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44 Cards in this Set

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Blood and Lymph- Anti-malarials by Boy Bridges
Blood and Lymph- Anti-malarials by Boy Bridges
Drug List
Primaquine
Chloroquine
Mefloquine
Doxycycline
Atovaquone + proguanil
Pyrimethamine + sulfadoxine
Quinine (oral only)
Quinidine (IV)
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
Suppressive Therapy, Clinical cure, Radical Cure
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
Name the 4 species of plasmodium and the type of disease for each...
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.
Drugs: hepatic schizonticides
Atovaquone-proguanil
Primaquine

-Eliminate developing or dormant liver forms
-Used for casual prophylaxis
-Used to prevent relapse and provide a radical cure
Drugs: Hyponozoiticide
Primaquine
Drugs: Blood-stage schizonticides
Atovaquone-proguanil
Doxycycline
Mefloquine
Chloroquine

-Act on erythrocytic parasites
-Used for clinical and suppressive care
Life cycle of P falciparum and P malariae
-Only one cycle of liver cell invasion and multiplication occurs
-Liver infection ceases spontaneously in < 4 wks
-**Treatment eliminating erythrocytic parasites will cure infection
Life cycle of P vivax and P ovale
-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
Prevention of Relapses of P vivax or P ovale. Why are there relapses? What is the drug for terminal prophylaxis?
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
DOC for eradication of dormant liver forms of P vivax and P ovale. What does it NOT work against?!
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
Primaquine uses
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
Primaquine Adverse effects
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
Primaquine and G6PD...what's going on?
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.
What do you use Chloroquine (CQ) for?
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.
What is CQ the DOC for?
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
MoA of CQ?
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
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 ??
PK of CQ
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
Adverse Effects
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)
Mefloquine is used for what?
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
Pharmacokinetics
Slow elimination
Total clearance mainly hepatic metabolism
Excretion mainly by fecal route

Weekly dosing
LONG elimination half-life ~ 21 days
Adverse Effects
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
Quinine / Quinidine uses (Tx of choice and DOC for what?)
**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
How does Quinine work? PK?
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)
Adverse effects
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
Adverse effects
**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
Adverse effects
**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
Pyrimethamine and sulfadoxine combination. why together?
prevent resistance. so its always used in combination.
Pyrimethamine. Where does it work? What is it effective against? less effective?
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
Uses of pyrimethamine
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 combo given as several tablets in a single dose
MoA of pyrimethamine? sulfadoxine?
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)
Pyrimethamine adverse effects
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
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
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
MoA of atovaquone + proguanil
Atovaquone
-selectively deprives the parasite of energy by inhibiting mitochondrial electron transport

Proguanil
-Dihydrofolate reductase inhibitor

Together … they inhibit nucleic acid synthesis and replication
Doxycycline used for what?
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
Chemoprophylaxis: CQ-sensitive areas
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
CQ-resistant areas
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
Treatment of Malaria:
CQ-sensitive P falciparum and P malariae infections
chloroquine

acute blood form
Treatment of Malaria:
P vivax and P ovale infections
chloroquine then primaquine (if G6PD normal)

combo because of liver forms; prevent recurrent attacks
Treatment of Malaria:
Uncomplicated infections with CQ-resistant P falciparum
quinine* plus one of following: doxycycline, tetracycline, clindamycin


alternative:
Atovaquone-proguanil OR mefloquine
Treatment of Malaria:
severe or complicated infections with P falciparum
quinidine** plus one of following: doxycycline, tetracycline, clindamycin

alternative:
artemether