HPDM 1 - toxins targeting cholinergic synapses

Question 1

What is Pharmacognosy?

Answer 1

The knowledge of drug from natural sources

Question 2

What cholinergic synapses does the brain, autonomic ganglia and skeletal neuromuscular junction contain?

Answer 2

• The brain contains nAChR and mAChR
• Autonomic ganglia contain nAChR
• The skeletal neuromuscular junction contains nAChR

Question 3

What are many of the CNS receptors involved in and how?

Answer 3

many of the CNS receptors are involved in neuromodulation – often by regulating the release of other neurotransmitters.

Question 4

What varies depended on where they are located with the acetylcholine receptors?

Answer 4

Their subtypes

Question 5

What is acetylcholinesterase?

Answer 5

The enzyme that terminates signalling by breaking down acetylcholine

Question 6

What do Snare proteins do?

Answer 6

mediate fusion of acetylcholine containing vesicles with the membrane

Question 7

Are acetylcholine receptors only postsynaptic?

Answer 7

No they can be presynaptic too

Question 8

What can the fact that one of the most common toxin targets is to target cholinergic transmission be explained by?

Answer 8

explained by the fact that cholinergic systems are very important in both vertebrates and invertebrates

Question 9

Where is nicotine found?

Answer 9

In the tobacco plant

Question 10

Is nicotine an agonist or antagonist and at what receptors?

Answer 10

Nicotine is an agonist at mammalian and insect nicotinic acetylcholine receptors and deters predators from eating tobacco

Question 11

Which other plants is nicotine found in?

Answer 11

• Nicotine is also found at lower concentrations in a wide range of plants related to tobacco:

• Aubergines
• Tomatoes
• Pepper and chilli plants
• Potatoes

Question 12

How are humans unusual in regard to nicotine?

Answer 12

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

Question 13

What is Ladburnum?

Answer 13

• 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’

Question 14

What is the toxic principle in ladburnum?

Answer 14

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

Question 15

What was Epibatidine isolated from?

Answer 15

the Phantasmal frog

Question 16

Is Epibatidine an agonist or antagonist and where does it target?

Answer 16

Epibatidine is a very potent agonist at neuronal nicotinic receptors and also has some muscarinic receptor activity.

Question 17

What is tubocuranine?

Answer 17

the main alkaloid component of curare

Question 18

What plant does Curare come from?

Answer 18

S. Toxifera

Question 19

Is Tubocuranine an agonist or antagonist, where and what does this mean?

Answer 19

Tubocurarine is a potent antagonist at muscle nAChRs and so interrupts neuromuscular transmission causing a flaccid paralysis

Question 20

How was tubocuranine used in the past?

Answer 20

as a surgical paralytic agent but it had too many side effects

Question 21

Why can’t TC by absorbed from the GI tract and where can it exert its toxic effect?

Answer 21

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

Question 22

What are cone snails?

Answer 22

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.

Question 23

What does each species of cone snail have?

Answer 23

an array of toxins in its venom, targeting an assortment of ion channels and receptors

Question 24

What do the peptide toxins from cone snails do?

Answer 24

incapacitate the prey, allowing the snail to reel it in and swallow it

Question 25

Talk about the toxins cone snails produce?

Answer 25

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)

Question 26

What are Elapids?

Answer 26

Elapids are hollow-fanged snakes that inject their victims with large quantities of venom.

Question 27

What are elapid venom glands?

Answer 27

The venom glands are modified salivary glands and usually contain a number of peptide toxins. These toxins have a variety of functions

Question 28

What are some functions elapid toxins have?

Answer 28

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

Question 29

What does a cobra toxin do?

Answer 29

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

Question 30

How does the cobra avoid paralysing itself with its venom?

Answer 30

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

Question 31

What else is resistant to cobratoxin and why?

Answer 31

The mongoose is also resistant to cobratoxin.. The mongoose nAChR is also glycosylated near the ACh binding site.

Question 32

What do Kimson weed and deadly nightshade produce and what are some examples of these?

Answer 32

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)

Question 33

What family do both Kimson weed and deadly nightshade belong to?

Answer 33

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.

Question 34

what do atropine and hyoscine do?

Answer 34

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

Question 35

What do actions at the CNS muscarinic receptors do?

Answer 35

can cause balance problems, hallucinations, convulsions and memory loss

Question 36

What are the therapeutic uses of atropine?

Answer 36

• 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)

Question 37

What are the therapeutic and non therapeutic uses of hyoscine?

Answer 37

• 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.

Question 38

What does mamba venom contain?

Answer 38

a number of different peptide components known as dendrotoxins.

Question 39

What do different dendrotoxins do?

Answer 39

• 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

Question 40

Where else apart from animals are acetylcholinesterase inhibitors found?

Answer 40

plants

Question 41

What does inhibiting Acetylcholine esterase do?

Answer 41

boost the levels of ACh in the synapse, resulting in overstimulation of ACh receptors

Question 42

What does Poisoning with Calabar beans (physostigmine) a plant acetylcholinesterase inhibitor do?

Answer 42

results in neuromuscular block (paralysis), seizures, loss or bladder and bowel control and eventually death by asphyxiation.

Question 43

What is the difference between the nerve gas sarin and Acetylcholinesterase?

Answer 43

The main difference is that sarin is an irreversible inhibitor of AChE but physostigmine is reversible

Question 44

What has Physostigmine used to treat?

Answer 44

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.

Question 45

What does the fact that cholinergic antagonists and inhibitors have opposite effects on transmission mean?

Answer 45

They can be used as antidotes for each-other

Question 46

What is the Botulinum toxin produced by?

Answer 46

the anaerobic bacterium Clostridium botulinum. It is most commonly a problem due to improperly canned food and badly prepared sausage

Question 47

How does the Botulinum toxin work?

Answer 47

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

Question 48

Why will botox relax muscles if locally injected into them and so what can it be used to treat?

Answer 48

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)

Question 49

When will Botox prove fatal and why?

Answer 49

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