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1. CHEMOTHERAPY

2. ANTI-MALARIAL DRUGS
Dr Sindwa Kanyimba
Lecturer, Pharmacology

3. INTRODUCTION
•
•
•
Anti-malarial drugs are designed to prevent or cure malaria
Anti-malarial drugs 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

4. INTRODUCTION …. CONT’D
Most anti-malarial 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)

5. LEARNING OBJECTIVES
1.
2.
3.
To classify anti-malarial drugs according to plasmodium
life-cycle stage affected, chemoprophylactic use and
mechanism of action
To describe the mechanisms of action of anti-malarial
drugs
Describe the relevant pharmacology (mechanisms of
actions, clinical indications, adverse effects, drug
interactions, precautions and contraindications) of
selected anti-malarial drugs

6. Life cycle of Plasmodiu*m
6

7. 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
7

8. CLASSIFICATION BASED ON LIFE-CYCLE STAGE
AFFECTED BY THE DRUG
•
•
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)
8

9. CLASSIFICATION BASED ON LIFE-CYCLE STAGE
AFFECTED BY THE DRUG …. CONT’D
•
•
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)
9

10. CLASSIFICATION BASED ON LIFE-CYCLE STAGE
AFFECTED BY THE DRUG …. CONT’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)
10

11. CLASSIFICATION BASED ON CHEMOPROPHYLACTIC
USE
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)
11

12. CLASSIFICATION BASED ON MECHANISM OF ACTION
1.
2.
3.
4.
5.
Quinolines: Inhibit polymerisation of haem (toxic to
plasmodia) to haemozoin which is non-toxic, thus cause
death of plasmodia
Artemisinins: 1. Binds haem iron and generate oxygen
radicals which damage proteins in the parasite 2. Damages
Ca2+ ATPase (calcium transporter)
Anti-folates: Inhibit DNA synthesis (pyrimethamine,
proguanil, sulfonamides and dapsone)
Atovaquone: Inhibits electron transport chain in the
mitochondria
Tetracyclines and clindamycin: Inhibit protein synthesis
(ribosome inhibition)
12

13. SPECIFIC ANTI-MALARIAL DRUGS
13

14. QUINOLINE DERIVATIVES
•
•
•
•
Include:
4-Methanolquinolines: quinine and quinidine
4-Aminoquinolines: chloroquine and amodiaquine
8-Aminoquinolines: primaquine and tafenoquine
Others: mefloquine, piperaquine, naphthoquine,
lumefantrine and halofantrine
14

15. QUINOLINE DERIVATIVES: MECHANISM OF ACTION
•
•
•
Quinolines have activity against the erythrocytic stage
of infection (primaquine also kills intrahepatic forms
and gametocytes)
They 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)
15

16. QUININE 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 anti-malarial than quinine
but more cardiotoxic
16

17. QUININE QUINIDINE …. CONT’D
•
•
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.
17

18. QUININE QUINIDINE …. CONT’D
•
•
•
Other adverse effects: Hypersensitivity reactions,
neurotoxicity, skeletal muscle paralysis and
hypoglycaemia
Quinine is associated with black-water 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
18

19. QUININE QUINIDINE: CLINICAL 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, in therapeutic doses, is safe in infants, children,
pregnancy (all trimesters) and lactation
19

20. QUININE QUINIDINE: CONTRAINDICATIONS
•
•
•
•
•
•
•
•
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
Haemolytic uremic syndrome
Thrombotic thrombocytopenia purpura and
thrombocytopenia
20

21. 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
21

22. MEFLOQUINE …. CONT’D
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
22

23. 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
23

24. CHLOROQUINE: ADVERSE EFFECTS
Include:
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.
24

25. 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)
25

26. PRIMAQUINE
•
•
•
Mechanism of action: Disrupts mitochondria (blocking
oxidative metabolism) and binds to DNA interfering with
DNA function
Active against blood schizonts (slow acting blood
schizonticide), tissue schizonts, hypnozoites of P.ovale and
P. vivax, sporozoites and gametocytes of P. falciparum
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.
26

27. PRIMAQUINE …. CONT’D
•
•
•
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
27

28. TAFENOQUINE
•
•
•
Analogue of primaquine with similar mechanism of
action and same clinical indications
The main advantage of tafenoquine is that it has a long
half-life (2–3 weeks) and therefore a single treatment
may be sufficient to clear hypnozoites
Like primaquine, tafenoquine causes hemolysis in
people with G6PD deficiency
28

29. ANTI-FOLATES
•
•
•
•
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
29

30. MECHANISMS OF ACTION OF ANTI-FOLATES
30

31. ANTI-FOLATES: ANTI-MALARIAL 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
31

32. ANTI-FOLATES: INDICATIONS IN MALARIA
1.
2.
3.
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
32

33. ANTI-FOLATES: ADVERSE EFFECTS
•
•
•
•
All: 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
33

34. 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
34

35. 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.
35

36. ATOVAQUONE-PROGUANIL …. CONT’D
•
•
•
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
36

37. HALOFANTRINE
•
•
•
Halofantrine is chemically related to quinine and acts
acting as a blood schizonticide effective against all
plasmodium parasites
Use: Treatment of multi-drug resistant P. falciparum
malaria
Oral absorption is increased by a fatty meal and it has
very variable bioavailability
37

38. HALOFANTRINE …. CONT’D
•
•
Adverse effects
Ventricular arrhythmias (prolongation of PR and QT interval)
that have 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, and patients that have taken
mefloquine previously
38

39. 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)
39

40. LUMEFANTRINE …. CONT’D
•
•
•
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
40

41. 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).
41

42. ARTEMISININS …. CONT’D
•
•
•
Artemisinins act rapidly, killing blood stages of all
plasmodium species
Artemisinins have the fastest parasite clearance times
of all anti-malarials 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
42

43. EXAMPLES OF ARTEMISININ DERIVATIVES
1.
2.
3.
Artemisinin
Dihydroartemisinin: Active metabolite to which
artemisinin is reduced. It is the most effective
artemisinin compound and the least stable.
Artemether: A methyl ether derivative of
dihydroartemisinin. Used in a fixed-dose combination
with lumefantrine.
43

44. EXAMPLES OF ARTEMISININ DERIVATIVES
4.
5.
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.
Arte-ether: An ethyl ether derivative of
dihydroartemisinin
44

45. ARTEMISININS: CLINICAL USE
•
•
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)
45

46. ARTEMISININS: 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
46

47. PYRONARIDINE
•
•
•
•
•
Mechanism of action: Unknown
Well absorbed orally
Used in combination with artesunate. Artesunate-
pyronaridine has generally demonstrated excellent
efficacy against falciparum and vivax malaria.
It is generally well tolerated
Adverse effects include eosinophilia and elevated
aminotransferases
47

48. TETRACYCLINES 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.
48

49. TETRACYCLINES CLINDAMYCIN …. CONT’D
•
•
•
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
49

50. CAUSES OF MALARIA TREATMENT FAILURE
•
•
•
•
•
•
•
•
•
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
50

51. ANTI-MALARIAL DRUG RESISTANCE
•
•
•
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 anti-
malarial drug
51

52. ANTI-MALARIAL DRUG 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
52

53. ANTI-MALARIAL DRUG COMBINATION THERAPY ….
CONT’D
1.
2.
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:
Non-artemisinin based combinations
Artemisinin based combinations (ACTs)
53

54. 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.
54

55. NON-ARTEMISININ BASED COMBINATIONS ….
CONT’D
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
55

56. 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 (7) Artesunate-pyronaridine
56

57. ARTEMISININ-BASED COMBINATION THERAPIES ….
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
57

58. END