Antimalarial drugs - SAR (Structure Activity Relationship )

Antimalarial drugs

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Sir Ronald Ross

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Life cycle of the malarial parasite

Sporogeny (sexual)

Schizogony (asexual)

Man : Intermediate host Mosquito : Definitive host

True causal prophylactics

Causal prophylactics

Supressives

Gametocidal

Sporonticide

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• Classification of antimalarial drugs

– Therapeutic classification

– Chemical classification

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Therapeutic classification

• Causal prophylaxis: (Primary tissue schizonticides)

– Destroy parasite in liver cells and prevent invasion of erythrocytes

– Primaquine, proguanil

• Supressives Prophylaxis:

– Supress the erythrocytic phase and thus attack of malarial fever can be used as prophylactics

– Chloroquine, proguanil, mefloquine, doxycycline

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Therapeutic classification

• Clinical cure: erythrocytic schizonticides

– used to terminate an episode of malarial fever

• Fast acting high efficacy

– Chloroquine, quinine, mefloquine, atovaquone, artemisinin

• Slow acting low efficacy drugs

– Proguanil, pyrimethamine, sulfonamides, tetracyclines

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Therapeutic classification

• Radical curatives:

– Eradicate (destroy completely) all forms of P.vivax & P.ovale from the body

– Supressive drugs + hypnozoitocidal drugs

– For vivax: primaquine 15 mg daily for 14 days

• Gametocidal:

– Destroy gametocytes and prevent transmission

– Primaquine, artemisinin – against all plasmodia

– Chloroquine, quinine – Pl Vivax

– Proguanil ,pyrimethamine – prevent development of sporozoites

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Chemical classification

• 4 aminoquinolines: – Chloroquine, Hydroxychloroquine, Amodiaquine,

Pyronaridine

• 8 aminoquinolines: – Primaquine, Tafenoquine, Bulaquine

• Cinchona alkaloids: – Quinine, Quinidine

• Quinoline methanol: – Mefloquine

• Biguanides – Proguanil, Chlorproguanil

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Chemical classification

• Diaminopyrimidines – Pyrimethamine

• Sulfonamides – Sulfadoxine, dapsone

• Tetracyclines: – tetracycline, doxycycline

• Naphthoquinone: – Atovaquone

• Sesquiterpene lactones: – Artesunate, artemether, arteether

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• Chloroquine:

– Synthesized by Germans in 1934 ( resochin)

– d & l isomers, d isomer is less toxic

– Cl at position-7 give maximal antimalarial efficacy

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Hemoglobin Globin utilized by malarial parasite

Heme (highly toxic for malaria parasite)

Chloroquine

Quinine, (+) Heme Polymerase

mefloquine (-)

Hemozoin (Not toxic to plasmodium)

Mechanism of action

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Chloroquine

Hydroxychloroquine

Amodiaquine

Pyronaridine

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SAR of chloroquine

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Pharmacological actions 1. Antimalarial activity:

– High against erythrocytic forms of vivax, ovale, malariae & sensitive strains of falciparum

– Gametocytes of vivax

– No activity against tissue schizonts

– Resistance develops due to efflux mechanism

2. Other parasitic infections: – Giardiasis (infection of the intestine), taeniasis,

extrainstestinal amoebiasis

3. Other actions: – Depressant action on myocardium, direct relaxant

effect on vascular smooth muscles, antiinflammatory, antihistaminic , local anaesthetic

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Dosage

• 600 mg of base stat

• 300 mg base after 8 hours

• 150 mg of base BD for 2 days

• 200 mg oral tablet of chloroquine phosphate consists of 150 mg base

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Chloroquine is administered in loading dose in malaria

• Chloroquine is well absorbed after oral administration. It is extensively tissue bound and sequestrated by tissues particularly liver, spleen, kidney it has got large apparent volume of distribution

• So it is given in loading dose to rapidly achieve the effective plasma conc.

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Therapeutic uses

1. Hepatic amoebiasis:

2. Giardiasis

3. Clonorchis sinensis

4. Rheumatoid arthritis

5. Discoid Lupus Erythematosus

6. Control manifestation of lepra reaction

7. Infectious mononucleosis

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• Hydroxychloroquine:

– Less toxic, properties &uses similar

• Amodiaquine:

– As effective as chloroquine

– Pharmacological actions similar

– Chloroquine resistant strains may be effective

– Adverse events: GIT, headache , photosensitivity, rarely agranulocytosis

– Not recommended for prophylaxis

• Pyronaridine: effective in resistant cases

Pyronaridine

Hydroxychloroquine

Amodiaquine

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Quinine

• 1820 Pelletier & caventou isolated quinine from cinchona bark.

• Mechanism of action:

– Similar to chloroquine

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Pharmacological actions

1. Antimalarial action: – Erythrocytic forms of all malarial parasites including

resistant falciparum strains .

– Gametocidal for vivax & malariae

2. Local irritant effect: – Local pain sterile abcess.

3. Cardiovascular:

– depresses myocardium, ↓ excitability, ↓ conductivity, ↑ refractory period, profound hypotension IV.

4. Miscellaneous actions:

– Mild analgesic, antipyretic activity , stimulation of uterine smooth muscle, curare mimitic effect

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Adverse drug reactions

Cinchonism:

• Tinnitus (ringing in the ears), nausea & vomiting

• Headache mental confusion, vertigo, difficulty in hearing & visual disturbances

• Diarrhoea , flushing & marked perspiration

• Still higher doses , exagerated symptoms with delirium , fever, tachypnoea, respiratory depression , cyanosis.

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Adverse drug reactions

• Idiosyncrasy : similar to cinchonism but occurs in therapeutic doses

• Cardiovascular toxicity: cardiac arrest, hypotension ,fatal arrhytmias

• Black water fever:

• Hypoglycemia:

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Uses

• Malaria:

– uncomplicated resistant falciparum malaria

– Cerebral malarial

• Myotonia congenita: 300 to 600 mg BD/ TDS

• Nocturnal muscle cramps: 200 – 300 mg before sleeping

• Spermicidal in vaginal creams

• Varicose veins: along with urethane causes thrombosis & fibrosis of varicose vein mass

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8-aminoquinolines

• Drugs in this group have amino group at position 8 of quinoline ring

• Important members of this

family include

1 Pamaquine

2 Primaquine, etc.

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• Such drugs have OCH3 group at position 6

• This molecule has

antimalarial activity but

when side chain

is introduced at amino

group antimalarial activity is

intensified e.g

pamaquine

• It causes hemolysis

of RBCs Diethyl amino pentyl side chain

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Pamaquine

• It contains tertiary amino group and when it is converted into primary amino group the compound is called primaquine, which is

– Less toxic

–Well tolerated

– It is the most commonly used agent in this group in the treatment of malaria

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Primaquine

• OCH3 is not necessary for antimalarial activity but when replaced by OC2H5 the compound became – less active

– Toxic in nature

• OCH3 when replaced by CH3 the compound become inactive

• Introduction of halogens increases toxicity

• Presence of quinoline ring is necessary for antimalarial activity. When pyridine ring is converted to piperidine (saturated) the compound became inactive

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• Pentyl side chain gives maximum activity, increase or decrease of chain result is reduction of activity.

• The branched side chain when converted into straight chain pentaquine is obtained

• It has less antimalarial activity as compared to both pamaquine and primaquine

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Chemical synthesis (pamaquine)

• Glycerol undergoes dehydration to produce propene aldehyde

• Dehydrating agent is sulphuric acid

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• Addition reaction of propene aldehyde and 4 methoxy 2-nitro aniline to form 4 methoxy 2- nitro propene aldehyde

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• Tautomerization: 4 methoxy 2-nitro propene aldehyde (keto form) converted in enol form

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• Enol form undergoes cyclization to form 8 nitro 6 methoxy dihydroquinoline which then oxidized to form 8 nitro 6 methoxy quinoline

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• 6-methoxy 8 nitro quinoline undergoes reduction to form 8 amino 6 methoxy quinoline

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• 8- amino 6 methoxy quinoline reacts with 2 chloro diethyl amino pentane to form pamaquine

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Therapeutic uses

• Active against hepatic stage of plasmodium

• Provide radical cure hepatic stage of P. vivax and P. ovale

• It also acts at gametocytes, hence used as prophylactic drugs

• Used in combination with chloroquine for complete eradication of malaria

• Side effect: hemolysis in G6 phosphate dehydrogenase deficient people

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• Primaquine: – Mechanism of action:

– Interferes with oxygen transport system

Primaquine

Converted to electrophiles

Generates reactive oxygen species

Oxidative damage to the cell

The exact mechanism of action is not fully understood 55

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Antimalarial action

• Liver hypnozoites

• Weak action against erythrocytic stage of vivax, so used with supressives in radical cure

• No action against erythrocytic stage of falciparum

• Has gametocidal action and is most effective antimalarial to prevent transmission disease against all 4 species

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Adverse effects

• Gastrointestinal: – epigastric distress,

abdominal cramps ,

• Hemopoetic: – mild anemia,

methaemoglobinemia, cyanosis, hemolytic anemia in G6PD deficiency

• Avoided during pregnancy, G6PD deficient

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Uses

• Primary use is radical cure of relapsing malaria 15 mg daily for 14 days with dose of chloroquine

• Falciparum malaria 45 mg of single dose with chloroquine curative dose to kill gametes & cut down transmission of malaria.

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• Tafenoquine:

– More active slowly metabolized analog of primaquine, has advantage that it can be given on weekly basis.

• Bulaquine:

– Congener of primaquine developed in india

– Comparable antirelapse activity when used for 5 days

– Partly metabolized to primaquine

– Better tolerated in G6PD deficiency

Tafenoquine Bulaquine

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Mefloquine

• Quinoline methanol derivative developed to deal with chloroquine resistant malaria

• Rapidly acting erythrocytic schizonticide , slower than chloroquine & quinine

• Effective against chloroquine sensitive & resistant plasmodia

• Mechanism of action similar to chloroquine

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Pharmacokinetics

• Good but slow oral absorption

• High protein binding

• Concentrated in liver, lung, intestine

• Extensive metabolism in liver, primarily secreted in bile , under goes enterohepatic circulation

• Long t1/2 = 2 – 3 weeks

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Adverse events • GIT:

– bitter in taste, nausea, vomiting , abdominal pain , diarrhoea

• Neuropsychiatric disturbances: – anxiety, hallucinations, sleep disturbances, psychosis,

errors in operating machinery, convulsions

• CVS: – Bradycardia, sinus arhythmia, & QT prolongation

• Teratogenicity: – Avoided in first trimester

• Miscellaneous: – allergic skin reactions, hepatitis & blood dyscrasias

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Uses • Effective drug for MDR falciparum

1. T/t of uncomplicated falciparum in MDR malaria should be used along with artesunate (ACT)

2. Prophylaxis in MDR areas 250 mg per week started 2- 3 weeks before to asses side effects

• Due to fear of development of drug resistance mefloquine should not be used as drug for prophylaxis in residents of endemic area

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Halofantrine

• Quinoline methanol

• Used in chloroquine resistant malaria since 1980

• Erratic bioavailabilty, lethal cardiotoxicity & cross resistance to mefloquine limited its use

• Now a days used only when no other alternative available

• Adverse events; Nausea, vomiting, QT prolongation , diarrhoea, itching , rashes

• C/I: along with quinine, chloroquine, antidepressants, antipsychotics.

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Atovaquone

• Synthetic Hydroxy-napthoquinone

• Rapidly acting erythrocytic schizonticide for plasmodium falciparum & other plasmodia

• MOA: Collapses mitochondrial membrane & interferes ATP production

• Proguanil potentiates action of atovaquone and prevents development of resistance

• Also used in P. Jivoreci & Toxoplasma gondii iAtovaquonenfections

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Atovaquone

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Dihydrofolate reductase inhibitors

• Proguanil : – Biguanide converted to cycloguanil active

compound

– Act slowly on erythrocytic stage of vivax & falciparum

– Prevents development of gametes

Adverse effects: Stomatitis, mouth ulcers, larger doses depression

of myocardium , megaloblastic anemia

Not a drug for acute attack

Causal prophylaxis: 100 – 200 mg daily 72

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Pyrimethamine

• Diaminopyrimidine more potent than proguanil & effective against erythrocytic forms of all species.

• Tasteless so suitable for children

Adverse events: megaloblastic anemia, thrombocytopenia, agranulocytosis.

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Sulfadoxine-pyrimethamine

• Sequential blockade

• sulfadoxine 500 mg + pyrimethamine 25 mg, 3 tablets once for acute attack

• Not recommended for prophylaxis

• Use:

– single dose treatment of uncomplicated chloroquine resistant falciparum malaria

– patients intolerant to chloroquine

– First choice treatment for toxoplasmosis

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Artemisinin

• Artemisinin is the active principle of the plant artimisia annua

• Sesquiterpine lactone derivative

• Most potent and rapid acting blood schizonticides

• Short duration of action

• high recrudescence rate

• Poorly soluble in water & oil

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Artemisinin derivatives

• Artesunate

• Artemether

• Arteether

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PLANT- ARTEMISIA ANNUA

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Mechanism of action • These compounds have presence of endoperoxide

bridge

• Endoperoxide bridge interacts with heme in parasite

• Heme iron cleaves this endoperoxide bridge

• There is generation of highly reactive free radicals which damage parasite membrane by covalently binding to membrane proteins

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Antimalarial action

Artemisinin

Artemisinin

Conventional Treatment

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Artesunate • Water soluble ester of dihydroartemisinin

• Dose: can be given oral, IM,IV, rectal

– Oral

• 100 mg BD on day 1

• 50 mg BD day 2 to day 5

– Parenteral

• 120 mg on day 1 (2.4 mg/kg BD )

• 60 mg OD ( 2.4 mg/kg) for 7 days

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The mechanisms of action of artesunate remains unclear and debatable.

Artesunate is a prodrug that is rapidly converted to its active form dihydroartemisinin (DHA).

This process involves hydrolysis of the 4-carbon ester group via plasma esterase enzyme.

It is hypothesized that the cleavage of endoperoxide bridge in the pharmacophore of DHA generates reactive oxygen species (ROS), which increases oxidative stress and causes malarial protein damage via alkylation.

In addition, Artesunate potently inhibits the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase. As a result, the amount of glutathione in the parasite is reduced.

In 2016, artemisinin has been shown to bind to a large number targets, suggesting that it acts in a promiscuous manner. There is evidence suggesting DHA inhibition of calcium-dependent ATPase on endoplasmic membrane, which disrupts protein folding of parasites. 84

MOA

Artemether • Methyl ether of dihydroartemisinin

• Dose: Oral & IM

• 80 mg BD on day 1 (3.2 mg/kg)

• 80 mg OD (1.6 mg/kg) for 7 days

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MOA

• Artemether is an artemisinin derivative and the mechanism of action for artemisinins is unknown

• One of the proposed mechanisms is that through inhibiting anti-oxidant and metabolic enzymes, artemistinin derivatives inflict oxidative and metabolic stress on the cell.

• Some pathways affected may concern glutathione and glucose metabolism. As a consequence, lesions and reduced growth of the parasite may result

• Another possible mechanism of action suggests that arteristinin drugs exert their cidal action through inhibiting PfATP6. Since PfATP6 is an enzyme regulating cellular calcium concentration, its malfunctioning will lead to intracellular calcium accumulation, which in turns causes cell death

Arteether

• Ethyl ether of dihydroartemisinin

• Therapeutically equivalent to quinine in cerebral malaria

• A longer t1/2 & more lipophilic than artemether favouring

accumulation in brain

• Dose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily for next 4 days

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Arteether Artemisinin

Adverse events • Leucopenia

• Hypersensitivity: Drug fever, itching

• GIT: nausea, vomiting, abdominal pain (common)

• ECG changes: ST-T changes, QT prolongation

• Abnormal bleeding, dark urine

• Reticulocytopenia

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Artemisinin based combination therapy (ACT)

• Artemisinin compunds are shorter acting drugs

• Monotherapy needs to be extended beyond disappearance of parasite to prevent recrudescence

• This can be prevented by combining 3-5 day regimen of artemisin compounds with one long acting drug like mefloquine 15 mg/kg single dose

• Indicated by WHO in acute uncomplicated resistant falciparum malaria

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Why combination therapy

• Rapid clinical & parasitological cure

• High cure rates and low relapse rates

• Absence of resistance

• Good tolerability profile

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ACT Regimens in use

• Artesunate – Sulfadoxine, pyrimethamine:

– Adopted as first line in india under NMP

– ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets

• Artesunate Mefloquine:

– By combining artesunate further spread of mefloquine resistance can be prevented

– Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second day & 500 mg on third day

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Artemether & Lumefantrine • Lumefantrine is highly effective , long acting oral erythrocytic schizonticide

related to mefloquine

• Highly lipophilic onset delayed , peak 6 hrs

• Lumefantrine has a much longer half-life compared to artemether

• Available as fixed dose combination

• 80 mg artemether BD WITH 480 mg lumefantrine BD for 3 days

Other ACTs:

– DHA – Piperaquine, Artesunate- pyronaridine

91 Lumefantrine Artemether The term "co-artemether" is sometimes used

to describe this combination

Tetracyclines

• Slow but potent action on erythrocytic stage of all MP & Pre-erythrocytic stage of falciparum

• Always used in combination with quinine or S-P for treatment of chloroquine resistant malaria

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Management of Malaria

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Prophylaxis of malaria

• Indication:

• Duration :1-2 weeks before to 4 weeks after returning from endemic area

• Drug regimens:

– Chloroquine sensitive malaria: 300 mg / week

– Chloroquine resistant malaria:

• Mefloquine 250 mg once a week ,

• Doxycycline 100 mg daily ,

• Atovaquone + proguanil daily

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Drugs not allowed for prophylaxis

• Quinine , artemisinin compounds

– Shorter acting, higher toxicity

• Pyrimethamine sulfadoxine

• Amodiaquine

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• Tab. Chloroquine phosphate 250 mg – Contains 150 mg of base

– Give 4 tablets stat , 2 tablets after 8 hours and , 1 tablet BD for 2 days

• Patients who cannot take orally – 3.5 mg/kg IM every 6 hrs for 3 days

• Tab primaquine 15 mg OD for 14 days in Plasmodium vivax, ovale

• Primaqine 45 mg single dose for falciparum after chloroquine (gametocidal)

Acute attack of chloroquine sensitive malaria:

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Acute attack of chloroquine resistant malaria

A. Pts who can take orally: – 3 tablets of (Pyrimethamine + sulfadoxine) single

dose followed by quinine 600 mg TDS for 2 days or

– Tab Quinine 600 mg TDS X 3 days with Cap doxycycline 100 mg BD for 7 days or

– Quinine 3 days with mefloquine or

– (Atovaquone 250 mg + proguanil 100 mg) 4 tab(Single dose ) for 3 days or

– artesunate 100 mg BD x 3 days with Sulfadoxine-pyrimethamine or mefloquine

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• Pts who cannot take orally

– Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline over 4 hrs then

– 10 mg/kg in dextrose saline over 2 hrs every 8 hrly till patient is able to swallow

– Then quinine 600 mg TDS for 7 days & tetracycline/ doxycycline

Or

– artemether / arteether injection

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When should resistance be suspected

• All pts with complication

• Any pt who has already received chloroquine last 1 month

• Hb continues to fall in absence of bleeding & asexual forms persist along with symptoms after 48 hrs of treatment

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Severe and complicated falciparum malaria

• Hyperparasitaemia • Hyperpyrexia • Fluid electrolyte disturbances, acidosis • Hypoglycemia • Cardiovascular collapse • Jaundice, severe anaemia • Spontaneous bleeding • Pulmonary edema • Renal failure • Hemoglobinuria, black water fever • Cerebral malaria

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Treatment of severe and complicated falciparum malaria

• Artesunate 2.4 mg/kg IV/IM, BD on day1 then 2.4 mg/kg daily for 7 days OR

• Artemether 3.2 mg/kg IM on day 1 then 1.6 mg/kg daily for 7 days OR

• Arteether 3.2 mg/kg IM on day1, followed by 1.6 mg/kg daily for next 4 days

– Switchover to 3 Day oral ACT in between whenever patient can take oral medication

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OR

• Quinine: 20 mg quinine salt/kg on admission (i.v. infusion in 5% dextrose/dextrose saline over a period of 4 hours) followed by maintenance dose of 10 mg/kg body weight 8 hourly.

– When ever patient can swallow orally switch over to oral quinine 10 mg/kg 8 hrly and complete 7 days course

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• Malaria in children:

– Quinine parenteral high toxicity / oral well tolerated

– Primaquine avoided in neonates

– Mefloquine not used in children below 15 kg weight

• Acute malaria in pregnant women

– Chloroqune in usual doses

– Mefloquine C/I in first trimester

– Primaquine/ tetracycline avoided

– Anemia: folic acid & iron

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Practice points

• Most antimalarials are bitter in taste give along with milk or fruit juice

• If vomiting occurs within hour of drug repeat full dose, in case of mefloquine repeat half dose

• If vomiting after 1 hour no need to repeat

• Postural hypotension : quinine, chloroquine

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Drugs used in chloroquine resistant malaria

• Mefloquine

• Quinine

• Sulfadoxine pyrimethamine

• Artemisinin compounds

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