Antimalarials Flashcards
LO
identify the key events in the life cycle of the malaria parasite and how these may be affected by antimalarial agents
Topics covered
- The prevalence/ vector / parasite / disease / diagnosis/ susceptibility
- Parasite life cycle
- Vector control (including larvicides, insecticides, genetics)
- Vaccine
- Drugs for prophylaxis, acute treatment, and radical cure
- Resistance and future therapies/targets
What is malaria?
RBC are invaded by the Plasmodium species which is carried by mosquitoes
Its eukaryotic, parasitic protozoan
Infection by mosquito vector (and mother-foetus)
Where is the term ‘malaria’ from and what is also sometimes referred to as?
Literally bad air (from Old Italian “mal” ‘aria”)
Sometimes known as “intermittent fever” / “marsh fever”
When were cases of Malaria first recorded?
Recorded as far back as 3000 BC in China, India, and Egypt / Roman times in the UK (parasite in humans ~100,000 years)
Why do the number of UK cases rise?
Number of UK cases on the rise due to global travel (~2,000 a year – ‘suitcase’ malaria)
Also climate change
Malaria is described as being one of the ‘big three’ diseases, alongside what two others?
HIV
TB
in 2019, what were the reported cases and deaths of malaria by the WHO
Who was it more prevelant in and why?
229 million cases a year / 409,000 deaths (WHO 2019)
Found mostly children <5 because they have not been exposed to it and have no defences against it
What are the regions in which malaria is endemic?
endemic: when a diseases is generally found among certain populations and places
Primarily in tropical and subtropical regions as that is where the mosquitoes are present
Tell me about the stats for the Morbidity and mortality in sub-saharan Africa where its mainly concentrated
Morbidity: The state of having a specific illness or condition
Mortality: Refers to the nunber of deaths that have occurred due to a specific illness or condition
Under 5s account for 52% of deaths (2/3rds for under 14s)
Sub-Saharan Africa: 94% cases and 95% of deaths
The global cases are falling but, successes in this since the 2000 are slowing due to what factors?
‘Success’ – sustainability/removal of funds
Resistance (mosquito and Plasmodium)
How is malaria transmitted?
Transmitted through the “bite” of the female mosquito genus Anopheles (~40 species associated with malaria)
What happens when a mosquito bites its target?
Parasite initially ingested during a blood meal of an infected individual, it grows replicates in gut, and is then passed on during subsequent meal (8-15 sporozoites)
Sporozoites: a motile spore-like stage in the life cycle of some parasitic sporozoans (e.g. the malaria organism), that is typically the infective agent introduced into a host.
Where are mosquitos usually found?
Abundant and distributed all over the globe, including the Arctic, but particularly widespread in tropical / sub-tropical regions, particularly around stagnant water (as larvae grow in stagnant water. Issue in places like Africa who will have large rainfalls and large water pools forming so trying to target this is quite difficult)
How can the parasites be transmitted/
Parasites can be transmitted through blood transfusions and contaminated needles (but generally rare), as well as intra-uterine (mother-baby); can lead to complications and potentially miscarriage
What are the 5 species of parasite that can form malaria and rank them from most to least dangerous
Which ones require radical cure and why?
P. falciparum (most serious / 90% deaths)
P. vivax*, ovale*, malariae (milder disease)
P. knowlesi (zoonotic - monkey & human)
*Requires radical cure- because they have a dormant state in the liver which can hide from the immune system and then erupt and come back later in life
How does the parasite uptake the nutrients it requires from the red blood cells?
Uptake material from RBC; haemoglobin and protein component. Has a food vacuole
Explain abit about the incubation period of the different malarial parasites
Can live in system for a few weeks without any symptoms. Only when its present in your blood is its known that you are infected
Tell me what the initial symptoms are for the malarial parasites
- flu like
- headache
- Photophobia
- muscle aches
- nausea
- vomiting
- chills (10-15 mins)
- Fells cold but is actually feverish
- Jaundice
Jaundice as RBC breaking down and bilirubin being present
Tell me about the periodicity of the malarial parasites
Goes through rounds of replications once in RBC leading to cycles of symptoms- periodicity
Tell me about the onset of diseases the the severity and duration (hr) for malarial parasites
Can cross BBB, clump RBC and this can lead to blocking blood vessels and brain swelling which leads to death- if survive it can lead to chronic conditions
With the malarial parasite if left untreated or not treated properly it can lead to relapses or recrudescences, explain this
If untreated by drugs, then it can come back during your lifetime
Recrudescence is when you haven’t fully cleared from blood, not completely killed, will come back
Why can one get anaemia from malarial parasites?
Anaemia as breaking over blood cells and have the side effects from this
The disease and the 5 malarial parasites
Some individuals can have genetic advantages which can help protect them against malaria. State 3 of them
- sickle cell disease
- Glucose-6-phosphate dehydrogenase deficiency
- Lack of Duffy antigens on RBC
How can sickle cell disease provide some protection against malaria?
Sickle Cell Disease (HbS, β-thalassemia etc.)
Heterozygous then can get resistance to malaria but homozygous you can get the disease
The sickle cells have membranes, stretched by their unusual shape, that become porous and leak nutrients that the parasites need to survive and the faulty cells eventually get eliminated quite fast by the organisms, destroying the parasite along the way.
How can Glucose-6-phosphate dehydrogenase deficiency (X-linked) provide one protection against malaria?
Glucose-6-phosphate dehydrogenase deficiency (X-linked)
if lack enzyme then the RBC are more susceptible to redox damage and breakdown, malaria is more susceptible to redox damage so is less likely to infect these cells
As G6PD deficiency leads to increased oxidative stress in red blood cells, this may in turn have a negative influence on the parasite. As such, individuals who possess this mutation have some protection against malaria
How can a lack of Duffy antigens provide one protection against malaria?
Lack of Duffy antigens on RBC
Duffy antigens plat a fundamental role on haematopoiesis (formation of blood cell components)
Duffy antigens are located on the surface of RBC
The protein encoded by this gene is a glycosylated membrane protein and a non-specific receptor for several chemokines
A lack of these antigens make the RBCs more resistant to invasion by a malarial parasite
What may some people have that puts them more at risk to malaria?
- Pregnancy
- Co-infection: HIV, helminths
What are some techniques into the clinical diagnosis of malaria?
Microscopic examination of blood smears using Giemsa/Wright stain
Giemsa stain: specific to phosphate groups of DNA. Attaches to regions of DNA with high amounts of AT bonding
Wright stain: Facilitates the differentiation of blood cell types. classically a mixture of eosin (red) and methylene blue dyes
Antigen-capture assay (‘dipsticks’) - 100 parasites/µl lower limit of detection
PCR for strain detection (for determining drug resistance)
Tell me the stages to the malarial life cycle and what can happen at each stage
- Injection of sporozoites into blood stream
- Sporozoites can pass quickly into the liver OR can remain dormant (Hypnozoites)
- Go through Asexual reproduction over roughly 10 days. Over this time no symptoms show
- Liver Schizonts are now present
- Merozoites are released into the blood where they can; invade RBC, asexually reproduce, cause cells to burst, repeat cycle, cause cyclic fever
- Blood Schizonts are now present
- Some Merozoites develop into Gametocytes that can circulate in the blood
- Moquito can ingest gametocytes, which develop into gametes and reproduce sexually
- Develop inot ookinetes that burrow through gut wall to form oocysts
- Oocyst bursts, releasing sporozoites that travel to salivary glands
- Cycle repeats when the mosquito bites another person
What are sporozoites?
a motile spore-like stage in the life cycle of some parasitic sporozoans (e.g. the malaria organism), that is typically the infective agent introduced into a host.
What are Hypnozoites?
Hypnozoites are dormant forms in the life cycles of certain parasitic protozoa that belong to the Phylum Apicomplexa (Sporozoa) and are best known for their probable association with latency and relapse in human malarial infections caused by Plasmodium ovale and P. vivax.
What are Schizonts?
They are mature malarial parasites in host liver cells or red blood cells that are undergoing nuclear division by a process called schizogony
What are gametocytes?
A eukaryotic germ cell that divides by mitosis into other gametocytes or by meiosis into gametides during gametogenesis
What are ookinetes?
The motile zygote that forms when the microgamete (derived from the male gametocyte) fertilises the macrogamete (derived from the female gametocyte) during the sexual reproduction of certain sporozoans such as the malaria causing plasmodium
What are oocysts?
A cyst containing a zygote formed by a parasitic protozoan such as the malaia parasite
Whats schizogony?
Asexual reproduction by multiple fission, found in some protozoa
This occurs at a phenomenal rate
What can Schizogony in parasites produce?
A single parasite of P. vivax can give rise to 250 million merozoites in 14 days!
To appreciate the action required of an antimalarial drug, note that the destruction of 94% of the parasites every 48 h will serve only to maintain equilibrium and not further reduce their numbers!- rapid reproduction
Produce a Schizont which can rapidly divide into many cells (merozoites) and infect
What are some approaches being developed to eradicate the parasites (mainly P. falciparum as its the most deadly)
- Vaccines to prevent infection
- Drugs for radical cure
- Drugs for prophylaxis (try to prevent infection. However these drugs cannot be taken over a long period of time due to severe side effects)
- Drugs to treat acute attack
- Drugs to prevent transmission
When trying to control vectors of diseases, what are some of the things you could potentially target?
What does the combination of these approaches do?
- Target the larvae life stage
- Target adult moquito
The combination of these non-pharmacological approaches decreased the number of malaria cases in Africa by two thirds between 2000-15 (but stalling…)
How do you target the larvae life stage?
- Use of larvicides
- Remove/ cover standing water e.g, drain swamps, oil films
How can you target the adult mosquito?
- Use of insecticides / repellents
- Long-lasting insecticidal nets (LLINs)
- Indoor residual spraying (IRS)
Whats different forms can Larvicides be?
- Chemical agents
- Biological agents
- Biodegradable oils
Tell me about Larvicides as chemical agents and provide an example
Chemical agents e.g. Methoprene
Juvenile Hormone Analogue: increasing levels stalls larval development
Note yet routinely used in Sub-Saharan Africa (cost/easier to target adults/toxic to other aquatic life)
Tell me about larvicides as biological agents
provide examples
Biological agents e.g., Bacillus thuringiensis var israelensis and Bacillus sphaericus
Apply pellets to water
Effective but complex considerations for deployment (mosquito species, water type etc.)
What do biodegradable oils do as larvicides?
Prevent the larvae from breathing
Give an example of a main insecticide
Dichlorodiphenyltrichlorethane (DDT)
Tell me the following about the insecticide DDT…
- when was it used
- how does it act
Extensively used in 1950s and 1960s in US, Southern Europe and South America
Acts by opening voltage gated Na+ channels in neurons, causing them to fire spontaneously, which leads to spasms and eventual death (1000-fold higher affinity for insect channels = selective toxicity)
Tell me about DDE bio-accumulates in the fat of animals
DDE bio-accumulates in the fat of animals (rarely excreted).
Responsible for the decline in many species of birds and fish and reproductive issues in humans (carcinogenic/endocrine disruptor) – largely banned in 1970s/80s
Whats the Stockholm convention
The Stockholm Convention is a global treaty that aims to protect human health and the environment from the effects of persistent organic pollutants (POPs)
·
Stockholm Convention – should only be used for vector control (IRS)
DDT…
Give an example of another insecticide
Pyrethrins/ Pyrethroids