Antimalarial drugs

1. Antimalarial drugs
Malaria is cause by four species of protozoa:
Plasmodium malariae.
P. falciparum.
P. vivax.
P. ovale (rare).
The plasmodium transmitted to human by the
bite of an infected female anopheles mosquito.

3. Malaria transmission life cycle:
• Sporozoites  tissue schizonts (in liver) 
merozoites infect RBC (blood schizonts)
rupture of RBC (clinical attack)  new crops
of merozoites
• Sexual form: some merozoites differentiate
into male & female gametocytes  ingested
by a mosquito where they form Sporozoites
human

4. • P. malariae & p. falciparum have one cycle of
liver invasion and end by the 4th week i.e. no
relapse occurs.
• P.ovale & p. vivax have dormant stages
(hypnozoites) in the liver. These hypnozoites
may rupture months or years later causing
relapse of the attacks.

5. Drug Classification
• Classified by their selective actions on
different phases of the parasite life cycle:
1. Tissue schizonticides: eliminate developing or
dormant liver forms.
2. Blood schizonticides: act on erythrocytic
parasites.
3. Gametocides: kill sexual stages and prevent
transmission to mosquitoes.
• No one available agent can reliably effect a
radical cures.

6. Blood Schizonticides
Chloroquine (4- aminoquinoline derivative)
Mechanism of action:
• Inhibits synthesis of DNA and RNA in the
plasmodium.
• Increases pH of the vacules in the parasite, so
prevent its utilization of erythrocyte hemoglobin.
Uses:
• Acute attack 600 mg base (4 tab.) then 300 mg after
6 h. then 150 mg bid for two more days.
• Add 100 mg proguanil/ day (2 tab.) in chloroquine-
resistant area.

7. Chemoprophylaxis:
• 300 mg base (2 tab.) / week,
• one week before entering the endemic area
• & 4 weeks after leaving.

8. Other uses:
• Amebic liver abscess (as chloroquine is concentrated
in the liver).
• Anti-inflammatory in autoimmune diseases e.g.
rheumatoid arthritis (unknown mechanism).
A/E: GIT upset, rash, headache, peripheral neuritis,
cardiac depressant, retinal damage (don’t use
chloroquin> 5 years without regular ophthalmic
examination), toxic psychosis and precipitates
porphyria.

9. Quinine:
Mechanism of action:
• Inhibits DNA strand separation.
• Inhibits transcription and protein synthesis.
Uses:
• Chloroquine-resistant P. falciparum (orally).
• Cerebral malaria (i.v infusion 10 mg/kg over 4 h.). it could
repeated at an intervals of 8-12 h. until patient can take the
drug orally.
A/E:
• Cinchonism i.e. headache, dizziness, & tinnitus.
• Inhibits cardiac conductivity, hemolysis in G-6-P D and black
water fever (intravascular hemolysis).

10. Quinidine:
• It is the dextro-isomer of quinine.
• It is used when quinine is not available.
Mefloquine:
• Its mechanism of action is unknown.
Uses:
• treatment & prophylaxis of chloroquine-resistant P.
falciparum.
A/E: GIT upset, headache, dizziness, syncope,
extrasystoles & seizures.

11. Halofantrine:
• Unknown mechanism of action.
• Used only by oral route in P. falciparum
cerebral malaria.
• No parenteral preparation.
• Not used for prophylaxis.
• Not used during pregnancy unless benefit
outweighs the risk.

12. Qinghaosu (Artemisinin):
• It is a Chinese herbal medicine was used as antipyretic.
• It is a blood schizonticide against all types of malaria including
chloroquine-resistant p. falciparum.
• Unknown mechanism of action.
Uses:
• P. falciparum cerebral malaria (oral & parenteral).
• Not used prophylactically.
• Not used in pregnancy as it is emberytoxic in rats.

13. Antifolates (sulfonamides & sulfones):
Synergistic blockade of folic acid synthesis
• Sulfonamide inhibits dihydropteroate
synthetase, so inhibits folic acid synthesis.
• Pyrimethamine and proguanil inhibit
dihydrofolate reductase, so inhibit
tetrahydrofolate (folinic acid synthesis).

14. Fansidar:
• It is a combination of sulfadoxin and pyrimethamine.
• It is used in chloroquine-resistant p. falciparum.
• Not used for prophylaxis as it causes agranulocytosis &
Stevens-Johnson syndrome.
A.E:
• Sulfonamide: rashes, kidney damage, hemolysis & GIT upset.
• Pyrimethamine: folic acid deficiency, agranulocytosis &
Stevens-Johnson syndrome.
Disadvantages: slow blood schizonticide activity, drug resistance
& numerous & serious adverse effects.
C/I: pregnancy & nursing women, G-6-PD, renal impairment &
children under 2 months of age.

15. Atovaquone:
• Unknown mechanism of action.
• Used alone for treatment of pneumocytosis and
toxoplasmosis in patients with AIDS.
• Atovaquone + proguanil (malarone) for treatment &
prophylaxis of chloroquine-resistant P. falciparum.
A/E: fever, rashes, cough, nausea, vomiting, diarrhea,
headache & insomnia.

16. Tissue Schizonticide
Primaquine (8- aminoquinoline derivative):
• It is a tissue schizonticide.
• It has a cellular oxidant activity and possibly interferes with
mitochondria function.
• Gametocide, so inhibits infection transmission by mosquito.
Uses:
• Eradication of liver stages (hypnozoites) of P.vivax & P.
ovale, after standard chloroquine therapy to prevent relapse.
• It should not be given if there is risk of reinfection.
A/E: GIT upset, pruritis, headache, methemoglobinemia,
hemolysis especially in G-6-PD.

17. Mefloquine
• A synthetic 4-quinoline methanol that is chemically
related to quinine.
• Pharmacokinetics
– Only be given orally because severe local irritation occurs
with parenteral use.
– Well absorbed.
– Highly protein-bound, extensively distributed in tissues,
and eliminated slowly. t1/2 is 20 days.
• Pharmacological Effects:
– Strong blood schizonticidal activity against P falciparum
and P vivax, but not active against hepatic stages or
gametocytes.

18. • Clinical Uses
– Chemoprophylaxis:
– Treatment: mainly for chloroquine-resistant
falciparum malaria.
• Adverse Effects and Cautions
– Nausea, vomiting, diarrhea, abdominal pain——
dose-dependent
– Neuropsychiatric toxicities: dizziness, headache,
behavioral disturbances, psychosis, seizures.

19. Pyrimethamine
• Pharmacokinetics
– Slowly but adequately absorbed from the gastrointestinal tract.
– Slowly eliminated and excreted from urine.
• Pharmacological Effects
– Kill schizonts of primary exoerythrocytic stage.
– Act slowly against premature schizonts of erythrocytic stage.
– No action against gametocytes, but can inhibit development of
plasmodium in mosquito.
– Inhibit plasmodial dihydrofolate reductase → inhibiting
breeding of plasmodium.

20. Treatment of malaria
P. vivax, P. ovale & P. malariae:
Chloroquine
NB: It is also allowed in pregnancy.
P. Falciparum (most cases are chloroquine-resistant):
• Quinine 600 mg salt/8h till patient become better and blood
is free of parasites (usually in 3-5 days).
• Followed by a single dose of fansidar (3 tablets).
• In pregnancy 7-day course of quinine alone should be given.

21. Alternative therapy
• Mefloquine 20 mg base/kg up to a maximum of 1.5 g
in two divided doses 8 hours apart.
• Mefloquine is contraindicated in pregnancy.
Cerebral malaria:
• Quinine 10 mg/kg i.v infusion over 4 h. could be
repeated at intervals of 8-12 h. until patient can take
drug orally.
• Or Halofantrine: orally only
• Or Qinghaosu (Artemisinin): oral & i.v

22. Chemoprophylaxis of malaria
Chloroquine-sensitive area:
• Chloroquine 150 mg base ( 2 tab/week)
Chloroquine-resistant area:
• Chloroquine ( 2 tab/week) plus proguanil
100 mg (one or two tab/ day)
or
• Mefloquine 250 mg (one tab./ week)

23. Anti-amebiasis Drugs
• Amebiasis is infection with Entamoeba
histolytic.
• Amebiasis is transmitted through
gastrointestinal tract.
• Ameba has two stages of development: cyst
and trophozoite.
Cysts → small intestine → little trophozoites (ileocecum)

24. Metronidazole
• A nitroimidazole . The nitro group of metronidazole
is chemically reduced in anaerobic bacteria and
sensitive protozoans. Reactive reduction products
appear to be responsible for antimicrobial activity.
• Pharmacokinetics
– Oral metronidazole is readily absorbed and permeates all
tissues by simple diffusion.
– Protein binding is low (<20%)
– Through blood brain barrier
– Metabolizing in liver.
– Excreted mainly in the urine.

25. • Pharmacological Effects and Clinical Uses
1. Anti-amebiasis: kills E histolytic trophozoites but
not cysts. Treatment of all tissue infections with
E histolytic. No effection against luminal
parasites and so must be used with a luminal
amebicide to ensure eradication of the infection.
2. Anti-trichomoniasis:
3. Anti-anaerobic bacteria:
4. Anti-giardiasis:

26. • Adverse Effects and Cautions
– Nausea, headache, dry mouth, a metallic taste in
the mouth.
– Infrequent: vomiting, diarrhea, rash, insomnia,
neutropenia, ……
– Rare: severe central nervous system toxicity
( ataxia, encephalopathy, seizures)——drug
withdrawal
– Has a disulfiram like effect, so that nausea and
vomiting can occur if alcohol is ingested during
therapy.

27. Emetine and Dehydroemetine
• Emetine, an alkaloid derived from ipecac, and
dehydroemetine, a synthetic analog, are effective
against tissue trophozoites of E histolytic .
• Because of major toxicity concerns they have
been almost completely replaced by
metronidazole.
• Administered subcutaneously (preferred) or i.m.
(but never i.v.) because oral preparations are
absorbed erratically.

28. • Pharmacological Effects and Clinical Uses
• kills E histolytic trophozoites of histolytic tissues
but no effection against luminal trophozoites. a
luminal amebicide should also be given.
• Rapidly alleviate severe intestinal symptoms,
used to treat amebic dysentery for the minimum
period because of toxicity.
• Occasionally as alternative therapies for amebic
liver abscess.

29. s
Inhibiting peptidyl-tRNA transposition →
inhibiting elongation of peptide chain
→inhibiting protein synthesis → interfering
cleavage and breeding of trophozoites

30. Diloxanide furoate
• Diloxanide furoateis a
dichoroacetamide(derivative.
• Effective luminal amebicide but is not active
against tissue trophozoites.
• The unabsorbed diloxanide in the gut is the active
antiamebic substance.
• Effective for asymptomatic luminal infections.
• It is used with a tissue amebicide, usually
metronidazole.
• Adverse Effects: flatulence, nausea, abdominal
cramps, rashes, abortion.

31. Paromomycin
• Aminoglycoside antibiotic.
• Not significantly absorbed from the
gastrointestinal tract.
• Only as a luminal amebicide and has no effect
against extraintestinal amebic infections.
• inhibiting protein synthesis → kill
trophozoites;
• inhibiting symbiosis flora → indirectly
inhibiting ameba protozoa.

32. • Chloroquine reaches high liver
concentrations → treatment of amebic liver
abscess.
• Not effective in the treatment of intestinal
or other extrahepatic amebiasis.
• Anti-trichomoniasis Drugs
• Metronidazole
• Acetarsol

33. Anthelmintic Drugs
• Classification of Helminth
a. Roundworms (nematodes) —— epidemic in
China
b. Tapeworms
c. Flukes (trematodes)

34. Mebendazole
• A synthetic benzimidazole that has a wide spectrum
of anthelmintic activity and a low incidence of
adverse effects.
• Pharmacokinetics
– Oral absorption ＜ 10 ％
– First pass elimination is high.
– Protein-binding ＞ 90 ％
– Excreted mostly in the urine, a portion of absored drug
and its derivatives are excreted in the bile.
– Absorption is increased if the drug is ingested with a fatty
meal.

35. • Pharmacologic Effects
– Inhibits microtubule synthesis in nematodes , thus
irreversibly impairing glucose uptake. Intestinal parasites
are immobilized or die slowly.
– Kills hookworm, ascaris , and trichuris eggs.
• Clinical Uses
– Pinworm infection
– Ascaris lumbricoides , Trichuris trichiura , Hookworm, and
Trichostrongylus.
– Other infections: intestinal capillariasis), trichinosis,
taeniasis, strongyloidiasis , dracontiasis, et al.

36. • Adverse Effects and Cautions
– Low-dose: nearly free adverse effects.
– Diarrhea, abdominal pain is infrequent.
– High-dose: pruritus, rash, eosinophilia, reversible
neutropenia, musculoskeletal pain, fever,
transient liver function abnormalities, alopecia,
glomerulonephritis, agranulocytosis

37. Albendazole
• A benzimidazole carbamate
• A broad-spectrum oral anthelmintic for
treatment of hydatid disease and
cysticercosis(, pinworm infection, ascariasis,
trichuriasis, strongyloidiasis, and infections
with both hookwormspecies.
• Effect better than Mebendazole.

38. • Clinical Uses
– Administered on an empty stomach when used
against intraluminal parasites but with a fatty
meal when used against tissue parasites.
1. Ascariasis, Trichuriasis, and Hookworm and
Pinworm infections.
2. Strongyloidiasis
3. Hydatid Disease
4. Neurocysticercosis
5. Other infections: cutaneous larva migrans,
gnathostomiasis

39. Piperazine
• Treatment of ascariasis.
• No longer recommended for treatment of
pinworm infection, because a 7-day couse of
treatment is required.
• Not useful in hookworm infection, trichuriasis, or
strongyloidiasis
• Causes flaccid paralysis of ascaris by blocking
acetylcholine at the myoneural junction.
• Neurotoxic adverse effects.

40. Pyrantel
• A tetrahydropyrimidine derivative.
• A broad-spectrum anthelmintic
• Highly effective for the treatment of pinworm,
ascaris, and Trichostrongylus orientalis infections.
• Moderately effective against both species of
hookworm but less so against N americanus.
• Not effective in trichuriasis or strongyloidiasis
• Oxantel, an analog of pyrantel, is effective
against in trichuriasis; the two drugs have been
combined for their broad-spectrum anthelmintic
activity.

41. • Effective against mature and immature forms of
helminths within the intestinal tract but not
against migratory stages in the tissues or against
ova.
• Inhibition of cholinesterase —— a depolarizing
neuromuscular blocking agent → spastic paralysis
• Used with caution in patients with liver
dysfunction.
• No combination with piperazine because of
antagonistic action.