Week 2: Cholinergic Drugs II Flashcards
Where might nicotinic antagonists be used?
Ganglia and NMJ
What is curare? Where does it act and by what mechanism?
D-tubocurarine, or curare is an anti-cholinergic (nicotinic) muscle relaxant that is commonly used in general anesthesia
Curare blocks nicotinic receptors that activate depolarizing ion channels at the motor end plate so that no action potential can be generated, and muscles cannot contract
What is hexamethonium? Where does it act and what is it’s general purpose? What issue does it cause?
“NiH”
Hexamethonium (remember it is a ganglionic blocker because of C6, hexa) is a nicotinic antagonist is used to significantly lower blood pressure when it is excessively high–acts on the ganglia and on the adrenal medulla
The issue is that while it blocks sympathetic BV tone, it also acts on nicotinic receptors at para/sympathetic ganglia, deactivating smooth and cardiac muscle, sweat glands, and somatic muscle. By blocking these nicotinic receptors, you will be blocking whatever system (para/symp) is more active at the time.
What is one of the main mechanisms by which acetylcholine’s effects are potentiated?
Blocking of the AChE in the synaptic cleft, allowing ACh to remain in the cleft and continue to act there.
What are the two forms of AChE?
Acetylcholinesterase, found at synapses and in RBCs - only degrades ACh
and
Butyrylcholinesterase, found in plasma and is a nonspecific esterase (will degrade any ester bonds), including cocaine and other esterified molecules
What are the steps by which AChE works?
See photo
What kinds of drugs inhibit AChE?
Carbamylated drugs (carbamic acid)
What are the major forms of AChE inhibitors? What group prevents the action of AChE, and what disease do they treat?
Physostigmine - formerly used for glaucoma treatment
Neostigmine - used to overcome curare blockade
Rivastigmine - Alzheimer’s treatment
Donepezil (Aricept) - Alzheimer’s treatment
All of the above have a bulky R-N-R group that prevents water from nucleophilically attacking the carboxyl group on the molecule
Edrophonium - a reversible, non-carbamic acid derivative used to reverse curare blockade after surgery
Why are AChE inhibitors not 100% effective in treating Alzheimer’s?
While the AChE inhibition is continuously useful, it doen’t prevent the degradation of nerves that is characteristic of Alzheimer’s patients
What is edrophonium and what is it’s function? What other drug is commonly given with edrophonium to reverse muscle relaxation, and why?
Edrophonium is a short-acting AChE blocker that is used to reverse the effects of curare
You would give an anti-muscarinic/cholinergic drug (like atropine) to block the exacerbation of ACh at muscarinic sites
What is an example of a few organophosphates? What is their function and mechanism of action?
Parathion, malathion, VX and Sarin are organophosphates, which are STRONG muscarinic potentiators. They accomplish this by blocking AChE.
The bulky and stable phosphate group cannot be nucleophilically attacked by water, so they cannot be easily unbound from muscarinic (cholinergic) binding sites, thereby inactivating AChE
Why are parathion and malathion used as herbicides and insectisides? Why are they so dangerous?
ACh is extremely evolutionarily conserved (i.e. in plants, insects, etc.) and showed up well before other signaling molecules (like dopamine, seratonin, etc.)
Thus, anticholinergic organophospates like these can kill weeds and insects, but also have significant adverse effects on humans, causing nerve damage, seizures, and even death
What are common chemical warfare agents and why are they similar to anticholinergic drugs? What symptoms are commonly seen with these agents?
Organophosphates like sarin, VX, and mustard gas are AChE blockers like parathion and malathion that prevent AChE activity, and thus leave ACh in the synaptic cleft.
Symptoms include:
Seizures, vomiting, bradycardia, suffocation, respiratory paralysis, bronchoconstriction, salivation and runny nose (can “drown in your own fluids”), sweating, hypotension
Death can occur within three minutes
How can the administration of toxic chemical warfare agents be treated?
Atropine administration, which blocks the effects of acetylcholine
Pralidoxime, which breaks the bond between the nerve agent and AChE (the oxime is HIGHLY nucleophilic)
Where do muscarinic receptors exist, what are the three forms, and what acts on them?
They exist in the nerve, heart, and glands
They are activated by ACh, methacholine (used to differentiate asthma from COPD), carbachols (eye drops to treat glaucoma), and bethanechol (use to regenerate GI motility after surgery)
Act on M1 (Gq), M2 (Gi) and M3 (Gq) receptors
