PHA Pharma-therapeutics Anti-Malaria, Anti-Protozoal & Anti-Helminthic Drugs PDF

PHA PHARMA-THERAPEUTICS SHIFT 3 Anti-Malarial, Anti-Protozoal, & LESSON Anti-Helminthic Agents...

PHA PHARMA-THERAPEUTICS SHIFT 3 Anti-Malarial, Anti-Protozoal, & LESSON Anti-Helminthic Agents 16 Flordeluna Z. Mesina, MD | Date: 23 Jan 2024 TABLE OF CONTENTS 1. MALARIA 1. Malaria 1 1.1. Life Cycle 1.1. Life Cycle 1.2. Classification of Anti-Malarial Drugs Based on the Stage of Plasmodium It Affects 1.3. Classification of Anti-Malarial Drugs Based on Clinical Indication 1.4. Goals of Treatment 1.5. Factors that Influence Treatment 2. Anti-Malarial Drugs 3 2.1. Quinine/Quinine-Like 2.2. Artemisinin Derivatives 2.3. Aryl Alcohols 2.4. Anti-Folates 2.5. Anti-Microbials 3. Anti-Malarial Drug Resistance 9 4. Anti-Malarial Drug Combination Therapy 5. Malaria in Pregnancy 9 6. Drugs Used for Chemoprophylaxis of Malaria 9 7. WHO/CDC Recommendations for Malaria Treatment 2021 10 8. Anti-Malarial Drugs Summary 11 9. Amebiasis 11 10. Ant-Protozoal Drugs 12 10.1. Classification Fig 1.1-1. Life cycle of Plasmodium 10.2. Tissue Amebicides 10.3. Luminal Amebicides Composed of 2 stages and 2 hosts (Complex) 10.4. Treating Amebiasis according to ○ Sexual stage / Sporogony (Host: Mosquito) Clinical Setting ○ Asexual stage / Schizogony (Host: Human) 11. Helminthic Infection & Anti-Helminthic Erythrocytic Cycle - inside the RBC Drugs 14 Exo-erythrocytic Cycle - outside the RBC = Liver 11.1. Benzimidazoles Vector: Anopheles mosquito 11.2. Pyrantel Pamoate 11.3. Diethylcarbamazine Citrate 11.4. Ivermectin 1.1.1. Asexual Stage/Schizogony 11.5. Therapy for Commonly Encountered Nematode Infection A female Anopheles mosquito introduces 12. Anti-Helminthics: Trematodes & Nematodes 17 sporozoites when biting a human (blood 12.1. Praziquantel meal). 12.2. Therapy for Commonly Encountered Exoerythrocytic The sporozoites infect the liver cells via Trematode Infection tropism Cycle 12.3. Therapy for Commonly Encountered In the liver, the sporozoites mature and Cestode Infection accumulate and eventually burst, 13. Summary Tables 19 releasing merozoites into the bloodstream LEGEND Merozoites then infect healthy RBC, ★ Important / Take Note ✤ Textbook Information these in turn become erythrocytic ➤ Lecturer’s Verbatim ❐ Other Transes/Resources schizonts Erythrocytic These once again accumulate and Cycle eventually burst, either infecting more RBC or develop into male and female gametocytes In the liver cycle, some sporozoites may In P. vivax & P. enter a dormant stage (Hepatic dormancy) lasting for months to years ovale which is responsible for the relapse of malaria. (Hypnozoites) UST MED 2026 | PHARMA-THERAPEUTICS  PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs 1.1.2. Sexual Stage/Sporogony 1.2.2. Blood Schizonticides Another bloody meal from Anopheles mosquito will transfer ➤ Targets the schizonts in the erythrocytic stage. the gametocytes from humans to the gut of the mosquito. ➤ Artemisinins – not used alone or monotherapy, although still The male and female gametocytes fuse to form a zygote. highly efficacious due to its high parasite clearance. The zygote develops into an ookinete and invades the mosquito midgut wall, later developing into an oocyst. Oocysts grow, rupture, and release sporozoites which migrate RAPID-ACTING & SLOW-ACTING & to the mosquito’s salivary glands. HIGH EFFICACY LOW EFFICACY As the mosquito bites a human host, sporozoites are Description Description inoculated and the cycle continues. ➤ Can stand alone ❐ Can’t stand as monotherapy ➤ Has high parasite ❐ Used in combination with clearance PLASMODIUM SPECIES highly efficacious blood ❐ Singly treat malarial schizonticide drugs Causes most severe form of disease, fever Plasmodium very sick and toxic patients ❐ Since it is fast, preferable falciparum Wide drug resistance to chloroquine Occurs worldwide for Falciparum malaria 48 hr fever spike Drugs Drugs Chloroquine Sulphadoxine + Have latent organism for years Artemisinin Pyrimethamine Plasmodium vivax (clinical relapse) Quinine Proguanil & Plasmodium P. vivax is common worldwide Mefloquine Clindamycin ovale P. ovale has limited distribution Atovaquone 48 hr fever spike Plasmodium Least common malariae 72 hr fever spikes 1.2.3. Gametocidal Drugs GAMETOCIDAL DRUGS Artemisinins 1.2. Classification of Anti-Malarial Drugs Based on the Stage Chloroquine & Quinine (P. vivax) of Plasmodium It Affects JED 1.3. Classification of Anti-Malarial Drugs Based on Clinical Indication Fig 1.3-1. Classification of anti-malarial drugs based on clinical indication. CLASSIFICATION OF ANTIMALARIAL DRUGS BASED ON CLINICAL INDICATION Chemoprophylaxis Fig 1.2-1. Classification of anti-malarial drugs based on the stage of Plasmodium it affects. ❐ For prevention ❐ A healthy person is going to an endemic area for malaria and 1.2.1. Tissue Schizonticides there is a potential to get infected, so we give prophylaxis for protection and prevention. ➤ Tissue schizontocidal drugs target the hepatic schizonts. ➤ Important for the radical elimination of P. vivax and P. ovale, Targets the link between exoerythrocytic and most of which will have latent infections. erythrocytic stage, preventing erythrocytic infection. DRUGS FOR TISSUE ACTIVE DRUGS FOR LATENT TISSUE Prevent maturation of or destroy the FORMS FORMS (HYPNOZOITES) ❐ sporozoites within the infected hepatic cell Primaquine Primaquine Causal thus prevent erythrocytic invasion. Atovaquone Tafenoquine Prophylactic o Patients given are usually asymptomatic Sulphadoxine + Agents Pyrimethamine so it is difficult to know who are on this Proguanil stage of the disease. o Individuals are given this based on their risk of acquiring the infection. UST MED 2026 | PHARMA-THERAPEUTICS 2  PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs o Primaquine – for all species of malaria 1.5. FACTORS THAT INFLUENCE TREATMENT but not used due to its toxic potential. Kill merozoites emerging from the liver Infecting Plasmodium species cells. Different species would vary in their characteristics and Recommended as a prophylactic agent to resistance patterns anyone traveling to malaria endemic areas. 1 P. falciparum can cause severe illness or mortality. No chemoprophylactic agent is 100% effective. P. vivax and P. ovale can cause uncomplicated malaria, Schizonticidal agents that inhibit but would have a dormant stage which makes them erythrocyte phase and prevent the rupture harder to eradicate. of the infected erythrocytes, leading to Clinical status of the patient freedom from rigors and pyrexia (symptoms 2 are suppressed by killing the schizonts in the Complicated vs. uncomplicated malaria ❐ RBCs). Area where the infection was acquired and its drug Suppressive o Quinine: Not generally used in 3 resistance status Prophylactic chemoprophylaxis owing to its toxicity, although a daily dose of 325 mg is Is it multi-drug resistant or chloroquine-resistant? Agents effective. Accompanying conditions o Chloroquine Such as pregnancy, drug allergy, other medications o Proguanil 4 In Africa, an endemic region for malaria, the kids, o Pyrimethamine pregnant patients, and elderly are mostly affected. o Artemisinin Anti-malarial drugs are known for drug interactions Clinical Cure ➤ Mostly composed of the blood schizonticides. ❐ Disappearance of signs & symptoms and improvement of clinical condition. 2. ANTI-MALARIAL DRUGS Radical Cure MAJOR CLASSES OF ANTI-MALARIAL DRUGS ➤ There is no single available agent that can reliably effect a Quinine/Quinidine radical cure. Chloroquine Quinine and o Radical cure = blood schizonticide + tissue Mefloquine Quinine-Like schizonticide Primaquine Atovaquone ▪ Eliminates both the erythrocytic and hepatic stage. Dihydroartemisinin ➤ Combination drugs Artemisinins Artemether ❐ Used in patients with P. ovale and P. vivax infection because Artesunate radical cure in this patient would entail eradication of Lumefantrine schizonts/hypnozoites in the liver. Aryl Alcohols Halofantrine Transmission Prevention Pyrimethamine Anti-Folates ➤ Composed of the gametocidal drugs. Sulfadoxine-Proguanil o Targets the sexual stage (gametocyte), preventing the Doxycycline Anti-Microbials transmission and reducing the spread of the parasite. Clindamycin o No benefit to the patient being treated. o Drugs used as gametocidal agents: 2.1. Quinine and Quinine-Like ▪ Primaquine + Artemisinins: Targets all 4 species 2.1.1. Quinine/Quinidine ▪ Chloroquine + Quinine: Targets P. vivax, P. ovale, ➤ Oldest drug because its discovery dates back to the time of and P. malariae Spaniards during the 14th century. ❐ This is what the National Malaria Control and Elimination ○ Found in the region of South America, where you can Program is targeting. see trees of cinchona plant. o Elimination of vector ○ The barks of cinchona trees were boiled and are used to o Prevention of mosquito bites, etc. lyse fever, which was considered effective ❐ More on environmental control to stop the gametocytes from Natural cinchona alkaloid reproducing and spreading. Rapidly acting blood schonticides against all 4 species Gametocidal against P. vivax, P. ovale, and P. malariae 1.4. GOALS OF TREATMENT Quinidine is MORE POTENT an an antimalarial but MORE To prevent and treat clinical attacks of malaria. TOXIC than quinine To completely eradicate the parasite from the patient’s body. To reduce human reservoir of infection - cut down Acts by concentrating in plasmodial food transmission vacuoles preventing the polymerization of Mechanism toxic free heme into harmless hemozoin of Action resulting in build-up of toxic free heme or heme-drug complex that damages the parasite’s membrane, leading to its death. UST MED 2026 | PHARMA-THERAPEUTICS 3 PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs Quinine + doxycycline / clindamycin - for treatment of multi-drug resistant falciparum malaria Doxycyline or clindamycin is commonly given with: ○ Quinine - for a shorter and better tolerated course of quinine. Quinidine/Quinine - not used for chemoprophylaxis (due to the presence of their side effects) Fig 2.1.1-1. Quinine mechanism of action. Cinchonism ○ Common (at therapeutic doses) ➤ Life sustenance of the malarial parasite is ○ Tinnitus headache, dizziness, vomiting, dependent on RBCs. flushing, visual disturbances ➤ Hemoglobin constitutes most of the RBC’s Hypoglycemia at therapeutic doses cytoplasm, and it contains two substances: Hypersensitivity reactions heme & globin. ○ Skin rash, angioedema, ○ Globin is recycled to make amino bronchospasm, black - water fever acids and proteins for the parasites. (tea-colored urine) ○ The heme that is not used is a toxic Hematologic abnormalities: hemolysis in by-product to the organism. G6PD deficiency ➤ The parasite has heme polymerase in the Adverse Quinine can stimulate mild uterine food vacuole that can polymerize heme to Effects contractions especially in the 3rd be converted into hemozoin (a non-toxic trimester of pregnancy (risk for preterm substance). labor) ★ Quinine is a heme polymerase inhibitor. IV Quinidine ★ ALL quinine derivates will have THE SAME ○ Thrombophlebitis mechanism of action. ○ QTc prolongation Absorption ○ Too rapid infusion → hypotension; ○ Rapidly & almost completely absorbed should be administered under cardiac from the GIT monitoring because of arrhythmias ○ Peak plasma levels in 1-3 hours Pregnancy Risk Category: Distribution Quinine/Quinidine: C ○ Protein binding, plasma levels, and Prolongation of QTc interval (risk for half-life increase in proportion tot he bradyarrhythmia) when given concurrently severity fo malaria with or shortly after mefloquine ○ Widely distributed to tissues including administration CSF Oral absorption is decreased by ➤ If there is CNS malaria, the quinine Drug aluminum-containing antacids & quinidine IV forms are used to Interactions Quinine increases plasma warfarin and eradicate the parasite. digoxin levels (especially in elderly patients Metabolism w/ cardiac problems) ○ Metabolized in the liver via CYP3A4 Antagonize the action of physostigmine on Pk ➤ Needs monitoring skeletal muscles ➤ Anti-malarials are usually given 3 to 7 days (not given as a maintenance medication) 2.1.2. Chloroquine Synthetic 4-aminoquinoline Elimination Rapidly acting blood schizonticide against all 4 sp. ○ Metabolites are excreted in the urine Moderately effective against P. vivax, P. ovale and P. within 24 hours malariae gametocytes ○ Half-life: 7-12 hours (healthy persons) CHLOROQUINE 18 hours (those with severe malaria due to the increase in the Acts by concentrating in plasmodial food level of alpha-1 glycoprotein) vacuoles preventing the polymerization of ★ Quinidine is a has a shorter half life as toxic free heme into harmless hemozoin Mechanism compared to quinine as a result of lower resulting in build-up of toxic free heme or of Action protein binding. heme-drug complex that damages the parasite's membrane leading to its death Quinine/Quinidine (parenteral) - DOC for Heme polymerase inhibitor severe falciparum malaria Quinine - 1st line drug for oral treatment of Drug of choice for the treatment of malaria uncomplicated falciparum malaria in areas in areas without documented Therapeutic chloroquine resistance with documented chloroquine resistance Therapeutic Indications Chemoprophylaxis in malarious areas ➤ Only a first line drug since there are other Indications drugs that have a better safety profile without resistant falciparum malaria Quinine - 1st line drug for uncomplicate d Other indications: malaria in pregnant women ○ Treatment of amebic liver abscess UST MED 2026 | PHARMA-THERAPEUTICS 4  PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs that failed initial metronidazole PHARMACOKINETICS treatment Slowly and well absorbed after an oral dose; ○ Treatment of rheumatic diseases as Absorption plasma levels rise in a biphasic manner to DMARD their peak in about 18 hours Common: unpleasant taste, pruritus Protein binding - 98%, VD is 13-40 L/kg Uncommon: vomiting, urticaria, blurring of Distribution Widely distributed to all tissues including the vision CSF Rare: impaired hearing, psychosis, Metabolism Human liver microsomes Adverse seizures, hemolysis in those with G6PD Effects deficiency, QT interval prolongation Terminal elimination half-life: 20 days weekly Long term/high dose-irreversible ototoxicity, prophylactic dosing Excretion retinopathy, peripheral neuropathy, Parent drug and its acid metabolites are myopathy slowly excreted mainly in the feces Pregnancy Risk Category: C Reduced absorption when given with 2.1.4. Primaquine and Tafenoquine antacids Synthetic 8-aminoquinoline Increased risk of convulsions with The drugs active against the dormant hepatic stage of P. vivax Drug mefloquine and P. ovale Interactions Increased risk of arrhythmias with Gametocidal against all 4 species halofantrine and drugs that prolong the QT interval PRIMAQUINE Africa Production of oxygen free radicals that Areas of Asia interfere with the plasmodial electron Drug Central America transport chain during respiration Resistance South America PHARMACOKINETICS Rapidly & completely absorbed Mechanism Absorption Peak plasma concentrations in 3 hours of Action Extensively distributed to body tissues Distribution Very large Vd (100-1000L/Kg) Slowly released from tissues and Metabolism metabolized in the liver Selectively accumulates in the retina Fig 2.1.4-1. Mechanism of Action of Primaquine Eliminated slowly via the kidneys Excretion Initial half-life of 3-5 days and a terminal half-life of 1-2 months PHARMACOKINETICS PRIMAQUINE TAFENOQUINE 2.1.3. Mefloquine Almost completely Rapidly absorbed Synthetic 4-quinoline methanol, chemically related to quinine absorbed Absorption Peak plasma levels Blood schizonticide against all 4 sp. (but slower acting Peak plasma levels in 2-15 hours than chloroquine and quinine) in 1-2 hours Widely distributed Acts by concentrating in plasmodial food Widely distributed to to tissues vacuoles preventing the polymerization of Distribution tissues High volume of toxic free heme into harmless hemozoin Mechanism distribution resulting in build-up of toxic free heme or of Action Rapidly metabolized heme-drug complex that damages the parasite's membrane leading to its death in the liver Heme polymerase inhibitor Its 3 major Metabolized in the metabolites have liver with activity of Chemoprophylaxis in malarious areas with Metabolism less antimalarial CYP2D6 liver documented chloroquine resistance Therapeutic activity but with more microsomal Treatment of uncomplicated falciparum Indications potential for inducing enzyme malaria (in combination with artemisinin hemolysis than the derivative) parent drug Vomiting, dizziness, sleep and behavioral Plasma half-life: 2 disturbances, confusion, psychosis/seizures Adverse weeks (at treatment doses) Effects Slowly excreted Prolongation of QTc interval Plasma half-life: 3-8 from the body Pregnancy Risk Category: C Excretion hours primarily in the Prolongation of cardiac conduction with Excreted in the urine feces Drug calcium channel blockers, quinine, quinidine Renal elimination of Interactions and halofantrine the unchanged form is very low UST MED 2026 | PHARMA-THERAPEUTICS 5  PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs ★ As compared to primaquine, tafenoquine is SLOW-ACTING Absorption as seen in its plasma half-life of 2 weeks. ○ Poor oral absorption ★ Tafenoquine, when used as terminal prophylaxis, would need ○ Bioavailability is low: 23% ○ Bioavailability with fatty food: 47% only a SINGLE DOSE. Distribution: high protein binding ★ Primaquine and tafenoquine would only differ in terms of their Metabolism pharmacokinetics, most importantly in plasma half-life. The rest ○ Not significantly metabolized or it has no Pk would be the same and would be tabulated in one table. metabolites ○ Excreted in the bile and 94% recovered unchanged in the feces PRIMAQUINE AND TAFENOQUINE Elimination For radical cure of P. vivax and P. ovale ○ Excreted unchanged in the feces malaria, in combination with chloroquine ○ Half-life: 2-3 days long due to Terminal prophylaxis of P. vivax and P. enterohepatic cycling ovale malaria (primaquine is given for 14 Stomach pain days after leaving the malarious area to Nausea decrease the likelihood of relapse). Vomiting Therapeutic Adverse Most effective drug for preventing Headache Indications Effects transmission of the disease in all species of human malaria ➤ Atovaquone has only a few but tolerable side A single dose of primaquine can be used as effects. a control measure to render P. falciparum gametocyte non-infective to mosquito, thus disrupting the transmission of the disease 2.2. Artemisinins and Derivatives ★ First line drug in malaria ★ Most common: hemolytic anemia of methemoglobinemia in G6PD deficiency ❐ known as Wonder drug (Batch 2025 Trans) Adverse The artemisinins are derived from the leaves of the Chinese Effects High dose: GI distress, headache, agranulocytosis sweet wormwood plant, Artemisia annua. Pregnancy Risk Category: D (to be avoided) They have been used in China for the treatment of malaria for over 2000 years and came to attention outside of China in the ➤ Diagnosing G6PD deficiency is part of newborn screening. 1970s and 1980s. However, at a certain age and for confirmatory purposes, the Only came into attention when there was an alarming test is repeated through a quantitative test. resistance to Chloroquine ➤ The confirmatory test would reveal the G6PD deficiency in Nobel Prize in 2015 percentage to determine if the deficiency is mild or severe. ➤ Severe G6PD Deficiency: Absolute Contraindication Sesquiterpene lactone with endoperoxide linkage (solution: look for an alternative drug to treat the disease) Insoluble and can only be used in orally ➤ Mild G6PD Deficiency: Can still give the drug to the patient ➤ In patients with severe malaria, those who are obtunded, but it must be supported with transfusion (inform the patient usually in coma, there should be a way to administer the drug. of the risks) Hence, the creation of analogs which can be administered orally, IM, IV, and rectal 2.1.5. Atovaquone Potent and very rapidly acting Synthetic naphthoquinone Blood schizonticides against all 4 species Blood schizonticide against all 4 species ★ Most potent gametocidal drugs ★ Usually available as combination: ATOVAQUONE + PROGUANIL → MALARONE ○ Active against gametocytes of all 4 species ○ Reduction in malaria transmission rates Produce rapid and substantial reduction of the parasite ATOVAQUONE biomass resulting in rapid parasite clearance and rapid Inhibits the parasite’s mitochondrial resolution of symptoms electron transport chain at complex III of respiratory chain by mimicking the natural ANALOGS substrate ubiquinone Water soluble Artesunate ❐ Can be given oral, IV, IM and rectal (Batch 2025 Trans) Mechanism Lipid soluble of Action ❐ Can be given IM, oral and rectal Artemether (Batch 2025 Trans) Dihydroartemisinin Water soluble ARTEMISININS AND DERIVATIVES Mechanism ➤ Production of oxygen free radicals that Fig 2.1.5-1. Mechanism of action of Atovaquone. of Action alkylates proteins UST MED 2026 | PHARMA-THERAPEUTICS 6 PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs ○ Different MOA from the conventional ○ Short half life (1-3 hrs) - limits their anti-malarial drugs efficacy as monotherapy and Heme iron-catalyzed cleavage of the chemoprophylactic agent artemisinin endoperoxide bridge In order for it to become effective, Production of highly reactive free radicals combine it with other drug Binding to the parasite membrane proteins Usually it comes in fixed dose Lipid peroxidation combinations Damage to the endoplasmic reticulum and ❐ If given as monotherapy, has to be ultimately lysis of the parasite given 4-5x a day (Batch 2025 Trans) ○ Rapidly eliminated via the kidney Ideal partners for other drugs Treatment for uncomplicated multidrug resistant falciparum malaria, in combination with lumefantrine or mefloquine or with FDC of sulfadoxine-pyrimethamine Treatment for complicated/severe Falciparum malaria in combination (Artesunate + Mefloquine) ★ Artemisinin-based combination therapy Fig 2.2-1. Mechanism of Action of Artemisinins (ACTs) is recommended ○ Provides rapid and substantial reduction ➤ Prodrug of parasite burden ○ Inactive when administered but because ○ Reduces the likelihood of resistance and of the iron that is inside the red blood decreases disease transmission cells, it will form the heme-iron complex ○ Combine the highly effective short acting inside the parasite and this becomes the artemisinins with a longer acting partner free radical Therapeutic to protect against artemisinin resistance ➤ Because it is a free radical, it is very active Indications and to facilitate dosing convenience and it can alkylate the proteins and the ○ Given for three days in fixed dose DNA structure of the parasite tablets ❐ Proposed mechanism of action of artemisinin ❐ Instead of 7 days (Batch 2025 Trans) (Batch 2025 Trans): 4 ACTs recommended by WHO for the ○ Artemisinin is a cyclic endoperoxide that treatment of uncomplicated malaria forms a free radical after activation by ○ Artemether lumefantrine (Coartem) iron (Fe). The mechanism of action of Most efficacious artemisinin is not known with certainty ○ Artesunate-amodiaquine but may involve the alkylation of ○ Artesunate-mefloquine macromolecules such as heme and Artesunate-sulfadoxine proteins, resulting in the formation of -pyrimethamine artemisinin-heme adducts and NOT used as monotherapy artemisinin-protein adducts that are toxic ○ To prevent emergence of drug resistance to plasmodia. One such adduct may and to avoid the need for prolonged involve PfATP6, a parasite Ca2+ATpase therapy (not shown) that is the ortholog of the NOT used as chemoprophylaxis mammalian SERCA calcium pump Most common: mild GI symptoms ❐ Act via 2-step mechanism (Batch 2025 Trans): Generally well tolerated ○ Artemisinin is first activated by the Adverse Type 1 hypersensitivity has been reported intra-parasitic heme iron which catalyzes Effects ★ Used with caution in very young children and the cleavage of the endoperoxide. This should be avoided during 1st trimester of will result in a free radical intermediate pregnancy which may then kill the parasite by alkylating and poisoning 1 or more Concurrent administration with Astemizole, essential malarial proteins. Drug anti-arrhythmic, TCAs and phenothiazines ○ In short, it produces oxygen free radicals interactions increases the risk of cardiac conduction that alkylates and disrupts protein defects (arrhythmias). synthesis Absorption 2.3. Aryl Alcohols ○ Rapidly absorbed after an oral dose Halofantrine and Lumefantrine ❐ Good bioavailability (Batch 2025 Trans) Potent blood schizonticides against all 4 species Distribution Pk ○ Peak plasma levels in 1-2 hrs HALOFANTRINE AND LUMEFANTRINE Metabolism ○ Rapidly metabolized via CYP2B6 to Formation of cytotoxic complexes with Mechanism dihydroartemisinin ferriprotoporphyrin IX that cause of Action Elimination plasmodial membrane damage PK Absorption: UST MED 2026 | PHARMA-THERAPEUTICS 7  PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs ○ Variable oral absorption but enhanced Absorption: Slow, adequate absorption with food Distribution: High protein binding Distribution: Metabolism: Extensive Metabolism ○ Plasma levels achieved after 16 hours Pk Elimination: Excreted in urine Excretion: ○ Excreted mainly in feces ○ Pyrimethamine half-life: 3.5 days ○ Lumefantrine t1/2 = 4.5h ○ Proguanil half-life: 16 hours ○ Halofantrine t1/2 = 1 - 5 days ❐ Relatively well-tolerated Halofantrine: GIT upset, elevated liver Gastric discomfort Adverse Adverse enzymes, dose-related prolongation of QT Effects High dose: Folic acid deficiency Effects interval Lumefantrine: mild GIT upset Pregnancy Risk Category: C FDC Lumefantrine-arthemeter (Coartem) FDC Proguanil-Chloroquine: Malaria Therapeutic ★ Treatment of choice of chloroquine-resistant chemoprophylaxis as alternative to indications falciparum malaria Therapeutic mefloquine Indications ❐ FDC Proguanil-Atovaquone (Malarone): 2.4. Anti-Folates Chemoprophylaxis in areas with chloroquine resistant falciparum malaria 2.4.2. Sulfadoxine Slow-acting blood schizonticides SULFADOXINE Mechanism of Analog and competitive antagonist of PABA Action to inhibit folic acid synthesis Absorption: Rapidly absorbed Distribution: Widely distributed to all tissues including CSF and has high protein binding Pk Metabolism: Acetylated in the liver Elimination: Slowly excreted with extensive tubular reabsorption of free form ○ Sulfadoxine half-life: 7-9 days FDC of Pyrimethamine-Sulfadoxime Adverse ○ Erythema multiforme Effects ○ Steven’s Johnson Syndrome ○ Pregnancy Risk Category: C Fig 2.4-1. Mechanism of Action of Antifolates. ➤ Anti-folates target the different enzymes that convert Fixed-Dose Combination (FDC) Para-aminobenzoic acid (PABA) to Tetrahydrofolic acid Sulfadoxine-Pyrimethamine which is important to produce purines and pyrimidine in the ○ Treatment of uncomplicated Therapeutic chloroquine-resistant falciparum formation of DNA. Indications ❐ Anti-folates are also called antineoplastic agents malaria ★ Folate synthesis inhibitors – not Sulfadoxine & recommended for prophylaxis Pyrimethamine & Proguanil Sulfamethoxazole Dihydropteroate synthetase Dihydrofolate reductase inhibitor inhibitor 2.5. Anti-Microbials with Anti-Malarial Activity Protein synthesis inhibitors 2.4.1. Pyrimethamine/Proguanil 2.5.1. Doxycycline/Clindamycin Slow-acting blood schizonticides against all 4 Plasmodium Slow acting blood schizonticides against all 4 spp. spp. or low efficacy Not used alone in the treatment of malaria ➤ Usually used in combination with rapidly acting and high ➤ They are combined mostly with Quinine/Quinidine to efficacy antimalarial drugs such as Chloroquine (Ex. shorten the course of treatment of severe falciparum and Proguanil-Chloroquine) in uncomplicated falciparum malaria with Chloroquine resistance PYRIMETHAMINE/PROGUANIL Inhibits plasmodial Dihydrofolate DOXYCYCLINE/CLINDAMYCIN Mechanism reductase (DHFR) for the inhibition of folic Mechanism of Inhibit protein synthesis of Action Action acid synthesis. UST MED 2026 | PHARMA-THERAPEUTICS 8  PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs Absorption: Oral absorption variable, and 5. MALARIA IN PREGNANCY impaired by food, antacids, divalent & Pregnant women as special populations as they are trivalent cations, dairy products associated with high risk of both maternal and perinatal Pk Distribution: Widely distribution except morbidity and mortality CNS; Bound to teeth, spleen and bone Pregnant women less effectively clear the infection and tend ❐ Metabolism: Extensive metabolism to have more severe disease Elimination: Hepatobiliary excretion GI upset, bone growth retardation, MALARIAL TREATMENT RECOMMENDATIONS IN permanent pigmentation and hypoplasia of PREGNANCY Adverse teeth Antimalarial drugs that can Effects Quinine OR Chloroquine OR Not given to children < 8 yrs. Old be safely given during the 1st Pregnancy Risk Category: D Pyrimethamine, Proguanil OR trimester (period of growth Mefloquine OR FDC of Given with quinine for treatment of and organogenesis) of sulfadoxine-pyrimethamine chloroquine-resistant falciparum malaria pregnancy Doxycycline: chemoprophylaxis in areas Chemoprophylaxis Chloroquine or Mefloquine Therapeutic with multi-drug resistance (as alternative Indications to Mefloquine) Uncomplicated Chloroquine ➤ Good to use alone (monotherapy) for chloroquine-sensitive malaria multi-drug resistance Uncomplicated falciparum Quinine (3 days) plus malaria during all trimesters Clindamycin (7 days) of pregnancy Uncomplicated falciparum Artesunate + clindamycin 3. ANTI-MALARIAL DRUG RESISTANCE malaria during the 2nd and or ➤ Infectious diseases such as Malaria, treatment guidelines are 3rd trimesters of pregnancy Quinine + clindamycin useful to prevent emergence of drug resistance for those who do Chloroquine not know how to prescribe and to not adaptt to resistance patterns Maintained on The ability of a parasite to survive and/or multiply despite the chlorquine prophylaxis administration of an antimalarial drug in doses equal to or for the duration of Uncomplicated P. vivax & P. higher than those usually recommended pregnancy ovale malaria Resistance to an anti-malarial drug arises because of the Primaquine should be selection of parasites with genetic mutations or gene given only after delivery if the woman is not amplifications that confer reduced susceptibility. G6PD deficient Mutation in the putative transporter Plasmodium falciparum Uncomplicated chloroquine resistance transporter (PfCRT) cloroquine-resistant P. vivax Quinine (7 days) ➤ Transporters of the parasite’s cytoplasm that pumps out the infections drug = Drug resistance IV infusion of quinidine for 24 Resistance to one drug may select resistance to another drug hours followed by oral quinine where the mechanosms of resistance are similar Severe malaria (for a total of 7 days) + Clindamycin (7 days) 4. ANTI-MALARIAL DRUG COMBINATION THERAPY ★ Artemisinin is not used for the first trimester Objectives: ○ To improve therapeutic efficacy ○ To prevent or delay the emergence of resistance 6. DRUGS USED FOR CHEMOPROPHYLAXIS OF MALARIA ❐ The simultaneous use of two or more blood schizonticidal drugs with different modes of action DRUGS USED FOR CHEMOPROPHYLAXIS OF MALARIA (Recommendations from National Malaria Control Elimination ❐ Allows a shorter course of artemisinin treatment and at Program NMCEP) the same time enhancing its efficacy and reducing the likelihood of resistance DRUGS USE ADULT DOSAGE ➤ Based on the artemisinin-derived combination with 500 mg (base) weekly other drugs starting 1-2 wks. Before The artemisinin derivative component of the combination Areas without entering an endemic area Chloroquine chloroquine-resistant must be given for at least 3 days for an optimum effect & continued for 4 wks. P. falciparum FDC of artemether-lumefantrine (Coartem) provides the After leaving the endemic highest cure rates followed by FDC of area artesunate-mefloquine (250 mg atovaquone & Advantages: 100 mg proguanil) 1 tablet ○ Rapid and substantial reduction of the parasite biomass Atovaquone– Areas with daily beginning 2 days Proguanil chloroquine-resistant before entering an ○ Rapid parasite clearance (Malarone) P. falciparum endemic area & ○ Rapid resolution of clinical symptoms continuing for 7 days after ○ Effective action against multidrug-resistant P. falciparum leaving ○ Reduction of disease transmission Areas with 250 mg weekly starting Mefloquine chloroquine-resistant 1-2 wks. Before entering P. falciparum an endemic area & UST MED 2026 | PHARMA-THERAPEUTICS 9  PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs continued for 4 weeks ➤ follow with 7 days oral therapy as for after leaving Most patients have course of Doxycycline artesunate 100 mg daily. Begin 2 CNS manifestations or Clindamycin or full days before travel to an so use IV for faster treatment course of OR Areas with endemic area and effect Coartem, Malarone, Doxycycline multidrug-resistant P. continued for 4 weeks or Mefloquine Quinine falciparum after leaving dihydrochloride OR 20 mg/kg IV then ➤ “Mahapdi sa tiyan” so 10 mg/kg q8 hrs give with a full stomach Quinidine gluconate Terminal prophylaxis 30 mg base (2 tablets) IV Primaquine of P. vivax and P. daily for 14 days after ovale infections travel to an endemic area Terminal prophylaxis 300 mg single dose Tafenoquine of P. vivax and P. ➤ For better compliance ovale infections ★ Drugs are given before entering to an area to increase plasma concentration and after leaving the area for those residual parasites 7. WHO/CDC RECOMMENDATIONS FOR MALARIA TREATMENT 2021 ALTERNATIVE CLINICAL SETTING DRUG THERAPY DRUG Chloroquine phosphate, 1 g, ff by Chloroquine-sensitiv 500 mg at 6, 24, 48 hrs e P. falciparum and P. malariae OR infections (uncomplicated Chloroquine and complicated or phosphate, 1 g at 0 severe) and 24 hrs, then 500 mg at 48 hrs Chloroquine (as For chloroquine above), then (if G6PD P. vivax and P. resistant areas: normal) Primaquine ovale infections ACT + (30 mg base) for 14 Primaquine days Atovaquone + Proguanil (Malarone) 4 tabs Fig. 7-1. Algorithm for diagnosis and treatment of malaria in the United States daily for 3 days ➤ WHO and US guidelines are similar. OR Mefloquine 15 mg/kg once or 750 Uncomplicated Coartem (artemether mg then 500 mg in infections with 20 mg + lumefantrine 6-8 hrs chloroquine 120 mg), 4 tablets 2x resistant P. daily for 3 days OR falciparum Quinine sulfate 650 mg TID for 3 days + Doxycycline 100 mg BID for 7 days OR Clindamycin 600 mg BID for 7 days Severe/Complicate Artesunate 2.4 Artemether 3.2 d infections with P. mg/kg/IV every 12 hrs mg/kg IM then 1.6 falciparum for 1 day then daily for mg/kg/day IM 2 additional days; follow with oral Fig. 7-2. Malaria cases and deaths in the Philippines (as of September 2018) UST MED 2026 | PHARMA-THERAPEUTICS 10  PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs Steady decrease in deaths and cases of malaria in the 9. AMEBIASIS Philippines Fig. 7-3. Distribution of cases in the Philippines (Palawan vs. other provinces) DOH-National Malaria Control and Elimination Program (NMCEP) ○ Goal: malaria-free PH by 2023 Palawan is still the most endemic, but compared to the early 2000’s, there is a significant decrease Fig. 9-1. Life cycle of E. histolytica Most endemic provinces: Palawan, Sulu, Occidental Mindoro, Sultan Kudarat A, B, May present in the body as non invasive colonizers C or as invasive extraintestinal disease Infection is through ingestion of mature cyst from 8. ANTI-MALARIAL DRUGS SUMMARY 1 contaminated food, water, or dirty hands. ERYTHR EXO-ERYTH Excystation occurs in the small intestines and GAMETOCYTES OCYTIC ROCYTIC 2 trophozoites are released which migrate to the large DRUGS P. vivax/ intestines P. vivax/ All 4 sp. P. falciparum P. ovale/ P. ovale Multiply by binary fission and produce cysts P. malariae 3 Chloroquine + - - + Cysts are passed in the feces and become the 4 Mefloquine + - - - infective form Because of the protection conferred by the cyst wall, it can Quinine + - - + survive for days to weeks in the external environment and be Proguanil + +/- * * transmitted Pyrimethamine +/- - * * Trophozoites can be passed in the stool but are rapidly Primaquine +/- + + + destroyed once outside the body Sulfadoxine + - - - ASSOCIATED DISEASES Doxycycline + - - - In many cases, the trophozoite remains in Artemisinin + - + + the colon as colonizer only. It does not Halofantrine + - - - elicit inflammation but it can produce cyst Cysts Passers as source of transmission * Does not kill gametocytes but inhibits development in mosquito / Colonizers Generally asymptomatic Amoebic cyst and trophozoites can be seen in fecalysis but no symptoms Amoebic colitis Clinical condition or manifestation where it causes inflammation in the colon Amoebic Liver / In immunocompromised (patients with Lung / Brain cancer, under chemotherapy, with HIV, Abscess etc.) UST MED 2026 | PHARMA-THERAPEUTICS 11  PHA SHIFT 3 | LESSON 16 | Anti-Malarial, Anti-Protozoal, & Anti-Helminthic Drugs (Extraintestinal Goes to the bloodstream and colonize the ○ Well absorbed after an oral dose disease) liver, lungs, or brain ○ Peak plasma concentration in 1-3 hr. Distribution Ent (Enteric) ; Histo (Tissue) ; Lytica (Lysis) ○ Low plasma protein binding (75% Unchanged: 10% Most frequent: Nausea, headache, dry mouth, metallic taste 10. ANTI-PROTOZOAL DRUGS Adverse Infrequent: Vomiting, diarrhea, insomnia, Effects dark urine 10.1. Classification of Anti-Protozoal Drugs Rare: Pancreatitis, CNS Toxicity Potentiates anti-coagulant effect of coumarin TISSUE AMOEBICIDES Elimination increased by phenytoin and phenobarbital Intestinal and Extraintestinal ○ Patients who have seizure disorders Amoebiasis Extraintestinal Amoebiasis should be warned (Mixed Amebicides) Elimination decreased by cimetidine for liver abscess ★ Disulfiram-like reaction with ethanol Nitroimidazoles: ○ Indication of Disulfiram is to control Metronidazole alcoholic disorders Tinidazole Chloroquine ○ ❐ Disulfiram causes unpleasant effects Akaloids Emetine when even small amounts of alcohol are Dehydroemetine consumed. ○ ➤ Drunk-like effects or severe hangover LUMINAL AMOEBICIDES Drug For cyst passers Interactions manifestation Diloxanide Furoate - not available in PH ○ ❐ Flushing of the face, headache, Iodoquinol - not available in PH nausea, vomiting, severe chest pain, Paromomycin - not available in PH weakness, blurred vision, mental confusion, sweating, choking, breathing Tetracycline/Erythromycin difficulty, and anxiety may be felt by the patient when disulfiram and large NOTE: amounts of alcohol are consumed Radical Elimination of Amoebiasis: Tissue together. Amoebicides + Luminal Amoebicides ○ Advise the patient not to take metronidazole and alcohol together. Extraintestinal Amoebiasis (e.g Liver Abscess) not ○ ➤ Do not drink and drive, and take Responsive to Metronidazole: Chloroquine metronidazole *Pregnancy Risk Category - B 10.2. Tissue Amebicides Intestinal & extra-intestinal infections Kills trophozoites 10.2.1. Metronidazole Amebic brain abscess Amebic colitis, amebic liver abscess METRONIDAZOLE DOC for all symptomatic amebiasis Nitro group acts as an electron acceptor Therapeutic Against: which is involved in a redox-reaction that o G. lamblia Indications forms nitrogen free radicals o E. histolytica ○ Nitrogen free radicals impairs the protein Mechanism o T. vaginalis synthesis of