parasympathetic nervous system Flashcards
muscarinic receptor antagonists: identify and explain the clinical uses and pharmacokinetic properties of muscarinic receptor agonists
what can replicate muscarinic effects
muscarine (selective agonist of mAChR)
at low doses, what can abolish muscarinic effects
antagonist atropine
what branch of PNS do muscarinic actions correspond to
PSNS
after atropine blockade of muscarinic actions, what can larger doses of ACh induce effects similar to
those caused by nicotine (more ACh required to stimulate nAChR)
where are muscarinic receptors found
in PSNS at effector organ; in SNS at effector organ of sweat gland
where are nicotinic receptors found
in between pre and post ganglion in ANS (pre: long and post: short in PSNS; pre: short and post: long in SNS); at skeletal muscle after motor neurone in somatic
3 main subtypes of muscarinic receptor and location; general property of muscarinic receptors
M1: salivary glands, stomach parietal cells, CNS; M2: heart (if vagus activated); M3: salivary glands, bronchial/visceral smooth muscle; sweat glands; eye [M4 and M5 in CNS]; generally muscarinic are excitatory (M2 is inhibitory)
what receptor are muscarinic receptors
G-protein coupled receptor
what G-protein coupled receptor (type 2) is M1, M3 and M5, and what are the secondary messengers
Gq (stimulatory); IP3 DAG (upregulate)
what G-protein coupled receptor (type 2) is M2 and M4, and what is the secondary messenger
Gi (inhibitory) cAMP (reduced production)
what type of receptor are nicotinic receptors
ligand gated ion channels (type 1)
what subunits can be present in nicotinic receptors
α β γ δ ε
in nicotinic receptors, what does subunit combination determine
ligand binding properties
nicotinic receptor: muscle type in NMJ in somatic nervous system
2α β δ ε
nicotinic receptor: ganglion type in ANS
2α 3β (similar to CNS but tend to be pre-synaptic)
strength of ACh effects in nicotinic receptors
relatively weak, so higher concentration required; most reponse is a Na+ influx so excitatory
muscarinic cholinergic target systems
eye, salivary glands, sweat glands, lungs, heart, gut, bladder, vasculature
3 muscarinic effects in eye and purpose
contraction of ciliary muscle (allowing lens to bulge so more convex, accomodating near vision), contract sphincter pupillae (constrict pupil (miosis) and improves drainage of intraocular fluid), lacrimation (tears)
how does contraction of sphincter pupillae reduce intraocular pressure and thus the risk of glaucomas
opens pathway for aqueous humour (produced by ciliary bodies), allowing it to bathe lens and cornea (nutrients and oxygen), and allowing drainage via the canals of Schlemm; in glaucomas, iris becomes ruffled, so rate of drainage decreases due to channel occlusion, increasing intraocular pressure and causing blindness (cholinomimetic drugs flatten iris, increasing rate of drainage again)
2 muscarinic effects in heart
decreased cardiac output (as decreased atrial contraction), decreased heart rate (bradycardia)
how does ACh cause decreased cardiac output (negative inotropic effect)
binds to M2 AChR in atria and nodes (SAN and AVN) -> downregulates cAMP -> decreases Ca2+ entry
how does ACh cause decreased heart rate (negative chronotropic effect)
binds to M2 AChR in atria and nodes (SAN and AVN) -> downregulates cAMP -> increases K+ efflux
how do muscarinic effects decrease TPR in vasculature
most have no PSNS innovation, so ACh binds to M3 AChR on vascular endothelial cells to stimulate NO generation and release -> NO induces vascular smooth muscle relaxation (vasodilation)
effect of muscarinic effects causing decreased heart rate, cardiac output and vasodilation on blood pressure
sharp drop
muscarinic effects of non-vascular smooth muscle that does have PSNS innovation: lung, gut and bladder
opposite so contracts (excitatory): lung: bronchoconstriction; gut: increased peristalsis and motility; bladder: increased emptying
4 muscarinic effects in exocrine glands: salivary, bronchial, GI and sweat
salivation, increased bronchial constriction, increased GI secretions (incl. gastric HCl production), increased SNS-mediated sweating
symptoms of muscarinic effects
decrease heart rate and BP, increase sweating, difficulty breathing, bladder contraction, GI pain (contraction of smooth muscle), increased salivation and tears
2 typical agonists at muscarinic receptors (directly acting cholinomimetic drugs)
choline esters e.g. bethanechol; alkaloids e.g. pilocarpine
2 examples of muscarinic receptor antagonists
atropine, hyoscine (very similar structures)
physiological responses influenced by muscarinic receptor antagonists
PSNS innervation, so influences: constriction of pupil, ciliary muscle, trachea and bronchioles, contraction of detrusor and relaxation of trigone and sphincter, copious and watery secretions, decreased heart rate and contractility, increased GI motility, tone and secretions; SNS innervation: increased sweating [limits/inhibits/does opposite of all of these]
CNS effect of atropine at normal dose
little effect
CNS effects of atropine at toxic dose
mild restlessness and agitation (less M1 selective, CNS excitation)
CNS effects of hyoscine at normal dose
depressive effect so sedation, amnesia
CNS effects of hyoscine at toxic dose
CNS depression or paradoxical CNS excitation (associated with pain) due to greater permeation into CNS and brain as passes through BBB more readily, or more M1 selective (influence at therapeutic dose)
opthalmic clinical uses of muscarinic receptor antagonist tropicamide
examination of retina (dilation) by paralysing cilliary muscle in iris
anaesthetic clinical uses of muscarinic receptor antagonists
blocks constriction of trachea and bronchioles (dilates if inhaling anaesthetic); blocks copious, watery secretions (prevents secretions going back down airways); blocks low heart rate and contractility (protect against slowing effects of other drugs); sedation (hyoscine)
neurological clinical uses of muscarinic receptor antagonists
motion sickness due to cholinergic sensory mismatch (eyes saying one thing, labyrinth saying another; cholinergic nerve to vomiting centre and induces nausea); treated with hyoscine patch (controls eye movements to maintain vision whilst in motion so no mismatch)
Parkinson’s disease clinical uses of muscarinic receptor antagonists
loss of dopaminergic neurones from substantia nigra to striatum (less dopamine binding to D1 so less fine muscle movement from basal ganglia); dopamine produced at lower level so D1 not sufficiently stimulated; M4 receptors suppress D1 receptors to provide control, so by antagonising M4 receptor it becomes blocked, so D1 receptor becomes more responsive even though less dopamine produced, so cholinergic/dopaminergic more balanced in basal ganglia, reducino Parkinson’s symptoms
respiratory clinical uses of muscarinic receptor antagonists
asthma/obstructive airways disease by blocking constriction of trachea and bronchioles; atropine (typical) and ipratropium bromide (specific to asthma as attempt to localise effect to lungs to reduce side effects: N+ so polar so less likely to cross lipid membranes)
GI clinical uses of muscarinic receptor antagonists
irritable bowel syndrome by being M3 receptor antagonist (selective to reduce side effects); blocks increased GI motility, tone and secretions
4 unwanted effects of muscarinic receptor antagonists
decreased sweating and thermoregulation so very hot; decreased secretions so very dry; cycloplegia (paralysis of the ciliary muscle causing loss of lens curvature and near vision) so blind; CNS disturbance and agitation
