Easy way of remembering anti-malaria drugs and side effects..

1. ANTI-MALARIA DRUGS
PHARMACOLOGY
[DR S. N. KANYIMBA]

2. Introduction
Antimalarial medications (antimalarials) are drugs designed to
prevent or cure malaria
Antimalarials may be used for some or all of the following:
• Treatment of malaria in individuals with suspected or
confirmed infection
• Prevention of infection in individuals visiting a malaria-
endemic region who have no immunity (malaria
chemoprophylaxis)
• Routine intermittent treatment of certain groups in endemic
regions (intermittent preventive therapy) e.g. in pregnancy
2

3. Life cycle of Plasmodium *
3

4. Introduction …. cont’d
• Most antimalarial drugs target the erythrocytic stage of
malaria infection, which is the phase of infection that causes
symptomatic illness
• Treatment of the acute blood stage infection is necessary for
malaria caused by all malaria species
• For infection due to P. ovale or P. vivax, terminal prophylaxis is
required with a drug active against hypnozoites (which can
remain dormant in the liver for months, and occasionally
years, after the initial infection)
4

5. Drug treatment of malaria
• Current practice in treating cases of malaria is based on the
concept of combination therapy
• Advantages of combination therapy: (1) reduced risk of
treatment failure (2) reduced risk of developing resistance (3)
reduced adverse effects
• Prompt parasitological confirmation by microscopy or rapid
diagnostic tests, is recommended in all patients suspected of
malaria before treatment is started
• Treatment solely on the basis of clinical suspicion should only
be considered when a parasitological diagnosis is not
accessible
5

6. Classification of antimalarial agents
Drugs acting on intrahepatic stages
• Causal prophylactic drugs: inhibit liver stage from initiating
erythrocytic stage (tetracyclines, primaquine, proguanil,
atovaquone-proguanil, pyrimethamine)
• Hypnozoitocidal: destroy exo-erythrocytic hypnozoites of P. vivax
and P. ovale after treatment of acute erythrocytic phase to produce
radical cure (primaquine)
Drugs acting on erythrocytic stages
• Clinical cure: fast action on erythrocytic stages (artemisinin
derivatives and quinolines)
• Suppressive therapy: slower suppressive action on erythrocytic
stages (anti-folates, tetracyclines, clindamycin)
6

7. Classification of antimalarial agents …. Con’t’d
Gametocytocidal drugs
Destroy sexual forms of the parasite in erythrocytes preventing
transmission to mosquito (artemisinin derivatives, primaquine)
Sporonticidal drugs
Destroy sporozoites (primaquine, pyrimethamine, proguanil)
Chemoprophylaxis
• Causal prophylaxis: inhibit liver stage from initiating erythrocytic
stage (atovaquone-proguanil, primaquine, chloroquine,
pyrimethamine, proguanil, doxycycline)
• Clinical or suppressive prophylaxis: inhibit development of
merozoites in erythrocytes (atovaquone-proguanil, mefloquine,
proguanil, pyrimethamine, primaquine, dapsone)
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8. Five broad groups based on mechanism of action
1. Quinolines: Inhibit polymerisation of haem (toxic to plasmodia) to
haemozoin which is non-toxic, thus cause death of plasmodia
2. Artemisinins: 1. Binds haem iron and generate oxygen radicals
which damage proteins in the parasite 2. Damages Ca2+ ATPase
(calcium transporter)
3. Anti-folates: Inhibit DNA synthesis (pyrimethamine, proguanil,
sulfonamides and dapsone)
4. Atovaquone: inhibit electron transport chain in the mitochondria
5. Protein synthesis inhibitors (ribosome inhibition) - tetracyclines,
clindamycin
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9. SPECIFIC ANTI-MALARIA DRUGS
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10. Quinoline derivatives
• Include chloroquine, amodiaquine, quinine, quinidine,
mefloquine, primaquine, piperaquine, naphthoquine,
lumefantrine and halofantrine
• These drugs have activity against the erythrocytic stage of
infection (primaquine also kills intrahepatic forms and
gametocytes)
• The drugs act by accumulating in the parasite food vacuole
and forming a complex with haem
• They inhibit haem polymerase activity resulting in
accumulation of cytotoxic free haem (haem polymerase
polymerises haem to the non-toxic haemozoin)
10

11. 4-methanolquinolines: quinine and quinidine
Quinine is a derivative from the bark of the South American Cinchona
tree and exists in oral and parenteral forms
Quinidine is a stereoisomer of quinine available in parenteral
formulation and is very effective for treatment of severe malaria
Quinidine is a more active antimalarial but more cardiotoxic
Antimalarial effects
• Blood schizonticide for all human plasmodia species
• Weak gametocide against P. vivax and P. malariae
Adverse effects
Cinchonism: tinnitus, high tone hearing impairment, vertigo, nausea,
vomiting, abdominal pain, dysphoria, headaches, dizziness and
disturbed vision. These effects typically resolve with cessation of the
medication.
11

12. Quinine and quinidine …. cont’d
• Other adverse effects: hypersensitivity reactions,
neurotoxicity, skeletal muscle paralysis and hypoglycaemia
• Quinine is associated with blackwater fever in patients
sensitized to quinine (characterised by intravascular
haemolysis, haemoglobinuria, disseminated intravascular
coagulation and renal failure)
• Quinine and quinidine have a narrow therapeutic window;
overdosage may lead to cardiotoxicity, including arrhythmias
and hypotension, respiratory depression, blindness or
deafness
12

13. Quinine and quinidine …. cont’d
Uses
• Used in the treatment of severe, acute P.falciparum malaria
• Quinine can be given oral, IM or by slow IV infusion. For severe
disease, quinine is given IM or IV.
• Quinidine is given by slow IV infusion
• Quinine is safe in infants, children, pregnancy (all trimesters)
and lactation
Contra-indications
Hypersensitivity to quinine, quinidine or mefloquine, prolonged QT
interval, myasthenia gravis, optic neuritis, glucose-6-phosphate
dehydrogenase deficiency (intravascular haemolysis may occur),
history of black water fever, thrombotic thrombocytopenia
purpura, haemolytic uremic syndrome and thrombocytopenia
13

14. Mefloquine
• Structurally similar to quinine
• It is active against all the four human malaria pathogens: P.
falciparum, P. vivax, P. malariae and P. ovale
• It is a blood schizonticide with a long half-life
• Used in the treatment of acute malarial infections and prophylaxis of
chloroquine-resistant P. falciparum malaria
Adverse effects: Nausea, vomiting, diarrhoea, abdominal pain, dizziness,
neuropsychiatric manifestations (affective and anxiety disorders,
hallucinations, sleep disturbances, nightmares, psychosis, toxic
encephalopathy and convulsions) and bradycardia
Contra-indications: Seizure disorders, psychiatric disorders, children
under 2 years, patients with cardiac conduction abnormalities,
concurrent administration with drugs that alter cardiac conduction,
pregnancy
14

15. 4-aminoquinolines: chloroquine and amodiaquine
Chloroquine
• Has activity against the blood stages of P. ovale, P. malariae, and susceptible strains
of P. vivax and P. falciparum
• Uses: treatment of acute malaria for chloroquine-sensitive malaria strains (P. ovale,
P. malariae, and some strains of P. vivax) and chemoprophylaxis for susceptible
strains of plasmodium. Given orally. Parental chloroquine is very toxic and cause
severe hypotension.
• Widespread resistance in most malaria-endemic countries has led to decline in its
use for the treatment of P. falciparum, although it remains effective for treatment
of P. ovale, P. malariae, and, in most regions, P. vivax
• Adverse effects: Headaches, dizziness, abdominal discomfort, vomiting, diarrhea
and rashes , pruritus in some patients, neuromyopathy with long-term prophylaxis,
retinopathy with prolonged high doses (as in treatment of rheumatoid arthritis)
and idiosyncratic reactions, such as erythema multiforme and bone marrow
toxicity, and haemolysis in patients with G-6-PD deficiency. Can provoke psoriasis.
Cardiotoxic in high doses and when given parenterally.
15

16. Amodiaquine
• It is similar in structure to chloroquine
• There is cross resistance between chloroquine and amodiaquine,
although amodiaquine retains some activity against chloroquine
resistant parasites in vivo and in vitro
• Amodiaquine is commonly used in malaria endemic countries to
treat chloroquine-resistant infections and is available in co-
formulation with artesunate. Given orally.
• Adverse effects: GI effects, bradycardia, agranulocytosis and
hepatotoxicity
• Amodiaquine is not used for chemoprophylaxis (increased risk of
agranulocytosis and hepatotoxicity with repeated doses)
16

17. Primaquine (an 8-aminoquinoline)
• Active against blood schizonts (slow acting blood schizonticide), tissue
schizonts, hypnozoites of P.ovale and P. vivax, sporozoites and gametocytes of
P. falciparum
• Mechanism of action: inhibits haem polymerase and disrupts mitochondria
(blocking oxidative metabolism) and binds to DNA interfering with DNA
function
• It is largely used to effect radical cure of P.ovale and P. vivax (prevents relapse
of P. ovale and P. vivax malaria by eliminating dormant hypnozoites). It is given
in conjunction with chloroquine or artemisinin derivatives in the treatment of
P. ovale and P. vivax.
• Also used as a gametocytocidal drug in P. falciparum infections to prevent
transmission (in conjunction with another effective blood schizonticidal drug)
• It is given orally
• Adverse effects: anorexia, nausea, vomiting, abdominal cramps, chest pain,
weakness, anaemia, bone marrow suppression, intravascular haemolysis in
people with G-6-PD deficiency 17

18. Anti-folates
• Include sulfonamides, pyrimethamine, proguanil and dapsone
• These drugs inhibit enzymes involved in folate synthesis, a pathway
in the biosynthesis of purines and pyrimidines, thereby halting the
processes of DNA replication, cell division and reproduction
• Type 1 anti-folate drugs: sulfonamides and dapsone - inhibit
dihydropteroate synthetase [thus inhibit synthesis of folic acid]
• Type 2 anti-folate drugs: pyrimethamine and proguanil - inhibit
dihydrofolate reductase thereby blocking the conversion of
dihydrofolate to tetrahydrofolate [thus inhibit utilization of folic
acid]
• The sulfonamides used in malaria treatment include sulfadoxine
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19. Mechanism of action of anti-folates
19

20. Antimalarial activity and use of the anti-folates
Antimalarial activity
• Have activity on sporozoites (proguanil and pyrimethamine), hepatic
schizonts (proguanil, pyrimethamine) and blood schizonts (all the anti-
folates)
• Are slow acting compared to quinolines and artemisinins
• Combination of pyrimethamine with sulfonamide or dapsone is synergistic
Uses
• Treatment of malaria (pyrimethamine-sulfonamide combination) [used in
combination with artemisinins]
• Chemoprophylaxis (dapsone, proguanil, pyrimethamine-dapsone)
• Intermittent preventive therapy in pregnancy (sulfadoxine-
pyrimethamine)
Sulfonamides are not recommended for chemoprophylaxis because of severe
skin reactions experienced
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21. Adverse effects of the anti-folates
• All: mild adverse effects include gastrointestinal upset,
headache and skin rashes
• Pyrimethamine: bone marrow suppression, megaloblastic
anaemia with high doses
• Sulfonamides: severe cutaneous toxicity, including erythema
multiforme, Stevens-Johnson syndrome and toxic epidermal
necrosis. Sulfadoxine can precipitate hemolysis in patients
with G-6-P-D deficiency.
• Proguanil: hair loss and mouth ulcers
21

22. Anti-folates: contra-indications
• Hypersensitivity to any sulfonamide, pyrimethamine, or any
component of the formulation
• Porphyria
• Megaloblastic anemia
• First trimester of pregnancy
• Sulfonamides: G-6-P-D deficiency, children <2 months of age
due to competition with bilirubin for protein binding sites (can
result in kernicterus); pregnancy (at term)
• Repeated prophylactic use of anti-folates is contraindicated in
patients with renal failure, hepatic failure, or blood dyscrasias
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23. Atovaquone-proguanil
• Atovaquone inhibits electron transport in mitochondria resulting in the
inhibition of key metabolic enzymes responsible for the synthesis of
nucleic acids and ATP
• Acts on hepatic schizonts and merozoites
• It is used for treatment and chemoprophylaxis of P. falciparum malaria
(always in combination with proguanil for synergy and to prevent
emergence of resistance). The combination retains excellent clinical
efficacy for P. falciparum treatment and prevention throughout the world
even in the presence of anti-folate resistance.
• It is administered orally with meals (absorption is significantly increased
with a high-fat meal)
• Adverse effects include: abdominal pain, vomiting, diarrhea, headache
and pruritus and transient increases in transaminases
• Contraindications: life-threatening allergic reaction to atovaquone or any
component of the formulation
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24. Halofantrine
• Halofantrine is chemically related to quinine and acts acting as a
blood schizonticide effective against all plasmodium parasites
• Use: treatment of multidrug resistant P. falciparum malaria
• Oral absorption is increased by a fatty meal and it has very variable
bioavailability
• Adverse effects: ventricular arrhythmias (prolongation of PR and QT
interval) – has been associated with death. Cardiotoxicity has limited
its use.
• Other adverse effects include nausea, abdominal pain, diarrhea, and
pruritus
• Contraindications: heart disease, infants and young children (weight
under 10 kg), pregnancy, lactation, patients that have taken
mefloquine previously
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25. Lumefantrine
• Is similar in structure to halofantrine, quinine and mefloquine, and has
same mechanism of action
• Is active against most chloroquine-resistant parasites although there is
cross-resistance with halofantrine and mefloquine
• Lumefantrine is a long-acting drug always given in combination with
artemether in a widely used fixed-dose combination (Zambia has adopted
this combination as first line antimalarial)
• The bioavailability is highly variable and increases up to three-to-four fold
when taken with a high fat meal
• Lumefantrine is well tolerated, with rare mild adverse reactions such as
diarrhea, nausea, abdominal pain and vomiting
• There is no evidence of significant cardiotoxicity associated with
lumefantrine use
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26. Artemisinin derivatives
• The artemisinins are derived from the leaves of the Chinese sweet
wormwood plant, Artemisia annua
• They have been used in China for the treatment of malaria for over
2000 years and came to attention outside of China in the 1970s and
1980s
• Artemisinins act by binding iron in haem, leading to the generation of
free oxygen radicals that damage parasite proteins. Binds and inhibits
Ca2+ ATPase (calcium transporter).
• They act rapidly, killing blood stages of all plasmodium species
• Artemisinins have the fastest parasite clearance times of all
antimalarials currently used
• Artemisinins act primarily on the trophozoite phase and are also active
against gametocytes, the parasite form that is infectious to mosquitoes,
and their use has been associated with reduced malaria transmission
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27. Artemisinin derivatives in clinical use
1. Artemisinin
2. Dihydroartemisinin: active metabolite to which artemisinin is
reduced. It is the most effective artemisinin compound and
the least stable.
3. Artemether: a methyl ether derivative of dihydroartemisinin.
Used in a fixed-dose combination with lumefantrine.
4. Artesunate: a hemisuccinate derivative of the active
artemisinin metabolite dihydroartemisin. Currently it is the
most frequently used of all the artemesinin-type drugs. It is
mostly used in combination therapy (with SP, mefloquine and
amodiaquine). Given IV or IM for severe malaria.
5. Arte-ether: an ethyl ether derivative of dihydroartemisinin
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28. Artemisinin derivatives …. cont’d
Clinical use of artemisinin derivatives
• WHO recommends the use of artemisinins (in combination with other
anti-malarials) as first line drugs for the treatment of P. falciparum malaria
• Treatment of severe malaria: IV/IM artesunate (it is superior to quinine for
treatment of severe malaria with respect to clearing parasitemia and
reducing mortality)
Adverse effects
• Artemisinins are generally well tolerated
• Adverse effects that have been associated with artemisinins include
headaches, nausea, vomiting, abnormal bleeding, dark urine, itching, drug
fever, transient neurological abnormalities (nystagmus and disturbances in
balance) and Type 1 hypersensitivity reactions
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29. Tetracyclines (doxycycline & tetracycline) and clindamycin
• Inhibit protein synthesis
• They all act on the trophozoite stage (erythrocytic). Tetracyclines
also act on hepatic schizonts.
• Tetracycline and doxycycline are used in combination with quinine
or artemisinin derivatives for the treatment of acute cases of P.
falciparum infections. Doxycycline has a longer half life than
tetracycline so is used more commonly.
• Clindamycin is used in conjunction with quinine for the treatment
of acute cases of P. falciparum malaria
• Tetracyclines and clindamycin have a very slow anti-malaria action
and should not be used as monotherapy for treatment of malaria
• Doxycycline is also used for P. falciparum malaria chemoprophylaxis
in areas where chloroquine resistance exists
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30. Malaria treatment failure
Why antimalarial drug treatments don’t always work:
• Wrong diagnosis
• Incorrect choice of drugs
• Sub-optimal regimen (dose, schedule, duration)
• Non-adherence
• Sub-optimal absorption (nausea, diarrhea, vomiting,
malabsorption)
• Idiosyncratic pharmacokinetics (e.g. increased drug elimination)
• Poor quality drugs
• Interactions with other pharmaceuticals
• Resistance of the pathogen to the drug
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31. Antimalarial resistance
• Antimalarial resistance is common
• Anti-malarial drug resistance has been defined as: "the ability of a
parasite to survive and/or multiply despite the administration and
absorption of a drug given in doses equal to or higher than those
usually recommended but within tolerance of the subject”
• The drug in question must gain access to the parasite or the
infected red blood cell for the duration of the time necessary for its
normal action
• Cases where anti-malarial prophylaxis has failed are excluded
• Drug resistance is caused by spontaneous mutations that result in
reduced sensitivity of the parasite to the antimalarial drug
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32. Combination therapy
Combination therapy is 'the simultaneous use of two or more blood
schizonticidal drugs with independent modes of action and different
biochemical targets in the parasite'.
Combination therapy reduces the emergence of resistant strains and
optimizes parasite clearance thus improving cure rates, with greater
reduction in morbidity and mortality compared to monotherapy
To realize the two advantages, the partner medicines in a combination
must independently be sufficiently efficacious in treating malaria
The combinations of drugs currently prescribed can be divided into
two categories:
1. Non-artemisinin based combinations
2. Artemisinin based combinations (ACTs)
32

33. Non-artemisinin based combinations
Sulfadoxine-pyrimethamine (SP)
This fixed-dose combination has been used for many years, causes few
adverse effects, is cheap and effective in a single dose, thus decreasing
problems associated with adherence and compliance. In technical terms
SP is not generally considered a true combination therapy since the
components do not possess independent curative activity (they have the
same biochemical target). SP should no longer be used alone for
treatment of falciparum malaria.
Quinine plus tetracycline/doxycycline
This combination retains a high cure rate in many areas.
Quinine plus clindamycin
Similar cure rate to quinine + tetracycline, therefore is an appropriate
alternative regimen
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34. Artemisinin-based combination therapies (ACTs)
• In general, artemisinins should not be used as a single agent,
to prevent emergence of drug resistance and to avoid the
need for prolonged therapy
• ACTs combine the highly effective short-acting artemisinins
with a longer-acting partner to protect against artemisinin
resistance and to facilitate dosing convenience
• Examples of ACTs: (1) artemether-lumefantrine (2)
artesunate-amodiaquine (3) artesunate-mefloquine (4)
artesunate-sulfadoxine-pyrimethamine (5)
dihydroartemisinin-piperaquine (6) artemisinin-naphthoquine
34

35. Artemisinin-based combination therapies (ACTs) …. cont’d
• Artemisinins have a very different mode of action from other
anti-malarials and this makes them particularly useful in the
treatment of resistant infections
• However in order to prevent the development of resistance to
artemisinins, it is recommended that they are only used in
combination with another non-artemisinin based therapy
• Artemisinins produce a very rapid reduction in the parasite
biomass and cause a reduction in the transmission of
gametocytes, thus decreasing the potential for the spread of
resistant strains
• At present there is no known resistance to artemisinins
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36. ENDE