0:00 In this video we're going to look at the treatment of malaria, basically the 0:11 pharmacology. 0:12 So of course a vaccine would be optimal to prevent people from getting malaria, 0:19 but developing 0:20 a vaccine has a lot of difficulties, cost and I guess the different strains of 0:27 the plasmodium 0:27 species and I guess the ever evolving mutations in the genetic material also 0:32 plays a role. 0:33 So before getting into the treatment of malaria let us again recap the life 0:38 cycle because treatment 0:39 targets different stages of the parasite's life cycle. 0:45 The parasite responsible for malaria are the plasmodium parasites. 0:50 The plasmodium parasite is carried by a female anophilus mosquito. 0:55 The female anophilus mosquito is infected with the parasite. 1:00 The anophilus mosquito carries the parasite in its salivary glands as sporozo 1:06 ites. 1:07 The sporozoites is a form the parasite is in when it enters the human body. 1:15 During feeding the mosquito will expose the sporozoites to human circulation. 1:22 The sporozoites will travel to the liver where it will enter the hepatocytes. 1:29 Within the hepatocytes the sporozoites will replicate, mature into schazon and 1:36 finally 1:37 rupturing, releasing many merozoites which is another form of the parasite. 1:44 And these can be called the daughter parasites which again have to mature. 1:49 So the merozoites then enters the human circulation, the blood. 1:55 But just going back to the sporozoites, the different plasmodium species, they 2:01 have different 2:02 abilities and there are four or five main plasmodium species. 2:09 So for example the plasmodium ovalae and vivax sporozoites are able to have the 2:16 ability 2:17 to remain dormant in the hepatocytes and form what's called a hypnozoite. 2:24 And after many months or years it will then replicate and then release its mer 2:29 ozoites 2:30 into circulation. 2:33 So now let's go back to the merozoites which are in circulation. 2:36 So the merozoites are bad and they invade red blood cells. 2:42 Within the red blood cells it enters the ring, it will enter what's called the 2:47 ring stage. 2:48 It will then replicate to form a trophozoite and mature to become a schizant 2:54 before rupturing 2:55 releasing again many merozoites. 2:59 This cycle can then continue. 3:03 So you produce more merozoites, more merozoites and yeah. 3:09 Now the rupturing of the red blood cells is responsible for anemia in malaria. 3:14 The rupturing of the red blood cells are also coincidal with the clinical 3:20 manifestations 3:21 of malaria which as we know are the fever, rigor, chills, tremors. 3:28 Now going back to the ring stage of the parasite's life cycle which is in the 3:33 red blood cells 3:35 right, the parasite can also enter a sexual cycle where it can become a female 3:41 or male 3:42 gametosite. 3:44 When a new uninfected anopheles mosquito then comes along for feeding it can 3:49 take in these 3:51 gametosites. 3:52 The gametosites will enter the mosquito's stomach. 3:56 The anopheles mosquito is now infected with the parasite. 4:01 But in the stomach now of the mosquito, the male and female gametosites which 4:06 have just 4:06 been taken in can form a zygote. 4:09 The zygote will mature into a eukenite. 4:13 Then be released by the stomach as an oocyte, the oocyte then matures and rupt 4:21 ures releasing 4:23 its content which are the sporozoites. 4:27 The sporozoites will remain in the salivary glands until the infected mosquito 4:34 will feed 4:35 again and then the whole cycle can continue. 4:40 The mosquito can feed on another human, another person that is healthy and then 4:47 if this person 4:48 was infected it will obviously be unhealthy. 4:51 Now malaria is a big problem worldwide particularly in developing countries. 4:57 In Africa many children under age of 5 die to a malaria infection. 5:03 Thus it is a very important public health issue. 5:08 Aside from prevention strategies there is also treatment option which is proph 5:14 ylaxis 5:15 prevention or treatment when the symptoms arise. 5:20 And we will now look at the drugs the pharmacology drugs used for malaria and 5:26 their mode of action 5:27 using this diagram we just drew. 5:31 I hope this will help. 5:33 So for anemia, I mean serious anemia, blood transfusion can help to replenish 5:38 the loss 5:38 of blood. 5:40 Now let us look at the big drug class known as quinolones. 5:45 To understand quinolones we have to understand how the plasmodium parasite 5:50 survives in red 5:52 blood cells. 5:56 So here is red blood cell and here is the parasite. 5:59 The parasite has what is called a vacuole which is important for basically 6:05 nutrition metabolism. 6:08 Now the red blood cell contains, the red blood cells are red blood cells they 6:12 contain many 6:13 hemoglobin right? 6:15 And the hemoglobin as we know are responsible for delivering oxygen to body 6:20 tissues. 6:21 Well, the parasite within the red blood cell will use the hemoglobin. 6:27 The hemoglobin is metabolized by the parasite in the vacuole in the parasites 6:33 vacuole. 6:34 It will break the hemoglobin into heme and protein. 6:38 The parasite will use the protein for some stuff but it's the heme that is 6:43 important 6:44 here. 6:46 See what happens is that the parasite uses heme for energy. 6:50 While metabolizing the heme, the parasite actually converts heme into hematin. 6:58 Now hematin is actually a dangerous chemical so hematin is toxic to the 7:02 parasite. 7:03 So what the parasite does is that it converts hematin into a non-toxic form 7:10 called hemozion. 7:12 So now the drug quinolones, the drugs under quinolones, they actually target 7:18 this conversion 7:19 from hematin which is the toxic, which is toxic to the parasite to hemozion. 7:27 So these quinolones I'm talking about are quinines, lumefantrine, chloroquine, 7:35 and amdia 7:37 quin. 7:38 Now I hope I pronounce these right but you know. 7:41 So these guys, these quinolones, these guys essentially inhibit hematin to 7:46 become hemozion. 7:48 Thus if we have hematin, thus if hematin is not converted, it will be very 7:54 toxic because 7:55 hematin is toxic to the parasite and the parasite dies. 8:00 However there is a particular strain of the parasite called the plasmodium falc 8:06 iparum 8:07 who has been able to develop resistance against chloroquine. 8:12 See what happens is that the parasite have been able to develop a pump. 8:17 That pump, this pump pumps out the drug from the vacuole so that the chloroqu 8:23 ine has no 8:24 effect and the hematin can be successfully converted to hemozion by the 8:29 parasite. 8:30 This resistance is known as chloroquine resistance. 8:33 As the pump, it specifically removes the chloroquine drug. 8:40 So those are the quinolones. 8:42 Now all these drugs are related in structure. 8:45 Just have to point that out. 8:48 The next anti-malero drug targets the mitochondria of the parasite. 8:53 This drug is known as aptovaquine, the next anti-malarial drug, which I will 9:02 most likely 9:02 mispronounce, targets the mitochondria. 9:04 This drug is known as aptovaquine, and it targets the cytochrome electron 9:10 transport chain 9:12 in the mitochondria. 9:14 Thus we can say that aptovaquine inhibits the parasite from making energy. 9:22 Their own bodies also have cytochromes, but this is distinctively different 9:27 from the 9:28 parasitic cytochrome. 9:31 Side effects of aptovaquine include skin rash, fever, insomnia, and nausea. 9:38 Some plasmodium parasites have actually been able to develop resistance to this 9:42 drug due 9:43 to mutations in their cytochrome gene. 9:48 The next anti-malarial drug we will talk about are the ones that target food 9:53 metabolism. 9:54 The parasite can use paba, P-A-B-A, and through the enzyme D-HPS can make fol 10:01 ate. 10:01 Folate can then be converted to tetrahydrofolate through the enzyme D-H-F-R. 10:07 Chetrahydrofolate can then be converted to thymidine through several reactions. 10:11 Thymidine will eventually be used for the genetic material of the parasite. 10:16 Thus if we have drugs that inhibit this process, we can kill the parasite. 10:21 These drugs are also antibiotics and include sulfanamides, which inhibit the 10:31 enzyme D-HPS 10:33 and diaminopyrimidines, which inhibit D-H-F-R. 10:38 The parasite have also been able to develop resistance to these drugs through 10:44 genetic mutations 10:45 of the enzyme, making it different enzymes. 10:53 So going back to Atova-Quone, Atova-Quone inhibits cytochrome, remember, and 11:02 specifically 11:03 actually it targets the sexual life cycle of the parasite, thus inhibiting gam 11:08 etocyte 11:08 formation. 11:11 So Atova-Quone targets the sexual cycle of the parasite. 11:17 There is another drug that targets the parasitic liver stage, so this drug I'm 11:23 talking about 11:24 is known as is called primaqueen. 11:27 Now primaqueen is a radical cure, and it prevents the relapse of latent liver 11:34 hypnozoides. 11:36 So it targets plasmodium ovale and vivax because these are the species, these 11:42 are the plasmodium 11:44 strains that can become dormant. 11:49 Now primaqueen is contraindicated in people who have glucose-6-fostase 11:55 deficiency because 11:57 it can cause hemolytic problems, and it is also contraindicated in pregnancy 12:03 like many 12:04 other drugs are. 12:07 The next anti-malio drug we will look at, and it's a very important one, are 12:13 known 12:14 as RT-Missins. 12:18 These guys are essentially inactive when they're given, and when they're given 12:23 to people, 12:24 they are activated by ferrous heme or free heme. 12:30 So when activated by the heme, the RT-Missins, they create a carbon-centered 12:36 radical which 12:37 will essentially kill the parasite. 12:40 The free radicals formed, kills the parasites in several ways. 12:45 These free radicals will kill the parasites through damage to their lipids and 12:50 vacuole 12:51 membranes, or they will inactivate the plasmodium proteins, alkylation of heme, 12:57 and also it 12:58 will interfere with the conversion of hematin to hemozoin, thus it will 13:05 increase hematin 13:06 in the parasite, which is toxic to the parasite. 13:09 So all in all, active RT-Missins is toxic to the parasite. 13:20 Doxycycline is another anti-malio drug which you might remember as being an 13:24 antibiotic. 13:25 Doxycycline is essentially a protein synthesis inhibitor. 13:30 Tetracycline, another antibiotic and protein synthesis inhibitor, is also used 13:35 for anti-malarial 13:35 treatment and prophylaxis. 13:38 Its side effects include esophagitis and photosensitivity, and they are cont 13:45 raindicated in pregnancy. 13:51 So now let us look at what to give to certain patients in different scenarios. 13:57 So for example, we'll actually mainly focus on p-falsiperum because that's the 14:03 main strain 14:04 of plasmodium that is associated with morbidity and mortality in the developing 14:11 countries that 14:12 have high prevalence of malaria. 14:14 So for uncomplicated p-falsiperum malaria, we would give a patient RT-Missins 14:22 plus a quinolone 14:23 such as firstly Lumifintrine, or if not Lumifintrine, we would give them 14:29 another type of quinolone. 14:32 Or if we can't give them a quinolone, we would give them RT-Missins plus a 14:36 protein synthesis 14:37 inhibitor such as Doxycycline or Tetracycline. 14:41 Now for complicated p-falsiperum, complicated is really when you have 14:46 association of really 14:47 organs, when the organs are affected, and you would give them IV, IV RT-Missins 14:54 or quinines. 14:58 For radical cure, which is basically targeting the dormant stages of the 15:03 malaria parasite, 15:04 so we're targeting the ovale or vivax in the liver, we would give them primoc 15:10 rine. 15:11 For prophylaxis, we would give a traveler, for example a traveler, chloroquine. 15:18 And we would give them chloroquine for areas which there is no resistance to 15:24 chloroquine, 15:25 so these are areas such as Central America. 15:29 If the traveler is going to places where the malaria and parasites are chloroqu 15:35 ine resistance, 15:37 we would give them amyvoquone or another type of chloroquine. 15:44 Anyway, I hope you enjoyed this video. 15:48 Thanks for watching. 15:49 Bye.
