malaria - ju medicine · malaria • is a mosquito-born disease causing about 3 million deaths a...
TRANSCRIPT
![Page 1: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/1.jpg)
Malaria• is a mosquito-born disease causing about 3 million
deaths a year world-wide. Many are children under theage of 5.
• The parasite is transmitted by bites from the femaleanopheles mosquito.
• Currently, there are over 300 million new infectionsannually.
• The disease is caused by several species of thePlasmodium parasite. The two most important are P.falciparum and P. vivax.
![Page 2: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/2.jpg)
Malaria
• P. falciparum causes “malignant tertian malaria”.“Malignant” because it is the most severe form ofmalaria and can be fatal. “Tertian” because it is saidto produce fever every third day.
• P. vivax produces “benign tertian malaria”. “Benign”because it is less severe than falciparum and is seldomfatal.
![Page 3: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/3.jpg)
![Page 4: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/4.jpg)
Life cycleTwo Interdependent Life Cycles
• Sexual cycle: in the mosquito
• Asexual cycle: in the human
– Knowledge of the life cycles is essential in understandingantimalarial drug treatment.
– Drugs are only effective during the asexual cycle.
Asexual cycle: two phases
• Exoerythrocytic phase: occurs “outside” the erythrocyte
• Erythrocytic phase: occurs “inside” the erythrocyte
Erythrocytes = RBCs
![Page 5: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/5.jpg)
Anti-malarial agents
• Drugs that eliminate developing or dormant liver forms arecalled tissue schizonticides;
• those that act on erythrocytic parasites are bloodschizonticides;
• and those that kill sexual stages and prevent transmission tomosquitoes are gametocides.
• No single available agent can reliably effect a radical cure, ie,eliminate both hepatic and erythrocytic stages.
![Page 6: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/6.jpg)
Chloroquine• It is a potent blood schizontocidal drug effective against
all four types of clinically important plasmodium species.
• Its mechanism of action is complex and not fullyunderstood.
➢ It is accumulated in parasite lysosomes. Chloroquineinhibits digestion of haemoglobin by the parasite andthus helps reduce its supply of amino acids.
➢ It also inhibits haem polymerase - the enzyme thatpolymerises toxic free haem to the innocuoushaemozoin.
![Page 7: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/7.jpg)
Chloroquine
• The drug of choice in the treatment of erythrocyticfalciparum malaria, except in resistant strains.
• Chloroquine is less effective against vivax malaria.
• It is also effective in the treatment of extraintestinalamebiasis.
• It is used for the treatment of malaria in pregnancy.
![Page 8: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/8.jpg)
Chloroquine
• At high doses toxic effects occur,
gastrointestinal upset, pruritus, headaches, and
visual disturbances (an ophthalmological examinationshould be routinely performed).
• Parenteral administration – hypotension and cardiacarrhythmia, convulsions.
• Contraindication: psoriasis or porphyria
![Page 9: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/9.jpg)
Countries with at least one study indicating chloroquine totalfailure rate > 10%
No failurereported
Chloroquine total failure rate< 10%
No recent dataavailable
P- falciparum resistance to chloroquineSource: WHO global database on drug resistance 1996-2004
![Page 10: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/10.jpg)
![Page 11: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/11.jpg)
Haemoglobin degradation pathway
O2
Free haemFe2+
Largepeptides
Smallpeptides
4 Aspartate protease (Plasmepsins I, II, IV and HAP)3 Cysteine proteases (Falcipains 1-3) 1 Zinc metallopeptidase (Falcilysin)
Aminoacids
Amino-peptidases
Haemoglobin
HaematinFe3+
O2-
Haemozoin
Food vacuole
β-HaematinH2O2
H2O Peroxidases
Superoxidedismutase
globin
Kumar et al., Life Sciences 80 (2007) 813-828
Cytoplasm
-Free haem is extremely toxic
-Can generate ROS
-Is lipophilic and can intercalate intomembranes causing cell lysis
Free haem metabolised to an inert chemicalform called haemozoin by a process known as
biomineralisation
![Page 12: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/12.jpg)
Detoxification of Haematin into Inert Haemozoin
Haematin β-HaematinHaemozoin
Phospholipids
His-rich proteinsand
Membrane lysis
Biomineralisation
β1-4 linkages ofhaematin
Freehaem
Fe2+
Fe3+oxidation
Dimers of haematin – β1-4 linkages are formed
Dimers then begin to crystallise in a process known as biomineralisation to generate haemozoin
Process not fully understood but is thought to be promoted by several factors including – the low pH of thefood vacuole, association of haematin with histidine-rich proteins and phospholipids
Ultimately haemozoin crystals are formed which are chemically inert and a safe storage mechanism for theparasite
![Page 13: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/13.jpg)
Quinine and Quinidine• is a rapid-acting, highly effective blood schizonticide against
the four species of human malaria parasites.
• The drug is gametocidal against P vivax and P ovale but notP falciparum. It is not active against liver stage parasites.
• Quinine and quinidine remain first-line therapies forfalciparum malaria—especially severe disease—althoughtoxicity may complicate therapy.
• Quinine is more toxic and less effective than chloroquineagainst malarial parasites susceptible to both drugs.
![Page 14: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/14.jpg)
Quinine and Quinidine
• Therapeutic dosages of quinine and quinidine commonlycause tinnitus, headache, nausea, dizziness, flushing, andvisual disturbances, a collection of symptoms termedcinchonism.
• Therapeutic doses may cause hypoglycemia throughstimulation of insulin release (pregnant patients).
• Quinine can raise plasma levels of warfarin and digoxin
![Page 15: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/15.jpg)
Atovaquone-proguanil
![Page 16: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/16.jpg)
Proguanil (Chloroguanide)
• slow-acting erythrocytic schizontocide,also inhibits thepreerythrocytic stage of P.F alciparum.
• Mechanism of action :
• It is cyclized in the body to cycloguanil which inhibits plasmodialDHFRase in preference to the mammalian enzyme.
• Current use of proguanil is restricted to prophylaxis of malaria incombination with chloroquine in areas of low level chloroquineresistance among P. falciparum. Safe during during pregnancy.
![Page 17: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/17.jpg)
Mefloquine
• Mefloquine is effective therapy for many chloroquine-resistant strains of P falciparum and against other species.
• Although toxicity is a concern, mefloquine is one of therecommended chemoprophylactic drugs for use in mostmalaria-endemic regions with chloroquine-resistant strains.
• Its mechanism of action appears to be associated withinhibition of the haem polymerase.
![Page 18: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/18.jpg)
Mefloquine
• Weekly dosing with mefloquine for chemoprophylaxis maycause nausea, vomiting, dizziness, sleep and behavioraldisturbances, epigastric pain, diarrhea, abdominal pain,headache, rash, and dizziness.
• Neuropsychiatric toxicities ????????????????
• is contraindicated in a patient with a history of epilepsy,psychiatric disorders, arrhythmia, cardiac conductiondefects
![Page 19: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/19.jpg)
Primaquine
• destroys primary and latent hepatic stages of P. vivax and P.ovale
• thus has great clinical value for preventing relapses of P.vivax or P. ovale malaria (Standard therapy).
• exert a marked gametocidal effect against all four species ofplasmodia that infect humans, especially P. falciparum.
• Because of its lack of activity against the erythrocytic schizonts,primaquine is often used in conjunction with a bloodschizonticide.
![Page 20: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/20.jpg)
Primaquine• induced hemolytic anemia in patients with genetically low levels of
glucose-6-phosphate dehydrogenase.
• Patients should be tested for G6PD deficiency before primaquine isprescribed.
• causes nausea, epigastric pain, abdominal cramps, and headache, andthese symptoms are more common with higher dosages and when thedrug is taken on an empty stomach.
• Primaquine should be avoided in patients with a history ofgranulocytopenia or methemoglobinemia, in those receiving potentiallymyelosuppressive drugs (eg, quinidine),
• Avoided in pregnancy & G6PD
![Page 21: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/21.jpg)
Artemisinin derivatives
Artemether / Arteether / Artesunate
• It is a potent and rapidly acting blood schizontocide andhave peroxide configuration – responsible for its action.
• Combination therapy.
• Duration of action: short
• Recrudescence rate is high
• When used alone in short courses
• Used only in combination
![Page 22: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/22.jpg)
Artemisinin Combination Therapy (ACT)current frontline therapy
• Artemisinins reduce parasite burden rapidly
• Used in combination with other drugs to protect emergence ofresistance to partner drug (ACT)
Artemisia annua – sweet wormwood Youyou TuNobel Prize – Medicine 2015
![Page 23: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/23.jpg)
Haematin β-Haematin Haemozoin
haem-artemesininadducts
(“haemarts”)
Carbon-centred freeradicals generated
Cleavage ofendoperoxide
bridge by haem
Endoperoxidebridge
FoodVacuole
Artemesininaccumulates in
the FV
Haem and Mode of Action of Artemisinins
Possible targets of artemisinin free radicals:TCTP (translationally controlled tumour protein homolog)SERCA (sarco/endoplasmic reticulum Ca2+ -ATPase)Cysteine proteases
![Page 24: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/24.jpg)
Pyrimethamine-sulphonamideand antibiotics
• Pyrimethamine inhibits plasmodial dihydrofolate reductaseat much lower concentrations than those that inhibit themammalian enzyme. ………… sulfa….
• Tetracycline and doxycycline are active against erythrocyticschizonts of all human malaria parasites. They are notactive against liver stages.
• Doxycycline is used in the treatment of falciparum malariain conjunction with quinine, allowing a shorter and better-tolerated course of that drug.
![Page 25: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/25.jpg)
Drug Use2
Adult Dosage3
Chloroquine Areas without resistant Pfalciparum
500 mg weekly
Atovaquone-proguanil(Malarone)
Areas with chloroquine-resistant Pfalciparum
1 tablet (250 mg atovaquone/100mg proguanil) daily
Mefloquine Areas with chloroquine-resistant Pfalciparum
250 mg weekly
Doxycycline Areas with multidrug-resistant Pfalciparum
100 mg daily
Primaquine4
Terminal prophylaxis of P vivaxand P ovale infections; alternativefor primary prevention
52.6 mg (30 mg base) daily for 14days after travel; for primaryprevention 52.6 mg (30 mg base)daily
![Page 26: Malaria - JU Medicine · Malaria • is a mosquito-born disease causing about 3 million deaths a year world-wide. Many are children under the age of 5. • The parasite is transmitted](https://reader034.vdocuments.us/reader034/viewer/2022042105/5e83148035287654a252037b/html5/thumbnails/26.jpg)
Clinical Setting Drug Therapy1
Alternative Drugs
Severe or complicatedinfections with P falciparum3
Artesunate, 2.4 mg/kg IV,every 12 hours for 1 day, thendaily for two additional days;follow with 7 day oral courseof doxycycline or clindamycinor full treatment course ofmefloquine or Malarone
Artemether, 3.2 mg/kg IM,then 1.6 mg/kg/d IM; followwith oral therapy as forartesunate
or–
Quinidine gluconate,2 10 mg/kg IV over 1–2 hours, then 0.02mg/kg IV/min
or–
15 mg/kg IV over 4 hours, then7.5 mg/kg IV over 4 hoursevery 8 hours