L28- Antimalarial Drugs Flashcards
list the Malaria causing species (parasites)
- plasmodium falciparum
- plasmodium vivax
- plasmodium malariae
- plasmodium ovale
describe the life cycle of plasmodium spp.
1) mosquito injects Gametoytes
2) Gametocytes fuse rapidly into Sporozoites into blood / lymph
3) Sporozoites travel and enter the liver
4) Merozoites are generated
5) release of Merozoites due to liver cell rupture
* 6) Merozoite feed on RBCs (repeated process)
7) asexual reproduction occurs produces male/female gametes
8) mosquitoes uptake gametes
(1) forms of plasmodium will have only one cycle of liver cell invasion. Liver infection will stop after (2) of time. Only (3) need to be dealt with clinically.
1- P. malariae, P. falciparum
2- 4 wks
3- erythrocytic parasites (to be eliminated)
(1) forms of plasmodium have dormant hepatic stages, therefore (2) needs to be dealt with clinically.
1- P. vivax, P. ovale
2- erythrocytic and hepatic parasites (to be eliminated)
describe the symptoms and occurrence of Malarial Paroxysm
Sxs: cyclical fever, anemia, jaundice, hepatosplenomegaly
Typically occurs every 2-3 days
(1) plasmodium causes the most severe malaria and its the only one that may cause (2), usually due to (3) symptoms which are unique to its species. (4) are the additional symptoms noted in malaria due to (1) infection.
1- P. falciparum
2- death
3- cerebral malaria: irritability –> seizures –> coma
4- respiratory distress syndrome, diarrhea, severe thrombocytopenia, spontaneous abortion, hypoglycemia
what are the 3 factors that guide malaria treatment
1) infecting Plasmodium species
2) clinical status of patient
3) drug susceptibility of infecting parasites
Name the infecting Plasmodium for the following:
-(1) can cause rapidly progressive severe illness or death
- (2) infection require treatment for the Hypnozoite forms dormant in the liver
- (3) forms have different drug resistance in different geographic areas
1- P. falciparum
2- P. vivax, P. ovale
3- P. falciparum, P. vivax
in uncomplicated malaria, treatment requires….
oral antimalarials
in complicated malaria treatment requires…
aggressive treatment with parenteral antimalarial
describe the factors that make malaria a ‘complicated malaria’
(1 or more of the following- essentially single organ failure)
- impaired consciousness / coma, repeated generalized convulsions
- severe normocytic anemia, parasitemia >5%, acidosis, circulatory shock
- renal failure, hemoglobinuria
- pulmonary edema, ARDS
- DIC, spontaneous bleeding
list the major antimalarial drugs
- chloroquine
- quinine, quinidine
- mefloquine
- primaquine
- atovaquone
- sulfadoxine-pyrimethamine
- doxycycline
- artemisinins
______ is the drug of choice for treatment and prophylaxis of all P. vivax and P. ovale infections
chloroquine
Chloroquine:
- use of it is changing due to (1)
- drug of choice for Tx of (2) and (3) malarias
- preferred prophylactic agent in (4) type areas
1- drug resistance (severely compromised use)
2- non-falciparum malaria
3- sensitive uncomplicated falciparum malaria
4- areas w/o resistant falciparum malaria
Chloroquine is highly effective against (1), but not active to fight against (2)
1- Blood parasites
2- Liver parasites
Chloroquine works by first adjusting to (1) which will then function to prevent (2).
1- become concentrate in parasitic food vacuoles
2- prevent biocrystallization of Hb breakdown product heme to non-toxic hemozoin
Chloroquine MOA:
- the parasite will digest (1) in order to obtain (2)
- the process of (1) generates a lot of (3) which is toxic to the parasites
- for protection from (3), parasites function to (4)
-chloroquine prevents (4), in order to raise levels of (3), which is toxic to the parasites
1- Hb
2- essential AAs
3- heme
4- polymerizes heme to nontoxic hemozoin (sequestered in parasitic food vacuole)
Chloroquine:
- (1) route of administration
- (2) half-life
- (3) frequency of taking drug
1- oral
2- 3-5 days
3- once a week
(1) species of malaria has resistance to chloroquine because of mutations in (2) which functions to (3)
1- P. falciparum
2- PfCRT, putative transporter
3- pump chloroquine out
Chloroquine AEs:
- (1) is common in Africans
- (2) is seen in G6PD deficient patients
- (3) are many other AEs
- (4) changes maybe seen during cardiac investigation
1- pruritus
2- hemolysis
3- n/v, abd. pain, HA, anorexia, malaise, blurry vision, urticaria (uncommon)
4- ECG changes
Chloroquine is not used in (1) or (2) patients, although it is safe in (3) and (4) patients.
1- psoriasis, porphyria –> may precipitate attacks
2- retinal or visual field abnormalities
3- young children
4- pregnancy
(1) are the first line treatment for P. falciparum malaria mainly because (2) is uncommon, but increasing
1- quinine, quinidine (stereoisomers)
2- drug resistance
(1) is parenteral Tx of severe P. falciparum malaria
(2) is oral Tx of falciparum malaria, and an alternative to (3) in (4) areas
1- quinidine
2- quinine
3- chloroquine
4- chloroquine-resistant areas
Quinine and Quinidine are rapidly, highly effective against (1), but not active to fight against (2)
1- Blood parasites
2- Liver parasites
Quinine and Quinidine work by decreasing (1) and (2) in parasites. It will also position itself in (3) in order to disrupt (4).
1- O2 uptake
2- carbohydrate metabolism
3- intercalates into DNA
4- disrupt parasitic transcription and replication
- Quinine is used for (1), administered in (2) fashion
- Quinidine is used for (3), administered in (4) fashion
1- uncomplicated malaria
2- oral (note- not usually used because other safer choice, just as effective choices)
3- severe, complicated malaria
4- IV
discuss resistance to Quinine and Quinidine
- an inc problem
- most prevalent in SE Asia
describe the microvascular effects of P. falciparum
- parasite attaches to RBC membrane
- -> RBCs become sticky and aggregate
- -> allows for vaso-occlusions
Quinine and Quinidine AEs:
- (1) cinchonism Sxs
- (2) hypersensitivity rxns
- (3) ECG effects
- (4) blackwater fever sxs
- (5) pregnancy uses
1- tinnitus, HA, nausea, dizziness, flushing, visual disturbances
2- skin rashes, urticaria, angioedema, bronchospasm
3- prolonged QT (remember its a arrhythmia drug)
4- hemolysis, hemoglobinuria (a (2) rxn)
5- causes uterine contractions; although still used for severe P. falciparum malaria
Quinine and Quinidine AEs:
- (1) hematologic abnormalities
- (2) blood level change due to stimulation of release of (3) hormone
- (4) effect with rapid IV infusion
1- BM suppression; hemolysis (G6PD def.). leukopenia, agranulocytosis, thrombocytopenia
2- hypoglycemia
3- insulin release
4- hypotension
Quinine and Quinidine contraindications:
- discontinue if (1) signs appear
- avoid if possible in patients with (2)
- use with caution in patients with (3)
1- severe cinchonism, hemolysis, hypersensitivity
2- visual / auditory issues
3- underlying cardiac abnormalities
Quinine and Quinidine contraindications:
- do not use with (1)
- it can inc levels of (2) drugs
- if (3) appears, dose reduction is necessary
- (4) use in pregnancy
1- mefloquine
2- warfarin, digoxin
3- renal insufficiency
4- catg. C, but benefits often outweigh risks
(1) is chemically related for quinine and effective against many (2)-resistant strains of malaria. (1) will destroy the (blood/liver/both) form via a (4) MOA.
1- mefloquine
2- chloroquine
3- blood
4- unknown
Mefloquine:
- prophylaxis for (1) strains
- Tx for (2) malarial infections
Note- mefloquine + (3) are used in Tx for uncomplicated malaria in SE Asia
1- P. falciparum, P. vivax (only prophylactic for pregnant women)
2- mild-to-moderate P. falciparum and P. vivax infections
3- artesunate
Mefloquine:
- (1) route of administration
- (2) half-life and dose frequency
- (3) resistance
1- oral
2- 20 days, take once a wk
3- uncommon
Mefloquine AEs:
- (1) neurological and psychiatric effects
- (2) AEs related to the weekly dosing
- (3) AEs related to high doses
1- dizziness, loss of balance, ear ringing, anxiety, depression, hallucinations
2- n/v/d, dizziness, sleep disturbances, rash
3- leukocytosis, thrombocytopenia, aminotransferase elevation, arrhythmias, bradycardia
Mefloquine contraindications:
- do not give to Pts with h/o (1)
- do not give with (2)
- (3) use in children and pregnancy
1- epilepsy, psychiatric disorders, arrhythmias, cardiac conduction defects, sensitivity to related drugs
2- quinine, quinidine, halofantrine
3- safe for pregnancy, young children
(1) is the drug of choice for eradicating dormant liver forms of (2) species. It is also used for prophylaxis for (3) species.
1- primaquine
2- P. vivax, P. ovale
3- all species (vivax, ovale, malaria, falciparum)
Primaquine clinical applications:
- used for (1) strains acutely
- used for (2) strains in terminal prophylaxis
- used for (3) strains for chemoprophylaxis
1- P. vivax, P. ovale
2- P. vivax, P. ovale
3- P. faliciparum, P. vivax (when others can’t be used)
Primaquine:
-(1) route of administration, which puts it at risk for (2) situations
-(3) is done in situations with resistant strains
1- oral
2- metabolites are less effective antimalarias, and more effective at hemolysis
3- repeat therapy with higher doses
Primaquine AEs:
- (1) frequent side effects
- (2) infrequent side effects
- (3) rare side effects
- (4) side effects worse in G6PD deficiency
1- generally well-tolerated
2- nausea, epigastric pain, abdominal cramps, HA
3- leukopenia, agranulocytosis, leukocytosis, cardiac arrhythmias
4- hemolysis or methemoglobinemia
Primaquine contraindications:
- (1) patients
- (2) use in pregnancy
1- G6PD deficiency
2- no use in pregnancy
Malarone composition = (1):
-used for (2)
1- atovaquone, proguanil
2- Tx and Prophylaxis of P. falciparum
Malarone is active against (1) and (2) forms in the body.
1- tissue schizonts (liver)
2- erythrocytic schizonts (blood)
Malarone chemoprophylaxis schedule starts (1) before travel and ends (2) after travel.
1- 2 days
2- 1 week after last exposure
Malarone:
- (1) MOA simply
- (2) route of administration
- (3) general AEs
1- disrupts mitochondrial ETC
2- oral
3- (generally well-tolerated) abdominal pain, n/v/d, HA, rash
list the combination inhibitors of folate used in antimalarial therapy
- pyrimethamine
- proguanil
- sulfadoxine
list the 3 clinical applications for combination Folate inhibitors
1- chemoprophylaxis
2- intermittent prevention therapy: ppl in high risk areas take regimen periodically (3 mos.)
3- Tx for choloroquine resistant P. falciparum (NOT severe form)
Folate Synthesis Inhibitors:
- (1) act slowly against erythrocytic forms of all species
- (2) acts against the hepatic forms (P. vivax, P. ovale)
- (3) act weakly against erythrocytic schizonts (blood)
1- pyrimethamine + proguanil
2- proguanil
3- sulfonamides
Folate Synthesis Inhibitors:
- (1) inhibits plasmodial DHF
- (2) inhibits dihydropteroate synthase
1- pyrimethamine + proguanil (no DHF –> THF)
2- sulfonamides (competes with PABA, no DHF formation)
Folate Synthesis Inhibitors:
- (1) route of administration
- (2) resistance strains
1- oral
2- common in P. falciparum
Folate Synthesis Inhibitors AEs:
- although well-tolerated, (1) may occur
- (2) are specific for proguanil
- (3) are specific for sulfadoxine
- (4) are specific for pyrimethamine-sulfadoxine combination
-(5) use in pregnancy
1- GI issues, rashes, itching
2- mouth ulcers, rarely alopecia
3- hematological, GI, CNS, dermatological, renal toxicity)
4- erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis
5- both proguanil and pyrimethamine-sulfadoxine are safe
Doxycycline is useful against (blood/liver/both) malaria forms of (2) species.
- it is used for Tx for (3) situations
- it is used as chemoprophylaxis in (4) situations
1- blood only
2- all species (P. malaria, falciparum, vivax, ovale)
3- severe P. falciparum given with quinine AFTER initial Tx w/ quinine, quinidine, or artesunate
4- all strains, taken daily
Doxycycline AEs:
- (1) general side-effects
- (2) use in pregnancy
1- GI issues, candidal vaginitis, photosensitivity, discoloration / hypoplasia of teeth, stunting of growth
2- fatal hepatotoxicity NO USE IN pregnancy and young children (<8y/o)
list the Artemisinins and indicate their routes of administration and what situations they are used in
*for severe malaria
- Artesunate: oral, IV, IM, rectal
- Artemether, oral, IM, rectal
- Dihydroartemisinin: oral
Coartem: artemether + lumefantrine
Artemisinins are used for treatment of (1) affecting the (blood/liver/both) forms. It is (not/usually) used in combination.
1- severe P. falciparum infections (IV)
2- blood only
3- always in combination due to resistance
Artemisinin MOA
- binds Fe
- breaksdown peroxide bridges => free radicals –> damage to parasite proteins
Artemisinin:
- half-life is (short/long) using (IV/oral) agent
- (3) is protocol if used in monotherapy
1- very short
2- IV followed by long-acting oral therapy
3- artesunate administers 5-7 days to avoid parasitemia
Artemisinin AEs:
- (1) general AEs
- (2) AEs at high doses
- (3) use in pregnancy
1- (remarkably safe) n/v/d
2- neurotoxicity, QT prolongation
3- mostly 2nd/3rd trimester, or for severe malaria in 1st trimester
‘OTHER’ Antimalarials:
-(1) alternative to doxycyclin
-Halofantrine is used against (blood/liver/both) forms of (3) species, but is limited by (4)
Lumefantrine is used against (blood/liver/both) forms of (6) species, but is limited by (7) dosing and (8) AEs
1- clindamycin
2- blood form
3- all species
4- irregular absorption, cardiac toxicity, teratogen
5- blood form
6- all species
7- fixed dose combination with artemether
8- clinically insignificant / minor QT prolongation
