Malaria - Resistance Mechanisms
Mutations in the gene coding for the enzyme DHFR
Parasite cell membrane: changes in two proteins: PfMRD-1 and Sodium/Hydrogen ion exchanger
Digestive Vacuole: changes in two proteins: PfCRT and Pgh-1
ACT - Artemisinin Combination Therapy should now be used. Combing short acting actimisinins with a longer acting partner. Protects against resistance
ARTEMISININ
Fast acting, effective against P. Falciparum, effective against gametocytes
Rapidly reduces blood stage parasites
MOA: Appears to act by binding to iron, causing the breakdown of peroxide bridges, leading to formation of free radicals that damage parasite proteins.
7. Lysis of the parasite
6. Inhibits protein synthesis
5. Damages ER
4. Causes lipid peroxidation
3. Binds with membrane protein
2. Release of free radicals
1. Haeme interacts with endoperoxide bridge in artemisinin
Poorly soluble in water - poor bioavailability
First line therapy now for the treatment of malaria is combination of artemisinin and its semi-synthetic derivatives with other drugs mentioned
ATOVAQUONE
Used with proguanil as proguanil potentiates the action of atovaquone and prevents the development of resistance
Use both prophylaxis and treatment. Activity against blood stage and the non-dormant liver form P. Falciparum
Inhibits the mitochondrial electron transport chain
ANTI-FOLATES
Anti-folate drugs target 2 enzymes
Acute Attacks - chloroquinine resistant P falciparum
Malaria parasites need to synthesise folates de novo.
PROTEIN SYNTHESIS INHIBITORS
Used in acute attack, slow acting drug so typically used in combination with fast acting
DOXYCYCLINE - tetracycline antibiotic
MOA: Reversible binding of the 30S ribosome and inhibits peptide synthesis
Use of cytotoxic antibiotics to work as protein synthesis inhibitors
Quinolones and Analogs
PRIMAQUININE
G6PD metabolic disorder - individuals that suffer with this can develop haemolytic anaemia if taking primaquine
Mechanism unclear - ROS involvement
Radical Cure for vivax and ovale
Mefloquinine
Side effects: NEUROPSYCHIATRIC SYMPTOMS
SAFETY LABEL - NEUROLOGICAL EFFECTS CAN OCCUR DURING AND PERMANENTLY AFTER USE!!!
Long half-life , only drug that can be taken during pregnancy
Used when there is chlorquinine resistant P. Falciparum
CHLOROQUININE
RESISTANCE is a major problem - P. Falciparum
Side effects are usually less severe than quinine: nausea and vomitting, dizziness and blurring of vision
More Effective than Quinine
QUININE
SIDE EFFECTS: hypoglycaemia, bitter taste, cinchonism, hypotension, cardiac arrhythmias
Usually taken with 1 of 3 other drugs - doxycycline, tetracycline or clindamycin
Kills gametocytes of P. Vivax and P. Malariae, used in treatment of severe illness
1st effective treatment against malaria and effective against all 4 species
Mechanism of action
CHLOROQUININE, QUININE, MEFLOQUININE
Quinine is found in sparkling water and anadin tablets
Chloroquinine is also a DMARD
HAEMOGLOBIN is degraded to HAEM which is polymerised to NON-TOXIC HAEM in the food vacuole of the parasite. These drugs inhibit the enzyme HAEM POLYMERASE so that there is a build up of TOXIC HAEM in the parasite
Used for:
some act on gametocytes and prevent transmission by the mosquito
RADICAL CURE
Treatment of prophylaxis - targeting merozites emerging from the liver cells and breaking the link between liver and blood stage
treatment of acute attacks - targeting the parasite in the blood stage
Malaria and Anti-Malarial Drugs
MALARIA CHEMOTHERAPY
ACT
Artemisinin and derivatives
Artemether
Arteflene
Artesunate
Artemisinin
Atovaquone and Proganaul
Anti-folates
Pyrimethamine
sulphadoxine
Protein Synthesis Inhibitors
Cytotoxic Antibiotics
Clindamycin
Doxyclycine
Quinolones and Analoges
Primaquine
Mefloquine
Chloroquine
Quinine
Plasmodium Protozoa Survival
Protozoa have a large food value where it digests the haemoglobin as a source of amino acid. Haemoglobin is digested to HAEM. A buildup of harm is toxic to the parasite so it must be polymerised into non-toxic harm.
They use large amounts of glucose for their own replications
They MUST synthesis folates
They digest haemoglobin as a source of amino acids
They cannot synthesis purines
They must synthesise pyrimidines for normal DNA synthesis, for normal cell replication
Recurrent Malaria
Caused by parasites SURVIVING in the blood as a result if inadequate or ineffective treatment. Or symptoms reappear after parasites have been eliminated from the blood but PERSIST as DORMANT HYPNOZOITES in liver cells. This is most commonly found with P. vivax and P. oval infections!
Cerebral Malaria
While available anti-malarial drugs are effective at clearing the parasites from the blood they do not have specific effects against CM
Death by CM is associated with brain swelling and vasogenic oedema. Increased brain volume has been associated with death in children with CM, suggesting that brain swelling is a casual mediator between P. falciparum infection and death
Only a small % of malaria infections result in CM but once neurological symptoms have appeared a high proportion (around 20%) succumb to CM and survivors frequently present permanent neurological sequelae.
It is caused by the Plasmodium falciparum infected erythrocytes adhering to the hosts brain endothelial cells and compromising the BBB
CM is the most virulent and deadliest manifestations of malaria.
Symptoms of Malaria
Stomach: Nausea and vomitting
Spleen enlargement
Respiratory: dry cough
Skin: chills and sweating
Back pain
Muscular: fatigue and pain
Systemic: fever
Central: Headache
Malaria Life Cycle in Humans
1. Bite from infected female
2. Sporozoites enter the bloodstream and migrate to the liver
3. They infect liver cells and multiply into merezoites
4. They then rupture the liver cells and enter the bloodstream and infect red blood cells
5. The multiply in RBC, lyse cells and then infect more RBC
6. Some develop into gametocytes
7. Gametocytes are taken up by a mosquito and infect the insect and continue on the life cycle
Types of Plasmodium Protozoa
There is over 400 species but only 4 species routinely infect humans
P. Ovale
P. Vivax
P. Malaria
Dominant species outside Africa
P. Falciparum
Dominant species in Africa
Accounts for 95% of deaths
New Research into the Area
There is a potential 2nd vaccine in the works in Oxford University
This vaccine will curb the infections from Plasmodium falciparum but is only 30% efficacious
First approved Anti-Malarial vaccine was developed in 2021 by GSK
Effects of Malaria
There is increasing resistance to established drugs
Kills more people than AIDS
According to the WHO: approx. 229 million cases of malaria globally in 2019 and 409,000 deaths
Children account for 2/3 of these deaths
World's most devastating parasitic infection, effecting 40% of the world's population
What is Malaria?
Transmitted from human to human through the bite of an infected female mosquito of the Anopheles species
Vector-born disease caused by Plasmodium Protozoa
