Source: Chapter 8, Lecture slides
Tags: pharmacology, Paracelsus, tetrodotoxin, TTX, blood-brain barrier, saxitoxin, batrachotoxin, cocaine, local anesthetic, nicotinic receptor, muscarinic receptor, atropine, botulinum toxin, LD-50, psychoactive drugs, voltage-gated sodium channel
This chapter covers the principles of pharmacology, focusing on how toxins and drugs interact with the nervous system. Key topics include neurotoxins that block or keep open voltage-gated sodium channels (TTX, saxitoxin, batrachotoxin), the blood-brain barrier, acetylcholine receptor subtypes, and the concept that dose determines whether a substance is a poison or a medicine.
Drug
A chemical that in small amounts has a significant effect on body function.
Pharmacology
The scientific study of drugs: their origins, compositions, and effects on the body. The term derives from the Greek word pharmakon, which means both medicine and poison simultaneously.
Paracelsus
A 16th-century Swiss physician and alchemist. Taught that all substances are poison, and that whether something acts as a poison or a medicine depends on the dose.
Tetrodotoxin (TTX)
One of the most poisonous substances known. Contains many polar "OH" groups. Found in pufferfish, salamanders/newts, octopus, crabs, and starfish. Because it appears in many unrelated species, it is believed to originate from a microorganism living within the animals rather than being synthesised by them directly.
TTX blocks voltage-gated Na⁺ channels by sticking to the outside surface and plugging the pore. Even a small amount is highly poisonous. Death from TTX occurs by respiratory paralysis and suffocation.
Two notable features of TTX poisoning: the heart does not stop beating (cardiac Na⁺ channels are resistant to TTX), and the brain is not affected (TTX cannot cross the blood-brain barrier).
Blood-brain barrier (BBB)
The way blood vessels in the CNS are constructed to regulate passage of material between blood and brain. The cells forming blood vessel walls in the CNS are tightly joined with no gaps, pores, or holes.
Two ways to cross the BBB:
Via transporter proteins that shuttle specific molecules across
By dissolving directly through the blood vessel cell walls (requires lipophilicity)
All known drugs that affect brain function cross the BBB because they are lipophilic enough to dissolve through the barrier cells.
TTX resistance
Animals containing TTX are not poisoned by it because their voltage-gated Na⁺ channels (particularly cardiac channels) are resistant to TTX blocking. Even small changes in the primary structure of the Na⁺ channel protein can dramatically reduce TTX sensitivity.
Saxitoxin (STX)
A toxin produced by dinoflagellates and other protists. Blocks voltage-gated Na⁺ channels in a manner similar to TTX. Does not cross the blood-brain barrier.
Humans are most commonly exposed via consumption of contaminated shellfish. The resulting condition is called paralytic shellfish poisoning (PSP). Symptoms: numbness, muscle weakness, paralysis, potentially death from respiratory paralysis. A bigger problem for whales and marine animals than for humans.
Batrachotoxin (BTX)
Found in the skin secretions of certain tropical frogs. Unlike TTX and STX (which block the pore), batrachotoxin prevents voltage-gated Na⁺ channels from closing. If channels stay open continuously, Na⁺ flows through without interruption, action potentials cannot fire, and nerve signalling fails. The end result (paralysis, respiratory failure) is the same as with TTX and STX, but the mechanism is opposite.
Cocaine
The first local anaesthetic chemical recognised by modern medicine. Derived from the coca plant (Erythroxylum coca) of South America.
Local anaesthetic
A substance that blocks nerve signalling in a localised area, preventing sensation (especially pain) without affecting consciousness. Cocaine was the first such substance identified.
Nicotinic acetylcholine receptor (nAChR)
An ionotropic acetylcholine receptor. Activated by nicotine, blocked by tubocurarine.
Muscarinic acetylcholine receptor (mAChR)
A metabotropic acetylcholine receptor. Activated by muscarine, blocked by atropine.
Atropine
An anticholinergic (parasympatholytic) drug derived from the Atropa belladonna plant. Blocks muscarinic acetylcholine receptors. Uses include treating heart rhythm problems, stomach/bowel problems, certain types of poisoning, reducing saliva before surgery, and dilating pupils for eye exams.
Botulinum toxin (Botox)
Produced by the bacterium Clostridium botulinum. Causes local paralysis in the injected area by blocking acetylcholine effectiveness at the neuromuscular junction.
LD-50
The lethal dose required to kill 50% of a test population. A standard measure of toxicity.
Top five psychoactive drugs (by global usage)
Caffeine
Alcohol
Tobacco
Arecoline
Cannabinoids
Paracelsus's principle: all substances are potentially poisonous; whether they act as poison or medicine depends on dose
Pharmacology literally means the study of substances that are both medicine and poison
Three major toxins, three different mechanisms, same ultimate effect (paralysis and potential death by respiratory failure):
TTX (tetrodotoxin): blocks the Na⁺ channel pore from the outside
STX (saxitoxin): also blocks the Na⁺ channel pore, similar to TTX
BTX (batrachotoxin): prevents the Na⁺ channel from closing, causing continuous Na⁺ flow
All three prevent normal action potential firing, causing nerve signalling failure.
CNS blood vessel walls have no gaps between cells
Only two methods of crossing: specific transporter proteins, or being lipophilic enough to dissolve through cell membranes
TTX and STX do not cross the BBB (polar molecules), so the brain is not directly affected
Drugs that affect brain function must be lipophilic
Nicotinic (ionotropic): activated by nicotine, blocked by tubocurarine
Muscarinic (metabotropic/GPCR): activated by muscarine, blocked by atropine (from Atropa belladonna)
Both types are acetylcholine receptors in the autonomic nervous system, but they respond to different agonists and antagonists
Produced by Clostridium botulinum
Blocks ACh release at the neuromuscular junction
Clinical use (Botox): controlled local paralysis
⚠️ Know the three neurotoxins and their distinct mechanisms at voltage-gated Na⁺ channels: TTX and STX block the pore, BTX prevents channel closing.
⚠️ Understand why TTX does not affect the brain (cannot cross the BBB) and why the heart keeps beating (cardiac Na⁺ channels are resistant).
⚠️ Know the two routes across the blood-brain barrier (transporter proteins, lipophilic dissolution).
⚠️ Be able to distinguish nicotinic (ionotropic) from muscarinic (metabotropic) ACh receptors, and know their agonists and antagonists.
⚠️ LD-50 is the dose lethal to 50% of a test population.
⚠️ Paracelsus's principle: the dose determines whether a substance is poison or medicine.
Q: How does tetrodotoxin (TTX) affect neurons?
A: TTX binds to the outside surface of voltage-gated Na⁺ channels and blocks the pore, preventing Na⁺ ions from passing through. This stops action potentials from firing, leading to paralysis and potentially death by respiratory failure.
Q: Why does the heart continue beating during TTX poisoning?
A: The voltage-gated Na⁺ channels in the heart are resistant to TTX blocking due to small differences in their primary protein structure.
Q: How does batrachotoxin differ from TTX in its mechanism?
A: TTX blocks the Na⁺ channel pore (prevents it from opening effectively). Batrachotoxin prevents the channel from closing, causing continuous Na⁺ flow. Both prevent normal action potentials, but by opposite mechanisms.
Q: What are the two ways a substance can cross the blood-brain barrier?
A: Via specific transporter proteins that shuttle molecules across the blood vessel wall cells, or by being lipophilic enough to dissolve directly through the cell membranes.
Q: What is the difference between nicotinic and muscarinic acetylcholine receptors?
A: Nicotinic receptors are ionotropic (ligand-gated ion channels), activated by nicotine, blocked by tubocurarine. Muscarinic receptors are metabotropic (GPCRs), activated by muscarine, blocked by atropine.
Q: What is LD-50?
A: The dose of a substance required to kill 50% of a test population. It is a standard measure of how toxic a substance is.
Drug, pharmacology, pharmakon, Paracelsus, dose-response, tetrodotoxin, TTX, pufferfish, voltage-gated sodium channel, blood-brain barrier, BBB, lipophilic, saxitoxin, STX, paralytic shellfish poisoning, PSP, dinoflagellate, batrachotoxin, BTX, poison dart frog, cocaine, local anaesthetic, Erythroxylum coca, nicotinic receptor, muscarinic receptor, ionotropic, metabotropic, acetylcholine, nicotine, muscarine, tubocurarine, atropine, Atropa belladonna, botulinum toxin, Botox, Clostridium botulinum, LD-50, psychoactive drugs, caffeine, alcohol, tobacco, arecoline, cannabinoids, MCB C61, UC Berkeley