Antimalarials Flashcards
P. falciparum and P. malariae life cycle.:
- How many cycles of liver cell invasion?
- Parasites in what stage have to be eliminated?
- Only have one cycle of liver cell invasion
- liver infection ceases in
P. vivax and P. ovale life cycle.:
Parasites in what stages have to be eliminated?
hepatic and erythrocytic stages have to be eliminated!
Incubation periods of malarial pathogens:
P. vivax 2 –> 17 days
P. falciparum 9 –> 14 days
P. ovale 16 –> 18 days
P. malariae 18 –> 40 days (can be years)
Treatment of malariae must be guided by 3 main factors?
- Infecting Plasmodium species
- Clinical status of patients
- Drug susceptibility
which 2 malarial forms have different resistance patterns in different geographical areas?
P. falciparum
P. vivax
how do you treat uncomplicated malaria?
use oral antimalarials
Complicated malariae tx.?
Tx aggressively with parenteral antimalarials.
Major antimalarial drugs
Choroquine (not for severe forms, prophylaxis)
Quinine and quinidine (for severe, major AEs)
primaquine (for liver hypnozoites)
Atovaquone
Sulfadoxine-pyrimethamine
Doxycycline
Aryemisinins
Chloroquine:
DOC?
DOC:
- as treatment and prophylaxis for P. vivax an ovale
- Non-falciparum and sensitive uncomplicated falciparum malaria.
- preferred chemoprophylactic agent in areas w/out resistant falciparum malaria.
Chloroquine:
Antimalarial action?
MOA?
Antiamalarial action:
- Highly effective agains blood parasites
- NOT active against liver stage
MOA:
- Concentrates in parasite food vacuoles
- Prevents biocrystallization of hemolobin breakdown product heme to non-toxix HEMOZOIN
Chloroquine:
PK:
Resistance:
PK:
- ORAL
- t1/2: 3-5 days (take once weekly)
Resistance
- P. falciparum: mutations in putative transport. PfCRT are common.
Chloroquine:
- AE?
- WELL TOLERATED
- pruritis in africans
- Nausea, vomiting, abdominal pain, headache, anorexia , malaise, blurring of vision, urticaria (uncommon)
- hemolysis (G6PD-defecient people)
- can cause electrocardiographic changes!
Chloroquine:
CI:
- patients with psoriasis or porphyria (may ppt attacks)
- retinal or visual field abnomalities
- SAFE IN PREGNANCY AND YOUNG
Quninine and Quinidine (stereoisomer):
- FIRST LINE FOR?
- resistance?
- CA?
- 1st line for: therapies for severe falciparum disease
- resistance is uncommon
CA:
- Parenteral tx. for severe falciparum malaria (QUINIDINE)
- Oral tx. of falciparum malaria (alternative in chloroquine-resistant areas) (Quinine)
Quninine and Quinidine (stereoisomer):
Antimalarial action:
MOA:
Antimalarial Action
• Rapidly-acting, highly effective against blood parasites
• NOT active against liver stage parasites
MOA
• Depresses O2 uptake and carbohydrate metabolism
• Intercalates into DNA, disrup gp p ting parasite’s replication and
transcription
Quninine and Quinidine (stereoisomer):
PK?
Resistance
Pharmacokinetics
• Quinine: oral treatment of uncomplicated malaria
• Quinidine: IV treatment for severe malaria
Resistance
• Likely to be increasing problem
• Already common in some areas of South-east Asia
Quninine and Quinidine (stereoisomer):
AE?
- Cinchonism: tinnitus headache nausea dizziness flushing & visual disturbances
- Hypersensitivity: skin rashes, urticaria, angioedema. bronchospasm
- Hematologic abnormalities: hemolysis (G6PD deficiency), leukopenia, agranulocytosis, thrombocytopenia
- Hypoglycemia: stimulation of insulin release
- Uterine contractions: still used in treatment of severe falciparum malaria in pregnancy
- Severe hypotension: too rapid IV infusion
- ECG abnormalities: QT prolongation
- Blackwater fever: hemolysis & hemoglobinuria (likely hypersensitivity reaction)
Quninine and Quinidine (stereoisomer):
CI:
Discontinue if signs of:
- severe cinchonism
- hemolysis
- hypersensivity
Avoid in patients with:
- auditory adn visual problems
Use with caution in patients with underlying cardiac abdnormalities (QT prolongation)
- Do not use concurrently with mefloquine
- can raise plasma levels of warfarin and digoxin
- reduce dose in renal insufficiency
PREGNANCY
- FDA Cat. C (however benefits do often outweigh risks in complicated malaria).
Mefloquine
similar to?
MOA
Effective agains many choroquine resistant strains
chemically related to quinine.
MOA: Kills parasite in blood
Mefloquine
Clinical applications
Tx?
Combination w/ what drug to treat malaria in SE Asia?
• Chemoprophylaxis: effective against most strains of P. falciparum and P.vivax
* Currently only medication recommended for chemoprophylaxis in pregnant women in chloroquine-resistant areas resistant areas***
- Treatment : can be used to treat mild to moderate acute malaria caused by P.falciparum and P.vivax
- Mefloquine + artesunate used in treatment of uncomplicated malaria in regions of Southeast Asia
Melfoquine
PK?
Resistance?
Oral only
t1/2 = 20 days (weekly prophylactic dosing)
Resistance is uncommon but has been reported
- associated w/ resistance to quinine but not chloroquine!
Mefloquine AE:
Serious neurological and psychiatric toxicities:
- Dizziness, loss of balance, ringing in the ears, anxiety , depression, hallucinations
Weekly dosing
- Nausea, vomiting, diarrhea, dizziness, sleep and behavioral disturbances, rash
Higher treatment doses:
- leukocytosis, thrombocytopenia, aminotransferase elevations, arryhthmias, bradycardia
Mefloquine CI
BLACK BOX WARNING!
•Patients with history of: Epilepsy, psychiatric disorders, arrhythmia,
cardiac conduction defects sensitivity to related cardiac conduction defects, sensitivity to related
drugs
• DO NOT coadminister coadminister with quinine, quinidine or halofantrine
• Considered safe in young children & pregnancy
Primaquine clinical application:
• Drug of choice for eradication of dormant liver forms of P. vivax and P. ovale (only available agent).
- chemoprophylaxis (all strains)
- Therapy of acute Therapy of acute vivax and ovale malaria malaria
- Terminal prophylaxis of vivax and ovale malaria
- Chemoprophylaxis: protection against falciparum & vivax (toxicities are a concern – reserved for when other drugs cannot be used)
Primaquine PK:
Ressistance?
Oral
metabolites have less antimalarial activity but more potential for inducing hemolysis
May require therapy to be repeated and dose to be increased!
Primaquine AE:
- G6PD interactions?
- G6PD def.?
- pregnancy?
- WELL TOLERATED
- Hemolysis or methemoglobinemia (especially in G6PD deficient patients)
- Primaquine oxidizes GSH to GSSG. Therefore less GSH is available to neutralize toxic compounds.
For severe G6PD def. patients withhold and treat relapses.
- CI’d in pregnant because fetus is G6PD deficient.
MALARONE
what 2 drugs make it up?
CA?
Antimalarial action?
Atovaquone + proguanil
Clinical Applications:
• Treatment; prophylaxis of P. falciparum
Antimalarial Action
• Active against tissue and erythrocytic schizonts
• Chemoprophylaxis can be started 1-2 days before travel and discontinued 1 week after exposure
MALARONE
MOA?
PK?
AE?
MOA
• Disrupts mitochondrial electron transport
Pharmacokinetics
• Oral only
Adverse Effects • Generally well tolerated • Abdominal pain, nausea, vomiting, diarrhea, headache, rash • Do not use in pregnancy
Inhibitorrs of folate synthesis
- how are they used?
Primethamine
Proguanil
sulfodoxine
- used in combination regimen
Inhibitorrs of folate synthesis: CA
- Chemoprophylaxis
- Intermittent Preventive Therapy:
- Treatment of chloroquine-resistant falciparum malaria
- only in combination. Proguanil + chloroquine = no longer recommended
- high-risk patients receive intermittent therapy regardless of infection status
- pyrimethamine-sulfadoxine commonly used. DO NOT use for severe malaria
Inhibitors of folate synthesis: Antimalarial action:
- Pyrimethamine + proguanil
- Proguanil
- sulfonamides
- Act slowly against erythrocytic forms of all
malaria species - Some activity against hepatic forms
- Weakly active against erythrocytic schizonts
Inhibitors of folate synthesis PK
AE:
Oral
resistance common for P. falciparum
AE:
• Well tolerated (GI problems rashes itching) (GI problems, rashes, itching)
• Proguanil (mouth ulcers, alopecia = rare)
• Pyrimethamine-Sulfadoxine (erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis)
• Sulfadoxine (hematologic, GI, CNS, dermatologic & renal toxicity)
Pregnancy:
• Proguanil = safe
• Pyrimethamine-sulfadoxine = safe
Doxycycline
- Active against erythocytic schizonts of all human malaria parasites
- NOT active against liver stage
Clinical Applications
• Used to complete treatment for severe falciparum malaria (given along with quinine) after initial treatment with quinine, quinidine or artesunate
• Chemoprophylaxis against most forms: must be taken daily
Doxycycline AE:
- GI, candidal candidal vaginitis PHOTOSENSITIVITY
- Discoloration & hypoplasia of teeth, stunting of growth
- Fatal hepatotoxicity (in pregnancy)
- DO NOT use in pregnancy or children
Artemisinin PK for the different types?
Coartem is a combination of ?
Derived from qinghaosu qinghaosu plant
• Artesunate : oral, IV, IM & rectal admin
• Artemether: oral, IM & rectal admin
• Dihydroartemisinin: oral admin
• Coartem = artemether + lumefantrine
Artemisinin Clinical App.
MOA
PK?
Treatment of severe falciparum malaria (given IV)
- NO EFFECT on hepatic stages
- dont use as single agen (resistance)
MOA
• Appears to act by binding iron, breaking down peroxide bridges leading to generation of free radicals that damage bridges leading to generation of free radicals that damage
PK:
very short t1/2 (IV therapy must be followed by longer acting agent once patient is able to tolerate oral therapy)
If used alone, artesunate must be used 5-7 days (otherwise recurrent parasitemia results)
Artemisinin AE
- Overall remarkably safe (nausea vomiting diarrhea)
- Very high doses: neurotoxicity, QT prolongation
- More evidence for use in 2nd and 3rd trimesters of pregnancy
- In 1st trimester can be used for treatment of severe malaria
Other Anti malarials
Clindamycin
- can be used as an alternate tp doxycycline
Halofantrine:
• Effective against erythrocytic stages of all parasites
• Use is limited by irregular absorption & cardiac toxicity Use is limited by irregular absorption & cardiac toxicity
• Teratogenic
Lumefantrine
• Effective against erythrocytic stages of all parasites
• Available only as fixed-dose combination with artemether
• Causes minor QT prolongation (clinically insignificant) Causes minor QT prolongation (clinically insignificant)
• Well tolerated
Tx Guidelines for Uncomplicated malaria:
- P falciparum w/ no resistance DOC?
- P. falciparum w/ chloroquine resistance or unknown
- P.malariae all regions (no known resistance)
- Chloroquine or hydroxychloroquine
2: i. Atovaquone-proguanil (malarone)
ii. Artemehter-lumefantrine (co-artem)
iii. Quinine + doxycycline
iv. mefloquine - Chloroquine/hydroxychloroquine
Tx Guidelines for Uncomplicated malaria:
1. P. vivax or P.ovale all regions little reported resistance.
- chloroquine + primaquine
2. Hydrochloroquine + primaquine
Tx Guidelines for Uncomplicated malaria:
P. vivax-chloroquine resistance
- quinine + doxy + Primaquine
- Atovaquone-proguanil + primaquine
- Mefloquine + primaquine
