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Artemisinin, Lumefantrine, Mefloquine, Primaquine, Atovaquone, Proguanil and Pyrimethamine

Qinghaosu (Artemisinin)

  • Derivatives are the most novel and recently introduced. Now highly recommended.
  • These drugs are artemisinin derivatives, discovered by Chinese scientisits.
Source:        

Plant source:      

a.      Qinghao,
b.      Artemisia annua

Chemistry: 

Sesquiterpene lactone endoperoxide

History:

Use dates back 2000 years, when plant was used in herbal tea for febrile illness. It was also known as “sweet swarm wood”. Chinese used its derivatives against tertian febrile illness particularly by mosquito plasmodium. In 1971 military institute started exploring alkaloids in this plant and in 1972 work was started on discovering a new antimalarial drug. In 1979, they were finally able to discover and synthesize derivatives.

Semisynthetic derivatives:

1.      Dihydroartemisinin –reduced form
2.      Artemether –oil soluble, given orally                         
3.      Artesunate –hemisuccinate salt of dihydroartemisinin, water soluble given oral, I/V, I/M or even rectally
4.      Arteether                            
5.      Artilonic

  • Used in developed countries and WHO recommended for multidrug resistant falciparum malaria, chloroquine resistant and severe malarial infections.
  • Chinese herbal medicines which were used as antipyretic.
  • Blood schizonticides against all types of malaria including chloroquine-resistant p. falciparum.
  • Unknown mechanism of action.
Mechanism of action

Consist of endoperoxide group

  1. Cleavage of endoperoxide group takes place, facilitated by heme component of human cells, plasmodium species itself liberates it from human species
  2. Next step is intramolecular rearrangement, radicals are produced,
  3. covalently inhibit protein synthesis within parasite
  4. hence metabolic processes are inhibited, further growth of plasmodium does not take place.
Pharmacokinetics
  1. Different compounds are given differently. Can be given orally, I/V, rectally or in suppositories.
  2. Artemether is mainly given orally as highly unstable and oil soluble
  3. When administered quickly absorbed, peak plasma levels occur within 30 minutes to 1 hour.
  4. Half life is in range of 1-3 hours
  5. Metabolized by liver CYP3A4 and CYP2C9
  6. Are converted into active metabolites
  7. Dihydroartemesinin is proven to have more potent antimalarial activity than parent compound
  8. Excreted by kidney.
Uses:
  1. P. falciparum cerebral malaria (oral & parenteral).

Rapidly acting, active against all species of plasmodium, target is trophozoite stage of asexual replication. Effects appear within 12 hours, improvement in febrile conditions occur. Rapidly acting blood schizonticidal agent. No activity on hepatic stage or tissue schizonticidal activity.

  1. Not used prophylactically as short half life.
  2. Use is recommended in children and pregnancy as easily tolerated, effects within pregnancy are not established, it is emberytoxic in rats.
  3. Also used effectively in severe cerebral malaria (artesunate is highly effective) although chloroquine is used as well
  4. Chloroquine resistant falciparum malaria
  5. Multidrug resistant falciparum malaria

Nowadays therapy is not initiated as resistance might occur, therefore combination therapy is given. One of most effective combination is CoArtem (artemether and lumefantrine) which is most promising combination therapy in endemic areas.

Adverse Effects

Highly safe drug, which is the reason why it is highly recommended in children. Adverse effects include:

  1. Nausea
  2. Vomiting
  3. Diarrhea
  4. Few studies indicate cardiac problems, still not alarming situation
  5. Some CNS manifestations including seizures, psychosis –data is little in humans, seen only in animal studies

Safely given to G6PD deficient patients as hemolytic anemia seen with conventional antimalarials is not seen with this.

Lumefantrine

Lumefantrine is not an effective antimalarial itself but in combination synergistic effects occur against falciparum malaria and resistant cases. Only disadvantage is that it is not cost effective.

Mefloquine 

Discovered during the Vietnam war to protect American soldiers from the multidrug resistant falciparum malaria, against which conventional antimalarials are not effective.

Restricted for use against multi-drug resistant P. falciparum only.

Chemistry

Resembles quinine, it is 4-amino quiniline.

Mechanism of action

Similar to quinine and quinidine. Inhibits heme polymerase enzyme, toxic heme is retained which is fatal to plasmodium.

Unlike quinine, it does not intercalate with DNA strand.

Pharmacokinetics:

–          Can only be given orally

–          Well absorbed , peak plasma conc. in 18 hrs.

–          Highly protein-bound, extensively distributed in tissues

–          Slow elimination – allow for single doses

–          Terminal half-life – 20 days – this is reason for weekly chemoprophylaxis dosing

–          Undergoes enterohepatic circulation

–          Mefloquine & acid metabolites excreted in feces

Uses
  1. Effective against multidrug resistant malaria
  2. Chloroquine resistant malaria
  3. Chemoprophylaxis –weekly dose

Safe in G6PD deficient state. More activity against P. falciparum and P. vivax. Cannot be given to treat severe falciparum malaria condition.

Adverse Effects

More common with high doses

  1. nausea,
  2. vomiting,
  3. dizziness,
  4. sleep/behavioral disturbances,
  5. epigastric & abdominal pain,
  6. diarrhea,
  7. headache,
  8. rash
  9. Neuropsychiatric toxicities
  10. Leukocytosis,
  11. thrombocytopenia &
  12. increases in aminotransferase

Most troublesome is neurotoxicity, more prone to cause:

  1. convulsions
  2. seizures
  3. psychosis
  4. confusion

Some cardiovascular manifestations:

  1. delayed cardiac conduction
  2. arrhythmias
  3. QT prolongation
Contraindications

Not used in:

  1. Patients with CNS disorders, psychosis
  2. CVS abnormality
  3. Not used with quinine and quinidine as both potentiate each others’ effect.
Tissue Schizonticide
Primaquine (8- aminoquinoline derivative)

It is a tissue schizonticide, effective against hepatic stages of plasmodium life cycle (P. vivax and ovale).

Mechanism of action

Exact mechanism is not known.

  1. May effect at cellular level. It inhibits electron transport mechanism within mitochondria.
  2. It has a cellular oxidant activity and possibly interferes with mitochondria function,
  3. Gametocide, so inhibits infection transmission by mosquito.
Uses:

1.      Eradication of liver stages (hypnozoites) of P.vivax & P. ovale, after standard chloroquine therapy to prevent relapse

In most cases blood schizonticide (chloroquine) is used, when erythrocytic stage is eliminated then primaquine is administered for about 14 days to eliminate liver stage as well.

Care is taken that primaquine is only administered if G6PD state of patient is evaluated as it is contraindicated in G6PD deficiency.

2.      If plasmodium has lodged into hepatocytes, capable of causing relapsis, it can be given to effectively inhibit relapsis chances.

It should not be given if there is risk of reinfection.

3.      Inhibits transmission by mosquito.
4.      Along with Clindamycin effective against Pneumocystis Jeroveci

Adverse effects:
  1. GIT upset,
  2. pruritis,
  3. headache,
  4. arrhythmias
  5. methemoglobinemia,
  6. hemolysis especially in G-6-PD deficient

Atovaquone

  • Component of Malarone (Atovaquone 250 mg + Proguanil 100 mg), recommended for prophylaxis & Treatment of P. falciparum, resistant cases as well.
  • Advantage with combination is that:
  1. duration of therapy is decreased
  2. well tolerated
  3. easily administered

But not cost effective

Mechanism of Action

At cellular level, appears to disrupt mitochondrial electron transport, as a result of which cellular metabolic processes are inhibited.

Pharmacokinetics

Only oral administration, bioavailability is low but increased by fatty food (absorption is increased)

  • Heavily protein-bound; half-life of 2-3 days
  • Eliminated unchanged in feces
Uses:
  1. Besides malaria, alternative treatment for Pneumocystis jiroveci pneumonia
  1. May be effective in immunocompromised with toxoplasmosis

Must be taken with food

Adverse Effects:
  1. Fever,
  2. rash,
  3. nausea,
  4. vomiting,
  5. diarrhea,
  6. headache,
  7. insomnia
Chlorguanide (Popular as Proguanil) and Pyrimethamine

Antimetablites, proguanil is biguanide. Pyrimethamine is antimetabolite within protozoa.

Mechanism

Same as trimethoprim, inhibit dihydrofolate reductase, sequential steps in which PABA is coverted into dihydrofolic acid and tetrahydrofolic acid in synthesis of purines and DNA.

Proguanil is a prodrug, mainly converted to an active metabolite called Cycloguanil pamoate, an active antimalarial agent.

It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. This enzyme is not effective in humans, very high concentration of drug is required for such effects, thus selective.

Both are given orally and excreted in urine.

Pyrimethamine Proguanil
Peak plasma levels 2-6 hours 5 hours
Elimination half life 3-5 days (85-90 hours) 16 hours
Uses

Pyrimethamine is given for prophylaxis, as once weekly dose is required due to long elimination half life.

Proguanil is given on daily basis

Proguanil has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection.

It is also effective in suppressing the clinical attacks of P. vivax malaria.

Adverse Drug Reactions
  • Produces occasional nausea and diarrhea, skin allergies
  • Safe drug and can be used in pregnancy.

Mainly given in combination for treating different infections, such as:

  1. Chloroguanide along with Chloroquine is used as prophylaxis effective against P. falciparum malaria.
  2. Sulfadoxine + Pyrimethamine (Fansidar) –highly convenient, cost effective, easily administered, effective, better compliance, less ADRs but resistance has limited its use.
  3. Chlorproguanil + Dapsone (LapDap) –effective where Fansidar is ineffective
  4. Pyrimethamine + sulfadiazine for toxoplasmosis (folic acid is administered on daily basis 6-10 mg daily)
Halofantrine
  • Previously used antimalarial, no longer recommended as having cardiovascular effects.
  • Unknown mechanism of action.
  • Used only by oral route in P. falciparum cerebral malaria.
  • No parenteral preparation.
  • Not used for prophylaxis.
  • Not used during pregnancy unless benefit outweighs the risk.
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