Pharmacology and therapeutics notes on Antiprozoal drugs

1. ANTIPROTOZOAL
DRUGS

2. Introduction
 Protozoal diseases remain a global concern
and they include:
 Malaria
 Amoebiasis
 Giardiasis
 Toxoplasmosis
 Trichomoniasis
 Trypanosomiasis
 Leishmaniasis

3. Antiprotozoal agents:
classification
 Antimalarial
agents:
 Chloroquine
 Mefloquine
 Primaquine
 Quinine
 Antifolates: SP,
Atovaquone +
proguanil
(Malarone)
 Artesunate,
Artemether

4. Antimalarial agents
 Malaria is one of the most common diseases
worldwide and a leading cause of death.
 Caused by Plasmodium.
 Species that infect humans:
 P falciparum,
 P malariae,
 P ovale,
 P vivax

5. Malarial Parasite (plasmodium)
Two Interdependent Life Cycles
 Sexual cycle: in the mosquito
 Asexual cycle: in the human
 Knowledge of the life cycles is essential in
understanding antimalarial drug treatment.
 Drugs are only effective during the asexual cycle.

6. Plasmodium Life Cycle
Asexual cycle: two phases
 Exoerythrocytic phase: occurs “outside” the
erythrocyte
 Erythrocytic phase: occurs “inside” the erythrocyte
 Erythrocytes = RBCs

7. Plasmodium Life Cycle
 An anopheles mosquito inoculates plasmodium
sporozoites to initiate human infection.
 Can also be transmitted by infected individuals via
blood transfusion, congenitally, or via infected
needles by drug abusers.
 Circulating sporozoites rapidly invade liver cells,
and exoerythrocytic stage tissue schizonts mature
in the liver.
 Merozoites are subsequently released from the
liver and invade erythrocytes.

8. Plasmodium Life Cycle
 Only erythrocytic parasites cause clinical illness.
 Repeated cycles of infection can lead to the
infection of many erythrocytes and serious
disease.
 Sexual stage gametocytes also develop in
erythrocytes before being taken up by
mosquitoes, where they develop into infective
sporozoites

9. Plasmodium Life Cycle
 In P falciparum and P malariae infection – single
cycle of liver cell invasion which ceases
spontaneously in less than 4 weeks.
 Thus, treatment that eliminates erythrocytic
parasites will cure these infections.
 In P vivax and P ovale infections – hypnozoites
develop in the liver (dormant)

10. Plasmodium Life Cycle
 Hypnozoites are not eradicated by most drugs,
and can therefore cause relapses after therapy
directed against erythrocytic parasites.
 Eradication of both erythrocytic and hepatic
parasites is required to cure these infections

11. Mechanism of action of
antimalarials:
 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.

12. Antimalarials – classifiaction
 Artemisinin and derivatives - artemether,
artesunate, hydroartemesinin
 Diaminopyrimidines – pyrimethamine
 Biguanide – Proguanil

13. Antimalarials – classifiaction
 Quinolines – chloroquine, quinine, quinindine,
mefloquine, primaquine
 Sulfonamides and sulfones – sulfadoxine
 Tetracycline – doxycycline

14.  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
 MOA: A blood schizonticide
Chloroquine

15. Clinical Uses
 Prophylaxis and treatment in areas without
resistant P falciparum;
 Currently not in use in Kenya due to resistance
 Treatment of P vivax and P ovale malaria
 Also used for amebic liver abscesses that fail
initial therapy with metronidazole.

16. Adverse reactions
 GI distress,
 Pruritus and rash,
 headache,
 auditory dysfunction and retinal dysfunction (high
dose),
 hemolysis in glucose-6-phosphate
dehydrogenase (G6PD)-deficient persons,
 Agranulocytosis

17. Amodiaquine
 Related to choroquine.
 Important toxicities have limited the use of the
drug
 These include
 agranulocytosis,
 aplastic anemia,
 hepatotoxicity

18. Quinine
 A blood schizonticide.
 Pharmacokinetics
 Quinine is rapidly absorbed orally
 metabolized before renal excretion.
 Intravenous administration of quinine is
possible in severe infections.

19. Clinical Use
 Treatment of multidrug-resistant malaria
 Remain first-line therapies for falciparum
malaria especially severe disease although
toxicity may complicate therapy

20. Adverse reactions
 Cinchonism:
 gastrointestinal distress,
 headache,
 vertigo,
 blurred vision,
 tinnitus.
 Hematotoxic effects
 Hemolysis in glucose-6-phosphate
dehydrogenase (G6PD)-deficient patients.

21. Adverse reactions
 Blackwater fever
 (intravascular hemolysis and hemoglobinuria) is a
rare and sometimes fatal complication in quinine-
sensitized persons.
 Intravenous administration may result to
hypoglycemia
 Severe overdose results in disturbances in
cardiac conduction that resemble quinidine
toxicity

22.  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 resistant P
falciparum.
Mefloquine

23. Adverse reactions
 gastrointestinal distress,
 skin rashes,
 headache,
 dizziness.
 At high doses, mefloquine has caused:
 cardiac conduction defects, psychiatric disorders,
neurologic symptoms, seizures

24.  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
Primaquine

25. Adverse reactions
 GI distress,
 Methemoglobinemia
 Hemolysis in G6PD deficiency
 Primaquine is contraindicated in
pregnancy

26.  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).
Antifolate drugs

27.  Blood schizonticides
 Sulfonamides inhibit dihydropteroate synthase.
 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.
Mechanisms of Action

28. Clinical Use
 Pyrimethamine with sulfadoxine (Fansidar):
 Used in the treatment of chloroquine-resistant
forms P. falciparum.
 However, the combination is not in
currently in kenya due to resistance

29. Proguanil with atovaquone
(Malarone)
 used (daily) for chemoprophylaxis of
chloroquine-resistant malaria
 also protective against mefloquine-resistant
falciparum strains

30.  skin rashes,
 gastrointestinal distress,
 hemolysis,
 kidney damage
 folic acid deficiency.
 Drug interactions may occur due to competition
for plasma protein binding sites
Adverse reactions

31.  Artemisinin is isolated from the plant Artemisia
annua
 Drugs:
 Artesunate:
 Artemether,
 Dihydroartemisinin
 Artemisinins are blood schizonticides active
against P falciparum and P vivax,
 including multidrug-resistant strains.
Artemisinin derivatives

32.  Artemisinin derivatives are preferably used in
combinations with other antimalarial agents:
 Lumefantrine (Artemether- lumefantrine)
 Mefloquine (Artesunate-mefloquine)
 Amodiaquine (Artesunate-amodiaquine)
 SP antimalarials
Artemisinin derivatives

33.  Preparations available in both oral and
parenteral formulations (IM)
 Indicated for all forms of malaria,
 Severe and multidrug resistant malaria
 These drugs are not used for chemoprophylaxis
because of their short half-lives of
Clinical use

34.  nausea,
 Vomiting
 diarrhea.
 The safety of artemisinin drugs in pregnancy
has not been established.
Adverse effects

35.  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)
Other antimalarials

36. Prophylaxis

37. Treatment of amebiasis
 Amebiasis is infection with Entamoeba histolytica.
 It may cause:
 asymptomatic intestinal infection,
 mild to moderate colitis,
 severe intestinal infection (dysentery),
 Liver abscess,
 other extraintestinal infections.
 The choice of drugs for amebiasis depends on the
clinical presentation.

38. Treatment of Specific Forms of
Amebiasis.
 Asymptomatic intestinal infection
 Asymptomatic carriers generally are not treated in
endemic areas
 But in nonendemic areas they are treated with a
luminal amebicide.
 A tissue amebicidal drug is unnecessary.

39. Treatment of Specific Forms of
Amebiasis.
 Asymptomatic intestinal
 Standard luminal amebicides are used: diloxanide
furoate, iodoquinol, and paromomycin.
 Single course of therapy eradicates carriage in about
80-90% of patients.
 Therapy with a luminal amebicide is also required in the
treatment of all other forms of amebiasis

40.  Amebic colitis
 Metronidazole plus a luminal amebicide is the
treatment of choice for colitis and dysentery.
 Tetracyclines and erythromycin are alternative
drugs for moderate colitis but are not effective against
extraintestinal disease.
 Dehydroemetine or emetine can also be used, but are
best avoided because of toxicity.

41.  Extraintestinal infections
 The treatment of choice is metronidazole plus a luminal
amebicide.
 A 10-day course of metronidazole cures over 95% of
uncomplicated liver abscesses.
 For unusual cases in which initial therapy with
metronidazole has failed, aspiration of the abscess and
the addition of chloroquine to a repeat course of
metronidazole should be considered.
 Dehydroemetine and emetine are toxic alternative drugs.

42. Drugs for amoebiasis
Metronidazole & Tinidazole
 Metronidazole, is the drug of choice in the
treatment of extraluminal amebiasis.
 It kills trophozoites but not cysts of E histolytica
and effectively eradicates intestinal and
extraintestinal tissue infections.
 Tinidazole, appears to have similar activity and a
better toxicity profile than metronidazole, and it
offers simpler dosing regimens.

43. Metronidazole & Tinidazole
 Pharmacokinetics
 Readily absorbed and permeate all tissues by
simple diffusion
 Intracellular conc’ rapidly approach extracellular
leves
 Low protein binding (10 – 20%)
 Half life of unchanged drug
 7.5hrs for metronidazole
 12 – 14 hrs for tinidazole
 Unchanged drug and metabolites are excreted in
urine
 Plasma clearance of metronidazole is decreased
in liver dysfunction

44. Metronidazole & Tinidazole
 Mechanism of action
 Anaerobic bacteria and sensitive protozoans
reduce the nitro group in metronidazole
 This reduction is responsible for antimicrobial
activity

45. Clinical Uses
 Amebiasis
 Metronidazole or tinidazole is the drug of choice in the
treatment of all tissue infections with E histolytica.
 They are not reliably effective against luminal parasites
and so must be used with a luminal amebicide to ensure
eradication of the infection.

46. Clinical Uses
 Giardiasis
 Metronidazole is the treatment of choice for giardiasis.
 The dosage for giardiasis is much lower and the drug
thus better tolerated than that for amebiasis.
 Efficacy after a single treatment is about 90%.
 Tinidazole is at least equally effective.

47. Clinical Uses
 Trichomoniasis
 Metronidazole is the treatment of choice.
 A single dose of 2 g is effective.
 Tinidazole may be effective against some of
metronidazole resistant organisms.

48. Iodoquinol
 It is an effective luminal amebicide that is
commonly used with metronidazole to treat
amebic infections..
 MoA of iodoquinol against trophozoites is
unknown.
 It is effective against organisms in the bowel
lumen but not against trophozoites in the
intestinal wall or extraintestinal tissues.

49. Adverse Effects
 Diarrhoea,
 anorexia,
 nausea, vomiting, abdominal pain,
 headache,
 rash,
 pruritus.
 Iodoquinol should be taken with meals to limit
gastrointestinal toxicity.

50. Diloxanide furoate
 It is an effective luminal amebicide but is not
active against tissue trophozoites.
 The mechanism of action of diloxanide furoate is
unknown.
 Diloxanide furoate is considered the drug of
choice for asymptomatic luminal infections.

51. Diloxanide furoate
 It is used with a tissue amebicide, usually
metronidazole, to treat serious intestinal and
extraintestinal infections.
 Diloxanide furoate does not produce serious
adverse effects.
 Flatulence is common, but nausea and abdominal
cramps are infrequent and rashes are rare.
 The drug is not recommended in pregnancy.

52. Paromomycin sulfate
 Paromomycin sulfate is an aminoglycoside
antibiotic.
 It is used only as a luminal amebicide and has
no effect against extraintestinal amebic
infections.
 In a recent study, it was found to be SUPERIOR
to diloxanide furoate in clearing asymptomatic
infections.
 Adverse effects include occasional abdominal
distress and diarrhea.

53. Paromomycin sulfate
 Paromomycin should be avoided in patients
with significant renal disease and used with
caution in persons with gastrointestinal
ulcerations.
 Parenteral paromomycin is under
investigation in the treatment of visceral
leishmaniasis.

54. Emetine & Dehydroemetine
 Emetine and dehydroemetine are effective
against tissue trophozoites of E histolytica,
 Because of major toxicity concerns they have
been almost completely replaced by
metronidazole.

55. Other antiprotozoal drugs
 PENTAMIDINE
 Pentamidine is only administered parenterally.
 MoA
 pentamidine is unknown.

56. Other antiprotozoal drugs
 Clinical Uses
 A. Pneumocystosis
 pulmonary and extrapulmonary disease
caused by P jiroveci.
 The standard dosage is 3 mg/kg/d
intravenously for 21 days.
 Alternative agent for primary or secondary
prophylaxis against pneumocystosis in
immunocompromised individuals, including
patients with advanced AIDS.

57. African trypanosomiasis (sleeping sickness)
 Pentamidine is an alternative to suramin for the
early hemolymphatic stage of trypanosomiasis
(especially by T brucei gambiense).
 The drug can also be used with suramin.
 Pentamidine should not be used to treat late
trypanosomiasis with central nervous system
involvement.

58. Leishmaniasis
 Pentamidine is an alternative to sodium
stibogluconate in the treatment of visceral
leishmaniasis
 resistance has been reported.
 Pentamidine is a highly toxic drug, with adverse
effects noted in about 50%.
 Adverse effects includes – severe hypotension,
tachycardia, dizziness, dyspnea, hypoglycaemia
and pancreatic toxicity.

59. Sodium stibogluconate
 First-line agent for cutaneous and visceral
leishmaniasis.
 Treatment is given once daily at a dose of 20
mg/kg/d intravenously or intramuscularly for 20
days in cutaneous leishmaniasis and 28 days in
visceral and mucocutaneous disease.
 MoA is unknown.

60. Sodium stibogluconate
 Few adverse effects occur initially, but the
toxicity of stibogluconate increases over the
course of therapy.
 Most common are gastrointestinal symptoms
 fever,
 headache,
 myalgias,
 arthralgias,
 rashes

61. Other drugs for trypanosomiasis &
leishmaniasis
A. Suramin
 It is the first-line therapy for early hemolymphatic
African trypanosomiasis (especially T brucei
gambiense infection),
 It is not effective against advanced disease since
its not distributed in the CNS.
 The drug's mechanism of action is unknown.

62. Other drugs for trypanosomiasis &
leishmaniasis
B. Melarsoprol
 First-line therapy for advanced central nervous
system African trypanosomiasis.
 Melarsoprol is extremely toxic but useful in
severe and advanced trypanosomiasis.
 Immediate adverse effects include fever,
vomiting, abdominal pain, and arthralgias.

63. Other drugs for trypanosomiasis &
leishmaniasis
 C. Eflornithine
 It is a second therapy for advanced central
nervous system African trypanosomiasis
 less toxic than melarsoprol but not as widely
available.
 Eflornithine appears to be as effective as
melarsoprol against advanced T brucei
gambiense infection,

64. Other drugs for trypanosomiasis &
leishmaniasis
 Eflornithine
 but its efficacy against T brucei rhodesiense is
limited by drug resistance.
 Adverse effects include
 diarrhea, vomiting,
 anemia,
 thrombocytopenia,
 leukopenia,
 seizures.
 These effects are generally reversible.

65. Other drugs for trypanosomiasis &
leishmaniasis
 D. Nifurtimox,
 a nitrofuran, is the most commonly used drug for
American trypanosomiasis (Chagas' disease).
 Nifurtimox is also under study in the treatment of
African trypanosomiasis.
 Nifurtimox is well absorbed after oral
administration and eliminated with a plasma half-
life of about 3 hours.

66. Other drugs for trypanosomiasis &
leishmaniasis
 E. Benznidazole –
 Used for treatment of acute chagas' disease.
 F. Amphotericin
 used for visceral leishmaniasis.
 G. Miltefosine
 used for treatment of visceral leishmaniasis

67. Antimalarial, Antiprotozoal, Antihelmintic
Agents: Implications
 Before beginning therapy, perform a thorough
health history and medication history, and
assess for allergies.
 Check baseline parameters.
 Check for conditions that may contraindicate
use, and for potential drug interactions.

68. Antimalarial, Antiprotozoal, Antihelmintic
Agents: Implications
 Some agents may cause the urine to have an
asparagus-like odor, or cause an unusual skin
odor, or a metallic taste; be sure to warn the
patient ahead of time.
 Administer ALL agents as ordered and for the
prescribed length of time.
 Most agents should be taken with food to
reduce GI upset.

69. Antimalarial Agents:
Implications
 Assess for presence of malarial symptoms.
 When used for prophylaxis, these agents
should be started 2 weeks before potential
exposure to malaria, and for 8 weeks after
leaving the area.
 Medications are taken weekly, with 8 ounces
of water.

70. Antimalarial Agents:
Implications
 Instruct patient to notify physician immediately
if ringing in the ears, hearing decrease, visual
difficulties, nausea, vomiting, profuse diarrhea,
or abdominal pain occur.
 Alert patients to the possible recurrence of the
symptoms of malaria so that they will know to
seek immediate treatment.

71. Antimalarial, Antiprotozoal, Antihelmintic
Agents: Implications
Monitor for side effects:
 Ensure that patients know the side effects that
should be reported.
 Monitor for therapeutic effects and adverse
effects with long-term therapy.

72.  End