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Antimalarials :

Antimalarials Dr.S.P.Dhanya


Species Malaria is cause by species of protozoa: Plasmodium malariae . P. falciparum . P. vivax . P. ovale (rare ). P knowlesi The plasmodium transmitted to human by the bite of an infected female anopheles mosquito.

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Exo- erythrocytic (hepatic) cycle Sporozoites Mosquito Salivary Gland Malaria Life Cycle Life Cycle Gametocytes Oocyst Erythrocytic Cycle Zygote Schizogony Sporogony Hypnozoites (for P. vivax and P. ovale ) Adopted slide

Objectives and Use of Antimalarials:

Objectives and Use of Antimalarials Prevent and treat clinical attack Complete eradication from patient’s body Reduce human reservoir -cut down transmission

Types of treatment:

Types of treatment Causal prophylaxis - target - pre erythrocytic phase Suppressive prophylaxis -Suppress the erythrocytic phase and thus attacks of malarial fever Clinical cure -terminate an episode of malarial fever Radical cure -attack the exo erythrocytic stage Gametocidal -elimination of male & female gametes

Classification -Site of action:

Classification -Site of action Tissue /Hepatic Schizonticides Pre-erythrocytic stage / Causal prophylaxis PROGUANIL Exo-erythrocytic stage/Terminal prophylaxis or Radical cure PRIMAQUINE

Blood/Erythrocytic Schizonticides :


Slower acting:



Gametocides Kill gametocytes PRIMAQUINE --- P Falciparum CHLOROQUINE, QUININE --- P Vivax , P Ovale .


Sporonticidal Make gametocytes ineffective within mosquito PYRIMETHAMINE PROGUANIL


Combinations Pyrimethamine & Sulfadoxine -Fansidar Mefloquine , Pyrimethamine & Sulfadoxine- Fansimef Atovaquone & Proguanil -Malarone Amodiaquine & Artisunate -Coarsucam Amodiaquine , Sulfadoxine -Pyrimethamine Piperaquine & Dihydroartemisinins -Artekin Pyrimethamine & Dapsone -Maloprim


Chloroquine 4 aminoquinoline Rapidly acting Erythrocytic schizonticide All species of plasmodia Control clinical attacks in 1-2 days Parasite disappears in 1-3 days

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Resistance Slow in Vivax species-recrudescences Falciparum species-widespread,R1 grade Decreased ability of parasite to accumulate chloroquine-Pf mdr1 gene

Other actions:

Other actions Effective against E.histolytica,G.lamblia Antiinflammatory Local irritant Local anaesthetic Weak smooth muscle relaxant antihistaminic


Pharmacokinetics Oral absorption excellent High affinity for melanin and chromatin Conc in liver spleen kidney,lungs,skin,leucocytes Large Volume of distribution Selective accumulation in retina-toxicity Partly metabolized in liver Excreted in urine T ½ =3-10 days, terminal t ½=1-2 months

Adverse Effects:

Adverse Effects Oral dose Pruritis (primarily in Africans)sometimes with Urticaria. Nausea, vomiting ,Abdominal Pain, Anorexia. Headache. Blurring of vision.

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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

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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. Large I/M or Rapid I/V administration: Excessive hypotension. Respiratory & cardiac arrest.

Contraindications & Precautions :

Contraindications & Precautions Contraindications 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 .

Use during pregnancy:

Use during pregnancy Can be used


Preparations Tablet-CQP-250 mg=150 mg base IV –HCl salt-250mg=200mg base


Uses Clinical cure and suppressive prophylaxis Extraintestinal amoebiasis Rheumatoid arthritis DLE Sjogren syndrome Lepra reactions Photogenic reactions IMN


Amodiaquine Bitter Faster acting For clinical attacks For CQ resistant malaria-as combination Agranulocytosis,Toxic hepatitis,aplastic anemia


Piperaquine Combined with Dihydroartemisinins- Artekin- first line therapy for falciparum malaria , without apparent resistance . longer t ½ —28d– longer period of post treatment prophylaxis Good safety profile and tolerability Dizziness, vomiting, GI symptoms


Mefloquine Fast acting erythrocytic schizonticide Effective against CQ sensitive and resistant pl Good oral absorption Conc in many organs, t ½=2-3 weeks Enterohepatic circulation Appears to be safe in pregnancy-avoid 1 st trimester Cross resistance with quinine & halofantrine

Adverse Effects:

Adverse Effects Bitter GI symptoms Neuropsychiatric reactions Sinus bradycardia QTc lengthening,cardiac arrest when Halofantrine/Quinidine/Quinine is given


Use Multiresistant P.falciparum Combination-Artesunate+Mefloquine-AS-MQ Prophylaxis –travellers to areas of MDR-250 mg per week 2-3 weeks before


Mepacrine Toxic Less effective Obsolete Giardiasis,tapeworm


Quinine Levo rotatory alkaloid d isomer quinidine Erythrocytic schizonticide,vivax gametes Less effective and toxic but pl still sensitive Sporadic quinine resistance in India Partial cross resistance with MQ Mechanism similar to CQ


Pharmacokinetics Rapid and complete absorption 70% bound to plasma proteins CYP3A4 metabolism t ½=10-12 hrs

Adverse Effects:

Adverse Effects Cinchonism-ringing in the ears, Nausea,vomiting-GI and CTZ Headache,mental confusion,vertigo,difficulty in hearing,visual defects-neurotoxicity,constriction of retinal and auditory vessels Diarrhoea,flushing,perspiration

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Delirium,fever,tachypnoea,weakness,prostration Purpura,rashes,itching,angioedema, bronchoconstriction Hemolysis ,abortion in pregnant women Hypoglycemia Hemoglobinuria-black water fever(Falciparum malaria) Renal damage Thrombophlebitis


Uses Uncomplicated resistant falciparum malaria Quinine+Doxycycline-2 nd line Alternative to S/P-ACT Complicated and severe malaria incl cerebral Quinine IV-DOC Hypoglycemia- hyperinsulinemia Now some experts prefer artemisinins-fast,better tolerated,more effective,convinient

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Nocturnal muscle cramps Myotonia congenita Provocative diagnosis of myasthenia-dangerous Varicose veins-along with urethane Babesiosis with clindamycin

Contraindications & cautions: :

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

Pyrimethamine & Proguanil:

Pyrimethamine & Proguanil Pyrimethamine ----related to trimethoprim . Proguanil ------ biguanide derivative. Slow acting blood schizonticides . Proguanil has some activity against primary liver forms. MOA: Antifolate drugs S electively inhibit plasmodial DHFR Combination-sequential blockade & synergistic effect

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Pyrimethamine Proguanil


USES Chemoprophylaxis: Proguanil safe in pregnancy, give Folic acid Treatment of chloroquine resistant P.falciparum Malaria. Combinations Pyrimethamine & Dapsone-1 st line Pyrimethamine 25 mg & Sulfadoxine 500 mg ( Fansidar) Mefloquine , Pyrimethamine & Sulfadoxine (Fansimef) Artesunate in combination Sulfadoxime & Pyrimethamine. Atovaquone & Proguanil (Malarone)

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Presumptive treatment of P falciparum in travellers. Toxoplasmosis: Pyrimethamine & Sulfadiazine add folinic acid. High doses for immunocompromized patients.

Adverse Effects:

Adverse Effects Allergic reactions , GIT upsets, Headache. Proguanil: mouth ulcers & Alopecia. Pyrimethamine ---- Megaloblastic anaemia, atrophic glossitis,granulocytopenia Fansidar: severe cutaneous reactions (erythema multiforme) Steven Johnson Sydrome & toxic epidermal necrolysis. Maloprim : Aganulocytosis


Primaquine 8-Aminoquinoline. Tissue schizonticide -against 1 and 2 tissue phases dormant hypnozoite liver forms of P vivax & P ovale. Gametocide for all 4 species. Given orally 3 metabolites can produce hemolysis, specially in G-6 phosphate –dehydrogenase deficiency. Exact MOA unknown .


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

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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.


Artemisinin Sesquiterpene lactone Artemisia annua-Quinghaosu Potent rapid short acting blood schizonticide & Falciparum gametes Quick defervescence and parasitaemia clearance(<48h) Action on wide range of stages Ring form to early schizonts Poorly soluble in water and oil

Pharmacokinetics :

Pharmacokinetics Absorption------complete from GIT t ½------------------------- 1-3 hrs Distribution------Rapid & wide Metabolised -----liver Artesunate & Artemether--------prodrugs metabolized to active metabolite dihydroartemisinin.


Derivatives Arteether : developed in India-I/M Artesunate :Water soluble, useful for oral I/V , I/M & rectal administration. Artemether :Lipid soluble, useful for oral I/M & rectal administration . Dihydroartemisinin : Water soluble, useful for oral administration

t 1/2:

t 1/2 Artemisinin-1-3 h Dihydroartemisinin-2-4 h Artesunate-30-60 min Artemether-3-10h Arteether-23 h

Short duration of action:

Short duration of action Cannot be used alone Recrudescence high when used alone Monotherapy - extended beyond the disappearance of parasite - prevent recrudescence After 5 days-10% After 3 days-50%

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Artemisinin has endoperoxide bridge Interacts with haeme in the parasite Cleavage of bridge Release of highly reactive free radicals Lipid peroxidation , damages ER Inhibits protein synthesis Lysis of parasite

Adverse effects:

Adverse effects Nausea, vomiting,abdominal pain Itching,drug fever Abnormal bleeding,dark urine S-T segment changes,QT prolongation First degree AV block Reticulopenia,leucopenia

Therapeutic Uses:

Therapeutic Uses -always used as ACT -Uncomplicated P falciparum malaria. -Complicated P falciparum malaria. -Not useful for prophylaxis-irrational short duration of action better and cheaper drugs available

Uncomplicated P falciparum malaria :

Uncomplicated P falciparum malaria Oral 100% effective High recrudescence Only as combination Gametocidal action cuts transmission & spread of resistant P.falciparum

Complicated P falciparum malaria:

Complicated P falciparum malaria Parenteral Advantages of IV Artesunate over IV quinine Faster parasitemia clearance Safe and better tolerated Simpler dosing schedule Higher efficacy Lower mortality

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Doxycycline: For chemoprophylaxis of chloroquine / Mefloquine resistant malaria For treatment of P falciparum malaria with quinine/quinidine.

Atovaquone: :

Atovaquone: Unknown mechanism of action. Used alone for treatment of pneumocytosis and toxoplasmosis in patients with AIDS. Atovaquone + proguanil (malarone) for treatment & prophylaxis of chloroquine-resistant P. falciparum . A/E : fever, rashes, cough, nausea, vomiting, diarrhea, headache & insomnia.


Halofantrine Unknown mechanism of action. Used only by oral route in P. falciparum resistant to CQ as well as P.vivax No parenteral preparation. t-1/2 =1 day,active metabolite- 3 days Prolongation of QTc , ventricular arrhythmia,abdominal pain,diarrhoea Teratogenic

Lumefantrine :

Lumefantrine Orally active, high efficacy,long acting erythrocytic schizonticide Used in combination with artemether ---Coartem as first line drug for resistant Falciparum malaria. Not cardiotoxic.

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Act in food vacoule Inhibit haeme polymerization Heme-drug complex destroys membranes Inhibits nucleic acid & protein synthesis Lysis of parasite


Pharmacokinetics Highly lipophilic Absorption after 2 h of ingestion Peak 6-8 h PPB-99% Metabolized by CYP3A4 t ½=2-3 days----upto 4-6 dyas in nalaria patients

Artemisinin based combination therapy:

Artemisinin based combination therapy Single drugs failed to curtail prevalence globally MDR P.falciparum only ACT Combine artemisinin compounds with another effective erythrocytic schizonticide

Choice of companion drug:

Choice of companion drug Elimination t ½=governing conc in body Effective conc in blood –atleast 3 asexual cycles---6 days Short t ½ -7 days, Long t ½-3 days Defacto monotherpy Artemisinin rapidly and drastically kill > 95%, leave only small biomass to be eliminated by long t ½ drugs


Advantages Rapid clinical and parasitological cure High cure and low recrudescence Absence of parasite resistance Good tolerability profile

Artesunate-Sulfadoxine+Pyrimethamine(AS/S/P) :

Artesunate-Sulfadoxine+Pyrimethamine(AS/S/P) First line drug in CQ resistant areas Oral Not effective Against MDR strains nonresponsive to S/P


Artesunate-Mefloquine(AS/MQ) Highly effective Well tolerated Now first line in SE Asia Prevents spread of MQ resistance


Artemether-Lumefantrine Only ACT available as FDC 2 components protect each other from plasmodial resistance Clinical efficay is high>95% Active in MDR areas incl.MQ resistance Artemether-quickly reduce parasite biomass and resolves symptoms Lumefantrine-prevents recrudescence Gametocides are rapidly killed

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Administered with fatty food/milk Well tolerated Headache,dizziness,abdominal pain,arthralgia,pruritus,rash Don’t combine with drugs metabolized by CYP2D6-metoprolol,TCA/ drugs prolonging QTc Not given in first trimester and breast feeding


DHA-Piperaquine(Artekin) 1:8 dose Good safety and tolerability Undergoing trials DHA 120 mg+Piperaquine 960mg x 3 days


Artesunate-Pyronaridine Phase III clinical trial 1:3 Abdominal pain, vomiting,headache,palpitation,loss of appetite Artesunate 100-200mg+Pyronaridine-300-600mg


Artesunate-Amodiaquine(AS/AQ) AS 200mg+AQ 600 mg Arterolane –Piperaquine Artesunate-Lapdap(choroproguanil+Dapsone)

Treatment of malaria:

Treatment of malaria

Causal Prophylaxis:

Causal Prophylaxis Proguanil

Suppressive prophylaxis:

Suppressive prophylaxis Travellers CQ6oomg(4 tablets) 1 week before travel CQ300 mg(2 tablets) weekly Continue for 1 month Last dose-CQ600mg followed by 300 mg after 8 hand then 300mg for next 2 days+ PQ 15 mg X 14 days


Other Proguanil 200mg daily with CQ 300mg weekly MQ 250mg wkly till 4 wks after return Doxycycline 100 mg daily starting before travel till 4 weeks after return

Clinical presentation:

Clinical presentation Early symptoms Headache Malaise Fatigue Nausea Muscular pains Slight diarrhea Slight fever, usually not intermittent Could mistake for influenza or gastrointestinal infection

Clinical presentation:

Clinical presentation Acute febrile illness, may have periodic febrile paroxysms every 48 – 72 hours with Afebrile asymptomatic intervals Tendency to recrudesce or relapse over months to years Anemia, thrombocytopenia, jaundice, hepatosplenomegaly , respiratory distress syndrome, renal dysfunction, hypoglycemia, mental status changes, tropical splenomegaly syndrome

Malarial Paroxysm:

Malarial Paroxysm Can get prodrome 2-3 days before Malaise, fever,fatigue , muscle pains, nausea, anorexia Slight fever may worsen just prior to paroxysm Paroxysm Cold stage - rigors Hot stage – Max temp can reach 40-41 o C, splenomegaly easily palpable Sweating stage Lasts 8-12 hours, start between midnight and midday

Malarial Paroxysm:

Malarial Paroxysm Periodicity Days 1 and 3 for P.v . , P.o . , (and P.f .) - tertian Usually persistent fever or daily paroxyms for P.f . Days 1 and 4 for P.m. - quartan

Uncomplicated malaria:

Uncomplicated malaria Vivax CQ 600mg day 1 600mg day 2 300mg day 3 PQ-15 mg x 14 days CQ resistance Quinine 600mgx 7 days+Doxy 100mg x 7 days+PQ 15 mgX 14 days

CQ resistant falciparum malaria:

CQ resistant falciparum malaria Artesunate 100 mg BD x 3 +S 1500 mg+ P 75 mg AS 100mg BD x 3+MQ 750 mg on 2 nd +500mg on 3 rd day Artemether 80 mg+ Lumefantrine 480 mg BDx 3 days Quinine 600 mg 8 hX 7 days+ Doxy 100 mg x 7 d

P. Falciparum-cerebral malaria:A symmetric encephalopathy :

P. Falciparum-cerebral malaria:A symmetric encephalopathy headache, vomiting, diplopia disoriented, confused or behaving abnormally then always think MALARIA. relatives may say---- he is always sleepy and had a few convulsions. On examination, varying levels of consciousness may be noted with divergent or convergent eyes, release of primitive reflexes, hyper/ hyporeflexia , hyper/ hypotonia , extensor/flexor plantars and absent abdominals- cremasterics . Signs of meningeal irritation may also be elicited .

As the disease progresses:

As the disease progresses Becomes more drowsy and breathless - ALI and ARDS . O 2 concentration starts to drop and respiratory alkalosis sets in. Eventually he may be started on mechanical ventillation . The kidneys start to fail and urine output lessens signifying acute renal failure. Shock,hypoglycemia , lactic acidosis and DIC complete the picture of MOSF.

Severe and complicated:

Severe and complicated Artesunate 2.4 mg/kg iv/im followed by 2.4 mg/kg after 12 and 24 h and then once daily for 7 days Artemether 3.2 mg/kg im on 1 st day followed by 1.6 mg/kg for 7 days Arteether 3.2 mg/kg im on 1 st day followed by 1.6 mg/kg for 4 days Quinine-20mg/kg dil in 10ml/kg 5% D/DNS over 4 h iv, followed by 10 mg/kg iv 4 h Oral quinine 10mg/kg-7 days

Radical cure:

Radical cure Pq 15 MG/KG for 14 days Gametocidal PQ 45mg/kg single dose



Malaria (cont’d):

Malaria (cont’d) Avoid mosquitoes by taking protective measures. Use protective clothing: long sleeved shirts/pants. Use DEET repellant. Use bed netting if rural or if locked windows not available. Prophylactic medications when indicated are widely used based on CDC recommendations for intended destinations.

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