Antiprotozoal drugs-

Antimalarial drugs
Dr. Geetha K.M

1
 Anti -Malarial Drugs

Four species of plasmodium are clinically important:

Plasmodium vivax

P. falciparum

P. ovale and

P. malariae
 Antimalarial drugs
• Signs and symptoms:
• Fever
• Shivering
• Pain in the joints
• Headache
• Repeated vomiting
• Generalized convulsions
• Symptoms become apparent only 7-9 days after being bitten by an infected
mosquito.
• Falciparum Malaria is characterized by – Persistent high fever, Orthostatic
hypotension and massive Erythrocytosis (an abnormal elevation in the number
of red blood cells, accompanied by swollen, reddish limbs)
 Life cycle of Malarial parasite-site of action of
Drugs

5
 Classification- based on chemical structure
1. Cinchona Alkaloids- Quinine, Quinidine

2. Quinoline Derivatives
•4-aminoquinilones - Chloroquinine, Amodiaquine, Hydroxy
quinoline
•8-aminoquinolines – Primaquine, Bulaquine, Tafenoquine
•Quinoline-methanol – Mefloquine, quinidine, quinine
•Phenanthrene methanol- Halofantrine, Lumefantrine
3. Antifolates
• Biguanides – Proguanil
• Diamino Pyrimidines – Pyrimethamine
• Sulfonamides and sulfones – Sulfadoxine, Dapsone

4. Artemisinin Compounds: Artesunate, Artemether, Artether

5. Antimicrobials: Doxycycline, Tetracycline, Atovaquone

 Chloroquine
• A synthetic 4-aminoquinilone derivative
• Available as chloroquine phosphate for oral use
Proposed MOA Uses
Effective against all
types of malaria
• Extraintestinal
Amoebiasis
• Giardiasis
• Lepra reaction
• Rheumatoid arthritis
 Chloroquine

Antimalarial spectra:

✓ against all 4 species

✓ Effective blood schizonticide
✓ Gametocidal activity except p. falciparum
✓ Safe in pregnancy

8
 Chloroquine
• Adverse effects:

– Nausea, vomiting, dizziness, headache, blurring vision,

urticarial symptoms.

IV- QRS complex widening, arrhythmia, respiratory and cardiac

arrest

• Large doses may result in cardiomyopathy , peripheral neuropathy,

ototoxicity, convulsions and Psychiatric disturbances
 Chloroquine
• Pharmacokinetics:

• Given orally or by I.M injection or by slow I.V infusion

• Almost completely absorbed from GIT

• Distributed – wide, extensively bound to liver, cornea and

RBCs

• Metabolism - liver

• Excretion - Urine (70% as unchanged, 30% as metabolites)

• Initial half life is 3-4 days
 Contraindications and Drug Interactions

• Avoid in patients with retinal and visual field abnormalities

• Aggravates psoriasis or porphyria
• In G6PD deficient persons may cause haemolytic anaemia
• Ca2+ and Mg2+ containing antacids decrease its absorption
• Chloroquine+ Halofantrine: Increased the risk of arrhythmia. Hence gap at least 12
hours
• Use of metoclopramide with chloroquine precipitates paradoxical
extrapyramidal side effects
 Chloroquine

• Therapeutic uses:
➢Malaria- Due to sensitive strains of all species
➢Extraintestinal amoebiasis
➢Rheumatoid arthritis
➢Photogenic reactions
➢Lepra reactions
➢Discoid Lupus erythematosus
➢Infectious mononucleosis

12
 Quinine

• Alkaloid obtained from cinchona bark

• Quinine destroys erythrocytic forms of the parasite and is used as
suppressive.
• It is rapidly acting and is effective in choloroquine resistant strains of P.
falciparam
• It is a gametocytocidal for three species of malarial parasite except for P.
falciparum
• Mech: It acts by inhibiting the enzyme haeme polymerase.
• Forms an hydrogen bonded complex with double stranded DNA that
inhibits strand separation, transcription, and protein synthesis.
 Quinine

• Mild analgesic and antipyretic activity

• It is a myocardiac depressant. IV administration can cause significant
hypotension
• It has local anesthetic properties – Sodium channel blocker
• It is a skeletal muscle relaxant
• It stimulates the uterus and is an abortifacient

14
 Adverse effects of Quinine
• Poor compliance – due to bitter taste

• Irritant to gastric mucosa - nausea and vomiting

• Potentially neurotoxic in higher dose

• Higher plasma level lead to cinchonism

• Occasionally - acute haemolytic anemia associated with renal
failure which is known as black water fever

• Higher doses - hypotension, severe CNS disturbances such as

delirium and coma
 Quinine-Therapeutic uses

Uses: Used for cerebral malaria and chloroquine resistant P. falciparum

malaria and Nocturnal muscle cramps

Drug interactions:
• Al 3+, Mg 2+ containing antacids decrease it’s absorption
• It raises plasma levels of digoxin
• Quinine should not be given concurrently with mefloquine, as both drugs
adversely effect cardiac conduction
• Persons with cardiac abnormalities should not use Quinine

16
 Artemisinin Derivatives
Artemisinin compounds are obtained from the Chinese plant
Artemisia annua

• Artemisinin is a prodrug and is rapidly metabolized to an active

metabolite dihydroartemisinin

• Artesunate- water soluble hemisuccinate derivative of Dihydroartemisinin

• Artether- oil soluble ethyl ester derivative of

dihydroartemisinin
 Artemisinin Derivatives
Mechanism of action
• Initially, the intraparasitic ferrous protoporphyrin-IV (present in
parasitic food vacuole) catalyses breakdown of endoperoxide
bridge of the artemisinin molecule
- This followed by the generation of the highly reactive free
radicals that damage the parasite membrane by covalently
binding to membrane proteins
 Artemisinin Derivatives
❑ Pharmacokinetics and Adverse effects
• Artemisinin compounds are well absorbed orally and widely
distributed
• Unwanted effects are rare and include nausea, vomiting,
abdominal pain
• Higher dose can cause ECG abnormalities, bradycardia
• Half life artesunate (1 hr)> Artemether (4-11 hr)> Arteether
(23 hr)
 Clinical Uses-Artemisinin Derivatives
• Very active against asexual erythrocytic forms of P. vivax,
ovale and falciparum and have little effect on
gametocytes
• The use of these compounds is restricted to the
treatment of multi resistant malaria and clinical cure of
falciparum malaria
Primaquine Halofantrine and Lumefantrine Proguanil

• Effective against all the • Potent blood • schizont

forms of parasites except
erythrocyte schizonticide against formation in
• Destroys Hypnozoites all four species erythrocytes and
• Gametocidal activity liver
• Not active against hepatic
forms and no gametocidal • it Inhibits the
activity dihydrofolate
reductase
(Thymidylate
synthase)
 Primaquine

• Primaquine is effective against all forms of the malarial parasite except

erythrocytic forms.
• It destroys the parasite in the liver cells and prevents the invasion of
erythrocytes – causal prophylactic.
• Primaquine destroys the hypnozoites (exoerythrocytic form) in the liver
and thereby prevents relapse of P. vivax and P. ovale malaria.
• It is also effective against the gametocytes of all four species of the
malarial parasite.
• It has weak and insignificant activity against the erythrocytic forms.

22
 Primaquine

• Primaquine is completely absorbed orally.

• It is well tolerated in therapeutic doses.
• Epigastric distress can occur. It may cause haemolysis in patients with G6
PD deficiency.
• Primaquine is used for radical cure along with a blood schizontocide in P.
vivax and ovale 15 mg /day for 14 days and as a gametocidal agent in P.
falciparum malaria - 45 mg single dose

23
 Proguanil

• Chloroguanide (Proguanil) is a schizonticide with causal prophylactic

activity against the pre-erythrocytic forms of the malaria parasite.
• It is used - with atovaquone in the treatment of MDR falciparum
malaria.
• for causal prophylaxis of falciparum malaria
• as an alternative to pyrimethamines-sulfadoxine for prophylaxis of MDR
falciparum malaria

24
 Pyrimethamine

• Pyrimethamine is effective against the erythrocytic forms of all 4 species

of plasmodia but it is slow acting
• Mechanism of Action: Pyrimethamine is a dihydrofolate reductase
inhibitor

25
 Pyrimethamine

• Therapeutic uses
• Malaria • Acute attacks – Pyrimethamine + sulfadoxine combination is used as an
alternative in uncomplicated, chloroquine resistant falciparum malaria. It is also
used as an adjunct to quinine in acute attacks of malaria.
• Prophylaxis–1-2 tablets once weekly for prophylaxis against MDR falciparum
• malaria–when a person is visiting an endemic area.
• Toxoplasmosis–Pyrimethamine + sulfadoxine combination is the treatment of
choice for Toxoplasma gondi infection. Pyrimethamine is given as 200 mg bolus
dose followed by 50 mg daily for 4 to 6 weeks along with sulfadoxine 4 g/day.
Leucovorin (folinic acid) should be given 10 mg daily to prevent severe folate
deficiency.

26
 Atovaquone
• It is a naphthaquinone, effective against the erythrocytic forms of plasmodia.
• When combined with proguanil, the activity is synergistic and development of
resistance is less common.
• Mechanism of action– Atovaquone inhibits the mitochondrial electron transport
and collapses the mitochondrial membrane in the malarial parasite. Proguanil
potentiates this action. Atovaquone is also effective against T. gondii and P. carinii
(P.jiroveci) infections.
• Adverse effects : include vomiting, headache and abdominal pain. It is
contraindicated in pregnancy.
• Uses: Atovaquone + Proguanil can be used in the treatment of chloroquine
resistant and multi drug–resistant falciparum malaria Atovaquone 250 mg +
proguanil 100 mg daily for three days. Atovaquone may also be used in P. carinii
infection as an alternative to cotrimoxazole.

27
 Halofantrine

• Halofantrine is schizonticidal against erythrocytic forms of all

Plasmodium species including MDR strains of P. falciparum.
• Actions are similar to mefloquine but the disadvantages are that
• • The response to oral dosage is unpredictable due to variable
absorption toxicity due to good absorption or therapeutic failure due to
poor absorption may result.
• It is used as an alternative in MDR strains of falciparum malaria.
• Cannot be given parenterally.
• It can cause cardiotoxicity apart from GI disturbances.

28
29
Antiamoebic drugs
Dr. Geetha K.M

30
 Amoebiasis

• Amoebiasis caused by the protozoan Entamoeba histolytia is a tropical

disease common in developing countries.
• It spreads by faecal contamination of food and water. Though it
primarily affects colon, other organs like liver, lungs and brain are the
secondary sites.
• Acute amoebiasis is characterised by bloody mucoid stools and
abdominal pain.
• Chronic amoebiasis manifests as anorexia, abdominal pain, intermittent
diarrhoea and constipation.
• Cyst passers or carriers are symptom free.

31
Life cycle of Entamoeba histolytica
Classification
• 1. Systemic Amoebicides
a) For both intestinal and extra intestinal amoebiasis
- Nitromidazoles: Metronidazole, Tinidazole,
Secnidazole, Ornidazole
- Alkaloids: Emetine, Dehydroemetine
b) For extra intestinal amoebiasis: Chloroquine
• 2. Luminal Amoebicides
a) Amides: Diloxanide furoate
b) 8-Hydroxyquinolines: Diiodohydroxyquin
c) Antibiotics: Tetracyclines, Paromomycin
Metronidazole
• It kills the trophozites of E. histolytica but has no effects on the
cysts
• It is often used in combination with Diloxanide furoate for the
treatment of amoebiasis
Anti microbial spectrum
• Metronidazole has a broad-spectrum cidal activity against
protozoa and many anaerobic bacteria
• It is drug of choice in treatment of infections caused by E.
histolytica, Giardia lamblia and Trichomonas vaginalis
• It is also active against Gram-positive bacilli such as Clostridia
and certain helminths
 Pharmacokinetics
• Metronidazole is well absorbed orally
• Metronidazole is the major component appearing in the
plasma, with lesser quantities of metabolites also being
present
• Protein binding less than 20%
• Major route for elimination- urine 60-80% of the dose

Adverse Effects
• Gastrointestinal disturbances, metallic, bitter taste in the
mouth
• CNS symptoms such as dizziness, headache and sensory
neuropathies are rarely observed
Contraindications
Metronidazole is contraindicated in:

• Neurological disease

• Blood dyscrasias

• First trimester of pregnancy (though no teratogenic

effect has yet been demonstrated, its mutagenic
potential warrants caution)

• Cautious use in chronic alcoholics.

Interactions
• Disulfiram-like effect with alcohol
• Enzyme inducers (phenobarbitone, rifampin) may
reduce its therapeutic effect
• Cimetidine + metronidazole can reduce
metronidazole metabolism: its dose may need to be
decreased
• Metronidazole enhances warfarin action by inhibiting
its metabolism
• It can decrease renal elimination of lithium and
precipitate toxicity
 Clinical Uses
• Amoebiasis

• Trichomonas vaginitis

• Giardiasis

• Anaerobic infections

• H pylori infections

• Pseudomembranous colitis

• Acute ulcerative gingivitis

• Topical preparations as gel in skin infections and acne

•
Emetine Diloxanide furoate Quiniodochlor,
Diiodohydroxyquin
Inhibit the protein synthesis Prevent the formation Kills the cyst forming
by arresting the of cysts trophozoites in the
intraribosomal intestine
translocation of tRNA-
aminoacid complex
Kills trophozoites but no Kills trophozoites Active against
action on cysts Entamoeba, trichomonas
and some fungi

ADR: GIT disturbance, CNS Hypotension, Iodism, Prolonged use

symptoms, Disulfiram tachycardia, ECG causes ‘Sub Acute Myelo-
changes, myocarditis optic Neuropathy’

Uses: Liver fluke infestation Asymptomatic amoebiasis

amoebiasis Giardiasis
Monolial vaginitis
Fungal infections
 Treatment of Different Forms of
Amoebiasis
➢Acute intestinal amoebiasis–one of the following can be given. • Metronidazole
400-800 mg TDS for 5- 7 days (METROGYL, FLAGYL) or • Metronidazole 2.4 g OD
for 3 days or • Tinidazole 2 g OD for 3 days (TINIBA) or • Secnidazole 2 g single
dose (SECZOL, SECNIL) This should be followed by diloxanide furoate 500 mg TDS
for 10 days to eradicate the cysts.
➢Chronic amoebiasis Diloxanide furoate 500 mg TDS for 10 days or tetracycline 250
mg qid for 10 days.
➢Hepatic amoebiasis requires intensive treatment for the complete eradication of
the parasite from the liver in order to avoid relapses. A course of metronidazole or
tinidazole are the first line drugs. In addition, chloroquine may be given to ensure
complete destruction of the liver forms. A course of diloxanide furoate should
follow in order to eradicate the cysts.

41
 Other protozoal infections
• Giardiasis: G. lamblia
Metronidazole, tinidazole, Secnidazole, Furazolidone
• Trichomoniasis: Trichomonas vaginalis
Metronidazole, diiodohydoxyquin, quinidochlor, Povidone-iodine
• Leishmaniasis: Leishmania genus
L. Donovani (Kala-azar), L. tropica, L.braziliences
Drugs: Sodium stibogluconate, meglumine antimonite, ethyl stibamine,
miltefosine, Amp-B, KTZ, allopurinol
• Trypanosomiasis: Trypanosoma genus
Africa: T.gambiense, T. rhodesiense: Suramin, Melasopprol, Eflornithine
America (Chaga disease): T. cruzi: nifurtimox and Benzinidazole
 Pneumocystosis

• Pneumocystis carinii is a micro-organism having features of both protozoa and fungi

though now considered by most to be a fungus
• It is now known to cause opportunistic infections particularly pneumonia in patients
with AIDS which can often be fatal.
• Drugs used in the treatment of pneumocystosis include • Cotrimoxazole - high oral
dose of Trimethoprim 20 mg/kg + sulphamethoxazole 100 mg/kg daily.
• Pentamidine - 4 mg/kg daily for 14 days parenterally. • Atovaquone - as an
alternative to cotrimoxazole.

43
 Leishmaniasis

• Leishmaniasis is caused by protozoa of the genus Leishmania. Kala-azar or visceral

leishmaniasis is caused by Leishmania donovani; oriental sore by L. tropica and
mucocutaneous leishmaniasis by L. braziliensis. The infection is transmitted by the
bite of the female sandfly phlebotomus.
• Drugs used in leishmaniasis include:
➢ Antimony compounds - Sodium stibogluconate, Meglumine antimonate
➢Diamidines- Pentamidine
➢Other drugs- Amphotericin B, Ketoconazole, Allopurinol, Paramomycin

44
 Trypanosomiasis

➢Trypanosomiasis is caused by protozoa of the genus Trypanosoma.

African trypanosomiasis or sleeping sickness is caused by T. gambiense
and T. rhodesiense while South American trypanosomiasis is caused by T.
Cruzi.
➢ Drugs used in trypanosomiasis are suramin, pentamidine,
Melarsoprol, eflornithine, nifurtimox and benznidazole. Suramin
sodium

45
 Trypanosomiasis- Suramin
• Is the drug of choice for early stage of trypanosomiasis but it does not cross the BBB
and therefore cannot be used in later stages of the disease.
• It is also useful for the prophylaxis but pentamidine is preferable. Suramin is given
IV;
• it is extensively bound to plasma proteins and may be traced for nearly 3 months in
the plasma.
• Suramin is also effective in eradicating adult forms of Onchocerca volvulus.
• Toxicity is high; vomiting, shock and loss of consciousness may follow IV injections.
Rash, neuropathies, haemolytic anaemia and agranulocytosis may also occur.
Melarsoprol is the preferred drug in later stages of trypanosomiasis which is
associated with encephalitis and meningitis. Eflornithine is used as an alternative in
CNS trypanosomiasis. Nifurtimox and benznidazole are useful in Chaga’s disease
(American trypanosomiasis).

46