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16 Treatment of Malaria
10/08/2019 Basic Pathologies 2
14:30-16:30 Julius Migriño, Jr., MD
PARASITOLOGY

TABLE OF CONTENTS

I. INTRODUCTION .................................................................................. 1
II. PHARMACOLOGY OF ANTI-MALARIAL DRUGS ............................. 1
A. MECHANISMS OF ACTION ...................................................... 1
B. MAIN TARGETS ........................................................................ 1
III. ANTI-MALARIAL DRUGS .................................................................. 2
A. MECHANISMS OF ACTION ...................................................... 2
B. TARGET LIFE CYCLE STAGES ............................................... 2
C. INDICATIONS ............................................................................ 2
D. SIDE EFFECTS AND CONTRAINDICATIONS ......................... 3
IV. PREVENTION AND CONTROL ........................................................ 3
A. CASE MANAGEMENT ............................................................... 3
B. VECTOR CONTROL .................................................................. 3
C. DOH MALARIA CONTROL PROGRAM .................................... 3
D. MALARIA VACCINES ................................................................ 3
V. EPIDEMIOLOGY ................................................................................ 3
QUICK REVIEW ...................................................................................... 3
REVIEW QUESTIONS ................................................................... 4
REFERENCES ........................................................................................ 4
REQUIRED ..................................................................................... 4
SUGGESTED ................................................................................. 4 Figure 1. Mechanisms of action and target life cycle stages of anti-
APPENDIX .............................................................................................. 4 malarial drugs

A. MECHANISMS OF ACTION
NEED TO KNOW Heme Accumulation
• No need to know the specific mechanisms of action and • Most important
indications for each of the drugs; just know the general • The drug is responsible for the accumulation of toxic heme within
mechanism per type the infected erythrocyte
• What will be asked in the exam J ® Heme is a byproduct formed when Plasmodium ingests
® Mechanism of action nutrients
® Stages affected ® Toxic heme is normally converted by Plasmodium into non-
® 2-step questions relating drugs with life cycle toxic hemozoin
4 Prevents the biocrystallization of heme
• Anti-malarial activity is accomplished by preventing the fusion or
interaction between the food vacuole with heme
ADDITIONAL REFERENCE
& Food vacuole or cup – organelle optimized for hemoglobin
• This trans was supplemented with information from the WHO metabolism
Guidelines for the Treatment of Malaria (2015) upon
• Effective during the early to middle stages of the erythrocytic
recommendation by Doc Julius
cycle
• Available here:
® “Eating phase”; “growing phase”
® https://drive.google.com/open?id=1Uo1Qkp3gdm-
® Targets the young trophozoite or ring stage
yppphUQrpzbeJXDo7KCOe
H2O2 or Free Radical Formation
I. INTRODUCTION • Recently discovered mechanism of action
Treatment for malaria should NOT be initiated until diagnosis has • Direct killing of Plasmodium through the production of H2O2 or free
been confirmed by lab investigation (microscopy or RDT)” radicals in the cytoplasm
(WHO Guidelines, 2015) • Hydrogen peroxide (H2O2) – not a free radical but is highly toxic
® Can also produce free radicals
• Malaria should not be treated empirically ® Unique MOA of primaquine
® Necessary to confirm diagnosis before anti-malarial drugs are
given Blocking of Protein or Folic Acid Synthesis
® This is to prevent antimicrobial resistance from developing • Inhibits protein or folic acid synthesis needed for cell division
• DOT strategy ® Blocks the S and M phases
® Directly observed treatment for patients on anti-malarials • Effective during the late stages of the erythrocytic cycle
® Necessary to observe patients taking the drug ® Targets the schizont

Treatment Guides Interference of the Electron Transport Chain

• Plasmodium species • Mechanism is not completely understood
® Progression and severity of symptoms • “Has something to do with the mitochondria and the electron
® Treatment for dormant hypnozoites transport chain” (Migriño, 2019)
• Patient status
® Uncomplicated malaria: oral treatment B. MAIN TARGETS
® Severe malaria: parenteral treatment • Hypnozoites
& Persistent liver stages of P. vivax and P. ovale malaria that
• Drug susceptibility
remain dormant in host hepatocytes for 3 to 45 weeks before
® Knowledge of geographic area
maturing to form hepatic schizonts
§ Only a few areas are still sensitive to chloroquine
& Cause of relapses
® If malaria is highly suspected or cannot be confirmed, treat as
• Ring stage
P. falciparum
® Aka early trophozoite stage
§ Infections by P. falciparum comprise ~75% of all cases
& Young, usually ring-shaped, intra-erythrocytic malaria
parasites, before malaria pigment is evident by microscopy
II. PHARMACOLOGY OF ANTI-MALARIAL DRUGS
• Trophozoite
® Aka mid trophozoite stage

Transcribed by TG 12: Barcia, Batiduan, Libatique, Mallillin, Ordoño†, Riegodedios, Topacio, Yuson
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 & The stage of development of malaria parasites growing within Antibiotics
host red blood cells from the ring stage to just before nuclear • MOA: Blocks protein synthesis or folic acid synthesis
division • All antibiotics are non-specific to Plasmodium
& Mature trophozoites contain visible malaria pigment • Drugs that belong to this group:
• Schizont ® Clindamycin – inhibits the 50s ribosomal subunit
® Aka late trophozoite stage ® Doxycycline – inhibits the 30s ribosomal subunit
& Mature malaria parasite in host liver cells (hepatic schizont) or ® Sulfadoxine-Pyrimethamine
red blood cells (erythrocytic schizont) that is undergoing
nuclear division by a process called schizogony B. TARGET LIFE CYCLE STAGES
• Gametocytes Quines
& The sexual stages of malaria parasites that infect anopheline • Target: RT(g)
mosquitoes when taken up during a blood meal
® Ring and trophozoite stages
® Secondary activity against gametocytes of non-falciparum
III. ANTI-MALARIAL DRUGS Plasmodium
§ Except mefloquine
NEED TO KNOW • Heme accumulation occurs during the early to middle stages
• All anti-malarial drugs are specific to Plasmodium except the
antibiotics Primaquine
• Target: HGb
® Very effective against hypnozoites (H)
Table 1. MOA and targets of anti-malarial Drugs § Important in preventing relapse of P. vivax and P. ovale
Drug Mechanism Target § Affects the dormant Plasmodium lurkers in the liver
Quines ® Have some activity against the blood stages (b) all
Amodiaquine RTg Plasmodium species
Chloroquine RTg § Ring stage, trophozoite stage, and schizont stage
Heme accumulation
Mefloquine RT ® Kills the gametocytes (G) of all Plasmodium species
Quinine RTg § Responsible for transmission of malarial infections
Primaquine H2O2 formation HGb between humans
Artemisinin § “Cured” patients can serve as reservoirs if free floating
Artemether RSg gametocytes are still present in the blood
Free radical formation § Primaquine is important in the public health setting to
Artesunate RSg
Dihydroartemisini Free radical formation + RSg control and prevent the spread of malaria
n-piperaquine* heme accumulation
Antibiotics (Non-specific) Artemisinins
Clindamycin S • Target: RSg
Blocks protein synthesis ® Ring stage and schizont stages
Doxycycline S
Sulfadoxine- Blocks folic acid TS ® Secondary activity against gametocytes of non-falciparum
Pyrimethamine synthesis Plasmodium
Others ® NOTE: Doc Julius mentioned that artemisinins also target
Lumefantrine Heme accumulation RSg trophozoites (T), although it is not indicated in the powerpoint
Atovaquone- all • Act on all the blood stages by producing free radicals
Interference of ETC ® Able to kill as long as the parasite is already inside the red
Proguanil
H: hypnozoite; R: ring stage; T: trophozoite; S: schizont; G: gametocyte blood cell
g: secondary activity against gametocytes of non-falciparum Plasmodium • Artemisinins are being taken care of by the medical
b: targets the blood stages of all Plasmodium species community
*Dihydroartemisinin-piperaquine is a combination drug which is made up ® MOA is broad and effective against the bigger part of the
of an artemisinin (dihydroartemisinin) and a quine (piperaquine) Plasmodium life cycle
® Needs to be regulated to prevent the development of
A. MECHANISMS OF ACTION antimicrobial resistance
Quines § This is the reason why we don’t empirically treat
• MOA: Heme accumulation suspected malaria patients
• Drugs that belong to this group (anything with “quine”):
® Amodiaquine Antibiotics
® Chloroquine • Target: (T)S
® Mefloquine ® Schizont stage
® Quinine ® Sulfadoxine-Pyrimethamine also targets the trophozoite stage
® Piperaquine • Synthesis of proteins, folic acid, and DNA, are tied to the late
• Exceptions: stages of Plasmodium development
® Primaquine – quine but with a different MOA (H2O2 formation)
® Lumefantrine – different class of drugs but with same MOA C. INDICATIONS
as quines (heme accumulation)
§ Cannot be given on its own; always paired with
artemether

Artemisinins
• Derived from Artemisia annua
• MOA: Free radical formation
• Drugs that belong to this group (anything with “arte”):
® Artemether
® Artesunate Figure 2. Revised policy and guidelines for the treatment of malaria
® Dihydroartemisinin (DHA) – metabolite of all artemisinin (AO 2009-0001)
drugs (i.e. needs to be converted into dihydroartemisinin to
exert effects) Uncomplicated Malaria
• First line drug
Atovaquone-Proguanil ® Before: Chloroquine
• MOA: Interference of ETC § Used to be the drug-of-choice, but now has limited use
® Disruption of the mitochondrial processes and electric due to the development of resistance
potential in the protozoan o Plasmodium have mutations in the food vacuole
® May also inhibit transport of molecules

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 o Recall: Quine drugs act by heme accumulation
through preventing fusion with the food vacuole
§ Typically only reserved for chloroquine-sensitive areas
® Now: Artemether-Lumefantrine (AL) combination
§ Most common ACT
§ Brand name: Coartem
• Artemisinin-based combination therapy (ACT)
® Artemisinin drug coupled with another drug
® Examples
§ Artemether-Lumefantrine
§ Artesunate-Amodiaquine
§ Artesunate-Clindamycin
NICE TO KNOW
• Why is Atovaquone-Proguanil not the first line drug if it can target
all stages in the life cycle?
® Has relatively higher toxicity levels
® Resistance is very common
Severe Malaria
• Quinine
® Reserved for severe complicated malaria or treatment failures
® Administered through IV or IM
§ All other anti-malarial drugs can be administered orally
except for quinine
® Contraindicated or used with caution for patients with heart
problems
Prophylaxis
• Given to those travelling to malarious areas to prevent infection
• 4 anti-malarial drugs can be used for prophylaxis
® Doxycycline
§ Most commonly used and most accessible
§ Taken OD every day starting 1 week before going to the
malarious area until 4 weeks after returning
® Mefloquine
§ Taken once a week starting 1 week before going to the
malarious area until 2-3 weeks after returning
® Atovaquone-Proguanil
§ Only considered for areas where you can be sure that
resistance will not be a problem
® Chloroquine
• All drugs (except doxycycline) are heavily regulated by DOH and
RITM to prevent the development of resistance
® Cannot be bought in drug stores
D. SIDE EFFECTS AND CONTRAINDICATIONS
• Hypersensitivity (allergy)
® Most common contraindication against any drug
• Heart problems
® Quinine is contraindicated or used with extensive caution for
patients with heart problems
§ Many side effects because it is administered
intravenously
® Can cause QT prolongation and other cardiac toxicity effects
• G6PD deficiency
® All quine drugs (especially quinine and chloroquine) are
contraindicated for patients with G6PD deficiency
§ Unable to efficiently metabolize quine drugs
§ Some quine drugs can be given with caution, but
quinine and chloroquine are absolutely contraindicated
® Need to screen for G6PD deficiency in malaria patients before
treatment
IV. PREVENTION AND CONTROL
NEED TO KNOW
• This section was not discussed during the lecture (except
bednets)
® “Basahin niyo na lang” (Migriño, 2019) J
A. CASE MANAGEMENT
• Prompt diagnosis and treatment
® For pregnant women, infants, under-five (u5), and travelers
• Scaling up of diagnostic testing
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B. VECTOR CONTROL
• Bednets (kulambo)
® Insecticide-treated bednets (ITL)
® Long-lasting insecticidal bednets (LLIN)
& Personal protection method that can reduce malaria rates by
exposing mosquitoes who land on the net to insecticides
® A cornerstone in public health management
§ Given for free by the government
• Indoor Residual Spraying (IRS)
& Coating the walls and other surfaces of the house with a
residual insecticide that can last several months
• Larval management
• Personal protection measures
C. DOH MALARIA CONTROL PROGRAM
Strategies
• Early diagnosis and treatment of patients
® Rapid diagnosis centers throughout the country with staff
capable of diagnosing through microscopy
® Training and development programs
® Improving the availability of drugs
• Vector control
® Long-lasting insecticide-treated nets and indoor residual
spraying
• LGU capacity and governance
® Program management orientation/training
® Data utilization à PIDSR, MMIS, micro-stratification
® Multi-stakeholder involvement
Barriers
• Physical
® Mountainous areas, isolated coasts and islands, GIDAs
• Socio-cultural
® Lack of money, difficulty in information dissemination, lack of
healthcare workers
D. MALARIA VACCINES
• Piloted in three Countries: Kenya, Malawi, and Ghana
& RTS,S/AS01 Vaccine (nice to know!)
§ First malaria vaccine candidate to advance this far into
clinical trials
§ Three-dose vaccine series plus booster
§ Test results released in 2015 showed a reduction in
about one-third of the population of test subjects 5-17
months old
§ Still under pilot testing as recommended by WHO in the
above stated countries
V. EPIDEMIOLOGY
• Reduction in admissions and deaths in the past few years
• 4 endemic provinces remaining: Palawan, Sulu, Sultan Kudarat,
and Tawi-Tawi
® Most prevalent in southern Palawan
® Low incidences in northern Palawan, but vectors can still be
found
® High incidence persists in Mindanao
4 At-risk-populations: farmers, indigenous cultural groups, forest
product gatherers, agricultural workers, miners, and soldiers
Figure 3. Trends in malaria-related admissions and deaths
QUICK REVIEW
• General guidelines
® Do not treat Malaria empirically
® Always use directly observed treatment for patients on anti-
malarials
• Treatment guides
® Plasmodium species
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 ® Patient status d) Doxycycline
§ Uncomplicated malaria à oral treatment 2. What is the first-line drug for uncomplicated malaria?
§ Severe malaria à parenteral treatment a) Artemether-Lumefantrin
® Drug susceptibility b) Chloroquine
§ Only a few areas are still sensitive to chloroquine c) Quinine
§ Treat as P. falciparum if malaria is highly suspected but d) Doxycycline
cannot be confirmed 3. What is contraindicated against quinine?
a) Heart problems
Mechanisms of Action b) G6PD deficiency
• Heme accumulation c) Hypersensitivity
• H2O2 or free radical formation d) AOTA
• Blocking of protein or folic acid synthesis e) NOTA
• Interference of the Electron Transport Chain 4. Which drug is important for preventing the transmission of malaria?
a) Primaquine
Main targets of Anti-Malarial Drugs b) Mefloquine
• Hypnozoite stage c) Clindamycin
d) Doxycycline
• Ring stage/Feeding stage
5. What drug acts on the 50S ribosome of the protein synthesis?
• Trophozoite stage/Mid-trophozoite stage
a) Doxycycline
• Schizont stage/Late trophozoite stage b) Clindamycin
• Gametocyte stage c) Chloroquine
d) Quinine
Anti-Malarial Drugs 6. What place is endemic to malaria in the Philippines?
*Please refer to Table 1, page 2 for the table. a) Taguig
b) Paranaque
Indications c) Sultan Kudarat
• Severe malaria – Quinine d) Davao del Norte
• Uncomplicated malaria – Artemether-Lumefantrin
® Artemisinin-based combination therapy (ACT) Answers (if self-explanatory)
• Prophylaxis – Doxycycline 1C 2A 3D 4A 5B 6C

Side effects and contraindications REFERENCES

• Hypersensitivity – most common contraindication REQUIRED
• Heart problems – Quinine can cause QT prolongation (1) Migriño. 9 October 2019. Malaria [Lecture slides].
• G6PD deficiency – All quine drugs, especially Quinine and
Chloroquine. SUGGESTED
(2) World Health Organization. 3rd ed. “Guidelines for the treatment of
Prevention and Control malaria.” World Health Organization,
• Vector and control [https://www.who.int/malaria/publications/atoz/9789241549127/e].
® Bed nets are personal protection methods that can reduce the Accessed 9 October 2019.
incidence of Malaria
§ Insecticide-treated bed nets
§ Long-Lasting Insecticide-treated Nets IMPORTANT LINKS
® Indoor Residual Spraying
§ Coating the walls and other surfaces of the house with a Trans feedback: https://tinyurl.com/AcadsTransFeedback
residual insecticide that can last several months Errata submission: https://tinyurl.com/ContentErrataSubmission
Errata tracker: https://tinyurl.com/ErrataTracker
® Biological Management
§ Using biological control agents that can kill larval
mosquitoes are also one of the CDC’s means of
combating malaria APPENDIX
• Vaccines
® New cases of vaccines against Malaria
§ Piloted in Kenya, Malawi, and Ghana
• DOH Malaria control program
® Strategies
§ Early diagnosis and treatment of patients
§ Vector Control measures of long-lasting insecticide-
treated nets and indoor resdual spraying
§ Improving LGU capacity through program management
orientations and data utilization
® Barriers
§ Physical: mountainous areas, isolated coasts and
islands, GIDAs
§ Socio-cultural: lack of money, difficulty in information
dissemination, and a lack of healthcare workers

Epidemiology
• Reduction in the trend of admission and death in the past few
years
• High incidence in Mindanao
• 4 endemic provinces
® Palawan (most prevalent in southern part)
® Sulu
® Sultan Kudarat
® Tawi-tawi

REVIEW QUESTIONS
1. What is the choice of drug for severe malaria?
a) Artemether-Lumefantrin
b) Chloroquine
c) Quinine

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