Antimalarial drug

Global Situation Of Malaria

• According to WHO,

• A significant public health problem

• More than 90 countries inhabited by some 2400 million people (about 40% of the world's population).

• The disease causes an estimated 300 million acute illnesses each year and at least 1 million deaths.

• More than 90% of these occur in sub-Saharan Africa, and it is estimated that the disease kills an African child every 30 seconds.

Situation Of Malaria In Bangladesh• The prevalence of malaria in the 13 endemic

districts is 3.97%.

• In five south-eastern districts weighted average prevalence rate is 6.00% and in the eight north-eastern districts weighted average prevalence rate is 0.40%.

• The highest prevalence is observed in Khagrachari district. The majority of the cases (90.18%) are P. falciparum infections.

• Malaria morbidity rates in five south-eastern districts is 2.94%.

Ref. Goodman & Gilman’s

Ref. Rang&Dales

• Infection usually is transmitted by the bite of infected female Anopheline mosquitoes.

• Sporozoites from the mosquito salivary glands rapidly enter the circulation after a bite and localize in hepatocytes, where they transform, multiply, and develop into tissue schizonts

• This primary asymptomatic tissue (preerythrocytic or exoerythrocytic) stage of infection lasts for 5 to 15 days, depending on the Plasmodium species.

• Tissue schizonts then rupture, each releasing thousands of merozoites that enter the circulation, invade erythrocytes, and initiate the erythrocytic cycle.

• Once the tissue schizonts burst in P.falciparum and P. malariae infections, noforms of the parasite remain in the liver.treatment that eliminates erythrocyticparasites will cure these infections.

• However, in P. vivax and P. ovale infections,tissue parasites (hypnozoites) persist that canproduce relapses of erythrocytic infectionmonths to years after the primary attack.Eradication of both erythrocytic and hepaticparasites is required to cure these infections.

• In erythrocytes, most parasites undergoasexual development & finally to matureschizonts.

• Schizont-containing erythrocytes rupture,each releasing 6 to 32 merozoites dependingon the Plasmodium species. Only erythrocyticparasites cause clinical illness. It is thisprocess that produces febrile clinical attacks.

• The merozoites invade more erythrocytes tocontinue the cycle

• Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites. which invade the salivary gland of the mosquito. The insect then can infect a human host by taking a blood meal.

Ref. Rang&Dales

Symptomatic malaria is typified by high spiking fevers that may have a periodic pattern chills, headache, myalgias, malaise, and gastrointestinal symptoms. In addition, each Plasmodium species causes a distinct illness:

(1) P. falciparum is the most dangerous. By invading erythrocytes of any age, sequestering in the vasculature, and producing endotoxin-like products, this species can cause an overwhelming parasitemia, hypoglycemia, and shock with multiorgan failure.

Delay in treatment may lead to death. If treated early, the infection usually responds within 48 hours. If treatment is inadequate, recrudescence of infection may result.

Cerebral malaria:Organism residesin the RBC, red cell become sticky,adhere to another RBC,Rouleux formation –cerebralcapillary blocks-ischemia, convulsion.

(2) P. vivax & P. ovale infection has a low mortality rate in untreated adults and is characterized by relapses caused by the reactivation of latent tissue forms.

(4) P. malariae causes a generally indolent infection that is common in localized areas of the tropics. Clinical attacks may occur years or decades after infection.

Classification

• Antimalarials can be categorized by the stageof the parasite that they affect and bytheir intended use for either prophylaxisor treatment.

• The various stages of the malaria life cycle thatoccur in humans differ from one another notonly in their morphology and metabolism butalso in their drug sensitivity. For this reason, theclassification of antimalarial drugs is best donein the context of the life cycle.

• Prophylaxis:

Since none of the drugs kills sporozoites, it is not truly possible to prevent infection but only to prevent the development of symptomatic malaria caused by the asexual erythrocytic forms.

• Treatment of an established infection:

None of the antimalarials is effective against all liver and red cell stages of the life cycle that may coexist in the same patient. Complete cure therefore may require more than one drug.

P. falciparum

P. ovale,p. vivax

Ref. Goodman & Gilman’s

• The patterns of clinically useful activity fall into threegeneral classes

• Class I agents action is directed against theasexual erythrocytic forms. These drugs willtreat, or prevent, clinically symptomatic malaria.

Prophylactically,must be taken for several weeksafter exposure until parasites complete the liverphase and become susceptible to therapy.

• The class II agents, which target not only theasexual erythrocytic forms but also the primary liverstages of P. falciparum. This additional activityshortens to several days the required periodfor postexposure prophylaxis.

• Finally, primaquine is unique in itsspectrum of activity, which includesreliable efficacy against primary andlatent liver stages (Hypnozoites) aswell as gametocytes.

• Primaquine has no place in the treatment of symptomatic malaria but rather is used most commonly to eradicate the hypnozoites of P. vivaxand P. ovale, which are responsible for relapsing infections.

• Quinine and Primaquine - short half-lives andcommon toxicities, generally are reserved for Rxof bvestablished infection & not used forprophylaxis in a healthy traveler.

• In contrast, chloroquine is relatively safe and has a one-week half-life that is convenient for prophylactic dosing (in those few areas still reporting chloroquine-sensitive malaria).

Briefly, causal prophylactics act on the initial hepatic stages, drugs for terminal prophylaxis and radical cure target hypnozoites, and agents for suppressive prophylaxis or cure target the asexual red cell forms.

• Tissue schizonticide:

To kill the hypnozoites. Dormant paracyte in liver. Clinical fever due to hypnozoites.

-Primaquine

Proguanil

• Blood schizonticidal:

Responsible for acute attack. Release ofmerozoites –Acute fever. Red cell debris – IL,TNF- Fever

↓

Cause rigor

- Chloroquine

Quinine

Mefloquine

Halofantrine

• Gametocidal: That prevent transmission of P. falciparam. gametocyte responsible for transmission.

-PrimaquineProguanil,Trimethoprim,

Chloroquine

• Antimetabolite:Pyrimethamine,

SulphadoxineProguanil

DapsoneTrimethoprim

• Antibiotic: Tetracycline DoxycyclineAzythromycin

• Drugs used for chemoprophylaxis (also known as causal prophylactic drugs) block the link between the exoerythrocytic stage and the erythrocyticstage, and thus prevent the development of malarial attacks.

• True causal prophylaxis-the prevention of infection by the killing of the sporozoites on entry into the host-is not feasible with the drugs at present in use, although it may be achieved in the future with vaccines.

• Chemoprophylactic agents are given to individuals who intend travelling to an area where malaria is endemic.

• Administration should start 1 week before entering the area and should be continued throughout the stay and for at least a month afterwards.

• No chemoprophylactic regimen is 100% effective, and the choice of drug is difficult.

• Chemoprophylexis with mefloquine should not be used unless high chance of chloroqineresistance.

Chemo

prophylaxis

Antimalarialtablet

Adult prophylactic dose

Regimen

Chloroquineresistance high

Mefloquine

Or Doxycycline

Or

Malarone

250 mg

100 mg

1 tab from 1-2 d before travelling to 1 week after return

One tablet weekly

Daily

Daily

Chloroquine resistance moderate

Chloroquine

Plus proguanil

150 mg base

100 mg

Two tablet weekly

Two tablets daily

Chloroquine resistance absent

Chloroquine

Or

Proguanil

150 mg base

100 mg

Two tablets weekly

One or two tablets daily

Anti malarial drugs

Malaria Drugs

Acute attack Chloroquine, quinine,

mefloquine, halofantrine,

sulphones, pyrimethamine,

doxycycline

Chemoprophylaxis Chloroquine, mefloquine,

proguanil, maloprim,

pyrimethamine, doxycycline

Radical cure Primaquine

Prevent

transmission

Primaquine, proguanil,

pyrimethamine

Selection of drug• The selection of antimalarial drug depends on

–Whether it is to be used for chemoprophylaxis or for treatment

–The species of Plasmodium

–The area of infection where it is used

• It also depends on

–The adverse effects of the drug

–Age of the patient

–Pregnancy

–Lactating mother

–Hepatic or renal impairment

Selection of drug

• Among the antimalarial drugs chloroquine is commonly used.

• Pyrimethamine, sulfones, & tetracyclines are slower acting, less effective, & nearly always used in combination with other antimalarialdrugs

• The artemisinins are potent and fast-acting antimalarials with no clinical evidence of resistance.

They are particularly well suited for the treatment of severe P. falciparum malaria and now play a key role in the combination therapy of drug-resistant infections.

Rational therapy for Malaria• Rx of Acute clinical Attack• Prevention of clinical attack• Radical cure.

Rx of Acute clinical Attack First try to diagnose the case. Dx should be confirmed by examination of RBC Quick detection of malaria parasite by deep stick

Ag assay for P. vivax. Sensitivity of this test depends upon the no. of

parasite. Parasite > 60/microgm per L is 100% sensitive.

Sensivity decreases to 10-60% if parasite count < 10 microgm per L

So, blood film study is appropriate for detection of malaria.

Thin blood film (parasite may be absent)

Thick blood film (more parasite)

Malaria parasite embaded in lymphocyte,so from head to tail –whole PBF must be examined.

Whenever detection of parsite, P.falciparum/P.Vivax , start RX of P.falciparum

• Drug acting faster shouldbe given in Rx of malaria.

• Blood schizonticidal Chloroquine given, if sensitive

• Quinine, meflaoquine,Artemethar,Artesunate

• Artemethar,Artesunate- clear parasite from blood v. quickly than quinine( 7days)

• Slower acting- pyrimethamine, proguanil, doxycycline, sulphadoxine,tetracycline

• They are never given alone.

Any fever in malaria zone should be treated as malaria

If there is doubt either chloroquine resistant /Not Rx as resistant malaria.

Pt must be aware of Recrudence & Relapse.

Halofantrine is contraindicated in pregnancy or in female who might become pregnant within the next 3 months

Clinical Setting Drug Therapy

Chloroquine-sensitive P

falciparum & P

malariae infections

Chloroquine phosphate, 1gm,

followed by 500 mg at 6, 24, &

48 hours

Or-

Chloroquine phosphate, 1g at 0

& 24 hours, then 0.5 g at 48

hours

P vivax &

P ovale infections

Chloroquine (as above), then (if

G6PD normal) primaquine, 26.3

mg daily for 14 days

Cl. Setting Drug Therapy Alternative Drugs

Uncomplicated infections with chloroquineresistant P .falciparum

Quine Plus one of the following-

Doxycycline, 100 mg twice daily for 7 days Or-

Clindamycin, 600 mg twice daily for 7 days Or-

Fansider, 3 tabs once

Artesunate or artemether, single daily doses of 4 mg/kg on day 0, 2 mg/kg on days 2 & 3,

1 mg/kg on days 4-7

Or

Coartem (coartemether 20 mg, lumefantrine 120 mg), 4 tablets twice daily for 3 days

Severe or complicated infections with P falciparum

Quinine gluconate, 10 mg/kg IV over 1-2 hours, then 0.02 mg/kg IV/minute

Or-15 mg/kg IV over 4 hours, then 7.5 mg/kg IV over 4 hours every 8 hrs

Artesunate, 2.4 mg/kg IV or IM, then 1.2 mg/kg every 12 hours for 1 day, then every day

Or-

Artemether, 3.2 mg/kg IM, then 1.6 mg/kg/d IM

Malaria Treatment Regimens

• Uncomplicated Malaria Confirmed:– Tab. Co-artem (Artemether 20 mg + Lumefantrine

120 mg Combination): The total recommended treatment is a 6-dose regimen of artemether-lumefantrine twice daily for 3 days. The second dose on the first day should be given any time between 8 h & 12 h after the first dose. Dosage on the second & third day is twice a day (morning & evening)

–OR• If for any reason co-artem can not be given –Pregnancy in 1st trimester–Children < 5 kg of body weight

– Tab. Quinine sulfate (300 mg). 600 mg 8 hourly for 7 days

• Alternative regimen may be:

–Quinine for 7 days + Tetracycline 250 mg 6 hourly for 7 days or

Quinine for 7 days + Doxycycline 100 mg 12 hourly for 7 days

–Artesunate (50 mg) + mefloquine (500 mg)

–Dose in mg (no. of tablets)

Artesunate Mefloquine

–Day 1 Day 2 Day 3 Day 1 Day 2 Day 3

–200 (4) 200 200 - 1000 (2) 500 (1)

• Uncomplicated Malaria Presumptive:

– The drug should be Chloroquine – 3 days

• Drug Day Weight in kg

• Chloroquine Day-1 4

Tab. 150 mg Day-2 4

base Day-3 2

But all efforts should be made for confirming the diagnosis as soon as possible by Blood Slide Examination (BSE) or Rapid Diagnostic Test (RDT). If BSE/RDT is positive treatment should be started in the line of uncomplicated malaria confirmed

• Treatment of Severe Malaria:

– IV Quinine drip/ IM Quinine followed by oral Quinine for a total of 7 days

or

– IM Artemether / IV Artesunate followed by oral Artesunate tablet

• Quinine:

– Loading dose: Quinine dihydrochloride 20 mg salt/kg of body weight (loading dose) by infusion over 4 hours, in 5% dextrose saline (5-10 ml/kg of body weight depending on the patient’s overall fluid balance).

– Maintenance dose: Eight hours after the start of the loading dose, maintenance dose of quinine 10 mg salt/kg of body weight in dextrose saline diluted as above over 4 hours. This maintenance dose should be repeated every 8 hours & up to six doses (including loading dose). Thereafter the quinine dose will be reduced to 15 – 20 mg salt/kg body weight, until the patient can take oral medication

• If the patient can take orally properly:

– Oral quinine: Quinine sulphate 10 mg salt/kg, 8 hourly to complete a 7 day course of treatment

• Artesunate:–2.4 mg/kg (loading dose) IV, followed by 1.2

mg/kg at 12 hours, then 1.2 mg/kg daily for 6 days, if the patient is able to swallow, the daily dose can be given orally

–Oral Artesunate:• 1st day – 2 mg/kg/dose• 2nd day – after 12 hours• 3rd dose – 8th – daily (total duration of

treatment 7 days & total 8 doses)• Artemether:–3.2 mg/kg (loading dose) IM followed by 1.6

mg/kg daily for 5 days• Arteether:–150 mg deep IM once daily for 3 days for adults

• Treatment of plasmodium Vivax case:–Chloroquine 3 days + Primaquine 14 days

(Primaquine: 1 tablet daily for 14 days inadults & 0.3 mg/kg daily for 14 days inchildren)

• Management of Severe Malaria In Pregnancy:–Quinine in the doses advocated for the

treatment of life-threatening malaria, is safein pregnancy. Quinine is not an abortificientin therapeutic doses & safe in all trimester inpregnancy. It has been shown that the initialIV infusion of quinine in woman who are >30 weeks pregnant is not associated withuterine stimulation or fetal distress. Its majoradverse effect if hypoglycemia. Artesunate &Artemether should not be used in firsttrimester of pregnancy

Blood schizontocide: Chloroquine

• A very potent blood schizontocidal drug, effective against all 4 plasmodial species (if sensitive to the drug), but it does not have any effect on sporozoite, hypnozoiteor gametocytes

• A synthetic, 4-aminoquinoline that has been the mainstay of antimalarial therapy– It has a complex mechanism of action

that is not fully understood.

Mechanism of action:

• Acts mainly on heme disposal by preventing digestion of hemoglobin by the parasite & thus reducing the supply of amino acids necessary for parasite viability.

• During the digestion process, large amounts of soluble heme (ferriprotoporphyrin IX) are released, which is toxic to the parasite.

• To protect itself, the parasite ordinarily polymerizes the heme to hemozoin (a pigment), which is sequestered in the parasite’s food vacuole.

• Chloroquine specifically binds to heme, preventing its polymerization to hemozoin.

• the accumulation of heme result in oxidative damage to the membranes, leading to lysis of both the parasite & the red blood cell.

• Pharmacokinetics:– Route of administration – oral, parenteral

– Absorption – well absorbed from the GIT

– Distribution – rapidly distributed to the tissues. Volume of distribution 100 – 1000 L/kg (due to extensive accumulation in organs – liver, spleen, lungs, heart, kidney, pancreas, brain, eyes, erythrocyte & skin) & is slowly released from tissues & metabolized in the liver

– Excretion – mainly in the urine with a initial t½ of 3-5 days but a much longer terminal elimination t½ of 1-2 months

• Indications:–Chemoprophylaxis & treatment of malaria

where there is no chloroquine resistance

–Hepatic amoebiasis (effective amoebicidal as it reaches high concentration in the liver)

–Rheumatoid arthritis -anti inflammatory action is due to –• inhibition of lymphocyte proliferation, decrease

leukocyte chemotaxis,• decrease lysosome enzyme release• & inhibit phospholpase A2 which decrease

prostaglandin & thus decreased inflammation

• Contraindications:

–Psoriasis

–Patient with retinal or visual field abnormality or myopathy

–History of liver disease or neurologic or hematologic disorders

• Adverse effects:

–Corneal deposits of chloroquine may be asymptomatic or may cause halos around lights or photophobia (these reverse when the drug stopped).

– Retinal toxicity is more serious, & may be irreversible. In early stage it takes the form of visual field defects; late retinopathy classically gives the picture of macular pigmentation surrounded by a ring of pigment (the ‘bull’s eye’ macula.

– In the extreme case, blindness

– Pruritus

– Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision & urticaria –uncommon

– Rare – hemolysis in G-6-PD deficiencientpatient.

– impaired hearing, confusion, psychosis, seizure, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair, hypotension

– Long term administration of high doses of chloroquine for rheumatoid disease can result in – irreversible ototoxicity, retinopathy, myopathy & peripheral neuropathy

– Larger I.M. injection or rapid I.V. infusion of chloroquine hydrochloride can result in severe hypotension & respiratory & cardiac arrest

• Chloroquine is the drug of choice because ––Rapidly causes remission of fever &

parasitemia within 24-48 hours after receiving therapeutic dose

–Well tolerated & more reliably administered than quinine

–No toxic synergism when given with primaquine

–Duration of treatment shorter with choroquine(3 days) than quinine (7 days)

–As a both suppressive & therapeutic agent chloroquine is superior to quinine i.e. more potent & less toxic than quinine

–Hypoglycemia less with chloroquine–Quinine cause more GI upset–Quinine narrow therapeutic index

Blood schizontocide: Quinine

• Quinine & Quinidine remain first-line therapies for falciparum malaria- specially severe disease

• Chemistry & pharmacokinetics:– Quinine is derived from the bark of cinchona tree, a

traditional remedy for intermittent fevers from South America

– Orally active. Rapidly & completely absorbed from the GIT.

– Widely distributed in body tissues. – Highly bound (90%) to plasma proteins. – The pharmacokinetics of quinine varies among

populations. Individuals with malaria develop higher plasma levels of the drug than healthy controls, but toxicity is not increased, apparently because of increased protein binding.

• The half-life is longer in those with severe malaria (18 hours) than in healthy controls (11 hours).Quinidine has a shorter half-life (6 hours) than quinine, mostly as a result of decreased protein binding.

• metabolize in the liver & excreted in the urine.

• Readily cross placental barrier

• CSF concentration is only 2-5 % of that in the plasma

• Mechanism of action:–Unknown.Quinine is a rapidly acting, highly

effective blood schizontocide against the fourspecies of human malarial parasites. The drug isgametocidal against P vivax & P ovale but notP.falciparum. It is not active against liver stageparasites.

• Pharmacological action:–Antiplasmodial action: quinine binds with

plasmodial DNA & thus inhibit protein synthesis. It also inhibit hemoglobin metabolism by parasite

–Antimalarial action: blood schizontocide.–Heart “quinidine like action”: a depressant action

on heart. Antidysrhythmic action.– Skeletal muscle: a slight blocking action on the

neuromuscular junction used in mytonia & muscle cramp because it prolongs the muscle refractory period

– Pancreas: stimulate insulin secretion –hypoglycemia

–Others:• Weak antipyretic action. • Mild oxytocic action on the gravid uterus

• Clinical use:– Parenteral treatment of severe falciparum

malaria– First-line therapy for uncomplicated falciparum

malaria & Chloroquine resistant malaria–Malarial chemoprophylaxis: not generally used

owing to toxicity, although a daily dose of 325 mg is effective

– Babesiosis: first-line therapy in combination with clindamycin, in the treatment of infection with Babesia microti or other human babesial infection

–Myotonia congenita–Nocturnal muscle cramp

• Contraindication:–Hypersensitivity to quinine– Pregnancy– Evidence of hemolysis, cinchonism–Optic neuritis–Myasthenia

• Adverse effects:

–Hearing & vision are particularly disturbed.

• Tinnitus, vertigo, decreased auditory acuity, blurred vision, disturbed color perception, photophobia, diplopia, night blindness, mydriasis

– Skin – hot & flushed. Sweating is prominent

–Nausea, vomiting, abdominal pain & diarrhoea, hypoglycemia – more in children, pregnant woman & the elderly patient

–Black water fever is a rare severe illness that includes marked hemolysis & hemoglobinuria due to hypersensitivity reaction to the drug, though its pathogenesis is uncertain

Points Chloroquine Quinine

Chemical nature 4-aminoquinoline Cinchona alkalloid

Effective against P falciparum

sensitive strains,

P malariae, P

ovale, P vivax

P falciparum

resistant strain, P

vivax, P ovale, P

malariae

Effect on sporozoite & pre-erythrocytic form of parasite

No action Little action

On relapse Does not prevent relapse of vivax malariae

Prevent relapse of

vivax malariae

Potency More potent Less potent

Toxicity Less More

Points Chloroquine Quinine

Duration of

treatment

Shorter (3 days) Longer (7 days)

Patient

compliance

Well tolerated,

reliable

Not well tolerated

t½ 50 hours 10 hours

Plasma protein

binding

50-65% 90%

Adverse effect Large dose causes –retinopathy, ototoxicity, cardiovascular toxicity

Hypoglycemia,

cinchonism

Blood schizontocide: Mefloquine• Mefloquine is effective therapy for many

chloroquine-resistant strains of P falciparum & against other species

• One of the recommended chemoprophylactic drugs for use in most malaria-endemic regions with chloroquine-resistant strains

• It is a synthetic 4-quinoline methanol that is chemically related to quinine

• It can only be given orally because severe local irritation occurs with parenteral use

• Pharmacokinetics:–Well absorbed –Highly protein bound, extensively distributed in

tissues, & eliminated slowly, allowing a single-dose treatment regimen

– t½ 15-30 days, allowing weekly dosing for chemoprophylaxis. Prolonged t½ probably due to fact that it undergoes extensive enterohepatic cycle & it has high tissue storage

–Mefloquine & acid metabolites of the drug are slowly excreted, mainly in the feces

–The drug can be detected in the blood for months after the completion of therapy

• Advantage for chemoprophylaxis:– It is active against multi-drug-resistant P

falciparum– It has extended duration of action &– It has relatively minor adverse effects

• Simultaneous administration of mefloquine & chloroquine increase the chance of convulsion, so this is not encouraged

• Clinical uses:–Chemoprophylaxis: against most strains of P

falciparum & probably all other human malarial species as well except for those with no chloroquine resistance (where chloroquine is preferred). Eradication of P vivax & P ovale requires a course of primaquine

– Treatment: most falciparum malaria

• Adverse effects:–GI disturbance: nausea, vomiting, abdominal

pain, diarrhoea & loss of appetite– Transient CNS toxicity: giddiness, confusion,

dysphoria & insomnia–Cardiac conduction defect, arrhythmia &

bradycardia–Rash – Leukocytosis, thrombocytopenia, &

aminotransferase elevations –Rarely neuropsychiatric reactions: depression,

confusion, seizure, acute psychosis & hallucination

• Disadvantage for treatment of acute malaria –– Expensive, about 50% of the patient complain of

GI disturbances, transient CNS toxicity.

• Contraindication & cautions:– if history of epilepsy, psychiatric disorders,

arrhythmia, cardiac conduction defects, or sensitivity to related drugs

– It should not be co administered with quinine, quinidine, or halofantrine, & caution is required if quinine or quinidine is used to treat malaria after mefloquine chemoprophylaxis

–Now considered safe in young children– should not be used in pregnant woman or in

woman liable to become pregnant within 3 months of stopping the drug

Tissue schizontocide: Primaquine

• Is the drug of choice for the eradication of dormant liver forms of P vivax & P ovale

• It is a synthetic 8-aminoquinoline• Well absorbed orally. t½ is 3-8 hours.• Widely distributed to the tissues, but a small

amount is bound there.• It is rapidly metabolized & excreted in the urine.• Its three major metabolites appears to have less

antimalarial activity but more potential for inducing hemolysis than the parent compound

• Primaquine is also gametocidal against the four human malarial species.

• Clinical uses:– Therapy (radical cure) of acute vivax & ovale malaria– Terminal prophylaxis of vivax & ovale malaria– Chemoprophylaxis of malaria– Gametocidal action– Pneumocystis jiroveci infection

• Adverse effects:– Primaquine in recommended doses is generally well

tolerated. Infrequently causes nausea, epigastricpain, abdominal cramps, & headache (with higher dosages & in empty stomach)

– Serious but rare adverse effects include leukopenia, agranulocytosis, leukocytosis, & cardiac arrhythmias

– Standard dose of primaquine may cause hemolysisor methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects

• Contraindication & cautions:– History of granulocytopenia or methemoglobinemia,

in those receiving potentially myelosuppressive drugs (e.g. quinidine)

– Never given parenterally because it may induce marked hypotension

– Avoided in patients with G6PD deficiency– Avoided in pregnancy because the fetus is relatively

G6PD-deficient & thus at risk of hemolysis

• Pyrimethamine–Pyrimethamine is a 2,4-diaminopyrimidine

related to trimethoprim– Effect a radical cure as a blood schizontocide &

strong sporontocide in the mosquito’s gut when the mosquito ingests it with the blood of human host

–Has an elimination half-life of about 3.5 days. Therefore it can be given once a week

• Proguanil – Is a biguanide derivative–Has an elimination half-life of about 16 hours,

therefore it must be administered daily for chemoprophylaxis

– is a prodrug; only its metabolite, cycloguanil, is active

• Both drugs are slowly but adequately absorbed from the GIT

• Mechanism of action of folate antagonist:

– Selectively inhibit plasmodial dihydrofolatereductase, a key enzyme in the pathway for synthesis of folate

– Sulfonamides & sulfones inhibit another enzyme in the folate pathway, dihydropteroatesynthetase. Combinations of inhibitors of these two enzymes provide synergistic activity

• Clinical uses:

–Chemoprophylaxis; Treatment of chloroquineresistant falciparum malaria; Presumptive treatment of falciparum malaria; Toxoplasmosis; pneumocystosis

• Adverse effects & caution:–Well tolerated–GI symptoms, skin rash & itching are rare–Mouth ulcer & alopecia (proguanil)– Fansider is no longer recommended for

chemoprophylaxis because of uncommon but severe cutaneous reactions, including erythemamultiforme, Stevens-Johnson syndrome, & toxic epidermal necrolysis

– Folate antagonists should be used cautiously in the presence of renal or hepatic dysfunction

– Proguanil is considered safe in pregnancy–With the use of any folate antagonist in pregnancy,

folate supplements should be co administered

Halofantrine• A phenanthrene-methanol related to quinine, is

effective against erythrocytic (but not other) stages of all four human malarial species

• Rapidly effective against most chloroquine-resistant strains of P falciparum

• Generally well tolerated, but use is limited by irregular absorption & cardiac toxicity

• Most common adverse effects are abdominal pain, diarrhoea, vomiting, cough, rash, headache, pruritus, & elevated liver enzymes

• Contraindicated in patients with cardiac conduction defects & should not be used in those who have recently taken mefloquine;

• contraindicated in pregnancy

Lumefantrine• An aryl alcohol related to halofantrine

• Available as a fixed-dose combination with artemether as Coartem

• Half-life, in combination, is 4.5 hours

• Coartem is highly effective in the treatment of falciparum malaria, but it is expensive & requires twice-daily dosing

• Despite these limitations, due to its reliable efficacy against falciparum malaria, Coartem has recently been selected as the first-line therapy for malaria in African countries

• Coartem does not appear to cause the cardiac toxicity as seen with halofantrine

Artemisinin & its derivatives• Artemisinin (qinghaosu) is a sesquiterpene lactone

endoperoxide, the active component of an herbal medicine that has been used as an antipyretic in China for over 2000 years

• Artemisinin can only be used orally• Analogs have been synthesized to increase solubility &

improve antimalarial activity. Most important of these analogs are –– Artesunate (water-soluble; useful for oral, IV, IM, &

rectal administration) & Artemether (lipid-soluble; useful for oral, IM, & rectal administration)

• Rapidly absorbed, half-life of 1-3 hours after oral administration

• Compounds are rapidly metabolized to the active metabolite dihydroartemisinin

• Artimisins have no effect on hepatic stages• The antimalarial effect may result from the

production of free radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxidebridge in the parsite food vacuole or from inhibition of a parasite calcium ATPase

• Artesunate & artemether are playing an increasingly important role in the treatment of multidrug-resistant P falciparum malaria

• They are the only drugs reliably effective against quinine-resistant strains

• The efficacy of artemisinins is limited by their short plasma half-life

• Also because of their short-half-lives, they are not useful in chemoprophylaxis

• Artesunate has also been effective in the treatment of severe malaria when administered rectally, offering a valuable treatment modality when parenteral therapy is not available

• In the setting of multidrug resistance, combination therapy with an artemisinin are: Artemether + lumefantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulfadoxin + pyrimethamine

• Most commonly reported adverse effects – nausea, vomiting & diarrhoea

• Artemisinins should be avoided in pregnancy because tertogenicity seen in animal studies

Fansidar • Pyrimethamine (25 mg) acts synergistically with

sulfadoxin (500 mg) as Fansidar to inhibit folic acid metabolism

• It is used with quinine to treat acute attack of malaria caused by susceptible strains of P falciparum resistant to chloroquine

• Mechanism of action:–Acts by reciprocal potential of its two components,

achieved by a sequential blockade of two enzymes involved in the biosynthesis of folinic acid in the parasites

–Dosage: a single dose of pyrimethamine 75 mg + sulfadoxin 1.5 gm (3 tablets) usually suffices

– Sulfadoxin is excreted in the urine

• Indication:–All forms of malaria

• Toxoplasmosis– Pneumonia due to pneumocystis carinii– For chemoprophylaxis of malaria

• Contraindications:–During pregnancy (because of antifolate action)– Pre mature or new born infants during 1st few

weeks of life (due to immaturity of enzyme system)– Sulfonamide hypersensitive patient

• Adverse effects:–Any sulfonamide induced allergic reaction can be

severe, e.g. erythema multiforme, Stevens Johnson syndrome & toxic epidermal necrolysis.

Drugs to prevent transmission

• Some drugs (e.g. primaquine, proguanil & pyrimethamine) have the additional action of destroying the gametocytes, preventing transmission by the mosquito & thus preventing the increase of the human reservoir of the disease – but they are rarely used for this action alone

Last minute traveler

• 500 mg of chloroquine phosphate (Tab 250 mg) (300 mg base) taken daily for 2-3 days then once weekly during staying in the malaria zone & continued for 4 weeks after leaving the area

• Or

• Mefloquine (Tab 250 mg) 250 mg daily for 2-3 days & then weekly continued up to 4 weeks after leaving the area

Management of cerebral malaria

• Diagnosis is made from cerebral manifestation ––Convulsion, hypoglycemia, difficulty in breathing

or pulmonary edema, oliguria or acute renal failure, hyperpyrexia, hyperparasitemia, change of behavior, drowsiness, altered consciousness, coma, severe anemia, circulatory collapse or shock, hemoglobinuria, jaundice, acidosis

• Exclusion of other causes of encephalopathy• Focal neurological signs absent• Neck rigidity & kernigs sign absent• Microscopic confirmation• CSF normal

• Injection chloroquine 5 mg/kg in 500 ml of 5% dextrose aqua over 4 hours stat & 8 hourly upto patient can take orally for 7 days orally

• Or if chloroquine resistant –• IV quinine dihydrochloride loading dose 20

mg/kg if not treated with quinine before• If treated then give 10 mg/kg body weight• It is given with 500 ml of 5% (10%) dextrose

over 4 hours & 8 hourly until patient can take the drug orally. Total duration for 7 days

• Treatment of convulsion – diazepam IV 0.2 mg/kg

• For hypoglycemia – IV glucose 10% or 25%• Correct fluid & electrolyte balance• If hemoglobin < 6 gm/dl – blood transfusion

with packed red cell• Ryles tube down for feeding

• Proper nursing care ––Clean airway– Frequently change of posture–Urethral catherization–Careful record of input/output chart–Check speed of infusion frequently–Monitoring of vital signs

• Treatment of pulmonary edema – propped up position, frusemide

• Hyperpyrexia – sponging, antipyretic• Hyparasitemia: if > 10% RBC are infected –

exchange blood transfusion• Antibiotic – if associated infection• If oliguria develops, frusemide or an infusion of

mannitol may forestall renal failure• Dialysis may be needed if renal failure develops