Antimalarial drugs _classification_overview.pptx

The presentation is on antimalarial drugs which gives a basic idea on the concerned topic. So that you can build a strong base on antimalarial drugs. Here it describes classification, mechanism of action, adverse effects, contra indications etc

1. Antimalarial Drugs

2. Antimalarial drugs Malaria is a protozoal infection caused by genus Plasmodium and transmitted to humans by the infected female Anopheles mosquito. The species of malarial parasites are Plasmodium vivax , Plasmodium ovale , Plasmodium malariae , P. Falciparum and Plasmodium knowlesi . The incidence of malaria is increasing due to the resistance of vectors to insecticides and drug-resistant parasites. In India, P. Vivax and P. Falciparum are common.

3. Chemical classification (a) 4-Aminoquinolines: Chloroquine , amodiaquine , piperaquine (b) 8-Aminoquinolines: Primaquine , tafenoquine (c) Quinoline methanol: Mefloquine (d) Alkaloids: Quinine, quinidine
(e) Antifolates : Pyrimethamine , sulphadoxine , dapsone , proguanil (f) Antibiotics: Doxycycline, clindamycin
(g) Hydroxynaphthoquinone : Atovaquone (h) Artemisinins : Artemisinin , artemether , artesunate , arteether , arterolane , dihydroartemisinin ( i ) Aryl alcohol: Lumefantrine

4. Based on the stage of the life cycle of parasite they affect ( i ) Tissue schizontocidal agents: These act on primary (pre- erythrocytic ) and latent ( hypnozoites ) tissue forms in the liver, e.g. Primaquine is effective against both forms; atovaquone and proguanil act on primary forms.

5. (ii) Blood schizontocidal agents: These act on erythrocytic stage of Plasmodium and, thereby, terminate the clinical attack.
• Rapid acting and high-efficacy agents, e.g. Chloroquine , artemisinin derivatives, quinine, mefloquine , atovaquone , amodiaquine and lumefantrine .
• Slow-acting and low-efficacy agents, e.g. Proguanil , pyrimethamine + sulfadoxine and clindamycin; used always in combination with rapid-acting agents.

6. (iii) Gametocidal agents These kill gametocytes of plasmodia in blood, e.g. Artemisinin and primaquine (active against all species); chloroquine and quinine ( vivax ). They reduce transmission to mosquitoes.

7. Based on clinical indication for use ( i ) Drugs used for causal prophylaxis, i.e. Act on pre- erythrocytic stage of Plasmodium in liver, e.g. Proguanil and primaquine . Primaquine is effective against all species but not used due to its toxic potential. Proguanil is effective mainly for P. Falciparum.
(ii) Drugs for suppressive prophylaxis: Suppress erythrocytic phase, thus prevent clinical attack of malaria – clinical disease is not manifested, e.g. Chloroquine , mefloquine and doxycycline.

8. (iii)  Drugs used for clinical cure : These agents act on erythrocytic stages of malarial parasite to terminate the clinical attack. They are rapid-acting and slow-acting blood schizontocidal agents. (iv)  Drugs used to prevent relapse : These drugs act on the latent tissue forms ( hypnozoites ) of  P. vivax  and  P. ovale  which cause relapse, e.g. primaquine and tafenoquine.Radical cure of  P. vivax  and  P. ovale  is achieved with the use of a blood schizontocidal agent along with primaquine which acts on latent tissue forms ( hypnozoites ) to prevent relapse.

9. (v) Drugs used to prevent the transmission of infection to Anopheles mosquito ( gametocidal agents): Primaquine has gametocidal effect against all species of plasmodia that infect humans.

10. Note: Points to remember 1. None of the agents available are effective against sporozoites .

2. Most of the antimalarials are effective against asexual blood stages except primaquine .

3. Only primaquine and tafenoquine are effective against hypnozoites (latent tissue forms).

4. All agents with ‘quine’ ( primaquine , chloroquine , quinine and Quinghaosu ) are effective against gametocytes except mefloquine and tafenoquine .

5. Primaquine and proguanil are effective against hepatic primary tissue forms.

11. 4-Aminoquinolines Chloroquine Chloroquine is a 4-aminoquinoline. It is very effective and rapidly acting blood schizontocide against P. Vivax , P. Ovale , P. Malariae , chloroquine -sensitive strains of P. Falciparum and P. Knowlesi . It has no activity against liver forms (pre- erythrocytic and hypnozoites ).

12. Mechanism of action. Chloroquine is a basic drug, which is taken up by the acidic food vacuoles of susceptible plasmodia and inhibits the conversion of haeme to haemozoin . The ‘drug– haeme ’ complex is toxic and kills the parasite. Resistance to chloroquine is common with P. Falciparum.

In the acidic vacuole of plasmodia:

13. Pharmacokinetics Chloroquine is commonly administered by oral route. It is well absorbed after oral and parenteral administration. It has strong affinity for melanin-containing tissues. It gets rapidly distributed to tissues (extensive tissue binding); therefore, to achieve an effective therapeutic plasma concentration, a loading dose is used during treatment of malaria. It gets concentrated in liver, spleen, kidney, lungs, skin, etc. Chloroquine is metabolized in the liver and slowly excreted in urine.

14. Adverse effects and contraindications. Chloroquine in antimalarial doses may cause nausea, vomiting, skin rashes, itching, headache and visual disturbances. Parenteral administration can cause hypotension, confusion, cardiac arrhythmias, convulsions and even cardiac arrest. Prolonged administration in large doses, as in rheumatoid arthritis, may cause irreversible retinopathy and ototoxicity. It can also cause myopathy, cardiomyopathy, neuropathy and rarely psychiatric disturbances. Long-term therapy requires ophthalmological examination once in 3–6 months. It should be avoided in patients with epilepsy. It should not be given with mefloquine (can precipitate seizures). It is safe for use in pregnancy.

15. Uses Malaria
(a) Chloroquine is the drug of choice for the treatment of acute attack of malaria caused by P. Vivax , P. Ovale , P. Malariae , chloroquine -sensitive P. Falciparum and P. Knowlesi (Table 12.22). Fever resolves within 24–48 hours; blood smear becomes negative within 2–3 days.
(b) For malaria due to P. Vivax and P. Ovale , primaquine is also administered in addition to chloroquine (for radical cure).
(c) Chloroquine is a very effective chemoprophylactic agent for all types of malaria (Table 12.23) except that caused by the resistant strains of P. falciparum

16. Other uses are as follows Amoebiasis – hepatic amoebiasis , as it is highly concentrated in the liver. Lepra reaction – anti-inflammatory effect is useful.
Rheumatoid Arthritis – it scavenges free radicals and stabilizes lysosomal membrane.
Infectious mononucleosis.
Autoimmune disorder – discoid lupus erythematosus.
Tablet chloroquine phosphate 500 mg = 300 mg chloroquine base
Tablet chloroquine phosphate 250 mg = 150 mg chloroquine base

17. Alkaloids Quinine and quinidine
Cinchona bark contains several alkaloids, of which quinine and quinidine are important. Mechanism of action.
It is similar to that of chloroquine .

18. Pharmacological effects 1. Antimalarial actions: Quinine is a highly effective blood schizontocide against all the four species of plasmodia. It has gametocidal activity against P. Vivax . It has no activity on hepatic forms (i.e. Pre- erythrocytic and latent tissue forms).

19. Other actions (a) GIT: Being bitter, quinine reflexly increases gastric acid secretion.
(b) CVS: Quinine directly depresses the myocardium and can cause hypotension. But this effect may not be seen with oral antimalarial doses.
(c) Skeletal muscle: Quinine directly depresses the skeletal muscle contraction. Response to Ach is also diminished – symptoms of myasthenia gravis are exaggerated, while symptoms of myotonia congenita are relieved.
(d) CNS: In therapeutic doses, quinine often causes disturbances of hearing and vision. It also has mild analgesic and antipyretic effects.

20. Local action Quinine has local anaesthetic effect, but there is invariably an initial irritation. Orally, it causes GI irritation with nausea, vomiting and abdominal discomfort. Intramuscularly, it causes local pain and necrosis. Intravenously, it can cause thrombophlebitis.

21. Pharmacokinetics Quinine is readily absorbed from the gut or i.m . Site, well distributed in the body, extensively metabolized in liver and excreted mainly in urine.

22. Adverse effects. Quinine causes dose-dependent toxicities. They are cinchonism , hypoglycaemia and hypotension. Cinchonism comprises tinnitus, deafness, visual disturbances like blurred vision and colour defects, headache, nausea and vomiting. These symptoms are reversible on stoppage of therapy. Hypoglycaemia is common with i.v. Quinine which is due to release of insulin – it is treated with intravenous glucose. Hypotension is also seen with intravenous administration of cinchona alkaloids. Quinine in large doses can cause hypotension, cardiac arrhythmias and A–V block. Quinidine is more cardiotoxic than quinine.

‘Blackwater fever’, a hypersensitivity reaction to quinine, is characterized by haemolysis, haemoglobinaemia and haemoglobinuria leading to renal failure.

Quinine/quinidine should not be used concurrently with mefloquine because of risk of serious cardiac toxicity. Quinine can be used in pregnancy.

23. Uses 1. Malaria: Quinine is effective for treatment of acute attack of chloroquine -resistant P. Falciparum malaria. Combination of clindamycin or tetracycline with quinine enhances the antimalarial efficacy of quinine. In severe malaria, quinine or quinidine is administered intravenously.
2. Nocturnal leg cramps: Quinine may be effective in some cases.

24. Quinoline methanol Mefloquine It is a synthetic quinoline methanol. Like quinine, it is a highly effective blood schizontocide and has no effect on hepatic forms, i.e. Pre- erythrocytic stages and hypnozoites of P. Vivax . It has no gametocidal activity.

25. Mechanism of action. It is similar to that of chloroquine and quinine. It binds to heme and causes damage to membrane of Plasmodium

26. Pharmacokinetics Mefloquine is administered orally and is not suitable for parenteral use because of its local irritant action. It is well absorbed, widely distributed, highly bound to plasma proteins, secreted in bile and undergoes extensive enterohepatic cycling. It is slowly excreted in the faeces with a terminal half-life of about 3 weeks.

27. Uses Mefloquine is used for prophylaxis of chloroquine -resistant P. Falciparum and P. Vivax malaria. It is used in combination with artesunate for the treatment of chloroquine -resistant P. Falciparum malaria.

28. Adverse effects. The common side effects include nausea, vomiting, diarrhoea and dizziness. Nausea and vomiting can be minimized by dividing the dose. Neuropsychiatric symptoms and seizures can occur. Mefloquine is contraindicated in patients with conduction defects, epilepsy and psychiatric disorders. It is safe for use in young children.

29. 8-Aminoquinoline Primaquine It is a synthetic 8-aminoquinoline. It is effective against hepatic stages, i.e. Primary and latent tissue forms of Plasmodia species that infect humans. It also has marked gametocidal activity but is ineffective against erythrocytic forms of malarial parasite. The exact mechanism of action of primaquine is unknown. It probably acts by generating reactive oxygen radicals and interfering with the mitochondrial electron transport in the parasite.

It is almost completely absorbed after oral administration, widely distributed, metabolized in liver and excreted slowly in urine. Primaquine is used for radical cure and terminal prophylaxis of P. Vivax and P. Ovale as it has strong activity against hypnozoites . For terminal prophylaxis, primaquine 15 mg daily is started shortly before or after return from an endemic area. For radical cure of relapsing malaria (P. Vivax and P. Ovale ), a 2-week course of primaquine is given concurrently with chloroquine or after the treatment of acute attack.

30. Adverse effects These include nausea, vomiting and epigastric distress – can be minimized by taking it with food. The important side effect with primaquine is haemolytic anaemia in people with G6PD deficiency. Methaemoglobinaemia can also occur with primaquine . Primaquine is contraindicated in pregnancy.

(Tablet primaquine phosphate 26 mg contains 15 mg base of primaquine base.)

31. Tafenoquine It is an 8-aminoquinoline. It is very effective against latent tissue forms ( hypnozoites ) of P. Vivax , and also has blood schizontocidal activity. It has a longer duration of action (t½ is 15–19 days), hence used as a single-dose antirelapse agent. It can cause hemolysis in G6PD deficient individuals.

32. Antifolates They are pyrimethamine , sulfadoxine , sulfones ( dapsone ) and proguanil . They are not used as single agents in malaria owing to rapid development of resistance.

33. Sulfadoxine-pyrimethamine Mechanism of action
Plasmodia utilize PABA for the synthesis of folic acid which, in turn, is necessary for DNA synthesis. Sulfadoxine inhibits folate synthetase , whereas pyrimethamine inhibits DHF reductase enzyme of the parasite. Sulfadoxine and pyrimethamine have a long half-life (5–9 days and 4 days, respectively). Combination of these drugs ( pyrimethamine + sulfadoxine ) inhibits two successive steps (sequential blockade) in the folate pathway, acts faster and produces enhanced antimalarial action (synergistic effect).

34. The combination of pyrimethamine with sulfadoxine along with artesunate is used in the treatment of chloroquine -resistant P. Falciparum malaria. Pyrimethamine –sulfadiazine combination is the treatment of choice for toxoplasmosis in immunocompromised patients. Dapsone inhibits plasmodial folate synthetase . Proguanil ( chloroguanide ) is an antifolate . It is used in combination with atovaquone

35. Pyrimethamine 25 mg
+ sulfadoxine 500 mg Pyrimethamine 25 mg
+ dapsone 100 mg

36. Atovaquone and proguanil Both atovaquone and proguanil are effective against erythrocytic stage and primary tissue forms (hepatic stage) of P. Falciparum. Atovaquone (a hydroxyaphthoquinone ) damages plasmodial mitochondrial membrane; proguanil ( antifolate ) inhibits dihydrofolate reductase (combination is synergistic).Adverse effects of these drugs are nausea, vomiting, diarrhea and rashes.

FDC of atovaquone-proguanil ( Malarone ) is used for prophylaxis of chloroquine resistant P. Falciparum malaria. Atovaquone is also useful against T. Gondii and P. Jiroveci in immunocompromised patients.

37. Artemisinin and its derivatives Artemisinin is derived from the plant Artemisia annua . The semisynthetic derivatives of artemisinin are dihydroartemisinin , artemether and artesunate . Another compound, arteether , was developed in India.

They are highly effective against erythrocytic stages of all plasmodia. They also have gametocidal action – reduce transmission of malarial parasite. They have no effect on hepatic stages of the parasite.

38. Mechanism of action

39. Pharmacokinetics Dihydroartemisinin : Oral
• Artesunate : Oral,, i.m ., i.v. , rectal
• Artemether : Oral, i.m .
• Arteether : i.m .

40. Artesunate and artemether are metabolized to the active metabolite, dihydroartemisinin . Artesunate can enhance its own metabolism ( autoinduction ). The half-life of dihydroartemisinin is about 2 hours. Arteether has a longer half-life.

41. Adverse effects They are generally well tolerated. Artemisinins can cause mild GI disturbances, neutropenia and prolongation of QT interval.

42. Arterolane It is a synthetic derivative of artemisinin which acts on erythrocytic stages of the parasite. It is potent and has a rapid onset and short duration of action. A combination of arterolane with piperaquine has been found to be effective and well tolerated for the treatment of P. Falciparum malaria.

43. Lumefantrine It is active against erythrocytic stages of all species of malarial parasite. Fatty meal increases its absorption. It can cause GI disturbances. It does not significantly prolong QT interval. It is used in the treatment of P. Falciparum malaria in combination with artemether .

44. Antibiotics Tetracyclines and clindamycin
Tetracycline, doxycycline and clindamycin are slow-acting blood schizontocides for all species of plasmodia that infect humans. They do not affect hepatic stages. They are used in combination with quinine or artesunate for the treatment of P. Falciparum malaria. Doxycycline can also be used alone as a chemoprophylactic agent for chloroquine resistant P falciparum malaria. Tetracyclines should not be used in pregnancy and young children (younger than 8 years); clindamycin can be used safely in such cases.

45. Treatment of malaria during pregnancy P. Vivax malaria is treated with chloroquine . For P. Falciparum malaria, quinine with clindamycin is administered in first trimester; ACT in 2 nd and 3 rd trimesters. Doxycycline and primaquine are contraindicated in pregnancy.

46. Treatment of mixed infection due to both P. Falciparum and P. vivax It should be treated as P. Falciparum malaria with ACT regimen (except ACT regimen of artesunete + sulfadoxine-pyrimethamine as it is not effective against P vivax ). A 14 day course of primaquine is also added.

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