Antiprotozoal drugs

Part I

Bonniface Obura, MSc.

Department of Pharmacology and Therapeutics
Lira Univ.

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Outline
 Introduction
 Drugs for
 Malaria
 Amebiasis
 Pneumocystosis
 Toxoplasmosis
 Leishmaniasis
 Trypanosomiasis

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Introduction
 Humans host a wide variety of protozoa parasites

 Transmitted by insect vectors, directly from other mammalian

reservoirs or from one person to another

 Protozoa multiply rapidly in their hosts and effective vaccines

are unavailable

 The immune system plays a crucial role in offering protection

 Opportunistic infections with protozoa are prominent

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MALARIA
 Malaria is an acute infectious disease caused by different
species of the protozoal genus Plasmodium

 P. vivax, P. malariae, P. ovale, P. falciparum and P. knowlesi

 P. falciparum and P. vivax malaria are the two most

common forms

 P. falciparum causes most of the serious complications and

deaths

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Life cycle of plasmodium

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Antimalarial drugs
 Antimalarial drugs are used for treatment and
prevention of malaria infection

 Most antimalarial drugs target the erythrocytic

stage of malaria infection

 Extent of preerythrocytic (hepatic stage) activity for

most antimalarial drugs is not well characterized

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Antimalarial drugs cont..
 Treatment of the acute blood stage infection is
necessary for malaria caused by all malaria species

 Terminal prophylaxis is required for infection due to

P. ovale or P. vivax, with a drug active against
hypnozoites

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Antimalarial drug classification
 Classified according to their selective actions on the parasite's life cycle into:

1. Tissue schizonticides:

 Eliminate tissue schizonts or hypnozoites in the liver (e.g. primaquine)

2. Blood schizonticides:

 Act on erythrocytic parasites (blood schizonts) e.g., chloroquine,

artemisinins, quinine

3. Gametocides

 Destroy gametocytes in the blood (e.g., primaquine for P falciparum and

chloroquine for P vivax, P malariae, and P ovale)

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Chloroquine
 Chloroquine is a synthetic 4-aminoquinoline

 Chloroquine has been the drug of choice for both treatment and
chemoprophylaxis of malaria since the 1940s

Mechanism of Action

❖ Accumulates in the food vacuole of plasmodia and inhibit heme

polymerase (prevents polymerization of the hemoglobin breakdown
product heme into hemozoin)

 Intracellular accumulation of heme is toxic to the parasite

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Chloroquine cont..
✓ Blood schizonticidal

• Highly effective for all except resistant falciparum species

✓ Gametocidal

− Moderately effective against gametocytes of P. vivax, P.

ovale, and P. malariae

− But not against those of P falciparum

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Chloroquine resistance
 It is common among strains of P
falciparum

 Uncommon but increasing for P vivax

 In P falciparum, mutations in a putative

transporter, PfCRT, have been
correlated with resistance

 Chlorpheniramine (CP) partially

resensitize resistant strains

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Chloroquine: clinical uses
Acute Malaria Attacks

– Chloroquine is effective for acute attacks of P vivax, P ovale, and P

malariae and of malaria due to nonresistant strains of P falciparum

– Fever (in 24–48 hours) and clears parasitemia (in 48–72 hours)
caused by sensitive parasites

Chemoprophylaxis

– Chloroquine is the preferred drug for prophylaxis against all forms

of malaria except in regions where P falciparum is resistant to it

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Chloroquine: adverse effects
 Pruritus is common, primarily in Africans

 Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision,

and urticaria are uncommon

• Severe adverse reactions are extremely rare

• Some are associated only with prolonged use, such as

• Neuromyopathy with long-term prophylaxis

• Retinopathy with high-dose administration for treatment of rheumatologic

diseases

• Rare cases of idiosyncratic reactions, such as erythema multiforme and bone

marrow toxicity

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Amodiaquine
 Is closely related to chloroquine, and it probably shares mechanisms
of action and resistance

 WHO lists amodiaquine plus artesunate as a recommended therapy

for falciparum malaria in areas with resistance to older drugs

 Chemoprophylaxis with amodiaquine is best avoided because of its

apparent increased toxicity with long-term use

 Reports of toxicities include: agranulocytosis, aplastic anemia, and

hepatotoxicity

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Quinine
 Used to treat malaria from as early as 1600

 The Spanish countess of cinchon while in peru contracted a fever that

was treated with bark of quina-quina tree

 She introduced it to Europe in 1638 and in 1742 botanist Carl linnaeus

called the tree cinchona in her honor

 In 1820 quinine was extracted from the cinchona bark

 It stayed as mainstay of treatment up to 1920 when more effective

synthetic antimalarial chloroquine become available

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Quinine: antimalarial action
 Mechanism of action—Quinine complexes with double stranded DNA to
prevent strand separation, resulting in block of DNA replication and
transcription to RNA.

 Blood schizonticide

− Rapidly acting, highly effective blood schizonticide against the four

malaria parasites

 Gametocidal

− For P vivax and P ovale but not very effective against P falciparum
gametocytes

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Quinine cont..
▪ Pharmacokinetics:

 Oral route- rapidly absorbed and is widely distributed in body tissues

 Also given IV

▪ Clinical Uses:

1. Parenteral Treatment of Severe Falciparum Malaria

2. Oral Treatment of Falciparum Malaria Resistant to Chloroquine

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Quinine cont..
▪ Adverse Effects:

 Tinnitus, headache, nausea, dizziness, flushing, and visual

disturbances, termed cinchonism

 Hypersensitivity reactions include skin rashes, urticaria, angioedema,

and bronchospasm

 Hematologic abnormalities include hemolysis (especially with G6PD

deficiency),leukopenia, agranulocytosis, and thrombocytopenia

 Hypoglycemia through stimulation of insulin release

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Quinine cont..
 Severe hypotension can follow too-rapid intravenous infusions of quinine or
quinidine
 Blackwater fever is a rare severe illness that includes marked hemolysis and
hemoglobinuria
Contraindications
 Quinine should not be given concurrently with mefloquine

 Haemoglobinuria, optic neuritis and in patients hypersensitive to quinine or

quinidine
 Should be discontinued if signs of severe cinchonism, hemolysis, or
hypersensitivity occur

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Artemisinin and its derivatives
 Artemisinin is a
sesquiterpene lactone
endoperoxide derived from
Artemisia annua

 Chinese scientists
discovered artemisinin for
malaria therapy in the
1970s

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Mechanism of action
 Interact with heme to produce carbon-centered free radicals
that alkylate protein & damage microorganelle & membranes of
parasites

 Active against blood stages, especially in patients with severe

manifestations, such as cerebral malaria and chloroquine-
resistant malarial infections

 Have no effect on exoerythrocytic stage of the parasite

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Artemisinin derivatives cont..
▪ Therapeutic use

− Are most useful in treating life-threatening cerebral edema

− For the treatment of severe, multidrug-resistant P. falciparum malaria

▪ pharmacokinetics

− Oral, rectal, and IV preparations are available

− The short half-lives preclude their use in chemoprophylaxis

− Metabolized in the liver and are excreted primarily in the bile

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Artemisinin derivatives cont..
▪ Adverse effects
 Include nausea, vomiting, abdominal pain and diarrhea, but
overall, artemisinin is remarkably safe.

 Extremely high doses may cause neurotoxicity and

prolongation of the QT interval

 Artemisinins have been embryotoxic in animal studies, but

rates of congenital abnormalities, stillbirths, and abortions
were not elevated, compared with those of controls, in
women who received artemisinins during pregnancy

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Artemisinin derivatives cont..

 WHO recommends artemisinin based combination therapies

for the treatment of uncomplicated falciparum malaria during
the second and third trimesters of pregnancy

 Intravenous artesunate or quinine for the treatment of severe

malaria during the first trimester

 Intravenous artesunate for treatment of severe malaria during

the second and third trimesters

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Lumefantrine
 Mechanism of action of is unknown

 Available in fixed dose combination with artemether as Coartem

 Coartem is very effective for Rx of uncomplicated P falciparum

 Half-life of lumefantrine, when used in combination, is approximately

4 days.

 Drug levels may be altered by interactions with other drugs, including

those that affect CYP3A4 metabolism

 Food increases absorption

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Primaquine
 Primaquine is a synthetic 8-aminoquinoline.

 Is the drug of choice for the eradication of dormant liver forms of P

vivax and P ovale

➢ Mechanism of action: forms quinoline-quinone metabolites, which are electron-

transferring redox compounds that act as cellular oxidants.

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

➢ Generally well tolerated, however, serious toxicity involves hemolysis in G6PD-

deficient patients

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Primaquine cont..
▪ Pharmacokinetics:
 Usually well absorbed after oral administration

 Half-life is short, and daily administration is usually required for radical

cure and prevention of relapses

▪ Clinical Uses:
 Terminal prophylaxis of vivax and ovale malaria

 Radical cure of acute vivax and ovale malaria

 Pneumocystis carinii pneumonia (+ clindamycin)

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Doxycycline

 Is generally effective against multidrug-resistant P

falciparum

 Is active against the blood stages of Plasmodium

species but not against the liver stages

 In the treatment of acute malaria, it is used in

conjunction with quinine

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AMEBIASIS
 Amebiasis is a protozoal infection of the intestinal tract that
occurs due to ingestion of foods or water contaminated with E.
Histolytica cysts

 This organism can cause

 Asymptomatic intestinal infection

 Mild to moderate colitis

 Severe intestinal infection (dysentery)

 Ameboma, liver abscess, and other extraintestinal infections

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Life cycle of E.histolytica
 Exists in two forms: cysts and trophozoites

Cysts
 Can survive outside the human body.

 Transform to trophozoites

Trophozoites
 Can reproduce

 They may feed on intestinal bacteria or invade and ulcerate wall

of large intestine, and may migrate to liver or other tissues
 Transform to cysts which are excreted in feces

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Amebiasis: clinical presentation
 Asymptomatic Intestinal infection (Carriers, passing
cysts)

 Mild to moderate intestinal disease (Nondysenteric

Colitis)

 Severe Intestinal infection (Dysentery)

 Hepatic abscess, ameboma and other extraintestinal

disease
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Antiamebic Drugs
I. luminal amebicides - act on the parasite in the lumen of
the bowel. e.g. paromomycin, iodoquinol, Diloxanide
furoate

II. Systemic amebicides - are effective against ameba in

the intestinal wall and liver. e.g. chloroquine, emetine,
dihydroemetine

III. Mixed amebicides - are effective against both the

luminal and systemic forms of the disease

 But luminal concentrations are too low for single-

drug treatment e.g. metronidazole and tinidazole
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Treatment of amebiasis
❖ Asymptomatic Intestinal Infection

✓ The drugs of choice, diloxanide furoate and

iodoquinol
✓ Alternatives are metronidazole plus iodoquinol or
diloxanide.
❖ Intestinal Infection

✓ The drugs of choice, metronidazole and a luminal

amebicide.
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Treatment cont..
❖ Hepatic Abscess

✓ The treatment of choice is metronidazole

− An advantage of metronidazole is its effectiveness

against anaerobic bacteria, which are a major cause of
bacterial liver abscess

 Diloxanide furoate or iodoquinol should also be given to

eradicate intestinal infection whether or not organisms
are found in the stools.
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 Treatment cont..
❖ Extraintestinal Forms of Amebiasis

 Metronidazole is the drug of choice

 Dehydroemetine is an alternative drug

 Chloroquine cannot be used because it does not reach high

enough tissue concentrations to be effective (except in the liver)

 A simultaneous course of a luminal amebicide should also be

given.

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 Metronidazole
 Is a mixed amebicide of choice

 Also extensively used in the treatment of infections caused by

Giardia lamblia, Trichomonas vaginalis, anaerobic cocci, and
anaerobic gram negative bacilli (for example, Bacteroides
species)

 Metronidazole is the drug of choice for the treatment of

pseudomembranous colitis

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Metronidazole: MOA

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Tinidazole
 Tinidazole is as effective as metronidazole, with a
shorter course of treatment

 Tinidazole has

 longer duration,

 simpler dosing regimen

 less toxicity, than metronidazole

 But is equally active.

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Diloxanide Furoate
 Is directly amebicidal, but its mechanism of action is not known

 Diloxanide furoate is the drug of choice for asymptomatic infections

 For other forms of amebiasis it is used with another drug

 Diloxanide furoate does not produce serious adverse effects

 Flatulence is common, but nausea and abdominal cramps are

infrequent and rashes are rare

 The drug is not recommended in pregnancy

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Iodoquinol
 Is a halogenated hydroxyquinoline.

 It is thought to inactivate essential parasite enzymes

 Iodoquinol is effective against organisms in the bowel lumen but not

against trophozoites in the intestinal wall or extraintestinal tissues.

▪ Adverse Effects

 Infrequent adverse effects include diarrhea—which usually stops after

several days—anorexia, nausea, vomiting, abdominal pain, headache,
rash, and pruritus

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Paromomycin sulfate
 An aminoglycoside antibiotic

 Only effective against the intestinal (luminal) forms of E.

histolytica and tapeworm (not significantly absorbed from
the gut)

 Paromomycin is an alternative drug for the treatment of

asymptomatic amebiasis

 Paromomycin is both directly and indirectly amebicidal

 Direct effect- leakage on cell membranes

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Emetine and dihydroemetine
 Emetine, an alkaloid derived from ipecac, and dehydroemetine,
a synthetic analog,

 Are effective against tissue trophozoites of E histolytica

 Dehydroemetine is preferred because of its somewhat better

toxicity profile

 Should be administered subcutaneously (preferred) or

intramuscularly in a supervised setting

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Emetine cont..
Adverse effects

 Adverse effects increase over time

 Include pain, tenderness, and sterile abscesses at the

injection site; diarrhea, nausea, and vomiting; muscle
weakness and discomfort; and minor electrocardiographic
changes

 Serious toxicities include cardiac arrhythmias, heart failure, and

hypotension

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References
 Bertram G. Katzung. Basic & Clinical Pharmacology.12th
edition, 2012

 Richard A. Harvey. Lippincott’s Illustrated Reviews

Pharmacology.2012

 Laurence L. Brunton, Goodman & Gilman, Pharmacological

basis of therapeutics , 12th edition

 WHO Guidelines for malaria. Geneva: World Health

Organization; 2021

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Thank you
Q?

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