Anti-malarials

Question 1

What is malaria?

Answer 1

Febrile illness where circulating RBCs are haemolysed by repeated attacks of protozoan parasites (Plasmodium) -

Anopheles mosquito leads to PLASMODIUM FALCIPARUM in red blood cels
PF causes 40-60% of global malaria and 95% of malaria deaths

Question 2

Life cycle in malaria?

Answer 2

Parasites sucked up by anopheles mosquito
Oocytes develop in gut wall
Sporozoites develop in oocyst
Sporozoites migrate to salivary glands and injected with bite

Liver stage 5-12 days (human)
Red blood cell stage (2-3 days)
Gametocytes in plasma

Question 3

What are the four plasmodium species?

Answer 3

FALCIPARUM:

• Malignant tertian - ‘Blackwater fever’
• Hb in urine turns it black
• ~50% of cases, 90% of deaths
• No dormant parasites (doesn’t produce forms that reside in liver for long periods and can emerge later on)

VIVAX/OVALE:

• Moderate, ‘benign’ tertian
• Dormant liver infections - dormant liver parasites (hypnozoites)

MALARIAE

• Mild, quartan
• Long-term dormant liver parasites

Question 4

What are tertian and quartan malarias?

Answer 4

Tertian: fever on first and third days (every two days)

• (M, W, F, Su)
• very sick one day
• exhausted next day
• fever next day

Quartan: fever on first and fourth days (every three days)
- (M, Th, Su)

Question 5

What are the stages of malaria? (P. vivax, P faclciparum)

Answer 5

P. vivax

1) PREMONITORY - lassitude, feeling tired/aching
2) COLD stage: shivering, 15-60 mins
3) HOT stage: fever, 2-6 hours
4) SWEATING: exhausted sleep, 2-10 hours

P. falciparum:
Fever 16-36 hours (50% RBCs affected by this point)
Renal failure (blocking of renal arterioles)
Cerebral malaria –> coma (damage to cerebral circulation)

Question 6

What is chemoprophylaxis?

Answer 6

Causal (true): prevent liver infection

Clinical: suppress blood parasites until risk of re-infection from liver is low

Radical cure: eliminate existing liver infection

Clinical prophylaxis generally given:
2-3 weeks before travel
During exposure
4 weeks after return

(except malarone - 1 day before, 1 week after)

Question 7

What are rapid-acting blood schizonticides? How do they work?

Answer 7

Quinine (alkaloid)
Chloroquine
Mefloquine (Larium)

Mechanism not entirely clear - binds to HAEMIN (Hb break down product), concentrated 100x in infected RBCs
- intercalation in plasmodial DNA? increase lysosomal pH?

Do not kill liver parasites

Question 8

What is chloroquine used for?

Answer 8

Acute malarial infection - high doses clear parasitaemia in 3-4 days

Clinical prophylaxis:
Weekly dose
A/E: NVD, retinopathy, hypersensitivity
C/I: ocular disease, hepatic disease

Chloroquine-resistant falciparum is common

Question 9

What is mefloquine (Larium) used for?

Answer 9

For chloroquine-resistant falciparum
Acute malaria: 3-4 day course

Clinical prophylaxis:
- (similar dosing to chloroquine, long-half life probably once a week?)
- Resistance increasing
- A/E: NVD, neuropsychiatric disorder (serious 0.01%, mild 0.1-1%)
- C/I: depression, fits, epilepsy
(Risk of mefloquine S/E is lower than risk of falciparum malaria)

Question 10

What are slow-acting blood schizonticides?

Answer 10

Folate inhibitors: PROGUANIL, PYRIMETHAMINE
Inhibit PLASMODIAL DHF REDUCTASE (DHF–> THF)

Slow-acting, used mainly for prophylaxis, DAILY dosing
Suppress blood infection (clinical prophylaxis)
Partly prevent liver infection (causal prophylaxis)
No effect on established liver infection

Often given with sulphonamides (antibacterials) - which inhibit conversion of PABA to DHF (in humans we just get DHF from diet)

Question 11

How are nucleotides synthesised in plasmodium?

Answer 11

PABA (required in plasmodium) –> Dihydrofolic acid (DHF) - found in human diet

DHF —> Tetrahydrofolic acid (THF) - plasmodial/ human DHF reductase (inhibited by proguanil, pyrimethamine)

THF –> nucleotide synthesis?

Question 12

Pyrimethamine?

Answer 12

Plus SULPHONAMIDE = FANSIDAR
Plus DAPSONE = MALOPRIM

Sulphonamide component S/E - severe skin reactions, fatal hepatitis (rare)

Question 13

Proguanil?

Answer 13

Often used alone

Pro-drug, CYCLOGUANIL = active metabolite
S/E: mild (NVD, mouth ulcers)
Safe during pregnancy

Plus ATOVAQUONE = MALARONE

Question 14

Malarone?

Answer 14

Proguanil plus atovaquone

ATOVAQUONE inhibits PLASMODIAL MITOCHONDRIA

Prophylaxis: 1 tablet/day, 1 day before, during and 1 week after

95-100% effective over 10-12 weeks against drug-resistant falciparum

Expensive - S/E NVD,
CI/ - renal failure, pregnancy

Question 15

Doxycycline?

Answer 15

Tetracycline antibiotic
Prophylaxis of mefloquine resistant falciparum
Useful in patients intolerant to other drugs
C/I: pregnancy, lactation, children

Question 16

What is a liver schizonticide?

Answer 16

Primaquine

Only agent for ‘radical cure’ (benign malarias) - rapidly kills liver parasite (12 days), combine with blood schizonticide

Blocks oxidative phosphorylation in plasmodia?

S/E: safe for short term use - NVD, rarely cyanosis
C/I: G6PD deficiency

Question 17

G6PD deficiency?

Answer 17

Glucose-6-phosphate dehydrogenase deficiency

X-chromosome linked disorder
10% of Mediterranean and Afrocarribean patients

Primaquine causes:
Intravascular haemolysis
Severe anaemia

Test for G6PD activity before giving primaquine

Question 18

Spectrum of malaria risk?

Answer 18

1=very low, 3= moderate, 5=severe

1) avoid bites (N africa, urban far East, Argentina, Indian sub-continent)
2) Proguanil or chloroquine (Middle East, Central America)
3) Proguanil AND chloroquine (Southern Africa, Indonesia, Tropical S. America)
4) Mefloquine or malarone (Subsaharan Africa, Amazon basin, rural S/E asia)
5) Doxycycline (thailand)

Question 19

Malaria diagnosis/recognition

Answer 19

Recognise symptoms
Need rapid-acting blood schizonticide to which local Plasmodium is sensitive

• If >24 hours away from medical facilities, carry:
• Chloroquine* then Fansidar
• Mefloquine* then Fansidar
• Quinine then Fansidar
• Malarone
• Artemisinin-based combination therapy (ACT) - Riamet

*If not resistance

Monitor fevers up to one year after exposure