Wk 1 - Pharmacology: Anti-Malarial Drugs Flashcards
What is malaria?
Febrile illness in which circulating red cells are haemolysed by repeated attacks of protozoan parasites (Plasmodium spp.)
What organism causes most malaria cases and almost all malaria-related deaths?
Protozan parasite ‘plasmodium falciparum’
List the different Plasmodium species that cause malaria.
-
Falciparum
- Most malignant tertian malaria
- ‘Blackwater fever’
- 50% of cases, 95% of deaths
-
Vivax/ovale
- Moderate, ‘benign’ tertian
- Dormant liver infections
-
Malariae
- Mild, quartan
- Long-term dormant liver parasite
Briefly describe the life cycle of the malaria parasite.
- Malaria infection begins when an infected female Anopheles mosquito bites a person, injecting Plasmodium parasites, in the form of sporozoites, into the bloodstream.
- The sporozoites pass quickly into the human liver (do not hang in circulation so cannot be attacked by immune system).
- The sporozoites multiply (x10-40K) in the liver cells over the next 5-12 days, causing no symptoms.
- In the bloodstream, the merozoites invade red blood cells (erythrocytes) and multiply again (x10-20 fold) until the cells burst.
- Then they invade more erythrocytes. This cycle is repeated, causing fever each time parasites break free and invade blood cells.
- Small leftover from the RBCs block vessels + other RBCs become gametocytes, which are taken up by other mosquitos then spread further to other humans.
What’s the difference between tertian and quartan malarias?
- Tertian: fever is on FIRST and THIRD days (every TWO days)
- Quartan: fever is on FIRST and FOURTH days (every THREE days)
List the 4 stages of malaria (p.vivax).
- Premonitory: lassitude (ie tiredness and fatigue)
- Cold stage: shivering, 15-60 mins
- Hot stage: fever, 2-6 hours
- Sweating: exhausted sleep, 2-10 hours
P.falciparum -
- Fever, 16-36 hours
- Renal failure
- Cerebral malaria -> coma
What are the ABCDs of malaria prevention?
- Awareness: know the risks
- Bites by mosquitoes: prevent or avoid
- Comply with Chemoprophylaxis
- Diagnose breakthrough malaria swiftly
How do you prevent malaria? (nb this is related to places like the UK - mainly people TRAVELLING not people living in countries with high levels of malaria).
Preventative measures: No adverse effects, but low efficacy!
-
Lifestyle:
- Air-conditioned hotel or camping?
- Dusk & dawn exposure, stagnant water
-
Barriers:
- Clothing
- Mosquito netting (beds, windows/doors)
- Skin repellent (DEET)
-
Insecticides:
- Knock-down sprays
- Room repellents / insecticides (permethrin)
What are the different ‘types’ of chemoprophylaxis?
- Causal (True) prophylaxis:
- prevent liver infection (not possible to do this practically)
-
Clinical prophylaxis:
- suppress blood parasites until risk of re-infection from liver is low (what we actually do)
- Radical cure:
- eliminate existing liver infection
When are clinical prophylaxis usually given?
- 2-3 weeks before travel
- During malaria exposure
- 4 weeks after return (most typical approach)
What are schizonticides?
Group of drugs used in prophylaxis ‘treatment’ of malaria
List the different prophylaxis drug groups used in malaria.
- Rapid-acting blood schizonticides e.g. quinine, chloroquine and mefloquine
- Slow-acting blood schizonticides e.g. folate inhibitors, proguanil and pyrimethamine
What are quinine, chloroquine and mefloquine?
Rapid-acting blood schizonticides
What is the mechanism of action of rapid-acting blood schizonticides?
Mechanism of action: not entirely clear!
- Bind to haemin (Hb breakdown product)
-
Concentrated 100-fold in infected RBCs
- Intercalation in plasmodial DNA?
- Increase in lysosomal pH of malarial parasite so stop them from digesting RBC?
- These drugs do NOT kill liver parasite
What is Chloroquine used for?
- Acute malarial infection: high doses clear parasitaemia in 3-4 days
- Clinical prophylaxis: weekly dose
Nb chloroquine-resistant falciparum is common
List some of the adverse effects of Chloroquine when prescribed as prophylaxis.
- NVD
- Retinopathy
- Hypersensitivity (skin reactions)
When is the use of Chloroquine contra-indicated?
- Ocular disease
- Hepatic disease
What is Mefloquine (Lariam) used for?
- Chloroquine-resistant falciparum
- Acute malaria: 3-4 day course
- Clinical prophylaxis
List the main adverse effects of Mefloquine.
- NVD
- Neuropsychiatric disorder (VERY RARE - serious, 0.01%, mild 0.1-1%)
Nb risk of mefloquine SE is LOWER than risk of falciparum malaria (so take the drug)
When is use of Mefloquine contraindicated?
- Depression
- Fits
- Epilepsy
Nb remember risk of drug SE is much lower than risk of malaria so still think of giving the prophylaxis
What are folate inhibitors, proguanil and pyrimethamine?
Slow-acting blood schizonticides
What is the mechanism of action of folate inhibitors (i.e. slow-acting schizonticides)?
Specific inhibition of plasmodial DHF reductase (BUT NOT HUMAN DHF reductase)
List the uses of slow-acting blood schizonticides.
- Slow-acting, used mainly for prophylaxis, daily dosing
- Suppress blood infection (clinical prophylaxis)
- Partly prevent liver infection (causal proph.)
- No effect on established liver infection
What other group of drugs are often prescribed with slow-acting blood schizonticides?
Sulphonamides (antibacterials) bs both act on DHF pathway
List the S/E of the Sulphonamide component in combined Pyrimethamine/Sulphonamide drugs.
- Sever skin reactions (this is why this drug not used as much)
- Fatal hepatitis (v rare)
What is Proguanil?
- Slow-acting blood schizonticide
- Often used alone (safe during pregnancy) or with atovaquone (C/I in pregnancy)
- Pro-drug – cycloguanil is the active metabolite
Name the active metabolite in Proguanil.
Cycloguanil
List some of the S/E of Proguanil.
- Mild NVD
- Mild mouth ulcers
What is Malarone?
Combination drug of Proguanil and Atovaquone
What is the mechanism of action of Atovaquone?
Inhibits Plasmodial mitochondria
What is Malarone used for? (and at what dosing)?
- Prophylaxis
- 1 tablet a day
- 1 day before
- during
- 1 week after
Name the drug that is 95-100% effective against drug-resistant falciparum.
Malarone (Proguanil + Atovaquone) - over 10 to 12 weeks treatment
List the S/E of Malarone.
NVD
When is Malarone contraindicated?
- Renal failure
- Pregnancy
When is Doxycycline (tetracycline antibiotic) given in malaria treatment?
- Prophylaxis of mefloquine-resistant falciparum
- Useful in Px intolerant to other drugs
What are the S/E of Doxycycline (tetracycline antibiotic)?
Photosensitivity* (3%) but sometimes very severe
*An extreme sensitivity to ultraviolet (UV) rays from the sun and other light sources
When is Doxycycline (tetracycline antibiotic) contraindicated?
- Pregnancy
- Lactation
- Children under 12
What are liver schizonticides?
- Only agent for radical cure (of benign malaria)
- Rapidly kills liver parasites (12 days)
- Often combined with blood schizonticide
Name a liver schizonticide drug.
Primaquine
What is the mechanism of action of liver schizonticides?
Blocks oxidative metabolism in plasmodia (unclear?)
List some S/E of Primaquine.
- Safe for short-term use
- NVD
- RARELY cyanosis
When is Primaquine contraindicated?
With people who have glucose-6-phosphate dehydrogenase deficiency!
What do you need to test for BEFORE prescribing Primaquine?
G6PD
Why is Primaquine C/I in G6PD?
Because it can cause:
- Intravascular haemolysis
- Severe anaemia
What is emergency treatment for malaria? (Nb always subject to change, check with BNF)
Rapid-acting blood schizonticide to which local Plasmodium is sensitive
What are some malaria emergency kits that can be found on in local pharmacies (ie in the UK)?
If >24 hrs away from medical facilities, carry:
- Chloroquine* then Fansidar® (pyrimethamine/sulphadoxine)
- Mefloquine* then Fansidar® (*if no resistance)
- Quinine then Fansidar®
- Malarone®
- Artemisinin-based combination therapy (ACT) (Riamet®)
What is ‘Fansidar’?
Combination drug of Pyrimethamine and Sulphadoxine
What is Maloprim?
Combination drug of Pyrimethamine and Dapsone
