Antimicrobial 4: Malaria Flashcards
(42 cards)
Vast majority of malaria cases arise from what?
- Infection from a mosquito belonging to the Anopheles
genus (Greek for “useless”) - Affects a quarter of a billion people and induces
~900,000 deaths/year
List the 5 Plasmodium genus of protozoan parasites:
- Plasmodium falciparum
Fever, followed by headache and chills
Organ failure
Lower pyretic threshold - lower number of parasites required to cause fever
- Plasmodium vivax
- Plasmodium ovale
- Plasmodium malariae
- Plasmodium knowlesi
Most malarial infections worldwide are due to
infection with either Plasmodium ___ or ___
Plasmodium falciparum or vivax
Plasmodium ____ causes the most severe form
of the disease (organ failure and death)
Plasmodium falciparum
Only Plasmodium ___ and ___ are capable of producing hypnozoites that can lead to recurrent 4
infections
Plasmodium vivax and ovale
Biology of the Malarial Infection:
See slide 5 picture for details!
cannot prevent as no drugs target sporocytes
• Sporozoites are injected into the bloodstream from
the salivary gland of the mosquito (no treatment
available that targets sporozoites)
- In the hepatocytes the parasites form thousands of merozoites that are then released into the bloodstream In P.vivax and P.ovale the liver forms persist and differentiate into dormant hypnozoites (asymptomatic)
- The merozoites infect the erythrocytes and develop into trophozoites and then multinucleated schizonts
• Schizonts divide into new merozoites that infect new erythrocytes
- this stage causes fever, symptoms
• After several cycles some merozoites develop into
female and male gametocytes and fuse together
forming a zygote when they reach the stomach of a
new mosquito
• The zygote colonizes the mosquito stomach wall,
where it grows forming thousands of new sporozoites.
These migrate to and colonize the mosquito salivary
glands
3 classes of antimalarial agents:
• Drugs for suppressive prophylaxis (Class I):
– Target the asexual red cell forms
- prevent the symptoms of malaria by targeting RBC stage
• Drugs for causal prophylaxis (Class II):
– Treatment of the initial hepatic stages
• Drugs for terminal prophylaxis and radical cure (Class III):
– Eradication of hypnozoites (only plasmodium vivax or ovale)
Class I antimalarial agents
Drugs
- Arteminsinins
- Chloroquine
- Mefloquine
- Quinine, Quinidine
- Pyrimethamine
- Sulfadoxine
- Tetracyclines
most class 1 inhibit at RBC asexual stage
Some drugs prevent formation of gametocytes
Prevent transmission of mosquitoes, stop spread
Pyrimethamine and sulfadoxine combo promotes the gametocyte pdtn
Class II antimalarial agents
Drugs
- Atovaquone
- Proguanil
Class 2 drug - can get off of therapy faster after travel, getting both
primary liver stages and asexual RBC stage
Class III antimalarial agents
Drugs
- Primaquine
primary liver, hypnozoite, gametocyte stages
Quinolines and Related Compounds
Heterocyclic aromatic compounds derived from
quinoline, also know as ?
1-benzazine or benzopyridine
Name most commonly used quinolines in the
treatment of protozoal infections: (4)
- Cinchona alkaloids (quinine and quinidine)
- chloroquine
- mefloquine
- primaquine
Quinoline
MOA
• Malaria parasites use the host’s hemoglobin and breaks it down as the
prime source for amino acids
• Heme is detoxified by polymerization into inert crystalline material called “hemozoin”, toxic
• Accumulation of chloroquine (and other quinolines, CQ) into the food vacuole causes:
– Inhibition of heme polymerization (via heme
polymerase) and generation of free radicals (ROS), buildup of heme, leads to damage to parasite membrane/proteins
– Increased vacuole pH and block of hemoglobin proteolysis
Development of Quinoline Resistance
How?
– Mutations in CQ transporters (Chloroquine resistance
transporter (CRT))
- pumps chloroquine out of vacuole
– Mutations in the plasmodium multidrug resistance protein (MDR)
• Resistance to other quinolines (quinine and
quinidine) may be determined by similar factors
• Resistance to mefloquine is often associated with
increased sensitivity to chloroquine and vice versa
- independent MOA
Cinchona Alkaloids - Quinine & Quinidine
Characteristics
• Quinoline methanol derivatives isolated from the
natural cinchona bark.
• They contain a quinuclidine ring attached to the
quinoline group
both are less effective and more toxic than chloroquine
• Quinine is a mixture of the d- and l-isomers
– Quinidine is the pure d-isomer and is more
effective as an antimalarial agent.
• Quinine and Quinidine are still used to fight
chloroquine-resistant P.falciparum or the erythrocytic
stages of the other malarias
Cinchona Alkaloids - Quinine & Quinidine
Pharmacology
• Quinine and quinidine acts primarily against
erythrocytic forms.
- Quinine is still one of the primary treatments of
choice for drug-resistant P. falciparum . It is also
gametocidal for P. vivax and P. malarie , but not for P.
falciparum .
• Generally not used for prophylaxis due to their
toxicity and short half-life.
• Curare-like effect on motor endplate of skeletal
muscle (used in the past for night cramps)
Cinchona Alkaloids - Quinine & Quinidine
AE
• * Cinchonism (tinnitus, high-tone deafness, visual
disturbances, headache, nausea & vomiting,
abdominal pain & diarrhea)
- visual, ear toxicity, GI fx
• * Hypoglycemia (due to insulin secretion)
- direct action on beta cells to release insulin
• * Blackwater fever
• Hypotension (rapid IV infusion) • Cardiac dysrhythmias and fibrillation (acute over dosage) • Hypersensitivity • Thrombocytopenia
Cinchona Alkaloids - Quinine & Quinidine
Contraindication/Precautions
• Patients with optic neuritis, cardiac dysrhythmias, or
G6PD deficiency
• Should not be administered with mefloquine
(additive effects), toxicities
Chloroquine
Pharmacology
• 4-aminoquinoline compound. The chlorine atom
attached to position 7 of the quinoline ring confers the
greatest antimalarial activity
• Highly active against erythrocytic forms of P.vivax , P.
ovale , P. malariae , and sensitive strains of P.
falciparum . Prophylaxis and treatment of choice with
these organisms. Also active on gametocytes of
P.vivax , P. ovale and P. malariae but not P. falciparum .
No activity against hypnozoites.
• Rapid activity. The erythrocytic forms of the parasite
can be eradicated in 48-72 hrs.
• Safely administered to children and pregnant women
Chloroquine
AE
• * Bleaching of hair and discoloration of mucus
membranes
• GI upset • Headache • Visual disturbances • Urticaria • Convulsions • Hypotension, vasodilation, cardiac arrhythmias (rapid parental injection)
Mefloquine
Pharmacology
• 4-quinoline-methanol compound structurally related
to quinine and developed to combat new strains of
drug-resistant P. falciparum
• Highly effective on erythrocytic forms of the parasite.
No activity against other stages
• Mainly used for prophylaxis and treatment of
chloroquine-resistant malaria caused by P. falciparum
and P. vivax
Mefloquine
AE
• * Neuropsychiatric effects
• * Severe but reversible CNS toxicity (seizures,
confusion, psychosis, dysphoria, insomnia, vertigo) in
0.5% of patients
• * Aberrant atrioventricular conduction
- before not for pregant women due to still birth, now shown to be ok
- GI disturbances (Vomiting)
- Dizziness
Mefloquine
Contraindication/Precautions
- Seizures or neuropsychiatric disturbances
* Avoid co-administration with quinine or chloroquine
Primaquine
Characteristics
• Effective against hepatic stages, latent tissue forms
and gametocytes of malaria parasites
• Mainly used for terminal prophylaxis and radical cure
of P. vivax and P. ovale malarias. Usually administered
in combination with drugs such as chloroquine that
will target the erythrocytic stages
- can be used with a class 1
