Antiprotozoal Drugs

Dr. Kaukab Azim

Israa Omer

Be able to recognize the main therapeutic uses of the drugs of each class

Be able to indicate the main contraindications of the drugs of each class if any

Be able to describe the adverse effects of the drugs of each class

Be able to describe the mechanism of action of each drug in each drug group if known

Be able to relate the action of drugs with the life cycle of the organism

Learning Objectives

Tissue

Schizonticides

Blood

Schizonticides

Gametocides

insect repellentsInsecticidesbed nets

Therapeutic options

Drugs used for treatment of Malaria

1. Chloroquine Phosphate

• Safe and low-cost • Rapidly absorbed through oral route• Very well tolerated even with prolonged use. • Highly effective blood schizonticide• Not effective liver stage parasites• Moderately gameticidal• Does not eliminate hypnozoites of P. vivax and

P. ovale

Chloroquine is the drug of choice in the treatment of nonfalciparum and sensitive falciparum malaria

Mechanism of action

• It accumulates in the food vacuole of plasmodia and prevents polymerization of Hb

breakdown products heme into hemozoin.

• Intracellular accumulation of heme is toxic to parasite

Adverse effects

• Pruritus is common, primarily in Africans.

• Uncommon side effects:

- Peripheral neuropathy,

- Retinal damage,

- Auditory impairment,

- Myocardial depression

- Toxic psychosis

• It can also precipitates porphyria attack

• Dosing after meals reduces some adverse effects.

2. Quinine and quinidine

• First line drugs for severe form of P. falciparum malaria

• Highly effective blood schizonticide against all four types of plasmodia

• Gameticidal against P. vivax and P. ovale

• Not active against liver stage parasites

• Resistance uncommon

Mechanism of action

• It complexes with double stranded DNA to prevent strand separation, resulting in block of DNA replication and transcription to RNA.

• Quinine is solely a blood schizonticide .

Clinical uses

• IV quinidine standard therapy for severe P. falciparum malaria e.g. cerebral malaria

• Administered with cardiac monitoring

• Oral quinine sulphate + doxycycline (clindamycin in children) first line therapy for chloroquine-resistant uncomplicated falciparum malaria

Clinical uses

BABESIOSIS

Quinine is first-line therapy, in combination with clindamycin, in the treatment of infection with Babesia microti or other human babesial infections

Adverse effects

• Cinchonism; Tinnitus, visual disturbances, dizziness, nausea, flushing, headache

• Rapid IV infusion leads to hypotension

• RBCs hemolysis in G6PD deficient patient, blackwater fever, is a rare fatal complication in quinine-sensitized person.

• Cardiotoxicity: ECG abnormalities with IV quinidine, hence cardiac monitoring

• Recommended chemoprophylactic drug for use in most malaria-endemic regions with chloroquine-resistant strains of P. falciparum.

• Strong blood schizonticide against P falciparum and P vivax

• but it is not active against hepatic stages or gametocytes.

• The mechanism of action of mefloquine is unknown.

• Resistance is uncommon (except Thailand)

3. Mefloquin

Adverse effects (More common with high doses)

• It can only be given orally because severe local irritation occurs with parenteral use

• Neuropsychiatric toxicities (depression, psychosis, confusion, or seizures – contraindicated if these are already present)

• nausea, vomiting, diarrhea, abdominal pain, dizziness, headache.

• altered cardiac conduction, arrhythmias and bradycardia

4. Primaquine

• Effective against liver stage of all four species of plasmodia

• Drug of choice for the eradication of hypnozoites of P vivax and P ovale

• Gametocidal against all four species of plasmodia

• Weak blood schizonticidal activity

Mechanism of action

• It forms quinoline-quinone metabolites, which are electron-transferring redox compounds that act as cellular oxidants.

• The drug is tissue schizonticide and also limits malaria transmission by acting as gametocide.

Clinical uses

• For malaria – in combination with a blood schizonticide, usually chloroquine

• The combination of clindamycin and primaquine is an alternative regimen in the treatment of pneumocystosis (Pneumocystis jiroveci )

Adverse effects

• Generally well tolerated

• More common with higher dosages and when the drug is taken on an empty stomach

• Primaquine may cause hemolysis in persons with G6PD deficiency

• Infrequently causes nausea, abdominal cramps, and headache

• CI in pregnancy.

5. Atovaquone

• MAO? In plasmodia it appears to disrupt mitochondrial electron transport.

• It is a quinine derivative• Malarone, a combination of atovaquone and

proguanil, is highly effective for both the treatment and chemoprophylaxis of falciparum malaria, and it is now approved for both indications in the USA

Clinical uses

• Malaria – treatment and prophylaxis

• P jiroveci pneumonia. Mild to moderate cases.

Adverse effects

• Generally well tolerated.

• Abdominal pain, nausea, vomiting, diarrhea, headache

6. Inhibitors of Folate synthesis

• Pyrimethamine

• Proguanil

• Both drugs act against erythrocytic forms of all four human malaria species.

• Both drugs also have some activity against hepatic forms of P. falciparum.

• Neither drug is effective against the persistent liver stages of P vivax or P ovale.

• Neither drug is adequately gametocidal

Clinical Uses

• MALARIA (uncomplicated cases only)

– Fansidar, a combination of sulfadoxine and pyrimethamine

• TOXOPLASMOSIS

• PNEUMOCYSTOSIS

7. Amodiaquine

• Closely related to chloroquine

• Probably shares mechanisms of action and resistance

• It is low cost

• Important toxicities

– agranulocytosis

– aplastic anemia

– hepatotoxicity

• World Health Organization lists amodiaquine plus artesunate as a recommended therapy for chloroquine resistant falciparum malaria in poor countries

8. Artemisinin, artemether, dihydroartemisinin

• Artemisinin and its derivatives are endoperoxide-containing compounds which represent a promising new class of antimalarial drugs

• In the presence of intra-parasitic iron, these drugs are converted into free radicals and other electrophilic intermediates which then alkylate specific malaria target proteins.

• Combinations of available derivatives and other antimalarial agents show promise both as first-line agents and in the treatment of severe disease

• It is not used as chemoprophylaxis because of the short half-life.

Drugs for amebiasis

• Tissue amebicide (chloroquine, emetine, metronidazole) act on organism in the bowel wall and the liver.

• Luminal amebicides (diloxinde furoate, idioquinol, paromomycin).

• For asymptomatic disease, diloxinde is the first choice.

• For mild to severe intestinal infection and amebic liver abscess metronidazole and tinidazole is used with luminal agent.

Metronidazole

• or tinidazole (better toxicity profile)• drug of choice in the treatment of extra-luminal

amebiasis • treatment of choice for giardiasis • treatment of choice for trichomoniasis• Oral metronidazole readily absorbed and permeates

all tissues by simple diffusion• It undergoes reductive bio-activation of its nitro

group by ferrodoxin to form reactive oxygen radical

Adverse effects• Nausea, headache, dry mouth, or a metallic taste in the

mouth occurs commonly • Nausea and vomiting can occur if alcohol is ingested

during therapy • Taking the drug with meals lessens gastrointestinal

irritation• Most serious adverse effect includes neutropenia,

dizziness and ataxia.

• Drug interaction includes disulfiram like reaction and potentiation of comarin anticoagulant effect.

Emetine

• Inhibit protein synthesis by blocking ribosomal movement along messenger RNA.

• Used as backup drugs for treatment of severe intestinal and liver amebiasis together with luminal agent in hospitalized patients.

• The drug can cause severe toxicity, including GI upset, muscle weakness, and cardiovascular dysfunction.

Diloxinde furoate

• Luminal Amebicides• Commonly used as the sole agent for the treatment of

asymptomatic amebiasis and is also useful in mild intestinal disease when used with other drug

• It is converted in the gut to diloxinde free base, which is active amebicide

• Toxic effect are mild restricted to GI symptoms and generally well tolerated

• Luminal Amebicides• Ninety percent of the drug is retained in the intestine and

excreted in the feces. • Active against trophozoites. • MOA - unknown• Active only in large bowel• Should be taken with meals to limit GIT toxicity • Adverse effects:

diarrhea, nausea, vomiting, abdominal pain, headache and thyroid enlargment.

Iodoquinol

Paromomycin

• It is an aminoglycoside antibiotic used as a luminal agent and may be superior to diloxinde in asymptomatic infection.

• Not significantly absorbed from the GIT• MOA: inhibition of protein synthesis

• Adverse effects: abdominal pain and diarrhea.

Treatment of leishmaniasis• Sodium stibogluconate (only injection)• For all forms of the disease; cutaneous, mucocutanous

and visceral leishmaniasis• MAO – inhibition of glycolsis or effects on nucleic acid

metabolism• Adverse effects : it is potentially cardiotoxic (QT

prolongation).• IM injections very painful – lead to sterile abscesses• Alternative agents include pentamidine or miltofosine

for visceral disease, fluconazole or metronidazole for cutaneous lesions and amphotericin B for mucocutanous disease

Trypanosomiasis

1. African trypanosomiasis occur in two stages: – The first stage, known as the haemolymphatic

phase– The second, neurological phase

2. American trypanosomiasis occur in two stages; – Acute stage, – Chronic stage

Treatment of trypanosomiasis• Pentamidine:used to treat the hemolymphatic stage of

T.gambiense and T.rhodesiense . The drug can not cross the BBB; so it is not used in the later stage of the disease

• Melarsoprol: inhibit enzyme sulfhydryl groups, these groups form the active sites of many enzymes (especially the kinases), and are involved in the maintenance of the secondary and tertiary structures of proteins.

• it enter the CNS so it is the treatment of choice for African sleeping sickness .

The drug can cause reactive encephalopathy• Nifurtimox: drug of choice for American trypanosomiasis

• Sumarin : used for early stage of African trypanosomiasis

• Eflornithine: suicide substrate for ornithine decarboxylase, This enzyme regulates cell division

• it is effective in some forms of African tryposomiasis, the drug can penetrate the BBB.

Good luck