CHEMOTHERAPY MBBS_BDS SEPTEMMBER 2025.pptx

Principles of Chemotherapy

1. CHEMOTHERAPY OF PARASITIC INFECTIONS Dr. Umar Sharif Abdussalam MBBS; MSc (BUK), PhD (ABU) Senior Lecturer Department of Clinical Pharmacology & Therapeutics Bayero University, Kano

2. COURSE OUTLINE Antiprotozoal Drugs: Drugs used in the Treatment of Malaria, Amoebiasis, Trypanosomiasis, Leishmaniasis Anthelmintics : Drugs used in Ascariasis Ancylostomiasis, Onchocerciasis, Dracunculiasis, Schistosomiasis and Tapeworms infestations

3. LEARNING OBJECTIVES At the end of this lecture, students should be able to know: Drugs used to treat Malaria, Amoebiasis , Trypanasomiasis and Leishmaniasis Drugs used to treat Infestations by Nematodes , Filarial Worms , Cestodes and Trematodes The first-line and alternative drugs for each infection/infestation

4. INTRODUCTION Germ Theory John Needham, Lazzaro Spallazani and Pasteur Microbes in the air Germ theory of Disease John Snow During Black Death in London, investigated water supply and showed the cholera cases were clustered around the pump Linked the disease with Germ theory

5. INTRODUCTION… Robert Koch discovered agar and invented petri dish He isolated Bacillus anthracis, Mycobacterium tuberculosis and Vibrio cholerae Koch's postulates stated that to cause a disease an organism must be: found in all cases of the disease examined, while absent in healthy organisms prepared and maintained in a pure culture capable of producing the original infection, even after several generations in culture retrievable from an inoculated animal and cultured sample

6. INTRODUCTION….. Paul Ehrlich introduced the term chemotherapy in 1907 to describe his important early studies of Trypanosoma brucei , the parasite that causes African trypanasomiasis The term chemotherapy, initially referring to antiparasitic therapy, now refers more broadly to the use of any chemical compound that selectively acts on microbes or cancer

7. Chemotherapeutic agents are drugs that are designed to act selectively on foreign organisms that have invaded and infected the body Chemotherapeutic agents range from antibacterials, antifungals, antivirals, antiprotozoals, antihelmintics and antimycobacterial INTRODUCTION…

8. INTRODUCTION… Ideal Chemotherapeutic agent Good cell and tissue penetration Not interfere with host’s defense mechanism Selective toxicity Unique target in parasite Discrimination between host and parasite targets Target more important to parasite than host Greater drug accumulation by parasite Drug activation by parasite

9. Toxic only to the invading pathogens Prevent development of resistance Broad spectrum of activity against many pathogens Cheap and readily available Chemical stability for long periods under different climatic conditions Highly soluble in body fluids Achieve high concentration to kill the parasite INTRODUCTION…

10. Inhibition of cell wall synthesis: Penicillins, Cephalosporins, Cycloserine, Vancomycin, Bacitracin Causing leakage from cell membranes: Polymyxins, Colistin, Bacitracin, Amphotericin B, Nystatin Inhibition of protein synthesis: Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin. Cause misreading of m-RNA code and affect permeability: Streptomycin, Gentamicin etc. MECHANISMS of ACTION

11. MECHANISMS of ACTION Inhibition of DNA gyrase: Ciprofloxacin Interfere with DNA function: Rifampin, Metronidazole Interfere with DNA synthesis: Idoxuridine, Acyclovir, Zidovudine Interfere with intermediary metabolism: Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine, Ethambutol, chloroquine

12. Mechanisms of Resistance Decrease drug accumulation (including increase in efflux): Antibiotics are unable to gain access to the site of action due to the presence of an efflux system that pumps out the drug e.g. CRT increase efflux of Chloroquine Drug inactivation: The ability to destroy or inactivate the antimicrobial agents can confer resistance on microorganisms e.g. β-lactamase destroy many penicillins and cephalosporins

13. Mechanisms of Resistance… Modification of target sites ( Increase production of target ): The β-lactamase producing bacteria can resist to antibiotic by alteration of the target site that is penicillin binding protein(PBP) Mutations in target gene: Specific genetic mutations are the molecular basis of drug resistance S treptomycin (ribosomal mutation), Q uinolones (DNA gyrase gene mutation), R ifampin (RNA polymerase gene mutation) Trimethoprim (Dihydrofolate reductase gene mutation )

14. CLASSIFICATION PROTOZOA METAZOA (HELMINTICS) (A) PROTOZOA BLOOD AND TISSUE PROTOZOA Plasmodium ( P. falciparum , P. ovale , P. malariae and P. vivax, P. Knowlesi ) Trypanosoma ( T. brucei and T. cruzi ) Leishmania ( L. donovani , L. tropica and L. braziliensis ) Others Toxoplasma gondii   Babesia ( B. microti )

15. CLASSIFICATION… INTESTINAL AND UROGENITAL PROTOZOA Entamoeba histolytica (Amebae) Giardia lamblia and Trichomonas vaginalis (Flagellates) Others Balantidium coli (Ciliates) Cryptosporidium parvum and Isospora belli (Sporozoa)

16. (B) HELMINTICS NEMATODES ALIMENTARY AND TISSUE WORMS Ascaris lumbricoides (round worm) Necator americanus (hook worm) Ancylostoma duodenale (hook worm) Entrobius vermicularis (pin worm) Tricuris tricura (whip worm) Strongoloides stercularis (thread worm) Dracunculus medinesis (guinea worm) BLOOD AND TISSUE (FILARIAL) WORMS Wuchreria brancrofti (elephantiasis) Oncocerca vulvulus (river blindness) Loa loa (microfilaria) Brugia malay i CLASSIFICATION…

17. CLASSIFICATION… TREMA T ODES Schistosoma japonic um Schistosoma mansoni Schistosoma haematobium Schistosoma intercalatum Fasciola hepatica CESTODES Taenia s a ginata (beef tape worm) Taenia solium (pig tape worm)

18. DRUGS USED IN THE TREATMENT OF MALARIA, AMOEBIASIS, TRYPANOSOMIASIS , LEISHMANIASIS

19. DRUGS USED IN THE TREATMENT OF MALARIA Malaria is a parasitic disease endemic in Nigeria The malaria parasite, Plasmodium is a single-cell, obligate, intracellular protozoa transmitted by the bite of female Anopheles mosquito P . knowlesi, P. malariae, P. ovale, P. vivax and P. falciparum

20. Humans are usually infected by sporozoites, injected by the bite of infected female mosquitoes Malarial parasite is also transmitted via the placenta of an infected mother P . falciparum causes the most dangerous form of human malaria, and accounts for about 98% of all malaria cases in Nigeria DRUGS USED IN THE TREATMENT OF MALARIA

21. Malaria can rapidly progress from acute febrile illness to severe illness and death, if left untreated Those at risk of malaria are: Infants Under five children Pregnant women People living with HIV/AIDS People with low immunity to malaria (Visitors from malaria-free area to malaria endemic regions/countries) INTRODUCTION.. 10/20/2025 21

22. In 2023, two hundred and sixty three (263) million cases of malaria and 597,000 deaths were reported globally: 83 countries with endemic transmission Nigeria accounted for 29.5% of the global cases followed by: DR Congo ( 12.6%) Uganda (4.8%) Ethiopia (3.6%) Mozambique (3.5%) African countries accounted for 94% of global malaria cases 10/20/2025 22 INTRODUCTION..

23. Malaria accounts for 30 % childhood mortality and 11% maternal deaths The disease remains a major public health problem and accounts for over 50% of all outpatient visits in Nigeria Malaria accounts for 30-50% of all hospital admissions in Nigeria 10/20/2025 23 INTRODUCTION..

24. 10/20/2025 24 Life cycle of Plasmodium falciparum

25. CLINICAL FEATURES Incubation period P. vivax, ovale and falciparum =10-14 days P. malariae = 18 days- 6 weeks Clinical presentation Varies: malaise, myalgia Fever, anaemia, splenomegaly and hepatomegaly are usually present Nausea, anorexia, vomiting and orthostatic hypotension are common Herpes labialis frequently occurs in established malaria 25

26. P. vivax and P. ovale Give rise to clinically mild infection Fever occurs every other day when established Responsible for relapse P. malariae Infection is usually mild Run a more chronic course May be complicated by nephrotic syndrome May be fatal between ages 4-5 yrs Marked muscle wasting, mild icterus and massive splenomegaly Growth retardation in children 26 CLINICAL FEATURES

27. P. falciparum Potentially most severe form (pernicious malaria) with high level of parasitaemia Infected RBCs develop knob-like projections, facilitate adhesion to the endothelium of blood vessels causing vascular occlusion leading to organ damage Prodrome tends to be severe Fever follows no specific pattern ( Quotidian / Quartan / Tertian ) 27 CLINICAL FEATURES

28. C. Site of action of drugs use in casual prophylaxis E Site of action of drugs which prevent transmission D Site of action of drugs which prevent transmission A. Site of action of drugs use in clinical attacks of malaria B. Site of action of drugs use in radical cure of vivax and ovale malaria Sites of Antimalarial Dugs Action

29. Drugs used for clinical and suppressive cure ( Blood schizonticides ) Act on asexual erythrocytic stages of malarial parasites to interrupt erythrocytic schizogony and thereby terminate clinical disease i.e. effect clinical cure Such drugs also may produce suppressive cure, which refers to complete elimination of parasites from the body by continued therapy Inadequate therapy with blood schizonticides may result in recrudescence of infection due to erythrocytic schizogony CLASSIFICATION OF ANITMALARIAL DRUGS

30. Drugs used to prevent relapse ( Hypnozonticides ) These drugs act on latent tissue forms of P. vivax and P. ovale Drugs active against latent tissue forms are used for terminal prophylaxis and for radical cure of relapsing malarial infections Primaquine is the prototype drug used to prevent relapse To achieve radical cure, the drug is taken together with an artemisinin, quinine or chloroquine, to eradicate erythrocytic stages of P. vivax and P. ovale CLASSIFICATION OF ANITMALARIAL DRUGS

31. CLASSIFICATION OF ANITMALARIAL DRUGS Drugs used for casual prophylaxis ( Tissue schizonticides ) Act on primary tissue forms of plasmodia Invasion of erythrocytes and further transmission of infection are thereby prevented e.g. Proguanil Primaquine also has such activity against P . falciparum, but it is reserved for other clinical applications because of its toxicity

32. Gametocytocides Act against sexual erythrocytic forms of plasmodia, thereby preventing transmission to mosquitoes Chloroquine and Quinine have gametocytocidal activity against P. vivax, P. ovale and P. malariae , whereas Primaquine has activity against gametocytes of P. falciparum Antimalarials are not used clinically just for gamecytocidal action CLASSIFICATION OF ANITMALARIAL DRUGS

33. Sporonticides They ablate transmission of malaria by inhibiting formation of malarial oocysts and sporozoites in infected mosquitoes They render gametocytes non-infective in the mosquito e.g. Pyrimethamine , Proguanil CLASSIFICATION OF ANITMALARIAL DRUGS

34. Fast-acting blood schizontocide: choloroquine (+ other 4-aminoquinolines), quinine, quinidine, mefloquine, halofantrine, antifolates (pyrimethamine, pro g uanil, sulfadoxine , dapsone), artemisinin derivatives Slow-acting blood schizontocide: doxycycline (+ other tetracycline antibiotics) Blood + mild tissue schizontocide: pro g uanil , pyrimethamine, tetracyclines Tissue schizontocide ( anti-relapsing ): Primaquine , tafenoquine Gametocidal: primaquine , artemisinin derivatives, 4-aminoquinolines CLASSIFICATION BASE ON ACTION

35. BASED ON CHEMICAL STRUCTURE 4-aminoquinoline e.g Chloroquine, Amodiaquine 8-aminoquinoline e.g Primaquine Quinoline methanol e.g Mefloquine, Quinine Sesquiterpene lactone e.g Arthemeter Hydroxynaphtoquinone e.g Atovaquone Phenanthrene methanol e.g Halofantrine Folate synthesis inhibitors and folate antagonists e.g Sulfones, Pyrimethamine, Proguanil Antimalarial Antibiotics e.g Tetracycline and Doxycycline Mannich bas acridine e.g. Pyronaridine

36. ARTEMISININS Artemisinin Qinghaosu (" ching -how- soo ") is the major antimalarial ingredient from the weed, Artemisia annua One of the most novel discoveries in recent medicinal plant research Orally administered Not very soluble either in water or oil. Has short elimination half life These led to the search for the derivatives that had improved pharmacological properties as well as better antimalarial activity Converted to dihydroartemisinin, which is a potent antimalarial compound Available for oral, parenteral and rectal use in several countries

37. MECHANISM OF ACTION OF ARTEMISININS 37 Heme/iron mediates breakage of endoperoxide bridge Artemisinin-derived free radicals bind to protein through alkylation May inhibit P falciparum encoded sarcoplasmic endoplasmic reticulum calcium ATPase

38. Administration of artemisinins can be through: oral (Dihydroartemisinin, Artesunate and Artemether) I.M (Artesunate, Artemether and Arteether) I.V (Artesunate) Rectal (Artesunate ) Artemether and Artesunate are both converted extensively to Dihydroartemisinin , and has a plasma t 1/2 of 1-2 hours ARTEMISININS-PK

39. Bioavailability after oral administration is about 30 % I.M administration of the lipid-soluble artemether peaks in 2-6 hours Artesunate and Artemether have modest levels of plasma protein binding (43-82%) Rectal administration of artesunate is very important, especially in tropical countries where malaria is endemic ARTEMISININS-PK

40. However , bioavailability via rectal administration is highly variable among patients With repeated dosing, artemisinin and artesunate induce their own CYP mediated metabolism, primarily via CYPs 2B6 and 3A4 This may enhance clearance by up to 5-fold ARTEMISININS-PK

41. CLINICAL USES OF ARTEMISININS Artemisinins are used to treat malaria, including infections due to chloroquine and multidrug- resistant strains of P. falciparum Artesunate is the first line drug used in the treatment of severe malaria including cerebral malaria Artesunate (2.4mg/Kg for adults and children weighing more than 20kg and 3mg/kg for children below 20kg: IV, IM, Rectal) They are not recommended for prophylactic use

42. ADVERSE EFFECTS Artemisinins are relatively safe in humans at therapeutic doses Side effects include nausea, vomiting, anorexia and dizziness Transient first-degree heart block Dose-related reversible decreases in reticulocyte and neutrophil counts Temporary elevation of serum aspartate transaminase Rare but serious adverse effect is allergic reaction

43. ARTEMISININ COMBINATION THERAPY (ACT) Artemisinin combination therapy (ACT) is a drug regimen/formulation containing an artemisinin derivative and other antimalarial drug(s ) Low bioavailability, poor pharmacokinetic properties, high rate of recrudescence, and high cost are major limitations of artemisinins Due to the limitations of monotherapy with artemisinins and to prevent development of resistance, the WHO has recommended ACT as the first-line therapy for P. falciparum malaria

44. The five ACT recommended for treatment of uncomplicated P. falciparum malaria are: Artemether + Lumefantrine Artesunate + Amodiaquine Artesunate + Mefloquine Artesunate + Sulfadoxine-Pyrimethamine Dihydroartemisinin + Piperaquine Artesunate + Pyronaridine ARTEMISININ BASED COMBINATION THERAPY (ACT)

45. CHLOROQUINE Chloroquine is a 4–aminoquinoline that is particularly effective against intra-erythrocytic forms of Plasmodium because it is concentrated within the parasitized erythrocyte Mechanism of Action: acts by inhibiting the conversion of toxic haeme to non-toxic haemozoin Antimalarial Spectrum It is effective against all four malaria parasites except chloroquine–resistant P. falciparum

46. CHLOROQUINE-MOA

47. CQ is rapidly and completely absorbed from the GIT It is distributed widely and is extensively bound to body tissues, with the liver containing 500 times the blood concentration Due to extensive tissue binding, a loading dose is required to produce effective concentrations in plasma Both the parent compound and its metabolites are slowly eliminated renally Resistance is related to genetic changes in transporters (PfCRT, PfMDR ) CHLOROQUINE-PK

48. Chloroquine is used in the treatment of malaria, extraintestinal amoebiasis, rheumatoid arthritis, lupus erythematosus, amoebic liver abscess Adverse Effects Dizziness, headache, itching, skin rash, vomiting, blurred vision may occur at low doses With higher doses, these symptoms are more common and exacerbation or unmasking of lupus erythematosus or discoid lupus as well as toxic effects on skin, blood and eyes can occur CHLOROQUINE- Clinical Uses

49. CHLOROQUINE- Adverse Effects CQ concentrates in melanin containing structures, prolonged administration of high doses can result in: Corneal deposits Retinopathy Blindness Prolonged medication with suppressive doses may result in: H eadache , C onfusion , Convulsions , Bleaching of hair, Widening of QRS interval, and T- wave abnormalities

50. CQ is contraindicated in the presence of: R etinal or visual field changes, E pilepsy M yasthenia gravis Large IM or rapid IV injection of Chloroquine HCl can result in severe hypotension and respiratory and cardiac arrest (should be avoided) Considered to be safe in pregnancy CHLOROQUINE- Contraindications

51. CQ is contraindicated in patients with psoriasis or porphyria Should be used with caution in patients with liver disease, neurologic or haematologic disorders (G6PD deficiency) Kaolin, Ca and Mg-containing antacids should not be co-administered with chloroquine Other drugs that have similar MOA with Chloroquine Amodiaquine Quinine Mefloquine 51 CHLOROQUINE- Contraindications

52. QUININE Quinine is an alkaloid derived from the bark of the cinchona tree Mechanism of Action Like chloroquine, quinidine concentrates in the Plasmodium acidic food vacuoles to inhibit the non-enzymatic polymerization of the highly reactive toxic haem molecule into the non-toxic polymer pigment, haemozoin Antimalarial Spectrum It is effective against chloroquine-resistant P. falciparum malaria

53. Quinine is well absorbed (oral/I.M ) and is widely distributed in body tissues It is primarily metabolized in the liver and excreted in the urine The pharmacokinetics of quinine varies among populations, and according to the severity of malarial infection Clinical Uses Despite its toxicity, it is still an important blood schizonticide for the suppressive treatment and cure of chloroquine-resistant and multidrug-resistant P. falciparum malaria QUININE-PK

54. QUININE- Adverse Effects Adverse effects of quinine include sweating, ringing in the ears (tinnitus) , impaired hearing, blurred vision, nausea, vomiting and diarrhoea ( chinchonism ) Hypoglycaemia, hypotension and haematological changes (e.g. Leucopenia, thrombocytopenia and agranulocytosis) Quinine is a potent stimulus to insulin secretion and a GIT mucosa irritant

55. MEFLOQUINE Mefloquine , a 4–aminoquinoline methanol derivative, is a highly effective blood schizonticide especially against mature trophozoites and schizont forms of malaria parasites The exact mechanism of action has not been clearly elucidated It is well absorbed on oral administration; absorption is increased by the presence of food It is taken orally because parenteral administration causes severe local reactions It undergoes enterohepatic recycling

56. Prevention and treatment of malaria especially those caused by chloroquine-resistant and multidrug-resistant P. falciparum Adverse effects Mefloquine causes nausea, vomiting, abdominal pain, diarrhoea, dizziness, headache, disorientation, seizures and encephalopathy Contraindications: in patients with history of seizures, (quinine, chloroquine and quinidine) should be avoided because of increased risk of convulsions and cardiotoxicity MEFLOQUINE- Clinical Uses

57. AMODIAQUINE Amodiaquine is also a 4 – aminoquinoline derivative, with antimalarial spectrum and adverse reactions similar to those of chloroquine, although chloroquine resistant parasites may not be amodiaquine resistant to the same degree Prolonged treatment may result in pigmentation of the palate, nail beds and skin

58. LUMEFANTRINE Lumefantrine belongs to the aryl aminoalcohol group of antimalarials It has similar mechanism of action with quinine a nd chloroquine It is available as an oral preparation co-formulated with artemether

59. ANTIFOLATE DRUGS CLASSIFIED INTO TYPE 1 & 2 Type 1 : folate synthesis inhibitors e.g sulphonamides and the sulphones Type 2 : folate antagonists e.g pyrimethamine and proguanil Combination of types 1 and 2 drugs results in sequential blockade affecting the same pathways at different points The biosynthesis of purine and pyrimidine, which are so essential for the parasite DNA synthesis and cell multiplication is inhibited 59

60. 60 P -Aminobenzoic acid Dihydrofolate Dihyd r opteroate synthase Dihyd r ofolate reductase Tetrahydrofolate Purines DNA Sulphonamides and sulphones (competes with PABA) Trimethoprim, pyrimethamine and proguanil Actions of sulfonamides, sulfones, pyrimethamine and proguanil

61. PYRIMETHAMINE Pyrimethamine is a 2, 4–diaminopyrimidine related to trimethoprim Mechanism of Action Pyrimethamine inhibits dihydrofolate reductase (DHFR) of plasmodium parasite Pyrimethamine and Trimethoprim inhibit the conversion of dihydrofolic acid to tetrahydrofolic acid, a reaction catalysed by DHFR

62. The combined use of sulphonamides or sulphones with DHFR inhibitors is a good example of synergism that results in sequential blockade Pharmacokinetics Pyrimethamine is slowly but completely absorbed It is significantly distributed in tissues, 90% bound to plasma proteins, and has elimination t 1/2 of about 3-4 days It is extensively metabolized, and several metabolites are excreted in the urine Pyrimethamine is also excreted in the breastmilk of nursing mothers PYRIMETHAMINE

63. Clinical Uses Pyrimethamine is co-administered with sulphonamides in the treatment of malaria, because of their synergistic effect Also, resistance develops more slowly to the combination Adverse effects include rashes, insomnia, and depression of haematopoiesis with high doses PYRIMETHAMINE

64. PROGUANIL /CHOLOROGUANIDE Cycloguanil , the active triazine metabolite of proguanil selectively inhibits the bifunctional dihydrofolate reductase-thymidylate synthetase of sensitive plasmodia , resulting in inhibition of DNA synthesis and depletion of folate cofactors Proguanil is slowly but adequately absorbed from the GIT Adverse effects include abdominal pain, nausea, diarrhoea, headache and fever

65. ATOVAQUONE Atovaquone , a hydroxynaphthoquinone , acts selectively at the cytochrome bc1 complex of malaria parasite to inhibit mitochondrial electron transport and interfere with ATP generation and pyrimidine synthesis Atovaquone is used as a fixed combination with proguanil H igh cure rates, few relapses and minimal toxicity are achieved Synergism between the two is possibly due to the ability of proguanil to enhance the membrane collapsing activity of atovaquone

66. A micro fine suspension of atovaquone has a two times greater oral bioavailability than tablets Absorption after a single oral dose is slow, erratic and variable; it is increased two to three-fold by fatty food Atovaquone is used in combination with a biguanide to treat malaria; e.g. 250 mg of atovaquone +100mg of proguanil HCl Adverse effects include rash, fever, vomiting, diarrhoea and headache ATOVAQUONE

67. PRIMAQUINE Primaquine is the only drug effective against the liver forms of the malarial parasite I t is given only orally; causes hypotension after parenteral administration It is readily absorbed from the GIT, not bound extensively to tissues, and is rapidly metabolized to active compounds Primaquine is primarily used to prevent relapse of malaria due to P. vivax and P. ovale

68. Adverse effects of primaquine include gastrointestinal distress, nausea, headache, pruritus, leucopenia and agranulocytosis especially with higher doses or prolonged administration It is contraindicated in G6PD deficient individuals as it can cause a lethal haemolysis PRIMAQUINE

69. ANTIBACTERIAL ANTIMALARIALS Sulphonamides and sulphones Sulphonamides e.g. sulphadoxine (a long acting sulphonamide ) + pyrimethamine Sulphone e.g. Dapsone Dapsone: chlorproguanil and pyrimethamine + dapsone for therapy of chloroquine-resistant falciparum malaria

70. Tetracycline or doxycycline, are slow-acting blood schizonticides that are used alone for short-term prophylaxis and combined with quinine for the treatment of malaria due to multidrug-resistant strains of P. falciparum Their relatively slow action makes concurrent treatment with blood schizonticides mandatory for rapid control of parasitaemia Tetracyclines are not administered to pregnant women or children less than 8 years, due to their adverse effects on bones and teeth ANTIBACTERIAL ANTIMALARIALS

71. DOSAGE REGIMEN OF ORAL DRUGS USED IN THE TREATMENT OF UNCOMPLICATED MALARIA

72. Dosage Regimen for co formulated Artesunate-Amodiaquine Treatment of Uncomplicated Malaria: Weight (Kg) Tablet strength   Dosage regimen 4.5 - < 9 2 – 11 months 25mg/67.5mg 1 Tablet od x 3/7 9 - < 18 1 – 5 years 50mg/135mg 1 Tablet od x 3/7 18 - < 36 6 – 13 years 100mg/270mg 1 Tablet od x 3/7 36 and above 14 years and above 100mg/270mg 2 Tablets od x 3/7

73. Dosage Regimen and Duration of Treatment of Uncomplicated Malaria with DHAP Weight (Kg) Tablet strength 20mg/160mg Tablet strength 40mg/320mg 5 - < 8 1 Tablet od x 3/7 - 8 - < 11 1 1/2 Tablet od x 3/7 - 11 - < 17 - 1 Tablet od x 3/7 17 - < 25 - 1 1/2 Tablet od x 3/7 25 - < 36 - 2 Tablets od x 3/7 36 - < 60 - 3 Tablets od x 3/7 60 - < 80 - 4 Tablets od x 3/7 ≥ 80 - 5 Tablets od x 3/7 DHPA: Dihydroartemisinin - Piperaquine

74. Dosage and Duration of Treatment of Uncomplicated Malaria with Artesunate-Pyronaridine Weight (Kg) No. of Sachets or Tablet strength   Regimen 5 - < 8 1 sachet OD X 3/7 8 - < 15 2 sachets OD X 3/7 15 - < 20 3 sachets OD X 3/7 20 - < 24 1 Tablet OD X 3/7 24 - < 45 2 Tablets OD X 3/7 45 - < 65 3 Tablets OD X 3/7 ≥ 65 4 Tablets OD X 3/7 Each sachet of Artesunate-Pyronaridine granules for oral suspension contains 20 mg Artesunate and 60 mg Pyronaridine tetraphosphate. (To be taken once daily for 3 days and can be administered with/without food). Each tablet of Pyronaridine and Artesunate contains 180 mg Pyronaridine and 60 mg of Artesunate

75. DRUGS USED IN THE TREATMENT OF SEVERE MALARIA

76. Artesunate Injection Artemether Injection Quinine Injection DRUGS USED IN THE TREATMENT OF SEVERE MALARIA Recommended Dosage for injectable Artesunate: Parenteral Artesunate is available as co-packaged product of Artesunate powder for injection and solvents Injectable Artesunate strengths are available in 30mg, 60mg and 120mg adapted to patient’s body weight. Children weighing less than 20kg should receive a higher parenteral dose of Artesunate (3mg/kg/dose) than larger children and adults (2.4mg/kg/dose) to ensure equivalent drug exposure

77. DRUGS USED IN THE TREATMENT OF SEVERE MALARIA Artemether: t he initial dose of Artemether is 3.2mg/kg body weight by intramuscular injection (anterior thigh ) The maintenance dose is 1.6mg/kg body weight daily for 3 – 5 days Then give a full dose of recommended ACT Note: Artemotil or Arteether is a first-generation artemisinin derivative, similar in characteristics to Artemether as oil based. It has erratic absorption and it is not recommended for treatment of severe malaria

78. It is administered by either IV or IM route, depending on the availability of infusion facilities The recommended dosage of intravenous Quinine in Children is: 20 mg/kg of Quinine dihydrochloride salt as loading dose diluted in 10 ml/kg of 4.3% dextrose in 0.18% saline or 5% dextrose over a period of 4 hours Then 12 hours after the start of the loading dose, give 10 mg salt /kg infusion over 4 hours every 8 hours until when patient is able to take orally Then give a full dose of recommended ACT DRUGS USED IN THE TREATMENT OF SEVERE MALARIA: QUININE

79. Adults : Quinine dihydrochloride 20 mg/kg of salt to a maximum of 1.2g (loading dose) diluted in 10 ml/kg 5% dextrose saline by intravenous infusion over 4 hours T hen , 8 hours after the start of the loading dose, give 10 mg/kg salt to a maximum of 600 mg over 4 hours every 8 hours until patient is able to take orally Then give a full dose of recommended ACT DRUGS USED IN THE TREATMENT OF SEVERE MALARIA: QUININE

80. Intramuscular Quinine: Where intravenous access is not possible, Quinine dihydrochloride can be given intramuscularly at a dosage of 20 mg/kg salt (loading dose), diluted to 60mg/ml, and continue with a maintenance dose of 10mg/kg 8hourly until the patient is able to take orally. Make sure to monitor glucose levels especially for IM Quinine DRUGS USED IN THE TREATMENT OF SEVERE MALARIA: QUININE If intravenous Quinine is required for over 48 hours, reduce the dose to 5-7mg/kg to avoid toxicity. A practical way of doing this is to reduce the dosing frequency to every 12 hours Intramuscular injections should be given with sterile precautions into the anterior or lateral thigh, NOT THE GLUTEAL REGION.

81. DRUGS USED IN THE TREATMENT OF AMOEBIASIS

82. Infection occurs by ingestion of mature cysts in faecally contaminated food, water, or hands Transmission can also occur through faecal exposure during sexual contact (both cysts and trophozoites could be infective) Life cycle of Entamoeba histolytica

83. AMOEBIASIS Drugs used to treat amoebiasis are classified into luminal, systemic and mixed amoebicides Luminal amoebicides are only active against intestinal forms of amoeba, e.g. Diloxanide furoate, Iodoquinol , Paromomycin They can be used alone to treat asymptomatic or mild intestinal forms of amoebiasis or after a systemic or mixed amoebicidal to eradicate the infection

84. Systemic amoebicides are effective only against invasive forms of amoebiasis They are used primarily to treat severe amoebic dysentery e.g. Dehydroemetine , or hepatic abscesses e.g. Dehydroemetine and Chloroquine Mixed amoebicides are active against both intestinal and systemic forms of amoebiasis e.g . Metronidazole, Tinidazole , Ornidazole and Secnidazole AMOEBIASIS

85. B C Diloxanide Life cycle of Entamoeba histolytica, showing the sites of action of Amoebicidal Drugs A

86. Diloxanide is a dichloroacetamide derivative that is effective against trophozoites in the intestinal tract It is only administered orally and is rapidly absorbed from the GIT following hydrolysis of the ester group to D iloxanide and F uroic acid Diloxanide is excreted in the urine, and 4 - 9% in the faeces largely as the glucuronide DILOXANIDE FUROATE

87. Diloxanide furoate is effective for treatment of asymptomatic passers of amoebic cysts It is also used with or after an appropriate systemic amoebicide to effect a cure of invasive and extraintestinal amoebiasis Adverse effects include flatulence, abdominal distension, anorexia, nausea, vomiting, diarrhea, pruritus and urticaria DILOXANIDE FUROATE

88. EMETINE AND DEHYDROEMETINE Emetine an alkaloid, was used years ago as a direct-acting systemic amoebicides Dehydroemetine has similar pharmacological properties but is less toxic Metronidazole , which is as effective and much safer, has largely replaced Emetine and Dehydroemetine in the treatment of severe invasive intestinal amoebiasis

89. IODOQUINOL Iodoquinol ( D iiodohydroxyquin ) is a halogenated 8-hydroxyquinoline derivative, whose precise mechanism of action is unknown It kills the trophozoite form of E. histolytica Iodoquinol is absorbed from the GIT and excreted in the urine and faeces Since D iloxanide furoate is also available as a luminal amoebicide and is safer, routine use of I odoquinol is not strongly recommended

90. Adverse effects: Skin reactions Thyroid enlargement Interference with thyroid function studies Headache Diarrhoea IODOQUINOL

91. METRONIDAZOLE Metronidazole is a nitroimidazole which exerts activity against most anaerobic bacteria and several protozoa It freely penetrates protozoal and bacterial cells but not mammalian cells Mechanism of Action The enzyme, pyruvate-ferredoxin oxidoreductase, found only in anaerobic organisms, reduces the 5-nitro group of metronidazole and thereby activates the drug Reduced metronidazole disrupts replication, transcription and inhibits DNA repair

92. Antimicrobial Spectrum Metronidazole inhibits E . histolytica , Giardia lamblia , T . vaginalis , Blastocystis hominis , Balantidium coli , and Dracunculus medinensis It is also bactericidal for obligate anaerobic Gram-positive and Gram-negative bacteria, except Actinomyces species It is inactive against aerobes or facultative anaerobes Metronidazole resistance is rare METRONIDAZOLE

93. Metronidazole is well absorbed from the GIT Food delays but does not reduce its absorption It is well distributed in body fluids including vaginal secretion, and seminal fluid High levels are found in plasma and cerebrospinal fluid It is metabolized in the liver and mainly excreted by the kidney although small amounts can be found in saliva and breast milk METRONIDAZOLE-PK

94. Metronidazole is the most effective agent available for the treatment of all forms of amoebiasis Metronidazole is active against intestinal and extraintestinal cysts and trophozoites of E. histolytica Treatment with metronidazole is generally followed by a luminal amoebicide e.g. D iloxanide to effect a cure Metronidazole is used to treat Giardiasis, Dracunculiasis and Trichomoniasis METRONIDAZOLE- Clinical Uses

95. It is also used in treatment of susceptible bacterial infections due to Bacteroides , Clostridium and Helicobacter among others P rophylaxis of postsurgical mixed bacterial infections It is a component of various regimens used to eradicate H . pylori METRONIDAZOLE- Clinical Uses

96. Adverse effects of metronidazole are nausea, vomiting, cramps, diarrhoea, metallic taste, and often dark or reddish-brown urine Unsteadiness , vertigo, ataxia, peripheral neuropathy, encephalopathy and neutropenia may also occur Alcohol must be avoided during treatment with metronidazole because it is a weak inhibitor of alcohol dehydrogenase and may cause disulfiram-like and psychotic reactions METRONIDAZOLE- Adverse Effects

97. Metronidazole interferes with the metabolism of warfarin and may potentiate its anticoagulant activity Phenobarbital , Rifampicin and Corticosteroids (e.g. prednisolone ) lower metronidazole plasma levels by increasing its metabolism Cimetidine raises metronidazole levels by inhibiting its metabolism Metronidazole is not recommended for use during pregnancy Other drugs in the same class as Metronidazole include Tinidazole , Ornidazole and Secnidazole METRONIDAZOLE- Drug Interactions

98. CHLOROQUINE Chloroquine has direct toxic action against trophozoites of E . histolytica and it is highly concentrated in the liver Chloroquine is used as a systemic amoebicide to treat hepatic amoebiasis only when treatment with metronidazole is unsuccessful or contraindicated

99. DRUGS USED IN THE TREATMENT OF TRYPANOSOMIASIS

100. Trypanosomiasis refers to several diseases in vertebrates caused by parasitic protozoa of the genus Trypanosoma In humans this includes African trypanosomiasis (sleeping sickness) and American trypanosomiasis (Chagas disease) The tsetse fly (Glossina) is the vector for the trypanosome parasites TRYPANOSOMIASIS

101. There are two types of African trypanosomiasis, the East African (Rhodesian) and West African (Gambian), caused by T. brucei rhodesiense and T. brucei gambiense T . brucei rhodesiense produces a progressive and rapidly fatal disease marked by early involvement of the central nervous system (CNS) and frequent terminal cardiac failure T . brucei gambiense causes illness that is characterized by later involvement of the CNS and a longer disease course that progresses to the classical symptoms of sleeping sickness over months to years TRYPANOSOMIASIS

102. The parasite is entirely extracellular, and early human infection by T. b. gambiense is characterised by the presence of replicating parasites in the bloodstream or lymph without CNS involvement (early haemolymphatic stage (stage 1 ) In stage 2 disease, the parasite has crossed the blood-brain barrier and infects the CNS TRYPANOSOMIASIS

103. PENTAMIDINE Pentamidine has activity against trypanosomatid protozoans and Pneumocystis jirovecii, but toxicity is significant Its mechanism of action is unknown Pharmacokinetics After parenteral administration, it leaves the circulation rapidly with an initial t 1/2 of about 6 hours It is bound avidly to tissues and thus accumulates, the terminal elimination t 1/2 is about 12 days

104. The drug can be detected in urine 6 or more weeks after treatment. Only trace amounts of pentamidine appear in the CNS, so it is not effective against CNS stage of African trypanasomiasis Pentamidine can also be inhaled as a nebulized powder for the prevention of pneumocystosis Pentamidine is primarily metabolized by hepatic CYP450 enzymes, about 12% is eliminated unchanged in the urine PENTAMIDINE

105. Pentamidine is used for the treatment of early haemolymphatic stage of West African sleeping sickness, before CNS involvement It is also used for chemoprophylaxis against African trypanosomiasis It is an alternative to sodium stibogluconate in the treatment of visceral leishmaniasis It is also used in the treatment and prevention of pneumocystis pneumonia PENTAMIDINE- Clinical Uses

106. Pentamidine is a highly toxic drug Rapid intravenous administration can lead to severe hypotension, tachycardia, dizziness, dyspnea and collapse of the patient With intramuscular administration, pain at the injection site is common, and sterile abscesses may develop Other adverse effects include pancreatic toxicity, nephrotoxicity , rash, metallic taste, fever, gastrointestinal symptoms, abnormal liver function tests, thrombocytopenia , hallucinations, and cardiac arrhythmias PENTAMIDINE- Adverse Effects

107. SURAMIN MOA: Suramin inhibits the parasite α - glycerophosphate oxidase, thymidylate synthetase, dihydrofolate reductase and protein kinase IV Suramin 200mg is given as a test dose 1g in 10ml of water every 5 days to make a total of 5 – 6 g

108. It is administered intravenously and displays complex pharmacokinetics with marked interindividual variability Suramin persists in the circulation due to extremely tight binding to plasma proteins (>99.7% is bound) Suramin has a short initial half-life but a terminal elimination half-life of about 90 days It is not appreciably metabolized, and is slowly cleared by renal excretion SURAMIN

109. Since only small amounts of suramin enter the brain, it is primarily used for the treatment of early-stage of both West and East African trypanosomiasis Suramin will clear the haemolymphatic system of trypanosomes even in late-stage disease, so it is often administered before initiating M elarsoprol to reduce the risk of reactive encephalopathy It is also effective for the prophylaxis of African trypanosomiasis SURAMIN- Clinical Uses

110. Immediate side effects include fatigue, nausea and vomiting Later reactions include fever, rash, headache, paraesthesia, neuropathy, renal abnormalities including proteinuria, chronic diarrhoea, haemolytic anaemia and agranulocytosis Rarely , seizures, shock, loss of consciousness and death may occur SURAMIN- Adverse Effects

111. MELARSOPROL Melarsoprol is a trivalent arsenical that has been available for the treatment of late-stage trypanosomiasis since 1949 Mechanism of action: The drug reacts with sulfhydryl groups of various substances, including enzymes in both the parasite and host Pharmacokinetics Melarsoprol is administered I.V A small but therapeutically significant amount of the drug enters the cerebrospinal fluid and has a lethal effect on trypanosomes infecting the CNS The compound is excreted rapidly, with 70-80% of the arsenic appearing in the faeces

112. Melarsoprol is used in the treatment of advanced CNS West and East African trypanosomiasis Adverse Effects Immediate adverse effects include fever, vomiting, abdominal pain, and arthralgias The most important toxic effect is a reactive encephalopathy that generally appears within the first week of therapy and is probably due to disruption of trypanosomes in the CNS Peripheral neuropathy, albuminuria, hepatic dysfunction, hypertension, myocardial damage, and hypersensitivity reactions may occur MELARSOPROL- Clinical Uses

113. EFLORNITHINE Eflornithine (α-D, L- difluoromethylornithine ; DFMO) is superior to M elarsoprol with respect to both safety and efficacy; the case fatality rate for E flornithine is significantly lower than for M elarsoprol Mechanism of Action Eflornithine is an irreversible catalytic (suicide) inhibitor of ornithine decarboxylase, the enzyme that catalyzes the first and rate-limiting step in the biosynthesis of polyamines

114. Eflornithine is administered intravenously, and adequate levels are achieved in the CNS The elimination half-life is about 3 hours There is rapid renal clearance after intravenous administration with >80% of the drug cleared by the kidney largely in unchanged form EFLORNITHINE-PK

115. Eflornithine is effective in advanced West African trypanosomiasis but not in East African disease Eflornithine is safer and has greater efficacy than M elarsoprol for late-stage Gambiense sleeping sickness Adverse Effects Adverse effects include reactions at the injection site, abdominal pain, diarrhoea, vomiting, headache, anaemia, thrombocytopenia, leucopenia, and seizures EFLORNITHINE- Clinical Uses

116. NIFURTIMOX Nifurtimox , a nitrofuran , is the most commonly used drug for American trypanosomiasis (Chagas’ disease) Nifurtimox is used in combination with E flornithine to treat late stage T . brucei gambiense sleeping sickness Adverse effects include nausea, vomiting, abdominal pain, fever, rash, restlessness, insomnia, neuropathy and seizures

117. DRUGS USED IN THE TREATMENT OF LEISHMANIASIS

118. LEISHMANIASIS A complex vector-borne disease caused by about 20 different species of obligate intramacrophage protozoa of the genus leishmania Small mammals and canines generally serve as reservoirs for these pathogens, which can be transmitted to humans by the bite of about 30 different species of female phlebotomine sand fly (disease vector) Flagellated extracellular free promastigotes, regurgitated by feeding flies, enter the host, where they attach to and become phagocytized by tissue macrophages

119. These transform into amastigotes, which reside and multiply within phagolysosomes until the cell bursts Released amastigotes then propagate the infection by invading more macrophages Amastigotes taken up by feeding sandflies transform back into promastigotes, thereby completing the transformation cycle LEISHMANIASIS

120. The major syndromes of human leishmaniasis are classified into cutaneous, mucocutaneous, diffuse cutaneous, and visceral (kala azar) forms Cutaneous forms of leishmaniasis generally are self-limiting, with cures occurring in 3-18 months after infection T his form of the disease can leave disfiguring scars LEISHMANIASIS

121. The mucocutaneous, diffuse cutaneous, and visceral forms of the disease do not resolve without therapy Visceral leishmaniasis caused by L . donovani is fatal unless treated Leishmaniasis is increasingly becoming recognized as an AIDS-associated opportunistic infection LEISHMANIASIS

122. Pentavalent A ntimonials : Sodium stibogluconate and M eglumine antimonate The mechanism of action of the antimonials is unknown Sodium stibogluconate (pentavalent antimonial) is reduced in vivo to the trivalent form The trivalent antimonials bind to sulfhydryl groups on proteins and inhibit phosphofructokinase, a rate-limiting enzyme in glycolysis

123. SODIUM STIBOGLUCONATE-PK Rapidly distributed after intravenous (preferred) or intramuscular administration and is eliminated in two phases, with short initial half-life (about 2 hours) and much longer terminal half-life (33 - 76 hours ) Clinical Uses Treatment of cutaneous, mucocutaneous and visceral leishmaniasis

124. Most common are gastrointestinal symptoms, fever, headache, myalgias, arthralgias, and rash I.M injections can be very painful and lead to sterile abscesses Electrocardiographic changes may occur, most commonly T-wave changes and QT prolongation Haemolytic anaemia and serious liver, renal, and cardiac effects are rare SODIUM STIBOGLUCONATE- Adverse Effects

125. MILTEFOSINE Miltefosine is an alkylphosphocholine analog that is the first effective oral drug for visceral leishmaniasis Adverse effects include vomiting, diarrhoea, transient elevations in liver enzymes and nephrotoxicity Miltefosine is contraindicated in pregnancy or in women who may become pregnant within 2 months of treatment, because of its teratogenic effects

126. ANTHELMINTHICS

127. INTRODUCTION Not limited to alimentary tract Larvae and a times adults migrate to blood and other tissues Cause complications Obstructions Hypersensitivity Upper GI haemorrhage Anaemia Malnutrition C arcinoma Helminths include Nematodes (round worms) Trematodes (flukes) Cestodes (tape worms)

128. INTESTINAL OBSTRUCTION

129. NEUROCYSTCERCOSIS

130. NEMATODES Nematodes are elongated, cylindrical and non-segmented worms Posses complex digestive system can be divided into (A) Alimentary and tissue worms Ascaris lumbricoides (round worm) Necator americanus (hook worm) Ancylostoma duodenale (hook worm) Entrobius vermicularis (pin worm) Tricuris tricura (whip worm) Strongoloides stercularis (thread worm) Dracunculus medinesis (guinea worm)

131. Transmitted via ingestion of food contaminated with faeces containing viable eggs Symptoms may include: Abdominal pain, Vomiting, Intestinal obstruction, Malnutrition and Sleep disturbances (B) Blood and tissue (filarial) worms Wuchreria brancrofti (elephantiasis) Oncocerca vulvulus (river blindness) Loa loa (microfilaria) Brugia malaya Transmitted by bite of various specie of mosquito Symptoms may include: fever, malaise, headache and local inflammation

132. Chemotherapy The goal is to: eradicate the parasite and prevent complication Antihelmintic drugs act by interfering with either The parasite metabolism (energy generation) e.g Benzimidazoles Or The parasite muscle function by competitive inhibition of Ach e.g. P iperazine Non-competitive inhibition of Ach e.g. P yrantel Potentiating GABAergic transmission e.g I vermectin Or Both

133. (A) Agents effective against alimentary and tissue worms 1. Benzimidazoles A re broad spectrum anthelmintics e.g. A lbendazole, M ebendazole, T hiabendazole Mechanism of action Inhibit microtubule synthesis and fumarate reductase in sensitive parasites Pharmacokinetics Oral absorption is variable; T hiabendazole > Mebendazole > Albendazole Poorly distributed

134. Spectrum and Use Effective against Ascaris lumbricoides (round worm ), Ancylostoma duodenale (hook worm), Entrobius vermicularis (pin worm), Tricuris tricura (whip worm), Strongoloides stercularis (thread worm) and less on Dracunculus medinesis (guinea worm ) Side effect Mild epigastric distress, headache, insomnia, hypersensitivity, convulsion and transient rise in liver enzymes levels (A) Agents effective against alimentary and tissue worms

135. 2. Levamisole Acts by inhibiting fumarate reductase in sensitive worms Also cause rapid muscle contraction of nematode muscle leading to spastic paralysis Poorly absorbed orally Effective against round worm and hook worms Side effects include GI upset, headache and fatigue 3. Piperazine Act by blocking Ach release at the myoneural junction Poorly absorbed and excreted unchanged via urine within 48h Effective against round worm and pin worm Side effects include GI disturbances, bronchospasm, allergic reaction, ataxia and may precipitate epilepsy

136. 4. Pyrentel Acts by inhibiting cholinesterase enzyme Poorly absorbed and excreted mostly unchanged via feces Effective against round worm, hook worms and thread worm Side effects include GI upset, headache, dizziness and insomnia

137. 1. Diethylcarbamazine Synthetic piperazine derivative Inhibit filarial worm cholinesterase and damage its muscle Is well absorbed and distributed Elimination t 1/2 is 2-3 hrs in acidic urine and up to 10 hrs in alkaline urine Effective on all forms of microfilaria and adult Loa- loa but ineffective against adult O. vulvulus DEC is the drug of choice in W. broncrofti infection Side effects include hypersensitivity, mild & transient headache, GI disturbances, malaise and anorexia (B) Agents effective against blood and tissue worms (anti-filarial)

138. 2. Ivermectin Semi-synthetic agent derived from actinomycetes Acts by facilitating GABAergic transmission Well absorbed orally with plasma t 1/2 of 11 hrs Distribute well and concentrate in liver and fat depots 98% excreted in feces Effective against O. vulvulus , W. broncrofti , round worm and pin worm Drug of choice in onchocerciasis Side effects include hypersensitivity, fever, GI disturbances, fatigue and dizziness

139. TREMATODES Tremaodes are leaf-shaped, flat worms Are characterized by the tissue they infect e.g. liver, intestinal or blood flukes The blood flukes ( schistosome ) are distinct from other flukes and consist of; Schistosoma japanicum Schistosoma mansoni Schistosoma haematobium Schistosoma intercalatum Fasciola hepatica

140. (C) Agents effective against blood and tissue flukes Praziquantel Prazinoquinoline derivative Acts by increasing the permeability of the parasite cell membrane to calcium Is rapidly absorbed with 80% oral bioavailability Plasma t 1/2 is 1 hr and achieve peak concentration in 3 hrs Effective against all forms of schistosomes and cestodes Drug of choice in both

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