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Flashcards in ANTIMALARIALS Deck (40):
1

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

2

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

3

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

4

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

5

MAJOR ANTIMALARIAL DRUGS

 

• Chloroquine
• Quinine and Quinidine
• Mefloquine
• Primaquine
• Atovaquone
• Sulfadoxine-pyrimethamine

Doxycycline
Artemisinins

6

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

 

7

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

A image thumb
8

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

9

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

10

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)

11

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

12

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)

13

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)

14

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

15

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

16

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

17

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)

18

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

19

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

20

MALARONE 

CLINICAL APPLICATIONS 

MOA 

 

MalarONE = atovaquone + proguanil

--> 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

 

21

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***

22

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) Sulfonamides (S FOR SYNTHASE)
Weakly active against erythrocytic schizonts

--> inhibit DIHYDROPTEROATE SYNTHASE 

A image thumb
23

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

24

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

25

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)

26

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

27

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

28

CLINDAMYCIN

-can be used as an alterative to doxycycline 

 

29

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***

 

30

LUMEFANTRINE

 

• Effective against erythrocytic stages of all parasites
• Available only as fixed-dose combination with artemether

• Causes minor QT prolongation (clinically insignificant)
• Well tolerated

31

P. FALCIPARUM: UNCOMPLICTED MALARIA

NO KNOWN RESISTANCE

DOC: 

1) CHLOROQUINE

OR

2) HYDROXYCHLOROQUINE

 

32

P. FALCIPARUM: UNCOMPLICATED MALARIA

CHLOROQUINE RESISTANT (or unknown resistance) 

1) MALARONE (Atovaquone-proguanil) 

2) COARTEM (Artemether-lumefantrine) 

3) QUININE + DOXYCYCLINE

4) MEFLOQUINE 

33

P. VIVAX OR P. OVALE: UNCOMPLICATED MALARIA

ALL REGIONS (little resistance reported) 

 

1. CHLOROQUINE + PRIMAQUINE

2. HYDROXYCHLOROQUINE + PRIMAQUINE 

34

P. VIVAX: UNCOMPLICATED MALARIA 

Chloroquine resistant

1) QUININE + DOXYCYCLINE + PRIMAQUINE

2) MALARONE (ATOVAQUONE-PROGUANIL) + PRIMAQUINE 

3) MEFLOQUINE + PRIMAQUINE 

35

UNCOMPLICATED MALARIA IN PREGNANCY: 

P VIVAX, P. OVALE. P. FALCIPARUM, OR P. MALARIA

RESISTANCE: CHLOROQUINE-SENSITIVE

 

CHLOROQUINE/HYDROCHLOROQUINE 

 

36

UNCOMPLICATED MALARIA IN PREGNANCY:  P. FALCIPARUM

RESISTANCE: CHLOROQUINE-RESISTANT FALCIPARUM 

1) MEFLOQUINE

2) QUININE + CLINDAMYCIN 

 

37

UNCOMPLICATED MALARIA IN PREGNANCY:  P. VIVAX

RESISTANCE: CHLOROQUINE-RESISTANT P. VIVAX

MEFLOQUINE 

38

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 

39

MALARIAL CHEMOPROPHYLAXIS

1) CHLOROQUINE SENSITIVIE?

2) CHLOROQUINE RESISTANT? 

1) CHLOROQUINE

if resistant

give MEFLOQUINE, DOXYCYCLINE, PRIMAQUINE

40

MALARIAL CHEMOPROPHYLAXIS FOR PREGNANT WOMEN

CHLOROQUINE SENSITIVE?

CHLOROQUINE RESISTANT? 

1) CHLOROQUINE

2) MEFLOQUINE