antimalarial drugs (vk)
TRANSCRIPT
ANTIMALARIAL DRUGS
Plasmodium species which infect humans
Plasmodium vivax
Plasmodium ovale
Plasmodium falciparum
Plasmodium malariae
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)
Classification of Malaria
• Severe Malaria
– Cerebral malaria (seizures, coma)
– Severe anemia
– Hemoglobinuria
– Abnormalities in blood coagulation
– Cardiovascular collapse and shock
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
• 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
CLASSIFICATION OF ANTIMALARIALS
• 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
– Artemisinin Derivatives: Artesunate, artemether,
arteether
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)
Malaria Transmission Cycle
Parasite undergoes sexual reproduction in the mosquito
Some merozoites differentiate into male or female gametocyctes
Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts
Dormant liver stages (hypnozoites) of P. vivax and P. ovale
Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood
MOSQUITO HUMAN
Sporozoites injected into human host during blood meal
Parasites mature in mosquito midgut and migrate to salivary glands
Components of the Malaria Life Cycle
Mosquito Vector
Human Host
Sporogonic cycle
Infective Period
Mosquito bitesgametocytemic person
Mosquito bitesuninfected person
Prepatent Period
Incubation Period
Clinical Illness
Parasites visible
Recovery
Symptom onset
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
Exo-erythrocytic (tissue) phase
• P. malariae or P. falciparum sporozoites do not
form hypnozites, develop directly into pre-
erythrocytic 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
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
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
Erythrocytic phasestages 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
Erythrocytic phasestages 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
Quinine• Oldest antimalarial alkaloid isolated from barks of chinchona tree.• Present indication-cerebral malaria
-chloroquine resistant p. falcifarumPharmacological actions1.Antimalarial :Suppressive agent2.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 ,vomiting4.CVS- myocardial depression, decrease excitability and conductivity iv. dose-
hypotension5. Miscellaneous- analgesic, antipyretic, sk. muscle relaxant
P/K-well absorbed ,peak 1-3 hrs, cross placenta, metabolized in liver, excreted in urine
Adverse effect1.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
Uses & Dose1.Malaria:• schizontocidal drug• very active against erythrocytic phase.• No effect against proerythrocytic, sexual gametocytes,
exoerythrocytic phase, relapse.2.Myotonia Congenita3.Nocturnal muscle cramps4.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
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 plasmodia.it is highly efficacious drug.
• It controls most clinical attack in 1-2 days.
• It does not prevent relapses in vivax & ovale malaria.
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
properties
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
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
Toxic effects• Toxicity of chloroquine is low but side effects
are frequent & unpleasant:• nausea • vomiting • anorexia • uncontrollable itching • epigastric pain• uneasiness• headache
…contd.
Parenteral administration can cause• hypotension• cardiac depression • arrythmias CNS toxicity including convulsions.• Prolonged use of high doses can cause loss of
vision.
…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.
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
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
…contd.
• Discoid lupus erythematosus
• Lepra reactions
• Photogenic reactions
• Infectious mononucleosis
Mefloquine
Introduction It is a quinoline methanol derivativeIt 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 plasmodiaIt has not been extensively used in India.
Mechanism of action
Acts on erythrocytic stageHighly 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.
Pharmacokinetics
Given orally
Rapidly and completely absorbed
Highly bound to plasma protein
Eliminated slowly with plasma half life of 20
days
Adverse effects
GITDizziness, nausea, vomiting, diarrhoea, abdominal
pain
Neuropsychiatric disturbancesAnxiety, halloucination, sleep disturbances,
Single dose may cause light headedness and loss of concentration
…Contd.CVS
Causes bradycardiaSinus arrhythmia
Teratogenicity Should be avoided in 1st trimester of pregnancyMay be used in 2nd and 3rd trimester
MiscellaneousAllergic skin reactionBlood dyscriasisHepatitis
Uses
Effective drug for multiresistant P.falciparumTreatment of uncomplicated falciparum
malaria in areas with multidrug resistanceDose -25 mg per kg (maximum 1.5 g)Prophylaxis of malaria among travellers to
areas with multidrug resistanceDose -5 mg per kg (adult 150 mg)
Proguanil
IntroductionCommonly used salt of these drug is proguanil hydrochlorideHas negligible antiplasmodial action in vitroSlow acting erythrocytic schizonticideCyclized in body to triazine derivative
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
Pharmacokinetics
Slowly absorbed from gut
Partly metabolized and excreted in urine
Non-cumulative
Plasma half life- 16-20 hrs
Adverse effects
GIT disturbanceStomatitsMouth ulcersReduction in leucocyte count Rarely megaloblastic anaemiaDosageTab Proguanil hydrochloride 100mg
Uses
Use dependent on sensitivity of strainIn multiresistant falciparum malariaCombination of proguanil 100mg and
atovaqoune 250mgUsed prophylactically (in dose of 1 tablet
taken with food)
PRIMAQUINE
Poor erythrocytic schizontocide : has weak action of P. vivax.
In contrast it is more active against pre-erythrocytic stage of P. falciparum than that of P. vivax
Highly active against gametocytes & hypnozoites.
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.
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.
Adverse effect
• Abdominal pain
• GI upset
• Weakness or uneasiness in chest
• CNS & cardiovascular symptoms are infrequent
leucopenia
• Haemolysis, methemoglobinemia, cyanosis
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
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.
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.
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
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.
Precautions
• Should not given during pregnancy, lactation
& in children.
• Should be avoided in patients on diuretics
• Do not inject tetracycline intrathecally.
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.
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.
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.
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.
Cont….
Contraindications• Infants• Individuals allergic to sulfonamide• Cautious use in pregnancyUses• Chloroquine resistant falciparum malaria.• ToxoplasmosisResistance• Pyrimethamine develops resistance quickly & cross
resistance to biguanides is seen.• It decreases due to sulfonamide & no cross
resistance seen
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-eastSome Combinations • Sulfonamide(500mg)+pyrimethamin(25mg• Sulfamethapyrasine+pyrimethamine• (500mg) (25mg)• Dapsone(100mg)+pyrimethamine(25mg)• As clinical curative- sulfadoxine(1500mg)
+pyrimethamine(75mg)
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
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
Artemsia annua
• Li Shizhen, a great Chinese herbalist
• Use of wormwood is also recorded in the “Great Compendium of Herbs” in 1596
“take a handful of sweet wormwood, soak it in a sheng (liter) of water, and squeeze out the juice and drink it all”
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
Key Features
• Rapid onset of actions
• Effective against severe malaria
• Rapid clearance rate
• Slow development of artemisinin resistance
• Frequent recurrence of infections
Site of Action
Artemisinin
Artemisinin
Conventional Treatment
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
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.
DERIVATIVES OF ARTEMISININ USED IN TREATMENT OF MALARIA
• Artemether
• Arteether
• Artesunate
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
ARTEETHER
• Ethyl ether of dihydroartemisinin
• Therapeutically equivalent to quinine in cerebral malaria • Available as arteether and / arteether
• arteether developed by WHO and The Special Programme for Research and Training in Tropical
Diseases (TDR)
• / arteether developed by CDRI
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
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
• 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
• 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
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
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
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.