Antiparasitics and Antifungals Flashcards
What is the only helminth that causes opportunistic infections in aids patients?
Threadworms - can complete life cycle in human host
What are three antihelminthic drugs?
Mebendazole
Ivermectin
Praziquantel
Which helminths infect by skin penetration?
Hookworm
Threadworms
All others oral
Which worms are treated with mebendazole?
Pinworms - intestine only
Whipworms - intestine only
Roundworm (ascaris) - intestine and lung
All infect orally with eggs
Hookworm - skin, lung, intestine - infects with larvae - suck blood leading to anemia
Trichinosis - from eating muscle of contaminated animals - disease proportional to number of larvae ingested
What species is Ivermectin used for?
Drug of choice for threadworms
Few side effects and excellent cure rates
Single oral dose
Kills microfilariae but not adults
Primary control strategy for filariasis in endemic countries
Heartworm in dogs
Mebendazole
Orally
Single dose often effective
Inhibit micro tubule assembly and block glucose uptake by nematodes
Drug resistance not a problem in humans
Ivermectin
Contraindicated when impaired BBB
Agonist of glutamate gated chloride channels leading to paralysis of worm
Praziquantel
Treatment of choice for tapeworms and fluke infections
Causes muscular paralysis and vacuolization in cells of infecting organism - May work by increasing calcium permeability
Oral dose well absorbed
Very low toxicity
Expensive
What is the basic life cycle of malaria?
Mosquito bites and sporozoites invade bloodstream then implants in liver
Mature there and burst into bloodstream as invasive merozoites that infect RBCs repeatedly
Some stay in liver and lie dormant as hypnozoites
What are the current recommendations for treatment of malaria?
Chloroquine unless resistant
If resistant -
Malarone - non pregnant adults or children
Artemether plus coartem - non pregnant adults or children
Quinine sulfate with something else
Mefloquine
All oral use
Chloroquine
Inhibits polymerization of heme in food vacuole of parasite - toxic
Quinine
Can be used for chloroquine resistant falciparum malaria
Typically in combo with doxycycline
Atovaquone plus proguanil
Malerone
Broad spectrum activity against various parasitic infections
Inhibits ETC at cytochrome bc1 complex
Parasite mitochondria inhibited selectively over host
Proguanil metabolized to DHFR
Artemisinins
Combo with coartem is recommended
Drug of first choice in resistant strains for the moment
Can cause neurotoxicity at high doses
Mefloquine
Effective in chloroquine resistant strains
Mechanism of action unknown
Neurological and psychiatric side effects
Doxycycline
Treatment and prophylaxis of chloroquine resistant
Don’t use in pregnant women
What is recommended for malaria treatment in pregnant women?
If chloroquine resistant -
Mefloquine or combo of quinine sulfate and clindamycin
What is recommended for treatment of severe malaria?
Parenteral admin
Only approved is quinidine gluconate
It is cardiotoxic
What is the only drug active against the dormant liver forms of malaria?
Primaquine
Not in pregnant women or people with g6pd deficiency
Iodoquinol
Antiamebic drug
Used for asymptomatic and mild intestinal inf
Can cause neurotoxicity in large doses
Metronidazole
Active against anaerobic bacteria, Protozoa (inc giardia, trichomoniasis), and amebiasis
Very well absorbed in gut
Require co treatment with luminal drug
Enzymatic reduction and auto oxidation generates free radicals that degrade DNA and macromolecules
Mild GI, CNS effects and blood dyscriasis
Less activity against virulent intestinal forms than systemic inf
What are the three classifications of chemotherapy against fungal infection?
Oral and parenteral drugs for systemic infections
Oral drugs for infections of skin and mucous membranes
Topical drugs for infections of skin and mucous membranes
What are the three major classes of anti fungal drugs?
Polyenes (inc amphotericin b)
Azoles
Echinocandins
Amphotericin b - mechanism of action
Used for deep systemic infections, esp in neutropenic patients
Fungicide
One side binds ergosterol and the other binds each other
Creates channel in membrane
Amphotericin b - pharmacokinetics
IV admin
Vd greater than total body water
Doesn’t cross BBB - intrathecally for brain
Slow metabolism
Amphotericin b - adverse effects
Most suffer immediate effects and slow toxicities
Immediate - fever, chills, vomiting, headaches
Nephrotoxicity
Intrathecally can cause seizure
Much of toxicity believed to be caused by detergent carrier - now available with lipids but expensive
Amphotericin b - therapeutic uses
Drug of choice for most life threatening disseminated fungal inf
Recently shifted to drug for induction of therapy
Azoles - mechanism of action
Include topical imidazoles (ketoconazole) and more potent systemic triazoles (fluconazole, itraconazole)
Inhibit p450 enzyme leading to depletion of ergosterol and altered membrane permeability
Accumulation of precursor is toxic
Azoles - pharmacokinetics
Oral admin
Hydrophobic - prevent IV
Absorption enhanced at low ph and by food
Wide distribution but not to CSF except fluconazole
Elim by hepatic metabolism
Azoles - adverse effects
Inhibit p450 can lead to drug drug interactions
Steroid hormones can drop
Rifampin induces p450 and will lower concentrations
Azoles - therapeutic uses
Ketoconazole for prostate cancer and Cushing’s
Fluconazole
High water solubility - oral or IV admin
Low potential for inhibition of p450 enzymes
High penetration into CNS - good for fungal meningitis
Resistance in AIDs patients with thrush, otherwise uncommon
Itraconazole
Most potent
Preferred oral for inf from dermatohytes
Less effect on p450 enzymes
Insufficient penetration across BBB
Flucytosine - mechanism of action
Prodrug used in combo with amphotericin b
Metabolized to 5 FU by enzyme not in mammalian cells
Further metabolized to 5 FdUMP which inhibits thymidine synthase needed for DNA replication
Flucytosine - pharmacokinetics
Oral admin
Wide distribution including CSF
Glomerular filtration
Flucytosine - adverse effects
High doses can cause bone marrow toxicity and blood dyscriasis
Fungi become resistant rapidly when given alone
Flucytosine - therapeutic uses
Amphotericin b used in combo is synergistic - makes membrane more permeable for flucytosine to enter more
Particularly useful for c. Neoformans that causes cryptococcal meningitis
Echinocandins - mechanism of action
Competitive inhibitors of beta 1,3 d glucan synthase
Inhibit cell wall synthesis
Echinocandins - pharmacokinetics
IV admin
Minimal distribution to CNS or ocular tissues
Not metabolized by p450 so few drug interactions
Excreted in kidneys
Echinocandins - adverse effects
Less frequent or serious than other antifungals
Infusion related hypersensitivity and histamine release
Sometimes hepatotoxicity but asymptomatic
Echinocandins - therapeutic uses
Active against yeast inf - first line for invasive candida in biofilms
Against aspergillus
Fungicidal in candida, otherwise fungistatic
Caspofungin
Echinocandin
Drug drug interactions
Can be hepatotoxic
