Pharmacology Aspect of Antimalaria_2009

8/10/2019 Pharmacology Aspect of Antimalaria_2009

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Dr. DATTEN BANGUN MSc,SpFK

Bagian Farmakologi danTerapeutik,

Fakultas Kedokteran

Pharmacology aspects of anti

malariaDr Tri Widyawati M.Si


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Introduction

Four species of plasmodium cause humanmalaria:

- Plasmodium falciparum,

- P vivax,- P malariae,

- P ovale.

Although all may cause signicant illness, P

falciparumis responsible for nearly all seriouscomplications and deaths.

Drug resistance is an important therapeuticproblem, most notably with P falciparum.


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Parasite ife !ycle

An anopheline mos"uito inoculates plasmodiumsporo#oites to initiate human infection.

!irculating sporo#oites rapidly in$ade li$er cells,and e%oerythrocytic stage tissue schi#onts mature

in the li$er. &ero#oites are subse"uently released from the li$erand in$ade erythrocytes.

'nly erythrocytic parasites cause clinical illness. (epeated cycles of infection can lead to the

infection of many erythrocytes and serious disease. )e%ual stage gametocytes also de$elop inerythrocytes before being ta*en up by mos"uitoes,where they de$elop into infecti$e sporo#oites.


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Parasite ife !ycle

In P falciparumand P malariae infection,only one cycle of liver cell invasion andmultiplication occurs, and liver infectionceases spontaneously in less than 4 weeks.

+hus, treatment that eliminates erythrocyticparasites will cure these infections. In P vivax and P ovale infections, a dormant

hepatic stage, the hypnozoite, is noteradicated by most drugs, and subsequentrelapses can therefore occur after therapydirected against erythrocytic parasites.

radication of both erythrocytic and hepaticparasites is re"uired to cure these infections.


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Drug !lassication

tissue schizonticides: Drugs that eliminatede$eloping or dormant li$er forms .

blood schizonticides: those that act onerythrocytic parasites

ametocides! those that *ill se%ual stages andpre$ent transmission to mos"uitoes are. o one a$ailable agent can reliably eect a radical

cure, ie, eliminate both hepatic and erythrocyticstages.

Few a$ailable agents are causal prophylactic drugs,ie, capable of pre$enting erythrocytic infection.

/owe$er, all eecti$e chemoprophylactic agents*ill erythrocytic parasites before they growsu0ciently in number to cause clinical disease.


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Drug !lassication


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Drug !lassication


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!hloro"uine

)ynthetic 1-amino"uinoline formulated asthe phosphate salt for oral use

Ph.*inetic:

- rapidly , almost completely absorbed fromthe gastrointestinal tract, distributed tothe tissue

- %creted in the urine

2lood schi#ontocide &oderately against gametocytes of P.vivax, P ovaleand P. malariae

ot acti$e against li$er stage parasites


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!hloro"uine: &echanism ofAction

!oncentrating in parasite food$acuoles, pre$enting thepolymeri#ation of the hemoglobin

brea*down product, heme, intohemo#oin and thus eliciting parasiteto%icity due to the build up of free

heme.

Hemoglobin-----------heme -------------------- hemozoin

polymerizationchloroquine

(-)


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!hloro"uine: Ad$erseeects

!ommon: Pruritus

3ncommon: ausea, 4omiting,Abdominal

pain, /eadache,Anore%ia,

&alaise, 2lurring of$ision,

urticaria


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!hloro"uine: (esistance

!ommon: P. falciparum

mutations in a putative transporter, PfCRT

3ncommon: P.vivax


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5uinine and 5uinidine

5uinine:

- the bar* of the cinchona tree

- rapidly acting, highly eecti$e bloodschizonticide against the four species of humanmalaria parasites

- gametocidal against P $i$a% and P o$ale butnot P. falciparum

- not acti$e against li$er stage parasites

- &oA: un*nown

5uinidine: de%trorotatory stereoisomer of "uinine


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5uinine and 5uinidine

P': rapidly absorbed

pea* plasma le$els in 6-7 hours

widely distributed in body tissues

Ph*inetic: $aries among population

metaboli#ed in the li$er

e%creted in the urine

Indi$iduals with malaria: protein binding higher plasma level

Quinidine: shorter t1/2 than quinine


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5uinine: Ad$erse ects

!inchonism tinnitus, headache, nausea,di##ines, 8ushing, $isual disturbances

After prolongoed th9: $isual and auditoryabnormalities, $omiting, diarrhea, andabdominal pain.

/ematologic abnormalities esp. ;


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5uinine : !ontraindication

5uinine9"uinidine: should bediscontinued if :

- signs of se$ere cinchonism,hemolysis, or hypersensiti$ity occur

- underlying $isual or auditoryproblems

ot be gi$en concurrently withme8o"uine


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Prima"uine

Drug of choice of dormant li$er formsof P vivax and P ovale

A synthetic >-amino"uinoline

?ell absorbed orally, reaching pea*plasma le$els in 6-@ hours

Distributed to the tissues

+he metabolites ha$e less antimalarialacti$ity but more potential for inducinghemolysis than the parent compound


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Prima"uine

Acti$e against hepatic stages of allhuman malaria parasites

Acti$e against the dormanthypno#oite stages of P vivaxand Povale

;ametocidal against the four humanmalaria species

&oA: un*nown


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Inhibitor of Folate )ynthesis

Pyrimethamine! - t69@: 7. days administered one a !ee"

Proguanil! - biguanide deri$ati$e - t69@: 6< hours administered dail# for

hemoproph#la$is

% pro drug: onl# its tria&ine meta'olite, #loguanil, is ative

P#rimethamine and proguanil seletivel# inhi'it plasmodial

dih#drofolate redutase Fansidar:fi$ed om'ination of the sulfonamide

sulfado$ine ()** mg/ta'+ and p#rimethamine (2) mg/ta'+


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"tovaquone Ato$a"uone is protein bound BCC= but

causes no signicant displacement of otherhighly protein-bound drugs.

/owe$er, concomitant administration ofato$a"uone with rifampin leads to a 1E to

E reduction in ato$a"uone le$els

Atovaquone is protein bound (>99%) but causes no

significant displacement of other highly protein-bounddrugs.

Hoever! concomitant administration of atovaquone ith

rifampin leads to a "# to $#% reduction in atovaquone

levels


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Ato$a"uone

For treatment and prophyla%is of malaria it hasbeen combined with the biguanide proguanil in a%ed combination

&oA:

- Ato$a"uone has broad-spectrum acti$ity againstPlasmodiumspp., P. carinii, Babesiaspp., andToxoplasma gondii.- Its mechanism of action has been mostcompletely elucidated for Plasmodiumspp.- +he drug is structurally similar to the innermitochondrial protein ubi"uinone also calledcoen#yme 5=, which is an integral component ofelectron 8ow in aerobic respiration


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Artemisinin Its Deri$ati$e Artemisinin "inghaosu=: a ses"uiterpine lactone endopero%ide,

the acti$e component of an herbal medicine that has been usedas an antipyretic in !hina for o$er @EEE years

Insoluble and can only be used orally

Analog: - artesunate water-soluble, useful for oral, I4,I&,rectal

- artemether lipid soluble, useful for oral, I&, and rectal

administration= +he compounds are rapidly metaboli#ed into the acti$e

metabolite dihydroartemisinin----short acting------monotherapy has to

e%tended beyond the disappearance of parasite to pre$ent recru-

descence,otherwiseGused in combination. 4ery rapidly acting blood schi#ontocidesagainst all human

malaria parasites.

/as no eect on hepatic stages-----do not *ill hypno#oites


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#echanism of artemisininaction!

H not denitely *nown

H artemisinin has endopero%ide bridge in

its molecule

H this will interact with haeme in theparasite

-------iron-mediated clea$age of the

bridge will release a highly reacti$e free-radicals species-----lysis of theparasites


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?hat is antimalarial drugresistance

Ability of a parasite strain to sur$i$e and9ormultiply despite the administration and absorptionof a drug gi$en in doses e"ual to or higher thanthose usually recommended but within tolerance

of the subJectK ?/', 6CL7=.

+he drug must gain access to the parasite or theinfected red blood cell for the duration of the timenecessary for its normal action ?/', 6C>


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drug resistance Increased morbidity and mortality

including anaemia, low birth weight

Increased of transmission switch to eecti$e drug combinations in situations of low to

moderate endemicity has always resulted in a dramaticdecrease in transmission

conomic impact increases cost to health ser$ices to both pro$ider and

patient= because of returning treatment failures

;reater fre"uency and se$erity of epidemics &odication of malaria distribution

;reater reliance on informal pri$ate sector with the ris* of using monotherapies, sub-standard and

counterfeit medicines which in turn will increase drugresistance


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)ur$eillance of antimalarialdrug resistance

6. A$oiding emergence of drugresistance

@. &onitoring drug e0cacy

7. !ontaining of drug resistance


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)trategies to a$oid drugresistance

$se of combination therapy ecti$e A!+s of good "uality

widely accessible

correctly used, particularly in the pri$ate sector, which

includes: education of the practitioners

increase compliance by use of co-pac*age or co-formulated A!+s.

super$ised drug administration can help to bac* up

adherence similar to D'+= 2etter diagnosis of the disease to a$oid misuse of the

medicines

Fight against drugs of poor "uality


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&onitoring drug e0cacy !ountries must closely monitor the

e0cacy of antimalarial medicines

recommended in their treatmentguidelines and rapidly change drugpolicy when no longer eecti$e, to

a$oid emergence of multidrug-

ransmission control to reduce the burden and the use of

antimalarial drugs (less drug pressure)

&vector control and bed-nets ('outh Africa)

&reduction of reservoir of infection (responsible for

the spread of drug resistance) in improvingtherapeutic practice! in particular early diagnosis!

effective treatment! and use of gametocytocidal drugs.

&accine

a ona e or


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a ona e orantimalarial combination

therapy "dvantages of combining two or more antimalarial

drugs: First cure rates are usually increased B C=---rapid clinical

and parasitological cure

)econd, in the rare e$ent that a mutant parasite which is resistant

to one of the drugs arises de-no$o during the course of theinfection, it will be *illed by the other drug. +his mutual protectionpre$ents the emergence of resistance.

;ood tolerability

%oth partner drugs in a combination must beindependently e&ective.

'isks! Increased costs and increased side e&ects


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(he choice ofartemisinin combination therapy )"*(+

+here are now more trials in$ol$ing artemisinin and itsderi$ati$es than other antimalarial drugs, so although there arestill gaps in our *nowledge, there is a reasonable e$idence baseon safety and e0cacy from which to base recommendations.

*ombinations which have been evaluated!

piperaquineartemisinin +mefloquine

artesunate

piperaquinedihydroartemisinin +mefloquine

lumefantrineartemether +mefloquine

naphthoquine

chloroquine

amodiaquine

sulfadoxinepyrimaethaminine

me-oquineproguanildapsone

chlorproguanildapsone

atovaquoneproguanil

clindamycin

tetracycline

doxycycline


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Response to increasing resistance:!ombination therapies (ecommended by ?/'

Artesunate M amodia"uine

Artemether/lumefantrine

Artesunate M )P

Artesunate M me8o"uine

*+,

WHO Technical Consultation on

Antimalarial Combination Therapy April 2001

A,s


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(emember about A!+Ns )hort shelf life @1 months=

Increased costs

onger lead time for deli$eries

!hallenging implementation

but also

)trong commitment from all the partners

3pscaled production from the manufacturers )hared *nowledge and e%perience

;lobal building capacity


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!ase &anagement: Drug 0cacyin Pregnancy

ecti$e drugs are needed for P.falciparummalaria as it can be fatal toboth mother and child

Drug of choice depends on thegeographic drug resistance prole:

!hloro"uine is the drug of choice in few areaswhere it is still eecti$e

)P often ne%t choice

5uinine is the drug of choice for complicatedmalaria

th t h ld t b d


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rugs that should not be usedduring

pregnancy (etracycline

!ause abnormalities of s*eletal and muscular growth,tooth de$elopment, lens9cornea

oxycycline

(is* of cosmetic staining of primary teeth is undetermined %creted into breast mil*

Primaquine /armful to newborns who are relati$ely ;lucose-


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+reatment of )ymptomatic Patients

3ncomplicatedmalaria

Pro$ide rst lineantimalarial drug

appro$ed for useduring pregnancy

+reat fe$er withanalgesics

Diagnose and treatanemia

Pro$ide 8uids

!omplicated malaria ?eigh patient

Administer "uinine as soon as itis diluted

&anage fe$er analgesics, tepidsponging=

Pro$ide rehydration as needed &onitor for se$ere anemia,

hypoglycemia, acute renalfailure and treat as needed

(efer, if not s*illed inmanaging complicated

malaria


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Amodia"uine


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&e8o"uine


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/alofantrine umefantrine


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Pharmacology Aspect of Antimalaria_2009

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