1. Pharmacology 3 antimalarial drugs lecture 11 by Prof.Dr. Mohamed Fahmy

2. Malaria Caused by four species of the plasmodia which are protozoa
These are Plasmodium falciparum, P vivax, P malariae & P ovale
P falciparum is the most dangerous (can lead to fatal cerebral malaria)

3. Life cycle 1- Asexual cycle a- Exoerythrocytic stage
Anopheles female mosquito inject saliva containing sporozoites into human
Sporozoites infect liver & developed into schizonts which release merozoites into blood
b- Erythrocytic stage
Merozoites infect RBCs & multiply
RBCs rupture & release merozoites that destroy more RBCs (clinical symptoms)

4. 2- Sexual cycle
Some merozoites differentiates into gametocytes (male & female) which are taken up by mosquito to begin another cycle
Note
In P vivax & P ovale a dormant stage (hypnozoites) can remain in the liver & causes relapses by invading the blood stream weeks or even years later

5. Sites of action of antimalarial drugs
1- Tissue schizonticides Prevent relapse e.g., Primaquine 2- Blood schizonticides Terminate clinical attack e.g., Chloroquine, Quinine, Mefloquine, Proguanil, Pyremethamine & tetracycline 3- Gametocyticides Prevent transmission e.g., Primaquine, Proguanil & Pyremethamine

6. Antimalarial drugs 1- Primaquine
It is a tissue schizonticide & gametocide
Mechanism of action
Acts by generating reactive oxygen species or by interfering with respiratory chain in parasite
Therapeutic uses
1- Radical cure of relapsing malaria
2- Prevent transmission of P falciparum
Adverse effects
GIT disturbances & bone marrow depression
Hemolytic anemia in patients with G6PD deficiency

7. 2- Chloroquine (Cidoquine, Alexoquine)
It is a blood schizonticide
Mechanism of action
1- Inhibits the digestion of hemoglobin by parasite ( pH) synthesis of amino acids
2- Inhibits polymerase enzyme which converts heme (toxic) into hemozoin (non toxic)
3- The accumulation of heme results in lysis of the parasite

8. Therapeutic uses
Treatment & prophylaxis against all types of plasmodium except for P falciparum
Resistance
Chloroquine resistant parasites are able to expel the drug via P-glycoprotein pump
Adverse effects
1- Low doses GIT disturbances, skin rash, headache & blurred vision
2- High doses Retinopathy, ototoxicity & myocardial depression

9. 3- Quinine An alkaloid derived from cinchona bark
Blood schizonticidal drug
Has no effect on liver stages of plasmodium
Mechanism of action
Inhibits heme polymerase with accumulation of toxic heme
Forms complex with parasite DNA
Therapeutic uses
Drug of choice for treatment of acute
P falciparum

10. Side effects
Cinchonism
Headache, nausea, blurred vision, tinnitus & vertigo
Hypotension & myocardial depression
Has oxytocic effect (contraindicated in pregnancy)

11. 4- Mefloquine (Lariam)
Chemically related to quinine
Very potent with a long half-life (17 days)
Acts by forming toxic complex with free heme that damages parasite membrane
Used only in P falciparum resistant to chloroquine
May cause fetal abnormalities (contraindicated in pregnancy)

12. 5- Proguanil &Pyremethamine
Mechanism of action
Inhibit malarial dihydrofolate reductase enzyme prevent formation of tetrahydrofolate inhibits DNA synthesis & cell division
The combination of pyremethamine with sulfadoxine (Fansidar) has a synergistic effect through blocking 2 steps in folic acid synthesis

13. Therapeutic uses
Fansidar is used in the treatment of chloroquine-resistant P falciparum
Adverse effects
Proguanil Mouth ulcer & stomatitis
Pyremethamine Megaloblastic anemia & skin rash

14. 6- Artemisinin derivatives
Isolated from the leaves of artemisia (Chinese herb)
Examples include Artesunate, Artemether & Arteether
These componds generate free radicals that oxidize proteins & lipids leading to parasite death
They are effective blood schizonticides against all types of malaria

15. 7- Antibiotics
Some antibiotics in addition to sulfonamides are active against malaria
The mechanism of action of these drugs are unclear
Examples:
- Tetracycline & doxycycline
- Clindamycin
- Azithromycin or fluoroquinolones