Antimalarial drugs (VK)


Published on

  • Be the first to comment

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide
  • I am giving the old names for these malarias in parentheses to give some historical perspective in case you see these terms again. I will also explain how these old terms relate to the pathogenesis of these respective diseases and the associated fever patterns.
  • Recrudescence:
    A fresh outbreak of a disorder in apt after a period during which its sign and symptoms had died down and recovery seemed 2 be taking place
  • The life cycle of all species that infect humans is basically the same. There is an exogenous asexual phase in the mosquito called sporogony during which the parasite multiplies. There is also an endogenous asexual phase that takes place in the vertebrate or human host that is called schizogeny. This phase includes the parasite development that takes place in the red blood cell, called the erythrocytic cycle and the phase tthat takes place in the parencymal cells in the liver, called the exo-erythrocytic phase. The exo-erthrocytic phase is also called the tissue phase. The schizogeny that takes place here can occur without delay during the primary infection or can be delayed in the case of relapses of malaria. I will focus on the development of the parasite in the human host.
  • Antimalarial drugs (VK)

    2. 2. Plasmodium species which infect humans Plasmodium vivax Plasmodium ovale Plasmodium falciparum Plasmodium malariae
    3. 3. Classification of Malaria • Uncomplicated Malaria • Cold stage (sensation of cold, shivering) • Hot stage (fever, headaches, vomiting; seizures in young children) • Sweating stage (sweats, return to normal temperature, tiredness)
    4. 4. Classification of Malaria • Severe Malaria – Cerebral malaria (seizures, coma) – Severe anemia – Hemoglobinuria – Abnormalities in blood coagulation – Cardiovascular collapse and shock
    5. 5. Types of Infections • Recrudescence – exacerbation of persistent undetectable parasitemia, due to survival of erythrocytic forms, no exo-erythrocytic cycle (P.f., P.m.) • Relapse – reactivation of hypnozoites forms of parasite in liver, separate from previous infection with same species (P.v. and P.o.) • Recurrence or reinfection – exo-erythrocytic forms infect erythrocytes, separate from previous infection (all species) • Can not always differentiate recrudescence from reinfection
    6. 6. CLASSIFICATION OF ANTIMALARIALS • Based on stage of parasite they affect: – Causal prophylactics: Primaquine, Pyrimethamine,proguanil – Supressives: Quinine, 4-aminoquinolines, mefloquine,artemisinin – Radical curatives: Primaquine,pyrimethamine – Gametocidal: • Supressives – Pl Vivax , • Primaquine – against all, • Proguanil ,pyrimethamine – prevent development also prevent development of sporozoites
    7. 7. • 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
    8. 8. – Antibiotics: Tetracycline, doxycycline, clindamycin – Hydronaphthoquinone: Atovaquone – Artemisinin Derivatives: Artesunate, artemether, arteether
    9. 9. Malaria Life Cycle Life Cycle Sporogony Oocyst Sporozoites Mosquito Salivary Gland Zygote Exoerythrocytic (hepatic) cycle Gametocytes Erythrocytic Cycle Schizogony Hypnozoites (for P. vivax and P. ovale)
    10. 10. Malaria Transmission Cycle Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood Sporozoites injected into human host during blood meal Parasites mature in mosquito midgut and migrate to salivary glands MOSQUITO Parasite undergoes sexual reproduction in the mosquito HUMAN Some merozoites differentiate into male or female gametocyctes Dormant liver stages (hypnozoites) of P. vivax and P. ovale Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts
    11. 11. Components of the Malaria Life Cycle Sporogonic cycle Infective Period Mosquito bites uninfected person Mosquito bites gametocytemic person Mosquito Vector Parasites visible Prepatent Period Human Host Symptom onset Recovery Incubation Period Clinical Illness
    12. 12. Exo-erythrocytic (tissue) phase • Blood is infected with sporozoites about 30 minutes after the mosquito bite • The sporozoites are eaten by macrophages or enter the liver cells where they multiply – pre-erythrocytic schizogeny • P. vivax and P. ovale sporozoites form parasites in the liver called hypnozoites
    13. 13. Exo-erythrocytic (tissue) phase • P. malariae or P. falciparum sporozoites do not form hypnozites, develop directly into preerythrocytic schizonts in the liver • Pre-erythrocytic schizogeny takes 6-16 days post infection • Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver
    14. 14. Exo-erythrocytic (tissue) phase • P. vivax and P. ovale hypnozoites remain dormant for months • They develop and undergo pre-erythrocytic sporogeny • The schizonts rupture, releasing merozoites and producing clinical relapse
    15. 15. Erythrocytic phase • Pre-patent period – interval between date of infection and detection of parasites in peripheral blood • Incubation period – time between infection and first appearance of clinical symptoms • Merozoites from liver invade peripheral (RBC) and develop causing changes in the RBC • There is variability in all 3 of these features depending on species of malaria
    16. 16. Erythrocytic phase stages of parasite in RBC • Trophozoites are early stages with ring form the youngest • Tropohozoite nucleus and cytoplasm divide forming a schizont • Segmentation of schizont’s nucleus and cytoplasm forms merozoites • Schizogeny complete when schizont ruptures, releasing merozoites into blood stream, causing fever • These are asexual forms
    17. 17. Erythrocytic phase stages of parasite in RBC • Merozoites invade other RBCs and schizogony is repeated • Parasite density increases until host’s immune response slows it down • Merozoites may develop into gametocytes, the sexual forms of the parasite
    18. 18. • • Quinine Oldest antimalarial alkaloid isolated from barks of chinchona tree. Present indication-cerebral malaria -chloroquine resistant p. falcifarum Pharmacological actions 1.Antimalarial :Suppressive agent 2.Local irritational action: General protoplasmic poison -decrease cilliary actvity -Inhibit phagocytosis & fibroblast growth Local anesthetic action, At high conc. edema , pain at site of inj. 3.GI tract- bitter, nausea ,vomiting 4.CVS- myocardial depression, decrease excitability and conductivity iv. dose- hypotension 5. Miscellaneous- analgesic, antipyretic, sk. muscle relaxant P/K-well absorbed ,peak 1-3 hrs, cross placenta, metabolized in liver, excreted in urine
    19. 19. Adverse effect 1.Cinchonism: Mild - ringing in ears, nausea, vomiting, headache, visual impairment. Large doses-Tinnitus, deafness, vertigo, blurring,photophobia, delirium, confusion. Poisoning progress- Skin pale, cold, resp. depress,BP falls, comma, death. 2.Idiosyncrasy 3.CVS toxicity-cardiac arrest 4.Black Water Fever -acute intravascular haemolysis,haemoglobinuria,fever, acute renal failure,focal hepatic necrosis 5.Hypoglycemia 6.Acute renal Failure
    20. 20. Uses & Dose 1.Malaria: • schizontocidal drug • very active against erythrocytic phase. • No effect against proerythrocytic, sexual gametocytes, exoerythrocytic phase, relapse. 2.Myotonia Congenita 3.Nocturnal muscle cramps 4.Cerebral malaria IV Quinine 600mg in 500ml of 5% dextrose slowly over 4 hrs repeated every 8 hrs till patient is conscious followed by oral treatment to complete 7 day coarse. Dose:300-600mg orally
    21. 21. Chloroquine • It is a 4-aminoquinolone • It was produced in USA as a less toxic alternative to mepacrine. • It is rapidly acting erythrocytic schizontocide against all species of is highly efficacious drug. • It controls most clinical attack in 1-2 days. • It does not prevent relapses in vivax & ovale malaria.
    22. 22. Mechanism of action • It is actively concentrated by sensitive intraerythrocytic plasmodia • It interfers with degradation of Hb by parasitic lysosomes • Heme itself or its complex with chloroquine damages plasmodial membrane • Clumping of pigment & changes in parasite membrane follows • It has anti-inflamatory, local irritant, local anaesthetic, weak smooth muscle relaxant, anti-histaminic & anti-arrhythmic
    23. 23. Resistance • Chloroquine resistance among P. vivax has been slow in developing. • However P. falciparum has acquired significant resistance • Resistance in P. falciparum is associated with a decreased ability of parasite to accumulate chloroquine
    24. 24. Pharmacokinetics • Oral absorption of chloroquine is excellent , about 50% gets bound in plasma • It gets bound to melanin & nuclear chromatin and is concentrated in liver, spleen, kidney, lungs, skin, leucocyte • Absorption after i.m. injection is also good • Plasma concentration is 15-30ng/ml • Chloroquine is partly metabolised by liver & slowly excreted in urine • Plasma t-1/2 varies from 3-10 days
    25. 25. Toxic effects • Toxicity of chloroquine is low but side effects are frequent & unpleasant: • nausea • vomiting • anorexia • uncontrollable itching • epigastric pain • uneasiness • headache
    26. 26. …contd. Parenteral administration can cause • hypotension • cardiac depression • arrythmias CNS toxicity including convulsions. • Prolonged use of high doses can cause loss of vision.
    27. 27. …contd. • Loss of hearing , rashes, photo allergy, mental disturbance, myopathy and graying of hairs can occur as long term use. • Attack of seizures, porphyria & psoriasis may be precipitated.
    28. 28. Routes of administration & dosage • Chloroquine phosphate is given orally • As prophylaxis – Dose: adults – 500mg once each week children – 5mg/kg weekly • For treatment – Initial dose - 600mg followed by 300mg after 6-8 hrs then 300mg on 2 consecutive days
    29. 29. Indications • Chloroquine is drug of choice for malaria • It completely cures sensitive falciparum disease, but relapses in vivax and ovale are not prevented . Other uses • Extra intestinal amoebiasis • Rheumatoid arthritis
    30. 30. …contd. • Discoid lupus erythematosus • Lepra reactions • Photogenic reactions • Infectious mononucleosis
    31. 31. Mefloquine Introduction It is a quinoline methanol derivative It is a drug developed to deal with problem of chloroquine resistant P.falciparum It is rapidly acting erythrocytic schizontocide. It is effective against chloroquine sensitive as well as resistant plasmodia It has not been extensively used in India.
    32. 32. Mechanism of action  Acts on erythrocytic stage  Highly effective in a single dose against P.falciparum including chloroquine resistant strains.  Appears to bind to heme and the complex damages membrane of the parasite  No action on persistant tissue form.
    33. 33. Pharmacokinetics  Given orally  Rapidly and completely absorbed  Highly bound to plasma protein  Eliminated slowly with plasma half life of 20 days
    34. 34. Adverse effects GIT Dizziness, nausea, vomiting, diarrhoea, abdominal pain Neuropsychiatric disturbances Anxiety, halloucination, sleep disturbances, Single dose may cause light headedness and loss of concentration
    35. 35. …Contd. CVS Causes bradycardia Sinus arrhythmia Teratogenicity Should be avoided in 1st trimester of pregnancy May be used in 2nd and 3rd trimester Miscellaneous Allergic skin reaction Blood dyscriasis Hepatitis
    36. 36. Uses  Effective drug for multiresistant P.falciparum  Treatment of uncomplicated falciparum malaria in areas with multidrug resistance  Dose -25 mg per kg (maximum 1.5 g)  Prophylaxis of malaria among travellers to areas with multidrug resistance  Dose -5 mg per kg (adult 150 mg)
    37. 37. Proguanil Introduction Commonly used salt of these drug is proguanil hydrochloride Has negligible antiplasmodial action in vitro Slow acting erythrocytic schizonticide Cyclized in body to triazine derivative
    38. 38. Actions  Effective schizonticide against P.vivax and P.falciparum  Effective against primary pre-erythrocytic forms of P.falciparum  Prevents development of gametes encysted in gut wall of mosquito  No action against persistant tissue forms P.vivax
    39. 39. Pharmacokinetics  Slowly absorbed from gut  Partly metabolized and excreted in urine  Non-cumulative  Plasma half life- 16-20 hrs
    40. 40. Adverse effects  GIT disturbance  Stomatits  Mouth ulcers  Reduction in leucocyte count  Rarely megaloblastic anaemia  Dosage  Tab Proguanil hydrochloride 100mg
    41. 41. Uses  Use dependent on sensitivity of strain  In multiresistant falciparum malaria  Combination of proguanil 100mg and atovaqoune 250mg  Used prophylactically (in dose of 1 tablet taken with food)
    42. 42. PRIMAQUINE  Poor erythrocytic schizontocide : has weak action of P. vivax.  In contrast it is more active against preerythrocytic stage of P. falciparum than that of P. vivax  Highly active against gametocytes & hypnozoites.
    43. 43. PHARMACOKINETICS  Readily absorbed by oral ingestion.  Oxidized in liver with a plasma t1/2 of 3-6 hrs.  Excreted in urine within 24 hrs.  Not a cumulative drug.
    44. 44. Mechanism of action :• Mechanism of action of primaqunine is not known. However it is difficult from that of chloroquine. Uses :• Radical cure of relapsing malaria : 15 mg daily for 2 weeks is given with full curative dose of chloroquine. • Falciparum malaria : single 45 mg dose of primaquine is given with curative dose of chloroquine to kill gametes & cut down transmission to mosquito.
    45. 45. Adverse effect • Abdominal pain • GI upset • Weakness or uneasiness in chest • CNS & cardiovascular symptoms are infrequent leucopenia • Haemolysis, methemoglobinemia, cyanosis
    46. 46. TETRACYCLINES Introduction • Broad spectrum antibiotic having a nucleus of four cyclic ring. • All are obtained from soil actinomycetes • Slowly acting & weak erythrocytic schizontocidal action against all plasmodial species
    47. 47. Mechanism of action • Tetracyclines are primarily bacteriostatic, inhibit protein synthesis by binding 30 s ribosomes in susceptible organism. To such binding attachment of aminoactyl – t- RNA to the m – RNA ribosomes complex is interfered with. Thus peptide chain fails to grow.
    48. 48. Adverse effects • Irritative effects :- epigastric pain, N, V & D • Dose related toxicity Liver damage :- fatty infiltration of liver & jaundice. Kidney damage :- It is prominent only in the presence of existing kidney disease. Phototoxicity:- A sun like or other severe skin reaction on exposed parts is seen Teeth & bones:- Tetracyclines have chelating property.
    49. 49. Cont…  Given between 3 months to 6 years of age affect permanent anterior dentition.  Antianabolic effect:- Reduce protein synthesis & have an overall catabolic effect  Increased intracranial pressure  Diabetes insipidus  Hypersensitivity  Super infection :- Tetracyclines are most common antibiotics response for superinfections
    50. 50. Uses • Used in combination with quinine or pyrimethamine sulfadoxine for the treatment of chloroquine resistant falciparum malaria. • Doxycycline 100 mg /day in used as a 2nd line prophylactic for travelers to chloroquine resistant p. falciparum areas.
    51. 51. Precautions • Should not given during pregnancy, lactation & in children. • Should be avoided in patients on diuretics • Do not inject tetracycline intrathecally.
    52. 52. PYRIMETHAMINE Mechanism of action  It is a directly acting inhibitor of plasmodial DHFRase.  It gradually reduces the schizogony of malarial parasite in blood.  It is slowly acting erythrocytic schizontocide.
    53. 53. Pharmacokinetics  Absorption from the gut is good but slow.  It is excreted in urine.  Half life time = 4 days. Adverse Effects  Nausea & rashes,  Folate deficiency,  Megaloblastic anemia & granulocytopenia.
    54. 54. Uses • Used only in combination with sulfonamide/dapsone to treat P.falciparum malaria. S/P Combination • Sulfonamide has some inhibitory action on erythrocytic phase of P.falciparum like pyrimethamine.. • It is a supra-additive synergistic combination by sequential block.
    55. 55. Cont…. • • • • PABA Folate synthetase DHFA DHFRase reductase THFA Combination acts faster than individual drug. Efficacy against P.vivax is low. When ultra long acting sulfonamides are used ; exfoliative dermatitis , Stevens-Johnson syndrome are seen. Used only as a single effective dose.
    56. 56. Contraindications • Infants • Individuals allergic to sulfonamide • Cautious use in pregnancy Uses • Chloroquine resistant falciparum malaria. • Toxoplasmosis Resistance • Pyrimethamine develops resistance quickly & cross resistance to biguanides is seen. • It decreases due to sulfonamide & no cross resistance seen
    57. 57. Cont… • Resistance was first noted in 1980. • It is more in south-east asia,s.america, southern Africa. • It is sporadic in India except for north-east Some Combinations • Sulfonamide(500mg)+pyrimethamin(25mg • Sulfamethapyrasine+pyrimethamine • (500mg) (25mg) • Dapsone(100mg)+pyrimethamine(25mg) • As clinical curative- sulfadoxine(1500mg) +pyrimethamine(75mg)
    58. 58. Artemisia annua • Also known as sweet wormwood • Origin from northern parts of China • Artemisinin present in leaves and flower of the plant in 0.01-0.08% dry weight
    59. 59. Artemisia annua • Used in Traditional Chinese Medicine for more than 2000 years • First antimalarial application described in “The Handbook of Prescriptions for Emergencies” in the 4th century by a Chinese chemist
    60. 60. Artemsia annua “take a handful of sweet wormwood, soak it in a sheng (liter) of water, and squeeze out the juice and drink it all” • Li Shizhen, a great Chinese herbalist • Use of wormwood is also recorded in the “Great Compendium of Herbs” in 1596
    61. 61. Artemisinin • One of the most novel discoveries in recent medicinal plant research • 1967- extracts of Artemisia was found to have antimalarial activity • 1972- artemisinin isolated from the plant • 1979- structure of artemisinin determined by X-ray analysis
    62. 62. Key Features • Rapid onset of actions • Effective against severe malaria • Rapid clearance rate • Slow development of artemisinin resistance • Frequent recurrence of infections
    63. 63. Site of Action Artemisinin Conventional Treatment Artemisinin
    64. 64. Mechanism of Action • Killing of malaria parasite is mediated by production free radicals – Artemisinin derivatives lacking endoperoxide bridge are devoid of antimalarial activity – Addition of free radical generating compounds enhances antimalarial activity – Antioxidants block antimalarial activity
    65. 65. ARTEMISININ • Oral formulation - 250mg capsule • Dosage Adults and children: 25mg/Kg on the first day followed by 12.5mg/Kg on the second and third day in combination with mefloquine (15mg/Kg) in a single dose on the second day. In some areas, a higher dose (25mg/Kg) of mefloquine may be required for a cure to be obtained.
    66. 66. DERIVATIVES OF ARTEMISININ USED IN TREATMENT OF MALARIA • Artemether • Arteether • Artesunate
    67. 67. ARTEMETHER • Methyl ether of dihydroartemisinin • Superior to intravenous quinine with respect to survival and parasite clearance • Available as tablets, capsules and as IM injectable form • In India, available as 40mg capsules and 80mg/ml ampoule
    68. 68. ARTEETHER • Ethyl ether of dihydroartemisinin • Therapeutically equivalent to quinine in cerebral malaria • Available as β arteether and α/β arteether • β arteether developed by WHO and The Special Programme for Research and Training in Tropical Diseases (TDR) • α/β arteether developed by CDRI
    69. 69. ARTEETHER • A longer t1/2 beta and more lipophilic properties than artemether favouring accumulation in brain tissue and thus the treatment of cerebral malaria were regarded as advantages over the other compounds. • Available as 150mg per 2ml ampoule
    70. 70. ARTESUNATE • Water soluble hemisuccinate derivative • Used for oral, rectal, intravenous and intramuscular administration. • Available as tablets and as powder with separate vial containing 5% sodium bicarbonate • In India, available as 50mg tablets and 60mg/ml injection • In China also available as 100mg suppository and in Switzerland available as 200mg rectocap
    71. 71. • Artemisinin based combination therapy: • WHO has recommended that 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 • Not effective against MDR strains which are non responsive to S/P • ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets – Artesunate Mefloquine: – Highly effective, well tolerated, first line of treatment for uncomplicated falciparum malaria • 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
    72. 72. • 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 lumefantrine BD for 3 days • DHA – Piperaquine, Artesunate- pyronaridine
    73. 73. Resistance • Currently no evidence for clinically relevant artemisinin resistance • Reasons for delay of artemisinin resistance: – Short half-life – Reduces transmission potential – Used in combination with other antimalarial drugs
    74. 74. PHARMACOKINETICS • Absorption of orally administered artemisinin or its derivatives seems to be rapid but incomplete • Substantial hydrolysis of artesunate (probable complete) and artemether into dihydroartemisinin probably occurs even before absorption • Elimination is mainly by hepatic metabolism • Arteether has much slower elimination • Artesunate, artemether, arteether and probably also artemisinin itself are transformed into dihydro-artemisinin, which is subsequently converted into inactive metabolites
    75. 75. ARTEMISININ DERIVATIVES IN PREGNANCY • Very limited data on the use of artemisinin group in pregnant women. • Artemisinin and derivatives should be avoided during first trimester of pregnancy, but in case of severe malaria the risks have to be balanced against the benefits. • No congenital malformations were detected in six children born to mothers who received intramuscular artemisinin or artemether at 17 to 27 weeks of gestation.