Malaria Flashcards
1
Q
Give 5 causative organisms of malaria
A
- Plasmodium vivax ( tertian)
- Plasmodium ovale ( tertian)
- Plasmodium malariae ( quartian)
- Plasmodium flaciparum ( tertian)
- Plasmodium knowlese (infects monkeys)
2
Q
The life cycle of a mosquito is divided into two. What and what?
A
Asexual cycle in man
Sexual cycle in mosquitoes
3
Q
The asexual cycle in mosquitoes is divided into 2. What and what?
A
exo-erythrocytic (in liver) and erythrocytic (in RBC)
4
Q
State the phases in the sexual cyccle in the mosquito.
A
Microgamete - Macrogamete - Zygote - Ookinete - Oocyst - Bursting cyst - Sporozoites (to salivary gland)
5
Q
State the phases in the asexual cyccle in the mosquito.
A
In the hepatic cell (for P.vivax and ovale)
Hepatic cell - Hypnozoite (hepatic dormancy) - Mature Liver Schizont - Merozoites
or
(for P. falciparum and malariae)
Hepatic cell - Mature Liver Schizont - Merozoites
In the erythrocyte
Erythrocyte - Tropnozoite - Erythrocytic schizont - Ruptured erythrocyte - Merozoites reinfect other erythrocytes or formation of gameteocyte
6
Q
What causes large numbers of circulating parasites and clinical illness?
A
Multiple rounds of erythrocytic development, with the production of merozoites that invade
additional erythrocytes. Release of merozoites after rupture of erythrocytes causes the clinical attack of malaria.
7
Q
What is Recrudescence?
A
Recrudescence is when symptoms return after a symptoms free period. It is due to parasites
surviving in the blood as a result of inadequate or ineffective treatment.
8
Q
What is relapse?
A
Relapse is when symptoms reappear after the parasites have been eliminated from blood but persist as dormant hypnozites in liver cells.
9
Q
Recrudescence is commonly seen in _____
A
P.falciparum
10
Q
Relapse is common in ____ and ____ infection
A
P.ovale and P.vivax
11
Q
The efficacy of an antimalarial drug depends on?
A
1) On its specific action on a given species, i.e the strain of a malaria parasite
2) Host-related factors e.g. The localization in the tissues, Rate of drug absorption, The metabolic profile, The degree of concentration in the plasma and in the erythrocytes
12
Q
What is paroxysm?
A
It includes fever spikes, chills and rigors are classical for malaria.
13
Q
Antimalarials can be classified based on?
A
a) According to their mode of action (MOA) in the malarial parasite life cycle.
b) According to their chemical structures.
14
Q
Classifiy antimalarials according to their MOA in the malarial parasite life cycle
A
Sporontocidal drugs
Schizontocidal drugs
Gametocidal drugs
Hypnozoitocidal drugs
15
Q
What are the characteristics of sporontocidal drugs?
A
- Usually acts generally at the pre-erythrocytic stage (primary tissue phase).
- They are capable of preventing or inhibiting the formation of oocysts and sporozoites
- They may have no direct
action on gametocytes in the human host - They are called prophylactic drugs
16
Q
Examples of sporontocides
A
- pyrimethamines,
- sulphonamides,
- proguanil,
- primaquine
17
Q
Give characteristics of schizontocides
A
- They have suppressive or curative activities.
- Two types of schizontocidal drugs :
a) Blood schizontocides
b) Tissue schizontocides
18
Q
Give the characterististics of tissue schizontocides
A
- They act on the pre-erythrocytic stages of the parasites (primary tissue forms or primary exo-erythrocytic forms) and thus completely
preventing invasion of the red blood cells. - They are also anti-relapse drugs.
19
Q
Examples of tissue schizontocides are:
A
➢ Proguanil
➢ Pyrimethamine
➢ Primaquine
➢ Tetracycline (antibiotic)
➢ Fansidar
20
Q
Give the characteristics of Blood/Erythrocytic Schizonticides
A
- They are used to terminate the episode of malarial fever.
- They act on erythrocytic stages of parasites
commonly associated with acute disease and also on the sexual erythrocytic forms of p.vivax, p.ovale and p.malariae - Classified as those of High and Low efficacy
21
Q
High efficacy erythrocytic schizontocides are
A
- Artemesinin
- Chloroquine
- Amodiaquine
- Quinine
- Mefloquine
- Halofantrine
- Lumefantrine
- Atovaquone
22
Q
Low efficacy erythrocytic schizontocides are
A
- Proguanil
- Pyrimethamine
- Sulfonamides
- Tetracyclins
- Clindamycin
22
Q
Examples of gametocidal drugs are?
A
▪ mepacrine
▪ primaquine
▪ quinine
22
Q
What are Gametocidal drugs?
A
They kill gametocytes in blood and prevent transmission to mosquitoes.
23
The major hypnozoitocide is
Primaquine
24
Treatment of malarial parasites are classified into:
Preventive (Prophylaxis): Casual and Suppressive
Curative: Clinical cure, radical cure and chloroquine resistance
25
Casual prophylaxis occurs in the ____ stage and an example is ____
Pre-erythrocytic phase, Primaquine
26
Supressive prophylaxis are schizonticides which suppress the ______.
Examples are ______, ______, ______, _____
Erythrocytic phase, Chloroquine, Mefloquine, Doxycycline, Pyrimethamine(75 mg)+ sulphadoxine (1500mg) [Fansidar]
27
Clinical cures cause _____ and are _____.
Termination of the episode of malarial fever, erythrocytic schizonticide
28
Radical cures cause _____ and are _____.
Elimination of both hepatic and erythrocytic stages, Erythrocytic schizonticide + Tissue schizonticide. Example: CQ + primaquine
29
What are the Chloroquine resistance cures?
a) Quinine + Doxycycline/clindamycin + Primaquine
b) Artemesinin based combination therapy + Primaquine
30
Classify anti-malarial agents according to chemical groups.
➢ Natural sources: Cinchona alkaloid: Quinine, Quinidine, cinchonine, Qinghaosu; leeches
(artemisinin), febrifugine, isofebrifugine
➢ 4-Aminoquinolines: chloroquine, amodiaquine, mefloquine.
➢ 8-Aminoquinolines: primaquine, tafenoquine
➢ Biguanides: proguanil, chloroguanide
➢ Diaminopyrimidines: pyrimethamine
➢ Antibiotics: tetracycline, primaquine, doxycycline, desoxytetracycline
➢Sesquiterpine lactones: Artesunate, Artemether, Arteether
➢Naphthyridine: Pyronaridine
➢Phenanthrene methanols: Halfan(s), halofantrine
➢Sulphonamides & Sulfones: sulphadoxine, dapsone, sulfamethopyrazine
➢ Aryl-amino alcohols : mefloquine, halofantrine, lumefantrine, quinine
➢Naphthoquinones: atovaquone
➢ Antifolates (dihydrofolate reductase inhibitors): proguanil, pyrimethamine.
31
Quinine contains two major fused-ring systems:
the aromatic quinoline and the
bicycclic quinuclidine
32
What is the MOA of quinine?
Quinine works by binding to 18S ribosomal RNA, which is essential for parasite protein synthesis. This disrupts the function of Ribosomal RNA thus inhiniting protein synthesis and leading to death.
33
What is the SAR of quinine?
1. The quinuclidine ring is important for binding quinine to certain specific proteins or receptors needed for ion transport, pH regulation.
2. The methanol at position 9 may indirectly influence solubility, bioavailability and metabolism
3. The quinoline moiety is essential for antimalarial activity as it allows for interactions with the malaria parasite's biomolecules
4. Oxidation of the vinyl to COOH leads to loss of antimalarial activity, but esterification of the COOH leads to partial activity.
5. Methylation of the methoxy group at 6' to OH forms cupreine and leads to loss of antimalarial activity. Alylation of that OH will form optochin and restore activity.
34
Give the metabolic profile of quinine
Quinine is eliminated in urine mainly as unchanged drug and as 3-hydroxyquinine (major metabolite of quinine).
35
What techniques are used in the assay of quinine?
1. Colorimetry
2. Fluorimetry
3. Spectrophotometry
4. Chromatography
36
What are the characterististics of artemisinin?
▪Soluble in organic solvent but almost insoluble in water due to large number of C-H bonds and lack of polar functional groups like OH, NH2, or COOH.
* It and its derivatives are highly effective against P. falciparum
* The main therapeutic efficacy is due to the (rapidly occurring) biotransformation into the primary metabolite, artenimol (β-dihydroartemisinin, DHA), which is considered to be the ultimate active agent.
37
What is the solubility and route of administration of artemisinin?
Solubility: Poorly soluble in water and oil
Route of administration: Rectal (rare, oral)
38
What is the solubility and route of administration of artemether?
Solubility: Soluble in oil (lipophilic)
Route of administration: Oral, IM
39
What is the solubility and route of administration of artesunate?
Solubility: Soluble in water (hydrophilic)
Route of administration: Oral, IM + IV
40
What is the solubility and route of administration of DHA?
It is the active metabolite.
Route of administration: Oral
41
What is the solubility and route of administration of arte-ether?
Solubility: Soluble in oil (lipophilic)
Route of administration: Injectible, IM in oil
42
Artemisinin is also known as ______ and is a _____ lactone
Qinghaosu, sesquiterpene
43
What are the chemical reactions taking place to form the various Artemisinin-derived compounds?
Artemisinin - DHA: Hydrogenation
DHA - Artemether: Methylation
DHA - Arte-ether: Ethylation
DHA - Deoxoartemisinin: Deoxygenation
DHA - Artesunate: Esterification
44
Give the SAR of artemisinin
1. Endoperoxide bridge essential for antimalarial activity
2. Trioxane moiety responsible for antimalarial activity
3. Reduction of the lactone carbonyl to -OH (dihydroartemisinin) increases antimalarial activity
4. Ester linkages such as acylated sugars, esters, and alpha-alkylbenzyl groups at
lactone carbonyl increase antimalarial activity
45
Give the characteristics of chloroquine
1. Chloroquine is the preferred drug for clinical cure of Vivax, Ovale, malariae, and some sensitive falciparum strains.
2. Controls most clinical attacks in 1-2 days with disappearance of parasites from
peripheral blood in 1-3 days.
46
What is the MOA of chloroquine?
* CQ accumulates in the acidic vesicles of the parasite and because of its weakly basic nature, it raises the vesicular pH and thereby interferes with degradation of haemoglobin by parasitic lysosomes ( Chloroquine is also a lysosomotropic agent)
* Polymerization of toxic heme to nontoxic parasite pigment hemozoin is inhibited by the formation of a chloroquine-heme complex.
* Chloroquine-heme complex, then damages the plasmodial membranes. Clumping of pigment and changes in the parasite membranes follow death.
47
What is the SAR of chloroquine?
➢Methyl substitution in position 3 reduces activities
➢ Methyl substitution in position 8 completely abolishes activities
➢ Substitution at position C-7 other than chlorine may alter activities as this position has
been found to be best for halogen substitution.
➢ Introduction of other groups on the quinolone nucleus reduces antimalarial activities
➢ Introduction of hydroxyl group OH on the side chain, especially at the ethyl group of
the terminal nitrogen reduces toxicity and also increases blood level concentration
48
What is the PK of chloroquine?
1. Mode of administration: Oral
2. Widely distributed & concentrated in tissues like liver, spleen, kidney, lungs , skin, leucocytes and some other tissues
3. Its selective accumulation in the retina is responsible for the ocular toxicity seen with prolonged use, metabolized by the liver and excreted in urine.
4. The early plasma t1/2 varies from 3-10 days. Because of tight tissue binding, small amounts
persist in the body for longer time.
49
What are the adverse effects of chloroquine?
* GI intolerance
Nausea, vomiting, abdominal pain, headache, anorexia, malaise, and urticaria are common. Dosing after meals may reduce some adverse effects.
* The long-term administration of high doses of chloroquine for rheumatologic diseases
can result in loss of vision due to retinal damage.
* Corneal deposits may occur and affect vision; reversible
50
What are the contraindications with chloroquine use?
Chloroquine can precipitate attacks of seizures and psoriasis or porphyria
51
During metabolism, chloroquine is converted into two active metabolites, which are and by?
Desethylchoroquine and bisdesethylchoroquine, by CYP-450 in the liver.
52
What are the major metabolic pathways of chloroquine?
1. N-dealkylation: Results in desethylchloroquine (removal of one ethyl group) and bisdesethylchloroquine (removal of two ethyl group.
2. C-hydroxylation: Increases water solubility and prepares the molecule for further metabolism and excretion
3. N-oxidation: Helps in detoxifying chloroquine for excretion
53
Chloroquine is well absorbed on oral administration from GIT and
absorption on i.m. or s.c. administration is rapid.
T or F?
True
53
What techniques are used in the assay of chloroquine?
1. Titrimetric method (acid-base titration)
2. HPLC
3. UV/Vis
53
What are the characteristics of amodiaquine?
1. Identical to chloroquine in mechanism and SARS.
2. Less bitter than chloroquine.
3. Faster acting than chloroquine.
4. Widely used; safety & activity against chloroquine-resistant P. falciparum
54
What is the active metabolite of amodiaquine?
Monodesethylamodiaquine
55
Give the SAR of primaquine
1. Methoxy group at position 6 is responsible for optimum activity but not essential for antimalarial activity
2. If the methoxy group at 6 were to be replaced by an OH group, it would show comparable activity, while an ethoxy group would show low or negligible activity.
3. If the methoxy group at 6 were replaced with a CH3, the compund would become inactive
4. Additional substitution on the quinoline nucleus tends to decrease both activity and toxicity.
5. Reduction of the quinoline nucleus at position 1 into 1,2,3,4 tetra hydro derivative will decrease potency and toxicity, requiring a higher dose.
6. In the amino acid side chain, there are two amino groups, for optimum activity, the distance between the two nitrogens of the amino acid side chain should be 3-6 carbons.
7. The greatest activity appears to be achieved in alkyl groups containing 5 carbon atoms.
56
What is the metabolic profile of primaquine?
Metabolised by the liver through the action of CYP450 enzymes, especially CYP2D6.
57
What are the metabolic pathways of primaquine?
1. N-dealylation to form carboxyprimaquine (major inactive metabolite) and primaquine aldehyde (an intermediate metabolite).
2. Hydroxylation
3. Oxidation to form primaquine-5,6-orthoquinone (active antimalarial form).
4. Phase II metabolism (conjugation through glucuronidation).
58
What combination treatment is used for Chloroquine Sensitive Falciparum Malaria
Cq + Primaquine
59
What is the MOA of Proguanil?
Proguanil is metabolised in the liver to cycloguanil, which selectively inhibits DHFRase disrupting folate metabolism and blocking DNA synthesis, ultimately leading to parasite death.
60
How does plasmodium develop resistance to proguanil?
Due to mutational changes in the plasmodial DHFRase enzyme.
61
Comment on the use of proguanil
1. Current use of proguanil is restricted to prophylaxis of malaria in combination with chloroquine in areas of low-level chloroquine resistance among P. falciparum.
2. Safe during during pregnancy
61
What is the MOA of antifolates?
They selectively inhibit DHFR, preventing the conversion of DHR to THF which is essential for DNA synthesis
61
SAR of antifolates
1. A pteridine ring system is crucial for binding to DHFR
2. Lipophilic side chains improve membrane permeability and increase binding affinity.
62
What is the IUPAC name of pyrimethamine?
2,4 – diamino-5-(p-chlorophenyl)-6-ethylpyrimidine
63
Give 6 characteristics of pyrimethamine.
1. It's available as the hydrochloride salt.
2. Pyrimethamine is a slowly acting erythrocytic schizontocide but does not eliminate the pre-erythrocytic phase of P. falciparum.
3. If used alone, resistance develops rather rapidly by mutation in the DHFRase enzyme of the parasite
4. Used only in combination with a sulfonamide (S/P) or dapsone.
5. The addition of sulfonamide retards the development of resistance.
Diaminopyrimidines
6. Clinical curative, particularly for P. falciparum. Efficacy against P.
vivax is rather low.
63
What are the aryl-amino alcohols
* quinine,
* mefloquine,
* halofantrine
64
What are the characteristicss of the tetracyclines
* Weak erythrocytic schizonticidal
* It is never used alone
* Combination with quinine for treatment of CQ resistant falciparum & vivax malaria
65
What chemical is used in mosquito nets and how does it work?
Permethrin.
Pyrethroids like permethrin work by disrupting the normal functioning of the mosquito's nervous system, leading to paralysis and death upon contact with the net.
