days

S Increase over time and include pain , tenderness, and sterile

abscesses at the injection site.

S Diarrhea, nausea , and vomiting; muscle weakness and

discomfort; and minor electrocardiographic changes.

S Serious toxicities include cardiac arrhythmias, heart failure,

and hypotension.
 OTHER
ANTIPROTOZOAL
DRUGS

S
S Pentamidine

S Sodium Stibogluconate

S Nitazoxanide
 PENTAMIDINE

S Aromatic diamidine which is administered parenterally. Also

used as nebulized powder to prevent pneumocystosis.

S Leaves the circulation rapidly with an initial half life of about

6 hours, thus accumulates and is eliminated very slowly with a
terminal elimination half life of about 12 days.

S Not effective in CNS African trypanosomiasis as only trace

amounts can appear in the CNS.
 Clinical Uses

A). Pneumocystosis :

S Used as the alternative therapy for pulmonary and

extrapulmonary disease caused by P.jiroveci.

Alternative agent for primary or secondary prophylaxis against

pneumocystosis in immunocomprised individuals, including
patients with advanced AIDS.
S Because of its cost and its ineffectiveness
against non pulmonary disease it is best
reserved for patients who cannot tolerate
oral chemoprophylaxis.
b). African trypanosomiasis (sleeping sickness)

S Drug of choice to treat early hemolytic stage of disease

caused by T.brucei gambiense.

Not used in the treatment of late trypanosomiasis , with

CNS involvement.
C). Leishmaniasis:

S Treatment of visceral leishmaniasis and also used as an

alternative to sodium stibogluconate.

S Given intramuscularly. Not routinely effective in treatment

of cutaneous leishmaniasis.
 ADVERSE EFFECTS:

S IV administration can lead to hypotension, tachycardia, dyspnea ,

so it is administered slowly and the patient is monitored slowly
during treatment.
S Pancreatic toxicity is common
S Reversible renal insufficiency
S Acute pancreatitis
S Abnormal liver function tests
S Hallucinations
S Hypocalcemia
S Thrombocytopenia

S Cardiac arrythmias.

S Inhaled pentamidine is generally well tolerated but causes

cough, dyspnea and bronchospasm.
 Sodium Stibogluconate

S First line agents for cutaneous and visceral

leishmaniasis.
S Given intramuscular and intravenous following
2 phases of elimination , with a short initial
half life(2hour) , much longer half life
(>24hour).
S Adverse effects:

S Fever, headache, arthralgia, myalgia.

S IM administration can be painful and lead to sterile

abscesses.
S Electrocardiograph changes such as T wave changes and
QT prolongation
S Hemolytic anemia is rare.
 NITAZOXANIDE

S Nitrothiazolyl salicylamide prodrug

S Used against G.lamblia and Cryptosporidium parvum.

S Active metabolite tizoxanide, inhibits the pyruvate

ferredoxin oxidoreductase pathway.
S It is active against metronidazole resistant protozoal strains.

S Organism susceptible includes A.lumbricoides, H.pylori,

F.hepatica, E.histolytica.
OTHER DRUGS FOR
TRYPANOSOMIASIS
& LEISHMANIASIS

S
 SURAMIN

S sulfated

S First line therapy: early hemolymphatic East African trypanosomiasis

S MOA is unknown

S Route: IV

S Half-life: 50 days

S Renal excretion

S Combination with Pentamidine may imporve efficacy

S a/e: fatigue, nausea, vomiting, and, more rarely, seizures, shock, and
death
 MELARSOPROL

S first-line therapy: advanced central nervous system East

African trypanosomiasis

S second-line therapy (after eflornithine): advanced West

African trypanosomiasis

S Slow IV infusion

S Extremely toxic--- Reactive encephalopathy

S a/e: fever, vomiting, abdominal pain and arthralgias

 EFLORNITHINE
(DIFLUOROMETHYLORNITHINE)

S only new drug registered to treat African trypanosomiasis

S first line drug: advanced West African trypanosomiasis

S use as a topical depilatory cream

S Administered Intravenously

S Half life: 3hrs

S a/e: diarrhea, vomiting, anemia, thrombocytopenia, leukopenia,

seizure
 BENZNIDAZOLE

S Orally administered

S Treatment for Chagas disease

S eliminate parasites and prevent progression to or treat the

serious syndromes associated with chronic Chagas disease

S a/e: rash, peripheral neuropathy, GI symptoms and

myelosuppression
 NIFURTIMOX
(A NITROFURAN)

S MECHANISM OF ACTION
S Inhibit the trypanothione reductase and peroxidase

S INDICATION
S DRUG OF CHOICE:
S American trypanosomiasis(Chaga’s Disease)
 NIFURTIMOX

S It is well absorbed after oral S ADVERSE DRUG EFFECTS

administration and eliminated S Nausea
with a plasma half-life of about 3
hours. S Vomiting
S Abdominal pain
S It is administered at a dose of 8- S Fever
10 mg/kg/d (divided into 3-4
S Rash
doses) orally for 3-4
months(Chaga’s Disease) S Restlessness
S Insomia
S Neuropathies
S Seizures.
 AMPHOTERICIN B
AMPHOTERIC POLYENE MACROLIDE
(polyene =containing many double bonds;
macrolide= containing a large lactone ring of 12 or more atoms)

S CHEMISTRY
S Amphotericin A and B ARE ANTIFUNGAL antibiotics
produced by Streptomyces nodosus.
S Amphotericin A is not in clinical use.
S It is nearly insoluble in water and is therefore prepared as a
colloidal suspension of amphotericin B and sodium
desoxycholate for intravenous injection.
 AMPHOTERICIN B
S PHARMACOKINETICS

S Amphotericin B is poorly absorbed from the gastrointestinal tract

.

S Oral amphotericin B is thus effective only in fungi within the

lumen of the tract and cannot be used for treatment of systemic
disease.

S The intravenous injection of 0.6mg/kg/d of amphotericin B

Results in average blood level of 0.3-1 mcg/ml the drug more than
90% bound by serum protiens.

S The serum t ½ is approximately 15 days.

 AMPHOTERICIN B

S MECHANISM OF ACTION
S Amphotericin B BINDS TO ERGOSTEROL and alters the
permeability of the cell by forming amphotericin b associated
pores in the cell membrane.
S The pore allows the leakage of intracellular ions and
macromolecules eventually leading to cell death.

S INDICATION
S Cryptococcus neoformans
S Candida albicans
S Histoplasma capsulatum
S Blastomyces dermatitidis
S Cocciodiodies immitis
S Aspergillus fumigatus.
 AMPHOTERICIN B

S ADVERSE DRUG EFFECTS S B. CUMULATIVE

S A. INFUSION-RELATED TOXICITY
TOXICITY S Nephrotoxic
S Fever S Hepatotoxic
S Chills S Neurotoxic
S Muscle spams
S Vomiting
S Headache
S Hypotension
 MILTEFOSINE
(AN ALKYLPHOSPHOCHOLINE ANALOG)

S MECHANISM OF ACTION
S Inhibits the synthesis of phosphatidylcholine
S Inhibits Cytochrome C oxidase

S INDICATION
S VISCERAL LEISHMANIASIS
 MILTEFOSINE

S Administered orally with daily S ADVERSE DRUG EFFECTS

doses of 2.5 mg/kg for 28 days. S Vomiting

S Recommended daily dose for S Diarrhea

adult is 100 mg. S Transient elevations in liver
enzymes
S Contraindicated S Nephrotoxicity
S Pregnant S Teratogenic
 PAROMOMYCIN
(AMINOGLYCOSIDE ANTIBIOTIC)

S It is used only as a luminal amebicide and has no effect

against extraintestinal amebic infections.

S The small amount absorbed slowly excreted unchanged

mainly by glomerular filtration

S The drug may accumulate with renal insufficiency and

contribute to renal toxicity.
 PAROMOMYCIN

S ADVERSE EFFECTS:
S Abdominal distress
S Diarrhea

S Parenteral Paromomycin is under investigation in the

treatment of visceral leishmaniastis..
Thank you! 