ANTIMALARIALS Flashcards
MALARIA PARASITE LIFE CYCLE
- Anopheline mosquito inoculates plasmodium sporozoites to initiate human infection
- Circulating sporozoites rapidly invade liver cells
- Exoerythrocytic stage tissue schizonts mature in the liver
- Merozoites are released from the liver and invade erythrocytes
- Gametocytes develop in erythrocytes before being taken up by mosquitoes and completing the cycle
P. Falciparum & P. Malariae = FM RADIO –> only blood parasites, NOT in the liver
- only one cycle of liver cell invasion
- liver infections ceases in < 4 weeks
- only erythrocytic parasites have to be
eliminated
P. vivax & P. ovale = OV –> involves the LIVER
• have a dormant hepatic stage
• erythrocytic and hepatic parasites have to be
eliminated
MALARIA INCUBATION PERIOD
+ SYMPTOMS
- P. vivax: 2-17 days
- P. falciparum: 9-14 days
- P. ovale: 16-18 days
- P. malariae: 18-40 days (can be years)
(a) P. falciparum can cause rapidly progressive severe illness or death (in other species is very rare)
(b) P. vivax and P. ovale infections require treatment for the hypnozoite forms dormant in the liver
(c) P. falciparum and P. vivax have different resistance patterns in different geographic areas
SYMPTOMS:
- Malarial paroxysm (fever, anemia, jaundice, splenomegaly, hepatomegaly)
- In established infections, malarial paroxysms typically occur about every 2-3 days
P. FALCIPARUM:
- Most severe disease (microvascular effects)
- Only species likely to cause fatal disease if untreated • Cerebral malaria (irritability–> seizures–> coma)
• Symptoms:
eg, respiratory distress syndrome, diarrhea, severe thrombocytopenia, spontaneous abortion,hypoglycemia
EVALUATION + DIAGNOSIS
PROPHYLAXIS
EVALUATION
- Misdiagnosis is common in US
- Should routinely be considered for anyone who has
traveled to area with known malaria transmission recently
- Symptoms are generally non-specific
- Treatment should not be initiated until diagnosis is confirmed
- Presumptive treatment reserved for extreme cases
DIAGNOSIS: via thick/thin blood smears
PROPHYLAXIS:
-insect repellents, insecticides, and bed nets
PHARMACOLOGY:
treatment guided on 3 main factors:
uncomplicated vs. complicated?
Treatment should be guided by 3 main factors:
(1) Infecting Plasmodium species
(2) Clinical status of patients
-
UNCOMPLICATED VS. COMPLICATED MALARIA
- UNCOMPLICATED: treat with ORAL ANTIMALARIALS
-
COMPLICATED:
- • One or more of following: impaired consciousness /coma, severe normocytic anemia, renal failure, pulmonary edema, acute respiratory distress syndrome, circulatory shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, repeated generalized convulsions, and/or parasitemia of >5%)
- • _Treat aggressively with **parenteral antimalarials**_
(3) Drug susceptibility of the infecting parasites
MAJOR ANTIMALARIAL DRUGS
- Chloroquine
- Quinine and Quinidine
- Mefloquine
- Primaquine
- Atovaquone
- Sulfadoxine-pyrimethamine
- Doxycycline
- Artemisinins
CHLOROQUINE
DOC
PROPHYLAXIS for OV!!!!
• Drug of choice for both treatment & prophylaxis of all
C QUINE = 1st queen, and most used, but resistance develops
P. vivax and P. ovale malaria infections since 1940’s
• Use severely compromised by drug resistance
Clinical Applications
- Drug of choice in the treatment of non-falciparum and sensitive uncomplicated falciparum malaria
- Preferred chemoprophylactic agent in areas without resistant falciparum malaria
CHLOROQUINE
MOA
Antimalarial Action –> can think of CHLORINE because chlorine is exchanged in RBCs –> basically the hemoglobin becomes toxic to the parasite and nORMALLY is converted to a nontoxic compound called HEMOZOIN –> can’t happen so hemoglobin becomes toxic to the parasite!
- Highly effective against blood parasites
- NOT active against liver stage parasites
MOA
- Concentrates in parasite food vacuoles
- Prevents biocrystallization of hemoglobin breakdown product heme to non-toxic hemozoin
1) The parasite digests the host cell’s hemoglobin to obtain essential amino acids
2) The process releases large amounts of heme, which is TOXIC to the parasite
3) To protect itself, the parasite ordinarily polymerizes the heme to nontoxic hemozoin, which is sequestered in the parasite’s food vacuole
4) Chloroquine prevents the polymerization to hemozoin –> the accumulation of heme results in lysis of both the parasite + the RBC
CHLOROQUINE
PK
AE
CHLORINE QUEEN CAN GET RETINOPATHY –> B/C is getting chlorine in her eyes!!!
PK
- Oral
- t1/2 = 3-5 days (only need to take once weekly)
AE:
- Generally well tolerated (at therapeutic doses)
- Pruritus (common in Africans)
- Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, urticaria (uncommon) (retinopathy)
- ***_Hemolysis (G6PD-deficient people)****_
- Can cause electrocardiographic changes
CHLOROQUINE
CONTRAINDICATIONS
CHLORINE POOL GUY –> has PSORIASIS/PORPHYRIA
also patietns with G6PD!!!! CHLORINE AGAIN!!!
Patients with:
- psoriasis or porphyria (may precipitate attacks) ****
- _retinal or visual field abnormalities*****_
SAFE IN PREGNANCY & YOUNG CHILDREN
QUININE + QUINIDINE
IF THE QUEEN COMES FIRST (Quinine or quinidine not chloroquine etc) then you know it’s IMPORTANT –> is the DOC for the WORST MALARIA (falciparium)
-are just stereoisomers of each other, but QUINIDINE is for IV, and Quinine = oral (note the DINE is the IV one, opposite of what you’d think)
- Derived from cinchona tree bark
- First-line therapies for severe falciparum disease
- Resistance is uncommon but increasing
- Quinidine (stereoisomer of quinine)
Clinical Applications
- 1) Parenteral treatment of severe falciparum malaria (Quinidine)
- 2) Oral treatment of falciparum malaria (alternative in chloroquine-resistant areas) (Quinine)
QUININE + QUINIDINE
MOA
PK
RESISTANCE
Antimalarial Action
- Rapidly-acting, highly effective against blood parasites
- NOT active against liver stage parasites
MOA = RUTHLESS QUEEN –> STARVES OF OXYGEN AND FOOD
- Depresses O2 uptake and carbohydrate metabolism
- Intercalates into DNA, disrupting parasite’s replication and transcription
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
QUININE + QUINIDINE
AE
QUEEN DRUGS –> they’re a CINCH to get them for her because she rules everything
_******• Cinchonism:_ tinnitus, headache, nausea, dizziness, flushing & visual disturbances********EXAM Q
- 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)
QUININE + QUINIDINE
CONTRAINDICATIONS
KNOW THIS SLIDE!!!
• Discontinue if signs of:
• severe cinchonism
- • hemolysis*
- • hypersensitivity*
• Avoid if possible in patients with:
• visual or auditory problems
• Use with caution in patients with:
• underlying cardiac abnormalities
- Do not use concurrently with mefloquine
- Can raise plasma levels of warfarin & digoxin
• Reduce dose in renal insufficiency
Pregnancy
• FDA Category C (however benefits do often outweigh risks in complicated malaria)
MEFLOQUINE
MOA
CLINICAL APPLICATIONS
‘ME-FLO”-QUINE –> look at “me flow” –> slow and easy, calm and cool, at a mild-to-moderate pace, so that young women and children can come –> can give to young children + in pregnancy and is effective against MILD-MODERATE CHLOROQUINE RESISTANT strains for PROPHYLAXIS
- Effective against many **_chloroquine-resistant strains**_
- Chemically related to quinine
MOA
• Destruction of the asexual blood forms of malarial pathogens. Details unknown.
CLINICAL APPLICATIONS:
- 1) Chemoprophylaxis: effective against most strains of P. falciparum and P.vivax
- ***Currently only medication recommended for chemoprophylaxis in pregnant women in _chloroquine-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
MEFLOQUINE
PK
RESISTANCE
ME FLO –> my shit comes in WEEKLYYYYY b/c it’ s aweekly prophylactic drug
Pharmacokinetics
• Oral only
• Elimination t1/2 = 20 days (weekly prophylactic dosing)
Resistance
- Uncommon but has been reported
- Associated with resistance to quinine but not chloroquine
MEFLOQUINE
AE
CONTRAINDICATIONS
ME FLOW is so chiill when he’s walking around the street, you know there’s SOMETHING fucking weird about the guy –> drug my cause NEUROPSYCHIATRIC TOXICITY (note this includes depression and hallucinations, but the cinchonism ie tinnitus ,headache etc for quinine/quinidine did NOT)
AE:
_*****Serious neurological and psychiatric toxicities_: Dizziness, loss of balance, ringing in the ears, anxiety, depression, hallucinations********
Weekly dosing:
Nausea, vomiting, diarrhea, dizziness, sleep & behavioral disturbances,rash
Higher treatment doses:
Leukocytosis, thrombocytopenia, aminotransferase elevations, arrhythmias, bradycardia
CONTRAINDICATIONS:
• Patients with history of:
Epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, sensitivity to related drugs
- DO NOT coadminister with quinine, quinidine or halofantrine
- Considered safe in young children & pregnancy
INHIBITORS OF FOLATE SYNTHESIS
ANTIMALARIAL ACTION
MOA
Antimalarial Action
• 1) Pyrimethamine + proguanil 2 P’s = inhibit DHF
-2P’s for REDUCTASE
Act slowly against erythrocytic forms of all malaria species
-both inhibit PLASMODIAL DIHYDROFOLATE REDUCTASE
• 2)Proguanil
Some activity against _hepatic forms_
_• 3) *S*ulfonamides (*S* FOR SYNTHASE)_
Weakly active against erythrocytic schizonts
–> inhibit DIHYDROPTEROATE SYNTHASE
