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Anti-Malarial Drugs

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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 ofmonkeys, 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 seriouscomplications and deaths.

Drug resistance is an important therapeutic problem, mostnotably with P falciparum.

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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.

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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 therapydirected against erythrocytic parasites.

Eradication of both erythrocytic and hepatic parasites is

required to cure these infections.

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Anti-malarial Drugs may be selected for:-

Prevention of clinical attacks --- Chemoprophylaxis

Treatment of clinical attack Radical cure

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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-erythrocyticstage/ for Causal prophylaxis

. Proguanil

b. Drug effective against developing or dormant tissue forms/ for

Terminal prophylaxis or Radical cure. Primaquine

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2.Blood Schizonticides /Drug acting on Erythrocyticparasites/for Suppressive cure

a. Rapidly acting Blood schizonticides

Chloroquine

Amodiaquine Piperaquine

Quinine

Mefloquine

Halofantrine

Artemisinin (Qinghaosu) & its derivatives i.e. Artemether,Artesunate, dihydroartemisinin

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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.

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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, Pyrimethamine6. Sulfonamides: Sulfadoxine

7.Sulphone: Dapsone

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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)

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Chloroquine Most widely used anti-malarial, blood schizonticide

Source:Synthetic drug.

chemistry: 4-Aminoquinoline.

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Pharmacokinetics: Orally Chloroquine phosphate & I/M / I/V injectionChloroquine sulphate

Abs. well & almost complete from GIT. by Kaolin & antacidscontaining 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 boundspecially to melanin containing

tissues .

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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

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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 malarialparasites.

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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 intoharmlessm hemozoin by enzyme heam polymerase.

Chloroquine prevents biocrystallization of heme in toHemozoin ,by inhibiting HAEM POLYMERASE.

3. Increased pH & accumulation of toxic heme, producesoxidative damage to the membranes,leading to lysis of

both the Malarial Parasites & RBCs.

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Resistance to chloroquine

V. common in P falciparum

Uncommon but for P vivax.

In P falciparum, it has been correlated withmutations in a transporter, PfCRT.

There is decreased accumulation of drug in MP.

It can be reversed by verapamil, desipramine andchlorpheniramine , clinical value not established .

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Therapeutic uses

Acute attack of Malaria Chemoprophylaxis of Malaria

Hepatic amebiasis / abscess

Rheumatoid diseases i.e.

Systemic lupus erythematosis, Sjogren syndromeRheumatoid Arthritis

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Therapeutic uses1. 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 forradical cure.

Safe in pregnancy & young children.

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Tab. Chloroquine Phosphate orally.(tab 250 mg, Chloroquine base is 150 mg)Dose:4 tablets (1gm)statThen 2 tab(500mg) at 6 , 24 ,48 hrs.

orChloroquine Phosphate---1gm at 0& 24 hrs thenThen 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.

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3. Rheumatoid diseasesi.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.

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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 respondingto Metronidazole

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

absorbed in upper intestine.

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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.

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Other A/E are

Haemolysisin G6PD deficiency

Impaired Hearing , confusion

Psychosis , Seizures

Agranulocytosis

Exfoliative Dermatitis

Alopecia, Bleaching of Hair Hypotension

ECG Changes: QRS widening & T wave changes

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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 / phenylbutazonetherapy.

3. Large I/M or Rapid I/V administration:

Excessive hypotension.

Respiratory & cardiac arrest.

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Contraindications & PrecautionsC/I in

Psoariasis , Porphyriaacute 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 & Neurologicalexam. of patients on long term therapy should be done .

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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 prophylaxisincreased toxicity with long termuse

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Piperaquine

Chemically it is Bisquinoline.

Piperaquine was used for treatment of malaria rfom1970s-1980s in China, the use waned due to resistance.

Now it is combined with Dihydroartemisinins

Piperaquine & Dihydroartemisinins (Artikin)

first linetherapy for falciparum malaria , without apparentresistance .

It has longer half life28dso longer period of posttreatment prophylaxis than other combinations of

artemisinins.

A ti i i i ( Qi h ) & it D i ti

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Artimisinin( Qinghaosu) & its Derivatives

Artemisinin:It is Sesquiterpene lactone

endoperoxide, active compound of a Herbalmedicine 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.

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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 bindingMet :in liver Artesunate & Artemether metabolized to active

metabolite dihydroartimisinin.

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MOA:

Rapidly acting blood schizonticide against all four

species of MP.No effect on hepatic stages.

They act by producing free radicals due to ironcatalyzed cleavage of the artemisinin endoperoxide

bridge in the parasite food vacuoleor

Inhibition of a parasite calcium ATPase.

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Therapeutic Uses

1. Treatment of uncomplicated P falciparum malaria.

Combination is preferred as standard treatment :

Artemetherin combination with lumefantrine.

Artesunate in combination with Mefloquine / Amodiaquine /

Sulfadoxime & Pyrimethamine.Dihydroartemisininswith Piperaquine (Artikin)

2. Treatment of complicated P falciparum malaria.

I/V Artemether& Artesunate

I/V Artemether has efficacy like Quinine & I/V Artisunate iseven superior--- in clinical trials.

3. Not useful for prophylaxis short half life.

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Adverse Effects

Nausea, Vomiting, Diarrhea & dizziness.

Rare toxicities: Neutropenia, anemia, hemolysis, eevated liverenzymes & Allergic reactions.

Irreversible neurotoxicity in animals at high doses.

Teratogenic in animals.

However WHO has recommended use of I/V artisunate inpregnancy, for treatment of severe Falciparum malaria.

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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 fourspecies of human M. Parasites.Gameticidal: against p vivax and P ovale but not p falciparum.

Resistance: Common in some areas .It is increasing.

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Therapeutic Uses

1. Severe P.falciparum malaria (cerebral Malaria)Quinidine is preferred over Quinine, Parenterally

2. P.falciparum malaria resistant to Chloroquine, orallyQuinine sulfate in combination with Doxycycline/Clindamycin.

3. Prophylaxis of malariagenerally not used

4. Babesiosis--- with clindamycin for infection with Babesiamicroti

Severe or complicated infections with p falciparum:

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p p p

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 hrsevery 8 hrs

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Adverse Effects1.Cinchonism:---- Dose related

a. Mild cases:Tinnitis, headache , Nausea, Dizziness, Flushing , visualdisturbances.

b. Severe case: More marked visual & auditory disturbances.,Vomiting ,Diarrhoea .2. Haematological disturbancesHaemolytic anaemia (in G6PD deficiency)Leucopenia, agranulocytosis ,thrombocytopenia3. Hypersensitivity reactions:

Skin rashes, urticaria, angioedema , bronchospasm

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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

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MEFLOQUINE

Synthetic 4-quinoline methanol

Used for Chemoprophylaxis & Treatment of P falciparummalaria.

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Primaquine

Synthetic 8-Aminoquinoline.

Given orally

3 metabolites can produce hemolysis, specially in G-6phosphate dehydrogenase deficiency.

Tissue schizonticide against dorment hypnozoit liver forms

of P vivax & P ovale.

Gametocide for all 4 species.

Exact MOA unknown.

Cli i l f P i i

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Clinical uses of Primaquine

Radical cureof acute Vivax & Ovale Malaria.-- drug of choiceprovided G6PD status is normal.

Terminal prophylaxisof Vivax & Ovale

Gameticidal. To disrupt transmission , rendering P falciparumgametocytes non-infective for Malarial Parasites.

Pneumocystis jiroveci infectionwith Clindamycinmild tomoderate cases.

Not recommended for routine chemoprophylaxis.

Adverse Effects

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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.

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Atovaquone

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Atovaquone

Quinone

Therapeutic uses:

1.For treatment & prophylaxis of resistant P. falciparum malaria incombination as Malarone:

Atovaquone (250mg) & Proguanil. (100mg)

2. Alternate therapy for Pneumocystis jevorici infection.

Pyrimethamine & Proguanil

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Pyrimethamine & Proguanil

Pyrimethamine is related to trimethoprim.

Proguanil is biguanide derivative.

MOA:Antifolate drugsThey selectively inhibit plasmodial DHFR.Combination produces sequential blockade of steps in Folatesynthesis.& synergistic effectSlow acting blood schizonticides.Proguanil has some activity against primary liver forms.

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Pyrimethamine/Proguanil

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Therapeutic uses

Chemoprophylaxis:. Proguanil is safe in pregnancy, give Folic acidalso.combinations preferred otherwise.Pyrimethamine & Dapsone ( Maloprim) is first line drug forprophylaxis of chloroquine / Mefloquine resistant malaria

Treatment of chloroquine resistantP.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)

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Presumptive treatmentof P falciparum intravelers.

Toxoplasmosis: Pyrimethamine & Sulfadiazine ,add folinic acid.High doses for immunocompromized patients.

Pneumocystosis jiroveci :Trimethoprim & Sulfamethoxazole.

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Adverse Effects

Both drugscan cause:

Allergic reactions , GIT upsets, Headache.

Proguanil: mouth ulcers & Alopecia.

Pyrimethamine: in high doses (used in Toxoplasmosis)----

Megaloblastic anaemia, atrophic glossitisFansidar:

With single dose A/E like sulfonamides.

If used for chemoprophylaxis: severe cutaneous reactions(erythema multiforme) Steven Johnson Sydrome & toxic

epidermal necrolysis.

Maloprim: Aganulocytosis

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ANTIBIOTICS

Doxycycline:

For chemoprophylaxis of chloroquine / Mefloquineresistant malaria

For treatment of P falciparum malaria withquinine/quinidine.

Clindamycin:slow blood schizonticide used withquinine/quinidine if doxycycline is contraindicated.

Azithromycin:under study for chemoprophylaxis.

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Halofantrine & Lumefantrine

Halofantrine:is related to quinine.

Effective against most chloroquine resistant Pfalciparum--- blood schizonticide

Limited use because of cardiac conductiondefects& it is Teratogenic.

Lumefantrine: isrelated to halofantrine.

Used in combination with artemether ---Coartemas first line drug for resistant Falciparum malaria.

Not cardiotoxic.

St d d R i f P h l i ( t t

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Standard Regimens for Prophylaxis (start oneweek before travel & continue for 4 weeksafter)

Exception: (start 2days before travel forDoxycycline & Malarone & continue for 1 week after,for Malarone.)

1. Chloroquine500 mg weekly

(Areas without resistant p falciparum)2. Mefloquine250 mg weekly

(Areas with chloroquine-resistant p falciparum)

3. Doxycycline100 mg daily

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y y g y

(Areas with multidrug-resistant p falciparum)

4. Malarone 1 Tab daily (250 mg atovaquone/

100mg proguanil daily)(Areas with chloroquine-resistant p falciparum)

5. Primaquine15 mg base daily for 14 days aftertravel.(G6PD status should be determined.)

for radical cure / terminal prophylaxis of p vivaxand p ovale infections .

Combination therapy forChloroquine Resistant Malaria

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1. Artemetherin combination with lumefantrine. (Coartem)

2.Artesunate in combination with Mefloquine /

Amodiaquine(Coarsucam) / Sulfadoxime & Pyrimethamine.3.Dihydroartemisininswith Piperaquine (Artikin)4.Pyrimethamine & Sulfadoxine ( Fansidar)5. Pyrimethamine & Dapsone ( Maloprim)6. Mefloquine, Pyrimethamine & Sulfadoxine (Fansimef)

7. Amodiaquine with Sulfadoxine -Pyrimethamine7. Atovaquone & Proguanil ( Malarone)8. Quinine & Doxycycline9. Quinine & Clindamycin

. Treatment of complicated P falciparum malaria.

I/V Artemether& Artesunate

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