Malaria and Anti-Malarial Drugs

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Birth Control Thesis Mind Map

Szerző: Maud Lunenfeld

Infectious diseases caused by organisms and lead to illnesses are increasing in the community "emerging" causes are multiple

Szerző: M Hass

Structural Engineering

Szerző: Juan Camilo Robayo

alloys

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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