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nagakrishna-yadav
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Antimalarials
• Introduction:
– Most devastating parasitic infection
– 1-3 million deaths world wide each year
– India 8 lac deaths
• Etiology: Plasmodium
• Transmission : Female anopheles
• Clinical features: a) Cold stage: onset with
fatigue, headache, chills, nausea, followed by rigors. Skin feels cold lasts for 1 hr
b) Hot stage: feels, burning hot , casts off his clothes , skin is hot & dry to touch, lasts for 2 to 6 hrs
c) Sweating stage: fever comes down with profuse sweating & temperature drops rapidly to normal. Skin is cool & moist. Pt feels relieved lasts for 2 to 4 hrs
Life cycle of malarial parasite
Sporogeny (sexual)
Schizogony (asexual)
Man : Intermediate hostMosquito : Definitive host
True causal prophylactics
Causal prophylactics
Supressives
Gametocidal
Sporonticide
• Classification of antimalarial drugs
– Based on stage of life cycle they affect
– Based on chemical structure
• Based on stage of parasite they affect: – True causal prophylactics:
– Causal prophylactics: Primaquine, Pyrimethamine,proguanil
– Supressives: quinine, 4-aminoquinolines, mefloquine,artemisinin
– Radical curatives: primaquine,pyrimethamine
– Gametocidal: • Supressives (Chloroquine, quinine, artesunate )
– Pl Vivax ,
• Primaquine – against all,
• Proguanil ,pyrimethamine – prevent development of sporozoites
• Based on chemical structure:– Cinchona alkaloids: quinine,quinidine
– 4 aminoquinolines: chloroquine, hydroxychloroquine, amodiaquine, pyronaridine
– 8 aminoquinolines:primaquine, tafenoquine, bulaquine
– quinoline methanol: mefloquine, halofantrine, lumefantrine
– Antifolates:• Diaminopyrimidine: pyrimethamine
• Biguanides: proguanil
• Sulfonamides: sulfadoxine
– Antibiotics: tetracycline, doxycycline, clindamycin
– Hydronaphthoquinone: Atovaquone
– Qinghaosu compounds: Artesunate, artemether, arteether
• Chloroquine:
– Germans 1934 resochin
– closely resembles 8 amino quinolines
– d & l isomers, d isomer is less toxic
– Cl at position 7 confers maximal antimalarialefficacy
• Mechanism of action
Hemoglobin Globin utilized by malarial parasite
Heme (highly toxic for malaria parasite)
Chloroquine
Quinine,
mefloquine (-) (+)Heme polymerase
Hemozoin (Not toxic to plasmodium)
• Pharmacological actions:
1. Antimalarial activity:
• Highly against erythrocytic forms of vivax, ovale, malariae & sensitive strains of falciparum
• Gametocytes of vivax , ovale, malariae
• No activity against tissue schizonts
• Resistance develops due to efflux mechanism
2. Other parasitic infections:
• Giardiasis, taeniasis, extrainstestinal amoebiasis
3. Other actions:
• Depressant action on myocardium, direct relaxant effect on vascular smooth muscles, antiinflammatory, antihistaminic , local anaesthetic
• Pharmacokinetics:– Well absorbed, tmax 2-3 hrs , 55 % protein bound
– Conc in liver , spleen, kidney, lungs , leucocytes
– T1/2 = 3- 5 hrs increases from few days to weeks
• Adverse drug reaction: – Intolerance:
• skin rashes, angioneuroticedema, photosensitivity, pigmentation, exfoliativedermatititis
• Long term therapy may cause bleaching of hair
• Rarely thrombocytopenia, agranulocytosis, pancytopenia
• Occular toxicity: High dose prolonged therapy– Temporary loss of accommodation
– Lenticular opacities, subcapsular cataract
– Retinopathy: constriction of arteries, edema, blue black pigmentation , constricted field of vision. These changes are reversible on stopping therapy
• CNS:– Insomnia, transient depression seizures,
rarely neuromyopathy & ototoxicity
• CVS:– ST & T wave abnormalities, abrupt fall in BP &
cardiac arrest in children reported
• Dosage:
• Therapeutic uses:
1. Hepatic amoebiasis:
2. Giardiasis
3. Clonorchis sinensis
4. Rheumatoid arthritis
5. DLE
6. Control manifestation of lepra reaction
• Hydroxy chloroquine:
– Less toxic, properties &uses similar
• Amodiaquine:
– As effective as chloroquine in single dose
– Pharmacological actions similar
– Chloroquine resistant strains may be effective
– Adverse events: GIT, headache , photosensitivity, rarely agranulocytosis
– Not recommended for prophylaxis
• Pyronaridine: China , effective in resistant cases
• Quinine: – 1820 Pelletier & caventou isolated quinine from
cinchona bark.
– Pharmacological actions:
1. Antimalarial action: primarily on erythrocyticforms of all malarial parasites especially resistant falciparum strains . gametocidal for vivax & malariae
2. Local irritant effect: depresses variety of enzymatic processes, reduces ciliary activity , inhibits phagacytosis & growth of protoplasm so called general protoplasmic poison. 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, curaremimitic effect on skeletal muscles
• Pharmacokinetics:
• administered orally is completely absorbed
• Tmax = 1-3 hrs , crosses placental barrier
• Metabolized in liver degradation products excreted in urine t ½ = 10 hrs
• Adverse drug reactions: • Cinchonism: – Mild: Nausea, headache visual impairment – Tinnitus, 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.
• Idiosyncrasy : similar to cinchonism but occurs in therapeutic doses
• Cardiovascular toxicity: cardiac arrest, hypotension ,fatal arrhytmias
• Black water fever: – Triad of hemolysis, hemoglobinemia, hemoglobinuria
with fever
– Rare type of hypersensitivity to quinine therapy having immunological basis. Presence of incompletely supressed falciparum malaria.
• Hypoglycemia:
• Uses: – Malaria:
• uncomplicated resistant falciparum malaria
• Cerebral malarial
– Myotonia congenita: heriditory myopathy characterized by tonic spasm of skeletal muscle, benefitted by 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
• Primaquine: – Mechanism of action:
– Interferes with oxygen transport system
Primaquine
Converted to electrophiles
Generates reactive oxygen species
• Antimalarial action: – Liver hypnozoites
– Weak action against erythrocytic stage ofvivax, so used with supressives in radical cure
– No action against erythrocytic stage offalciparum
– Has gametocidal action and is most effectiveantimalarial to prevent transmission diseaseagainst all 4 species
• Pharmacokinetics:– Readily absorbed, t1/2 = 3-6 hrs
– Oxidised in liver, excreted in urine
• Adverse effects: – Gastrointestinal: epigastric distress, abdominal
cramps , can be minimised by taking drug with or after food , or with antacids
– Hemopoetic: mild anemia, methemoglobinemia, cyanosis, hemolytic anemia in G6PD deficiency
– Avoided during pregnancy, G6PD deficient
• Uses:– Primary use is radical cure of relapsing malaria 15
mg daily for 14 days with dose of chloroquine
– India 5 day therapy
– Falciparum malaria 45 mg of single dose with chloroquine curative dose to kill gametes & cut down transmission of malaria.
• 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
• 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
• 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
• Adverse events: 1. GIT: bitter in taste, nausea, vomiting , abdominal
pain , diarrhoea
2. neuropsychiatric disturbances: disturbed sense of balance, anxiety, hallucinations, sleep disturbances, psychosis, errors in operating machinery, convulsions
3. CVS: Bradycardia, sinus arhythmia, & QT prolongation
4. Teratogenicity: avoided in first trimester
5. Miscellaneous: allergic skin reactions, hepatitis & blood dyscrasias
• Uses: – Effective drug for MDR falciparum
1. T/t of uncomplicated falciparum in MDR malaria 25 mg/kg (1.5 gm) in 2 divided doses taken on same day
2. Prophylaxis in MDR areas 5 mg/kg (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 single drug for prophylaxis.
• 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.
Drugs affecting synthesis & utilisation of folate:
PABA + Dihydropterine+ Glutamic acid
Di hydrofolicacid
Tetra hydrofolicacid
Dihydrofolatereductase
Ѳ
sulfonamides
Ѳ
DHFRinhibitors
Sulfonamides: Sulfanilamide moeity structural analog of PABA, PABA essential for folate synthesis Sulfonamides compete with PABA for folate synthetaseWeak effect , potentiate action of DHFR inhibitors ,hence used in combination
Advantages of combination Supradditive , sequential block Combination faster acting
Dihydrofolate reductase inhibitors:
• Proguanil :
– Biguanide converted to cycloguanil active compound
– Act slowly on erythtocytic stage of vivax & falciparum
– Sporonticidal & also 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
• Pyrimethamine: – Diaminopyrimidine more potent than proguanil &
effective against erythrocytic forms of all species.
– Tasteless so suitable for children
Adverse events: megaloblasticanemia, thrombocytopenia, agranulocytosis.
– Generally combined with sulfadoxine 500 mg + pyrimethamine 25 mg, 3 tablets once for acute attack
– Not recommended for prophylaxis due to severe cutaneous reactions like exfoliative dermatitis & stevenson johnson syndrome.
ARTEMISININ DERIVATIVATIVES: • Mechanism of action:• Antimalarial action:
Shorter acting drugs, so recrudescence Prevented by combining with long acting drugs
• Dose: Artesunate, arteether, artemether• Adverse events:
– No serious adverse events– Most common GIT , Itching & fever – Abnormal bleeding, dark urine , ST-T changes,
QT prolongation– Transient reticulocytopenia & leucopenia
• Use:
Artemisinin based combination therapy:
• WHO: acute uncomplicated Pl Falciparum be treated only by combining one Artemisinin with other effective erythrocytic schizonticide?
• 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
• Artemether & lumefantrine: – Lumefantrine is highly effective , long acting oral
erythrocytic schizonticide related to mefloquine
– Same mechanism of action
– Highly lipophilic onset delayed , peak 6 hrs
– Slower acting than chloroquine, 99 % bound , metabolized by CYP3A4, T1/2= 2-3 days
– Available as fixed dose combination
– Adverse events: headache, dizziness, sleep disturbances, abdominal pain, arthralgia, pruritis & rash
– 80 mg artemether BD WITH 480 mg lumefantrineBD for 3 days
• DHA – Piperaquine, Artesunate- pyronaridine
• 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
• Atovaquone: – Synthetic napthoquinone derivative, rapidly
acting erythrocytic schizonticide for plasmodium falciparum & other plasmodia
– Pnemocystis carinnii & toxoplasma gondii– Mechanism of action: – Combined with proguanil– 250 mg of atovaquone + 100 mg proguanil
Management of malaria:• Prophylaxis;
– Indication – Duration :– Drug regimens:
• Chloroquine sensitive malaria: 300 mg / week • Chloroquine resistant malaria:
mefloquine, doxy, malarone• Drugs not allowed for prophylaxis:
quinine, artemisinin, pyrimethamine, sulfadoxine, amodiaquine
– Other measures – Causal prophylaxis – Supressive prophylaxis
Treatment of acute attack • Diagnosis , thick & thin smear • Acute clinical attack of chloroquine
sensitive malaria: – Chloroquine /– Amodiaquine: 600 mg base followed by 200
mg base on day1 then 400 mg OD on day 2 & day3/
– Quinine– Patients who cannot take orally
• 2.5 mg/kg IM every 4 hrs or 3.5 mg/kg IM every 6 hrs
• 10 mg/kg IV over 4 hrs then 5 mg/kg over 2 hrs BD
– Role of primaquine– Precautions:
• Treatment of chloroquine resistant malaria acute attack
A. Pts who can take orally:– Pyrimethamine sulfadoxine 3 tabs , quinine for 2 days
or
– Quinine 3 days with doxy 7 days or
– Quinine 3 days with mefloquine
– (Atovaquone 250 mg + proguanil 100 mg) 4 tab 3 days
– Sodium artesunate 100 mg BD day1 , 50 mg BD for 4 days
• 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 pt able to swallow – Then quinine 600 mg TDS for 7 days &
tetracycline/ doxycycline– Or artemether / arteether injection
• 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
• Severe / Complicated / cerebral malaria – CNS symptoms, convulsions, coma
– Hypoglycemia, metabolic acidosis, renal failure or other complications
– Quinine is drug of choice IV dose
– S-P , doxycycline added with oral therapy
– BP, blood sugar, ECG Monitored during quinine therapy.
– Supportive measures:• ICU administration
• Good nursing care,Tepid sponging, Na bicarbonate
• Hypoglycemia, anemia, BP , Increase ICT
– GC, urea, mannitol not used now a days
• Malaria in children:– Quinine parenteral high toxicity / oral well tolerated
– Chloroquine convulsions in infants & small children
– Primaquine avoided in neonates
– Mefloquine not used in children below 15 kg weight
• Acute malaria in pregnant women– Chloroqune, quinine, S-P in usual doses
– Mefloquine C/I in first trimester
– Primaquine/ tetracycline avoided
– Anemia: folic acid & iron
• Vaccines for malaria:– Pre-erythrocytic stage vaccines
• RTS VACCINE designed to prevent invasion of hepatocytes by sporozoites
– Erythrocytic stage vaccine: • Aim is to reduce or eliminate number of blood stage
parasites • Malarial surface protein 1 (MSP1) vaccine• Apical merozoite antigen 1 (AMA1) vaccine
– Transmission blocking vaccines:• Designed to prevent mosquitoes that feed on
vaccinated individuals from becoming infected & reduce transmission (indirect prevention)
– Multicomponent vaccines: combination vaccines • Combination vaccine of 3 blood stage antigens