Pharmacology of Antiamoebic and Antiprotozoal Drugs

Introduction/Overview

The pharmacological management of protozoal infections represents a critical component of global infectious disease therapy. Protozoal parasites, including amoebae, plasmodia, leishmania, and trypanosomes, are responsible for significant morbidity and mortality worldwide, particularly in tropical and subtropical regions and among immunocompromised populations. These eukaryotic pathogens present unique therapeutic challenges due to their complex life cycles, intracellular locations, and ability to develop resistance. The clinical relevance of these agents extends from common conditions like intestinal amoebiasis and giardiasis to life-threatening diseases such as cerebral malaria and visceral leishmaniasis.

The development of effective antiprotozoal chemotherapy has been instrumental in reducing the burden of these diseases, though therapeutic gaps and drug resistance remain persistent concerns. An understanding of the pharmacology of these agents is essential for rational prescribing, optimizing therapeutic outcomes, and minimizing adverse effects. This chapter systematically examines the major drug classes used to treat protozoal infections, with emphasis on their mechanisms of action, pharmacokinetic properties, clinical applications, and important safety considerations.

Learning Objectives

• Classify the major antiprotozoal drugs based on their chemical structure, mechanism of action, and target organisms.
• Explain the molecular and cellular mechanisms by which nitroimidazoles, antimalarials, and other antiprotozoal agents exert their parasiticidal effects.
• Analyze the pharmacokinetic profiles of key agents, including absorption, distribution, metabolism, and excretion, and relate these properties to dosing regimens and therapeutic applications.
• Evaluate the clinical indications, major adverse effects, and significant drug interactions for the principal antiprotozoal drugs.
• Apply knowledge of special considerations, including use in pregnancy, pediatric populations, and patients with organ impairment, to clinical decision-making.

Classification

Antiprotozoal drugs are categorized according to their chemical structure, mechanism of action, and the specific protozoal organisms they target. A functional classification provides a framework for understanding their therapeutic roles.

Drugs for Intestinal and Tissue Amoebiasis

• Nitroimidazoles: Metronidazole, Tinidazole, Secnidazole, Ornidazole. These are the cornerstone drugs for invasive amoebiasis and other anaerobic protozoal infections.
• Luminal Amoebicides: Diloxanide furoate, Paromomycin, Iodoquinol. These agents act primarily within the intestinal lumen and are used for eradication of cyst forms.
• Systemic Tissue Amoebicides: Emetine and Dehydroemetine. These alkaloids are used rarely for severe invasive amoebiasis due to significant cardiotoxicity.

Drugs for Malaria

• Blood Schizonticides (for acute attack):
  • Artemisinin and Derivatives (ARTs): Artesunate, Artemether, Dihydroartemisinin.
  • 4-Aminoquinolines: Chloroquine, Amodiaquine.
  • Quinoline-methanols: Quinine, Quinidine.
  • Antifolates: Sulfadoxine-Pyrimethamine (SP), Proguanil.
  • Antibiotics: Doxycycline, Clindamycin.
• Tissue Schizonticides (for radical cure/prevention):
  • 8-Aminoquinolines: Primaquine, Tafenoquine. Active against hypnozoites of Plasmodium vivax and P. ovale.

Drugs for Leishmaniasis

• Pentavalent Antimonials: Sodium stibogluconate, Meglumine antimoniate.
• Polyene Antibiotics: Amphotericin B (including lipid formulations).
• Alkylphosphocholines: Miltefosine.
• Aminoglycosides: Paromomycin.
• Others: Pentamidine.

Drugs for Trypanosomiasis

• African Trypanosomiasis (Sleeping Sickness): Pentamidine, Suramin, Melarsoprol, Eflornithine, Nifurtimox.
• American Trypanosomiasis (Chagas Disease): Benznidazole, Nifurtimox.

Drugs for Other Protozoal Infections

• Giardiasis: Nitroimidazoles (Metronidazole, Tinidazole), Nitazoxanide, Albendazole.
• Trichomoniasis: Nitroimidazoles (Metronidazole, Tinidazole).
• Toxoplasmosis: Pyrimethamine plus Sulfadiazine (with leucovorin), Spiramycin, Atovaquone, Clindamycin.
• Cryptosporidiosis: Nitazoxanide.

Mechanism of Action

The mechanisms by which antiprotozoal drugs exert their effects are diverse, often exploiting biochemical pathways unique to or critically important for the parasite. Understanding these mechanisms is fundamental to predicting efficacy, toxicity, and the potential for resistance development.

Nitroimidazoles (Metronidazole and Analogues)

The parasiticidal action of nitroimidazoles depends on intracellular nitroreduction. In anaerobic or microaerophilic organisms like Entamoeba histolytica, Giardia lamblia, and Trichomonas vaginalis, the drug’s nitro group (R-NO₂) is reduced by low-redox potential electron transport proteins, such as ferredoxin or nitroreductases. This reduction generates short-lived, cytotoxic nitro radical anions (R-NO₂^•−) and other reactive intermediates. These species cause extensive damage to critical macromolecules, including DNA. They induce DNA strand breaks, destabilize the helical structure, and inhibit nucleic acid synthesis, leading to cell death. In aerobic mammalian cells, this reductive activation occurs to a much lesser extent, contributing to selective toxicity. Metronidazole also appears to disrupt the redox balance within the parasite by consuming reducing equivalents.

Antimalarial Agents

The mechanisms of antimalarial drugs are closely linked to the parasite’s unique biology, particularly its digestion of host hemoglobin within the acidic food vacuole.

• 4-Aminoquinolines (Chloroquine): Chloroquine, a weak base, accumulates to high concentrations in the parasite’s acidic food vacuole via ion trapping. Within the vacuole, it inhibits the polymerization of toxic heme (ferriprotoporphyrin IX) into non-toxic hemozoin. The resulting accumulation of free heme is membrane-lytic and leads to parasite death. Chloroquine may also interfere with other vacuolar enzymes.
• Artemisinin and Derivatives (ARTs): The endoperoxide bridge within the artemisinin sesquiterpene lactone structure is essential for activity. Upon contact with intraparasitic iron (likely from heme or ferrous iron), the bridge undergoes reductive cleavage, generating carbon-centered free radicals and reactive oxygen species. These highly reactive intermediates alkylate and damage parasite proteins, including the sarco/endoplasmic reticulum calcium ATPase (SERCA) ortholog PfATP6, and cause general macromolecular damage.
• Quinine/Quinidine: Similar to chloroquine, these alkaloids concentrate in the food vacuole and inhibit heme polymerization, though they may have additional, less well-defined mechanisms involving interference with nucleic acid synthesis and glycolysis.
• Antifolates (Pyrimethamine, Proguanil, Sulfadoxine): These drugs inhibit sequential steps in the folate biosynthesis pathway essential for parasite pyrimidine synthesis. Sulfadoxine inhibits dihydropteroate synthase (DHPS), while pyrimethamine and the active metabolite of proguanil (cycloguanil) inhibit dihydrofolate reductase (DHFR). The combination results in synergistic folate antagonism.
• 8-Aminoquinolines (Primaquine, Tafenoquine): The exact mechanism against hypnozoites is not fully elucidated but is believed to involve the generation of reactive oxygen species through redox cycling of quinone metabolites. These drugs also have activity against gametocytes, the sexual blood stages responsible for transmission to mosquitoes.

Drugs for Leishmaniasis

• Pentavalent Antimonials (Sb^V): These prodrugs are reduced intracellularly, likely by parasite thiols like trypanothione, to the more toxic trivalent form (Sb^III). Sb^III inhibits trypanothione reductase and other essential enzymes, disrupts energy metabolism by inhibiting glycolysis and fatty acid β-oxidation, and induces apoptosis-like death in the amastigote form within macrophages.
• Amphotericin B: This polyene antibiotic binds selectively to ergosterol, the dominant sterol in the parasite’s cell membrane, forming pores that lead to increased membrane permeability, leakage of intracellular components, and cell death. Lipid formulations enhance delivery to infected macrophages.
• Miltefosine: Originally an anticancer agent, this alkylphosphocholine disrupts parasite membrane synthesis and integrity, inhibits cytochrome c oxidase, and induces apoptosis. Its mechanism may involve interference with lipid-dependent signal transduction pathways.

Drugs for Trypanosomiasis

• Benznidazole/Nifurtimox (Chagas Disease): Both are prodrugs activated by parasite-specific nitroreductases. Their nitroaromatic structures undergo reduction to generate nitro anion radicals and other reactive nitrogen species, which cause oxidative damage to DNA, proteins, and lipids through redox cycling. They also deplete intracellular thiols like trypanothione.
• Pentamidine: This diamidine accumulates in the parasite’s kinetoplast, the mitochondrial DNA network of trypanosomes. It binds to AT-rich regions of kinetoplast DNA (kDNA), inhibiting its replication and transcription. It may also interfere with polyamine biosynthesis and disrupt membrane potential.
• Eflornithine: This drug is an irreversible inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme in the biosynthesis of polyamines (putrescine, spermidine). Depletion of polyamines, critical for cell proliferation and differentiation, leads to cytostasis and death of Trypanosoma brucei gambiense.

Pharmacokinetics

The pharmacokinetic properties of antiprotozoal drugs determine their absorption, distribution to sites of infection, metabolic fate, and elimination. These parameters directly influence dosing schedules, route of administration, and therapeutic efficacy.

Nitroimidazoles

Metronidazole is well absorbed orally with a bioavailability exceeding 90%. It distributes widely throughout body tissues and fluids, including cerebrospinal fluid, abscess cavities, and bone, achieving concentrations of 50-100% of plasma levels. The volume of distribution is approximately 0.6-0.8 L/kg. Plasma protein binding is low (<20%). Metabolism occurs primarily in the liver via oxidation and glucuronidation. The hydroxy metabolite retains some activity. The elimination half-life (t_1/2) is approximately 8 hours. Excretion is mainly renal (60-80% as metabolites, 10% unchanged); dosage adjustment is required in severe hepatic impairment but not typically in renal failure. Tinidazole and Secnidazole share similar properties but have significantly longer half-lives (12-14 hours and 17-29 hours, respectively), permitting once-daily or single-dose regimens.

Chloroquine

Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract. It exhibits extensive tissue binding and sequestration, particularly in the liver, spleen, kidney, and melanin-containing tissues (retina), resulting in an enormous volume of distribution (100-1000 L/kg). This extensive distribution and slow release from tissue stores account for its very long terminal half-life of 1-2 months. Metabolism is partial, involving hepatic cytochrome P450 enzymes (mainly CYP2C8, CYP3A4) to active (desethylchloroquine) and inactive metabolites. Renal excretion of unchanged drug is significant (50-60%), necessitating caution in renal impairment.

Artemisinin Derivatives

These compounds have rapid onset of action but short half-lives. Artesunate, given intravenously or intramuscularly, is hydrolyzed rapidly to the active metabolite dihydroartemisinin (DHA). Oral bioavailability is variable but good. DHA has a t_1/2 of about 1 hour. Artemether is lipid-soluble, administered orally or intramuscularly, and is metabolized to DHA. Their rapid clearance necessitates administration every 12-24 hours and underpins the rationale for Artemisinin-based Combination Therapy (ACT), where a long-acting partner drug eradicates residual parasites.

Quinine

Quinine is well absorbed orally, though absorption can be delayed with severe malaria. It is approximately 70-90% protein-bound, primarily to alpha-1-acid glycoprotein. It distributes widely but has limited penetration into the cerebrospinal fluid (CSF). Metabolism is hepatic, primarily via CYP3A4, to less active hydroxylated metabolites. Only about 20% is excreted unchanged in urine. Its elimination half-life is approximately 11 hours in healthy adults but may be prolonged in malaria infection and in patients with hepatic impairment.

Primaquine

Primaquine is rapidly absorbed after oral administration but undergoes extensive first-pass metabolism. Its bioavailability is therefore limited and variable. It is metabolized primarily by monoamine oxidase (MAO) to inactive carboxylic acid derivatives, although some conversion to active metabolites may occur. Its half-life is short (3-6 hours). The pharmacokinetics of its active metabolites are less well characterized but are critical for its hypnozoiticidal activity.

Miltefosine

Miltefosine has a long terminal half-life of approximately 150-200 hours (6-8 days) due to its affinity for tissues and enterohepatic circulation. Oral bioavailability is high (>90%). It is extensively distributed and has a slow, biphasic elimination. Excretion is minimal, with a long residence time in the body. This property allows for once-daily oral dosing but also raises concerns about the selection of drug-resistant parasites and necessitates pregnancy prevention measures due to long-term teratogenic risk.

Therapeutic Uses/Clinical Applications

The clinical application of antiprotozoal drugs is guided by the specific pathogen, the stage and severity of infection, geographic patterns of resistance, and patient-specific factors.

Amoebiasis

Treatment is stratified based on disease manifestation. For asymptomatic intestinal colonization (cyst passers), a luminal agent such as paromomycin or diloxanide furoate is used to eradicate cysts and prevent transmission. For intestinal amoebiasis (dysentery) and extraintestinal disease (e.g., liver abscess), a nitroimidazole (metronidazole or tinidazole) is the drug of choice for tissue invasion, followed by a luminal agent to eliminate any remaining intraluminal cysts and prevent relapse. For severe cases or those not tolerating nitroimidazoles, alternatives like emetine/dehydroemetine (with close cardiac monitoring) or chloroquine (for hepatic abscess) may be considered.

Malaria

Treatment depends on the Plasmodium species, severity of illness, and local resistance patterns.

• Uncomplicated P. falciparum Malaria: Artemisinin-based Combination Therapy (ACT) is the global standard. Examples include artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine. ACTs combine the rapid parasiticidal action of an artemisinin with a longer-acting partner drug to ensure complete cure and prevent recrudescence.
• Severe P. falciparum Malaria: Parenteral artesunate is the treatment of choice. Intravenous or intramuscular quinine is an alternative if artesunate is unavailable.
• P. vivax and P. ovale Malaria: Treatment requires both a blood schizonticide (typically chloroquine in areas without resistance, otherwise an ACT) to treat the acute attack, and primaquine or tafenoquine for radical cure to eliminate dormant hypnozoites in the liver and prevent relapse. Glucose-6-phosphate dehydrogenase (G6PD) status must be checked prior to primaquine/tafenoquine administration.
• Chemoprophylaxis: Drugs include atovaquone-proguanil, doxycycline, mefloquine, and primaquine (for terminal prophylaxis in P. vivax areas). Choice depends on destination, duration, and patient factors.

Leishmaniasis

Therapy varies by disease form and geographic region. Visceral leishmaniasis (kala-azar) is treated with liposomal amphotericin B (first-line in many regions), miltefosine, pentavalent antimonials, or combination therapies. Cutaneous leishmaniasis may be treated with local therapies (intralesional antimonials, cryotherapy) or systemic drugs (miltefosine, oral azoles) depending on the species and risk of mucosal spread. Mucocutaneous leishmaniasis requires aggressive systemic therapy, often with amphotericin B.

Trypanosomiasis

For African Trypanosomiasis, treatment is stage-dependent. Early hemolymphatic stage disease is treated with pentamidine (T. b. gambiense) or suramin (T. b. rhodesiense). Late-stage disease with CNS involvement requires drugs that cross the blood-brain barrier: eflornithine (often combined with nifurtimox for T. b. gambiense) or melarsoprol (for T. b. rhodesiense). For Chagas disease, benznidazole or nifurtimox are used, with greatest efficacy in the acute phase and early chronic phase. Their role in late chronic disease with cardiomyopathy is more limited.

Other Infections

Giardiasis is typically treated with a single dose of tinidazole or a 5-7 day course of metronidazole; nitazoxanide is an alternative. Trichomoniasis is treated with a single 2g dose of metronidazole or tinidazole, with treatment of sexual partners. Toxoplasmosis in immunocompromised patients (e.g., encephalitis) is treated with pyrimethamine plus sulfadiazine and leucovorin; alternatives include pyrimethamine-clindamycin or TMP-SMX. Spiramycin is used for prophylaxis in pregnant women with primary infection to prevent fetal transmission. Cryptosporidiosis in immunocompetent patients may be treated with nitazoxanide; in AIDS patients, immune reconstitution with antiretroviral therapy is paramount.

Adverse Effects

The adverse effect profiles of antiprotozoal drugs range from common, mild gastrointestinal disturbances to severe, life-threatening toxicities. Awareness of these effects is crucial for monitoring and patient counseling.

Nitroimidazoles

Common adverse effects include a metallic taste, nausea, vomiting, and anorexia. A disulfiram-like reaction, characterized by flushing, headache, nausea, and palpitations, can occur with concurrent alcohol ingestion due to inhibition of aldehyde dehydrogenase. Peripheral neuropathy, characterized by paresthesias, is a dose- and duration-dependent toxicity that may be irreversible. Seizures and encephalopathy are rare but serious neurological effects. Metronidazole is considered a potential mutagen and carcinogen in rodents, though this risk has not been conclusively demonstrated in humans at therapeutic doses.

Chloroquine and Hydroxychloroquine

At doses used for malaria prophylaxis and treatment, side effects include pruritus (common in dark-skinned individuals), headache, dizziness, nausea, and blurred vision. At the higher, chronic doses used for autoimmune diseases, irreversible retinotoxicity is the most significant concern, requiring regular ophthalmological screening. Other chronic toxicities include myopathy, cardiomyopathy, and ototoxicity. Acute overdose can be fatal, causing cardiovascular collapse and severe CNS toxicity including seizures and coma.

Artemisinin Derivatives

These drugs are generally well-tolerated. Common effects include nausea, vomiting, dizziness, and transient neutropenia. A concerning adverse effect is delayed hemolysis following treatment for severe malaria, particularly with intravenous artesunate. This “post-artesunate delayed hemolysis” (PADH) occurs 1-3 weeks after treatment as young erythrocytes (reticulocytes) infected at the time of therapy mature and are cleared. Neurotoxicity (ataxia, hearing loss) has been observed in animal studies with very high doses but is not a common clinical issue at therapeutic doses.

Quinine and Quinidine

A cluster of symptoms known as cinchonism is common, comprising tinnitus, hearing loss, headache, nausea, and visual disturbances. Hypoglycemia is a serious and potentially life-threatening effect, resulting from quinine-induced hyperinsulinemia. Cardiac effects include QT interval prolongation and arrhythmias (quinidine > quinine). Severe immune-mediated thrombocytopenia, hemolytic anemia, and hypersensitivity reactions can also occur.

Primaquine and Tafenoquine

The most significant adverse effect is acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. This is an absolute contraindication unless G6PD status is confirmed normal. Primaquine can also cause methemoglobinemia, abdominal cramps, and, rarely, neutropenia. Tafenoquine shares the hemolytic risk and has additional concerns regarding neuropsychiatric effects and its long half-life, which prolongs the risk period in cases of undiagnosed G6PD deficiency.

Pentavalent Antimonials

Toxicity is common and often treatment-limiting. Effects include arthralgias, myalgias, pancreatitis, elevated liver enzymes, and ECG changes (T-wave flattening or inversion, QT prolongation). Sudden death due to cardiac arrhythmia is a rare but feared complication.

Amphotericin B

Immediate infusion-related reactions (fever, chills, rigors, hypotension) are common with the deoxycholate formulation. Dose-limiting nephrotoxicity, characterized by reduced glomerular filtration rate, renal tubular acidosis, and electrolyte disturbances (notably hypokalemia and hypomagnesemia), is a major concern. Lipid formulations significantly reduce nephrotoxicity but are more costly.

Miltefosine

Gastrointestinal disturbances (nausea, vomiting, diarrhea) are very common. Elevation of serum creatinine and liver transaminases may occur. Due to its long half-life and known teratogenicity, strict pregnancy prevention is mandatory for women of childbearing potential during and for several months after treatment.

Drug Interactions

Significant drug interactions can alter the efficacy or toxicity of antiprotozoal agents. Key interactions are driven by effects on metabolic enzymes, particularly cytochrome P450 isoforms, and additive toxicities.

Enzyme Inducers and Inhibitors

• Metronidazole can inhibit the metabolism of warfarin (CYP2C9), phenytoin, and lithium, potentially increasing their serum concentrations and toxicity. Coadministration with drugs that cause disulfiram-like reactions (e.g., certain cephalosporins) or with alcohol should be avoided.
• Quinine/Quinidine are potent inhibitors of CYP2D6 and CYP3A4. They can significantly increase levels of drugs metabolized by these pathways, such as certain antiarrhythmics (e.g., flecainide), antidepressants (e.g., tricyclics), and opioids (e.g., codeine, whose activation is CYP2D6-dependent). Coadministration with other QT-prolonging agents (e.g., macrolides, antipsychotics) increases the risk of torsades de pointes.
• Artemisinin derivatives may induce their own metabolism and that of other drugs via CYP450 induction, though clinically significant interactions are less well-documented.
• Chloroquine may increase digoxin levels and potentiate the effects of hypoglycemic agents. It may antagonize the efficacy of anticonvulsants (e.g., carbamazepine, phenytoin).

Additive Toxicities

• Concurrent use of azathioprine or 6-mercaptopurine with allopurinol (which inhibits their metabolism) and pyrimethamine (a folate antagonist) can lead to severe pancytopenia.
• The combination of quinine/quinidine with mefloquine is contraindicated due to an increased risk of seizures and cardiotoxicity.
• Amphotericin B with other nephrotoxic drugs (e.g., aminoglycosides, cyclosporine, cisplatin) or with corticosteroids (which promote hypokalemia) increases the risk of renal damage and electrolyte disturbances.
• Pentavalent antimonials should be used with extreme caution with other drugs that prolong the QT interval or cause pancreatitis.

Special Considerations

Pregnancy and Lactation

The use of antiprotozoal drugs in pregnancy requires careful risk-benefit analysis, weighing the threat of the infection against potential fetal harm.

• Malaria in Pregnancy: P. falciparum malaria poses severe risks to both mother and fetus. For treatment, artemisinin derivatives are recommended in the second and third trimesters; quinine plus clindamycin is an alternative, especially in the first trimester. For prophylaxis in endemic areas, mefloquine or chloroquine (in chloroquine-sensitive areas) are options. Sulfadoxine-pyrimethamine is used for intermittent preventive treatment (IPTp) in Africa. Primaquine and tetracyclines are contraindicated.
• Amoebiasis/Giardiasis: Paromomycin, a non-absorbable aminoglycoside, is the preferred luminal agent. For invasive disease, metronidazole can be used after the first trimester, though its use in the first trimester is sometimes considered if benefits outweigh risks.
• Lactation: Metronidazole is excreted in breast milk; while single-dose therapy is considered compatible with breastfeeding, some authorities recommend interrupting breastfeeding for 12-24 hours after a high dose. Chloroquine and quinine are considered compatible. Data on many newer agents are limited.

Pediatric Considerations

Dosing is typically based on body weight or surface area. Pediatric formulations (e.g., dispersible tablets for ACTs) are critical for accurate dosing and adherence. For malaria, artesunate suppositories can be used as pre-referral treatment in remote settings. The risk of vomiting with bitter drugs like quinine may be higher. The use of tetracyclines is contraindicated in children under 8 years due to effects on teeth and bone.

Geriatric Considerations

Age-related declines in renal and hepatic function may alter drug pharmacokinetics, necessitating dose adjustments for renally excreted drugs (e.g., chloroquine, quinine) or those with hepatically generated toxic metabolites. Comorbid conditions and polypharmacy increase the risk of drug interactions and additive toxicities, such as QT prolongation or hypoglycemia.

Renal and Hepatic Impairment

• Renal Impairment: Dosage reduction is required for drugs primarily excreted unchanged by the kidneys, such as chloroquine, pentamidine, and flucytosine. Amphotericin B nephrotoxicity is of particular concern. Metronidazole dose reduction is advised only in severe renal failure due to accumulation of metabolites.
• Hepatic Impairment: Caution and potential dose reduction are needed for drugs extensively metabolized by the liver, such as chloroquine, quinine, primaquine, and miltefosine. Metronidazole should be used with caution, and its dosage may need reduction in severe liver disease due to impaired metabolism. Many antimalarials can cause asymptomatic elevations in liver enzymes.

Summary/Key Points

• Antiprotozoal drugs target a diverse group of eukaryotic parasites, with mechanisms of action that often exploit unique parasitic pathways, such as heme polymerization inhibition in malaria parasites or nitroreduction in anaerobic protozoa.
• The nitroimidazoles (metronidazole, tinidazole) are first-line for invasive amoebiasis, giardiasis, and trichomoniasis, with their activity dependent on anaerobic activation to cytotoxic radicals.
• Malaria treatment is guided by species, severity, and resistance. Artemisinin-based Combination Therapies (ACTs) are the cornerstone for uncomplicated P. falciparum, while radical cure of P. vivax requires primaquine or tafenoquine after G6PD screening.
• Pharmacokinetic properties vary widely, from the short half-lives of artemisinins (requiring combination therapy) to the extremely long half-lives of chloroquine and miltefosine, impacting dosing and safety monitoring.
• Serious adverse effects are drug-specific and must be monitored: hemolysis with primaquine in G6PD deficiency, cinchonism and hypoglycemia with quinine, retinopathy with chronic chloroquine, nephrotoxicity with amphotericin B, and GI/teratogenic risks with miltefosine.
• Significant drug interactions occur, particularly with quinine (CYP inhibition, QT prolongation) and metronidazole (disulfiram reaction, warfarin potentiation).
• Special populations require tailored therapy: avoidance of tetracyclines and primaquine in specific pediatric groups, careful antimalarial selection in pregnancy, and dose adjustments in renal/hepatic impairment.

Clinical Pearls

• Always follow treatment of invasive amoebiasis with a luminal agent to prevent relapse from persistent intestinal cysts.
• Test for G6PD deficiency before administering primaquine or tafenoquine; this is not optional.
• In severe malaria, intravenous artesunate has superior efficacy and safety compared to quinine and is the treatment of choice.
• Consider “post-artesunate delayed hemolysis” (PADH) in patients who develop anemia 1-3 weeks after treatment for severe malaria.
• The long half-life of miltefosine necessitates rigorous pregnancy testing and contraception for women of childbearing potential for several months after the last dose.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.