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
PRIMAQUINE
CLINICAL APPLICATIONS
MOA
PRIMO –> DOC –> gets to slay those PRIMO girls while they’re DORMANT (only active on OV chicks ie ovale or vivax that have drank too much) –> note CANNOT get to pregnant chicks (use Mefloquine then switch once baby is born)
- Drug of choice for eradication of dormant liver forms of P. vivax and P. ovale
- Also used for chemoprophylaxis (all strains)
Clinical Applications
- Therapy of acute vivax and ovale 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)
ANTIMALARIAL ACTION: ***_Only available agent active against dormant liver forms of P. vivax and P. ovale***_
MOA
• Not completely understood (primaquine metabolites believed to act as oxidants, disrupting mitochondria and binding to DNA)
PRIMAQUINE
PK
RESISTANCE
AE
Pharmacokinetics
- Oral
- Metabolites have less antimalarial activity but more potential for inducing hemolysis
Resistance
• Resistant strains may require therapy to be repeated & dose to be increased
PRIMAQUINE
AE
CONTRAINDICATIONS
don’t get to slay the PRIME DORMANT girls if they are PREGNANT or if they drive a G6(PD) car
• Generally well tolerated
• Infrequent (nausea, epigastric pain, abdominal cramps,
headache)
• Rare (leukopenia, agranulocytosis, leukocytosis, cardiac arrhythmias)
_• ****Hemolysis or methemoglobinemia (especially in G6PD deficient patients)***** = EXAM Q_
-G6PD deficiency results in a decrease in NADPH and GSH synthesis, making the cell more sensitive to oxidative agents –> this causes HEMOLYSIS
Primaquine oxidizes GSH to GSSG. Therefore, less GSH is available to neutralize toxic compounds
• Patients should be tested for G6PD deficiency before
primaquine is prescribed.
• For severely G6PD deficient patients withhold therapy & treat relapses
CONTRAINDICATIONS:
- 1) G6PD deficiency
- 2) Pregnancy: fetus is relatively G6PD deficient (FDA category not yet assigned). DO NOT use during pregnancy
MALARONE
CLINICAL APPLICATIONS
MOA
MalarONE = atovaqu*one* + progua*nil*
–> ie is MALARIA’s drugs in ONE combo (one + nil ending = one) –> used in the treatment of ***_UNCOMPLICATED FALCIPARUM ***_
–> MOA –> causes MAL-“AIR” –> b/c it fucks iwth the mitochondrial electron transport chain
Clinical Applications
• Treatment & prophylaxis of P. falciparum
Antimalarial Action
- Active against tissue & erythrocytic schizonts
- Chemoprophylaxis can be started 1-2 days before travel and discontinued 1 week after exposure
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
INHIBITORS OF FOLATE SYNTHESIS
NAMES?
CLINICAL APPLICATIONS?
Used generally in combination regimens:
• 1) Pyrimethamine
- 2) Proguanil
- 3) Sulfadoxine
Clinical Applications
• Chemoprophylaxis: only in combination.
Proguanil + chloroquine = no longer recommended
- Intermittent Preventive Therapy: high-risk patients receive intermittent therapy regardless of infection status
- Treatment of chloroquine-resistant falciparum malaria: pyrimethamine-sulfadoxine commonly used.
–> ***DO NOT use for severe malaria***
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
INHIBITORS OF FOLATE SYNTHESIS
PK
RESISTANCE
AE
Pharmacokinetics
• Oral
Resistance
• Relatively common for P. falciparum
AE:
- Well tolerated (GI problems, rashes, itching)
- Proguanil (mouth ulcers***, alopecia = rare)
–> PROGUANIL = MOUTH ULCERS b/c he’s a PRO and chews tobacco all the time
- 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 vaginitis, photosensitivity
- Discoloration & hypoplasia of teeth, stunting of
growth
- Fatal hepatotoxicity (in pregnancy)
- ***_DO NOT use in pregnancy or children < 8y***_ (FDA Category D)
ARTEMISININ
KINDS:
CLINICAL APPLICATIONS;
See “ARTE” in anything –> know that it should be for treating SEVER FALCIPARUM
Derived from qinghaosu plant
• Artesunate: oral, IV, IM & rectal admin
- Artemether: oral, IM & rectal admin
- Dihydroartemisinin: oral admin
- Coartem = artemether + lumefantrine
Clinical Applications
- ***_Treatment of severe falciparum malaria (given IV)***_
- NO effect on hepatic stages
- Should not (in general) be used as single agent to protect against resistance
ARTEMISININ
MOA
PK
AE
ARTE –> binds IRON –> breaks down peroxide pridges and leads to generation of free radicalas that damage parasite proteins
MOA
• Appears to act by binding iron, breaking down peroxide bridges leading to generation of free radicals that damage parasite proteins.
Pharmacokinetics
- Very short t1/2 (IV therapy must be followed by a longer- acting agent once patient is able to tolerate oral therapy)
- If used alone, artesunate must be administered 5-7 days (otherwise recurrent parasitemia results)
AE:
- Overall remarkably safe (nausea, vomiting, diarrhea)
- Very high doses: neurotoxicity, QT prolongation
CAN BE USED IN PREGNANCY:
• More evidence for use in 2nd and 3rd trimesters of pregnancy
• In 1st trimester can be used for treatment of severe malaria
CLINDAMYCIN
-can be used as an alterative to doxycycline
HALOFANTRINE
HALO FAN –> know that it is BAD FOR HEART and is TERATOGENIC –> b/c always around wires and also because always eating like shit
- Effective against erythrocytic stages of all parasites
- 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)
- Well tolerated
P. FALCIPARUM: UNCOMPLICTED MALARIA
NO KNOWN RESISTANCE
DOC:
1) CHLOROQUINE
OR
2) HYDROXYCHLOROQUINE
P. FALCIPARUM: UNCOMPLICATED MALARIA
CHLOROQUINE RESISTANT (or unknown resistance)
1) MALARONE (Atovaquone-proguanil)
2) COARTEM (Artemether-lumefantrine)
3) QUININE + DOXYCYCLINE
4) MEFLOQUINE
P. VIVAX OR P. OVALE: UNCOMPLICATED MALARIA
ALL REGIONS (little resistance reported)
- CHLOROQUINE + PRIMAQUINE
- HYDROXYCHLOROQUINE + PRIMAQUINE
P. VIVAX: UNCOMPLICATED MALARIA
Chloroquine resistant
1) QUININE + DOXYCYCLINE + PRIMAQUINE
2) MALARONE (ATOVAQUONE-PROGUANIL) + PRIMAQUINE
3) MEFLOQUINE + PRIMAQUINE
UNCOMPLICATED MALARIA IN PREGNANCY:
P VIVAX, P. OVALE. P. FALCIPARUM, OR P. MALARIA
RESISTANCE: CHLOROQUINE-SENSITIVE
CHLOROQUINE/HYDROCHLOROQUINE
UNCOMPLICATED MALARIA IN PREGNANCY: P. FALCIPARUM
RESISTANCE: CHLOROQUINE-RESISTANT FALCIPARUM
1) MEFLOQUINE
2) QUININE + CLINDAMYCIN
UNCOMPLICATED MALARIA IN PREGNANCY: P. VIVAX
RESISTANCE: CHLOROQUINE-RESISTANT P. VIVAX
MEFLOQUINE
SEVERE MALARIA
ALL SPECIES
RESISTANCE: ALL REGIONS
RECOMMENDED IV DRUG:
1) QUINIDINE AND
2) DOXYCYCLINE OR 2) CLINDAMYCIN
(can progress to oral quinine + doxycycline)
OPTION 2:
1) ARTESUNATE followed by
2) ATOVAQUONE-PROGUANIL, CLINDAMYCIN, or MEFLOQUINE
NOTE:
1ST TRIMESTER –> use QUINIDINE/ARTESUNATE
2ND/3RD TRIMESTER –>
- first option = artesunate
- second option = artemether
MALARIAL CHEMOPROPHYLAXIS
1) CHLOROQUINE SENSITIVIE?
2) CHLOROQUINE RESISTANT?
1) CHLOROQUINE
if resistant
give MEFLOQUINE, DOXYCYCLINE, PRIMAQUINE
MALARIAL CHEMOPROPHYLAXIS FOR PREGNANT WOMEN
CHLOROQUINE SENSITIVE?
CHLOROQUINE RESISTANT?
1) CHLOROQUINE
2) MEFLOQUINE
