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ID exam 4 > antiparisitic drugs > Flashcards

antiparisitic drugs Flashcards

1
Q

malaria parasite

A

Plasmodium falciparum - Responsible for most malaria deaths
Plasmodium vivax - Relapsing malaria - caused by hypnozoites in liver
Plasmodium ovale - Relapsing
Plasmodium malariae (72 h life cycle)
Plasmodium knowlesi

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2
Q

uncomplicated malaria

A 
Classic symptoms
-Cold stage
-Hot stage
-Sweating stage
-48 hour periodicity for Falciparum and Vivax malaria
More usual symptoms
-Fever and flu-like symptoms - chills, headache, myalgias, and malaise
-Anemia and jaundice
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3
Q

severe malaria

A 
Serious organ failures, including kidney
Cerebral malaria
-abnormal behavior, impairment of consciousness, seizures, coma, or other neurologic abnormalities
Severe anemia and hemoglobinuria (hemoglobin in the urine) due to hemolysis
Acute respiratory distress syndrome
Placental malaria
-Especially during first pregnancy
-Causes low birth weight and miscarriage
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4
Q

malaria chemoprophylaxis

A

Prevention! - Insect repellents, Insecticides, Bed nets
Chemoprophylaxis
-Should be taken before, during and after travel,
-Consult the CDC Travel Vaccines & Malaria Information, by Country
Factors to consider: Species present, Level and type of drug resistance, Lead time before travel
Common options
-Atovaquone-proguanil or doxycycline - Daily admin + short pretreatment
Chloroquine – only if sensitive parasites
Mefloquine – weekly admin, good for long trips
Primaquine – if >90% P. vivax in area

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5
Q

antimalarial drugs

A

Drug classification
-Tissue schizonticides - kill liver stage parasites
-Blood schizonticides - kill erythrocytic forms
-Gametocytocides - Kill sexual stages; Block transmission
No single drug is active against all stages
Multiple drugs may be necessary
Artemisinin
4-aminoquinolines
8-aminoquinolines
Atovaquone
Antifolates
Antibiotics

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6
Q

artemisinin

A

Sesquiterpene lactone endoperoxide - Endoperoxide is active group
Potent and fast acting - 10,000-fold reduction in 48 h
Low toxicity
Counterfeits are common
Rapidly acting blood schizonticide
Kills liver stage, but not hypnozoites
short half-life – 1-2 h - recrudescence rate is high after short course of treatment; Not appropriate for chemoprophylaxsis
Commonly paired with other drugs - Mefloquine or lumefantrine frequently used

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7
Q

artemisinin MOA and MOR

A

Mechanism of action
-Must be activated – likely via heme-iron
-Activated artemisinin may form free radicals - Target parasite proteins and lipids (phosphatidylinositol-3-kinase (PfPI3K) is a direct target, but more are likely)
Mechanism of resistance
-Mutations in Kelch 13 gene
-Delays progress through the life cycle
-May alter stress response

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8
Q

artemisinin combo therapy

A 
Artemisinin derivatives are paired with longer half-life drugs - Artemisinin provides rapid knockdown; Longer half-life component eliminates remaining parasites
Combinations
-Lumefantrine most
common (Coartem)
-amodiaquine
-mefloquine
-piperaquine
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9
Q

artemisinin PKs

A

Artemisinin is insoluble
-Can only be used orally
-low bioavailability
semisynthetic artemisinins are available
-different routes of administration
—oral (dihydroartemisinin, artesunate, and artemether)
—intramuscular (artesunate and artemether)
—intravenous (artesunate)
—rectal (artesunate)
Artesunate now available in U.S. via CDC for treatment of severe malaria
Artemether - Converted to dihydroartemisinin by CYPs (CYP3A4&raquo_space; CYP2B6, CYP2C9, CYP2C19)
Artesunate - Converted to dihydroartemisinin by by plasma esterases (and possibly CYP2A6)
Dihydroartemisinin glucuronidated in gut and liver – excreted in urine
antimalarial effect associated with Cmax (bolus better than infusion)

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10
Q

4-aminoquinolines examples

A

quinine, chloroquine, mefloquine

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11
Q

hbg metabolism

A

Malaria parasites ingest hemoglobin from host cell
Degrade hemoglobin to amino acids and free heme in food vacuole
Free heme is toxic
Parasite polymerizes heme into hemozoin, which is nontoxic
Chloroquine accumulates in food vacuole and inhibits heme polymerization

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12
Q

4-substituted quinolines

A

Interfere with heme polymerization

Resistance associated with lack of accumulation in food vacuole

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13
Q

chloroquine

A

Drug of choice since 1940s
Pharmacokinetics: Formulated for oral use, Well absorbed, Very large volume of distribution (Slowly released from tissues), Initial half-life of 3-5 days; terminal half-life 1-2 months
Note: Hydroxychloroquine more commonly stocked in U. S. pharmacies - Same as CQ, but with a hydroxyl at end of sidechain; More water soluble, but both are soluble
antimalarial effect associated
with T>MIC (infusion better than bolus)

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14
Q

chloroquine resistance

A

Developed in P. falciparum in at least 2 foci in 1950’s and spread
Primary mechanism: mutations in PfCRT1
-Localized to food vacuole
-Causes reduced accumulation of chloroquine
-No cross-resistance with mefloquine or quinine
Over-expression of PfMDR1 (drug transporter)
P. vivax developed resistance 30 years later and by a different mechanism

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15
Q

quinine

A

Mechanism thought to be similar to CQ
Resistance rare but increasing
Blood schizonticide
Treatment of choice for:
-Chloroquine-resistant falciparum malaria - Quinine sulfate - orally availableSevere falciparum malaria - quinidine gluconate - administered by IV; Cardiac monitoring should be in place
Shorter half-life and toxicity make it inappropriate for chemoprophylaxis
Adverse effects
-Cinchonism: tinnitis, headache, nausea, dizziness, flushing, & visual disturbances
-Can stimulate uterine contractions
-Hemolysis: G6PD deficiency, Blackwater fever - rare, severe, marked by hemoglobinuria
Metabolized by CYP3A4 - can raise levels of warfarin and digoxin
Severe hypotension can occur from too-rapid infusion

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16
Q

primaquine

A

8-aminoquinoline
Metabolized by by the cytochrome P450 (CYP) 2D6 in humans - Metabolism required for activity, Mechanism may involve free radicals
Drug of choice for liver stages (actively growing and hypnozoites) of P. vivax and P. ovale* (in combination
with chloroquine)
Tafenoquine is a related compound - Same spectrum of activity, Same toxicities, does not seem to be affected by CYP2D6 polymorphisms
Well absorbed orally
Some resistance has been noted
High risk of hemolysis in patients with G6PD deficiency - Establish normal G6PD levels before use; Use with caution if G6PD deficient - Discontinue if indication of hemolytic anemia
Should not be used in pregnant women - If breast feeding – CDC, no restrictions if G6PD normal (UK recommends avoiding)
Contraindications: Granulocytopenia, Concurrent use of other potentially hemolytic drugs or drugs that suppress myeloid cell development

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17
Q

malarone

A

Combination of proguanil and atovaquone
-Atovaquone failed as monotherapy - resistance developed rapidly
-Combination is synergistic
Kills liver and blood stages (but not hypnozoites)
-Effective as treatment for uncomplicated malaria and chemoprophylaxsis - Atovaquone also used to treat Toxoplasma gondii and Pneumocystis jiroveci

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18
Q

atovaquone

A

Selective inhibitor of malaria mitochondrial cytochrome bc1 complex - inhibits electron transport, mitochondrial membrane potential collapses
Main role for mitochondrial electron transport in P. falciparum - regenerate ubiquinone
-Atovaquone is a ubiquinone analog
-electron acceptor for parasite dihydroorotate dehydrogenase - essential for pyrimidine biosynthesis in the parasite

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19
Q

proguanil

A

Converted to cycloguanil
-selective inhibitor of the bifunctional plasmodial dihydrofolate reductase-thymidylate synthetase
-crucial for parasite purine and pyrimidine synthesis
Proguanil also has inherent antimalarial activity
-Enhances mitochondrial toxicity of atavaquone

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20
Q

pyrimethamine sulfadoxine

A

Folate synthesis inhibitors
Slow acting erythrocytic schizonticides
Similar combination used to treat Toxoplasmosis
Pyrimethamine – inhibits plasmodia DHF reductase (1,000-fold selectivity for Plasmodium)

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21
Q

other uses of antifolates

A

Toxoplasmosis
-Pyrimethamine plus sulfadiazine is first-line therapy - Clindamycin can replace sulfadiazine
Pneumocystis
-trimethoprim plus sulfamethoxazole is first-line therapy
-Atavaquone is alternative

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22
Q

antibiotics as antimalarial drugs

A

Tetracycline, doxycycline, and clindamycin are blood schizonticides
Target components of the apicoplast
-Plant-like organelle that carries out many biochemical processes
Doxycycline commonly paired with quinine or quinidine for treatment of falciparum malaria
Doxycycline is used for chemoprophylaxsis in areas with high resistance to mefloquine

23
Q

toxoplasma gondii

A

Related to Plasmodium • Infects most mammals - cat is the definitive host
Transmission: Eating raw meat, Cat feces
3rd most common food-borne illness
1.5 million infections in the U.S. each year
life cycle: Sexual development only in cat; Cysts develop in other mammals; Can get infected from oocysts shed by cats
or by eating raw meat containing tissue cysts
Usually not a problem in people with functioning immune systems
Severe toxoplasmosis: HIV/AIDS, Organ transplants, Chemotherapy
Congenital toxoplasmosis - Fetus becomes infected via placenta in women who are infected for the first time
Drug treatment
-First line therapy: pyrimethamine + sulfadiazine
-Alternatives: atovaquone or pentamidine

24
Q

pentamidine

A

Aromatic diamidine
Parental administration
Mechanism unknown - Preferentially accumulates in parasites
Highly toxic - 50% of patients show side effects
First line agent for West African trypanosomiasis - Also used to treat leishmania and pneumocystosis

25
Q

kinetoplastid parasites

A

Leishmania
African trypanosomes
-Trypanosoma brucei gambiense – West African trypanosomiasis – accounts for 95% of cases
-Trypanosoma brucei rhodesiense– East African trypanosomiasis – accounts for 5% of cases
American trypanosomes - Trypanosoma cruzi
Share common features
-Unique organelles - kinetoplast, glycosome
-Distinct mechanisms of gene expression

26
Q

leishmania

A

At risk: 350 million people, 88 countries
12 million people infected
Annual incidence: 2 million
Transmitted by sandflies
Intracellular parasite - Replicates in phagolysosome

27
Q

leishmania and HIV

A

Found in 34 countries; most common in southern Europe and Brazil
Immunocompromised people unable to control leishmania infections
Accelerating spread of visceral leishmaniasis
leishmaniasis accelerates the onset of AIDS by cumulative immunosuppression and by stimulating replication of the virus
IV drug users at greatest risk
Different patterns of drug susceptibility

28
Q

african trypanosomiasis

A

African sleeping sickness - Fatal if untreated
Extracellular parasite - Trypanosoma brucei - Initial phase - hemolymphatic; Late phase - CNS
~ 20,000 cases in 2015
Transmitted by tsetse fly
Avoids immune response by changing coat protein

29
Q

american trypanosomiasis

A

Also called Chaga’s disease
Trypanosoma cruzi
Endemic in Latin America - Mexico, Central and S. America; 6-8 million people infected (2015); 300,000 in U.S. (no transmission)
Transmitted by reduviid bugs - Blood transfusion
Intracellular - Replicates in cytoplasm

30
Q

anti-kinetoplastid drugs

A

Leishmaniasis - Sodium stibogluconate or Amphotericin B; Alternatives - pentamidine or miltefosine
African trypanosomiasis - Early stage - pentamidine (West) or Suramin (East); Late stage - Melarsoprol (East and West) or Eflornithine (West; combination with nifurtimox is promising))
American trypanosomiasis - Nifurtimox or Benznidazole

31
Q

nifurtimox and benznidazole

A

Most commonly used drugs for T. cruzi; also used incombo therapy for T. brucei
Mechanism unknown - activated by a NADH-dependent mitochondrial nitroreductase; generation of nitro radical anions
Reduces severity of acute phase - Eliminates parasite in 80% of acute infections and ~50% of chronic infections; Does not reverse tissue damage in chronic infections
Orally available - 3-4 month course of treatment
Toxicity common - hypersensitivity, GI complications - Leads to premature stoppage of treatment

32
Q

anaerobic protozoa

A 
Entamoeba histolytica (amebiasis) - 50 million cases per year; 40,000 to 110,000 deaths; 1 - 2 % of US population
Giardia lamblia (giardiasis) - One of the most common water- borne diseases in U.S.; 5% of US population
Trichomonas vaginalis - Sexually transmitted; 200 million cases per year; 20 -25 % of women in US
33
Q

amebiasis

A

Poor sanitation and fecal contamination of food and water promote spread
Can occur any where - More common in Latin America, Africa, and the Indian subcontinent
Initially infects the intestine - Sometimes reaches other organs, such as the liver
Most infections are asymptomatic
Symptoms include diarrhea, increased flatulence, abdominal cramps - Some people develop liver abscesses

34
Q

giardia lamblia

A

Diarrheal disease - Infections range from asymptomatic to severe diarrhea &
malabsorption
Treatment of choice: metronidazole; Nitazoxanide

35
Q

cryptosporidium

A

300,000 infections per year in the U.S.
Most frequent cause of recreational water-related disease outbreaks
Most common symptom is watery diarrhea
Other symptoms: Stomach cramps or pain, Dehydration, Nausea & vomiting, Fever, Weight loss
More serious illness in immunocompromised people
Drug of choice: Nitazoxanide***

36
Q

trichomonas

A

Resides in the female lower genital tract and the male urethra and prostate
Frequently
symptomatic in women - Vaginitis with a purulent discharge; vulvar and cervical lesions, abdominal pain, dysuria and dyspareunia
Frequently asymptomatic in men

37
Q

metronidazole for anaerobic parasites

A

Drug of choice for extraintestinal Entamoeba histolytica, giardiasis and trichomoniasis
Kills trophozoites but not cysts
Treatment usually followed by luminal drug to eliminate asymptomatic infection
Mechanism not definitively known - Anaerobes have electron transport proteins with low redox potential – activate metronidazole
Tinidazole is a similar drug with less toxicity

38
Q

amebiasis treatment

A

Drugs for intestinal forms:

  • Paromomycin: Aminoglycoside; Not significantly absorbed in GI tract; Only used as an intestinal amebicide; Similar efficacy and less toxic than other drugs; Also active against Cryptosporidium
  • Iodoquinol: Alternative to paromomycin; Commonly used in combination with metronidazole; Mechanism unknown
39
Q

nitazoxanide

A

rapidly metabolized to the active metabolite
(tizoxanide)
Mechanism uncertain - interferes with pyruvate:ferredoxin
oxidoreductase (PFOR) enzyme-dependent electron transfer reaction; Inhibits anaerobic metabolism
inhibits the growth of sporozoites and oocysts of Cryptosporidium parvum and trophozoites of Giardia lamblia

40
Q

helminth infections

A

Worm infections: ~25% of the world’s population is infected; ~15% of the U.S. population is infected
Worms have unique biology: Multiply outside of their definitive host in contrast to other parasites; Evade immune system - Infections are chronic - last for the lifetime of host

41
Q

flatworms - tapeworm infections

A 
Beef Tapeworm (Taenia saginata) - Global distribution; Transmitted by eating undercooked meat
Pork Tapeworm (Taenia solium) - Global distribution; Bladders worms; Occasionally found in uncooked pork
Fish Tapeworm (Diphyllobothrium latum) - Largest tapeworm - can reach 10 m in length; Transmitted by eating undercooked fish; Northern hemisphere; Rob host of nutrients, especially vitamin B12
42
Q

echinococcosis

A

Dog Tapeworm
Dogs are definitive hosts
Humans are an intermediate hosts for larval forms of Echinococcus species - cause “cystic” (E. granulosus) and “alveolar” (E. multilocularis and E. vogeli) hydatid disease; Parasite eggs from canine stools are a major cause of disease; produces slowly growing cysts usually in liver and lung
Preferred treatment - Removal of the cysts by surgery - Prolonged regimens of albendazole - some patients are not cured despite multiple courses of therapy; lifelong therapy may be required.

43
Q

cysticerosis

A

Caused by autoinfection by ingesting eggs produced by T. solium
After ingestion, oncospheres hatch in the intestine, invade the intestinal wall, and migrate to striated muscles (and brain, liver, and other tissues)
Develop into cysticerci • Can cause serious disease in the brain (neurocysticercosis)

44
Q

flatworms - dwarf tapeworm

A

Most common cestode infections
Can be transmitted directly between humans
3 - 4 cm in length Found in temperate regions worldwide
Children predominantly infected
Infected by ingesting eggs
Generally not serious, but chronic infections can cause more severe symptoms

45
Q

schistosomiasis

A 
Bloodflukes
appear w big bellies
Three species infect humans: Schistosoma hematobium, Schistosoma mansoni, Schistosoma japonicum
200 million people infected worldwide
Caribbean, S. America, Africa, Mid East
Snails are intermediate host
Can live for 5 - 10 years in host
symptoms due to immune reaction to eggs - Headaches, fatigue, fever, gastrointestinal problems; Hepatic fibrosis and ascites; Bladder cancer
46
Q

benzimidazoles

A

Drug therapy for helminths
Broad spectrum activity
Three currently on the market:
-Mebendazole; 1st in this class
-Thiabendazole; Toxicity limits use
-Albendazole; Useful against both GI and tissue infections
Mechanism of action - Binds to tubulin; Inhibits formation of microtubules - Microtubules grow from “plus” end; Benzimidazoles cap microtubules; Microtubules continue to be shortened from minus end
Can bind to mammalian tubulin - Reason for specificity not clear

47
Q

albendazole

A

Drug of choice for cysticercosis
Variable absorption
Rapidly converted to albendazole sulfoxide – active metabolite
Also used for pinworms, hookworms, ascariasis, trichuriasis, and strongyloidiasis

48
Q

Mebendazole

A

Used for pinworms, hookworms, ascariasis, and trichuriasis

49
Q

praziquantel

A

Highly effective against cestodes and trematodes - No activity against nematodes
Mechanism of action
-At lower concentrations - increased muscular activity - contraction and spastic paralysis; worms detach from blood vessel walls; migrate from the mesenteric veins to the liver
-At higher concentrations - tegumental damage and exposes a number of tegumental antigens
-May also disrupt calcium homeostasis
therapeutic uses:
-Drug of choice for all forms of schistosomiasis - Two or three doses yield high cure rates; Dramatically reduces egg burden in those not cured; Used in mass treatment programs
-Single dose kills 100% of T. saginata, T. solium, and D. latum - Does not kill eggs of T. solium
-toxicity: Mild and transient adverse effects are common; More severe reaction to dying worms

50
Q

ivermectin

A

Drug of choice for strongyloidiasis and onchocerciasis
Semisynthetic macrocyclic lactone
Mechanism of action:
-Paralyzes microfilariae
-binds to glutamate-activated Cl− channels found in nematode nerve or muscle cells
-causes hyperpolarization by increasing intracellular chloride concentration
-also binds with high affinity to γ-aminobutyric acid (GABA)-gated and other ligand-gated Cl−channels
-Allows host cytotoxic cells to adhere
-Does not kill adult worms
-Blocks release of progeny
Therapeutic uses:
-Primarily used to treat onchocerciasis
-Single dose
-Used in mass treatment programs - once a year - Treatment must be continued for lifespan of adult worm
-Also used for: Ascariasis, Enterobiasis, Strongyloidiasis, Filariasis

51
Q

pyrantel pamoate

A

Broad-spectrum antihelminth
Available over the counter
Highly effective for treatment of pinworms and ascaris
Moderately effective against hookworms
Active against adult and immature worms - Not active against migratory stages or ova
Mechanism of action: Depolarizing Neuromuscular blocking agent; Causes release of acetylcholine and inhibition of cholinesterase; Worms are paralyzed & expelled
Clinical uses: Ascariasis - one dose (11 mg/kg) is 85 - 100 % effective; Pinworms - two doses two weeks apart - 95% cure rate
Adverse effects are mild and infrequent

52
Q

diethylcarbamazine

A

Mechanism unknown – requires host components
Drug of choice for filariasis and loiasis - Microfilariae are rapidly killed; Adults are killed more slowly
Well absorbed from GI tract
Generally well-tolerated
Reactions to dying worms can be severe - May also lead to systemic inflammation from release of bacterial endosymbiont

53
Q

doxycycline

A

filarial parasites harbor bacterial symbionts of the genus Wolbachia
doxycycline kills Wolbachia
adult female Onchocerca worms become
sterile

ID exam 4 (9 decks)

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