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Anti Protozoa

Anti Protozoa

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Pharmacology (dra Dando)
Anti-Protozoa
30 January 08
PRINCIPLES OF ANTIPARASITIC CHEMOTHERAPHY 
 TARGETS OF CHEMOTHERAPHY OF PARASITIC DISEASE1) unique essential enzymes found only in the parasiteEx. Pyruvate serotoxin oxidoreductase 
produce by anaerobic protozoa 
nitroimidazole2) similar enzymes found in both host and parasite butindispensable only for the parasiteEx.
α
-Difluromethylornithine 
acts on orthinine decarboxylase of African trypanosome (sleepingsickness)3) common biochemical functions found in both parasiteand host but with different pharmacologic properties.Ex. Microtubules --in helminthes
Benzomidazole------------------------
ANTIPROTOZOALDRUGS-----------------------TREATMENT OF MALARIA
Four species of plasmodium that cause human malaria:a) Plasmodium falciparum= responsible for nearly all serious complication anddeaths= drug resistance is an important therapeutic problemb) Plasmodium vivaxc) Plasmodium malariaed) Plasmodium ovalePARASITIC LIFE CYCLE1) Anopheline mosquito
inoculates plasmodiumporosities to initiate human infection.2) Circulating SPOROZOITES rapidly invade liver cells3) EXOERYTHROCYTIC stage tissue schizonts mature inthe liver4) MEROZOITES release from liver and invadeerythrocytes*** During the
asexual erythrocytic stage of infection,
parasites develop from trophozoites toschizonts and then rupture host erythrocytes, releasingmultiple merozoites that invade other erythrocyte toreinitiate the cycle.ERYTHROCYTIC PARASITES = causes clinical illness*** Sexual stage GAMETOCYTES also develop inerythrocytes before being taken up by mosquitoes,where they develop into infective porosities.NOTE:
P. faclciparum & malariae= only one cycle of liver cell invasion &multiplication occurs, and liver infection ceasesspontaneously in less than 4weeks. Thus,treatment that eliminates erythrocytic parasiteswill cure these infection
P. vivax & P. ovale= a dormant hepatic stage, the HYPNOZOITE, isnot eradicated by most drugs and subsequentrelapses can therefore occur after therapydirected against erythrocytic parasites= eradication of both erythrocytic and hepaticparasites is required to cure these infection.ANTIMALARIAL DRUGS:SITE OF ACTION1) Drugs used to treat acute attack- blood schizonticidal agents- drugs for suppressive/clinical use2) drugs that affect the exoerythrocytic hypnologists &results in radical cure of P.vivax & P.ovale3) drugs that block the link between exoerythrocyticstage & erythrocytic stage- used for chemoprophylaxis (casual prophylactic)- prevent the development of malarial attacks- acts on Merozoites emerging from the liver cells4) drugs that prevent transmission and thus preventincrease the human reservoir of the disease-act on gametocytesSUMMARY OF DRUGS USED FOR TX &CHEMOPROPHYLAXIS OF MALARIAINFECTIONDRUG FOR TXOF CLINICALINFECTIONDRUG FORCHERMOPROPHYLAXISAll plasmodialinfectionexceptchloroquineresistant P.faclcifarumOralchloroquine orsulfadoxine-pyrimethamine(FANSIDAR)Oralchloroquine orproguanilInfection withchloroquineresistantP.falciparumOralchloroquine +tetracycline/doxycycline/oralhalofantrine/oralmefloquineOralchloroquine +proguanil/doxycycline/pyrimethanine-dapsone/mefloquine
ANTIMALARIAL DRUGSI. CHLOROQUINE
DOC: treatment and chemoprophylaxis of malaria but its utility against P.falciparum hasbeen seriously compromised by drug resistance
Synthetic 4-aminoquinoline
Oral use: formulated as a phosphate salt
 T1/2: 3-5 days
 Anti-malarial action and resistance:
a)ANTI-MALARIAL ACTION-Blood schizonticide-Moderately effective against gametocytesof P. vivax, P. ovale and P.malariae but not
 
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Pharmacology –
Endocrine Drugs
by 
 Dra Dando
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against those of P.falciparum-Not active against liver stage parasiteb)MOA-Concentrating in parasite food vacuoles-Preventing the polymerization ohemoglobin breakdown product, heme,into hemozoin and thus eliciting parasitetoxicity due to the build-up of free hemec)RESISTANCE-Common among strains of falciparum-Chloroquine resistance can be reversed:1) verapamil, 2) desipramine, and 3)pheniramine
Clinical uses:
a)TREATMENT-both for treatment and prophylaxis of non-falciparum and sensitive faciparummalaria-it rapidly terminates fever and clearsparasitemia cost by sensitive parasites-with PRIMAQUINE = eliminates dormantliver forms of P.vivax and P.ovaleb)CHEMOPROPHYLAXIS-Preferred chemoprophylactic agent inmalarious regions without resistantfacliparum malaria\c)AMEBIC LIVER ABSCESS-Combination with METRONIDAZOLE
 ADR:
(usually very well tolerated even withprolonged use)a)Pruritus is common primarily in Africansb)N&V, abdominal pain, HA, Anorexia, Malaise,blurring of vision and urticaria areuncommonc)Dosing after meals may reduce someadverse effects
Contraindication:
a)px w/ psoriasis and porphyria,b)with retinal or visual field abnormalities ormyopathyc)caution in px w/ hx of liver disease/neurologic/ hematologic disordersd)antidiarrheal agents: kaolin & Ca++ & Mg++containing acids interfere w/ absorption of chloroquine.
Considered safe: pregnancy & for young adults
II. QUININE
DOC: Chloroquine resistant P. Falciparum
First-line therapies for falciparum malaria---especially in severe disease--- though toxicityconcerns complicate therapy
 T1/2: 11 hours
 Anti-malarial action:
-Rapidly acting, highly effective bloodschizonticide against four species of human malaria parasite-Gametocidal against P.vivax and P.ovale-Not active against liver stage parasites
Clinical Use:
a)PARENTERAL TX OF SEVERE FALCIPARUMMALARIA-May cause cardiac toxicity in IV route,so it should be administered w/cardiac monitoringb)ORAL TX OF FALCIPARUM MALARIA-First-line therapy for uncomplicatedfalciparum malaria except wheninfection was transmitted in an areaw/o documented chloroquine resistantmalaria-Less effective than chloroquineagainst other human malarias and ismore toxic, and it is therefore notused to treat infections with theseparasitesc)MALARIAL CHEMOPROPHYLAXIS-Not generally used in chemoprophylaxisowing to its toxicityd)BABESIOSIS-First line therapy, in combination w/CLINDAMYCIN, for the treatment of infection w/ Babesia microti or otherHuman Babesial infection
 ADR:
a)CINCHONISM-Tinnitus, HA, N&V, dizziness, flushing andvisual disturbance (constellation of symptoms)b)BLACKWATER FEVER-Hemolysis(pallor & anemia) andhemoglobinuria (pallor & bloody urine)-Hypersensitivity to drugc)Severe Hypotension(too rapid IV infusion;Prolong QT (IV)
Contraindication &Caution:
a)Visual & auditory problemsb)Cardiac abnormalitiesc)Should not be given concurrently w/mefloquine and caution in Px w/ malaria whopreviously received mefloquinechemoprophylaxisd)Absorption may be block by aluminum-containing antacide)Can rise plasma levels of warfarin & digoxinf)Dosage must reduce in renal insufficiency
Given in combination w/:
a)Pyrimethamine - folate antagonist that acts asblood schizonticide given orally(t1/2=4days)b)Dapsone – a sulfone, oral (T1/2= 24-48hrs)c)Sulfadoxine – long-acting sulfonamide (T1/2=7-9days)
III. MEFLOQUINE
Effective therapy for many chloroquine-resistantstrains of P.falciparum and against other species
Recommened chemoprophylactic drug use inmost malaria-endemic regions w/ chloroquineresistant strains
Synthetic of 4-quinoline methanol
Given ORALLY bec svere local irritation occurs w/parenteral use
 T ½ = 30days
MOA: Inhibits parsites heme polymerase
 Antimalarial action:
 
Pharmacology –
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 Dra Dando
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a)strong blood schizonticidal activity againstP.falciparum & P.vivaxb)not active against hepatic stages orgametocyte
 ADR:
a)GI disturbanceb)Neurotoxicityc)Psychiatric problems ( depression, confusion,acute psychosis, or seizures)d)Leukocytosis, thrombocytopenis andaminotransferase elevatione)Can also alter cardiac conduction andarrhythmias & bradycardia have beenreported
Contraindication:
a)Hx of epilepsy, psychiatric disorders,arrhythmia, cardiac conduction defects, orsensitivity to related drugsb)Should not be coadministered w/ quinine,quinidine,or halofantrinec)SAFE: children, pregnancy
IV. PRIMAQUINE
DOC: eradication of dormant liver forms of P.vivax& P.ovale
Synthetic 8-amino quinolone
ORAL
 T1/2: 36 hrs
 Antimalarial action:
a)Active against hepatic stages of all humanmalarial parasitesb)Dormant hypnozoite stages of P.vivax &P.ovalec)Gametocidal against the four malarial humanspecies
Clinical Use:
a)Therapy (radical cure) of Acute Vivax andOvale Malaria-Standard therapy for these infectionincludes chloroquine to eradicateerythrocyticforms and primaquine toeradicate live hypnozoites and prevent asubsequent relapseb)Terminal Prophylaxis of Vivax & Ovale Malariac)Chemoprophylaxis of Malariad)Gametocidal Action
e)
Pneumocystis carinii infection-Combination w/ CLINDAMYCIN is analternative regimen for the tx of pnuemocystosis, particularly mild tomoderate disease
 ADR:
a)GI disturbances
b)
Methehemoglobinemia = w/ large doses; decoxygen capacity causing cyanosis; Fe+
2
→Fe
+3
c)Hemolysis = individual w/ G6PD geneticdeficiency in erythrocyted)Leucopenia, agranulocytosis, leukocytosis andcardiac arrhythmias
Contraindication:
a)Hx of granulocytopenia/methehemoglobinemia, in those receivingpotential myelosuppressive drugsb)Never given parentally because it inducemarked hypotensionc)G6PD deficient
V. ATOVAQUONE
a hydroxynaphthoquinone
ORAL
Initially developed as an antimalarial and ascomponent of MALARONE is recommended asprophylaxis
It has been approved by the FDA for thetreatment of mild to moderate P.jirovecipneumonia
Absorption is increase by FATTY FOOD
Resistance develop rapidly if given alone
 T1/2 = 2-3 days
In plasmodia it appears to disrupt mitochondrialelectron transport
MALARONE = combination of atovaquone &proguanil highly effective as tx &chemoprophylaxis of falciparum malaria= use for tx of simple, acute, uncomplicated P.falciparum
It has advantage over mefloquine & doxycyclinein requiring shorter period of tx, before and afterthe period of risk of malarial transmission, but it ismore expensive than other drugs
 Taken w/ food
Alternative therapy for p. jiroveci but its efficacyis lower than trimethoprim-sulfamethoxazole
ADR: fever rash, N&V, diarrhea, HA and insomnia
Plasm concn is decrease in combination w/tetracycline & rifampin
INHIBITOR OF FOLATE SYNTHESISI. PYRIMETHAMINE
Can be given once a week for chemoprophylaxis
Combination w/:a)Sulfadoxine----FANSIDARb)Dapsone -----MALOPRIM
c)
Suldiazine ---1
st
line tx for toxoplasmosis
II. PROGUANIL
Biguanide derivative
Administered daily for chemoprophylaxis
It is Prodrug
only its triazine metabolite: CYCLOQUANIL, isactive
folate antagonist
slow acting blood schizonticide
some action on primary liver forms of vivax
ORAL
Have some activity against hepatic form
SAFE: Pregnancy but folate supplements shouldbe coadminsteredANTIMALARIAL ACTION & RESISTANCEA.Antimalarial action-Acts slowly against erythrocytic forms of susceptible strains of all four humanmalaria species

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