5. Antimalarial agents
• Malaria is one of the most common diseases
worldwide and a leading cause of death.
• Plasmodium species that infect humans:
– P falciparum,
– P malariae,
– P ovale,
– P vivax
6. • Upon inoculation by an infected mosquito, the parasites
undergo a primary developmental stage in the liver and then
parasitize erythrocytes.
• P falciparum and P malariae have only 1 cycle of liver cell
invasion.
• The other species- P ovale and P vivax- have a dormant
hepatic stage responsible for recurrent infections and
relapses.
• Mechanism of action:
– Primary tissue schizonticides (eg, primaquine) kill schizonts in the
liver
– Blood schizonticides (eg, chloroquine, quinine) kill these parasitic
forms only in the erythrocyte.
– Sporonticides (proguanil, pyrimethamine) prevent sporogony and
multiplication in the mosquito.
7. Chloroquine
• A blood schizonticide
• The drug is rapidly absorbed when given
orally,
– is widely distributed to tissues, and has an
extremely large volume of distribution.
• Antacids may decrease oral absorption of the drug.
– Chloroquine is excreted largely unchanged in the
urine
Antimalarial agents
8. • Uses:
– Prophylaxis and treatment in areas without resistant P
falciparum;
• Currently not in use in Kenya due to resistance
– Treatment of acute attacks of P vivax and P ovale malaria
(Chloroquine is not active against liver stage parasites and
therefore does not eliminate P vivax and P ovale)
• Adverse reactions
– GI distress,
– rash,
– headache;
– auditory dysfunction and retinal dysfunction (high dose)
9. Quinine
• A blood schizonticide.
• Pharmacokinetics
– Quinine can be administered either orally or
parenterally
– When given orally the drug is rapidly absorbed
– metabolized before renal excretion.
– Intravenous administration of quinine is indicated
in severe infections.
• Clinical Use
– Treatment of multidrug-resistant malaria
Antimalarial agents
11. – Blackwater fever: a rare severe illness that includes
marked hemolysis and hemoglobinuria occurring in
quinine-sensitized persons.
– Therapeutic doses of quinine may cause hypoglycemia; the
drug stimulates insulin release
– Severe overdose results in disturbances in cardiac
conduction that resemble quinidine toxicity- QT interval
prolongation
Quinine is not contraindicated in pregnancy, but should be
used with caution due to associated risks:
– Hypoglycemia
– Stimulation of uterine contractions especially in the third
trimester
12. Mefloquine
• Its mechanism of action is not known
• Because of local irritation, mefloquine can only be
given orally, although it is subject to variable
absorption.
• Clinical Use
– Prophylaxis and treatment in areas with chloroquine
resistant P falciparum
– Mefloquine is an alternative drug to quinine in acute
attacks and uncomplicated infections resulting from P
falciparum
Antimalarial agents
14. Primaquine
• A tissue schizonticide
– Also limits malaria transmission by acting as a
gametocide
• Pharmacokinetics:.
– Absorption is complete after oral administration
and is followed by extensive metabolism.
• Clinical Use
– Eradication of liver stages of P vivax and P ovale.
Antimalarial agents
15. • Adverse reactions:
– GI distress,
– Methemoglobinemia: excess methemoglobin in
blood
• Methemoglobin is an oxidized form of hemoglobin that
has a decreased affinity for oxygen, resulting in an
increased affinity of oxygen to other heme sites and
overall reduced ability to release oxygen to tissues
– Hemolysis in G6PD deficiency.
Primaquine is contraindicated in pregnancy.
16. Antifolate Drugs
• Pyrimethamine
• Proguanil
• Sulfadoxine
• Dapsone
• Pharmacokinetics:
– All these drugs are absorbed orally and are
excreted in the urine, partly in unchanged form.
– Proguanil has a shorter half-life (12–16 h) than
other drugs in this subclass (half-life >100 h).
Antimalarial agents
17. • Mechanisms of Action
– Blood schizonticides
– Sulfonamides act as antimetabolites of PABA and block
folic acid synthesis in certain protozoans by inhibiting
dihydropteroate synthase.
– Proguanil (chloroguanide) is bioactivated to cycloguanil.
– Pyrimethamine and cycloguanil are selective inhibitors
of protozoan dihydrofolate reductases.
– The combination of pyrimethamine with sulfadoxine has
synergistic antimalarial effects through the sequential
blockade of 2 steps in folic acid synthesis.
18. • Clinical Use
– Pyrimethamine with sulfadoxine (Fansidar):
• used in the treatment of chloroquine-resistant forms P.
falciparum.
• However, the combination is not currently in routine use
in Kenya due to resistance;
– Proguanil with atovaquone (Malarone):
• used (daily) for chemoprophylaxis of chloroquine-
resistant malaria
• also protective against mefloquine-resistant falciparum
strains
Antimalarial agents
19. • Adverse reactions:
– skin rashes,
– gastrointestinal distress,
– hemolysis,
– kidney damage
– folic acid deficiency.
• Drug interactions may occur due to
competition for plasma protein binding sites
20. Artemisinin derivatives
• Artemisinin is isolated from the plant
Artemisia annua
• Drugs:
– Artesunate:
– Artemether,
– Dihydroartemisinin
Antimalarial agents
21. • Artemisinins are blood schizonticides active
against P falciparum and P vivax,
– including multidrug-resistant strains.
• Artemisinin derivatives are preferably used in
combinations with other antimalarial agents:
– Lumefantrine (Artemether- lumefantrine)
– Mefloquine (Artesunate-mefloquine)
– Amodiaquine (Artesunate-amodiaquine)
– SP antimalarials
22. • Preparations available in both oral and parenteral
formulations (IM)
• Clinical use:
– Indicated for all forms of malaria,
• Severe and multidrug resistant malaria
• These drugs are not used for chemoprophylaxis because of
their short half-lives
• Adverse effects:
– nausea,
– Vomiting
– diarrhea.
• The safety of artemisinin drugs in pregnancy has not been
established.
Antimalarial agents
23. • Other antimalarials:
– Doxycycline: used for prophylaxis
– Amodiaquine:
• available in combination with artesunate
– Atovaquone: used in combination with proguanil for
prophylaxis
– Halofantrine/lumefantrine:
• Halofantrine: Not used currently for prophylaxis due to its
associated QT prolongation
• Lumefantrine is preferred in combination with artemether
(AL)
Antimalarial agents
24. Drugs for Amebiasis
• Based on site of action, amebicides may be
classified into:
– Tissue amebicides: act in the intestinal tissue
• emetine,
• metronidazole,
• tinididazole
– Luminal amebicides: act in the intestinal lumen
• diloxanide furoate,
• iodoquinol,
• Paramomycin ( aminosidine)
See TABLE 52–2 Drugs used in the treatment of
amebiasis
25. Drugs used in the treatment of amebiasis
Disease Form Drug(s) of Choice Alternative Drug(s)
Asymptomatic, Intestinal
infection
Diloxanide furoate Iodoquinol, paramomycin
Mild to moderate intestinal
infection
Metronidazole or tinidazole
plus luminal agent (see above)
Tetracycline, or erythromycin
plus luminal agent
Severe intestinal infection Metronidazole or tinidazole
plus luminal agent
Tetracycline or emetine or
dihydroemetine plus luminal
agent
Hepatic abscess and other
extraintestinal disease
Metronidazole or tinidazole
plus luminal agent
Emetine or dihydroemetine
plus chloroquine (for liver
abscess) plus luminal agent
26. Drugs used in the treatment of other protozoal
infections
• Includes:
– Melarsoprol
– Metronidazole
– Nifurtimox
– Pentamidine
– Pyrimethamine plus clindamycin or sulfadiazine plus folinic
acid
– Sodium stibogluconate
– Suramin
– Trimethoprim-sulfamethoxazole
See TABLE 52–3: Drugs used in the treatment of other
protozoal infections
28. Antihelminthic Drugs
• Antihelminthic drugs have diverse chemical
structures, mechanisms of action, and properties.
• Most were discovered by empiric screening
methods;
– many act against specific parasites, and few are
devoid of significant toxicity to host cells.
• In addition to the direct toxicity of the drugs,
– reactions to dead and dying parasites may cause
serious toxicity in patients.
29. • Classification
– Categorized into 3 groups on the basis of the type of
helminth primarily affected:
• Nematodes- round worms e.g Ascaris lumbricoides
• Trematodes - leaf like and cylindrical in appearance (flukes)
• Cestodes- flat and segmented worms (tape worms)
– The drugs of choice and alternative agents for
selected important helminthic infections are listed in
Table 53–1.
Antihelminthic Drugs
30. Bibliography
– Anthony J. Trevor, Bertram G. Katzung & Susan B.
Masters (2013) Pharmacology- Examination And
Board Review 10th ed., McGraw Hill, Lange
– Katzung B.G (2007) Basic & Clinical Pharmacology,
11th ed, McGraw Hill, Lange
