Week 2: Cholinergic Drugs I Flashcards
Where does ACh act?
It acts at the pre/postganglionic nerve connections in all nerves
It primarly acts at parasympathetic postganglionic nerve endings that contact cardiac and smooth muscle, gland cells, and nerve terminals.
It also acts at sympathetic sweat gland endings and the ends of somatic nerve connections (although these nerves are direct, without ganglionic connections)
What is the effect of blocking ACh receptors?
Decrease both parasympathetic and sympathetic tone (ACh acts on both parasymp and symp nerve connections in the ANS)
What NTs stimulate blood vessels?
NE can act on nicotinic alpha receptors via the sympathetic pathway to help blood vessels constrict, thereby increasing blood pressure
ACh receptors in blood vessels also exist, which stimulate the release of NO and cause vasodilation, thereby decreasing blood pressure
How is ACh synthesized? How is it broken down?
AChE in the synaptic cleft breaks down ACh into choline and acetate
Choline from the cleft is taken back up into the presynaptic nerve, and reacts with Acetyl-CoA to form ACh. Choline acetyltransferase (ChAT) catalyzes this formation.
What are the terms for drugs that mimic, block, or enhance the effects of cholinergic receptors?
Mimic = Agonist
Block = Antagonist
Enhance = Potentiator
What kinds of receptors are muscarinic receptors? What is their duration of action like?
Muscarinic receptors are G-protein coupled receptors (GPCRs). There are 5 subtypes, and three of the major ones are:
“Grand Mal Seizures”
M1 - ganglia of the PNS/CNS, Gq that increases Ca2+
M2 - heart, Gi that decreases cAMP and inc. K+ conductance (muscle hyperpolarization, less able to transduce nerve signal)
M3 - smooth muscle, glands, Gq that increases Ca2+
They have a long activation phase but also a long duration of action
What is a nicotinic receptor? What are it’s activation and action phases like?
A cationic ion channel that is activated by ACh
It has a fast onset but a short duration of action.
What are the effects of ACh on the
Eye
Heart
BVs
Lung
GI tract
Urinary bladder
Glands
Eye = contraction of pupils (miosis) for near vision
Heart = action on SA node, decrease in HR, action on AV node, decrease in conduction velocity
BVs = dilation of BVs via NO
Lung = bronchoconstriction, and stimulation of secretions
GI tract = increased motility, relaxed sphincters, stimulation of HCl secretion
Urinary bladder = contraction, relaxation of the sphincter
Glands = increased sweat, salivation, lacrimal gland secretions
What are the two major binding elements of ACh?
The quaternary nitrogen (positive charge) and the carbonyl oxygen (negative charge)
How can ACh act on both nicotinic and muscarinic receptors?
In one rotational conformation, it has the same distance between reactionary molecule elements as muscarine (4.4A). If you rotate it around the linear bond molecules, it can also have the same length between major reactionary molecule elements as nicotine (5.9A)
What side effect do we deal with most consistently when it comes to drugs?
Large, bulky antagonists can often have molecular elements that fit into and block the activity of muscarinic receptors. Anti-muscarinic side effects, therefore, are one of the most common side effects of bulky antagonist drugs.
Why can ganglia and NMJ ACh receptors both be activated by ACh, but a blocker for ganglia cannot block NMJ and vice versa?
Both contain the 5.9A-separated binding sites for ACh, so acetylcholine can bind to both ganglionic and NMJ receptors.
However, the blocking site for ganglia receptors has a 6C gap that can only be occupied by specific blockers for that length.
The blocking site for NMJ receptors has a 10Cgap that can only be occupied by specific blockers for that length, thus the two cannot block one anothers’ active sites.
What are the major muscarinic agonists to know? Why might they be preferable to ACh as agonists?
MBC
Methacholine - more specific for muscarinic sites, beta-methyl group prevents hydrolysis, used as a diagnostic tool to differentiate asthma from COPD
Bethanechol - used to treat iliac paralysis, activate smooth movement in GI tract after surgery, methyl group prevents hydrolysis
Carbachol - terminal NH2 prevents hydrolysis, positively charged so it cannot be absorbed well, used to treat glaucoma
What are the two major nicotinic agonists?
Acetylcholine and nicotine
What are the muscarinic antagonists and what are their effects? What are the two names for them?
Anti-muscarinic and anti-cholinergic drugs are synonymous for drugs that block muscarinic sites
“ACH”
Atropine - competitive antagonist for ACh at muscarinic sites, prevents bradycardia and reduces bronchiolar/salivary secretions prior to surgery
Curare - a competitive antagonist for ACh at muscarinic somatic muscle sites, a muscle relaxant used in general anesthesia that prevents muscular contraction
Homatropine - rapid-acting anti-muscarinic drug used for eye exams, eye drops to dilate pupils
Scopolamine - atropine analog, treats motion sickness
Ipratropium/tiotropium - quaternary nitrogen means it cannot pass through membrane (charge), prevents bronchoconstriction
Glycopyrronium - nonpolar, can be taken orally, treats excessive sweating (Qbrexza)
