Antiparasitic Drugs - LaCount Flashcards
Lice Treatments
Only kill live lice, not unhatched eggs ( ___ is only exception)
OTC options
- naturally occurring pyrethrins
- extracts from the ___ flower
- Brand names A–200, Pronto, R&C, Rid, and Triple X
- use with caution if history of ragweed or chrysanthemum allergy
- Synthetic pyrethroids - aimilar to pyrethrin
Prescription options
- Spinosad 0.9% topical suspension (Natroba)
- Benzyl alcohol lotion, 5% (Ulesfia lotion)
- Ivermectin lotion, 0.5% (Sklice)
- Malathion lotion, 0.5% (Ovide) - organophosphate insecticide acetylcholinesterase inhibitor (> __ y old)
- Spinosad
- chrysanthemum
- 6
Mechanisms of lice treatments
Spinosad
- Natural product produced by the bacterium Saccharopholyspora spinose
- 12-member ___
- mixture of spinosyn A and D
- Broad spectrum insecticide extensively used in agriculture
- nicotinic ___ receptor ___
- rapid ___ of the insect nervous
system causes death
- macrolide
- ACh, agonist
- excitation
Mechanisms of lice treatments
Perethrins
- Esters of chrysanthemic acid (II is more effective)
- Isolated from chrysanthemum flowers
- ___ synergistically enhances activity
- Nerve membrane ___ channel toxins that do not affect potassium channels
- Rapidly ___ if absorbed -relatively nontoxic
- Piperonyl butoxide
- Na
- metabolized
Entorobiasis (pinworm infection)
Enterobius vermicularis
- Most common helminthic infection worldwide
- most common in kids
- ___ - ___transmission
- diagnosis - ___ test
- fecal - oral
- tape
Drug therapy for helminths
Benzimidazoles (4)
1) ___ - 1st in this class
2) ___ - toxicity limits
3) ___ - useful against both GI and tissue infections
4) ___ - used in combo with ivermectin to treat Fasciola hepatica (liver flukes), roundworms and ectoparasites
1) Mebendazole
2) Thiabendazole
3) Albendazole
4) Triclabendazole
helminth
Benzimidazoles MOA:
- binds to ___ , inhibits formation of ___
- inhibits cell division, secretion of parasite molecules, glucose uptake
Can bind to mammalian tubulin
- Binds with higher affinity to helminth tubulin
- tubulin, microtubules
helminth treatment Benzimidazoles
Albendazole
- Drug of choice for ___
- Variable absorption
- Rapidly converted to albendazole sulfoxide - active metabolite with increased activity
- Also used for cysticercosis, hookworms,
ascariasis, trichuriasis, and strongyloidiasis
Mebendazole
- Used for pinworms, hookworms, ascariasis, and trichuriasis
Should not be used in ___ women
___ no longer preferred due to
toxicity and potential teratogen
- pinworms
- pregnant
- Thiabendazole
Pyrantel pamoate
- Broad-spectrum antihelminth
- Available ___
- Highly effective for treatment of pinworms and ascaris
- Highly insoluble (improves utility for ___ infections)
MOA: ___ Neuromuscular blocking agent
- Causes release of ___ and inhibition of ___
- Worms are ___ & expelled
OTC
intestinal
depolarizing
ACh, cholinesterase
paralyzed
Malaria
One ___ available – RTS,S
- Targets parasites that are injected by
mosquitoes
- 4 shot regimen beginning at 5 months
- 30% reduction in deaths from severe malaria
Drug resistance widespread and increasing
New drugs continually needed
vaccine
Malaria
5 human malaria parasites
Plasmodium ___
- Responsible for most malaria deaths
- Predominant in tropics
Plasmodium ___
- Relapsing malaria - caused by hypnozoites in liver
- 50% of infections in S&E Asia; 80% in Americas
Plasmodium ovale
- Relapsing
- Found in West Africa
Plasmodium malariae (72 h life cycle)
Plasmodium knowlesi
- Parts of SE Asia
- 24 h life cycle
- falciparum
- vivax
Antimalarial drugs
Drug classification
1) Tissue schizonticides - kill ___ stage parasites
2) Blood schizonticides - kill ___ forms
3) Gametocytocides
- Kill ___ stages
- Block ___
No single drug is active against all stages
Multiple drugs may be necessary
- liver
- erythrocytic
- sexual
- transmission
Antimalarial drugs - Artemisinin
Sesquiterpene lactone endoperoxide
- ___ is active group
Chinese wormwood (Artemesia)
Potent and ___ acting
- 10,000-fold reduction in 48 h
- Low ___
MOA: Must be activated – likely via heme-iron in food vacuole
- Activated artemisinin may form ___
- alkylates parasite proteins, lipids, DNA
- Triggers unfolded protein response
- Inhibits translation, proteasome, mitochondria
May inhibit ___ (PfPI3K)
- Endoperoxide
- fast
- toxicity
- free radicals
- phosphatidylinositol-3-kinase (PfPI3K)
Antimalarial drugs - Artemisinin
Rapidly acting ___ schizonticide
- Not active against ___ stage or hypnozoites
___ half-life – 1-2 h
- recrudescence rate is high after short course of treatment
- Not appropriate for chemoprophylaxsis
Commonly paired with longer half-life drugs
- Artemisinin provides ___ knockdown
- ___ half-life component eliminates remaining parasites
- Lumefantrine most common (Coartem)
- Amodiaquine, mefloquine, piperaquine
- blood
- liver
- short
- rapid
- longer
Artemisinin
Artemisinin is insoluble
- Can only be used ___
- Low bioavailability
semisynthetic artemisinins are available
- different routes of administration
- oral (dihydroartemisinin, artesunate, and artemether)
- intramuscular (artesunate and artemether)
- intravenous (artesunate)
- rectal (artesunate)
All are converted to ___ (active form)
- orally
- dihydroartemisinin
Artemisinin resistance
Mechanism
- Mutations in ___ gene (likely others as well)
- ___ progress through the life cycle
- remains in ring stage longer - drug has short half-life (waits it out)
- Dormant until [Artemisinin] decrease
- Altered stress response? – repair damage
- Less activation of Artemisinin?
- Kelch 13
- Delays
Antimalarial drugs: 4-aminoquinolines
Hemoglobin metabolism
- Malaria parasites ingest ___ 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 ___
- hemoglobin
- polymerization
4-substituted quinolines
- Interfere with heme ___
- Resistance associated with lack of accumulation in ____
- polymerization
- food vacuole
4-substituted quinolines - Chloroquine
Pharmacokinetics
- Formulated for oral use
- Well absorbed
- Very ___ volume of distribution
- ___ released from tissues
- Initial half-life of 3-5 days; terminal half-life 1-2 ___
Note: Hydroxychloroquine more commonly
stocked in U. S. pharmacies - more water soluable (but both are soluble)
- large
- slowly
- months
Chloroquine resistance
Developed in P. ___ in 1950’s in at least twice independently and spread
Primary mechanism: mutations in ___
- Localized to food vacuole
- Causes reduced accumulation of chloroquine
- No cross-resistance with mefloquine or quinine
- Over-expression of PfMDR1 (multidrug
transporter)
- P. ___ developed resistance 30 years later and by a different mechanism
- falciparum
- PfCRT1
- vivax
Antimalarial drugs: Primaquine
8-aminoquinoline
- Drug of choice for ___ stages (actively growing and hypnozoites*) of P. ___ and P. ___ (in combination with chloroquine)
Metabolized by the ___ in humans
- Metabolism required for activity
- Mechanism may involve ___
Tafenoquine is a related compound
- Same spectrum of activity
- Same toxicities
- does not seem to be affected by CYP2D6 polymorphisms
- Should be used with ___ only (other combos less effective)
- liver, vivax, ovale
- CYP2D6
- free radicals
- chloroquine
Primaquine mechanism
2 step process
Step 1: hydroxylation by ___ (OH-PQm)
Step 2
- spontaneous oxidation to quinoneimines (O- PQm) – produces ___
- Human CYP NADPH: oxidoreductase (CPR) reduces quinoneimines back to OH-PQm to create a catalytic cycle of ___ production
- ___ kills plasmodium parasites
- CYP2D6
- H2O2
- H2O2
- H2O2
Antimalarial drugs: Primaquine
Well absorbed orally
High risk of hemolysis in patients with ___ deficiency
- Establish normal levels before use
- Use with caution if deficient
- Discontinue if indication of hemolytic ___
Should not be used in ___ women
- If breast feeding – CDC, no restrictions if G6PD normal (UK recommends avoiding)
Contraindications
- ___
- Concurrent use of other potentially hemolytic drugs or drugs that suppress myeloid cell development
Some resistance has been noted
G6PD
hemolytic anemia
pregnant
Granulocytopenia
Antibiotics as antimalarial drugs
Tetracycline, doxycycline, and clindamycin are ___ schizonticides
Target components of the ___
- Plant-like organelle that carries out many essential biochemical processes
- Slow acting drugs
- Doxycycline commonly paired with quinine or quinidine for treatment of ___ malaria
- ___ is used for chemoprophylaxsis in areas with high resistance to mefloquine
- blood
- apicoplast
- falciparum
- Doxycycline
