Anti-Malarial Drugs

TREATMENT OF MALARIA
Four species of plasmodium typically cause human malaria: Plasmodium falciparum P vivax P malariae, P ovale. A fifth species, P knowlesi, is primarily a pathogen of monkeys, but has recently been recognized to cause illness, including severe disease, in humans in Asia. Although all of the species may cause significant illness, P falciparum is responsible for the majority of serious complications and deaths. Drug resistance is an important therapeutic problem, most notably with P falciparum.

PARASITE LIFE CYCLE

An anopheline mosquito/ infected syringe inoculates plasmodium sporozoites to initiate human infection. Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver Merozoites are subsequently released from the liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness. Repeated cycles of infection can lead to the infection of many erythrocytes and serious disease. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.

In P falciparum and P malariae infection, only one cycle of lever cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure these infections. In P vivax and P ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most drugs, and subsequent relapses can therefore occur after therapy directed against erythrocytic parasites. Eradication of both erythrocytic and hepatic parasites is required to cure these infections.

Anti-malarial Drugs may be selected for: Prevention of clinical attacks --- Chemoprophylaxis Treatment of clinical attack Radical cure

Classification of Anti-malarial Drugs according to Site of action

1.Tissue Hepatic Schizonticides /Acting on Hepatic cycle/ a. Drug effective against primary tissue forms-- Pre-erythrocytic stage / for Causal prophylaxis . Proguanil b. Drug effective against developing or dormant tissue forms/ for Terminal prophylaxis or Radical cure . Primaquine

2.Blood Schizonticides / Drug acting on Erythrocytic parasites/ for Suppressive cure a. Rapidly acting Blood schizonticides Chloroquine Amodiaquine Piperaquine Quinine Mefloquine Halofantrine Artemisinin (Qinghaosu) & its derivatives i.e. Artemether, Artesunate, dihydroartemisinin

b.

Slower acting Blood schizonticides

Proguanil Doxycycline Pyrimethamine 3. Gametocides/ Against sexual Erythrocytic forms Primaquine --- Against P Falciparum
Chloroquine, Quinine --- Against P Vivax, P Ovale. They kill sexual forms & prevent transmission to mosquitoes.

Chemical Classification
1. Cinchona Alkaloids: Quinine
2. 4-Aminoquinolines: Chloroquine Amodiaquine 3. Bisquinoline: Piperaquine

8-Aminoquinolines: Primaquine
4. Quinoline Methanols: Mefloquine , Quinidine 5. Folate antagonists: Proguanil, Pyrimethamine 6. Sulfonamides: Sulfadoxine 7. Sulphone: Dapsone

8. Antibiotics: Doxycycline, Clindamycin 9. Miscellaneous Halofantrine & Lumefantrine Atovaquone Artemisinin (Qinghaosu) & its derivatives i.e. Artemether, Artisunate. 10. Combinations Pyrimethamine & Sulfadoxine ( Fansidar) Mefloquin , Pyrimethamine & Sulfadoxine (Fansimef) Atovaquone & Proguanil (Malarone) Amodiaquine & Artisunate (Coarsucam) Amodiaquine , Sulfadoxine -Pyrimethamine Piperaquine & Dihydroartemisinins (Artikin) Pyrimethamine & Dapsone (Maloprim)

Chloroquine

Most widely used anti-malarial, blood schizonticide Source: Synthetic drug. chemistry: 4-Aminoquinoline.

Pharmacokinetics: Orally Chloroquine phosphate & I/M / I/V injection Chloroquine sulphate Abs. well & almost complete from GIT. by Kaolin & antacids containing Calcium & Magnesium. PPL: 3 hrs Dist Rapid & wide. Concentrated in RBCs, liver, spleen, kidney, lung, melanin containing tissues. It also penetrates into the CNS & traversesplacenta. PPB: 50% & extensively tissue bound specially to melanin containing tissues

Vd: large,100-1000 L/ kg. Met: slowly released & metabolized in the liver Exc: Some parent drug & metabolites excreted in urine. Excretion rate is enhanced if urine is acidified. Initial t: 1-2days Terminal elimination t: 1-2 months

MOA of Chloroquine as Antimalarial

It is highly effective blood schizonticide . Moderate gametocide for P vivax.P ovale & P malariea. No effect on liver stages of malarial parasites.

MOA : Chloroquine probably acts as follows:

Chloroquine is a weak base, it is concentrated in parasite s food vacuoles by ion trapping. Malarial Parasites utilize hemoglobin as food, it is broken down in to heme which is toxic but it is polymerized into harmlessm hemozoin by enzyme heam polymerase. Chloroquine prevents biocrystallization of heme in to Hemozoin ,by inhibiting HAEM POLYMERASE. 3. Increased pH & accumulation of toxic heme, produces oxidative damage to the membranes,leading to lysis of both the Malarial Parasites & RBCs.

Resistance to chloroquine

V. common in P falciparum Uncommon but for P vivax. In P falciparum, it has been correlated with mutations in a transporter, PfCRT. There is decreased accumulation of drug in MP. It can be reversed by verapamil, desipramine and chlorpheniramine , clinical value not established .

Therapeutic uses

Acute attack of Malaria Chemoprophylaxis of Malaria Hepatic amebiasis / abscess Rheumatoid diseases i.e. Systemic lupus erythematosis, Sjogren syndrome Rheumatoid Arthritis

Therapeutic uses
1.

Acute attack of Malaria Effective ,safe & cost effective. DOC for non-falciparum & sensitive falciparum Malaria. Terminates fever rapidly in 24-48hrs. Clears parasitemia in 48-72 hrs. It is highly effective blood schizonticide for all species. Moderate Gametocide for P vivax.P ovale & P malariea. No effect on liver stages., so primaquine is added for radical cure. Safe in pregnancy & young children.

Tab. Chloroquine Phosphate orally. (tab 250 mg, Chloroquine base is 150 mg) Dose:4 tablets (1gm)stat Then 2 tab(500mg) at 6 , 24 ,48 hrs. or Chloroquine Phosphate---1gm at 0& 24 hrs then Then 500mg at 48 hrs.
2. Chemoprophylaxis of Malaria:

Preferred in region without resistant falciparum Malaria. Dose: 500 mg weekly. begin 1-2 week before departure & continue for 4 weeks after leaving the endemic area. For eradication of liver stages of P vivax.P ovale , primaquine is added.

3. Rheumatoid diseases i.e.

Systemic lupus erythematosis, Sjogren syndrome Rheumatoid Arthritis MOA not clear, proposed mechanism are: Suppression of T lymphocyte responses to mitogens. Decreased leukocyte chemotaxis Stabilization of lysosomal enzymes. Inhibition of DNA & RNA synthesis. Trapping of free radicals.

Chloroquine & hydroxychloroquine are used. It takes 2-3 months to obtain a response. Often used for skin manifestation, serositis, & joint pains of systemic lupus erythematosus. They improve symptoms but do not alter bony damage in RA

4. Hepatic amoebiasis / abscess not responding to Metronidazole

Concentrated in liver kills trophozoits of E. histolytica Not effective for amoebic colitis or luminal amoebae because absorbed in upper intestine.

Adverse Effects
A/E are minimal with low doses for chemoprophylaxis. After oral doses for Acute attack of Malaria: Common A/E Pruritis (primarily in Africans)sometimes with Urticaria. Nausea, vomiting ,Abdominal Pain, Anorexia. Headache. Blurring of vision.

Other A/E are

Haemolysis in G6PD deficiency Impaired Hearing , confusion Psychosis , Seizures Agranulocytosis Exfoliative Dermatitis Alopecia, Bleaching of Hair Hypotension ECG Changes: QRS widening & T wave changes

2.Chronic use of high daily doses in Rheumatoid diseases: Discoloration of nail beds and mucus membranes Bleaching of hair & Alopecia Irreversible Ototoxicity , Retinopathy myopathy & Peripheral Neuropathy. It can exacerbate dermatitis produced by gold / phenylbutazone therapy. 3. Large I/M or Rapid I/V administration: Excessive hypotension. Respiratory & cardiac arrest.

Contraindications & Precautions

C/I in Psoariasis , Porphyria acute attack may be precipitated. With retinal or visual field abnormalities. Caution Hepatic diseases, Neurological & blood diseases. Patients with G6PD deficiency. Baseline & 3-6 monthly Ophthalmological & Neurological exam. of patients on long term therapy should be done .

AMODIAQUINE
Closely related to chloroquine MOA & MOR similar to chloroquine. Low cost, limited toxicity. A/E: Rare-- Agranulocytosis, aplastic anemia & hepatotoxicity. Therapeutic Uses: Treatment of malaria with chloroquine resistant P falciparum in combination : Amodiaquine with Artesunate (Coarsucam). It is first line therapy in many African countries.

Amodiaquine with Sulfadoxine -Pyrimethamine

Not used for prophylaxis increased toxicity with long term use

Piperaquine

Chemically it is Bisquinoline. Piperaquine was used for treatment of malaria rfom1970s1980s in China, the use waned due to resistance. Now it is combined with Dihydroartemisinins Piperaquine & Dihydroartemisinins (Artikin) first line therapy for falciparum malaria , without apparent resistance . It has longer half life28d so longer period of post treatment prophylaxis than other combinations of artemisinins.

Artimisinin( Qinghaosu) & its Derivatives Artemisinin: It is Sesquiterpene lactone endoperoxide, active compound of a Herbal medicine used in China for 2000 yrs Insoluble --- only used orally. Analogs: Artisunate & Artemether. Artesunate :Water soluble, useful for oral I/V , I/M & rectal administration. Artemether :Lipid soluble, useful for oral I/M & rectal administration . Dihydroartimisinin :Water soluble, useful for oral administration.

Ph. Kinetics of Artemisinin( Qinghaosu) & its Analogs: Abs. Given orally well & almost complete from GIT. PPL: 1-2 hrs . t : 1-3 hrs Dist Rapid & wide, some tissue binding Met : in liver Artesunate & Artemether metabolized to active metabolite dihydroartimisinin.

MOA: Rapidly acting blood schizonticide against all four species of MP. No effect on hepatic stages. They act by producing free radicals due to iron catalyzed cleavage of the artemisinin endoperoxide bridge in the parasite food vacuole or Inhibition of a parasite calcium ATPase.

Therapeutic Uses 1. Treatment of uncomplicated P falciparum malaria.

Combination is preferred as standard treatment : Artemether in combination with lumefantrine. Artesunate in combination with Mefloquine / Amodiaquine / Sulfadoxime & Pyrimethamine. Dihydroartemisinins with Piperaquine (Artikin)

2. Treatment of complicated P falciparum malaria.

I/V Artemether & Artesunate I/V Artemether has efficacy like Quinine & I/V Artisunate is even superior--- in clinical trials. 3. Not useful for prophylaxis short half life.

Adverse Effects

Nausea, Vomiting, Diarrhea & dizziness. Rare toxicities: Neutropenia, anemia, hemolysis, eevated liver enzymes & Allergic reactions. Irreversible neurotoxicity in animals at high doses. Teratogenic in animals. However WHO has recommended use of I/V artisunate in pregnancy, for treatment of severe Falciparum malaria.

Quinine & Quninidine

Blood schizonticides Source: Quinine: Natural alkaloid, Bark of Cinchona. Quninidine: dextrorotatory stereoisomer of quinine. Chemistry: Quinoline methanol. MOA:Exact MOA not known. Rapidly acting Blood schizonticide. , highly effective against four species of human M. Parasites. Gameticidal: against p vivax and P ovale but not p falciparum. Resistance: Common in some areas .It is increasing.

Therapeutic Uses
1. Severe P.falciparum malaria (cerebral Malaria) Quinidine is preferred over Quinine, Parenterally 2. P.falciparum malaria resistant to Chloroquine, orally Quinine sulfate in combination with Doxycycline /Clindamycin. 3. Prophylaxis of malaria generally not used 4. Babesiosis --- with clindamycin for infection with Babesia microti

Severe or complicated infections with p falciparum: Quinidine is preferred over Quinine. Cardiac monitoring mandatory. Slow I/V infusion or I/M Loading dose is given. Changed to oral as patient recovers. Quinidine gluconate 10mg/kg IV over 1-2 hrs, then 0.02 mg/kg IV/min or 15 mg/kg IV over 4 hrs, then 7.5 mg/kg IV over 4 hrs every 8 hrs

Adverse Effects 1.Cinchonism: ---- Dose related a. Mild cases:Tinnitis, headache , Nausea, Dizziness, Flushing , visual disturbances. b. Severe case: More marked visual & auditory disturbances., Vomiting ,Diarrhoea . 2. Haematological disturbances Haemolytic anaemia (in G6PD deficiency) Leucopenia, agranulocytosis ,thrombocytopenia 3. Hypersensitivity reactions: Skin rashes, urticaria, angioedema , bronchospasm

4. Black Water Fever: Rare, Serious. Hemolysis ,haemolytic anemia & Hemoglobinuria--- hypersensitivity reaction. 5.Hypoglycemia: 6. Abortion as it stimulates uterine contractions. 7. Thromophlebitis with I/V inj. 8. Severe hypotension/Cardiac arrhythmias 9. Drug interactions:

Al. containing antacids delay the absorption. It may decrease the renal clearance of Digoxin & warfarin --increased levels---- toxicity

Contraindications & cautions: Underlying visual & auditory disturbances Discontinue on severe Cinchonism. G6PD deficient patient. Cardiac abnormalities. C/I with Mefloquine. Dose reduction in renal insufficiency.

MEFLOQUINE
Synthetic 4-quinoline methanol Used for Chemoprophylaxis & Treatment of P falciparum malaria.

Primaquine

Synthetic 8-Aminoquinoline. Given orally 3 metabolites can produce hemolysis, specially in G-6 phosphate dehydrogenase deficiency. Tissue schizonticide against dorment hypnozoit liver forms of P vivax & P ovale. Gametocide for all 4 species. Exact MOA unknown.

Clinical uses of Primaquine

Radical cure of acute Vivax & Ovale Malaria.-- drug of choice provided G6PD status is normal. Terminal prophylaxis of Vivax & Ovale Gameticidal. To disrupt transmission , rendering P falciparum gametocytes non-infective for Malarial Parasites. Pneumocystis jiroveci infection with Clindamycin mild to moderate cases. Not recommended for routine chemoprophylaxis.

Adverse Effects GIT upsets Haemolytic anaemia & Methaemoglobinaemia (in G6PD deficiency) Rarely Leucopenia, agranulocytosis & Cardiac arrhythmias. Contra indications & cautions: NEVER given parenterally--- marked hypotension. Patients with myelosuppression. Pregnancy. G6PD status should be checked.

Atovaquone
Quinone Therapeutic uses: 1.For treatment & prophylaxis of resistant P. falciparum malaria in combination as Malarone: Atovaquone (250mg) & Proguanil. (100mg) 2. Alternate therapy for Pneumocystis jevorici infection.

Pyrimethamine & Proguanil

MOA:

Pyrimethamine is related to trimethoprim. Proguanil is biguanide derivative.

Antifolate drugs

They selectively inhibit plasmodial DHFR. Combination produces sequential blockade of steps in Folate synthesis.& synergistic effect Slow acting blood schizonticides. Proguanil has some activity against primary liver forms.

Pyrimethamine/ Proguanil

Therapeutic uses
Chemoprophylaxis:. Proguanil is safe in pregnancy, give Folic acid also. combinations preferred otherwise. Pyrimethamine & Dapsone ( Maloprim) is first line drug for prophylaxis of chloroquine / Mefloquine resistant malaria Treatment of chloroquine resistant P.falciparum Malaria. Combinations Pyrimethamine 25 mg & Sulfadoxine 500 mg ( Fansidar) Mefloquine , Pyrimethamine & Sulfadoxine (Fansimef) Artesunate in combination Sulfadoxime & Pyrimethamine. Atovaquone & Proguanil (Malarone) Pyrimethamine & Dapsone ( Maloprim)

Presumptive treatment of P falciparum in travelers. Toxoplasmosis: Pyrimethamine & Sulfadiazine , add folinic acid. High doses for immunocompromized patients. Pneumocystosis jiroveci : Trimethoprim & Sulfamethoxazole.

Adverse Effects
Both drugs can cause: Allergic reactions , GIT upsets, Headache. Proguanil: mouth ulcers & Alopecia. Pyrimethamine: in high doses (used in Toxoplasmosis)---Megaloblastic anaemia, atrophic glossitis Fansidar: With single dose A/E like sulfonamides. If used for chemoprophylaxis: severe cutaneous reactions (erythema multiforme) Steven Johnson Sydrome & toxic epidermal necrolysis. Maloprim: Aganulocytosis

ANTIBIOTICS
Doxycycline: For chemoprophylaxis of chloroquine / Mefloquine resistant malaria For treatment of P falciparum malaria with quinine/quinidine. Clindamycin: slow blood schizonticide used with quinine/quinidine if doxycycline is contraindicated. Azithromycin: under study for chemoprophylaxis.

Halofantrine & Lumefantrine

Halofantrine: is related to quinine. Effective against most chloroquine resistant P falciparum--- blood schizonticide Limited use because of cardiac conduction defects & it is Teratogenic. Lumefantrine: is related to halofantrine. Used in combination with artemether ---Coartem as first line drug for resistant Falciparum malaria. Not cardiotoxic.

1.

2.

Standard Regimens for Prophylaxis (start one week before travel & continue for 4 weeks after) Exception: (start 2days before travel for Doxycycline & Malarone & continue for 1 week after, for Malarone.) Chloroquine 500 mg weekly (Areas without resistant p falciparum) Mefloquine 250 mg weekly (Areas with chloroquine-resistant p falciparum)

3. Doxycycline 100 mg daily

(Areas with multidrug-resistant p falciparum) 4. Malarone 1 Tab daily (250 mg atovaquone/ 100mg proguanil daily) (Areas with chloroquine-resistant p falciparum) 5. Primaquine 15 mg base daily for 14 days after travel.(G6PD status should be determined.) for radical cure / terminal prophylaxis of p vivax and p ovale infections .

Combination therapy for Chloroquine Resistant Malaria

1. Artemether in combination with lumefantrine. (Coartem) 2.Artesunate in combination with Mefloquine / Amodiaquine(Coarsucam) / Sulfadoxime & Pyrimethamine. 3. Dihydroartemisinins with Piperaquine (Artikin) 4.Pyrimethamine & Sulfadoxine ( Fansidar) 5. Pyrimethamine & Dapsone ( Maloprim) 6. Mefloquine, Pyrimethamine & Sulfadoxine (Fansimef) 7. Amodiaquine with Sulfadoxine -Pyrimethamine 7. Atovaquone & Proguanil ( Malarone) 8. Quinine & Doxycycline 9. Quinine & Clindamycin . Treatment of complicated P falciparum malaria. I/V Artemether & Artesunate