Anti-Malarial Drugs Flashcards by Iseoluwa Ojo

Malaria is a/an (acute or chronic?) infectious disease caused by 4 species of the protozoa genus _____.

Acute

plasmodia

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P.________ is the most dangerous species.

Others are _______,______,_______

falciparum

P. malariae, P.ovale, P.vivax

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One ______ of the world population is at risk of malaria more than 300 million cases each year. (WHO 1998).
•

fifth

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Malaria kills more than a million people annually

T/F

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Majority of mortality due to malaria are children under _____ who die cause they do not receive treatment quickly enough. (Alnwick 2000).

five

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Nigeria is a malaria-endemic area

T/F

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_______ is the principal cause of childhood mortality.

malaria

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At least 20% of all childhood deaths are due directly to malaria

T/F

F(10)

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_____-_____ children die from malaria each day! (FMOH)

300 – 500

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________ countries accounted for 95% of malaria cases globally.

Twenty-nine

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Nigeria (_____%), and _____ other countries accounted for about 51% of all cases globally. Similar stats for death
■

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SUMMARY OF LIFE CYCLE of MALARIA

• Infected mosquito inject _________
• this migrate to _____ where they form ______
• these are ________ and invade _________

•________ of these cells releases ______, which (can or can’t?) infect other red cells.
• (Male or Female?) mosquito picks up _________ from infected individual

sporozoites

liver; merozoites

released; red blood cells

Rupture; merozoites; can

Female; gametocytes

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Signs and symptoms of UNCOMPLICATED MALARIA

______
_______

____________ pains
_________

Malaise

_______
___________
Nightmares

Fever
Headache

Joint and body
Weakness

Vomiting
Diarrhea

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Severe malaria

The presence of one or more of the following clinical or laboratory features
classifies the patient as suffering from severe malaria:

Clinical features: (WHO)
– impaired _______ or ___________
– ___________, i.e. generalized ______ so that the patient is unable walk
or sit up without assistance

– failure to ______
– multiple _______ – more than ___ episodes in ______

– deep breathing, respiratory distress (_______ breathing)

consciousness or unrousable coma

prostration; weakness

feed; convulsions

two; 24 h

acidotic

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The presence of one or more of the following clinical or laboratory features
classifies the patient as suffering from severe malaria:
Clinical features: (WHO)

-__________ collapse or ______

– clinical _______ plus evidence of other vital organ dysfunction
– __________uria
– abnormal spontaneous _______
– _________ oedema (radiological)

circulatory; shock

jaundice

haemoglobin

bleeding

pulmonary

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circulatory collapse or shock, in severe malaria may be characterized by systolic blood pressure < ____ mm Hg in adults
and < _____ mm Hg in children

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SEVERE MALARIA
Laboratory findings:

– _____glycaemia
– (metabolic or respiratory ?) (acidosis or alkalosis?)
– severe ______cytic anaemia (Hb < 5 g/dl, packed cell volume < 15%)

hypo

metabolic; acidosis

normo

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SEVERE MALARIA
Laboratory findings:

– __________uria
– hyper ___________
– hyper_________
–______ impairment (serum creatinine > 265 μmol/l).

haemoglobin

parasitaemia

lactataemia

renal

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Malaria in Pregnancy

Despite _________________________, women living in endemic areas suddenly become _____________ when they become pregnant.

being clinically immune from P. falciparum malaria

susceptible to the disease

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Malaria during pregnancy is characterised by very ___________ of the placenta.

heavy parasitization

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Protection against P. falciparum malaria acquired prior to the first pregnancy works against the parasites

T/F

Protection against P. falciparum malaria acquired prior to the first pregnancy for some reason does not work against the parasites causing pregnancy-associated malaria.

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Malaria in Pregnancy

The severity and prevalence of parasitaemia both rapidly decline with ______________

increasing parity

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The Available Antimalarial Medicines

List them allllll

NAPS BAA (sleep and mosquitoes bite you)

The Naphthoquinolines
The Antibiotics
The Peroxides
Sulphones

The Biguanides
The Arylaminoalcohol
4-Aminoquinolines
8-Aminoquinolines

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The Arylaminoalcohols

Divided into 2

________ methanols

___________ methanols

Quinoline

Phenanthrene

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The Arylaminoalcohols Quinoline methanols (______,______,______) Phenanthrene methanols ( ________,_______)

Quinine, Quinidine, Mefloquine Halophanthrene, Lumefantrine

The Arylaminoalcohols: Mefloquine Aka: _______________ Mode of Action Activity on the ____________. Alters the binding affinity of the parasite through the _____-binding _______

4-quinoline methanol mid- to late trophozoite ATP; cassette transporter.

The Arylaminoalcohols: Mefloquine Mode of Action Is a ———- ________cide active against _____,_______,________

Blood schizonticide P.falciparum, P.malariae, P.vivax

The Arylaminoalcohols: Mefloquine Adverse Effects Dizziness, nausea, vomiting, diarrhoea and abdominal pain. Major adverse effects include ________ reactions and _______ abnormalities. However, these effects seem to be dose- related and possibly associated with prophylactic use. Concurrent use with quinine can potentiate the dose-related adverse reactions to mefloquine.

neuropsychiatric; cardiovascular

Quinoline methanols :Quinine, Quinidine Efficacy Is a ______ ————cide effective against P.__________

Blood schizonti Falciparum

Quinoline methanols : Quinine, Quinidine Mode of Action Acts like CQ _______________ stage of the parasite.

Mid to late trophozoite

Quinoline methanols : Quinine, Quinidine Adverse Effects _______,________, sometimes ______ or dizziness. Quinine can cause severe _____tension if _____________. May cause enhanced ______ toxicity when administered to individuals who have taken ________. Hypoglycaemia

Tinnitus, muffled hearing; vertigo hypo; injected too rapidly cardiac; mefloquine

Quinidine is cardiotoxic T/F

4-Aminoquinolines ________ ,________ ,_________, _________, Mepacrine (______), Pyronaridine (benzonaphthyridine)

Chloroquine Amodiaquine Piperaquine; Naphthoquinoline acridine

4-Aminoquinolines Mode of Action Activity on _____________ stage Prevents ____________ by ________ or _____

mid- to late trophozoite detoxification of haem by polymerization to haemozoin or malaria pigment.

4-Aminoquinolines Efficacy •Marked and rapid _______cidal activity against all infections of ________________ in areas •_______cidal against P.vivax, P.malariae and P.ovale •Has both _________ and _________ effect.

schizonti P.falciparum, P.malariae, P.ovale and P.vivax Gametocyto; an antipyretic and anti inflammatory

4-Aminoquinolines Chloroquine Adverse Effects Nausea, vomiting, headache, GIT symptoms _______ disturbance and ——— (commoner in ___-skinned people). (Irreversible or reversible?) _____ impairment. _________ has rarely, if ever, resulted from doses recommended for malaria prophylaxis. Attacks of porphyria and psoriasis may be precipitated in susceptible individuals.

visual; pruritus; dark Irreversible; visual Retinopathy

4-Aminoquinolines Amodiaquine Adverse Effects Repeated and prolonged use of AQ has been associated with __________ and __________. However, adverse reactions to standard doses of AQ used in the treatment of malaria are generally similar to those of _________.

leucopaenia and agranulocytosis chloroquine

Itching is more common with which AQ or CQ

Itching is less common with AQ. Itching is more common with CQ

8-Aminoquinolines Examples ______,_________

Primaquine, Pamaquine

8-Aminoquinolines Mode of Action The mechanism of action is ____________.

unknown

8-Aminoquinolines Efficacy Effective against _______ forms of ___ types of malaria parasite. For radical cure of _____________ Gametocytocidal against _______ significant blood stage activity against P. ________ (and some against asexual stages of P. ________).

intrahepatic All types P. V and P. O, Falciparum vivax; falciparum

8-Aminoquinolines Efficacy For radical cure of _____________ Gametocytocidal against _______ significant blood stage activity against P. ________ (and some against asexual stages of P. ________).

P. V and P. O Falciparum vivax; falciparum

8-Aminoquinolines Adverse Effect ________ in individuals with _________

Haemolysis G6PD Deficiency

Sulfones Examples •Sulphonamides (_____,________,_________), •_________

sulphadoxine, sulphalene, co- trimoxazole Dapsone

Sulfones Mode of Action Works synergistically with ________ against the parasite specific enzymes, _____ and _____. Activity on ________ to _________ stage. Inhibits ___________, which is essential for _______ synthesis

pyrimethamine DHPS DHFR mature trophozoite to early schizont parasite synthesis of folate; pyrimidine

Sulfones Adverse Effects Serious adverse reactions to sulfa drugs include severe _______ reactions, such as _________ and __________.

cutaneous Stevens Johnson syndrome and TEN

DHPS acts as __________

PABA analogues

Severe cutaneous reactions to sulfones are Commoner amongst the ______ and _______ taking the drug for ———-.

Europeans and North Americans prophylaxis

TEN appears to be more common in ____________ patients. Dapsone causes varying degree of ———— and _________

HIV infected haemolysis Methemoglobinemia

The Biguanides Examples _______,__________,______,_____ and , ___________

Proguanil, Chlorproguanil, cycloguanil, chlorcycloguanil Pyrimethamine

The Biguanides Mode of Action Also known as ____________ Cycloguanil inhibits _______ Active against ___________ forms of the parasite _____cidal activity, rendering the gametocytes ________ In co-formulation with ________

Type 2 Antifolate DHFR pre-erythrocytic Sporonto; non-infective atovaquone

The Biguanides Adverse Effect Haematological changes (__________ and ________) have been reported in patients with severe ______ impairment. Mild gastric intolerance, diarrhoea, occasional ————- and ________ , there are few adverse effects associated with usual doses of proguanil hydrochloride

megaloblastic anaemia and pancytopenia renal aphthous ulceration and hair loss

The Antibiotics Mention 4

Tetracyclines, Doxycycline, clindamycin, fluoroquinolones

Biguanides are in co formulation with ________

atovaquone

The Antibiotics Mode of Action Tetracyclines are inhibitors of ___________ during protein synthesis.

aminoacyl-tRNA binding

The Antibiotics Adverse Effects GIT effects , ________ failure, Oesophageal ulceration, Diarrhoea etc.

Renal

The Naphthoquinones Examples???

Atovaquone

The Naphthoquinones Mode of Action Active against ________ Plasmodium species. Inhibits _________ development in the ——-, and ———- development in the ________. Act in synergy with ————

all pre-erythrocytic; liver oocyst; mosquito; Proguanil

The Naphthoquinones Act in synergy with _________

Proguanil

The Naphthoquinones Adverse Effects Skin rashes, headache, fever, insomnia, nausea, diarrhoea, vomiting, raised liver enzymes, hyponatraemia, and, very rarely, haematological disturbances, such as anaemia and neutropenia have all been reported. Agree?

Sure🍻

The Naphthoquinones High affinity for ____________

plasmaproteins

The Peroxides _______,________,________,________,________,___________

Artemisinin, Arthemeter, Artemotil, Artesunate, Artelinic acid, Dihydroartemisinin

The Peroxides Artemisinin, also known as _______, is a sesquiterpene lactone extracted from the leaves of _________ (__________).

qinghaosu Artemisia annua sweet wormwood

The Peroxides Mode of Action Inhibits an essential _______________, PfATPase 6 (29). Inhibits the conversion of ______ to ____ coverts ______ to _______ Potent and rapidly acting blood _______cide and is active against ____ Plasmodium species.

calcium adenosine triphosphatase haem to haemozoin haemozoin to haem; schizonto; all

The Peroxides Mode of Action It has an unusually (broad or narrow?) activity against (sexual or asexual?) parasites, killing all stages from ______ to ________.

Broad Asexual young rings to schizonts

The Peroxides Adverse Effect Artemisinin and its derivatives are not safe and remarkably poorly tolerated T/F

F Very safe Well tolerated

In P. falciparum malaria, artemisinin Kills the ______ – including the stage _____ ————-, which are otherwise sensitive only to __________.

gametocytes 4 gametocytes primaquine

The elimination half-life of all Artemisinin is approximately _______

1 h

The Peroxides Adverse Effect The only potentially serious adverse effect reported with this class of drugs is ________________ in approximately 1 in 3000 patients

type 1hypersensitivity reactions

COMBINATION DRUGS Can either be: _________ based Combinations ____________ based Combinations

Artemisinin Non-Artemisinin

COMBINATION DRUGS Artemisinin based Combinations _________ and ______ ________ and _________ Co-artem(_______ and ______) __________ and _______

Artesunate and SP Artesunate and Amodiaquine Artemeter and lumefantrine Artesunate and Mefloquine

COMBINATION DRUGS Non-Artemisinin based Combinations Malarone (________ and ———-) Maloprim(_______ and _________ ) LAPDAP (_______ and ________) Mefloquine-SP ______ and ________

Proguanil and Atovaquone Dapsone and Pyrimethamine Dapsone and Chlorproguanil Sulfalene –Pyrimethamine

COMBINATION DRUGS Non-Artemisinin based Combinations ________ (Proguanil and Atovaquone) ________( Dapsone and Pyrimethamine) ________ ( Dapsone and Chlorproguanil) Mefloquine-SP Sulfalene –Pyrimethamine

Malarone Maloprim LAPDAP

WHO WORLD MALARIA REPORT 2020 In the WHO African Region, the first-line treatments for P. falciparum include : ___________ (AL) _____________ (AS- AQ) and _______________________(DHA_x0002_PPQ).

artemether- lumefantrine artesunate-amodiaquine dihydroartemisinin-piperaquine

WHO WORLD MALARIA REPORT 2020 The overall average efficacy rates for P. falciparum –_____% for AL, ——-% for AS-AQ and _____% for DHA-PPQ – remained consistent over time

98.0 98.4 99.4

PROBLEMS WITH CHEMOTHERAPY AND CHEMOPROPHYLAXIS Drug ______ _______ drug reaction Cost Limited dosage forms Unfavorable pharmacokinetics __________.

resistance Adverse Availability

RATIONAL USE OF ANTIMALARIAL DRUGS This refers to _________________ for the right indications and at the correct/adequate dosages.

appropriate use of antimalarials

Antimalarial drugs will be needed for treatment of uncomplicated malaria, severe malaria and chemoprophylaxis for groups at risk. T/F

Appropriate use of antimalarial drug is determined by _________ and the _________ for taking the primary decision on use of the drug either at home or at the different health care levels.

the goal of treatment person responsible

Background to the Use of ACTs ___________ and _________ are Inappropriate for use in the treatment of uncomplicated malaria in Nigeria. In line with WHO recommendation, Nigeria embarked on drug trial of some selected ________________ Therapies and found them to be very safe and effective. This lead to the change in the first line antimalarial drug in Nigeria from ________ to _________

Chloroquine and Sulphadoxine-Pyrimethamine Artemisinin-based Combination Chloroquine to ACTs.

Artemisinin One of the most novel discoveries in recent medicinal plant research 1967-_________ was found to ———- 1972-_________ from the _____ 1979-____________ determined by ______

extracts of Artemisia; have antimalarial activity artemisinin isolated; plant structure of artemisinin; X-ray analysis

Artemisinin One of the most novel discoveries in recent medicinal plant research _____- extracts of Artemisia was found to have antimalarial activity _____- artemisinin isolated from the plant ______- structure of artemisinin determined by X-ray analysis

1967 1972 1979

QUALITIES OF ACTs Rapid and substantial reduction of the __________, Rapid parasite ________, Rapid ________ of _________,

parasite biomass clearance resolution of clinical symptoms

QUALITIES OF ACTs Reduction of ______ carriage, which potentially reduces _________________

gametocyte transmission of resistant alleles.

ACT is ineffective against multidrug-resistant P. falciparum T/F

F Effective action against multidrug-resistant P. falciparum,

UNIQUE QUALITIES OF ACTs Artemisinin kills (slowly or rapidly?) and substantially most of the parasites. Remaining are then killed by a (low or high?) conc of the companion drug.

Rapidly High

UNIQUE QUALITIES OF ACTs The efficacy and (short or long?) half life (______) of the artemisinins offer protection against ________. The (short or long ?) half life companion drug kills the rest of the parasites.

Short; < 1 hr resistance Long

In ACTs the probability that mutant parasites survive and emerge from these combined two drugs is high T/F

F It’s low

Currently no evidence for clinically relevant artemisinin resistance T/F

Reasons for delay of artemisinin resistance: (Short or long?) half-life (Decreases or Increases?) transmission potential Used in combination with other antimalarial drugs

Short Reduces

Use of artemisinin-based combined therapies would help delay antimalarial drug resistance T/F

Summary of ACT Artemisinin induce (slow or rapid ?) killing of parasites (Slow or Fast ?) clearance rate Very (few or plenty ?) side effects

Rapid Fast Few

Artemsinin-resistant parasites have not been identified T/F

Mechanism of Action Killing of malaria parasite is mediated by ____________

production of free radicals

Mechanism of Action Artemisinin derivatives lacking _____________ are devoid of antimalarial activity Addition of _______ generating compounds enhances antimalarial activity

endoperoxide bridge free radical

Antioxidants aids antimalarial activity T/F

F Antioxidants block antimalarial activity

Mechanism of Action Heme/iron mediates ______________ _____ chelators antagonize antiparasitic effect of artemisinin Artemisinin-derived free radicals bind to protein through ______

breakage of endoperoxide bridge Iron alkylation

Mechanism of Action Iron chelators antagonize antiparasitic effect of _______

artemisinin

Chloroquine antagonizes the antimalarial activity T/F

Mechanism of Action Inhibit hemozoin __________ or cause hemozoin _______ Inhibit hemoglobin ________ by malaria parasites Forms ______ adducts with malarial proteins

biosynthesis degradation Digestion covalent

Adverse Reactions of ACT (Fee or Plenty?) adverse reactions Common side effects include Nausea Vomiting Anorexia dizziness (Safe or Unsafe?) for pregnant women

Very few Safe

A trial conducted in northwest Thailand has found that it is safe to use artemisinin combination therapy (ACT) to treat pregnant women (_________ trimester) with malaria, but that efficacy is inferior to ___________ treatment.

2nd or 3rd single-drug artesunate

DOSAGE REGIMEN The following ACTs are currently recommended: Artemether-___________, Artesunate + __________, Artesunate + __________, Artesunate + _______________—

lumefantrine amodiaquine mefloquine sulfadoxine-pyrimethamine.

DOSAGE REGIMEN The following ACTs are currently recommended: _________-lumefantrine, ___________ + amodiaquine, ___________ + mefloquine, ___________ + sulfadoxine-pyrimethamine.

Artemether Artesunate Artesunate Artesunate

DOSAGE REGIMEN Officially adopted ACT for uncomplicated malaria in Nigeria is __________________

Artemether-Lumefantrine (AL)

DOSAGE REGIMEN The partner medicines of all other ACTs have been previously used as monotherapies T/F

Lumefantrine absorption is reduced with fat

F Lumefantrine absorption is enhanced with fat

Lumefantrine absorption is enhanced with ____ hence the need to take AL with _____ or ____-containing food – particularly on the _______________ days of treatment.

fat milk or fat second and third

AL This is currently available as co-formulated tablets containing ____mg of artemether and ____ mg of lumefantrine. The total recommended treatment is a ____- dose regimen of artemether-lumefantrine _____ a day for ____ days.

20 120 6; twice; 3

SEVERE MALARIA For severe malaria: ______ 2.4 mg/kg bw i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day; ________ 3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day; _________ 20 mg salt/kg bw on admission (i.v. infusion or divided i.m. injection), then 10 mg/kg bw every 8 h; infusion rate should not exceed 5 mg salt/kg bw per hour.

Artesunate Artemether Quinine

PREGNANCY For severe malaria in full doses. Where available, _____ is the first, and ______ the second option in the second and third trimesters. In the first trimester, until more evidence becomes available, _______________ may be considered as options.

artesunate artemether both artesunate and quinine