ANTIPROTOZOANS AND DRUGS USED IN TREATMENT OF MALARIA.pptx

Breif note of drugs

1. ANTI-PROTOZOANS: DRUG TREATMENT OF MALARIA

2. IBEKWE, Chinonyerem 21/3260 ESO, Gerald 20/1906 20/0997 NWA, Utibeabasi 20/3264 AJAYI, Victoria 21/2815

3. Introduction Malaria constitutes a potentially fatal illness transmitted to humans through specific mosquito species, primarily prevalent in tropical regions. It is both preventable and treatable. The causative agent is a parasite, and transmission does not occur through person-to-person contact. Symptoms range from mild, encompassing fever, chills, and headache, to severe manifestations such as fatigue, confusion, seizures, and respiratory distress.

4. Certain demographics, including infants, children under 5 years, pregnant women, travelers, and individuals with HIV or AIDS, face an elevated risk of severe infection. Preventive measures include mitigating exposure to mosquito bites and the judicious use of prophylactic medications. Introduction

5. Five main species pathogenic to man P. falciparum, P. malariae , P. vivax, P. ovale & P. knowlesi P. simium now known to infects man . P. falciparum also now known to infect animals – this has implications for malaria control. P. falciparum most virulent with multiple and complex genetic structures P. falciparum also most prone to develop drug resistance. ETIOLOGY OF SPECIES

6. Acute/Uncomplicated malaria. Symptomatic malaria parasitaemia with no signs of severity and/or evidence of vital organ dysfunction. Severe/Complicated malaria. Severe malaria usually manifests with one or more of the following: Coma (cerebral malaria, metabolic acidosis, severe anaemia , hypoglycaemia , acute renal failure or acute pulmonary edema. If left untreated, severe malaria is fatal in majority of cases.. Cerebral malaria Defined as unarousable coma not attributable to any other cause in patients with proven  P. falciparum  infection Severe falciparum malaria with coma persisting for> 30 min after a seizure. Asymptomatic parasitaemia . The presence of asexual. parasites in the blood without symptoms of illness. NB : Relapse : Reactivation of dormant liver-stage parasites causing recurrent symptoms, common in P. vivax and P. ovale malaria. Recrudescence : Recurrence of symptoms due to incomplete treatment or drug resistance, involving surviving parasites from the initial infection. Reinfection: Acquisition of a new malaria infection from a mosquito bite, within a short period after initial treatment distinct from relapse or recrudescence. Types of Malaria Infections

7. EPIDEMIOLOGY Per the WHO, as of 2021 malaria was endemic in 84 countries, placing nearly half the world’s population at risk of contracting the disease. Modern US travelers acquire almost 90% of malaria by traveling to Africa; almost 9% of the disease is acquired in Asia, whereas South and Central America/ the Caribbean make up the remainder. In these patients, there is a 14% risk for severe disease, and 13% of the cases initially are misdiagnosed

8. EPIDEMIOLOGY Malaria is widespread in Nigeria, affecting 97% of the population. The transmission season varies, lasting year-round in the south and three months or less in the north. The primary malaria species is Plasmodium falciparum, and the main vector is Anopheles gambiae s.s., making up 67.1% of collected vectors. In 2021, Nigeria had the highest global malaria cases (26.6% of cases) and deaths (31% of deaths), contributing to 54% of malaria cases in West Africa. Between 2020 and 2021, case numbers decreased by 2% (from 312.7 to 306 per 1000 people at risk), while deaths increased by 3.5% (from 0.94 to 0.91 per 1000 people at risk).

9. LIFE CYCLE OF PLASMODIUM PARASITE The malaria parasite completes its life cycle in two hosts: Humans and the mosquitoes. The asexual stage occurs in man, while the sexual stage occurs in mosquitoes. ASEXUAL STAGE IN MAN: This could be divided into exoerythrocytic and erythrocytic stages. During the process of a blood meal by the infected female anopheles mosquito, sporozoites are inoculated into the bloodstream of man. The sporozoites drops as droplets and escape into the liver within the space of one hour via mosquito salivary gland.

10. LIFE CYCLE OF PLASMODIUM PARASITE Each sporozoite infects a hepatocyte. In the liver cells, they transform, multiply and develop into schizonts. The schizonts ruptures out of the hepatocytes as merozoites and enters into the red blood cells to form early trophozoite stage. Immature trophozoite stage can progress to either mature trophozoite or gametocyte stage. The mature trophozoites can then progress to form schizont that can rupture as merozoites and re infect the blood cells. The gametocytes is then ingested by an uninfected female anopheles mosquito.

11. LIFE CYCLE OF PLASMODIUM PARASITE SEXUAL STAGE IN MOSQUITO This is also called the sporogonic cycle. The mosquito ingests a macrogametocyte and a microgametocyte. The microgametocyte enter the macrogametocyte to form ookinete. The ookinete forms the oocyst. The oocyst ruptures to form the sporozoites that will begin the cycle again in man.

12. CLINICAL MANIFESTATIONS OF MALARIA Malaria clinical manifestations are not specific, but they have the similitude of systemic illness. They could include: Headache, Fatigue, Abdominal pain, Fever, Chills, Perspiration, Anorexia, Vomiting, Progressive malaise. Specifically in children, additional manifestations could be: Enlarged spleen or liver, Pallor, Lethargy, Poor feeding, Cough.

13. DIAGNOSIS OF MALARIA Malaria diagnosis typically involves a combination of : 1. Clinical assessment 2. M icroscopic examination of blood smears for the presence of malaria parasites (GOLD STANDARD ) 3. Rapid diagnostic tests (RDTs) detecting parasite antigens 4. Molecular techniques like polymerase chain reaction (PCR) for accurate species identification and detection of low parasitemia .

14. MALARIA CHEMOTHERAPY AIMS & OBJECTIVES OF ANTIMALARIAL DRUG USE To prevent clinical attack of malaria (prophylactic). To treat clinical attack of malaria (clinical curative). To completely eradicate the parasite from the patient’s body (radical curative): Combination therapy of antimalarial is the most significant attempt towards achieving radical cure. To cutdown human-to-mosquito transmission (gametocidal).

15. ANTIMALARIAL DRUG CLASSIFICATIONS According to mechanism of action, antimalarial drugs are classified into: 1. Tissue Schizonticides: Eliminate developing or dormant liver forms (pre-erythrocytic as well as exoerythrocytic stages, such as P. vivax). 2. Erythrocytic Schizonticides: Act on Erythrocytic schizogony 3. Gametocides: Kill sexual stages (gametocytes) in the blood and prevent transmission to mosquitoes.

16. FORMS OF ANTIMICROBIAL THERAPY CAUSAL PROPHYLAXIS: The preerythrocytic phase (in liver), which is the cause of malarial infection and clinical attacks, is the target for this purpose. Most commonly used are peimaquine and proguanil. SUPPRESSIVE PROPHYLAXIS: The schizontocides which suppress the erythrocytic phase and thus attack of malarial fever are used as suppressive prophylaxis. Chemoprophylaxis of malaria should be limited to short-term use in special risk groups, such as — non immune travellers , nonimmune persons living in endemic areas for fixed periods (army units, labour forces), infants, children and pregnant women.

17. FORMS OF ANTIMICROBIAL THERAPY 3. CLINICAL CURE: The erythrocytic schizontocides are used to terminate an episode of malarial fever Classified as High efficacy drugs(artemisinin, amodiaquine, quinine, mefloquine, halofantrine, lumefantrine and atovaquone) & Low efficacy drugs ( Proguanil, pyrimethamine, sulfonamides, tetracyclines and clindamycin ; used only in combination as a clinical cure. 4. RADICAL CURE: . A radical curative is needed in relapsing malaria About 8–30% P.v. cases relapse due to persistance of exoerythrocytic stage. Drugs which attack this stage (hypnozoites) given together with a clinical curative achieve total eradication of the parasite from the patient’s body. Drugs of choice include: primaquine , tafenoquine.

18. FORMS OF ANTIMICROBIAL THERAPY 5. GAMETOCIDAL : elimination of the male and female gametes of Plasmodia formed in the patient’s blood Primaquine is gametocidal to all species of Plasmodia, while artemisinins have weak lethal action on early-stage but not mature gametes Adequate control of clinical attacks will reduce formation of gametes

19. OVERVIEW OF ANTIMALARIAL DRUGS

20. OVERVIEW OF ANTIMALARIAL DRUGS

21. MAJOR ANTIMALARIAL DRUGS CLASSES Structurally, anti-malarial drugs are classified as: Quinoline-related Compounds Artemisinin derivatives Quinine Proguanil Sulfonamide-Pyrimethamine Primaquine Antimicrobials

22. QUINOLINE-RELATED COMPOUNDS Chloroquinine Amodiaquine Piperaquine Drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s. Usefulness against P. Falciparum has been compromised greatly by resistance.

23. CHLOROQUINE CHEMISTRY & PHARMACOKINETICS Synthetic 4-Aminoquinolone Orally formulated into a phosphate Rapidly absorbed from the Gastrointestinal tract, reaching maximum plasma concentration in 3 hours Therapeutic plasma concentrations are in the range of 15–30 ng/ml. It is rapidly distributed into tissues, having a very large Vd = 100 - 1000 L/kg T1/2 = 3-5 days Prinicipally excreted in the urine PHARMACODYNAMICS: Blood Scizonticide Not effective against tissue Schizonts or gametocytes MOA: The drug is concentrated in parasite food vacuoles, preventing the biocrystallization of the hemoglobin breakdown product, heme , into hemozoin , and thus eliciting parasite toxicity due to the buildup of free heme .

24. CHLOROQUINE RESISTANCE Resistance is common amongst strains of P. Falciparum. Not as common, but on the rise in P. Vivax strains. Because P. falciparum produces the more severe forms of malaria with considerable mortality, emergence of such strains is the biggest threat to the antimalaria programmes , and is the focus of attention for current research efforts

25. CHLOROQUINE MECHANISM OF P. FALCIPARUM RESISTANCE: An efflux transporter encoded by the pfcrt ( P.f . chloroquine-resistance transporter) gene, has been identified in the membranes of the acidic vacuoles of CQ-resistant P.f . It serves to pumpout CQ from the vacuoles and thus protects the haeme detoxifying mechanism of the resistant parasite. This results in a decreased ability of the parasite to accumulate Chloroquine.

26. CHLOROQUINE CLINICAL USES: Treatment Chemoprophylaxis Amoebic liver Abscess ADVERSE EFFECTS: Pruritus & Urticaria GIT Adverse effects: Nausea, Vomiting, Abdominal Pain, Anorexia CNS Adverse Effects: Headache, Blurring of Vision, Impaired Hearing, Confusion, Psychosis, Seizures Dermatological complications:exfoliative dermatitis, alopecia, bleaching of hair CVS Complications: hypotension, and electrocardiographic changes, cardiac arrest. Hemolysis in G6PD Deficiency Agranulocytosis LONG TERM USE: irreversible ototoxicity, retinopathy, myopathy, and peripheral neuropathy,

27. CHLOROQUINE CONTRAINDICATIONS: Psoriasis Porphyria G6PD Deficiency Retinal or Visual Field Abnormalities Myopathy DRUG-DRUG INTERACTIONS: Antidiarrhoeal Agents: Kaolin and calcium- and magnesium-containing antacids interfere with the absorption of chloroquine and should not be co-administered.

28. AMODIAQUINE Closely related to chloroquine, and it probably shares mechanisms of action and resistance. Amodiaquine was widely used to treat malaria because of its low cost, limited toxicity, and, in some areas, effectiveness against chloroquine-resistant strains of P falciparum. ADR: Agranulocytosis, Aplastic anemia, and Hepatotoxicity. These adverse drug reactions have limited its use. The most important current use of amodiaquine is in Combination therapy.

29. PIPERAQUINE A bisquinoline that was used widely to treat chloroquine-resistant falciparum malaria in China in the 1970s–1980 Its use waned after resistance became widespread. Used effectively as combination therapy, E.g : Piperaquine combined with dihydroartemisinin ( Artekin , Duocotecxin ) showed excellent efficacy and safety for the treatment of Falciparum malaria although very recently decreased efficacy has been seen in southeast Asia, linked to decreased activity of both components of the combination.

30. PIPERAQUINE PIPERAQUINE COMBINATION THERAPY: DIHYDROARTEMISININ-PIPERAQUINE: Piperaquine has a longer half-life (~28 days) than amodiaquine (~14 days), mefloquine (~14 days), or lumefantrine (~4 days), leading to a longer period of post-treatment prophylaxis with dihydroartemisinin-piperaquine than with the other leading artemisinin -based combinations; this feature should be particularly advantageous in high-transmission areas such as Asia, in which it is now the first-line therapy for the treatment of uncomplicated falciparum malaria.

31. PIPERAQUINE As dihydroartemisinin-piperaquine offers extended protection against Malaria. There is interest in chemoprevention with monthly dosing of the drug, which has shown excellent efficacy in children and pregnant women in Africa.

32. ARTEMISININ & ITS DERIVATIVES Artemisinin Artemisinin analogs: Artesunate Artemether Dihydroartemisinin Sesquiterpene lactose endoperoxide extracted from herb called “Sweet Wormwood” (Artemesia annua) Artemisinin is insoluble and can only be administered orally. Analogs have been synthesized to increase solubility and improve antimalarial efficacy.

33. ARTEMISININ & ITS DERIVATIVES Artemisinin Artemisinin analogs: Artesunate Artemether Dihydroartemisinin The most important of these analogs are: Artesunate (water soluble; oral, intravenous, intramuscular, and rectal administration), Artemether (lipid-soluble; oral, intramuscular, and rectal administration), Dihydroartemisinin (water-soluble; oral administration). Arteether (I.m. administration) Arterolone (oral administration)

34. ARTEMISININ & ITS DERIVATIVES CHEMISTRY & PHARMACOKINETICS: Artemisinin and its analogs are complex 3- and 4-ring structures. They are rapidly absorbed, with peak plasma levels occurring promptly. Half-lives after oral administration are 30–60 minutes for artesunate and dihydroartemisinin , and 2–3 hours for artemether. Artemisinin, artesunate, and artemether are rapidly metabolized to the active metabolite dihydroartemisinin . PHARMACODYNAMICS: Monotherapy is strongly discouraged for the treatment of uncomplicated malaria due to high recrudescence rates. Co-formulated artemisinin-based combination therapies with a long-acting schizonticide are recommended to improve efficacy and prevent the selection of artemisinin-resistant parasite

35. ARTEMISININ & ITS DERIVATIVES MOA: Blood Schizonticides against all malaria parasites Production of free radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge. Mechanism of Artemisinin Resistance has not been clearly established.

36. ARTEMISININ ANALOGS ARTESUNATE: The sodium salt of artesunate is water-soluble and is administered by oral, i.m. or i.v. routes. After oral ingestion, absorption is incomplete but fast, reaching peak in <60 min. It is rapidly converted to the active metabolite dihydroartemisinin (DHA) with a t½ of 30–60 min. The t½ of DHA is 1–2 hours. After repeated dosing, artesunate causes autoinduction of its own metabolism by CYP2B6 and CYP3A4. Intravenous artesunate is the 1st choice drug for severe malaria Orally, it is used as ACT with 3 different partner drugs for uncomplicated falciparum malaria Examples: FALCIGO, FALCYNATE, ARTINATE ; LARINATE, ARNATE

37. ARTEMISININ ANALOGS ARTEMETHER lipid-soluble and is administered orally or i.m. , but not i.v undergoes substantial first pass metabolism and is converted to DHA. Extensive metabolism by CYP3A4 yields a t½ of 5–8 hours For severe malaria, it is a 2nd choice option when i.v. artesunate is not available or cannot be used. Oral artemether is used in combination with lumefantrine. Examples: PALUTHER, LARITHER,MALITHER . ARTHEETER: available for i.m. administration only to adults for complicated malaria Long half life of 23 hours Examples: E-MAL, FALCY, RAPITHER-AB; LEOTHER. DIHYDROARTEMISININ AND ARTEROLANE available for oral use only in combination, and are considered with ACT

38. ARTEMISININ & ITS DERIVATIVES CLINICAL USES: Uncomplicated Falciparum Malaria Treatment: used in endemic areas due to high efficacy, safety and tolerance, as ACTs. In Pregnancy: 1st Trimester: Quinine i.v. plus clindamycin 2nd & 3rd Trimesters: Artemisinin-based combination theaarapies for the treatment of uncomplicated falciparum malaria. Complicated Falciparum malaria Treatment: Parenteral artemisinins are highly effective and are the drugs of choice irrespective of CQ resistance status

39. ARTEMISININ & ITS DERIVATIVES ADVERSE EFFECTS: GIT Adverse Effects: Nausea, Vomiting, Diarrhoea , Abdominal Pain, itching Delayed Hemolysis Dizziness, Tinnitus, headache, bleeding, dark urine Toxicities: Neutropenia, Anaemia , Transient Reticulopenia hemolysis, elevated liver enzymes, and allergic reactions. DRUG-DRUG INTERACTIONS: Concurrent administration of artemisinins with drugs prolonging Q-T, like antiarrhythmics, tricyclic antidepres sants and phenothiazines may increase the risk of cardiac conduction defects.

40. ARTEMISININ-BASED COMBINATION THERAPY (ACT) Due to the emergence of CQ-resistant, followed by multidrug-resistant P. falciparum, the WHO has recommended that all cases of acute uncomplicated falciparum malaria should be treated only by combining one of the artemisinin compounds with another effective erythrocytic schizontocide . In choosing the companion drug, the most important consideration is its elimination t½ Short t½ drugs have to be given for 7 days, while longer acting drugs can be given for 1–3 days. because effective concentrations in blood must be maintained for at least 3–4 asexual cycles of the parasite, i.e. 6–8 days, to exhaust the parasite burden. Artemisinin compounds fulfil this requirement, as they rapidly kill > 95% plasmodia. They leave only a small biomass of the parasites to be eliminated by the long t½ drug, reducing the chances of selecting resistant mutants.

41. ARTEMISININ-BASED COMBINATION THERAPY (ACT) - Some ACTs include: Artemether-lumefantrine , Artesunate-mefloquine , Artesunate-amodiaquine , Artesunate-sulfadoxine + pyrimet hamine , Dihydroartemisinin (DHA)- piperaquine,Arterolane-piperaquine , Artesunate-pyronaridine , amongst others. ADVANTAGES OF ACT OVER OTHER ANTIMALARIALS: Rapid clinical and parasitological cure. High cure rates (>95%) and low recrudescence rate. Absence of parasite resistance (the components prevent development of resistance to each other). Good tolerability profile.

42. ARTEMISININ & ITS DERIVATIVES ARTHEMETER-LUMEFANTRINE: orally active, high efficacy, long-acting erythrocytic schizontocide Lumefantrine is highly lipophilic; absorption starts after 2 hours of ingestion and peaks at 6–8 hours Plasma protein binding is 99%, and it is metabolized predominantly by CYP3A4. The two components protect each other from plasmodial resistance. As such, no clinically relevant resistance has developed so far. Artemether-lumefantrine is active even in multidrug resistant P.f . areas. While artemether quickly reduces parasite biomass and resolves symptoms, lumefantrine prevents recrudescence. Gametocyte population is reduced, checking transmission. Artemether-lumefantrine must be administered with fatty food or milk, which markedly enhances lumefantrine (and to some extent artemether) absorption, and ensures adequate blood levels.

43. ARTEMISININ & ITS DERIVATIVES Artemether-lumefantrine should not be given with drugs metabolized by CYP2D6 (metoprolol, neuroleptics, tricyclic antidepressants, etc.), because lumefantrine inhibits the isoenzyme CYP2D6. It is to be avoided in first trimester of pregnancy and during breast feeding. ARTESUNATE-AMODIAQUINE (AS/AQ) While AQ itself has a short t½ due to rapid metabolism, its metabolite, an equally potent antimalarial has long t½ of 10–18 days Trials were conducted in Africa with AS/AQ coformulated as FDC tablets, which produced high cure rates, and now this ACT has become the first-line therapy of uncomplicated falciparum malaria in many African countries.

44. ARTEMISININ & ITS DERIVATIVES DIHYDROARTEMISININ (DHA)-PIPERAQUINE Piperaquine is a bisquinoline congener of CQ developed in China as a high efficacy longacting (t½ 3–4 weeks) erythrocytic schizontocide with a slower onset of action because of larger volume of distribution It is more active against CQ-resistant P. falciparum and retains equal activity against CQ sensitive organisms. The efflux transporters of the resistant parasite are believed to be unable to pump out the bulky molecule of piperaquine. Safety profile of DHA- piperaquine is good and it is well tolerated even by children. ADRs: dizziness, vomiting and other g.i. symptoms are common; rashes are rare.

45. ARTEMISININ & ITS DERIVATIVES ARTEROLANE-PIPERAQUINE Arterolane acts rapidly at all stages of asexual schizogony of malarial parasite including multidrug resistant P.f ., but has no effect on the hepatic stages. It accumulates in the food vacuole of the parasite, and thus differs from artemisinins which do not accumulate at this site It also has moderate gametocidal activity similar to that of artemether-lumefantrine. Peak plasma arterolane concentration is reached in 3–5 hours and it has a large volume of distribution The major metabolic pathway is oxidation, mainly by CYP3A4, which is also the primary isoenzyme responsible for piperaquine metabolism ADRs: mild headache, postural dizziness, vomiting, abdominal pain and diarrhoea .

46. ARTEMISININ-BASED COMBINATION THERAPY

47. ANTIMICROBIALS Doxycycline Tetracycline Clindamycin A number of antibiotics are modestly active antimalarials . Bacterial protein synthesis inhibitors appear to act against malaria parasites by inhibiting protein synthesis in a plasmodial prokaryote-like organelle, the apicoplast . None of the antibiotics should be used as single agents in the treatment of malaria because their action is much slower than that of standard antimalarials .

48. DOXYCYCLINE AND TETRACYCLINE Tetracycline and doxycycline are active against erythrocytic schizonts of all human malaria parasites. They are not active against liver stages. Doxycycline is used in the treatment of falciparum malaria in conjunction with qui- nine, allowing a shorter and better-tolerated course of that drug. Doxycycline is also used to complete treatment courses after initial treatment of severe malaria with intravenous quinine, quinidineor artesunate. In all of these cases a 1-week treatment course of doxycycline is carried out. Doxycycline has also become a standard chemoprophylactic drug, especially for use in areas of Southeast Asia with high rates of resistance to other antimalarials, including mefloquine. ADVERSE EFFECTS OF DOXYCLINE : gastrointestinal symptoms, esophagitis, candidal vaginitis, and photosensitivity.

49. CLINDAMYCIN Clindamycin is slowly active against erythrocytic schizonts and can be used after treatment courses of quinine, quinidine, or artesunate in those for whom doxycycline is not recommended, such as children and pregnant women.

50. QUININE PHARMACOKINETICS Quinine is derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America. The alkaloid quinine was purified in 1820 and has been used in the treatment and prevention of malaria since that time. Quinidine, the dextrorotatory stereoisomer of quinine, is at least as effective as parenteral quinine in the treatment of severe falciparum malaria. After oral administration, quinine is rapidly absorbed, reaches peak plasma levels in 1–3 hours, and is widely distributed in body tissues. ANTIMALARIAL ACTION AND RESISTANCE Quinine is a rapid-acting, highly effective blood schizonticide against the four species of human malaria parasites. The drug is gametocidal against P vivax and P ovale but not P. falciparum. It is not active against liver stage parasites. The mechanism of action of quinine is unknown. Resistance to quinine is common in some areas of South- east Asia, especially border areas of Thailand, where the drug may fail if used alone to treat falciparum malaria.

51. QUININE USES 1. Parenteral treatment of severe falciparum malaria—For many years quinine dihydrochloride or quinidine gluconate were the treatments of choice for severe falciparum malaria, although intravenous artesunate is now preferred. Quinine can be administered slowly intravenously or, in a dilute solution, intramuscularly 2. Oral treatment of falciparum malaria—Quinine sulfate is appropriate therapy for uncomplicated falciparum malaria except when the infection was transmitted in an area without documented chloroquine resistance. Quinine is commonly used with a second drug (most often doxycycline or, in children, clindamycin) to shorten the duration of use (usually to 3 days) and limit toxicity. Quinine is not generally used to treat nonfalciparum malaria.

52. QUININE ADVERSE EFFECTS Therapeutic dosages of quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness, flushing, and visual disturbances, a constellation of symptoms termed cinchonism . Mild symptoms of cinchonism do not warrant the discontinuation of therapy Hypersensitivity reactions include skin rashes, urticaria, angioedema, and bronchospasm. Hematologic abnormalities include hemolysis (especially with G6PD deficiency), leukopenia, agranulocytosis, and thrombocytopenia. Quinine can stimulate uterine contractions, especially in the third trimester. However, this effect is mild, and quinine and quinidine remain appropriate for treatment of severe falciparum malaria during pregnancy. Intravenous infusions of the drugs may cause thrombophlebitis. Blackwater fever is a rare severe illness that includes marked hemolysis and hemoglobinuria in the setting of quinine therapy for malaria. It appears to be due to a hypersensitivity reaction to the drug, although its pathogenesis is uncertain.

53. QUININE CONTRAINDICATIONS Quinine (or quinidine) should be discontinued if signs of severe cinchonism , hemolysis, or hypersensitivity occur. It should be avoided if possible in patients with underlying visual or auditory problems. It must be used with great caution in those with underlying cardiac abnormalities. Quinine should not be given concurrently with mefloquine and should be used with caution in a patient with malaria who has recently received mefloquine.

54. MEFLOQUINE CHEMISTRY AND PHARMACOKINETICS Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is chemically related to quinine. It can only be given orally because severe local irritation occurs with parenteral use. It is well absorbed, and peak plasma concentrations are reached in about 18 hours. It is highly protein-bound, extensively distributed in tissues, and eliminated slowly, allowing a single-dose treatment regimen. The terminal elimination half-life is about 20 days, allowing weekly dosing for chemoprophylaxis.. ANTIMALARIAL ACTIONS AND RESISTANCE Mefloquine has strong blood schizonticidal activity against P falciparum and P vivax , but it is not active against hepatic stages or gametocytes. The mechanism of action is unknown. Sporadic resistance to mefloquine has been reported from many areas, but resistance appears to be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of Thailand). Mefloquine resistance does not appear to be associated with resistance to chloroquine.

55. MEFLOQUINE CLINICAL USES 1. Chemoprophylaxis—Mefloquine is effective in prophylaxis against most strains of P falciparum and probably all other human malarial species. Treatment—Mefloquine is effective in treating uncomplicated falciparum malaria. The drug is not appropriate for treating individuals with severe or complicated malaria. ADVERSE EFFECTS Weekly dosing with mefloquine for chemoprophylaxis may cause nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash, and dizziness. Neuropsychiatric toxicities CONTRAINDICATIONS : Mefloquine is contraindicated in a patient with a history of epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, or sensitivity to related drugs Mefloquine is also now considered safe in young children, and it is the only chemoprophylactic other than chloroquine approved for children weighing less than 5 kg and for pregnant women.

56. PRIMAQUINE Primaquine is the drug of choice for the eradication of dormant liver forms of P vivax and P. ovale and can also be used for chemo- prophylaxis against all malarial species. CHEMISTRY AND PHARMACODYNAMICS Primaquine phosphate is a synthetic 8-aminoquinoline. The drug is well absorbed orally, reaching peak plasma levels in 1–2 hours. The plasma half-life is 3–8 hours. Primaquine is widely distributed to the tissues ANTIMALARIAL ACTION AND RESISTANCE Primaquine is active against hepatic stages of all human malaria parasites. It is the only available agent active against the dormant hypnozoite stages of P vivax and P ovale . The drug is also game- tocidal against the four human malaria species and it has weak activity against erythrocytic stage parasites. The mechanism of antimalarial action is unknown.

57. PRIMAQUINE USES 1. Therapy (radical cure) of acute vivax and ovale malaria—Standard therapy for these infections includes chloroquine to eradicate erythrocytic forms and primaquine to eradicate liver hypnozoites and prevent a subsequent relapse. Chloroquine is given acutely, and therapy with primaquine is withheld until the G6PD status of the patient is known. If the G6PD level is normal, a 14-day course of primaquine is given. 2. Terminal prophylaxis of vivax and ovale malaria: Standard chemoprophylaxis does not prevent a relapse of vivax or ovale malaria, because the hypnozoite forms of these parasites are not eradicated by available blood schizonticides completion of travel to an endemic area. 3. Chemoprophylaxis of malaria—Daily treatment with 30 mg (0.5 mg/kg) of primaquine base provided good protection against falciparum and vivax malaria. 4. Gametocidal action—Primaquine renders P falciparum gametocytes noninfective to mosquitoes.

58. PRIMAQUINE ADVERSE EFFECTS Primaquine in recommended doses is generally well tolerated. It infrequently causes nausea, epigastric pain, abdominal cramps, and headache, and these symptoms are more common with higher dosages and when the drug is taken on an empty stomach. More serious but rare adverse effects are leukopenia, agranulocytosis CONTRAINDICATIONS : Primaquine should be avoided in patients with a history of granulocytopenia or methemoglobinemia, in those receiving potentially myelosuppressive drugs ( eg , quinidine), and in those with disorders that commonly include myelosuppression. Patients should be tested for G6PD deficiency before primaquine is prescribed.

59. INHIBITORS OF FOLATE SYNTHESIS PYRIMETHAMINE PROGUANIL CHEMISTRY AND PHARMACOKINETICS Pyrimethamine is a 2,4-diaminopyrimidine related to trimethoprim . Proguanil is a biguanide derivative . Both drugs are slowly but adequately absorbed from the gastrointestinal tract Fansidar , a fixed combination of the sulfonamide sulfadoxine (500 mg per tablet) and pyrimethamine (25 mg per tablet), is well absorbed. Its components display peak plasma levels within 2–8 hours and are excreted mainly by the kidneys. The average half-life of sulfadoxine is about 170 hours.

60. INHIBITORS OF FOLATE SYNTHESIS ANTIMALARIAL ACTIONS AND RESISTANCE Pyrimethamine and proguanil act slowly against erythrocytic forms of susceptible strains of all four human malaria species. Sulfonamides and sulfones are weakly active against erythrocytic schizonts but not against liver stages or gametocytes. Resistance of P falciparum to folate antagonists and sulfon - amides is common in many areas. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. . ANTIMALARIAL ACTIONS AND RESISTANCE Resistance seriously limits the efficacy of sulfadoxine -pyrimethamine for the treatment of malaria in most areas, but in Africa most parasites exhibit an intermediate level of resistance, such that antifolates may continue to offer some preventive efficacy.

61. INHIBITORS OF FOLATE SYNTHESIS USES 1.Chemoprophylaxis—Chemoprophylaxis with single folate antagonists is no longer recommended because of frequent resistance and toxicity. However, the antifolate combination trimethoprim-sulfamethoxazole is commonly used as a daily pro- phylactic therapy for HIV-infected patients in developing countries, and this regimen offers partial preventive efficacy against malaria in Africa. USES 2. Intermittent preventive therapy—A new strategy for malaria control is intermittent preventive therapy, in which high-risk patients receive intermittent treatment for malaria, regardless of their infection status. This practice is most accepted in pregnancy, with the use of two or more doses of sulfadoxine - pyrimethamine after the first trimester now standard policy in Africa, although efficacy is limited

62. INHIBITORS OF FOLATE SYNTHESIS 3. Treatment of chloroquine-resistant falciparum malaria— Fansidar is no longer a recommended therapy for malaria, and in particular it should not be used for severe malaria, since it is slower-acting than other available agents. Fansidar is also not reliably effective in vivax malaria, and its usefulness against P ovale and P malariae has not been adequately studied. Artesunate plus sulfadoxine -pyrimethamine is listed by the WHO to treat falciparum malaria ADVERSE EFFECTS AND CAUTIONS: Most patients tolerate pyrimethamine and proguanil well. Gastrointestinal symptoms, skin rashes, and itching are rare. Mouth ulcers and alopecia have been described with proguanil. Fansidar uncommonly causes severe cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

63. TREATMENT OF UNCOMPLICATED MALARIA

64. CHEMOPREVENTION Chemoprevention is the use of antimalarial drugs to prevent development or progression of infectious diseases, such as malaria. At risk groups include; •Infants and children less than 5 years of age •Pregnant women living in malaria endemic areas •People suffering from HIV/AIDS disease •Immunosuppressed people, e.g cancer, chemotherapy, diabetes, e.t.c. •Non-immune travelers traveling to an area with on-going malaria infection •Individuals born in malaria endemic countries, but travelled to a non-malaria endemic country and are returning home.

65. Types of Chemoprophylaxis Primary prophylaxis : Use of antimalarial drugs at recommended dosage, starting 2-20 days before departure to a malaria endemic area and continued for the duration of stay and 1-4 weeks after return. Intermittent Preventive Treatment (IPT): •IPT in pregnancy: Aimed at preventing malaria during pregnancy, it involves administering a full course of an anti-malarial drug to a pregnant woman, regardless of being infected or not. It helps protect both the mother and the developing fetus. WHO recommends sulfadoxine -pyrimethamine for pregnant women. •IPT in infants: Similar to that in pregnancy, it focuses on infants. It involves administering anti-malarial drugs at specific intervals to infants, especially in malaria endemic areas.

66. Types of Chemoprophylaxis Ø Casual Prophylaxis: This prevents the establishment of infections in the liver, by inhibiting the pre-erythrocytic schizogony. •Atovaquone + proguanil ( malarone ) and primaquine and proguanil are effective as casual prophylactic drugs. •Potential adverse effects on long term use and non-availability of primaquine make it a difficult drug for this purpose. Ø Seasonal Malaria Chemoprophylaxis (SMC): The intermittent administration of full treatment course of an antimalarial drug during high transmission seasons to prevent malaria illness in children. Ø Suppressive Prophylaxis: Use of blood schizonticides to suppress blood forms of malaria parasite and thus protect against clinical illness. However, P. vivax and P. ovale may cause relapses from the hypnozoites.

67. Antimalarial Drugs Used for Chemoprophylaxis 1. Chloroquine: Historically, chloroquine was widely used for malaria prophylaxis in areas where Plasmodium falciparum was sensitive to the drug. –Considerations: Due to the emergence of chloroquine-resistant strains, its use has declined in many regions. However, it may still be effective in certain areas where the parasite remains sensitive. 2. Mefloquine: Mefloquine is a once-weekly medication commonly used for prophylaxis in areas with chloroquine-resistant strains. –Considerations: It may not be well-tolerated by some individuals, and potential side effects, such as neuropsychiatric symptoms, need to be considered. Mefloquine is not recommended for individuals with a history of certain psychiatric conditions. 3. Doxycycline: Doxycycline, an antibiotic, is used as a daily prophylactic agent against malaria. –Considerations: While effective, it is not recommended for pregnant women and young children due to potential adverse effects on developing teeth and bones. It may also cause photosensitivity.

68. Antimalarial Drugs Used for Chemoprophylaxis 4. Atovaquone/Proguanil: This combination drug is often prescribed for prophylaxis in regions with chloroquine-resistant strains. –Considerations: Well-tolerated and suitable for pregnant women and children, it is taken daily and has a relatively low side effect profile. 5. Primaquine: Primaquine is used for the prevention of relapse in individuals infected with Plasmodium vivax or Plasmodium ovale , as it targets the liver stages of the parasite. –Considerations: G6PD deficiency testing is essential before prescribing primaquine, as the drug can cause hemolysis in individuals with this genetic condition. 6. Tafenoquine: Tafenoquine is similar to primaquine and is used for the prevention of relapse in Plasmodium vivax infections. –Considerations: G6PD deficiency testing is also necessary before prescribing tafenoquine. It has a longer half-life than primaquine, allowing for less frequent dosing.

69. Malaria vaccine RTS,S/AS01 malaria vaccine, also known as Mosquirix , is the first and only malaria vaccine to receive regulatory approval. It targets the Plasmodium falciparum parasite, which is the most deadly species of malaria parasite. However, the efficacy of the vaccine varies by age group and region, and it provides only partial protection against malaria. It has been recommended by the World Health Organization (WHO) for use in children in selected areas of sub-Saharan Africa where malaria is prevalent.

70. QUESTIONS 1. Which of the following groups are considered at risk for malaria and may benefit from chemoprophylaxis? a) Adults aged 25-40 b) Pregnant women living in non-malaria endemic areas c) People suffering from seasonal allergies d) Infants and children less than 5 years of age 2. What is the primary purpose of Intermittent Preventive Treatment (IPT) in pregnancy? a) To prevent malaria in pregnant women only b) To treat malaria in pregnant women who are already infected c) To prevent malaria in both pregnant women and the developing fetus d) To induce labor in pregnant women 3. Which antimalarial drug is generally not recommended for pregnant women and young children due to potential adverse effects on developing teeth and bones? a) Chloroquine b) Mefloquine c) Doxycycline d) Primaquine

71. QUESTIONS 4.Which of the following is NOT an aim/objective of antimalarial drug use? a) To prevent clinical attack of malaria (prophylactic) b) To treat clinical attack of malaria (clinical curative) c) To induce liver stage dormancy in patients d) To completely eradicate the parasite from the patient’s body (radical curative) 5. Which of the following antimalarial drug classifications acts on erythrocytic schizonts? a) Tissue Schizonticides b) Gametocides c) Erythrocytic Schizonticides d) Antifolates 6. Which antimalarial drug, despite being historically widely used, has seen its usefulness compromised greatly by resistance against strains of Plasmodium falciparum? a) Doxycycline b) Artemisinin c) Chloroquine d) Quinine

72. QUESTIONS 7. Which demographic groups are identified as facing an elevated risk of severe malaria infection? a) Middle-aged adults b) Elderly individuals c) Pregnant women d) Individuals with a history of heart disease 8. What is a unique feature of Plasmodium falciparum among malaria species? a) It typically causes a milder infection compared to other species. b) It does not have the ability to convert to its cytoadherent phenotype. c) It produces hypnozoites in the hepatic phase of its life cycle. d) It can convert to its cytoadherent phenotype, leading to sequestration of infected erythrocytes THEORY : Write up on the Treatment of Uncomplicated Malaria

73. Conclusion It is worthy to note that there are challenges in Malaria eradication in Nigeria such as Drug resistance, treatment failure, insecticide resistance, global warming and change in climate, conflicts, insurgency, and internally displaced persons, migration, lack of political will, inadequate malaria leadership, funding, and adequate local research. Addressing these challenges is central to achieving malaria elimination. Malaria remains the most important public health parasitic disease and a major global health problem with the greatest burden in sub-Saharan Africa

74. Thank you! ANY QUESTIONS ?