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44 Cards in this Set
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Blood and Lymph- Anti-malarials by Boy Bridges
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Blood and Lymph- Anti-malarials by Boy Bridges
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Drug List
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Primaquine
Chloroquine Mefloquine Doxycycline Atovaquone + proguanil Pyrimethamine + sulfadoxine Quinine (oral only) Quinidine (IV) |
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Chemoprophylaxis (or prophylaxis)
Primary vs Terminal |
Primary
Use of medications prior to, during, and after the exposure period to prevent the initial infection Terminal Use of medications toward the end of the exposure period (or immediately thereafter) to prevent relapses or delayed-onset clinical presentations of malaria caused by P vivax or P ovale |
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Suppressive Therapy, Clinical cure, Radical Cure
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Suppressive therapy
Attempts to destroy the parasite in its erythrocytic stage as it enters blood stream i.e., tries to prevent the erythrocytic infection, which causes the symptoms of malaria Clinical cure When suppressive therapy has failed and larger doses of prophylactic drugs are used to eliminate erythrocytic parasites Even after clinical cure… relapses may occur with P ovale or P vivax because hepatic hypnozoites not eliminated Radical cure Remission free cure of P ovale or P vivax When clinical cure has failed and stronger drugs are used to eliminate both erythrocyte and hepatic forms; P. falciparum tends to make erythrocytes sticky & plug cerebral (cerebral malaria), pulmonary, renal vessels |
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Name the 4 species of plasmodium and the type of disease for each...
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Plasmodium falciparum
-most dangerous, potentially fatal -accounts for most serious complications & deaths -pts should be hospitalized for treatment Plasmodium malariae – common to tropics Plasmodium vivax** – milder disease Plasmodium ovale** – rarely encountered **P. ovale and vivax are relapsing malarias ***malarie, vivax and ovale tx usually outpt basis. |
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Drugs: hepatic schizonticides
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Atovaquone-proguanil
Primaquine -Eliminate developing or dormant liver forms -Used for casual prophylaxis -Used to prevent relapse and provide a radical cure |
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Drugs: Hyponozoiticide
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Primaquine
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Drugs: Blood-stage schizonticides
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Atovaquone-proguanil
Doxycycline Mefloquine Chloroquine -Act on erythrocytic parasites -Used for clinical and suppressive care |
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Life cycle of P falciparum and P malariae
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-Only one cycle of liver cell invasion and multiplication occurs
-Liver infection ceases spontaneously in < 4 wks -**Treatment eliminating erythrocytic parasites will cure infection |
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Life cycle of P vivax and P ovale
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-Hypnozoite (dormant hepatic state)
-not eradicated by most drugs -Subsequent relapses can occur after therapy directed against erythrocytic parasites -Eradication of both erythrocytic and hepatic parasites is required to cure these infections |
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Prevention of Relapses of P vivax or P ovale. Why are there relapses? What is the drug for terminal prophylaxis?
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P. vivax and P. ovale parasites can persist in the liver and cause relapses for as long as 4 years or more after routine chemoprophylaxis is discontinued
Terminal prophylaxis with primaquine decreases the risk of relapses by acting against all the liver stages of P vivax or P ovale |
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DOC for eradication of dormant liver forms of P vivax and P ovale. What does it NOT work against?!
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Primaquine, a tissue schizonticide.
Effective against: -Gametocytes -Liver schizonts -Liver hypnozoites This is the only effective drug; only one drug … the prime drug … primaquine **Not effective against blood schizonts Mechanism of action is unknown |
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Primaquine uses
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Uses
Terminal prophylaxis -NOT recommended for chemoprophylaxis -Use only in special situations when other drugs cannot be taken Radical cure -Used in combo w/ blood schizontocide (usually chloroquine) to do this -Only agent active against hypnozoite stages -Prevents relapse of ovale and vivax Not effective in acute attacks -Has no effect on erythrocyte forms; the cause of clinical symptoms |
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Primaquine Adverse effects
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Adverse effects:
Generally well tolerated (low incidence of AEs) **Acute hemolytic anemia!! -Due to glucose-6-phosphate dehydrogenase deficiency -**G6PD deficiency -Most common enzymatic red blood cell disorder (X-linked) -G6PD screening needed before use -Don’t give to pregnant women or newborns because of hemolysis risk -**fetus/newborn is relatively G6PD-deficient |
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Primaquine and G6PD...what's going on?
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Glucose 6-P-dehydrogenase deficiency results in a decrease in NADPH and GSH synthesis, making the cell more sensitive to oxidative agents, such as primaquine. This causes hemolysis.
Primaquine oxidizes GSH to GSSG. Therefore, less GSH is available to neutralize toxic compounds. |
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What do you use Chloroquine (CQ) for?
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A blood schizonticide
Highly effective & inexpensive !!! Effective against: -Erythrocytic forms -all Plasmodia except CQ-resistant falciparum -Gametocytes -all species except CQ-resistant falciparum Not effective against tissue schizonts!! *sucks because there's a lot of resistance to overuse and misuse. |
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What is CQ the DOC for?
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Uses
**DOC for chemoprophylaxis & acute attacks … except for CQ-resistant falciparum (major limitation these days) Course of primaquine required to clear hepatic stages **Safe for use in children and pregnancy Other uses: Amebic liver abscess Rheumatoid arthritis **DOC for everything if the parasite is sensitive to it |
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MoA of CQ?
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Selective toxicity
-**Actively concentrated in parasitized erythrocytes -concentrated ~100x more in infected RBCs -concentrates in parasite’s food vacuole -Chloroquine binds to heme -prevents heme polymerization to hemozoin (an insoluble pigment) -Causes accumulation of free heme which is cytotoxic |
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Selective toxicity
Actively concentrated in parasitized erythrocytes concentrated ~100x more in infected RBCs concentrates in parasite’s food vacuole Chloroquine binds to heme prevents heme polymerization to hemozoin (an insoluble pigment) Causes accumulation of free heme which is cytotoxic |
Resistance
A serious medical problem in most parts of the world most P falciparum are CQ resistant Transporter mutation correlated with resistance Less drug accumulation in food vacuoles decrease influx or trapping ?? increase efflux ?? |
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PK of CQ
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Pharmacokinetics
Concentrates in Liver, spleen, kidney, lung, brain &melanin-containing tissues Parasite (100X the plasma concentration) VERY large apparent Vd (100-1000L !!!) Loading dose required to achieve effective plasma levels Slow elimination – 50:50 liver and kidney Weekly dosing CQ resides in tissue for weeks to months! *huge volume of distribution, so only need to give once a week |
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Adverse Effects
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Very well tolerated, even with prolonged use
Pruritus – common Uncommon adverse effects GI: NV, abdominal pain Urticaria & itching (non-allergic) CNS – headache, malaise, anorexia, blurred vision Hematological- Acute hemolysis (G6PD deficiency) -super rare (not seen with normal dosing) |
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Mefloquine is used for what?
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Treatment of mild to moderate acute malaria(P falciparum or P vivax)
-Recommended for CQ-resistant or multidrug resistant P falciparum Chemoprophylaxis -Very useful as a prophylactic agent in areas with drug-resistant strains of P falciparum -Primaquine required to clear hepatic stages A blood schizonticide Effective against erythrocytic forms CQ-resistant P falciparum Not effective against tissue schizonts |
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Pharmacokinetics
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Slow elimination
Total clearance mainly hepatic metabolism Excretion mainly by fecal route Weekly dosing LONG elimination half-life ~ 21 days |
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Adverse Effects
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Prophylaxis (low dose)
-**mild and transient Treatment (higher dose) -**more frequent and severe -50% have **nausea and vomiting **Neuropsychiatric effects (worst of the bunch) -Confusion, dysphoria, insomnia, anxiety, vivid dreams/nightmares, depression, hallucinations -Rarely psychosis, convulsions -Contraindicated in pts with neurologic & psychiatric disorders **Cardiovascular Conduction abnormalities in combo w/ other drugs Don’t use in patients taking **Beta blockers; Calcium channel blockers |
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Quinine/ Quinidine uses (Tx of choice and DOC for what?)
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**Severe or complicated falciparum infections
-**Treatment of Choice -**Quinidine IV in US, quinine outside the US Oral treatment of falciparum malaria -**DOC for uncomplicated CQ-resistant strains -Used in combo with 2nd drug to shorten duration of use and limit toxicity -most often doxycycline or clindamycin (kids) Chemoprophylaxis -Not generally used due to toxicity |
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How does Quinine work? PK?
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A blood schizonticide
-Effective against all Plasmodia erythrocytic forms -Not active against liver stages Mechanism of Action -Not well understood -May act by mechanism similar to chloroquine Pharmacokinetics -Orally effective (tablets available in USA) -Quinine IV not available in USA -**Quinidine (IV) used in USA (it’s a stereoisomer of quinine) |
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Adverse effects
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Considerably more toxic than chloroquine or mefloquine
Cardiovascular -severe hypotension if infused to rapidly -**QT prolongation (quinidine more cardiotoxic) **Curare-like effects -has neuromuscular blocking activity, and may exacerbate muscle weakness in patients with **myasthenia gravis -use of neuromuscular blocking agents should also be avoided |
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Adverse effects
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**Oxytocic
-promotes rapid labor by stimulating contractions of the myometrium -especially last trimester of preg at high doses **Cinchonism -Observed to some extent in all patients -tinnitus, headache, nausea, dizziness, flushing, visual disturbances; vomiting, diarrhea, abdominal pain Hypersensitivity reactions urticaria, skin rashes, angioedema & bronchospasm |
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Adverse effects
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**Hypoglycemia
-One of most frequent and serious SE -**Stimulates insulin secretion **Blackwater fever - rare severe illness (true zebra) -**Massive hemolysis, hemoglobinemia, hemoglobinuria, renal failure, ~ 25-50% fatality rate -Pathogenesis uncertain – possibly drug hypersensitivity reaction Hematologic abnormalities – -**hemolysis (G6PD deficiency), leukopenia, agranulocytosis, and thrombocytopenia |
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Pyrimethamine and sulfadoxine combination. why together?
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prevent resistance. so its always used in combination.
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Pyrimethamine. Where does it work? What is it effective against? less effective?
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A blood schizontocide
-Slow acting -Folate synthesis inhibitor -Used in combination with sulfadoxine Effective against: -Erythrocytic forms -Active against P falciparum including CQ-resistant falciparum -Less active against other species -Not effective against liver stages |
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Uses of pyrimethamine
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Clinical cure for CQ-resistant falciparum
-Less optimal regimen than quinine (if available) Always used in combination with sulfadoxine** -Sulfadoxine is a sulfonamide drug -**Combination is synergistic -**Combination retards the emergence of drug resistance Emergency treatment of febrile illness (presumptive treatment) -Pyrimethamine + sulfadoxine combogiven as several tablets in a single dose |
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MoA of pyrimethamine? sulfadoxine?
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Pyrimethamine:
-Inhibits plasmodial dihydrofolate reductase (DHFR) -Synergistic with sulfonamides and sulfones in sequential inhibition of folate synthesis Sulfadoxine: -Inhibits dihydropteroate synthase enzyme -a folate synthesis inhibitor (step before pyrimethamine) |
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Pyrimethamine adverse effects
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Adverse Effects
Generally well tolerated (as single agent) Drug Combination -Too toxic for prophylaxis -Hemolytic anemia and agranulocytosis (high doses) -Sulfa’s usually account for toxicities in combo preps -Hematologic, GI, CNS & renal -Dermatologic; Potentially fatal reactions including Stevens-Johnson syndrome & toxic epidermal necrolysis |
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Atovaquone and proguanil...do you use these alone?
what is proguanil? |
proguanil:
-**Prodrug – requires metabolic activation -Prophylactic doses – few side effects -Slow acting; **never used alone -**Inhibits dihydrofolate reductase (DHFR) -a folate synthesis inhibitor -Has both tissue and blood schizonticidal activity -No activity against hypnozoites Not effective against liver hypnozoites |
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atovaquone + proguanil is used for prevention and treatment of...
who should avoid? |
Prevention and treatment of P. falciparum incl CQ-resistant and MDR strains
Presumptive self-treatment Avoid in pregnant females |
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MoA of atovaquone + proguanil
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Atovaquone
-selectively deprives the parasite of energy by inhibiting mitochondrial electron transport Proguanil -Dihydrofolate reductase inhibitor Together … they inhibit nucleic acid synthesis and replication |
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Doxycycline used for what?
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Prophylaxis for drug resistant falciparum
Treatment of falciparum malaria -Adjunctive therapy with quinine Mechanism of action is unknown -Protein synthesis inhibition?? No kids, pregnant or lactating females, and avoid sun |
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Chemoprophylaxis: CQ-sensitive areas
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For travel to areas of risk where CQ-resistant P falciparum has NOT been reported
-chloroquine Travelers unable to take chloroquine -atovaquone + proguanil (Malarone) -doxycycline -mefloquine |
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CQ-resistant areas
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For travel in areas with risk of CQ-resistant P falciparum exist…
-mefloquine (makes you wig out, go mental, M, mefloquine) -doxycycline -atovaquone + proguanil (Malarone) In mefloquine-resistant areas (P falciparum) -Either doxycycline or atovaquone + proguanil can be used |
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Treatment of Malaria:
CQ-sensitive P falciparum and P malariae infections |
chloroquine
acute blood form |
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Treatment of Malaria:
P vivax and P ovale infections |
chloroquine then primaquine (if G6PD normal)
combo because of liver forms; prevent recurrent attacks |
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Treatment of Malaria:
Uncomplicated infections with CQ-resistant P falciparum |
quinine* plus one of following: doxycycline, tetracycline, clindamycin
alternative: Atovaquone-proguanil OR mefloquine |
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Treatment of Malaria:
severe or complicated infections with P falciparum |
quinidine** plus one of following: doxycycline, tetracycline, clindamycin
alternative: artemether |