18 - Malaria Flashcards by Karlo Sison

What Drug?

SESQUITERPENE LACTONES

Artemisinin** & **ARTHEMETHER** & **Artesunate
artesunate is still investigational

Target
BLOOD SHIZONTS** & **YOUNG GAMETOCYTES

MoA:
Free Radical Formation = ENDEPEROXIDE
oxidative dmg to parasite’s membrane

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Mefloquine

Class / Target / Use

*4 - Substituted Quinolines**
*4-chinoline-methanols**

BLOOD SCHIZONTS

Treatment for:

P. falciparum** or *non-ID species in areas with CQ RESISTANCE
*Pregnant women** = Mefloquine + Clindamycin

Prevention for:
Long Trips

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Chloroquine RESISTANCE
4-sub-quinine
Blood Schizonts Only

Spontaneous Gene Mutations
pfcrt transporter protein on digestive vacuole membrane
Plasmodium falciparum CQ resistance transporter
↑drug efflux against ION TRAPPING

↑Plasmodial P450 Metabolism

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4-Substituted Quinolones
&
Their TARGET?

BLOOD SCHIZONTS
can only treat the ACTIVE FORM in BLOOD, not dormant liver form

Quinine

Chloroquine

Mefloquine

Halofantrine

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Atovaquone + Proguanil
for Prevention of Malaria

Use / Dosing / CI’s

Last Minute & short Trips

Prior to Travel: 1-2 DAYS

After Travel: 7 Days

250/100mg one tablet a day

CI’s
PREGNANCY / BREASTFEEDING (infant < 5kg)
RENAL Impairment

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What Drug?

*Atovaquone**
*UBIQUINONE REDUCTASE INHIBITOR** –> collapse of mitochondrial membrane potential

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What Malaria Drug?

ANTIFOLATE

PYRIMETHAMINE
used typically in combination with Sulfadoxine

Target only:
BLOOD SHIZONTS

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Quinine

Class / Target / Use

*4 - Substituted Quinolines**
*4-chinoline-methanols**

BLOOD SCHIZONTS

Essential Stereoconfiguration
8S - 9R = Quinine
8R - 9S = Quinidine
quinidine for MORE SEVERE malaria forms

Treatment for:

*P. Falciparum** or non-ID species in CQ resistant areas
*Quinine Sulfate + Doxy/Tetra**

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Uncomplicated vs SEVERE
Malaria

Uncomplicated = Severe Cold Symptoms

Severe Malaria:
Parasitemia > 5%
Hemoglobinuria / Jaundice / ANEMIA
Impaired Conciousness + Coma
Renal Failure / Respiratory Distress / HypoTension
Convulsions / Bleeding / Intravascular coagulation

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How do we get the drug into the food vacuole of plasmodium?

4-Sub-Quinolines

ION TRAPPING

Food Vacoules = ACIDIC (5.5pH)

drug = BASIC –> move towards acidic pH & become protonated

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Malaria Life Cycle

in
HUMANS

Female anopheles –> blood meal
1. Sporozoites enters with saliva
Enter human liver & divide
1. burst out –> MEROZITES in blood stream
Merozites enter RBC’s & replicate
1. burst out & re-infect RBCs = MALARIA FEVER
Some intracellular merozites develop into:
1. sexual forms = GAMETOCYTES
2. –> ingested by ANOTHER MOSQUITO

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What drugs can be used for the

PREVENTION OF MALARIA

Longer Trips
Chloroquine & Mefloquine

Short Trip
Doxycycline

Last Minute / Short
Atovaquone + Proguanil

Preventing P. Vivax
Primaquine

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ARTEMISINS

DRUGS & TARGET

Artemisinin** & **ARTHEMETHER** & **Artesunate
artesunate is still investigational

Target
BLOOD SHIZONTS** & **YOUNG GAMETOCYTES

MoA:
Free Radical Formation = ENDEPEROXIDE
oxidative dmg to parasite’s membrane

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8-Substituted Quinolines = PRIMAQUINE

MoA

Generation of:
ROS
via autooxidation of 8-amino group

H2O2 / Superoxide / Hydroxyl Radical
VV
Oxidative Cell Damage

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How can P.vivax and P. ovale escape drug treatment?
(M. Tertiana)

*DORMANT LIVER FORMS**
*HYPNOZOITES**
*1st Line Quinolones –> blood schizonts only**
ineffective vs dormant hepatic stage*

To Prevent RELAPSE:
Primaquine = 8-subquinolone

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Chloroquine = CQ

Class / Target / Use

*4 - Substituted Quinolines**
*4-chinoline-AMINE**

BLOOD SCHIZONTS

Treatment for:

CQ Sensitive** P. Falciparum or Non-ID species *_w/o CQ resistance_
*P. Malariae_ & _P. Knowlesi**
*P. Vivax_/_Ovale** taken with Primaquine Phos
*Pregnant Women**

Prevention for:
Longer Trips

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Chloroquine
for Prevention of Malaria

Use / Dosing / CI’s

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Longer Trips

Prior to Travel: 1-2 Weeks

After Travel: 4 weeks

600mg (300mg base) on exact same day of each week

CI’s

*VISON PROBLEMS**
irreversible retinal dmg may occur with PROLONGED treatment*

Treatment of Malaria

P. Vivax & P. Ovale
Relapsing
M. Tertiana

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CQ + PP

*ChloroQuine Phosphate_ + _Primaquine Phosphate**
except for certain areas*

for 2 Weeks

Mefloquine
for Prevention of Malaria

Use / Dosing / CI’s

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Longer Trips

Prior to Travel: 2-3 Weeks

After Travel: 4 weeks

250mg (228mg base) on exact same day of each week

CI’s
MENTAL ADR + TINGLING FEET & FINGERS
SEIZURES
cardiac conduction / PREGNANCY

8-Substituted Quinolones
&
Their TARGET?

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LIVER Hypnozoites & Schizonts

*BLOOD Gametocides**
does NOT work on BLOOD SCHIZONTS*
*PRIMAQUINE**
do NOT give to pregnant women*

PRIMAQUINE
for Prevention of Malaria

Use / Dosing / CI’s

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Preventing P. VIVAX
good for places with >90% P. Vivax

Prior to Travel: 1-2 DAYS

After Travel: 7 DAYS

30mg QD

CI’s
G6PD DEFICIENCY –> NEED TESTING
PREGNANCY & BREASTFEEDING

PYRIMETHAMINE

Class / Target / Uses

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DHFR Inhibitor = Antifolate
Blood Schizonts

Used in combination with:
Sulfadoxine** + **Pyrimethamine = FANSIDAR

Treatment & Prevention for:
QC-RESISTANT MALARIA
Used with quinine

If the diagnosis of malaria is suspected and cannot be confirmed,
or
if the diagnosis is confirmed but species determination is not possible

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treat against

*CQ-RESISTANT P.F**
*immediately**

Treatment of Malaria

PREGNANT WOMAN

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can NOT use PRIMAQUINE

ChloroQuine
or
Mefloquine + Clindamycin

For P.Vivax & Ovale:
maintain with CQ prophylaxis during pregnancy
then Primaquine AFTER delivery

if Severe –> use Parenteral treatment

**_Treatment of Malaria_** **_SEVERE_**

**Require _IV THERAPY_** **_QuiniDINE Gluconate IV_** for **24 h+** (**Parasitemia \< 1%)** (if not available --\> **_Artesunate)_** THEN **Oral: Quinine**or**Atovaquone-Guanil**or**Artemether-Lumefantrine**

**What organisms cause Malaria?** **Vector = FEMALE ANOPHELES MOSQUITO** plasmodium genus

**FOVM-k** * *_P. Falciparum_** * *M. Tropica** = **fulminating disease** * *_P. Vivax / Ovale_** * *M. Tertiana** = **RELAPSING** * *_P. Malariae_** * *M. QUARTana** P.Knowlesi = ZOONOTIC --\> monkey transmition

**DHFR Inhibitor = Antifolates** **TARGET**

**_PYRIMETHAMINE_** used typically in combination with **Sulfadoxine** Target only: **_BLOOD SHIZONTS_**

**What Drug?**

**_Proguanil_** inhibit the **enzyme DHFR (anti-folate)** **Guanidine Derivative**

**_Doxycycline_** for **Prevention of Malaria** ## Footnote **Use / Dosing / CI's**

**_SHORT Trips_** Prior to Travel: **1-2 DAYS** After Travel: **4 weeks** **100mg/daily** CI's **Pregnancy / Children \<8 y/o** / **SUN EXPOSURE** MoA: * *impairs reporduction of malaria specific plastids** * *only Prophylaxis** *not treatment*

**Malaria Life Cycle** **in MOSQUITO**

1. Mosquito **blood meal** 1. **** --\> **_ingest GAMETOZYTES_** 2. **Male + Female --\> form zygote** in **GI** of mosquito 1. mature to **mobile form = _OOKINETE_** 3. **Ookinte** --\> migrates to **cell wall of gut** 1. matures into **_OOCYST_** 4. **__****Oocyst** replicates new **sporoids** 1. **ruptures --\> releases _SPOROZOITES_** 1. **_SALIVA GLANDS_** --\> **human infection**

**If malaria infection occurred _despite use of a preventive drug..._**

**that DRUG should NOT be used** in part of the **treatment regimen**

**_Quinidine_** ## Footnote **Class / Target / Use**

* *_4 - Substituted Quinolines_** * *4-chinoline-methanols** **BLOOD SCHIZONTS** **_Essential Stereoconfiguration_** 8S - 9R = Quinine **_8R - 9S = Quinidine_** *quinidine for MORE SEVERE malaria forms* Treatment for: **_SEVERE MALARIA_** -- **IV Quinidine Gluconate**

**MALARONE Atovaquone / Proguanil** **MoA / Uses**

* *_Atovaquone_** * *UBIQUINONE REDUCTASE INHIBITOR** --\> collapse of **mitochondrial membrane potential** * *_Proguanil_** * inhibit the enzyme* **DHFR** (**anti-folate**) Target only **BLOOD SCHIZONTS** for **CQ Resistant & Multidrug Resistant _P. Falciparum**_&_**P.Vivax_**

**_Treatment of Malaria_** **CQ sensitive P. falciparum** or **species not identified in areas *_w/o CQ resistance_***

**_ChloroQuine Phosphate_** CQ 600mg base @0h 300mg base @6/24/48h

**_Treatment of Malaria_** **P. falciparum** or **species not identified in area** **_WITH CQ RESISTANCE_**

**_Atovaquone - Proguanil_** or **_Artemether-Lumefantrine_** or **_Quinine Sulfate_** + **Doxycycline or Tetracycline** or **_Mefloquine_**

**Which Malaria drug can cause: VISION PROBLEMS?**

**_CHLOROQUINE_** used for **Long Trips - Prevention of Malaria** irreversibal retinal dmg with prolonged treatment

**Which Malaria drug can cause: Mental Side Effects & Tingling Feet/Fingers?**

**_MEFLOQUINE_** used for **Long Trips - Prevention of Malaria** Also: **SEUIZURES Cardiac Conduction Problems PREGNANCY**

**_Treatment of Malaria_** **P. malariae & P. Knowlesi**

**CQ resistance is UNUSUAL for these species** **_ChloroQuine Phosphate_** CQ or same treatment for CQ resistant

**_Halofantrine_** ## Footnote **Class / Target / Use**

* *_4 - Substituted Quinolines_** * *4-chinoline-methanols** **BLOOD SCHIZONTS** * *Same use as Mefloquine?** * both are 4-chinoline methanols*

**MoA of 4- Sub Quinolines** Quinine / Quinidine Mefloquine / Halofantrine / Chloroquine (CQ)

1. **Hemoglobin** --\> **food vacuoles of Plasmodium** 1. ******digestion (protein)** --\> source of Amino Acids 1. also **_HEME_** = **_TOXIC TO PLASMODIUM CELLS_** 2. **_HEME DETOXIFICATION_** 1. Heme --\> **HEMOZOIN,** *not toxic*** **_Quinolines bind to HEMAZOIN_** aromatic system binds via p-bonds to porphyrin nucleus **blockage of polymer extention & _↑_****_Toxic Heme_** VVV **CELL DEATH**

18 - Malaria Flashcards

(40 cards)