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PHARMACOLOGY (sahrgeant) > Antimalarial > Flashcards

Antimalarial Flashcards

1
Q

What are sulfonamides and sulfones classified as?

A

Slow-acting blood schizonticides

They are more active against P. falciparum than P. vivax.

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2
Q

What is the mechanism of action of sulfonamides?

A

They are p-aminobenzoic acid analogues that competitively inhibit Plasmodium dihydropteroate synthase.

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3
Q

What enhances the antimalarial action of sulfonamides?

A

Combination with an inhibitor of parasite dihydrofolate reductase.

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4
Q

What genetic mutations confer resistance to sulfadoxine?

A

Several point mutations in the dihydropteroate synthase gene.

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5
Q

What is the consequence of combining sulfadoxine resistance mutations with mutations of dihydrofolate reductase?

A

Greatly increased likelihood of sulfadoxine-pyrimethamine treatment failure.

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6
Q

When is sulfadoxine-pyrimethamine routinely administered during pregnancy?

A

Intermittently during the second and third trimesters.

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7
Q

What is a potential benefit of intermittent preventive treatment strategies?

A

They may also benefit infants.

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8
Q

What is the expected trend for the use of antimalarials without novel anti-folates?

A

Continued decline in the use for either prevention or treatment.

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9
Q

Which antibiotics are useful in malaria treatment?

A

Tetracycline, doxycycline, and clindamycin.

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10
Q

What type of action do tetracycline and doxycycline have in malaria treatment?

A

Slow-acting blood schizonticides.

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11
Q

Which antibiotic is recommended for malaria chemoprophylaxis?

A

Doxycycline.

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12
Q

What mechanism leads to the delayed death of malaria parasites treated with antibiotics?

A

Inhibition of protein translation in the parasite apicoplast.

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13
Q

What is a consequence of the slow mode of action of tetracyclines?

A

Ineffectiveness as single agents for malaria treatment.

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14
Q

What are the restrictions on tetracycline use?

A

Should NOT be given to pregnant women or children younger than 8 years.

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15
Q

What recent technological developments may revolutionize mosquito control?

A

Engineering resistance to infection by P. falciparum in mosquitoes.

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16
Q

What does the gene editing technology CRISPR/cas9 offer for mosquito control?

A

High-efficiency expression of resistance genes.

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17
Q

What is a ‘mutagenic chain reaction’ in the context of CRISPR/cas9?

A

It spreads a mutation from one chromosome to its homologous chromosome.

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18
Q

How can CRISPR/cas9 gene drive technology affect mosquito populations?

A

By introducing antiplasmodium effector genes into the germline.

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19
Q

What factors influence the success of gene drive technology for vector control?

A

Choice of suitable promoters, phenotype of disrupted genes, robustness of the nuclease, ability to generate compensatory mutations.

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20
Q

Have CRISPR/cas9 gene drives been released into the wild?

A

No, they have not yet been released.

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21
Q

What must be understood before using gene editing techniques in the field?

A

Ecological consequences and ethical and regulatory issues.

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22
Q

4 of 13

A
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23
Q

Artemisinin and Its

A
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24
Q

Derivatives

A
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25
Q

Mechanism of Action

A
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26
Q

• The activity seems to result from cleavage

A
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27
Q

of the drug’s peroxide bridge by reduced

A
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28
Q

heme-iron

A

produced inside the highly

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29
Q

acidic digestive vacuole of the parasite as

A
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30
Q

it digests hemoglobin

A
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31
Q

• activated artemisinin might in turn generate

A
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32
Q

free radicals that alkylate and oxidize

A
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33
Q

macromolecules in the parasite.

A
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34
Q

ADME

A
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35
Q

• semisynthetic artemisinins:

A
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36
Q

Oral (dihydroartemisinin

A

artesunate

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37
Q

Intramuscular (artesunate and artemether)

A
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38
Q

Intravenous (artesunate)

A
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39
Q

Rectal (artesunate)

A
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40
Q

• Blay siati ater ora dosing 30 or shins and in 2-6 h with intramuscular artemether

A
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41
Q

• Both artesunate and artemether have modest levels of plasma protein binding

A

ranging from 43% to 82%

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42
Q

• These derivatives are extensively metabolized and converted to dihydroartemisinin

A

Which has a plasma 4/2°1 1-2 h

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43
Q

• Drug bioavailability via rectal administration is highly variable among individual patients

A
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44
Q

• With repeated dosing

A

artemisinin and artesunate induce their own CYP-mediated metabolism

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45
Q

• primarily via CYPs 2B6 and 3A4

A

which may enhance clearance by as much as 5-fold.

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46
Q

• Artemisinin and its three major semisynthetic derivatives in clinical use

A

dihydroartemisinin

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47
Q

artemether

A

and artesunate

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48
Q

• are potent and fast-acting antimalarials

A
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49
Q

• optimized for the treatment of severe P. falciparum malaria

A
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50
Q

• also effective against the asexual erythrocytic stages of P. vivax

A
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51
Q

• Increasingly

A

the standard treatment of malaria employs artemisinin-based combination

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52
Q

therapies (ACTs) to increase treatment efficacy and reduce selection pressure for the emergence

A
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53
Q

of drug resistance

A
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54
Q

• P. falciparum artemisinin “resistance” do not indicate true resistance but reflect delayed

A
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55
Q

parasite clearance time on the order of hours

A
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56
Q

• mutations in the P. falciparum gene P 13 encoding the kelch13 propeller protein have been

A
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57
Q

associated with these delayed parasite clearance times

A
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58
Q

• mechanism of kelch13 propeller protein mediates delayed parasite clearance remains unknown

A
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59
Q

• True resistance to artemisinin has not been reported

A
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60
Q

• no infection from this parasite has been reported to survive ACT due to delayed clearance times

A
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61
Q

• Moreover

A

in the presence of mutations that confer resistance to partner drugs (e.g.

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62
Q

partner drug piperaquine)

A

clinically significant ACT failure is substantial

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63
Q

rates reported to exceed 50%

A
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64
Q

• Resistance of non-P. falciparum malaria parasites to artemisinin class drugs has not been

A
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65
Q

reported.

A
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66
Q

• Artemisinins cause a significant reduction of the parasite burden

A
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67
Q

• with a 4-log10 reduction in the parasite population for each 48-h cycle of intraerythrocytic

A
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68
Q

invasion

A

replication

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69
Q

• Only three to four cycles (6-8 days) of treatment are required to remove all the parasites from

A
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70
Q

the blood

A
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71
Q

• In addition

A

artemisinins possess some gametocytocidal activity

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72
Q

malarial parasite transmission.

A
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73
Q

Therapeutic Uses

A
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74
Q

• rapid and potent activity against even multidrug-

A
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75
Q

resistant parasites

A
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76
Q

• the artemisinins are valuable for the treatment of

A
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77
Q

severe P. falciparum malaria

A
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78
Q

• generally are not used alone because of their

A
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79
Q

limited ability to eradicate infection completely

A
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80
Q

• highly effective for the first-line treatment when

A
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81
Q

combined with other antimalarials

A
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82
Q

• should NOT be used for chemoprophylaxis

A
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83
Q

because of their short ty/2 values

A
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84
Q

Toxicity and Contraindications

A
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85
Q

• Preclinical toxicity studies have identified the

A
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86
Q

brain (and brainstem)

A

liver

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87
Q

marrow as the principal target organs.

A
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88
Q

• no systematic neurological changes have

A
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89
Q

been attributed to treatment in patients 5

A
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90
Q

years of age or older

A
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91
Q

• may develop dose-related and

A
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92
Q

REVERSIBLE DECREASE in reticulocyte

A
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93
Q

and neutrophil counts and INCREASE in

A
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94
Q

transaminase levels

A
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95
Q

• About 1 in 3000 patients develops an

A
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96
Q

• Although studies during the first trimester

A
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97
Q

have found no evidence of adverse effects on

A
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98
Q

• it is recommended that ACTs NOT be used

A
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99
Q

during the FIRST trimester of pregnancy or

A
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100
Q

for the treatment of children 5 kg or less

A
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101
Q

What are the criteria for choosing partner drugs for ACT?

A

Potency and t1/2 that substantially exceeds that of the artemisinin partner

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102
Q

List the primary ACT regimens well tolerated in adults and children 5 kg or more.

A
  • Artemether-lumefantrine
  • Artesunate-amodiaquine
  • Dihydroartemisinin-piperaquine
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103
Q

Which drug is probably the drug of choice for all malaria cases if oral drug treatment is appropriate?

A

Artemether-lumefantrine

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104
Q

Is Pyronaridine licensed for use?

A

No, it remains in clinical trials and is not licensed.

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105
Q

What structural similarities does Lumefantrine share?

A

It shares structural similarities with mefloquine and halofantrine

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106
Q

What is Lumefantrine’s role in malaria treatment?

A

Highly effective for the treatment of uncomplicated malaria and is the most widely used first-line antimalarial across Africa

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107
Q

What are the pharmacokinetic properties of Lumefantrine?

A
  • Large apparent volume of distribution
  • Terminal elimination t1/2 of 4-5 days
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108
Q

How does food affect the absorption of Lumefantrine?

A

Administration with a high-fat meal significantly increases absorption

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109
Q

What formulation of Artemether-lumefantrine has been approved for children?

A

A sweetened dispersible formulation

110
Q

What type of compound is Piperaquine?

A

A potent and well-tolerated bisquinoline compound

111
Q

What is the Tmax of Piperaquine after a single dose?

112
Q

What is the terminal plasma t1/2 of Piperaquine?

113
Q

What has been reported regarding the efficacy of Piperaquine in Cambodia?

A

Reduced efficacy primarily associated with mutations leading to piperaquine resistance

114
Q

How quickly does fever resolve with Piperaquine treatment?

115
Q

What is the clearance time for parasites with Piperaquine treatment?

116
Q

What is Amodiaquine a congener of?

A

Chloroquine

117
Q

Why is Amodiaquine no longer recommended in the U.S. for chemoprophylaxis?

A

Due to toxicities (hepatic and agranulocytosis)

118
Q

What is the plasma t1/2 of monodesethyl-amodiaquine?

119
Q

What is the peak concentration of monodesethyl-amodiaquine after oral administration?

A

About 500 nM 2 hours after administration

120
Q

What are the clearance rates for Amodiaquine?

A

Vary widely among individuals (78-943 mL/min/kg)

121
Q

What is atovaquone used for?

A

Malaria chemoprophylaxis and treatment of uncomplicated P. falciparum malaria in adults

A fixed combination of atovaquone with proguanil hydrochloride is available in the U.S.

122
Q

What is the mechanism of action of atovaquone?

A

Inhibits electron transport in the parasite’s mitochondrial cytochrome bc1 complex

Atovaquone binds at the Q site of cytochrome bc1, collapsing the mitochondrial membrane potential.

123
Q

Why does atovaquone show selective toxicity for Plasmodium?

A

Structural differences in the amino terminal regions of plasmodial and human cytochrome b

This allows atovaquone to target the parasite without affecting the human host.

124
Q

Against which malaria stages is atovaquone highly active?

A

P. falciparum asexual blood-stage parasites and liver stages

Not active against P. vivax liver-stage hypnozoites.

125
Q

What is the significance of proguanil in combination with atovaquone?

A

Enhances the mitochondrial toxicity of atovaquone

This synergy reduces the frequency of resistance.

126
Q

What side effects may atovaquone cause?

A

Abdominal pain, nausea, vomiting, transient elevations of serum transaminase or amylase

Readministration within an hour of vomiting may still be effective.

127
Q

How is atovaquone absorbed and excreted?

A

Slow and variable absorption; excreted in bile, >94% recovered unchanged in feces

Absorption improves with a fatty meal.

128
Q

What is the elimination half-life of atovaquone in adults?

A

2-3 days

In children, the half-life is 1-2 days.

129
Q

What is the fixed dose of atovaquone and proguanil hydrochloride in the tablet?

A

250 mg atovaquone and 100 mg proguanil hydrochloride

Taken orally for treating mild-to-moderate attacks of resistant P. falciparum malaria.

130
Q

What precautions should be taken when using atovaquone?

A

Evaluate in children <11 kg, pregnant women, and lactating mothers

Atovaquone may compete with certain drugs for plasma protein binding.

131
Q

True or False: Atovaquone is metabolized significantly in humans.

A

False

Humans do not significantly metabolize atovaquone.

132
Q

Fill in the blank: Atovaquone may compete with certain drugs for binding to _______.

A

plasma proteins

133
Q

What impact does rifampin have on atovaquone therapy?

A

Reduces plasma levels of atovaquone substantially

The mechanism of this effect is not clear.

134
Q

What is the effect of coadministration with tetracycline on atovaquone?

A

40% reduction in plasma concentration of atovaquone

135
Q

What was a primary treatment for uncomplicated P. falciparum malaria?

A

Sulfadoxine-pyrimethamine

Especially effective against chloroquine-resistant strains.

136
Q

Why is sulfadoxine-pyrimethamine no longer recommended for uncomplicated malaria?

A

Due to widespread resistance.

137
Q

How long does it take for oral pyrimethamine to reach peak plasma levels?

A

2-6 hours.

138
Q

What percentage of pyrimethamine is bound to plasma proteins?

A

About 90%.

139
Q

What is the half-life (ty/2) of pyrimethamine?

A

85-100 hours.

140
Q

For how long do suppressive concentrations of pyrimethamine remain in the blood?

A

About 2 weeks.

141
Q

What is a therapeutic use of pyrimethamine-sulfadoxine despite resistance?

A

Intermittent preventive treatment of malaria in pregnancy.

142
Q

What type of drug is pyrimethamine classified as?

A

A slow-acting blood schizontocide.

143
Q

What does pyrimethamine inhibit in Plasmodium?

A

Folate biosynthesis.

144
Q

How does the efficacy of pyrimethamine against hepatic forms of P. falciparum compare to proguanil?

A

It is less effective.

145
Q

True or False: Pyrimethamine can eradicate P. vivax hypnozoites.

146
Q

What metabolic steps do pyrimethamine and sulfonamides inhibit in folate biosynthesis?

A
  • Utilization of p-aminobenzoic acid
  • Reduction of dihydrofolate to tetrahydrofolate.
147
Q

What may affect the therapeutic response to antifolates?

A

Dietary p-aminobenzoic acid or folate.

148
Q

What causes resistance to pyrimethamine?

A

Mutations in dihydrofolate reductase.

149
Q

What is a common toxicity associated with antimalarial doses of pyrimethamine?

A

Occasional skin rashes and reduced hematopoiesis.

150
Q

Excessive doses of pyrimethamine can produce what condition?

A

Megaloblastic anemia.

151
Q

What combination may cause birth defects in humans?

A

Trimethoprim-sulfamethoxazole.

152
Q

What severe reactions can result from the combination of pyrimethamine and sulfadoxine?

A
  • Erythema multiforme
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis.
153
Q

Who should pyrimethamine-sulfadoxine be contraindicated for?

A
  • Individuals with previous reactions to sulfonamides
  • Lactating mothers
  • Infants less than 2 months of age.
154
Q

What adverse effect has been associated with the combination of pyrimethamine and dapsone?

A

Agranulocytosis.

155
Q

What is the active metabolite of proguanil responsible for its antimalarial activity?

A

Cycloguanil

Cycloguanil is a cyclic triazine metabolite structurally related to pyrimethamine.

156
Q

What enzyme does cycloguanil selectively inhibit in plasmodial species?

A

Bifunctional dihydrofolate reductase-thymidylate synthetase

This enzyme is crucial for parasite de novo purine and pyrimidine synthesis.

157
Q

In drug-sensitive P. falciparum malaria, what stages does proguanil act against?

A

Both primary liver stages and asexual red blood cell stages

This action helps control the acute attack and usually eradicates the infection.

158
Q

True or False: Proguanil is effective against the latent tissue stages of P. vivax.

A

False

Relapses may occur after proguanil is withdrawn because these latent stages are unaffected.

159
Q

What effect does proguanil have on gametocytes?

A

Does not destroy gametocytes

However, oocytes in the mosquito gut can fail to develop normally.

160
Q

What is the consequence of amino acid changes near the dihydrofolate reductase-binding site?

A

Causes resistance to cycloguanil, pyrimethamine, or both

This resistance affects the efficacy of these antimalarial drugs.

161
Q

Is the presence of Plasmodium dihydrofolate reductase required for the intrinsic antimalarial activity of proguanil?

A

No

The molecular basis for this alternative activity is unknown.

162
Q

What is the effect of proguanil on atovaquone’s action against P. falciparum?

A

Accentuates the mitochondrial membrane-potential-collapsing action

Proguanil does not display this activity by itself.

163
Q

What is the absorption characteristic of proguanil from the GI tract?

A

Slowly but adequately absorbed

Peak plasma concentrations are attained within 5 hours after a single oral dose.

164
Q

What is the mean plasma elimination half-life of proguanil?

A

About 180-200 hours or longer

This indicates a prolonged duration of action.

165
Q

What enzyme family is involved in the activation and metabolism of proguanil?

A

CYP2C subfamily

About 3% of whites are deficient in this oxidation phenotype, contrasting with about 20% of Asians and Kenyans.

166
Q

What percentage of absorbed proguanil is excreted in urine?

A

40%-60%

This is excreted either as the parent drug or as the active metabolite.

167
Q

What are common adverse effects of proguanil at chemoprophylactic doses?

A

Occasional nausea and diarrhea

Large doses may lead to more severe side effects.

168
Q

True or False: Proguanil is safe for use during pregnancy.

A

True

It is also safe when used in conjunction with other antimalarial drugs.

169
Q

What is the chief alkaloid of cinchona?

A

Quinine

Quinine and its derivatives have been used for malaria treatment for centuries.

170
Q

How do asexual malarial parasites thrive in host erythrocytes?

A

By digesting hemoglobin

This process generates free radicals and iron-bound heme as by-products.

171
Q

What is hemozoin?

A

Insoluble, chemically inert malarial pigment

Formed by the sequestration of heme.

172
Q

What do quinolines interfere with in malaria treatment?

A

Heme sequestration

Failure to inactivate heme is thought to kill the parasites via oxidative damage.

173
Q

What is chloroquine and how does it function in treating malaria?

A

Chloroquine is a weak base that concentrates in the highly acidic digestive vacuoles of susceptible Plasmodium, where it binds to heme and disrupts its sequestration.

174
Q

How does hydroxychloroquine compare to chloroquine in terms of effectiveness against P. falciparum malaria?

A

Hydroxychloroquine is essentially equivalent to chloroquine against P. falciparum malaria.

175
Q

What is the primary cause of chloroquine resistance in P. falciparum?

A

Chloroquine resistance results from mutations in the polymorphic gene pfcrt that encodes a putative transporter in the membrane of the acidic digestive vacuole.

176
Q

Which transporters may play a role in chloroquine resistance?

A
  • PfCRT
  • P-glycoprotein transporter encoded by pfmdr1
  • P. falciparum multidrug resistance-associated protein (PfMRP)
177
Q

What is chloroquine’s therapeutic effectiveness against other Plasmodium species?

A

Chloroquine is highly effective against the erythrocytic forms of P. vivax, P. ovale, P. malariae, P. knowlesi, and chloroquine-sensitive strains of P. falciparum.

178
Q

What is the agent of choice for chemoprophylaxis and treatment of infections caused by P. ovale and P. malariae?

A

Chloroquine remains the agent of choice.

179
Q

What has largely replaced chloroquine for treating P. falciparum infections?

A

Artemisinin-based combination therapies (ACTs) have largely replaced chloroquine.

180
Q

In which situations is chloroquine still effective?

A

Chloroquine is effective in chemoprophylaxis or treatment of acute attacks caused by P. vivax, P. ovale, and P. malariae, except in areas with resistant strains of P. vivax.

181
Q

What is the role of primaquine in relation to chloroquine?

A

Primaquine can be given with chloroquine or used after a patient leaves an endemic area to prevent relapses in P. vivax and P. ovale infections.

182
Q

How quickly does chloroquine control the symptoms of acute malarial attacks?

A

Chloroquine rapidly controls clinical symptoms and parasitemia, with most patients becoming completely afebrile within 24-48 hours.

183
Q

What should be suspected if patients fail to respond within the second day of chloroquine therapy?

A

Resistant strains should be suspected.

184
Q

What are the recommended alternative treatments if chloroquine is ineffective?

A
  • Quinine plus tetracycline or doxycycline
  • Atovaquone-proguanil
  • Artemether-lumefantrine
  • Mefloquine
185
Q

What are the absorption characteristics of chloroquine?

A

Chloroquine is well absorbed from the GI tract and rapidly from intramuscular and subcutaneous sites.

186
Q

What is the significance of chloroquine binding to plasma proteins?

A

Chloroquine binds moderately (60%) to plasma proteins.

187
Q

What are the active metabolites produced by hepatic CYPs from chloroquine?

A
  • Desethylchloroquine
  • Bisdesethylchloroquine
188
Q

What is the terminal half-life of chloroquine?

A

The terminal half-life ranges from 30 to 60 days.

189
Q

What can cause acute chloroquine toxicity?

A

Acute chloroquine toxicity is most frequently encountered when therapeutic or high doses are administered too rapidly by parenteral routes.

190
Q

What are some cardiovascular effects of chloroquine overdose?

A
  • Hypotension
  • Vasodilation
  • Suppressed myocardial function
  • Cardiac arrhythmias
  • Cardiac arrest
191
Q

What symptoms may result from chloroquine overdose?

A
  • Confusion
  • Convulsions
  • Coma
192
Q

What gastrointestinal side effects can occur with oral chloroquine therapy?

A
  • GI upset
  • Headache
  • Visual disturbances
  • Urticaria
193
Q

What is the risk associated with high doses of chloroquine or hydroxychloroquine?

A

High daily doses (>250 mg) can lead to irreversible retinopathy and ototoxicity.

194
Q

Which patient conditions should chloroquine not be prescribed for?

A
  • Epilepsy
  • Myasthenia gravis
  • Psoriasis or other exfoliative skin conditions
  • Porphyria cutanea tarda
195
Q

What should be monitored in patients receiving long-term high-dose chloroquine therapy?

A

Patients should undergo ophthalmological and neurological evaluations every 3-6 months.

196
Q

True or False: Chloroquine can interact with CYP2D6.

197
Q

What effect does chloroquine have on the yellow fever vaccine?

A

Chloroquine attenuates the efficacy of the yellow fever vaccine when administered at the same time.

198
Q

What are the FDA-approved uses of quinine and quinidine?

A

Treatment of uncomplicated P. falciparum malaria

Quinine and quinidine are specifically approved for uncomplicated malaria cases.

199
Q

How does quinidine compare to quinine in terms of potency and toxicity?

A

More potent as an antimalarial and more toxic than quinine.

200
Q

What is the effect of quinine on skeletal muscle?

A

Increases tension response to maximal stimulus and increases refractory period, reducing tetanic stimulation response.

201
Q

True or False: Quinine has a significant effect on hepatic forms of malarial parasites.

202
Q

What is a major reason quinine is not used for chemoprophylaxis?

A

Its toxicity and short half-life.

203
Q

What factors contribute to the complexity of P. falciparum resistance to quinine?

A

Correlates with resistance to chloroquine, mefloquine, and halofantrine.

204
Q

How is quinine absorbed in the body?

A

Orally absorbed mainly from the upper small intestine, >80% complete.

205
Q

What is the typical time to reach maximum plasma levels after an oral dose of quinine?

A

3-8 hours.

206
Q

What happens to the pharmacokinetics of quinine during severe malarial infection?

A

Apparent volume of distribution and systemic clearance decrease, increasing elimination half-life to 18 hours.

207
Q

What is the fatal oral dose range of quinine for adults?

208
Q

What are the dose-related toxicities associated with quinine?

A

Cinchonism, hypoglycemia.

209
Q

What are mild forms of cinchonism?

A

Tinnitus, high-tone deafness, visual disturbances, headache, dysphoria, nausea, vomiting, postural hypotension.

210
Q

True or False: Quinine can cause hyperinsulinemia and severe hypoglycemia.

211
Q

What is ‘blackwater fever’?

A

A rare hypersensitivity reaction to quinine therapy characterized by massive hemolysis, hemoglobinemia, and hemoglobinuria.

212
Q

What is the therapeutic range for ‘free’ quinine?

A

0.2 to 2.0 mg/L.

213
Q

What is the recommended initial dose of quinidine by the CDC?

A

10 mg salt/kg initially, followed by 0.02 mg salt/kg/min.

214
Q

Fill in the blank: Quinine should be avoided in patients with _______.

A

Tinnitus or optic neuritis.

215
Q

True or False: Quinine is considered safe in pregnancy.

216
Q

What can delay the absorption of quinine from the gastrointestinal tract?

A

Antacids that contain aluminum.

217
Q

What effect does quinine have at neuromuscular junctions?

A

Enhances effect of neuromuscular blocking agents and opposes action of acetylcholinesterase inhibitors.

218
Q

What is a potential interaction of quinine with cardiac glycosides?

A

Delays absorption and elevates plasma levels.

219
Q

What serious cardiac complications can result from acute over-dosage of quinine?

A

Sinus arrest, junctional rhythms, atrioventricular block, ventricular tachycardia, and fibrillation.

220
Q

What is Mefloquine and where did it emerge from?

A

Mefloquine is a drug that emerged from the Walter Reed Malaria Research Program as safe and effective against drug-resistant strains of P. falciparum.

221
Q

What is the primary action of Mefloquine?

A

Mefloquine is a highly effective blood schizonticide.

222
Q

With which substance does Mefloquine associate, suggesting similarities to chloroquine’s mode of action?

A

Mefloquine associates with intraerythrocytic hemozoin.

223
Q

What genetic factor is associated with reduced parasite susceptibility to Mefloquine?

A

Increased pfmdr copy numbers are associated with reduced parasite susceptibility to Mefloquine.

224
Q

What does increased PfMDR1-mediated solute import suggest about Mefloquine’s target?

A

It suggests that the drug’s target resides outside the vacuolar compartment.

225
Q

Which enantiomer of Mefloquine is associated with adverse CNS effects?

A

The (-)-enantiomer is associated with adverse CNS effects.

226
Q

How does the (+)-enantiomer of Mefloquine differ in terms of side effects?

A

The (+)-enantiomer retains antimalarial activity with fewer side effects.

227
Q

What combination can reduce the selection pressure for resistance when using Mefloquine?

A

Mefloquine can be paired with artesunate.

228
Q

Why is Mefloquine taken orally?

A

Parenteral preparations cause severe local reactions.

229
Q

How long does it take for plasma levels of Mefloquine to peak?

A

Plasma levels of Mefloquine rise to their peak in about 17 hours.

230
Q

What is the half-life range of Mefloquine?

A

The half-life of Mefloquine ranges from 13 to 24 days.

231
Q

What significant property contributes to the slow elimination of Mefloquine?

A

Its high lipophilicity and extensive tissue distribution.

232
Q

How is Mefloquine primarily metabolized and excreted?

A

Mefloquine is extensively metabolized in the liver by CYP3A4 and excreted mainly by the fecal route.

233
Q

What type of warning has the U.S. FDA added to Mefloquine labeling?

A

A ‘black box’ warning noting the drug’s potential to cause severe, possibly permanent, neurological and psychiatric adverse effects.

234
Q

What are common short-term adverse effects of Mefloquine?

A

Nausea, vomiting, and dizziness.

235
Q

What should be done if vomiting occurs within the first hour of taking Mefloquine?

A

The full dose should be repeated.

236
Q

What symptoms can indicate CNS toxicity from Mefloquine?

A

Symptoms include seizures, confusion, acute psychosis, and disabling vertigo.

237
Q

What are some mild-to-moderate toxicities associated with Mefloquine?

A

Disturbed sleep, dysphoria, headache, GI disturbances, and dizziness.

238
Q

What contraindications exist for Mefloquine use?

A

History of seizures, depression, bipolar disorder, or adverse reactions to quinoline antimalarials.

239
Q

What is the recommendation regarding pregnancy after using Mefloquine?

A

Pregnancy should be avoided for 3 months after Mefloquine use.

240
Q

Is Mefloquine considered first-line treatment for malaria?

A

No, it is no longer considered first-line treatment of malaria.

241
Q

For what specific cases should Mefloquine be reserved?

A

For the prevention and treatment of malaria caused by drug-resistant P. falciparum and P. vivax.

242
Q

In what situations is Mefloquine especially useful?

A

As a chemoprophylactic agent for travelers spending weeks to years in endemic areas.

243
Q

What is the benefit of using Mefloquine in combination with an artemisinin compound?

A

It is more effective in areas with multiply drug-resistant strains of P. falciparum.

244
Q

What is the primary action of primaquine?

A

Acts on exoerythrocytic tissue stages of Plasmodium spp. in the liver to prevent and cure relapsing malaria.

245
Q

What should patients be screened for before therapy with primaquine?

A

G6PD deficiency.

246
Q

What is the mechanism of action of primaquine?

A

Not fully elucidated.

247
Q

Against which stages of Plasmodium spp. does primaquine act?

A

Primary and latent hepatic stages.

248
Q

What types of infections does primaquine prevent relapses in?

A

P. vivax and P. ovale infections.

249
Q

What type of activity does primaquine display against P. falciparum?

A

Gametocytocidal activity.

250
Q

Is primaquine active against asexual blood-stage parasites?

A

No, it is inactive.

251
Q

What is the absorption rate of primaquine from the GI tract?

A

Approaches 100%.

252
Q

When does peak plasma concentration of primaquine occur?

A

Within 3 hours.

253
Q

What is the average half-life (t1/2) of primaquine?

254
Q

What is the fate of primaquine after administration?

A

Rapidly metabolized; only a small fraction is excreted as the parent drug.

255
Q

What enzyme does primaquine induce?

256
Q

What is the major metabolite of primaquine?

A

Carboxyprimaquine, which is inactive.

257
Q

For what purposes is primaquine primarily used?

A

Terminal chemoprophylaxis and radical cure of P. vivax and P. ovale infections.

258
Q

When should primaquine regimens be initiated for terminal chemoprophylaxis?

A

Shortly before or immediately after leaving an endemic area.

259
Q

What is required for a radical cure of P. vivax or P. ovale malaria?

A

Administration during an asymptomatic latent period or during an acute attack.

260
Q

Is simultaneous administration of a schizonticidal drug plus primaquine more effective than sequential treatment?

A

Yes, it is more effective.

261
Q

What are the common side effects of primaquine?

A

Mild-to-moderate abdominal distress, mild anemia, and leukocytosis.

262
Q

How can abdominal distress caused by primaquine be alleviated?

A

Taking the drug at mealtime.

263
Q

What serious condition can occur in individuals with congenital deficiency of NADH methemoglobin reductase when taking primaquine?

A

Methemoglobinemia.

264
Q

What should be monitored if a daily dose of more than 30 mg primaquine is given?

A

Blood counts.

265
Q

Should primaquine be given to pregnant women?

A

No, it should not be given.

266
Q

What is tafenoquine a derivative of?

A

Primaquine.

267
Q

How is tafenoquine absorbed after oral administration?

A

Slowly, with maximum plasma concentrations occurring about 12 hours after dosing.

268
Q

What is the elimination half-life of tafenoquine?

A

About 14 days.

269
Q

What are the common gastrointestinal side effects of tafenoquine?

A

Heartburn, gas, vomiting, and diarrhea.

270
Q

Is there any reported QTc effect from tafenoquine?

A

No reported detectable QTc effects.

271
Q

What possible serious side effects are associated with tafenoquine?

A

Methemoglobinemia, hemolytic anemia, and thrombocytopenia.

272
Q

Has tafenoquine been tested in pregnant women or children?

A

No, it has not been tested.

PHARMACOLOGY (sahrgeant) (3 decks)

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