Cell surface acting drugs Flashcards
Sterols
In eukaryotes, but not prokaryotes, sterols are an essential part of the membrane and alter its properties. Thus agents acting on sterol biosynthesis will have no antibacterial activity. In mammals cholesterol is the main sterol, in fungi and some protozoa it is ergosterol.
Amphotericin B
Amphiphillic Antibiotic
Binds to ergosterol to make pores in the fungal plasma membranes
This causes leakage of intracellular cations
Ergosterol
Essential for fungI
Its biosynthesis is therefore a valid drug target.
Unique pathway not present in mammalian cells
Complex biosynthesis pathway with many essential enzymes, each being a potential drug target.
HGMR inhibited by statins (mevinolin)
SEO inhibited by allylamines (terbinafine)
14-DM inhibited by azoles, triazoles (ketoconazole)
SMT inhibited by azasterols
Leishmaniasis
Around 2 million affected per year
Old and New varients
Drugs exist but New ones are needed
Leishmania have ergosterol, so are susceptible to antifungal agents such as amphotericin b.
Schistosomiasis (bilharzia)
Caused by parasites that live in fresh water in tropical or subtropical regions.
Burrow through skin, lay eggs in abdomen, worms pass out in urine and faeces.
Praziquantel is drug of choice.
Antihelmintics
Praziquantel -
Active against trematodes, cestodes and schistosomiasis
Verh selective, acts mostly on adult worms by disrupting their calcium homeostasis.
Early effects -
Sustained muscular contraction (sarcolemma)
Tegumental disruption
Exposure of antigens on schistomes surface
Calcium influx dependant processes.
Appears to act on voltage gated calcium channels
Schistomes contain a unique b subunit not present on other phyla. The varient B subunit confers praziquantel sensitivity to mammalian a1 subunits.
Phospholipid bilayer
Lipid bilayers separte compartments.
It is critical that compartments can communicate
This is thtough channels, receptors, transporters.
Ion channel play key role in cellular homeostasis.
A number of microbially derived anti-microbials act as ionophores, chaning flux of ions.
Ion channels good sites for pharmaceutical action in man
Also where microbes have unusual ion channels these can be selectively targetted. (glutamate gated chloride channel in nematode helminths).
River blindness
Transmitted by blackflies thag breed near fast flowing water courses.
Caused by the nematode onchocerca volvulus.
Common in tropical countries.
Blindness caused by adult worms
Microfilaria cause skin itching
Ivermectin (mectizan) a macrocycle lactone used for control of riverblindness.
Activity of macrocyclic lactones
Induce a flaccid paralysis of the worm musculature
Inhinit feeding by blocking pharyngeal pumping.
Target - invertebrate specific gkutamate activated chloride channels (related to GABAa receptors)
Channel has multiple a and B subunits
Glutamate binds to b subunit to activate channel
Ivermectin binds to a2 subunit, leadjng to irreversible opening of the channel, this causes hyperpolarisation of muscle cells giving them inability to contract.
Ivermectin effects worm neural system
Chloride channels also present in neurons
Ivermectin induces hyperpolarisation in pharyngeal neurons which spreads to the pharynx.
Resistance - so far only in nematodes of goat and sheep, none so far in onchocerciasis
Praziquantel-resistant beef tapeworm (taenia saginata)
Treat with nitazoxanide
Rare Transient side effects
Outlook of helminth infection therapy
Curent therapy is efficacious, free of side effects and cheap
This has led to complacency in drug discovery, no new R and D for 20-30yrs.
Almost no new drugs for when resistance becomes severe.
