This document discusses various antimalarial drugs, their classifications, mechanisms of action, and uses in treating malaria caused by Plasmodium species. It highlights the increasing incidence of malaria due to drug resistance and details the effects of specific drugs including chloroquine, quinine, primaquine, and artemisinin derivatives. Additionally, it describes the pharmacokinetics, adverse effects, and clinical indications for these medications, emphasizing their roles in prevention, treatment of acute attacks, and reduction of transmission.

1. Antimalarial Drugs

2. Antimalarial drugs
• Malaria is a protozoal infection caused by genus Plasmodium and
transmitted to humans by the infected female Anopheles mosquito.
The species of malarial parasites are Plasmodium vivax, Plasmodium
ovale, Plasmodium malariae, P. Falciparum and Plasmodium knowlesi.
The incidence of malaria is increasing due to the resistance of vectors
to insecticides and drug-resistant parasites. In India, P. Vivax and P.
Falciparum are common.

3. Chemical classification
(a) 4-Aminoquinolines: Chloroquine, amodiaquine, piperaquine
(b) 8-Aminoquinolines: Primaquine, tafenoquine
(c) Quinoline methanol: Mefloquine
(d) Alkaloids: Quinine, quinidine
(e) Antifolates: Pyrimethamine, sulphadoxine, dapsone, proguanil
(f) Antibiotics: Doxycycline, clindamycin
(g) Hydroxynaphthoquinone: Atovaquone
(h) Artemisinins: Artemisinin, artemether, artesunate, arteether, arterolane,
dihydroartemisinin
(i) Aryl alcohol: Lumefantrine

4. Based on the stage of the life cycle of parasite
they affect
• (i) Tissue schizontocidal agents: These act on primary (pre-
erythrocytic) and latent (hypnozoites) tissue forms in the liver, e.g.
Primaquine is effective against both forms; atovaquone and proguanil
act on primary forms.

5. (ii) Blood schizontocidal agents:
These act on erythrocytic stage of Plasmodium and, thereby, terminate
the clinical attack.
• Rapid acting and high-efficacy agents, e.g. Chloroquine, artemisinin
derivatives, quinine, mefloquine, atovaquone, amodiaquine and
lumefantrine.
• Slow-acting and low-efficacy agents, e.g. Proguanil, pyrimethamine +
sulfadoxine and clindamycin; used always in combination with rapid-
acting agents.

6. (iii) Gametocidal agents
• These kill gametocytes of plasmodia in blood, e.g. Artemisinin and
primaquine (active against all species); chloroquine and quinine
(vivax). They reduce transmission to mosquitoes.

7. Based on clinical indication for use
• (i) Drugs used for causal prophylaxis, i.e. Act on pre-erythrocytic stage
of Plasmodium in liver, e.g. Proguanil and primaquine. Primaquine is
effective against all species but not used due to its toxic potential.
Proguanil is effective mainly for P. Falciparum.
• (ii) Drugs for suppressive prophylaxis: Suppress erythrocytic phase,
thus prevent clinical attack of malaria – clinical disease is not
manifested, e.g. Chloroquine, mefloquine and doxycycline.

8. • (iii) Drugs used for clinical cure: These agents act on erythrocytic
stages of malarial parasite to terminate the clinical attack. They
are rapid-acting and slow-acting blood schizontocidal agents.
• (iv) Drugs used to prevent relapse: These drugs act on the latent
tissue forms (hypnozoites) of P. vivax and P. ovale which cause
relapse, e.g. primaquine and tafenoquine.Radical cure of P.
vivax and P. ovale is achieved with the use of a blood
schizontocidal agent along with primaquine which acts on
latent tissue forms (hypnozoites) to prevent relapse.

9. • (v) Drugs used to prevent the transmission of infection to Anopheles
mosquito (gametocidal agents): Primaquine has gametocidal effect
against all species of plasmodia that infect humans.

10. Note: Points to remember
1. None of the agents available are effective against sporozoites.
2. Most of the antimalarials are effective against asexual blood stages except
primaquine.
3. Only primaquine and tafenoquine are effective against hypnozoites (latent tissue
forms).
4. All agents with ‘quine’ (primaquine, chloroquine, quinine and Quinghaosu) are
effective against gametocytes except mefloquine and tafenoquine.
5. Primaquine and proguanil are effective against hepatic primary tissue forms.

11. 4-Aminoquinolines
• Chloroquine
• Chloroquine is a 4-aminoquinoline. It is very effective and rapidly
acting blood schizontocide against P. Vivax, P. Ovale, P. Malariae,
chloroquine-sensitive strains of P. Falciparum and P. Knowlesi. It has
no activity against liver forms (pre-erythrocytic and hypnozoites).

12. Mechanism of action.
• Chloroquine is a basic drug, which is taken up by the acidic food
vacuoles of susceptible plasmodia and inhibits the conversion of
haeme to haemozoin. The ‘drug–haeme’ complex is toxic and kills the
parasite. Resistance to chloroquine is common with P. Falciparum.
•
• In the acidic vacuole of plasmodia:

13. Pharmacokinetics
• Chloroquine is commonly administered by oral route. It is well
absorbed after oral and parenteral administration. It has strong
affinity for melanin-containing tissues. It gets rapidly distributed to
tissues (extensive tissue binding); therefore, to achieve an effective
therapeutic plasma concentration, a loading dose is used during
treatment of malaria. It gets concentrated in liver, spleen, kidney,
lungs, skin, etc. Chloroquine is metabolized in the liver and slowly
excreted in urine.

14. Adverse effects and contraindications.
• Chloroquine in antimalarial doses may cause nausea, vomiting, skin
rashes, itching, headache and visual disturbances. Parenteral
administration can cause hypotension, confusion, cardiac
arrhythmias, convulsions and even cardiac arrest. Prolonged
administration in large doses, as in rheumatoid arthritis, may cause
irreversible retinopathy and ototoxicity. It can also cause myopathy,
cardiomyopathy, neuropathy and rarely psychiatric disturbances.
Long-term therapy requires ophthalmological examination once in 3–
6 months. It should be avoided in patients with epilepsy. It should not
be given with mefloquine (can precipitate seizures). It is safe for use
in pregnancy.

15. Uses
• Malaria
• (a) Chloroquine is the drug of choice for the treatment of acute attack
of malaria caused by P. Vivax, P. Ovale, P. Malariae, chloroquine-
sensitive P. Falciparum and P. Knowlesi (Table 12.22). Fever resolves
within 24–48 hours; blood smear becomes negative within 2–3 days.
• (b) For malaria due to P. Vivax and P. Ovale, primaquine is also
administered in addition to chloroquine (for radical cure).
• (c) Chloroquine is a very effective chemoprophylactic agent for all
types of malaria (Table 12.23) except that caused by the resistant
strains of P. falciparum

16. Other uses are as follows
• Amoebiasis – hepatic amoebiasis, as it is highly concentrated in the
liver.
• Lepra reaction – anti-inflammatory effect is useful.
• Rheumatoid Arthritis – it scavenges free radicals and stabilizes
lysosomal membrane.
• Infectious mononucleosis.
• Autoimmune disorder – discoid lupus erythematosus.
• Tablet chloroquine phosphate 500 mg = 300 mg chloroquine base
• Tablet chloroquine phosphate 250 mg = 150 mg chloroquine base

17. Alkaloids
• Quinine and quinidine
• Cinchona bark contains several alkaloids, of which quinine and
quinidine are important.
• Mechanism of action.
• It is similar to that of chloroquine.

18. Pharmacological effects
• 1. Antimalarial actions: Quinine is a highly effective blood
schizontocide against all the four species of plasmodia. It has
gametocidal activity against P. Vivax. It has no activity on hepatic
forms (i.e. Pre-erythrocytic and latent tissue forms).

19. Other actions
• (a) GIT: Being bitter, quinine reflexly increases gastric acid secretion.
• (b) CVS: Quinine directly depresses the myocardium and can cause
hypotension. But this effect may not be seen with oral antimalarial
doses.
• (c) Skeletal muscle: Quinine directly depresses the skeletal muscle
contraction. Response to Ach is also diminished – symptoms of
myasthenia gravis are exaggerated, while symptoms of myotonia
congenita are relieved.
• (d) CNS: In therapeutic doses, quinine often causes disturbances of
hearing and vision. It also has mild analgesic and antipyretic effects.

20. Local action
• Quinine has local anaesthetic effect, but there is invariably an initial
irritation. Orally, it causes GI irritation with nausea, vomiting and
abdominal discomfort. Intramuscularly, it causes local pain and
necrosis. Intravenously, it can cause thrombophlebitis.

21. Pharmacokinetics
• Quinine is readily absorbed from the gut or i.m. Site, well distributed
in the body, extensively metabolized in liver and excreted mainly in
urine.

22. Adverse effects.
• Quinine causes dose-dependent toxicities. They are cinchonism, hypoglycaemia
and hypotension. Cinchonism comprises tinnitus, deafness, visual disturbances
like blurred vision and colour defects, headache, nausea and vomiting. These
symptoms are reversible on stoppage of therapy. Hypoglycaemia is common with
i.v. Quinine which is due to release of insulin – it is treated with intravenous
glucose. Hypotension is also seen with intravenous administration of cinchona
alkaloids. Quinine in large doses can cause hypotension, cardiac arrhythmias and
A–V block. Quinidine is more cardiotoxic than quinine.
•
• ‘Blackwater fever’, a hypersensitivity reaction to quinine, is characterized by
haemolysis, haemoglobinaemia and haemoglobinuria leading to renal failure.
•
• Quinine/quinidine should not be used concurrently with mefloquine because of
risk of serious cardiac toxicity. Quinine can be used in pregnancy.

23. Uses
• 1. Malaria: Quinine is effective for treatment of acute attack of
chloroquine-resistant P. Falciparum malaria. Combination of
clindamycin or tetracycline with quinine enhances the antimalarial
efficacy of quinine. In severe malaria, quinine or quinidine is
administered intravenously.
• 2. Nocturnal leg cramps: Quinine may be effective in some cases.

24. Quinoline methanol
• Mefloquine
• It is a synthetic quinoline methanol. Like quinine, it is a highly
effective blood schizontocide and has no effect on hepatic forms, i.e.
Pre-erythrocytic stages and hypnozoites of P. Vivax. It has no
gametocidal activity.

25. Mechanism of action.
• It is similar to that of chloroquine and quinine. It binds to heme and
causes damage to membrane of Plasmodium

26. Pharmacokinetics
• Mefloquine is administered orally and is not suitable for parenteral
use because of its local irritant action. It is well absorbed, widely
distributed, highly bound to plasma proteins, secreted in bile and
undergoes extensive enterohepatic cycling. It is slowly excreted in the
faeces with a terminal half-life of about 3 weeks.

27. Uses
• Mefloquine is used for prophylaxis of chloroquine-resistant P.
Falciparum and P. Vivax malaria. It is used in combination with
artesunate for the treatment of chloroquine-resistant P. Falciparum
malaria.

28. Adverse effects.
• The common side effects include nausea, vomiting, diarrhoea and
dizziness. Nausea and vomiting can be minimized by dividing the
dose. Neuropsychiatric symptoms and seizures can occur. Mefloquine
is contraindicated in patients with conduction defects, epilepsy and
psychiatric disorders. It is safe for use in young children.

29. 8-Aminoquinoline
• Primaquine
• It is a synthetic 8-aminoquinoline. It is effective against hepatic stages, i.e. Primary and latent
tissue forms of Plasmodia species that infect humans. It also has marked gametocidal activity but
is ineffective against erythrocytic forms of malarial parasite. The exact mechanism of action of
primaquine is unknown. It probably acts by generating reactive oxygen radicals and interfering
with the mitochondrial electron transport in the parasite.
•
• It is almost completely absorbed after oral administration, widely distributed, metabolized in liver
and excreted slowly in urine.
•
• Primaquine is used for radical cure and terminal prophylaxis of P. Vivax and P. Ovale as it has
strong activity against hypnozoites. For terminal prophylaxis, primaquine 15 mg daily is started
shortly before or after return from an endemic area. For radical cure of relapsing malaria (P. Vivax
and P. Ovale), a 2-week course of primaquine is given concurrently with chloroquine or after the
treatment of acute attack.

30. Adverse effects
• These include nausea, vomiting and epigastric distress – can be
minimized by taking it with food. The important side effect with
primaquine is haemolytic anaemia in people with G6PD deficiency.
Methaemoglobinaemia can also occur with primaquine. Primaquine
is contraindicated in pregnancy.
•
• (Tablet primaquine phosphate 26 mg contains 15 mg base of
primaquine base.)

31. Tafenoquine
• It is an 8-aminoquinoline. It is very effective against latent tissue
forms (hypnozoites) of P. Vivax, and also has blood schizontocidal
activity. It has a longer duration of action (t½ is 15–19 days), hence
used as a single-dose antirelapse agent. It can cause hemolysis in
G6PD deficient individuals.

32. Antifolates
• They are pyrimethamine, sulfadoxine, sulfones (dapsone) and
proguanil. They are not used as single agents in malaria owing to
rapid development of resistance.

33. Sulfadoxine-pyrimethamine
• Mechanism of action
• Plasmodia utilize PABA for the synthesis of folic acid which, in turn, is
necessary for DNA synthesis. Sulfadoxine inhibits folate synthetase,
whereas pyrimethamine inhibits DHF reductase enzyme of the
parasite. Sulfadoxine and pyrimethamine have a long half-life (5–9
days and 4 days, respectively). Combination of these drugs
(pyrimethamine + sulfadoxine) inhibits two successive steps
(sequential blockade) in the folate pathway, acts faster and produces
enhanced antimalarial action (synergistic effect).

35. • The combination of pyrimethamine with sulfadoxine along with
artesunate is used in the treatment of chloroquine-resistant P.
Falciparum malaria. Pyrimethamine–sulfadiazine combination is the
treatment of choice for toxoplasmosis in immunocompromised
patients.
•
• Dapsone inhibits plasmodial folate synthetase. Proguanil
(chloroguanide) is an antifolate. It is used in combination with
atovaquone

36. • Pyrimethamine 25 mg
• +
• sulfadoxine 500 mg
• Pyrimethamine 25 mg
• +
• dapsone 100 mg

37. Atovaquone and proguanil
• Both atovaquone and proguanil are effective against erythrocytic stage and
primary tissue forms (hepatic stage) of P. Falciparum.
•
• Atovaquone (a hydroxyaphthoquinone) damages plasmodial mitochondrial
membrane; proguanil (antifolate) inhibits dihydrofolate reductase (combination is
synergistic).Adverse effects of these drugs are nausea, vomiting, diarrhea and
rashes.
•
• FDC of atovaquone-proguanil (Malarone) is used for prophylaxis of chloroquine
resistant P. Falciparum malaria.
•
• Atovaquone is also useful against T. Gondii and P. Jiroveci in
immunocompromised patients.

38. Artemisinin and its derivatives
• Artemisinin is derived from the plant Artemisia annua. The
semisynthetic derivatives of artemisinin are dihydroartemisinin,
artemether and artesunate. Another compound, arteether, was
developed in India.
•
• They are highly effective against erythrocytic stages of all plasmodia.
They also have gametocidal action – reduce transmission of malarial
parasite. They have no effect on hepatic stages of the parasite.

39. Mechanism of action

40. Pharmacokinetics
Dihydroartemisinin: Oral
• Artesunate: Oral,, i.m., i.v., rectal
• Artemether: Oral, i.m.
• Arteether: i.m.

41. • Artesunate and artemether are metabolized to the active metabolite,
dihydroartemisinin.
•
• Artesunate can enhance its own metabolism (autoinduction). The
half-life of dihydroartemisinin is about 2 hours. Arteether has a longer
half-life.

42. Adverse effects
• They are generally well tolerated. Artemisinins can cause mild GI
disturbances, neutropenia and prolongation of QT interval.

43. Arterolane
• It is a synthetic derivative of artemisinin which acts on erythrocytic
stages of the parasite. It is potent and has a rapid onset and short
duration of action. A combination of arterolane with piperaquine has
been found to be effective and well tolerated for the treatment of P.
Falciparum malaria.

44. Lumefantrine
• It is active against erythrocytic stages of all species of malarial
parasite. Fatty meal increases its absorption. It can cause GI
disturbances. It does not significantly prolong QT interval. It is used in
the treatment of P. Falciparum malaria in combination with
artemether.

45. Antibiotics
• Tetracyclines and clindamycin
• Tetracycline, doxycycline and clindamycin are slow-acting blood
schizontocides for all species of plasmodia that infect humans. They
do not affect hepatic stages. They are used in combination with
quinine or artesunate for the treatment of P. Falciparum malaria.
Doxycycline can also be used alone as a chemoprophylactic agent for
chloroquine resistant P falciparum malaria. Tetracyclines should not
be used in pregnancy and young children (younger than 8 years);
clindamycin can be used safely in such cases.

46. Treatment of malaria during pregnancy
• P. Vivax malaria is treated with chloroquine. For P. Falciparum malaria,
quinine with clindamycin is administered in first trimester; ACT in 2nd
and 3rd trimesters. Doxycycline and primaquine are contraindicated in
pregnancy.

47. Treatment of mixed infection due to both P.
Falciparum and P. vivax
• It should be treated as P. Falciparum malaria with ACT regimen
(except ACT regimen of artesunete + sulfadoxine-pyrimethamine as it
is not effective against P vivax). A 14 day course of primaquine is also
added.

48. Thank you