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Drugs: From Molecules to Man - Lecture 9 (26/02/2018)

*HD1* (Toxins Targetting Cholinergic Transmission)
 Plant Defence toxins:
 Nicotinic agonists, Antagonists.
 Muscarinic antagonists and their therapeutic applications.
 Cholinesterase inhibitors and their therapeutic applications.
 Animal Paralytic toxins:
 Cobra toxin, conotoxins: nicotinic receptor antagonists.
 Dendrotoxin: muscarinic receptor antagonist.
 Animal Defence toxins:
 Epibatidine: nicotinic receptor agonist.
 Botulinum toxin: SNARE proteins

Pharmacognosy - The study of drugs from natural sources.

Cholinergic Transmission

There are nAChR and mAChR located in the CNS. Instead of being just postsynaptic receptors directly involved in transmission, many of these CNS receptors are instead involved in neuromodulation - often by regulating the release of other neurotransmitters.

What makes things even more complex is that the subtypes nAChR or mAChR present in these different tissues can vary: there are neuromuscular junction nicotinic receptors and autonomic ganglia nAChR.

The mAChR in the ANS are different to those located in the brain and so this means that drugs targeting nAChR and mAChR may have different effects in each of these different tissues.


Plant Defence Toxins

Although some plants depend on animals for the dispersal of their seeds, most find it an evolutionary advantage to deter insects and animals from eating their foliage.

Unpleasant tasting, or toxic substances can achieve this goal.

Interestingly, the most common strategy seems to be the targeting of cholinergic transmission. However, this can probably be explained by the fact that cholinergic systems are very important in both vertebrates and invertebrates. Tobacco

Probably the most widely consumed and best-known plant toxin is Nicotine.

Nicotine is highly toxic to humans as it activates nAChR in the autonomic ganglia.
Tobacco pickers can absorb enough through their skin, if the plants are wet, to suffer from this effect, giving them 'green tobacco sickness'.

However, at lower doses, and providing it can be delivered in a way that will bypasses the liver metabolism, Nicotine can have pleasurable/addictive effects in the CNS.

Nicotine is also a very effective insecticide, and probably one of the reasons why tobacco evolved the ability to make this alkaloid.

Laburnum (Cytisine)

Laburnum is a very distinctive plant and is also known as 'golden rain'. Its seed pods look very much like pea pods and therein lies the danger, as its very tempting to children.

The toxic principal in laburnum is Cytisine (not to be confused with Cytosine).

This drug is a potent agonist at the ganglionic nAChR and CNS subtypes, but is not so potent at the muscle nAChR.

It causes a variety of nasty effects such as Tachycardias, Diarrhea, Convulsions and a
Coma as well as the possibilities of it being fatal.

It can be used as a smoking cessation aid but is expensive in the UK and no better than cheaper alternatives like Nicotine and Varenicline.

Laburnum trees are so toxic that kittens have died after using them as scratching posts.

Curare Alkaloids (Tubocurarine)

Whilst Cytisine is a nicotinic agonist, other plants have adopted a different strategy and make nicotinic antagonists.
The best-known example is Tubocurarine, the main component of Curare.
(Curare refers to the 'arrow poison' and is not a chemical name in itself.)

Curare is prepared from the plant S.toxifera and is used to coat arrows and blow gun darts by South American native people, such as the Huaroani. They used it to hunt animals that live in dense forests. The animals could be eaten as the Curare molecule is too large to be ingested.

Tubocurarine is a potent antagonist at the muscle nAChRs and it interrupts neuromuscular transmissions, causing a flaccid paralysis. In the past, Tubocurarine was used as a surgical paralytic agent, to stops unwanted movements and gagging reflexes, but it has too many side effects and has now been replaced by safer drugs.

Definition of an alkaloid is that its a nitrogen-containing compound of plant origin.

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