Antimalarials

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Antimalarials :

Antimalarials Dr.S.P.Dhanya

Species:

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 :

Blood/ Erythrocytic Schizonticides for Suppressive prophylaxis/clinical cure Rapidly acting CHLOROQUINE AMODIAQUINE PIPERAQUINE QUININE MEFLOQUINE ATOVAQUONE MEPACRINE HALOFANTRINE ARTEMISININ ,DIHYDROARTEMISININ, ARTEMETHER ,ARTESUNATE,ARTETHER

Slower acting:

Slower acting PROGUANIL DOXYCYCLINE PYRIMETHAMINE TETRACYCLINE

Gametocides:

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

Sporonticidal:

Sporonticidal Make gametocytes ineffective within mosquito PYRIMETHAMINE PROGUANIL

Combinations:

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

Chloroquine:

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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HEME POLYMERASE CHLOROQUINE

Resistance:

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:

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:

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

Uses:

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

Amodiaquine:

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

Piperaquine:

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:

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:

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

Mepacrine:

Mepacrine Toxic Less effective Obsolete Giardiasis,tapeworm

Quinine:

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:

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:

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:

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:

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:

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.

PowerPoint Presentation:

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:

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:

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%

PowerPoint Presentation:

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:

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.

PowerPoint Presentation:

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

Pharmacokinetics:

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:

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):

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

Artemether-Lumefantrine:

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):

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

Artesunate-Pyronaridine:

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):

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:

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:

Malaria

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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