hemolytic anemia, malaria, G6PD, and pharm - Stillwell/Lee

Question 1

malaria

Answer 1

• single cell protozoa
• deaths usually due to P. falciparum –> stick to endothelial cells obstructing microcirculation (ex. cerebral malaria)**
• anopheles mosquito
• P. vivax in US

Question 2

malaria life cycle

Answer 2

• sporozoite (mosquito saliva) –> exoerythrocytic form in liver (schizonts –> merozoites) –> erythrocytic phase (merozoites –> trophozoites –> schizonts –> merozoites)
• vivax and oval can live dormant in liver (hypnozoite)** –> high risk of reinfection
• merozoites can infect gametocytes (taken up by mosquitos)

Question 3

which forms banana gametocytes?

Answer 3

P. falciparum

-all of them have ring forms

Question 4

malaria signs/symptoms

Answer 4

• paroxysms = cyclic fevers, chills, sweats (from schizont rupture and cytokine response)
• vivax and ovale –> tertian fever (2 days)**; can also lie dormant for months
• malariae –> quartan fever (3 days)**
• falciparum –> irregular fevers; no dormancy
• sever infection –> hemolytic anemia (from parasite) and blackwater fever (bilirubin, Hb, and renal failure)**
• blackwater only from P. falciparum*
• other sever symptoms with P. falciparum –> pulmonary edema, cerebral malaria, stillbirth, miscarriage

Question 5

malaria protection

Answer 5

• sickle cell disease trait (HbS trait)**
• Hb C, E trait
• G6PD deficiency
• thalassemia

Question 6

malaria diagnosis

Answer 6

• thick/thin blood smears on Wright/Giemsa stain**
• thick more sensitive (identify parasites), thin for speciation
• smears every 12-24 hr 3x**
• only do PCRs 1x
• serology antibodies take a long time to turn +
• ringforms on thin smear**

Question 7

P. falciparum on smears

Answer 7

• banana gametocyte and high parasitemia (lot of RBCs infected)
• may have >60% parasitemia
• transfusions with >10% parasitemia

Question 8

malaria treatment and prophylaxis

Answer 8

-slide 22,23

Question 9

malaria treatment

Answer 9

• artemisinins and combined coartem –> for very sick people; obtained through CDC
• malarone –> for mild-moderate malaria in US (GI side effects)**
• mefloquine –> CNS side effects**
• chloroquine –> for malaria in Central America, haiti, Dominican, and Middle East (everywhere else is resistant)**
• quinine –> toxicity called cinchoism (tinnitus, nausea, headaches, dizziness, hemolytic anemia)

Question 10

terminal therapy for malaria**

Answer 10

• used to eliminate dormant hypnozoites of ovale/vivax in liver to prevent relapse**
• give primaquine (daily for 2 weeks) or tafenoquine (1x)**
• these drugs can cause hemolytic anemia with G6PDH deficiency**

Question 11

babesia

Answer 11

• can mimic malaria; parasite
• cause hemolytic anemia
• ring forms - Maltese cross**
• spread by ticks

Question 12

bartonella bacilliformis

Answer 12

• cause hemolytic anemia; bacteria
• spread by sandflies** –> Oroya fever/Carrion’s disease**
• look like spikes
• hemolytic phase –> skin lesion phase (verruga peruana)**

Question 13

toxoplasma gondii

Answer 13

• cause hemolytic anemia; parasite

- undercooked meat and cat feces**

Question 14

liver stage drugs

Answer 14

1. atovaquone-proguanil (malarone)

2. primaquine

Question 15

blood stage drugs

Answer 15

1. artemether + Lumefantrine (Coartem) - an artemisinin
2. antifolates
3. quinolones (chloroquine, quinine, mefloquine)

Question 16

gametocyte drugs

Answer 16

1. primaquine

2. coartem - artemisinin

Question 17

interferes with heme polymerization?

Answer 17

quinolones –> prevent sequestering of heme in hemosome –> toxicity to malaria**

1. chloroquine
2. quinine
3. mefloquine

Question 18

disrupt electron transport chain?

Answer 18

1. atovaquone

Question 19

inhibit folate synthesis?

Answer 19

antifolates

1. sulfadoxine
2. pyrimethamine

Question 20

inhibit protein synthesis?

Answer 20

antimicrobials

1. clindamycin
2. doxycycline
3. tetracycline

Question 21

production of free radicals?

Answer 21

oxidative stress

1. artemether + lumefantrine (coartem) - an artemisinin

Question 22

chloroquine

Answer 22

• against erythrocytic form**
• action: in food vacuoles and inhibits heme polymerization (hemozoin) –> heme toxicity to malaria**
• indications: effective against non-falciparum and sensitive falciparum**
• resistance high for falciparum (maybe vivax)**
• contraindications: psoriasis, porphyria, retinal deficits, myopathy
• not effective in exoerythrocytic forms –> relapse of vivax and ovale (even malariae)**

Question 23

primaquine

Answer 23

• hydroxylated metabolites form free radicals and reactive oxygen species** –> oxidative stress
• effective against liver forms (hypnozoites from ovale/vivax) and gametocytes; not erythrocytic form**
• prevents relapse
• combined with chloroquine for erythrocyte form
• contraindications/side effects: pregnancy (G6PD deficiency)** –> can form malaria if deficient**; also rheumatoid arthritis or lupus

Question 24

G6PD

Answer 24

• enzyme used to make NADPH for GSH to remove oxidative stress
• X linked deficiency –> can’t remove oxidative stress
• see Heinz bodies and bite cells

Question 25

tafenoquone

Answer 25

- derivative of primaquine but 2x longer half life - adverse effects if G6PD deficient - give one dose

Question 26

atovaquone-proguanil (malarone)

Answer 26

- effective against both erythrocytic and hepatic forms of malaria - atovaquone --> disrupts electron transport chain, rifampin reduces levels* - proguanil --> inhibitor of dihydrofolate reductase thymidylate synthase (enhance mitochondrial toxicity), GI side effects - both effective against falciparum in combination

Question 27

mefloquine

Answer 27

- only effects erythrocytic form --> against schizont activity** - effect heme polymerization - drug of choice for chloroquine resistant malaria** - contraindications/adverse effects: epilepsy, psychiatric disorder, GI, seizures, psychosis

Question 28

quinine and quinidine

Answer 28

- affects the erythrocyte form - heme polymerization to prevent detoxification --> toxic to malaria - no effect on sporozoites or hepatic forms** - 1st line of defense for falciparum malaria (especially severe disease)** - standard for parenteral treatment** - contraindications: sever cinchonism (tinnitus, headache, nausea), hemolysis, hypersensitivity, renal problems - adverse effects: cinchonism, cardiac arrhythmia, antimuscarinic - avoid mefloquine - can raise plasma levels of warfarin and digoxin**

Question 29

artemisinin

Answer 29

- only erythrocytic forms | - get from CDC

Question 30

artemether-lumefantrine

Answer 30

- an artemisinin - inhibit nucleic acid and protein synthesis** (prophylaxis does not always work) - treat severe P. falciparum** - adverse effects: teratogen in animals

Question 31

pyrimethamine

Answer 31

- only against erythrocytic forms - inhibit DHFR (folate pathway)** - combined with sulfdoxin (inhibits DHPS in folate path)** - both inhibit folate --> no DNA --> cell death - against erythrocytic forms of ALL 4 P. malaria species** - contraindications: not given to someone who is folate deficient (ex. pregnancy) - adverse effects: GI, skin rashes (ex. SJS, TEN) - falciparum sometimes resistant to folate antagonists and sulfonamides