Antimalarial drugs Dr. yasodha krishna janapati Associate Professor Dept. of Pharmaceutical Chemistry, College of Health Sciences (CHS), Ayder Campus, Mekelle University, Mekelle, ETHIOPIA. 1

Plasmodium species which infect humans Plasmodium vivax (tertian): Plasmodium ovale (tertian) Plasmodium falciparum (tertian) Plasmodium malariae (quartan)  Malaria is caused by Plasmodium parasites.  The parasites are spread to people through the bites of infected female Anopheles mosquitoes, called "malaria vectors."  There are 4 parasite species that cause malaria in humans, and 2 of these species – P. falciparum and P. vivax – pose the greatest threat. 2

Sir Ronald Ross History Nobel Prize for Physiology or Medicine in 1902 for his work on malaria. His discovery of the malarial parasite in the gastrointestinal tract of the Anopheles mosquito led to the realization that malaria was transmitted by Anopheles, and laid the foundation for combating the disease. Charles Laveran first found the malaria parasite in blood. Charles Laveran 3

Facts about Malaria  Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes.  In 2015, 95 countries and territories had ongoing malaria transmission.  About 3.2 billion people – almost half of the world’s population – are at risk of malaria.  Malaria is preventable and curable, and increased efforts are dramatically reducing the malaria burden in many places. 4

 Between 2000 and 2015, malaria incidence among populations at risk (the rate of new cases) fell by 37% globally. In that same period, malaria death rates among populations at risk fell by 60% globally among all age groups, and by 65% among children under 5.  Sub-Saharan Africa carries a disproportionately high share of the global malaria burden. In 2015, the region was home to 88% of malaria cases and 90% of malaria deaths.  Angola, Burundi, Cape Verde, Central African Republic, Chad, Comoros, Djibouti, Equatorial Guinea, Eritrea, Gabon, Gambia, Guinea-Bissau, Liberia, Mali, Mauritania, Sao Tome and Principe, the Seychelles, Somalia, South Sudan, Sudan or Zimbabwe. 5

Life cycle of the malaria parasite In mosquito  The mosquito acquires gametocytes when it bites an infected person. These fertilise in the gut and eventually migrate as sporozoites to the saliva. In humans  The erythrocytic cycle inside human red blood cells (RBC). (Easiest phase to treat)  The exo-erythrocytic cycle outside RBC. (Difficulty phase to treat) 6

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Chemical classification 4 aminoquinolines: – Chloroquine, Hydroxychloroquine, Amodiaquine, Pyronaridine 8 aminoquinolines: – Primaquine, Tafenoquine, Bulaquine Cinchona alkaloids: – Quinine, Quinidine Quinoline methanol: – Mefloquine Biguanides – Proguanil, Chlorproguanil 8

Chemical classification Diaminopyrimidines – Pyrimethamine Sulfonamides – Sulfadoxine, dapsone Tetracyclines: – tetracycline, doxycycline Naphthoquinone: – Atovaquone Sesquiterpene lactones: – Artesunate, artemether, arteether 9

Cinchona alkaloids:  Cinchona bark extracts were identified as early as 1632 to be effective in treating fevers, particularly the tertian fever of malaria.  For 400 years, quinine has been the effective antimalarial.  Cinchona is a dried bark obtained from trees of Cinchona calisaya, Cinchona ledgeriana, Cinchona officinalis, Cinchona succirubra of the family Rubiaceae.  Cinchona is called as Jesuit’s bark as this bark was identified and used by the Jesuits for its anti-pyretic property.  As it was first discovered in Peru it is also known as Peruvian bark. 10

SAR  None of the alterations to quinine have improved its action against the parasites.  The methoxy group of the quinoline ring and the vinyl group of quinuclidine are not required for antimalarial activity.  Saturation of Vinyl group result in formation of dihydroquinidine which slightly more potent than quinine.  The secondary alcohol group is essential for activity. Reduction of the alcohol group increases toxicity as well as mitigating antimalarial activity.  Quinidine (8R, 9S)  Quinine (8S, 9R)  The stereoisomer, quinidine, is a more potent antimalarial, but it is also more toxic (less selectively toxic). 11

Chemical constituents  cinchonine and cinchonidine (stereoisomers with R 1 = vinyl, R 2 = hydrogen)  quinine and quinidine (stereo isomers with R 1 = vinyl, R 2 = methoxy)  dihydroquinine and dihydroq uinidine (stereoisomers with R 1 = ethyl, R 2 = methoxy) 12

Hemoglobin Globin utilized by malarial parasite Heme (highly toxic for malaria parasite) Chloroquine Quinine, (+) Haem Polymerase mefloquine (-) Hemozoin (Not toxic to plasmodium) Mechanism of action 13

Metabolism of Quinine 14

Uses  Quinine is still indicated for malaria caused by P. falciparum resistant to other agents including chloroquine.  Cerebral malaria  Many times it is administered in combination with pyrimethamine and sulfadoxine, doxycycline, or mefloquine depending the specific form of malaria and geographical location.  Myotonia congenita: heriditory myopathy characterized by tonic spasm of skeletal  Nocturnal muscle cramps  Spermicidal in vaginal creams 15

Adverse drug reactions Cinchonism: Tinnitus, nausea & vomiting Headache mental confusion, vertigo, difficulty in hearing & visual disturbances Diarrhoea, flushing & marked perspiration Still higher doses, exagerated symptoms with delirium, fever, tachypnoea, respiratory depression, cyanosis. 16

4-Aminoquinolines: They have quinoline structure 17

SAR  3 o amine is important for activity, -C 2 H 5 best for activity  Substitution of –OH on one of the -C 2 H 5 group on 3 o amine reduce the activity and increase plasma Conc. eg: Hydroxy chloroquine  4 to 6 carbon side chain optimum for activity  Incorporation of an aromatic ring in the side chain reduce the activity and toxicity. Eg Amodiaquine  7-Cl on quinoline ring optimum for activity 18

Hemoglobin Globin utilized by malarial parasite Heme (highly toxic for malaria parasite) Chloroquine Quinine, (+) Haem Polymerase mefloquine (-) Hemozoin (Not toxic to plasmodium) Mechanism of action 19

Pharmacological actions 1.Antimalarial activity: – High against erythrocytic forms of vivax, ovale, malariae & sensitive strains of falciparum – Gametocytes of vivax – No activity against tissue schizonts – Resistance develops due to efflux mechanism 2.Other parasitic infections: – Giardiasis, taeniasis, extrainstestinal amoebiasis 3.Other actions: – Depressant action on myocardium, direct relaxant effect on vascular smooth muscles, antiinflammatory, antihistaminic, local anaesthetic 20

Pharmacokinetics Well absorbed, tmax 2-3 hrs, 60 % protein bound Concentrated in liver, spleen, kidney, lungs, leucocytes Selective accumulation in retina: occular toxicity T1/2 = 3-10 days increases from few days to weeks 21

Adverse drug reactions Occular toxicity: High dose prolonged therapy Temporary loss of accommodation Lenticular opacities, subcapsular cataract Retinopathy: constriction of arteries, edema, blue black pigmentation, constricted field of vision. CNS: Insomnia, transient depression seizures, rarely Neuromyopathy & ototoxicity CVS: ST & T wave abnormalities, abrupt fall in BP & cardiac arrest in children reported 22

8-Aminoquinolines: They have quinoline structure  6-OCH 3 and 4 to 6 carbon side chain provide best for activity  The extract of substitution of amine is not critical as 4- aminoquinolines.  Aromatic amine should be 2 o 23

Primaquine: – Mechanism of action: – Interferes with protein synthesis Primaquine Converted to Electrophiles Generates reactive oxygen species 24

Antimalarial action  Act against exo-erythrocytic schizonticides Liver hypnozoites  No action against erythrocytic stage.  It is mainly used to treat P. vivax/ P. ovale malaria.  Used for prophylactic purpose and radical cure.  Once the parasite has been eliminated from the blood stream, the remaining hypnozoites must be eliminated from the liver and this is done by administering a 14 day course of primaquine. This process is called radical cure.  Has gametocidal action and is most effective antimalarial to prevent transmission disease against all 4 species 25

Adverse effects Gastrointestinal: – epigastric distress, abdominal cramps, Hemopoetic: – mild anemia, methaemoglobinemia, cyanosis, – hemolytic anemia in G6PD deficiency Avoided during pregnancy, G6PD deficient 26

Mefloquine  Quinoline methanol derivative developed to deal with chloroquine resistant malaria  Rapidly acting erythrocytic schizonticide, slower than chloroquine & quinine  Effective against chloroquine sensitive & resistant plasmodia  Mechanism of action similar to chloroquine 27

Artemisinin It is the active principle of the plant Artimisia annua  Sesquiterpenes (3 isoprene units) lactone derivative containing peroxide bridge.  Artimisia annua is used in chinese traditional medicine as quinghauso as  Elicit quicker defervescence (decreasing elevated temperature) and clearing of parasite in 48 hours.  Most potent and rapid acting blood schizonticides  Short duration of action  high recrudescence rate (recurrence) 28

PLANT- ARTEMISIA ANNUA aArtemisinin derivatives Artesunate Artemether Arteether 29

Mechanism of action  These compounds have presence of endoperoxide bridge  Endoperoxide bridge interacts with heme in parasite  Heme iron cleaves this endoperoxide bridge  There is generation of highly reactive free radicals which damage parasite membrane by covalently binding to membrane proteins 30

Artemisinin based Combination Therapy (ACT )  Artemisinin compunds are shorter acting drugs  Monotherapy needs to be extended beyond disappearance of parasite to prevent recrudescence  This can be prevented by combining 3-5 day regimen of artemisin compounds with one long acting drug like mefloquine 15 mg/kg single dose  Indicated by WHO in resistant falciparum malaria 31

Necessary for combination therapy: Rapid clinical & parasitological cure High cure rates and low relapse rates Absence of resistance Good tolerability profile Examples Artesunate – Sulfadoxine, pyrimethamine: Artesunate Mefloquine: 32

Artemether & lumefantrine  Lumefantrine is highly effective, long acting oral erythrocytic schizonticide related to mefloquine  Highly lipophilic onset delayed, peak 6 hrs  Available as fixed dose combination  80 mg artemether BD WITH 480 mg lumefantrine BD for 3 days 33

Synthesis of Chloroquine 34

THANK YOU Dr. Yasodha Krishna Janapati, M.Pharm, PhD Associate Professor, Dept. Pharmacy, CHS, Mekelle University, Mekelle. 35