CS1 - NTD 1b Malaria Flashcards
What are the common symptoms of malaria?
Common symptoms of malaria include:
Fever (often cyclical)
Chills
Sweating
Headache
Fatigue
Muscle aches
Nausea and vomiting
General malaise
How does P. falciparum affect red blood cells (RBCs)?
P. falciparum infects all stages of RBCs, leading to:
Increased severity of the infection as parasites grow in all RBC stages
RBC rupture causing release of merozoites, which can reinfect new RBCs
Intravascular hemolysis and worsening anemia
How does P. falciparum impact metabolism and what are the resulting complications?
P. falciparum metabolism is about 70 times faster than that of RBCs, resulting in:
Hypoglycemia due to rapid parasite consumption of glucose
Lactic acidosis as a result of anaerobic metabolism of the parasite
What are the consequences of RBC rupture in P. falciparum infection?
RBC rupture leads to:
Release of merozoites, allowing for reinfection of new RBCs
Toxic waste (e.g., hemozoin) accumulating in the bloodstream
Intravascular hemolysis, causing worsening anemia
Blackwater fever, where hemoglobin is released into the urine, causing dark urine
How does the release of toxic waste during P. falciparum infection affect the immune system?
The toxic waste from P. falciparum induces:
Release of cytokines, particularly TNF-α (tumor necrosis factor-alpha)
Fever and rigors, causing an increase in body temperature, sweating, and chills
Why does P. falciparum infection lead to jaundice?
Jaundice in P. falciparum infection occurs due to:
Excess bilirubin, a breakdown product of hemoglobin released from destroyed RBCs
Excess hemoglobin breakdown contributes to the yellowing of the skin, eyes, and mucous membranes
How does merozoite surface antigen affect the immune system in P. falciparum infection?
Merozoite surface antigen stimulates the immune system to release cytokines (e.g., ILs and IFN-γ), which lead to:
Suppression of RBC production
Impaired restoration of hemoglobin levels
Increased fever
Formation of reactive nitrogen species (RNS), causing tissue damage
How do cytokines contribute to the pathology of P. falciparum malaria?
Cytokines play a role in:
Inducing endothelial expression of PfEMP1 (P. falciparum erythrocyte membrane protein 1), leading to:
Sequestration (RBC adhesion to blood vessel walls)
This sequestration prevents parasitized RBCs from circulating and causes further tissue damage
What role do cytokines play in vomiting during P. falciparum infection?
Cytokines influence the brain’s vomiting centers, contributing to:
Vomiting as a complex response involving immune signaling and possibly neural interactions
What is the role of PfEMP1 in P. falciparum malaria?
PfEMP1 is clonally expressed on infected erythrocytes (IE), which makes them “sticky.” This allows cytoadherence (adhesion to blood vessel walls) and the formation of rosettes (IE clumping), leading to sequestration in microvessels.
How does the PfEMP1-mediated sequestration affect the body?
Sequestration of infected erythrocytes (IE) causes:
Anaemia (due to RBC destruction)
Obstruction of blood flow, leading to:
Reduced tissue perfusion
Fatigue and general body weakness
Ischaemia (lack of oxygen in tissues)
What are the downstream effects of endothelial activation by developing P. falciparum parasites?
Endothelial activation leads to:
Secretion of proinflammatory cytokines
Deposition of fibrin
Loss of barrier integrity, contributing to:
Microvascular inflammation
Obstruction of blood flow
Perivascular leakage (fluid leakage around blood vessels)
What contributes to oxidative stress during malaria infection?
Oxidative stress arises from:
Host factors: Activated neutrophils produce reactive oxygen species (ROS), such as superoxide anion and hydroxyl radical.
Parasite factors: ROS are generated during the degradation of haemoglobin (Hb) by the parasite.
How does oxidative stress affect the inflammatory response in malaria?
ROS play a dual role:
Regulate inflammation by acting on immune cells.
Induce inflammation by promoting the secretion of inflammatory cytokines.
Why is malaria considered a highly inflammatory and oxidative disease?
Malaria triggers significant oxidative stress from both the host and the parasite, which drives an inflammatory cascade. This contributes to symptoms like fever, tissue damage, and immune activation.
What is a cytokine storm, and how does it relate to malaria?
: A cytokine storm occurs when the immune system responds excessively to infection, producing high levels of inflammatory markers (e.g., TNF⍺, IL-10, IFN-γ). In malaria, this aggressive immune response can exacerbate inflammation and tissue damage.
How does parasitaemia contribute to fatal malaria?
As parasitaemia rises:
Inflammatory markers (e.g., TNF⍺) increase.
Parasite-modified RBCs develop an adhesive phenotype.
Infected RBCs adhere to the endothelium, platelets, and uninfected RBCs, causing sequestration.
What is sequestration in malaria, and why is it dangerous?
Sequestration is the adhesion of infected RBCs in the microvasculature of organs, leading to:
Microcirculation obstruction
Impaired tissue perfusion
Lactic acidosis
End-organ damage (e.g., brain, kidneys).
How does malaria affect pregnancy?
Prominent sequestration in the placenta causes:
Low birth weight
Maternal anaemia
Miscarriage
Why is lactic acidosis significant in fatal malaria?
Lactic acidosis results from impaired tissue perfusion due to sequestration, which leads to anaerobic metabolism and contributes to organ failure and death.
What is cerebral malaria, and why is it critical?
Cerebral malaria is the most severe pathology caused by P. falciparum. It is a medical emergency requiring urgent clinical assessment and treatment to prevent life-threatening complications.
What happens to the brain in cerebral malaria?
The brain can become severely swollen due to inflammation and sequestration of infected RBCs, causing:
Increased intracranial pressure.
Brain herniation (downward displacement into the skull base).
Why is brain herniation in cerebral malaria fatal?
Herniation compresses the brainstem into the foramen magnum, compromising the respiratory center and leading to respiratory failure and death.
What structural feature of the skull worsens the risk in cerebral malaria?
The limited space within the skull restricts expansion during swelling, exacerbating pressure on critical brain regions like the brainstem.
Why does P. falciparum often cause cerebral malaria compared to other Plasmodium species?
P. falciparum infects all stages of RBCs, leading to higher parasitaemia, severe sequestration in brain capillaries, and intense inflammatory responses.
What are the main biological difficulties in developing a standard malaria vaccine?
P. falciparum has a highly complex biology, life cycle, and genome.
It effectively evades the human immune system.
There is no sterile immunity (the ability to completely eliminate the pathogen before replication).
Why is the absence of sterile immunity a problem for malaria vaccine development?
Without sterile immunity, even vaccinated individuals may still develop some level of infection, reducing vaccine effectiveness.
What financial and logistical barriers exist in developing a malaria vaccine?
Malaria primarily affects low-resource countries, reducing financial incentives for research and development.
Limited funding for vaccine development due to low profitability in affected regions.
Why is a standard malaria vaccine for travelers unavailable?
A:
P. falciparum’s complexity and immune evasion make vaccine creation challenging.
Vaccines for travelers face additional hurdles, including the need for broad efficacy against multiple strains and variable exposure conditions.
What stages of P. falciparum are targeted in vaccine development, and why are they challenging?
Trophozoite-infected RBCs and merozoites are key stages.
These stages involve immune evasion mechanisms, making it difficult to elicit an effective immune response.
What is RTS,S/AS01, and what does it target?
RTS,S/AS01 is a recombinant protein vaccine targeting the circumsporozoite (CSP) protein of P. falciparum, expressed at the pre-liver stage. R21/MM is a recombinant
protein malaria vaccine
targeting the P. falciparum CSP
protein (pre-erythrocytic stage).
How does RTS,S/AS01 work to prevent malaria?
t contains a partial CSP protein sequence, prompting a strong immune response that prevents sporozoites from entering the liver.
What target does the Oxford R21 vaccine share with RTS,S/AS01?
Both vaccines target the circumsporozoite (CSP) protein of P. falciparum, expressed at the pre-liver stage.
How does Oxford R21 work to prevent malaria?
t prompts a strong immune response, preventing sporozoites from entering the liver.
How does Oxford R21 compare to RTS,S/AS01 in terms of effectiveness?
Oxford R21 appears to be significantly more effective than RTS,S/AS01.
Why is Oxford R21 considered a promising alternative?
It is not only more effective but also considerably cheaper than RTS,S/AS01.
How is doxycycline absorbed and how quickly is it detectable in the blood?
Doxycycline is rapidly absorbed orally and detectable in the blood within 15–30 minutes. Peak plasma levels are achieved approximately 2 hours after a 200 mg oral dose.
What is the mechanism of action of doxycycline in malaria prophylaxis?
Doxycycline is a bacteriostatic antibiotic that acts on the erythrocytic cycle of P. falciparum. It is active against the merozoite stages in red blood cells but does not affect gametocytes.
What stages of P. falciparum does doxycycline target?
Doxycycline targets the intraerythrocytic stages, including merozoites, rings, trophozoites, and schizonts, but it does not act on gametocytes.
Why is doxycycline effective for malaria prophylaxis but not transmission prevention?
Doxycycline inhibits the replication of erythrocytic stages but does not affect gametocytes, which are responsible for transmission to mosquitoes.
What organelles are present in P. falciparum that are crucial for its survival?
P. falciparum has a mitochondrion and an apicoplast, both essential for its survival and replication.
What is an apicoplast?
The apicoplast is a secondary endosymbiont organelle found in P. falciparum, critical for parasite replication and continued infection of host cells.
Why is the apicoplast indispensable for P. falciparum?
The apicoplast is involved in vital metabolic pathways, including the synthesis of fatty acids, isoprenoids, and haem, which are essential for parasite survival and replication.
How does the apicoplast contribute to P. falciparum’s infection process?
The apicoplast supports key metabolic functions necessary for the parasite’s growth, development, and ability to infect host cells effectively.
ow does doxycycline kill P. falciparum parasites?
Doxycycline inhibits prokaryotic-like 70S ribosomal translation, blocking protein synthesis in the apicoplast organelle, preventing parasite development into merozoites.
What stage of the P. falciparum lifecycle is targeted by doxycycline?
Doxycycline targets the erythrocytic stages of P. falciparum, preventing further development and replication.
How is doxycycline used for malaria prophylaxis?
Doxycycline is taken as one 100 mg dose daily, starting a few days before travel, continuing during the trip, and for 28 days after returning.
Why is the apicoplast a critical target for doxycycline in P. falciparum?
The apicoplast is essential for parasite replication; disrupting its function by inhibiting protein synthesis halts parasite development.
How does doxycycline affect P. falciparum parasites in vitro?
Parasites continue to grow for 72–96 hours when treated with doxycycline, but they only die after the second 48-hour intraerythrocytic growth cycle due to failure to expand into the third cycle.
Why is doxycycline used for prophylaxis and not for treatment of malaria?
Doxycycline’s slow-acting, delayed schizonticidal activity means it prevents parasite development over time, but it does not provide rapid parasite clearance, which is needed for treatment.
What is the mechanism behind doxycycline’s delayed schizonticidal effect in P. falciparum?
Doxycycline inhibits protein synthesis in the apicoplast, preventing parasite development, which causes the failure to transition into a third intraerythrocytic growth cycle and eventual parasite death.
What are the major side effects of doxycycline?
Common side effects include gastrointestinal disturbances (nausea, vomiting), photosensitivity, and possible allergic reactions (rash, urticaria).
What populations should avoid doxycycline use?
Doxycycline is contraindicated in:
Infants and children <8 years of age (can cause permanent yellow-brown tooth discoloration, enamel damage, and skeletal growth impairment).
Pregnant women (may cause tooth discoloration, enamel damage, and skeletal growth impairment in the fetus).
Breastfeeding women (can cause similar effects in infants).
What is the effect of doxycycline on the CNS?
Doxycycline can penetrate the CNS, although central nervous system side effects are rare.
Why is doxycycline not recommended for children under 8 years of age?
Tetracyclines, including doxycycline, bind to calcium and can cause permanent yellow-brown tooth discoloration, enamel damage, and impairment of skeletal growth in children under 8 years of age.
What are the contraindications for doxycycline in pregnancy?
Doxycycline crosses the placenta and can cause permanent discoloration of teeth, damage to tooth enamel, and impairment of skeletal growth in the developing fetus.
Why should breastfeeding mothers be cautious when using doxycycline?
Doxycycline is excreted in breast milk and can cause tooth discoloration, enamel damage, skeletal growth impairment, and photosensitivity in breastfeeding infants.
What is mefloquine and how does it compare to quinine?
Mefloquine is a synthetic analogue of quinine, used primarily in regions where chloroquine resistance is established.
What is the primary action of mefloquine in malaria treatment?
Mefloquine is a potent blood schizonticide, meaning it is active against the erythrocytic forms of malaria parasites. It targets and kills the parasites in the red blood cells.
Which species of malaria does mefloquine target?
Mefloquine is effective against sensitive strains of all species of malaria, including Plasmodium falciparum, Plasmodium vivax, and others.
Why is mefloquine used in areas with chloroquine resistance?
Mefloquine is used in regions where Plasmodium falciparum and other malaria species have developed resistance to chloroquine, providing an alternative treatment.
What form of malaria does mefloquine target?
Mefloquine targets the erythrocytic (blood) forms of the malaria parasite, specifically acting against the schizont stage, which is responsible for the symptoms of malaria.
What is the role of the digestive vacuole (DV) in malaria parasite metabolism?
The digestive vacuole (DV) of the malaria parasite is key to its metabolism and survival. It degrades host hemoglobin through proteases to produce vital amino acids and detoxifies free heme by converting it into insoluble haemozoin.
How does mefloquine affect the malaria parasite’s digestive vacuole?
Mefloquine prevents the polymerization of heme into haemozoin in the parasite’s digestive vacuole. This inhibition leads to toxic accumulation of free heme, resulting in parasite death.
Why is the prevention of haemozoin formation important in malaria treatment?
Haemozoin formation is crucial for detoxifying free heme, which can be toxic to the parasite. By preventing its formation, mefloquine causes heme toxicity, which disrupts the parasite’s metabolism and leads to death.
Where does mefloquine act in the malaria parasite’s life cycle?
Mefloquine acts within the parasitophorous vacuole membrane (PVM) of the malaria parasite, targeting the process of haem detoxification and protein digestion, both essential for parasite survival.
What is the dosing regimen for mefloquine in malaria prophylaxis, and why is it beneficial?
Mefloquine is typically administered once weekly due to its very long half-life, which promotes good adherence to the regimen.
Who can use mefloquine for malaria prophylaxis?
Mefloquine can be used by long-term travelers, pregnant women, breastfeeding women, and small children weighing over 5 kg.
Why is mefloquine a popular choice for families visiting friends and relatives?
Mefloquine is a popular choice for families visiting friends and relatives because it is low-cost and the once-weekly dosing regimen makes it easy to manage.
What is the main drawback of using mefloquine for malaria prophylaxis?
The main drawback of mefloquine is its potential to cause adverse neuropsychiatric events, which can impact its use in some individuals.
What are some common psychiatric side effects of mefloquine?
Common psychiatric side effects include abnormal dreams, insomnia, anxiety, panic attacks, paranoia, persecutory delusions, dissociative psychosis, and anterograde amnesia.
What severe psychiatric reactions can occur with mefloquine use?
Severe psychiatric reactions may include acts of violence, suicidal ideation, and suicide, in addition to the more common psychiatric symptoms.
Why is mefloquine’s neuropsychiatric toxicity a concern?
The neuropsychiatric toxicity of mefloquine is a concern because it can cause significant mental health disturbances, including psychosis, memory loss, and potentially dangerous behaviors like suicide or violence.
In which patients is mefloquine contraindicated due to liver issues?
Mefloquine should be used with caution in individuals with liver problems, as it may take longer to eliminate the drug from the body in such patients.
What are the cardiac and neurological concerns associated with mefloquine use?
Mefloquine is contraindicated in patients with cardiac conduction disorders, epilepsy (should be avoided for prophylaxis), and those with a history of seizures.
Why is mefloquine not recommended for infants or very young children?
Mefloquine is not recommended for infants less than 3 months old or for children weighing less than 5 kg due to the risks of toxicity and adverse effects.
What psychiatric history increases the risk of adverse effects with mefloquine?
Mefloquine is contraindicated in individuals with a history of depression, generalized anxiety disorder, psychosis, schizophrenia, suicide attempts, suicidal thoughts, self-endangering behavior, or any other psychiatric disorder.
In which other clinical situations should mefloquine be avoided?
Mefloquine should also be avoided in patients with a history of traumatic brain injury or those taking drugs or alcohol that affect the liver.
What is chloroquine and how does it compare to quinine?
Chloroquine is an aminoquinoline antibiotic and a synthetic analogue of quinine. It is considered to have better tolerability and fewer side effects compared to quinine.
What is the pharmacological property of chloroquine that makes it effective against malaria?
Chloroquine is a potent blood schizonticide, meaning it is effective against the erythrocytic forms of malaria parasites, including all species of malaria-sensitive strains.
Which malaria species does chloroquine act against?
Chloroquine is effective against erythrocytic forms of all species of malaria, and it is also gametocidal against P. vivax, P. malariae, and P. ovale.
What is the chemical nature of chloroquine?
Chloroquine is a lipophilic weak base and a racemate, meaning both enantiomers of the drug have equal antimalarial activity.
How does chloroquine accumulate in malaria parasites?
Chloroquine accumulates in the digestive vacuoles (DVs) of the parasite.
What happens to chloroquine inside the parasite’s digestive vacuole?
nside the digestive vacuole, chloroquine gets protonated (CQ++), which decreases the pH within the vacuole.
What effect does chloroquine have on the malaria parasite’s haem metabolism?
Chloroquine prevents the polymerization of haem into haemozoin, leading to toxic levels of free haem.
How does the accumulation of free haem affect the parasite?
The accumulation of free haem induces oxidative stress, which leads to parasite death.
Where in the parasite does chloroquine exert its action?
Chloroquine acts at the parasitophorous vacuole membrane (PVM) of the parasite.
What are some common side effects of chloroquine?
Common side effects include headache, nausea, loss of appetite, stomach upset, stomach pain, diarrhoea, rash, itching, and hair loss.
What is a rare side effect of chloroquine regarding blood sugar?
A rare side effect of chloroquine is hypoglycaemia, which can occur due to decreased clearance of insulin, increased insulin sensitivity, and increased release of insulin from the pancreas.
What are the adverse drug reactions for chloroquine at high doses?
At high doses, chloroquine can cause toxicity leading to adverse effects such as retinopathy, cardiac arrhythmias, and seizures, among others.
What are the cautions/contraindications for chloroquine use?
Cautions and contraindications include hypersensitivity to 4-aminoquinoline compounds, G6PD deficiency (with rare haemolysis at prophylactic/therapeutic doses), pre-existing retinopathy, CNS diseases, myasthenia gravis, and history of epilepsy or psychosis.
Which drug interactions should be considered with chloroquine?
Chloroquine can interact with monoamine oxidase (MAO) inhibitors, digoxin, corticosteroids, and can increase the activity of methotrexate and other folic acid antagonists.
How should chloroquine be monitored in Type 1 diabetic patients?
Type 1 diabetics treated with chloroquine should be monitored closely for hypoglycemia.
What class of antibiotic is hydroxychloroquine and how is it similar to chloroquine?
Hydroxychloroquine is an “aminoquinoline” antibiotic structurally similar to quinine and chloroquine. Its pharmacology is similar to that of chloroquine.
What are the mechanisms of action of hydroxychloroquine?
The mechanisms of action of hydroxychloroquine are the same as chloroquine. It accumulates in the parasite’s digestive vacuole, becomes protonated, and prevents the polymerization of haem into haemozoin, causing haem toxicity and parasite death.
What does protonation mean in the context of hydroxychloroquine’s action?
Protonation refers to the addition of a proton (H⁺) to a molecule, forming a conjugate acid. This process is essential for hydroxychloroquine’s accumulation in the parasite’s digestive vacuole and its antimalarial effects.
What is proguanil and how is it used in the treatment of malaria?
Proguanil is an antimalarial prodrug used since the 1950s. It is metabolized to its active form, cycloguanil, which is effective against pre-erythrocytic (hepatic) forms of the parasite (causal prophylaxis) and slow-acting against the erythrocytic forms (blood schizonticide). It is also sporonticidal against P. falciparum
What makes proguanil unique among antimalarial drugs?
Proguanil is one of the few drugs that kills both hepatic (liver) and erythrocytic (blood) stages of the malaria parasite, making it effective in both causal prophylaxis and suppressive prophylaxis
What role does dihydrofolate reductase (DHFR) play in cell growth?
DHFR is crucial for cell proliferation and growth as it is involved in the biosynthesis of purines and pyrimidines, which are necessary for DNA synthesis and repair.
How does cycloguanil work as an antimalarial agent?
Cycloguanil, the active metabolite of proguanil, inhibits Plasmodium DHFR, blocking purine and pyrimidine biosynthesis. This disrupts DNA synthesis and repair, preventing nuclear division at schizont formation in both the liver and erythrocytic stages of the parasite.
Why does cycloguanil selectively target Plasmodium and not human cells?
Cycloguanil targets Plasmodium DHFR due to structural differences between parasite and human DHFR, allowing it to kill the parasite without harming human cells.
What is the solubility and bioavailability of atovaquone?
Atovaquone is highly lipophilic but has poor bioavailability.
How does atovaquone work as an antimalarial agent?
Atovaquone selectively inhibits the mitochondrial electron transport chain of Plasmodium, specifically the cytochrome bc1 complex. This disrupts the mitochondrial membrane potential, affecting parasite metabolism and survival.
Why is atovaquone considered to have a unique mechanism of action?
Atovaquone’s mechanism is unique because it targets the mitochondrial electron transport chain in Plasmodium, which is essential for energy production and maintenance of the mitochondrial membrane potential, leading to parasite death.
What is a significant concern with the development of novel antimalarial drugs targeting the parasite’s bc1 complex?
A significant concern is the potential for host mitochondrial toxicity, particularly cardiotoxicity, as human mitochondria are less sensitive to atovaquone than plasmodial mitochondria.
Why is the Atovaquone/Proguanil (AP) combination a good choice for last-minute travelers?
Atovaquone/Proguanil (AP) is effective for last-minute travelers because it can be started 1-2 days before traveling to an area where malaria transmission occurs.
What makes Atovaquone/Proguanil (AP) a good choice for shorter trips?
AP is ideal for shorter trips because it only needs to be taken for 7 days after travel, unlike other antimalarial options that require 4 weeks of use.
What is a drawback of Atovaquone/Proguanil (AP) for long-duration trips?
AP tends to be more expensive than other options, especially for long-duration trips.
How effective and tolerable is Atovaquone/Proguanil (AP) based on controlled trials?
Controlled trials indicate that AP at prophylactic doses is highly efficacious and well-tolerated by both adults and children.
What are the common adverse drug reactions (ADRs) of Atovaquone/Proguanil (AP)?
Common ADRs include abdominal pain, decreased appetite, cough, depression, diarrhea, dizziness, fever, headache, nausea, skin reactions, sleep disorders, and vomiting.
Name some uncommon ADRs associated with Atovaquone/Proguanil (AP).
Uncommon ADRs include alopecia, anxiety, blood disorders, hyponatraemia, oral disorders, and palpitations.
What ADRs of Atovaquone/Proguanil (AP) have an unknown frequency?
ADRs with unknown frequency include hallucinations, hepatic disorders, photosensitivity, seizures, tachycardia, and vasculitis.
How do the neuropsychiatric event rates of Atovaquone/Proguanil (AP) compare to mefloquine?
Atovaquone/Proguanil has lower rates of neuropsychiatric events and drug discontinuation compared to mefloquine.
What is notable about Atovaquone/Proguanil (AP) overdose?
Overdoses as large as 31,500 mg have been reported to cause little or no symptomatology.
What is the recommendation for Atovaquone/Proguanil (AP) use during pregnancy?
The manufacturer advises using Atovaquone/Proguanil (AP) during pregnancy only if the potential benefit outweighs the risk.
Can Atovaquone/Proguanil (AP) be used during breastfeeding?
Atovaquone/Proguanil (AP) should be used during breastfeeding only if no suitable alternative is available.
Why is Atovaquone/Proguanil (AP) avoided in individuals with renal impairment?
Atovaquone/Proguanil (AP) is contraindicated for malaria prophylaxis in patients with renal impairment due to safety concerns.
Is Atovaquone/Proguanil (AP) safe for infants?
Atovaquone/Proguanil (AP) should not be prescribed for infants weighing less than 5 kg.
Which Plasmodium species are responsible for relapsing malaria?
Plasmodium vivax and Plasmodium ovale.
How do P. vivax and P. ovale cause relapsing malaria?
They can arrest growth at an early, asymptomatic stage as liver hypnozoites.
What are liver hypnozoites?
Dormant forms of the parasite that remain quiescent in the liver for months or years.
How do hypnozoites lead to symptomatic malaria?
Hypnozoites reactivate after dormancy, leading to symptomatic malaria.
When was primaquine developed, and by whom?
Primaquine was developed by the US Army in the 1950s.
What is the main challenge in treating P. vivax and P. ovale malaria?
The dormant liver hypnozoites, which are not susceptible to most other antimalarials.
What is primaquine indicated for?
The treatment of P. vivax and P. ovale malaria, targeting liver hypnozoites.
What is the mechanism of action of primaquine?
The exact mechanism of action is still a topic of debate.
What is the proposed mechanism of action for primaquine?
It involves a complex two-step biochemical relay.
Why is primaquine’s mechanism of action not fully understood?
The exact biochemical processes it undergoes in targeting malaria hypnozoites remain under investigation.
What happens in the first step of primaquine’s mechanism of action?
Primaquine (PQ) is converted into hydroxylated metabolites (OH-PQm) via the CYP2D6 metabolic complex.
What happens in the second step of primaquine’s mechanism of action?
Hydroxylated metabolites (OH-PQm) undergo spontaneous oxidation to O=PQm, generating hydrogen peroxide (H₂O₂). O=PQm is then reduced back to OH-PQm, creating a catalytic cycle that leads to H₂O₂ accumulation in the liver and bone marrow. Parasites are killed by H₂O₂-induced oxidative stress.
What are the common adverse drug reactions (ADRs) of primaquine?
Nausea, vomiting, and stomach cramps.
Why is primaquine contraindicated in people with G6PD deficiency?
It increases the risk of haemolysis due to RBC oxidative stress.
Can primaquine be used during pregnancy?
No, it is not recommended during pregnancy.
Can primaquine be used while breastfeeding?
t may be used if the baby is not G6PD deficient.
How should patients with any form of complicated or severe malaria be treated?
They should be treated parenterally (via intravenous or intramuscular routes).
Who discovered artemisinin and when?
Artemisinin was discovered in 1972 by Tu Youyou, who was awarded the 2015 Nobel Prize in Physiology or Medicine.
From which plant is artemisinin extracted?
Artemisinin is extracted from Artemisia annua (sweet wormwood), also known as Qinghao in traditional Chinese medicine.
What is the standard treatment for Plasmodium falciparum worldwide?
Artemisinin-based Combination Therapies (ACTs) are the standard treatment for P. falciparum worldwide.
What is the solubility of artemisinin?
Artemisinin is poorly soluble in both water and oil.
What is the significance of carbonyl reduction in artemisinin?
Carbonyl reduction produces dihydroartemisinin (DHA) and other derivatives like artesunate (water-soluble), artemether, and arteether (oil-soluble), all of which have greater antimalarial activity.
What is the fastest-acting drug against erythrocytic stages of malaria?
Artemisinin and its derivatives are the fastest drugs against all erythrocytic stages of malaria.
Why can’t artemisinin be used for malaria prophylaxis?
Artemisinin has a very short half-life (∼1 hr), which precludes its use for malaria prophylaxis.
How are artemisinin derivatives biotransformed in humans?
In humans, artemisinin derivatives are rapidly biotransformed into their bioactive metabolite, dihydroartemisinin (DHA), by liver cytochrome P450 enzyme CYP2B6.
Does the rate of conversion to DHA vary among artemisinin derivatives?
Yes, the extent of conversion to DHA varies depending on the derivative. Artesunate is converted to DHA within minutes, while conversion of artemether and arteether is slower.
How is the endoperoxide ring of DHA activated in the parasite?
The endoperoxide ring of DHA is broken by contact with haem (from haemoglobin) inside the red blood cells.
What is the result of the activation of artemisinin in the parasite?
The activated artemisinin alkylates and damages proteins inside the parasite, disrupting cellular pathways and leading to parasite death.
What is unique about the activity of artemisinins compared to other antimalarials?
Unlike other antimalarials, artemisinins are active during all stages of the malaria parasite life cycle.
What is Artemisinin Combination Therapy (ACT)?
ACT is a treatment regimen that combines an artemisinin derivative (e.g., artemether) with a non-artemisinin partner drug, such as lumefantrine, to enhance efficacy and reduce resistance.
What is the mechanism of action of artemether in ACT?
Artemether acts as an artemisinin derivative, where it undergoes a similar mechanism to other artemisinins, but it is slower acting compared to other derivatives.
What is Lumefantrine?
Lumefantrine is a lipophilic drug used exclusively in combination with artemether in Artemisinin Combination Therapy (ACT) to treat malaria.
What is the half-life of Lumefantrine compared to artemether?
Lumefantrine has a much longer half-life and slower clearance compared to artemether, which allows it to clear any residual parasites remaining after combination treatment.
Why is Lumefantrine used in combination with artemether?
Lumefantrine is used in combination with artemether because it has a slower acting, longer duration of action, which helps to clear remaining parasites after the fast-acting artemether has reduced the parasite load.
What is the exact mechanism of action of Lumefantrine?
The exact antimalarial mechanism of Lumefantrine is unknown, but it may inhibit haematin formation, leading to a toxic build-up of haem in the parasite, which is detrimental to its survival.
How does the build-up of haem affect the malaria parasite?
The accumulation of haem from inhibited haematin formation leads to oxidative stress, which is toxic to the parasite, ultimately causing its death.
What are the common or very common side effects of Artemether/Lumefantrine (ACT)?
Common or very common side effects include abdominal pain, decreased appetite, arthralgia, asthenia, cough, diarrhea, dizziness, gait abnormalities, headache, movement disorders, myalgia, nausea, palpitations, QT interval prolongation, abnormal sensations, skin reactions, sleep disorders, and vomiting.
What are some uncommon side effects of Artemether/Lumefantrine (ACT)?
Uncommon side effects include drowsiness.
What are the known rare or unknown side effects of Artemether/Lumefantrine (ACT)?
Rare or unknown side effects include angioedema.
Is Artemether/Lumefantrine safe to use during pregnancy or breastfeeding?
The manufacturer suggests that Artemether/Lumefantrine is safe for use during both pregnancy and breastfeeding.
What family history contraindicates the use of Artemether/Lumefantrine (ACT)?
A family history of congenital QT interval prolongation, sudden death, arrhythmias, or clinically relevant bradycardia contraindicates the use of Artemether/Lumefantrine (ACT).
What medical history contraindicates the use of Artemether/Lumefantrine (ACT)?
A history of congestive heart failure accompanied by reduced left ventricular ejection fraction contraindicates the use of Artemether/Lumefantrine (ACT).
How do drugs affecting the liver enzyme CYP3A4 influence the use of Artemether/Lumefantrine (ACT)?
Drugs and substances that influence the activity of CYP3A4, including grapefruit juice, can either increase or lower the blood levels of Artemether/Lumefantrine. This can lead to more severe side effects or reduced efficacy.
How does food intake affect the absorption of Artemether/Lumefantrine (ACT)?
Food, particularly lipid-rich food, enhances the absorption of both Artemether and Lumefantrine. Patients are advised to take the tablets with food as soon as a meal can be tolerated.
What is Long QT Syndrome (LQTS)?
Long QT Syndrome (LQTS) is a condition affecting the repolarization (relaxation) of the heart, leading to an irregular heart rhythm detectable by ECG.
How does Long QT Syndrome (LQTS) affect the heart’s electrical activity?
LQTS reflects a disturbance in how the ventricles send signals, causing the heart to take longer than usual to recharge between beats.
What is the significance of an abnormally prolonged QT interval?
An abnormally prolonged QT interval is associated with an increased risk of ventricular arrhythmias.
How is Long QT Syndrome detected?
LQTS is detectable by an ECG (electrocardiogram), which shows a prolonged QT interval.
How does malaria induce oxidative stress?
Malaria induces oxidative stress in both the host and parasite. Increased reactive oxygen species (ROS), such as superoxide anion and hydroxyl radicals, arise from activated neutrophils in the host and during hemoglobin degradation in the parasite.
How does oxidative stress contribute to inflammation during malaria infection?
Oxidative stress can induce inflammation by regulating the inflammatory response in immune cells. ROS activate NF-kB, which triggers the secretion of inflammatory cytokines.
What role do reactive oxygen species (ROS) play in malaria?
ROS, including superoxide anion and hydroxyl radicals, are generated during malaria infection and contribute to oxidative stress, which influences both the host’s immune response and the parasite’s life cycle.
