Antiparasitics #1 -- Malaria Flashcards
Name the five human malaria parasites
Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae Plasmodium knowlesi
Which malaria parasite is responsible for the most deaths?
Plasmodium falciparum
Which malarias are known to be relapsing?
Vivax and Ovale
What causes malaria relapse?
Hypnozoites in the liver
In vivax can stay for weeks-months
Describe the life cycle of Plasmodium falciparum.
- Mosquito Bite
- Sporozites from bite form merozoites in liver
- These invade RBCs and mature to trophozoite
- Multiply, make mero., released with RBC rupture
- Some meros become gametocytes, taken up by mosquito.
Circle of life and shit.
How does cerebral malaria happen
Occlusions of vessels outside of capillary beds
What makes malaria especially dangerous in pregnant women
It binds chondroitin sulfate A allowing it to latch onto the placenta
Primoquine is an important malarial drug because it…
targets the liver stage
Classic symptoms of uncomplicated malaria?
Cold Stage
Hot Stage
Sweating Stage
48 hour periodicity for Falciparum + Vivax
Less Classic symptoms of malaria
Fever + Flu-like symptoms
Chills, Headache, Myalgias, and Malaise
Anemia and Jaundice
What do you see in severe malaria cases (5)…
Organ failures (esp. kidney) Cerebral Malaria Severe Anemia and hemoglobinuria Acute Respiratory Distress Syndrome Placental Malaria
What is seen in a cerebral malaria patient?
Abnormal behavior Impairment of consciousness Seizures Coma Other neurologic abnormalities
Cause of hemoglobinuria in malaria?
hemolysis
Placental malaria is especially common with….
first pregnancy
Three types of antimalarial drugs
Tissue schizonticides
Blood schizonticides
Gametocytocides
What is a Schizont
The malarial form between trophozoite and merozyte
What do tissue schizonticides do?
Kill liver stage parasites
What do blood schizonticides do?
Kill erythrocytic forms
What do gametocytes for malaria do
Kill sexual stages of the parasite to block transmission
How to not get malaria?
Insect repellants
Insecticides
Bed Nets
Chemoprophylaxis
Factors that may influence choice of chemoprophylactic?
Species present
Level and type of drug resistance
Lead time before travel
Malarone is made of…
Atovaquone + Proguanil
Where is Malaron effective?
All areas
Timeline for Malaron dosing
Start 1-2 days prior, continue 7 days after
Daily administration
Where is Doxycycline effective?
All areas
Timeline for doxycycline dosing
Start 1-2 days prior, continue for 4 weeks
What is Chloroquine comprised of?
Aralen and generic
Where is Chloroquine effective?
Chloroquine sensitive areas
Preferred in Central and South America
Chloroquin dosing timeline.
Start 1-2 weeks prior and continue 4 weeks after out of area
What is Mefloquine comprised of?
Lariam and generic
Where is Mefloquine effective?
Mefloquine sensitive areas
Whoops – Note taking fail – sorry gang
Timeline of mefloquine dosing.
Start more than 2 weeks early and continue for 4 weeks
Important reason to start doing with Mefloquine early
You want to take it long enough to establish a high enough concentration to reveal any toxicity symptoms before traveling abroad
Perks of Mefloquine
Taken once per week
When is Primaquine usually given?
Its given if an area is comprised to 90% Plasmodium vivax
Timeline for Primaquine dosing.
Start 1-2 days prior and continue for 7 days after
Important considerations when evaluating treatment options for malaria
Type of infecting parasite
Area where infection was acquired/drug resistant status
Clinical Status of Patient
What components of the clinical status of the patient are important guides in gauging clinical options
Accompanying illness/condition (G6PD deficient)
Pregnancy
Drug Allergies
Other Meds that may cross react
In a case of uncomplicated malaria/unidentified species contracted in a chloroquine sensitive area, how would you treat
Chloroquine (Aralen) and Hydroxychloraquine sulfate (Plaquenil)
In a case of uncomplicated malaria/unidentified species contracted in a chloroquine resistant area, how would you treat
Malarone (Atovaquone + Proguanil)
Coartem (Artemether + lumefantrine)
Quinine Sulfate + (Doxy, tetracycline, or clindamycin)
Mefloqine (Lariam)
What is Coartem?
Artemether + lumefantrine
Treatment of uncomplicated malaria with P. vivax or P. ovale infection (hypnozoites in liver) in a CQ sensitive area
Chloroquine OR
Hydroxychloroquine + Primaquine
Treatment of uncomplicated malaria with P. vivax or P. ovale infection (hypnozoites in liver) in a CQ resistant area
Quinine Sulfate + (Doxy or tetra) + Primaquine
Malarone + Primaquine
Mefloquine + Primaquine
Treatment of uncomplicated malaria with P. marariae or P. knowlesi
Chloroquine or Hydroxychloroquine sulfate (Plaquenil)
Symptoms of Severe Malaria
Impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, etc.
Go To Treatment for complicated malaria
Quinidine gluconate (IV) + (Doxy/Tetra/Clinda)
When giving quinidine gluconate, what do you need to be watching out for?
Blood pressure – hypotension
Cardiac function – Widening of the QRS complex or lengthening of the QT interval
Blood Glucose - hypoglycemia
If you can’t get ahold of quinidine gluconate, what should you give a complicated malaria patient?
Artesunate (IV)
Artesunate should be followed by…
Malarone
Doxy (Clinda for preggers)
Mefloquine
So what is artemisinin anyway?
Sesquiterpene lactone endoperoxide
T or F. Artemisinin is a potent and fast acting drug
T. 10,000 fold reduction in 48 hours
Resistance to Artemisinin is observed where…
SE Asia
How does Artemisinin work?
Rapidly activing schizonticide
Activated by heme iron
May form free radicals that target parasite proteins and lipids
How have parasites adapted to resist Artemisinin?
Mutations in Kelch 13
Delays progress through the life cycle, may alter the stress response
Effect of artemisinin on liver stages of malaria
None
Why is Artemisinin inappropriate for chemoprophylaxis?
It has a short half life (1-2 hours) that would require constant dosing
Leaves high recrudescence rates if used alone
How can Artemisinin be made prophylactically useful?
Pairing with other drugs like Mefloquine or lumefantrine
Two effects of the insolubility of artemisinin
Only used orally
low bioavailability
How can artemisinin be made to be dosed in other routes?
Semisynthetic artemisinins can be given orally, intramuscularly, IV, and rectally – which is very imortant in severe cases.
Ex. Artesunate
Top Five Artemisinin derivatives
Artemininin Dihydroartemisinin Artemether Arteether Artesunate
Is Artemisinin more effective as a bolus or infusion
bolus
Describe Artemisinin combination therapy
Artemisinin bolus provides rapid knockdown
Longer half-life drugs eliminate remaining parasites
Longer halflife drugs commonly used in artemisinin combination therapyq
Lumefantrine (Coartem)
Amodiaquine
Mefloquine
Piperaquine
Adverse effects of Artemisinin?
Nausea, Vomiting, Diarrhea, Dizziness
Embryotoxic in animal studies
Who are the three 4-aminoquinolines?
Quinine
Chloroquine (Aralen)
Mefloquine (Lariam)
How do malaria parasites eat normally?
They ingest hemoglobin from host and degrade it into amino acids and free heme. Then the parasite polymerizes the heme into hemozoin to prevent free heme toxicity.
How does chloroquine work?
Accumulates in food vacuole, inhibits heme polymerization
How is chloroquine resistance developed
Lack of accumulation of chloroquine in the vacuole
PK details about Chloroquine?
Formulated for oral use
Well absorbed
Large Vd
Half-life of 3-5 days, terminally 1-2 months
Chloroquine – more effective as bolus or infusion?
Infusion
Maintaining Concentration for the win.
Adverse effects of chloroquine
IN HEALTHY FOLKS
usually nothing, sometimes Pruritis
Chloroquine is contraindicated in which patients?
Psoriasis, Porphyria
Retina/Visual Field Abnormalities
Myopathy
Glucose 6PD
______ and ______ interfere with chloroquine absorption
Kaolin (antidiarrheal agent) and antacids
Two mutations associated with CQ resistance
PfCRT1
PfMDR1
What does PfCRT1 mutation do?
Caused reduced accumulation of chloroquine in the food vacuole
No cross resistance with mefloquine or quinine
What does overexpression of PfMDR1 do?
Over expression of drug transporter pumps out the anti-malarials
Quinine acts as which kind of medication?
Blood schizonticide
Quinine is the treatment of choice for…
CQ resistant F. malaria (use quinine sulfate orally)
Severe F. malaria (use quinidine gluconate by IV)
Why is Quinine inappropriate for chemoprophylaxis?
Shorter half life and toxicity
Adverse effects of quinine
Cinchonism
Can stimulate uterine contractions
Hemolysis
Severe hypotension if infused too quickly
What is cinchonism?
Tinnitis, headache, dizziness, flushing, and visual disturbances
Hemolysis following Quinine dose is associated with…
G6PD deficiency
Blackwater fever
What is blackwater fever?
Rare, Severe, Marked by hemoglobinuria
Quinine is metabolized by…
Who the fuck cares?
CYP3A4
People on Warfarin and Digoxin care
Which drug gives Elliot hypersexual dreams?
Mefloquine
Is mefloquine used for prophylaxis or treatment?
Both.
Mefloquine is effective against which malarial strains
P. falciparum, and P. vivax
Adverse effects of Mefloquine.
Neuropsychiatric toxicity (seizures, toxic psychosis, sleep disturbance)
Other than the big three, who are some super lame less important chloroqine related compounds
Lumefantrine
Piperaquine
Amodiaquine
Halofantrine
What is Primaquine’s chemical name?
What kind of drug is it.
8-aminoquinoline
Pro-drug
Which CYP metabolizes Primaquine
CYP 2D6
Primaquine is the drug of choice for..
Liver stages (actively growing and hypnozoites) of P. vivax and P. Ovale (Combine with CQ)
How does Primaquine work?
Gametocidal against all four parasites
Contraindications for Primaquine.
G6PD deficiency Pregnancy Breast Feeding Granulocytopenia Taking hemolytic drugs
Related compound to primaquine that was apparently important enough to bring up, but all of the details on it are essentially “ditto on primaquine”
Tafenoquine
Malarone is made of _____ and _____ because
Proguanil and Atavaquone
Resistance to Atavaquone happens really quickly if used as monotherapy
Malarone kills…
Liver + Blood Stages
Not Hypnozoites
Malarone is effective for….
Uncomplicated malaria
Chemoprophylaxis
Atavaquone is also used to treat….
Toxoplasma gondii
Pneumocystis jiroveci
How does Atavaquone work?
It is a selective inhibitor of malaria mitochondrial cytochrome bc1 complex. It inhibits electron transport and causes the mitochondrial membrane potential to collapse.
What’s the point of mitochondrial electron transport in P. falciparum anyway?
To regenerate ubiquinone – which acts as an electron acceptor for parasite dihydroorotate dehydrogenase – which is essential for pyrimidine synthesis in the parasite.
How does Proguanil work?
In the body, it is converted to cycloguanil, a selective inhibitor of thymidylate synthetase. This enzyme is crucial for parasite purine and pyramidine synthesis.
It also enchances mito. toxicity of atavaquone
What is Thimidylate Synthetase
a bifunctional plasmodial dihydrofolate reductase
What is Pyrimethamine-Sulfadoxine (Fansidar)?
A folate synthesis inhibitor that acts as a slow acting erythrocytic schizonticide
How does primathamine work?
It inhibits plasmodia DHF-reductase, preventing pruduction of purines, thymidine
How does sulfadoxine work?
It inhibits the activity of dihydropteroate synthase, preventing production of purines and thymidines
Why is it idiotic that we are taking the time to cover Fansidar?
Because resistance is so common that this drug basically isn’t used anymore.
Other than malaria, what might you treat with antifolates?
Toxoplasmosis (pyrimethamine+sulfadizine)
Pneumocystis (Trimethoprim+sulfamethoxazole)
Why shouldn’t you use single anti-folates?
Resistance develops easily
Pairing allows lots of synergistic effects that allow lower doses
Antibiotics commonly used as anti-malarial drugs
Tetracycline, Doxycycline, and Clindamycin
How do antibiotics work against malaria?
Target components of the apicoplast
What the fuck is an apicoplast anyway?
Plant-like organelle that carries out many biochemical processes
Doxy is commonly pairs with ____ or _____ for freatment of F malaria
Quinine or Quinidine
Where might Doxy be used for prophylaxis
Areas with high resistance to mefloquine
