Antiprotozoal

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Questions and Answers

What is the first stage of Plasmodium falciparum in the human body after invasion by the Anopheles mosquito?

Merozoite

Sporozoite (correct)

Trophozoite

Gametocyte

What is the consequence of red blood cell rupture in malaria?

Release of merozoites into the bloodstream. (correct)

Reduction in parasitic load.

Increased production of white blood cells.

Enhanced oxygen delivery to tissues.

What medication is indicated for the treatment of acute malaria ?

IV artesunate or IV quinidine (correct)

Azithromycin

Metronidazole

Hydrochloroquine

Which of the following statements about sickle cell trait is accurate?

Normal hemoglobin is composed of two alpha and two beta globulin chains. Signup and view all the answers

Which of the following outcomes is most likely associated with high levels of Plasmodium falciparum infection?

Severe anemia and oxygen starvation. Signup and view all the answers

What stage follows the trophozoite stage in the life cycle of Plasmodium falciparum within red blood cells?

Schizont Signup and view all the answers

What causes sickle-shaped red blood cells to be removed from circulation more quickly than normal red blood cells?

A single amino acid substitution Signup and view all the answers

What does the term 'recrudescence' refer to in the context of malaria treatment?

Residual parasites that become active again Signup and view all the answers

Which of the following describes the primary effect of quinine on the malaria parasite?

Inhibits parasite from sequestering toxic heme Signup and view all the answers

What is cinchonism, and what are its common symptoms?

Adverse effects of quinine, including tinnitus and headache Signup and view all the answers

Which compound is a stereoisomer of quinine and is used against human malarial parasites?

Quinidine Signup and view all the answers

How does malaria impact the life span of sickle cell red blood cells compared to normal red blood cells?

Normal cells have a significantly longer life span Signup and view all the answers

What potential adverse effect can quinine cause in individuals with G6PD deficiency?

Hemolytic anemia Signup and view all the answers

What is the primary reason that antimalarial drugs may eventually stop being effective?

Development of parasite resistance to the drugs Signup and view all the answers

What is the primary indication for primaquine in the treatment of malaria?

Eradication of dormant liver forms of P.vivax and P.ovale Signup and view all the answers

Which statement accurately describes the use of melarone?

It is a combination treatment used for both therapy and prophylaxis. Signup and view all the answers

Which of the following statements is true regarding folate inhibitors used in malaria treatment?

They selectively inhibit plasmodial dihydrofolate reductase. Signup and view all the answers

What are the primary side effects associated with metronidazole treatment?

Metallic tasting dry mouth and a disulfiram-like reaction with alcohol Signup and view all the answers

Which drug is a fixed combination used to treat malaria?

Lumefantrine and artemether Signup and view all the answers

What is a key mechanism of action of chloroquine in malaria treatment?

Blocking the ability of the parasite to pack toxic heme into storage cells. Signup and view all the answers

What characteristic of chloroquine enables it to remain the drug of choice when resistance is not an issue?

It has a large volume of distribution around 1000 L/Kg. Signup and view all the answers

What major side effect can chloroquine cause in patients?

Cardiac changes such as QRS widening. Signup and view all the answers

Which combination is suitable for use alongside amodiaquine to enhance its effectiveness?

Amodiaquine and artesunate Signup and view all the answers

What is the source of artemisinin?

A plant known as sweet wormwood. Signup and view all the answers

What mechanism does the malaria parasite develop to resist chloroquine?

Development of a cell wall pump preventing drug entry. Signup and view all the answers

What is the significance of Artemisinin's LD50 in mice being 4228 mg/kg?

It suggests low toxicity for humans. Signup and view all the answers

How effective has Artemisinin been in treating malaria cases as reported in 1979?

Success rate of almost 100%. Signup and view all the answers

Which of the following is TRUE about Artemisinin's effectiveness against malaria?

It destroys all stages of the parasite life-cycle. Signup and view all the answers

What accounted for the high mortality rate in malaria cases worldwide?

Resistance to all current drugs. Signup and view all the answers

What is the primary reason that ATN is considered the most effective new drug for malaria in the last century?

It is derived from a natural herbal product. Signup and view all the answers

Which of the following statements regarding ATN is true?

ATN requires higher concentrations to harm mammalian cells than to kill the malaria parasite. Signup and view all the answers

What major challenge does ATN face in treating malaria?

The plant source for ATN has become scarce. Signup and view all the answers

What is a crucial strategy used in combination therapy involving ATN?

It prevents the development of resistance to ATN. Signup and view all the answers

Which of the following is a potential concern when using mefloquine to treat malaria?

Possible neurological and psychiatric side effects. Signup and view all the answers

What mechanism of action is suggested for ATN within the parasite?

It intercalates with proteins and causes free radical damage. Signup and view all the answers

Which drug was known as the "Cardinal's Cure"?

Quinine Signup and view all the answers

What is a protozoa?

Unicellular animal-like organisms Signup and view all the answers

Which is the most lethal and important malarial parasite?

Plasmodium falciparum Signup and view all the answers

Match each antimalarial drug combination to its description

<h1>Tissue Schizonticides = kills the organism in the liver Blood Schizonticides = kills the organism in the red cells Gametocides = kills sexual stages and prevents transmission to mosquitoes</h1> Signup and view all the answers

Match each artemisinin drug to its administration

artesunate = po, iv, im rectal artemether = po, im, rectal dihydroartemisinin = po artemether-lumefantrine = Most common co-administered drug. Blood schizonticides with no effect on hepatic stage of the parasite Signup and view all the answers

What is a major adverse drug reaction (ADR) of Artemisinin?

GI upset Signup and view all the answers

Artemisinin can be used during pregnancy.

True Signup and view all the answers

Which of the following best fits this description:

-used in chloroquine resistant areas of the world

po dosing only, too irritating for parenteral use

blood schizonticidal but not against liver stages -MOA: unknown -CDC drug of choice for prophylaxis in areas where there is no resistance?

Mefloquine Signup and view all the answers

Which of the following combinations is used as a first-line therapy in a number of countries in Asia and South America?

artesunate-mefloquine Signup and view all the answers

Primaquine is blood schizonticidal.

False Signup and view all the answers

What is the mechanism of action (MOA) for Atovaquone?

Inhibit mitochondrial electron transport in parasite Signup and view all the answers

What is proguanil converted into?

Cycloguanil Signup and view all the answers

What is the first-line treatment for falciparum malaria infection in most countries today?

Artemether-lumefantrine Signup and view all the answers

What drugs are used to treat Entamoeba histolytica? (Select all that apply)

tinidazole Signup and view all the answers

What is the drug of choice for extraluminal infection?

Tinidazole Signup and view all the answers

What are three possible adverse drug reactions (ADRs) of chloroquine?

Retinopathy Signup and view all the answers

Study Notes

Antiprotozoal Drugs

PM 716 course, Chapter 52, Antiprotozoal Drugs, by Richard M. Rocco, PhD
PM 719 C12 Antimalarial course

Case Study (Patient)

9-year-old boy with intense chills, high fever (4 days), drenched in sweat, exhausted
Diarrhea, nausea, abdominal pain
Immigrated to the US from West Africa 3 weeks prior to illness

Case Study (Workup)

Workup included tests to rule out bacterial and viral infections
Thin-film blood smear for blood-born parasites confirmed malaria

Case Study (Treatment)

Treat acute malaria with IV artesunate or IV quinine or quinidine
If quinine or quinidine is used, monitor for potential cardiac toxicities

Plasmodium falciparum

One of four infectious protozoal parasites
Only P. falciparum causes life-threatening illness
Four major stages in parasite development: ring, trophozoite, schizont, gametocyte

Malaria

Anopheles mosquito inoculates sporozoites into human host
Sporozoites infect liver cells (asexual stage) and mature into merozoites
Merozoites release from liver, invade red blood cells (RBCs), feed on hemoglobin (Hb) and mature into trophozoites
Trophozoites divide in RBCs into 16-32 new parasites
RBC ruptures, releasing new parasites
Anemia results, pain from sickle cell trapping in capillaries, oxygen starvation from anemia

Malaria (Epidemiology)

300-500 million cases worldwide per year
41% of the world's population lives in areas with endemic malaria
Malaria kills 3 million humans per year
P. vivax and P. falciparum account for 95% of cases, with P. falciparum being the more severe infection

Sickle Cell Trait

Normal hemoglobin (Hb) contains two alpha and two beta globulin chains
In sickle cell Hb, a single amino acid substitution occurs in one beta chain (trait) or both beta chains (disease)
Glutamic acid is replaced with valine

Malaria (Sickle Cell)

Sickle cell red blood cells (RBCs) are infected with the parasite similar to normal RBCs
Decreased oxygen tension causes sickle shape in sickle cell RBCs
Sickled cells removed from circulation in ~4 days (compared to 40 days for normal RBCs)
Parasite dies before maturity

Malaria (Treatment: The Three "R" Problems)

(1) Recrudescence: residual parasites remain, not destroyed by the drug, lie dormant in RBCs, and reemerge
(2) Relapse: sporozoites lie dormant in the liver
(3) Resistance: antimalarial drugs no longer work

Quinine

Drug derived from the bark of the Cinchona tree
Discovered by Native South Americans in the Andes of Peru
Taken back to Europe by 16th-century Western explorers
Called the "Cardinal's Cure"
Isolated from Cinchona bark in 1820
ADRs (Adverse Drug Reactions) include tinnitus, headache, nausea, dizziness, flushing, visual disturbances
May cause hemolytic anemia in G6PD deficiency
MOA: Parasite feeds on human hemoglobin to produce toxic heme which parasite sequesters into protective "cells"
Quinine appears to block the parasite's ability to sequester toxic heme

Quinine & Quinidine

Both derived from the bark of the Cinchona tree (Andes mountains)
Quinidine is the dextrorotatory stereoisomer of quinine
Schizonticide against all four species of human malarial parasites
Exact mechanism is unknown
ADRs: cinchonism (tinnitus, headache, etc.)
Hemolysis (red cells) can occur
Reduce dosage in renal insufficiency

Quinacrine (Atabrine)

Yellow pills issued before WWII to South Pacific military personnel, not used today
Required 3x daily oral dosing
Causes major GI disturbances and turns skin yellow
Non-compliance is a major issue due to ADRs
Guadalcanal battle (1942-1943) up to 75% of hospitalizations due to malaria and not war wounds

B.B. Brodie (1909-1989)

Goldwater Memorial Hospital, Roosevelt Island, NYC
Considered one of the founders of modern pharmacology
Determined quinacrine is effective at reduced dosing
Lower doses prevent yellow skin and GI disturbances

Chloroquine

Not effective against liver stage parasites
Same MOA as quinine; blocks the parasite's ability to pack toxic heme into storage cells (hemzoins)
Parasite develops a cell wall pump to block drug entry into the cell
Drug of choice since 1940s, resistance not an issue
Synthetic drug; high volume
Drug causes heme buildup in RBCs (toxic to parasite)
Side effects vary widely; cardiac changes (QRS widening, T-wave changes)

Amodiaquine

Similar to chloroquine
Used in combination drugs (amodiaquine + artesunate, amodiaquine + sulfadoxine + pyrimethamine)

Artemisinin (ATN)

Qinghaosu (pronounced Ching-how-sue), also known as Artemisia annua plant (sweet wormwood)
Used in China for over 2000 years for fever reduction
Plant related to family that produces absinthe, tarragon, sagebrush
Zhou Hou Bei Ji Feng (Handbook of Prescriptions for Emergency Treatments) by Ge Hong (340AD) advocated the use of this herb for fevers and chills.
Li Shizen's Compendium of Materia Medica (Ben Cao Gang Mu, 1546) advocated its use to treat malaria
50% of the world's population at malaria risk
250 million have malaria
1 million die yearly (primarily children in Africa)
Mortality rate for serious infection is 20-50%
All current drugs have shown resistance
1972: Artemisinin extracted from the Qinghaosu plant
1979: X-ray crystallography determined the structure
One of the few naturally occurring endoperoxide compounds
Semisynthetics produced to improve solubility
Artemether is an example used in clinical trials.
LD₅₀ in mice 4228 mg/kg
In vitro studies show effectiveness against the malarial parasite
In 1979, treatment with ATN for Malaria in 2099 patients exhibited a 100% success rate (Chinese Med J. 92:811, 1979)
1979-Vietnam malaria epidemic saw a 97% reduction in deaths due to ATN
Very rapid symptom reversal (down to 0 within 8 hours).
Clears within 2 days
Destroys all chloroquine resistant strains and all plasmodial forms
High cure rates with 5–7 day dosage regimens

ATN (Drug details)

Drug derivatives (semisynthetics) are synthesized from ATN extracted from the plant
Total synthesis is difficult
Cultivated plants yield 2% dry weight of ATN
Wild plants yield ~ 0.3%
Plant takes 8 months to grow
Chloroquine (synthetic introduced in the 1940s), costing 20 cents/dose, and ATN, costing 90 cents/dose
WHO has ordered 100 million doses of ATN
Global Fund will spend $450 million on this drug over the next five years
Chloroquine-resistant strains of Plasmodium falciparum have developed worldwide
ATN is the only drug able to treat large numbers of the population living in parasite resistant locations
ATN has become the world's most effective new drug for malaria in the last 100 years
Herbal product since discovery of quinine in 1530.
Drug taken up into parasite-infected RBCs 100x more than non-infected cells
Kills parasite at nanomolar concentrations
Needs micromolar concentrations to harm mammalian cells
Intercalates with parasite proteins, causing free radical damage to the RBC, resulting in parasite death

Riamet

Combination of ATN derivative (artemether) and lumefantrine (secondary antimalarial)
Widely used in Europe for travelers
Required for preventing ATN resistance
It took almost 400 years to discover a new antimalarial. Every drug since quinine has become resistant .

Amebiasis Treatment

Infection with Entamoeba histolytica causes intestinal infections (colitis, dysentery), liver abscesses
Metronidazole and tinidazole are drugs of choice to treat amebiasis, giardiasis, and trichomonas infection

Metronidazole & Tinidazole

Nitro groups reduced by protozoans, forming toxic compounds for the organism
ADRs include metallic taste, dry mouth
Metronidazole has a disulfiram-like effect; avoid alcohol ingestion

Mefloquine

Often used to treat chloroquine-resistant strains of P. falciparum
Chemically related to quinine
Mechanism of action is unknown
Effective when used for prophylaxis
FDA black box warning about potential neurological and psychiatric toxicities

Primaquine

Drug of choice for eradicating dormant liver forms of P. vivax and P. ovale
Active in the hepatic stage of all parasite forms
Can be used for chemo prophylaxis
Poor activity against red blood cell stages
ADRs are common

Melarone

Combination drug for treating malaria
Atovaquone (250 mg) + proguanil (100 mg)
PO daily dosing can be used for prophylaxis

Folate Inhibitors

Mostly used in combination regimens
Pyrimethamine (related to trimethoprim)
Proguanil (biguanide derivative)
Fansidar (sulfadoxine + pyrimethamine)
Selective inhibitors of plasmodial dihydrofolate reductase (a key enzyme in folate synthesis)

Antibiotics

Lumefantrine (available only in fixed combinations with artemether in Coartem and Riamet)
See notes on artemisinin derivatives

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