HPDM 1 - toxins targeting cholinergic synapses Flashcards
What is Pharmacognosy?
The knowledge of drug from natural sources
What cholinergic synapses does the brain, autonomic ganglia and skeletal neuromuscular junction contain?
- The brain contains nAChR and mAChR
- Autonomic ganglia contain nAChR
- The skeletal neuromuscular junction contains nAChR
What are many of the CNS receptors involved in and how?
many of the CNS receptors are involved in neuromodulation – often by regulating the release of other neurotransmitters.
What varies depended on where they are located with the acetylcholine receptors?
Their subtypes
What is acetylcholinesterase?
The enzyme that terminates signalling by breaking down acetylcholine
What do Snare proteins do?
mediate fusion of acetylcholine containing vesicles with the membrane
Are acetylcholine receptors only postsynaptic?
No they can be presynaptic too
What can the fact that one of the most common toxin targets is to target cholinergic transmission be explained by?
explained by the fact that cholinergic systems are very important in both vertebrates and invertebrates
Where is nicotine found?
In the tobacco plant
Is nicotine an agonist or antagonist and at what receptors?
Nicotine is an agonist at mammalian and insect nicotinic acetylcholine receptors and deters predators from eating tobacco
Which other plants is nicotine found in?
• Nicotine is also found at lower concentrations in a wide range of plants related to tobacco:
- Aubergines
- Tomatoes
- Pepper and chilli plants
- Potatoes
How are humans unusual in regard to nicotine?
Humans are unusual in that some members of our species actively seek the ‘hit’ that nicotine induces in our CNS. However, nicotine is still toxic to humans
What is Ladburnum?
- Another plant that defends itself with a nicotinic agonist
- Laburnum is a very distinctive plant – due to its copious yellow flowers it is also known as ‘golden rain’
What is the toxic principle in ladburnum?
cytisine. This drug is a potent agonist at ganglionic nAChR and CNS subtypes (but not so potent at muscle nAChR). It causes a variety of nasty effects and can be fatal
What was Epibatidine isolated from?
the Phantasmal frog
Is Epibatidine an agonist or antagonist and where does it target?
Epibatidine is a very potent agonist at neuronal nicotinic receptors and also has some muscarinic receptor activity.
What is tubocuranine?
the main alkaloid component of curare
What plant does Curare come from?
S. Toxifera
Is Tubocuranine an agonist or antagonist, where and what does this mean?
Tubocurarine is a potent antagonist at muscle nAChRs and so interrupts neuromuscular transmission causing a flaccid paralysis
How was tubocuranine used in the past?
as a surgical paralytic agent but it had too many side effects
Why can’t TC by absorbed from the GI tract and where can it exert its toxic effect?
The two nitrogen’s in TC are quaternary amines and so have a permanent positive charge. This means that TC can’t be absorbed form the GI tract, however, if it gets into the bloodstream it will exert its toxic effect
What are cone snails?
predatory marine molluscs that live in tropical waters. Their prey ranges (species dependent) from fish, through other molluscs, to marine worms
• All of them hunt by firing a ‘harpoon’ into their prey. The harpoon, which is an adapted tooth and made from chitin is loaded with a cocktail of Peptide toxins.
What does each species of cone snail have?
an array of toxins in its venom, targeting an assortment of ion channels and receptors
What do the peptide toxins from cone snails do?
incapacitate the prey, allowing the snail to reel it in and swallow it
Talk about the toxins cone snails produce?
Each species of cone snail produces a unique range of toxins. They are all small, compact peptides with cysteine bridges that give them stability. The toxins are named after the species and the target:
- Alpha (a) conotoxins target nicotinic receptors
- E.g. a conotoxin M1 (from C. magnus)
- Omega (w) conotoxins target calcium channels
- w conotoxin G VIA (from C. geographus)
- w conotoxin M VIIC (from C. magnus)
What are Elapids?
Elapids are hollow-fanged snakes that inject their victims with large quantities of venom.
What are elapid venom glands?
The venom glands are modified salivary glands and usually contain a number of peptide toxins. These toxins have a variety of functions
What are some functions elapid toxins have?
Some are enzymes that serve to ‘predigest’ the prey while others target the heart. Some toxins also target the nervous system and incapacitate the prey
What does a cobra toxin do?
71 amino acid peptide. It is an almost irreversible antagonist of muscle nicotinic acetylcholine receptors and binds to the same site as ACh itself. This causes the prey to become paralysed
How does the cobra avoid paralysing itself with its venom?
the cobra nAChR has a glycosylation site positioned such that it blocks the binding of the large size cobra toxin but not the much smaller ACh
What else is resistant to cobratoxin and why?
The mongoose is also resistant to cobratoxin.. The mongoose nAChR is also glycosylated near the ACh binding site.
What do Kimson weed and deadly nightshade produce and what are some examples of these?
Kimson weed and deadly nightshade produce a range of alkaloids that are antagonists at muscarinic AChR. Examples include the structurally related compounds atropine and hyoscine (also known as scopolamine)
What family do both Kimson weed and deadly nightshade belong to?
Both plants belong to the Solanaceae family which also includes tobacco, potato, tomato and peppers. Although many members of this family are used as foods by humans, many produce or are capable of producing highly toxic alkaloids.
what do atropine and hyoscine do?
block muscarinic receptors in the parasympathetic nervous system so are sometimes called ‘parasympatholytics.’ This produces a range of symptoms including increased heart rate, dilated pupils, dry mouth and blurred vision
What do actions at the CNS muscarinic receptors do?
can cause balance problems, hallucinations, convulsions and memory loss
What are the therapeutic uses of atropine?
- Atropine is used in eye examinations to dilate the pupil, which is where the plant Atropa belladonna gets its name from – it was used by women in the renaissance to dilate their pupils and make them look sexually aroused
- Atropine is also used to treat bradycardia and to reduce respiratory tract secretions during surgery.
- As it reduces sweating atropine is sometimes given to people who suffer from hyperhidrosis (excess sweating)
What are the therapeutic and non therapeutic uses of hyoscine?
- Hyoscine is mostly used to treat motion sickness – it is the active ingredient of Kewllls, or IBS – it is the active ingredient of Buscopan
- Hyoscine’s CNS effects have led to it being used in roberries and rapes to incapacitate the victim
- Unlike benzodiazepine based date-rape drugs, hyoscine does not render victims unconscious but instead places them into a trance like state in which they have little free will.
What does mamba venom contain?
a number of different peptide components known as dendrotoxins.
What do different dendrotoxins do?
- Some dendrotoxins target voltage gated potassium channels, which can lead to a range of effects on the nervous system and block of neuromuscular transmission.
- In addition, some dendrotoxins block muscarinic receptors.
- The mambas also posses a toxin called fasciculin which is a potent inhibitor of acetylcholinesterase
Where else apart from animals are acetylcholinesterase inhibitors found?
plants
What does inhibiting Acetylcholine esterase do?
boost the levels of ACh in the synapse, resulting in overstimulation of ACh receptors
What does Poisoning with Calabar beans (physostigmine) a plant acetylcholinesterase inhibitor do?
results in neuromuscular block (paralysis), seizures, loss or bladder and bowel control and eventually death by asphyxiation.
What is the difference between the nerve gas sarin and Acetylcholinesterase?
The main difference is that sarin is an irreversible inhibitor of AChE but physostigmine is reversible
What has Physostigmine used to treat?
myasthenia gravis and glaucoma. It has also been tested in Alzheimer’s disease, as have huperzine A and galantamine.
• However, AChE inhibitors only have a marginal effect in Alzheimer’s and coupled with their numerous side effects, some healthcare organisations have advised against their use.
What does the fact that cholinergic antagonists and inhibitors have opposite effects on transmission mean?
They can be used as antidotes for each-other
What is the Botulinum toxin produced by?
the anaerobic bacterium Clostridium botulinum. It is most commonly a problem due to improperly canned food and badly prepared sausage
How does the Botulinum toxin work?
Botulinum toxin as actually a group of 7 different proteolytic enzymes (BoNT A-G). They act by cleaving the SNARE proteins (synaptobrevin, syntaxin and SNAP-25) that are needed for neurotransmitter containing vesicles to fuse with the cell membrane. This means that chemical signalling cannot take place
Why will botox relax muscles if locally injected into them and so what can it be used to treat?
Because botox prevents the release of ACh at skeletal neuromuscular junctions, it will relax muscles if injected locally into them. This can have therapeutic (muscle spasm treatment) and cosmetic benefits (smoothing of wrinkles)
When will Botox prove fatal and why?
If botox gets into the systemic circulation it will rapidly prove fatal due to its ability to shut down chemical signalling throughout the peripheral nervous system
