Drugs and the parasympathetic nervous system Flashcards
List the poisoning symptoms of amanita muscaria (mushroom)
Increased salivation, excessive sweating, lacrimation, bronchial secretions, bronchoconstriction, bradycardia, hypotension, miosis (papillary constriction), blurred vision, abdominal cramping, diarrhoea, tremor, convulsions, hypothermia
List the poisoning symptoms of atropa belladonna
Dr mouth, dry eyes, reduced bronchial secretions, tachycardia, dilated pupils, blurred vison, diarrhoea, stupor, delirium, hallucinations
What is muscarine?
Found in the mushrooms
Direct-acting acetylcholine receptor agonist
How is the acetylcholine receptor family split up?
Class nicotinic (ligand-gated ion channels)= Skeletal NMJ, Ganglionic, Neuronal CNS Class Muscarinic (selective)= G protein coupled
Describe the anatomy of the PNS
Cranial outflow (3, 7, 9, 10) from medullary to eye/ lacrimal gland/ salivary glands/ heart, lungs, upper GI tract Sacral outflow to lower GI tract, bladder, genitalia
Contrast sympathetic and parasympathetic neuron pathways
- Sympathetic= short pre-ganglionic, nicotinic ACh synapse at sympathetic chain ganglion, long post-ganglionic, noradrenaline and adrenoreceptors
- Para= long pre-ganglionic, Nicotinic ACh receptors ganglion, short post-ganglionic, ACh at muscarinic ACh
What are the names and characteristics of the sub types of muscarinic receptors?
M1= neural (slow EPSP in ganglia)- mediate slow excitation
M2- Cardiac- regulate heart rate and force of contraction
M3- glandular secretion, contraction of visceral smooth muscle, vascular relaxation
M4, M5
What are the cellular signalling pathways linked to muscarinic receptor activation?
- Activate Phospholipase C leading to the production of IP3 (releasing intracellular Ca2, contraction of muscle) and diacyl glycerol (DAG) (activator of Protein Kinase C= phosphorylation)- M1,3,5
- Inhibit adenylate cyclase causing decrease in cAMP levels- M2,4
- Open/ activate K+ channels, PNS and heart, M2
- Inhibit Ca2 channels, M2
What does parasympathomimetic/ cholinomimetic mean?
Drugs that mimic the effect of parasympathetic nerve stimulation, particularly by activation of responses mediated by muscarinic cholinergic receptors
Describe the effect of drugs affecting the synthesis and release of ACh
- ACh transporter blocked by vesamicol, no vesicles
- Exocytosis Ca2 dependent blocked by botulinum toxin
- Acetylcholinesterase inhibited to prolong lifetime in cleft (breakdown into Acetate and choline inhibited)
- Choline transporter into presynaptic terminal blocked by hemicholinium
What are the types of direct acting agonists?
Choline esters (all quaternary ammonium esters) Natural plant compounds (similar structures to acetylcholine)
What are the types of choline esters?
- Acetylcholine- too unstable in plasma to be effective, muscarinic and nicotinic effects, not used
- Bethanechol- not hydrolysed by cholinesterase, weak nicotinic agonist, selective muscarinic agonist
What are the natural plant compounds?
- Muscarine
- Pilocarpine
Neither selective for subtypes
What are the types in indirect acting agonists?
Reversible/ irreversible inhibitors of acetylcholinesterase
Increase concentration of ACh and prolong lifetime in synapse/ junction
What are the types of reversible inhibitors?
- Physostigmine= tertiary plant alkaloid
- Neostigmine= synthetic quaternary compound
(Insecticide= synthetic tertiary compound)
What are the types of irreversible inhibitors?
Organophosphates - Insecticides (accidental poisoning) - Ecothiopate (open angle glaucoma) - Military nerve gases (poisoning) - Novichok Extremely lipophilic- cross all barriers including blood-brain barrier
What are the pharmacological actions of direct acting agonists?
Mainly muscarinic effects at end effectors
Most synthetic direct acting compounds do not have CNS effects but plant alkaloids muscarine and pilocarpine can enter CNS
What are the pharmacological actions of indirect acting agonists?
Potentiate transmission at all cholinergic junctions- muscarinic, ganglionic and skeletal muscle effects
Have CNS effects in permeable to blood-brain barrier
How are symptoms bradycardia and hypotension caused?
M2 receptors in heart at SAN, AVN and atrial muscle= bradycardia (dec. rate, force, conduction velocity)
No effect on ventricular muscle
ACh dilates blood vessels, lower bp- hypotension
generally no PNS nerves in tissues except erectile tissue and salivary glands- M3 mediates dilation
How does signal transduction in the heart affecting by M2 receptors lead to bradycardia?
ACh binding to M2 receptors= K+ channels opening (direct action of G protein beta gamma subunits)
Elicits hyperpolarisation of cardiac muscle membrane potential- shortens duration of cardiac action potential, increases interval between potentials
Reduced contraction= inhibited Ca2 channels
How are symptoms abdominal cramping, increased gastric acid secretion and diarrhoea caused?
M3 receptors in GI tract causes increased motility of smooth muscle (contraction= spasms), dilation of sphincter, secretion of glands
Gastric acid secretion= M1
What are the therapeutic uses for cholinomimetics in intestinal atony and urinary bladder atony?
Bethanechol (direct), neostigmine (indirect)- build up ACh
- Increase peristalsis by activation of muscarinic receptor
- Stimulate micturition by activating muscarinic receptors on bladder detrusor muscle
Useful in postpartum or postoperative non-obstructive urinary retention
How are symptoms pupillary constriction and blurred vision caused?
M3 receptors in pupils= constriction
M3 receptors in ciliary muscles= contraction (width of lens to focus affected)
What are the therapeutic uses of cholinomimetics for glaucoma?
Glaucoma= build up of aqueous humour, obstruction where normally drained, optic nerve damage (pressure)
Pilocarpine= direct, lipid soluble so rapidly diffuses locally, eye drops
Ecothiopate= indirect, longer acting, CNS effects so local administration
Relax lens, open Canal of Schlemm
What are the therapeutic uses of cholinomimetics for Alzheimer’s?
Muscarinic receptors involved in transmission in hippocampus- Donepezil/ Aricept, mild anticholinesterase acting on specific forms of the enzyme in the brain, beneficial effects for cognitive symptoms in early stages
What are the types of anticholinergic drugs?
Atropine= tertiary amine, prototypical muscarinic receptor antagonist
Hyoscine/ scopolamine= tertiary amine, lipophilic so absorbed by gut/ patch, readily crosses into CNS
All functions mediated by muscarinic receptors blocked
Little effect on nicotinic- selective
What are the pharmacological effects of muscarinic antagonists in the heart?
SAN, AVN, atrial muscle= inc. rate, force, conduction velocity so tachycardia
Ventricular muscle no effect
Atropine blocks effects of vagus nerve stimulation
What are the pharmacological effects of muscarinic antagonists in the eye and glands?
- Eye- pupil dilation (mydriasis), ciliary muscle relaxation= paralysis of accommodation (inability to focus)
- Salivary and lacrimal glands= inhibition of secretion (dry)
What are the pharmacological effects of muscarinic antagonists in the viscera?
- Bronchi smooth muscle dilation
- Bladder smooth muscle relaxation
- Reduced motility of smooth muscle in GI tract, constriction of sphincter, moderate inhibition of glands and inhibition of gastric acid secretion
List the therapeutic uses of antimuscarinics
Pre-anaesthetic medication
Ophthalmological uses
Gastrointestinal antispasmodic agents
Treatment of poisoning by cholinomimetics
How are antimuscarinics used in pre-anaesthetic medication?
Hyoscine, Atropine
Reduction of salivary and bronchial secretions minimises postoperative pulmonary complications
How are antimuscarinics used in ophthalmology?
Atropine, shorter lasting derivatives topically (tropicamide)
Muscarinic receptor blockade on concentric muscle of iris causes pupil dilation and paralysis of accommodation - eye surgery
How are antimuscarinics used as GI antispasmodic agents?
Atropine derivatives- dicycloverine
Relaxes smooth muscle to facilitate endoscopy
How are antimuscarinics used in treatment of poisoning?
Atropine derivatives
Antagonise lethal effects of high level muscarinic activation in periphery and CNS
