Antiprotozoal Drugs
Pharmacology · Antimicrobials · lean revision notes
Antiprotozoal Drugs
Antiprotozoal pharmacology is a perennial NEET PG favourite, especially antimalarials (resistance mechanisms, primaquine and G6PD haemolysis), antiamoebic luminal-vs-tissue agents, and the rapidly evolving anti-leishmanial drugs. This note organises the entire group around the parasite, the drug of choice, mechanism, and the high-yield toxicities most often examined.
Classification overview
Antiprotozoals are best learnt parasite-wise rather than as one alphabet soup. The four exam-relevant clusters are: antimalarials, antiamoebics, anti-leishmanials/anti-trypanosomals, and drugs for giardiasis/trichomoniasis/toxoplasmosis.
| Parasite/disease | First-line drug(s) | Key alternative |
|---|---|---|
| P. falciparum (uncomplicated) | Artemisinin-based combination therapy (ACT) | Quinine + doxycycline |
| P. falciparum (severe) | IV artesunate | IV quinine |
| P. vivax (blood stage) | Chloroquine (where sensitive) / ACT | — |
| P. vivax (radical cure) | Primaquine / tafenoquine | — |
| Intestinal amoebiasis + liver abscess | Metronidazole + luminal agent | Tinidazole |
| Asymptomatic cyst passer | Diloxanide furoate (luminal) | Paromomycin |
| Visceral leishmaniasis (India) | Liposomal amphotericin B | Miltefosine, paromomycin |
| Giardiasis | Metronidazole / tinidazole | Nitazoxanide |
| Trichomoniasis | Metronidazole (single 2 g dose) | Tinidazole |
| Toxoplasmosis | Pyrimethamine + sulfadiazine + folinic acid | Spiramycin (pregnancy) |
High-yield: ACT is the universal first line for uncomplicated falciparum malaria; IV artesunate is the global drug of choice for severe/complicated malaria, having replaced quinine (SEAQUAMAT and AQUAMAT trials showed mortality benefit).
Antimalarials
Parasite life cycle and drug targets
The life cycle determines drug action. Sporozoites enter from the mosquito bite → liver (pre-erythrocytic/exo-erythrocytic schizogony) → release merozoites into blood → erythrocytic schizogony (causes clinical illness) → some form gametocytes (transmissible) → in vivax/ovale, dormant liver hypnozoites cause relapse.
- Tissue schizonticides (causal prophylaxis): primaquine, tafenoquine, atovaquone-proguanil — act on liver stage.
- Hypnozoiticides (anti-relapse): primaquine, tafenoquine — only these kill vivax/ovale dormant forms.
- Blood schizonticides (clinical cure): chloroquine, quinine, artemisinins, mefloquine, ACTs.
- Gametocidal: primaquine (all species), artemisinins (against falciparum gametocytes — blocks transmission).
High-yield: Only primaquine and tafenoquine are hypnozoiticidal → essential for radical cure of P. vivax and P. ovale. Chloroquine clears the blood stage but never prevents relapse.
Chloroquine
A 4-aminoquinoline. Mechanism: concentrates in the parasite's acidic food vacuole, inhibits haem polymerase, preventing conversion of toxic free haem (ferriprotoporphyrin IX) into inert haemozoin → toxic haem accumulates and kills the parasite.
- Uses: chloroquine-sensitive malaria, P. vivax blood stage, hepatic amoebiasis (reaches high liver concentrations), rheumatoid arthritis, SLE, lepra reactions, photogenic/discoid lupus.
- Resistance mechanism (very high-yield): mutation in pfcrt gene (P. falciparum chloroquine resistance transporter) → increased efflux of chloroquine from the food vacuole, lowering drug concentration at the target. pfmdr1 mutations modulate resistance.
- Toxicity: retinopathy (irreversible, bull's-eye maculopathy with chronic high-dose use — needs baseline and periodic eye screening), pruritus (common in dark-skinned patients), QT prolongation, acute overdose → cardiotoxicity/hypotension. Cinchonism is a quinine/quinidine feature, not chloroquine.
High-yield: Chloroquine resistance = pfcrt mutation → drug efflux. Bull's-eye retinopathy is the classic chronic toxicity.
Artemisinins (artesunate, artemether, dihydroartemisinin)
Derived from Artemisia annua (Qinghaosu — Tu Youyou won the 2015 Nobel). Mechanism: the endoperoxide bridge is cleaved by haem iron generating carbon-centred free radicals that alkylate parasite proteins (and PfATP6). Fastest-acting blood schizonticides — rapid parasite clearance.
- Always used as combinations (ACT) to prevent resistance and recrudescence (short half-life ~1 h).
- Common ACTs: artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-sulfadoxine-pyrimethamine (older Indian regimen), dihydroartemisinin-piperaquine.
- India NVBDCP regimen: for P. falciparum, artesunate + sulfadoxine-pyrimethamine (AS+SP) in most states; artemether-lumefantrine in the Northeast (because of SP resistance there). Add single-dose primaquine as gametocidal.
- Toxicity: generally safe; neurotoxicity in animals (not clinically relevant at therapeutic doses), rare delayed haemolysis after artesunate in severe malaria, type-1 hypersensitivity.
High-yield: Artemisinins are activated by haem iron → free radicals. Single low-dose primaquine added to ACT for falciparum acts as a gametocidal/transmission-blocking agent (G6PD testing not mandatory for the single low dose per WHO).
Quinine and quinidine
Cinchona alkaloids; blood schizonticides. Quinine + doxycycline/clindamycin is the alternative for uncomplicated falciparum and a backup for severe malaria where artesunate is unavailable.
- Toxicity — cinchonism: tinnitus, headache, nausea, blurred vision, vertigo. Hypoglycaemia (quinine stimulates pancreatic insulin release — dangerous in pregnant women with severe malaria). Quinine can cause blackwater fever (massive intravascular haemolysis + haemoglobinuria) and QT prolongation.
Mefloquine, atovaquone-proguanil, lumefantrine, piperaquine, amodiaquine
- Mefloquine: long half-life; used for prophylaxis and in ACT. Neuropsychiatric toxicity (vivid dreams, anxiety, seizures) — avoid in those with psychiatric illness/epilepsy.
- Atovaquone-proguanil (Malarone): atovaquone inhibits the parasite cytochrome bc1 (mitochondrial electron transport); proguanil (a biguanide) is converted to cycloguanil, a dihydrofolate reductase inhibitor. Good for prophylaxis and treatment; causal prophylactic.
- Pyrimethamine-sulfadoxine: sequential blockade of folate synthesis (sulfa inhibits dihydropteroate synthase; pyrimethamine inhibits DHFR).
Primaquine and tafenoquine (8-aminoquinolines)
The only drugs that kill hypnozoites (radical cure) and are strongly gametocidal.
- Primaquine: 14-day course for vivax/ovale radical cure. Active metabolites generate oxidative free radicals.
- Tafenoquine: single-dose anti-relapse drug (longer half-life) — newer, convenient.
- CRITICAL toxicity: oxidative haemolysis in G6PD deficiency (and methaemoglobinaemia). G6PD-deficient RBCs cannot regenerate NADPH/glutathione to counter oxidative stress → acute haemolytic anaemia. Screen for G6PD before a full radical-cure course.
High-yield: Primaquine + G6PD deficiency = acute intravascular haemolysis. Both primaquine and tafenoquine are contraindicated in pregnancy (foetal G6PD status unknown). Tafenoquine is also contraindicated in G6PD deficiency.
Stepwise approach to confirmed P. vivax malaria:
Confirm diagnosis (smear/RDT) → Chloroquine (or ACT) to clear blood-stage parasites → Check G6PD status → If G6PD normal: primaquine ×14 days (or single-dose tafenoquine) for radical cure → If G6PD deficient: weekly primaquine ×8 weeks under supervision, or avoid.
Drug of choice summary — malaria
| Scenario | Drug of choice |
|---|---|
| Uncomplicated falciparum | ACT (artemisinin combination) |
| Severe/cerebral malaria | IV artesunate |
| Chloroquine-sensitive vivax (blood stage) | Chloroquine or ACT |
| Vivax/ovale radical cure | Primaquine (after G6PD test) |
| Malaria in 1st trimester pregnancy | Quinine + clindamycin (avoid artemisinins traditionally; ACT now used 2nd/3rd trimester) |
| Causal prophylaxis (traveller) | Atovaquone-proguanil / doxycycline / mefloquine |
Antiamoebic drugs
The key conceptual split: luminal (contact) amoebicides act in the gut lumen on cysts/trophozoites in the bowel wall; tissue (systemic) amoebicides act in the bowel wall, liver, and other organs. Eradication needs both.
| Class | Drugs | Site of action |
|---|---|---|
| Tissue amoebicides | Metronidazole, tinidazole, ornidazole | Intestinal wall + liver/systemic |
| Luminal amoebicides | Diloxanide furoate, paromomycin, iodoquinol, nitazoxanide | Gut lumen only |
| Both (mixed) | Nitazoxanide | Lumen + tissue |
Metronidazole (nitroimidazole)
Mechanism: its nitro group is reduced by parasite/anaerobe ferredoxin systems → cytotoxic reactive intermediates that damage DNA. Active against anaerobic bacteria, Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis, and H. pylori regimens.
- Toxicity: metallic taste, nausea, disulfiram-like reaction with alcohol (avoid alcohol during and 3 days after), peripheral neuropathy (prolonged use), seizures, dark/red-brown urine, reversible neutropenia. Mutagenic in animals → avoid in 1st trimester if possible.
High-yield: Metronidazole clears the invasive (tissue) infection but does not reliably eradicate luminal cysts → always follow with a luminal agent (diloxanide furoate) to prevent relapse and stop cyst shedding.
Diloxanide furoate
The prototype luminal amoebicide; drug of choice for the asymptomatic cyst passer. Poorly absorbed, acts in the gut. Paromomycin (an aminoglycoside) and iodoquinol are alternatives.
Approach to amoebic liver abscess: Metronidazole/tinidazole (tissue cure) → followed by diloxanide furoate (luminal cure) → percutaneous aspiration only if large (>5–10 cm), left-lobe, impending rupture, or no response in 72 h.
High-yield: Amoebic liver abscess = anchovy-sauce/chocolate-coloured pus, usually right lobe, single. Serology (IHA) positive; pus is usually sterile (trophozoites are at the wall, not centre). Medical therapy first; aspiration is selective.
Anti-leishmanial drugs
Visceral leishmaniasis (kala-azar; Leishmania donovani) is endemic in Bihar/eastern India. Drug choice has shifted dramatically due to antimony resistance.
| Drug | Mechanism / note | Toxicity |
|---|---|---|
| Liposomal amphotericin B | DoC in India for VL (single high dose feasible) | Nephrotoxicity (less with liposomal), infusion reactions, hypokalaemia |
| Sodium stibogluconate (pentavalent antimony) | Historic first line; high resistance in Bihar | Cardiotoxicity (QT, arrhythmia), pancreatitis |
| Miltefosine | Only oral anti-leishmanial; phospholipid analogue | Teratogenic — contraindicated in pregnancy, GI upset |
| Paromomycin (aminoglycoside) | IM; used in combination regimens | Ototoxicity, nephrotoxicity |
| Pentamidine | Second-line; also PCP prophylaxis | Hypoglycaemia then diabetes, hypotension |
High-yield: In India, liposomal amphotericin B is the drug of choice for visceral leishmaniasis (high antimony resistance in Bihar). Miltefosine is the only oral agent and is teratogenic — mandatory contraception. The National Kala-azar Elimination Programme favours single-dose liposomal amphotericin B.
Anti-trypanosomal drugs (brief, exam-relevant)
- African sleeping sickness (T. brucei): early haemolymphatic stage — suramin (rhodesiense) or pentamidine (gambiense). CNS stage — melarsoprol (arsenical, causes reactive encephalopathy) or eflornithine (DFMO, "resurrection drug", ornithine decarboxylase inhibitor) for T.b. gambiense. NECT (nifurtimox-eflornithine) is now used.
- Chagas disease (T. cruzi): nifurtimox or benznidazole.
High-yield: Eflornithine (an ornithine decarboxylase inhibitor) is the "resurrection drug" for West African (gambiense) sleeping sickness CNS stage. Melarsoprol causes a dangerous reactive encephalopathy.
Drugs for giardiasis, trichomoniasis, toxoplasmosis
- Giardiasis: metronidazole or tinidazole (single dose); nitazoxanide (broad antiprotozoal/antihelminthic, also cryptosporidiosis) is an alternative and is preferred in children.
- Trichomoniasis: metronidazole single 2 g oral dose; treat the partner simultaneously. Tinidazole alternative.
- Toxoplasmosis: pyrimethamine + sulfadiazine + folinic acid (leucovorin). In pregnancy use spiramycin to reduce vertical transmission (does not cross placenta well, so used to prevent foetal infection before it occurs).
- Cryptosporidiosis: nitazoxanide (limited efficacy in HIV unless ART started).
High-yield: Folinic acid (leucovorin), not folic acid, is co-administered with pyrimethamine to protect host bone marrow from megaloblastic anaemia without rescuing the parasite. In pregnant toxoplasmosis, spiramycin is the agent of choice.
Key toxicity mnemonics and eponyms
- "PRIMAquine → haemolysis PRIMArily in G6PD." Always test G6PD first.
- Cinchonism (tinnitus, headache, visual disturbance) → quinine/quinidine.
- Metronidazole + alcohol → disulfiram reaction.
- Mefloquine → Mind problems (neuropsychiatric).
- Chloroquine → bull's-eye retinopathy (Cardiac + retinal).
- Miltefosine → Mother harm (teratogenic).
- Eponyms: Tu Youyou (artemisinin, Nobel 2015); anchovy-sauce pus (amoebic abscess); blackwater fever (quinine/falciparum haemolysis).
Key differentials (concept clarifications)
- Amoebic vs pyogenic liver abscess: amoebic = single, right lobe, young male, anchovy pus, serology+, responds to metronidazole; pyogenic = multiple, septic, needs drainage + antibacterials.
- Relapse vs recrudescence: relapse = reactivation of hypnozoites (vivax/ovale — needs primaquine); recrudescence = incompletely cleared blood-stage parasites (falciparum — inadequate treatment/resistance).
- Causal vs suppressive prophylaxis: causal kills liver stage (atovaquone-proguanil, primaquine); suppressive acts on blood stage (chloroquine, mefloquine, doxycycline) and must continue 4 weeks post-exposure.
Recently asked / exam angle
- Mechanism of chloroquine resistance → pfcrt gene mutation causing drug efflux from the food vacuole (very frequently asked).
- Primaquine causing haemolysis in G6PD deficiency — single best answer and assertion-reason format.
- Drug of choice for severe malaria = IV artesunate (replaced quinine).
- Hypnozoiticidal drugs = primaquine + tafenoquine only.
- Diloxanide furoate = drug of choice for asymptomatic cyst passer / luminal amoebicide.
- Liposomal amphotericin B = DoC for kala-azar in India; miltefosine = only oral, teratogenic.
- Folinic acid with pyrimethamine in toxoplasmosis; spiramycin in pregnancy.
- Mechanism of artemisinin = endoperoxide bridge + haem iron → free radicals.
- Metronidazole + alcohol = disulfiram-like reaction; mechanism = nitro-group reduction.
- Atovaquone mechanism = inhibits parasite cytochrome bc1 (mitochondrial ETC).
- Eflornithine (ODC inhibitor) for gambiense trypanosomiasis.
Rapid revision
- ACT = first line uncomplicated falciparum; IV artesunate = severe malaria DoC.
- Only primaquine + tafenoquine kill hypnozoites → radical cure of vivax/ovale.
- Primaquine + G6PD deficiency → acute haemolysis; test G6PD first; both 8-aminoquinolines contraindicated in pregnancy.
- Chloroquine resistance = pfcrt mutation (drug efflux); chronic toxicity = bull's-eye retinopathy.
- Chloroquine inhibits haem polymerase → toxic free haem accumulates.
- Artemisinin activated by haem iron, generates free radicals; short t½ → always combined.
- Quinine → cinchonism + hypoglycaemia (insulin release) + blackwater fever.
- Metronidazole = tissue amoebicide; always follow with diloxanide furoate (luminal) to clear cysts.
- Amoebic liver abscess = right lobe, anchovy-sauce pus; metronidazole then luminal agent; aspirate selectively.
- Kala-azar India DoC = liposomal amphotericin B; miltefosine = only oral, teratogenic.
- Toxoplasmosis = pyrimethamine + sulfadiazine + folinic acid; spiramycin in pregnancy.
- Trichomoniasis/giardiasis = metronidazole; nitazoxanide for cryptosporidiosis and a broad alternative.