9a - Parasympathetic Flashcards
Meiosis
Pupil constriction
What inhibits transport of choline
Hemicolinium
What is the cholinesterase in the blood called ? 2 names
pseudocholinesterase / butirylcholineesterase
What is the amino acid at the esoteric site of acetylcholineesterase (cleavage site)
Serine
Nicotinic is ionotropic or nicotinic?
ionotropic
What effect does nicotinic receptor have on the cell
Sodium influx and depolarisation and thus stimulation
Muscarinic - are they metabotropic or ionotropic
metabotropic
M1 - receptor -where and action
Salivation and enteric nerves - contraction of smooth muscle
M2 - receptor -where and action
Heart decreasing contractility, smooth muscle
M3 - receptor -where and action
increases exocrine gland secretion (lacrimal, sweat, salivary, gastric), increases gut peristalsis, increase bladder contraction, bronchoconstriction, increase pupillary sphincter muscle contraction (miosis) ciliary muscle contraction (accommodation) increase insulin release, ENDOTHELIUM MEDIATED VASODILATION.
M4 - receptor -where and action
brain and lungs
M5 - receptor -where and action
brain and eye
Mechanism of action of M1/M3 (cascade)
Stimulate phospholipase C–> IP3 and DAG –> calcium release –> calcium dependent kinase = contraction of smooth muscle
M2 channel mechanism of action
Coupled to potassium channels in the heart (parasympathetic) causing K+ outflow = hyper polarisation = decreased heart activity.
Do blood vessels have parasympathetic innervation
no!!!
Vascular M3 receptors (not innervated!) Explain mechanism of action:
Ach –> M3 receptor = conversion of l-argenine to NO. This then acts on cGMP to be released causing relaxation of the vascular smooth muscle. Ach would need to be in the blood as there is NO PARASYMPATHETIC INNERVATION OF BLOOD VESSELS
CLASSIFY cholinomimetics
Directly: nicotinic or muscarinic –>muscarinic has natural alkaloids or choline esters.
Indirectly (Ach-esterase inhibitors): reversible/irreversible
Bethanacol mainly used for: why
there is also methacholine and Carbachol but Bethanacol used the most
-post operation ileus - triggers contraction of the GI
- makes you pee (after op)
- reflux
Works only on muscarinic receptor (not nicotinic) and its not susceptible to achE = longer effect.
It is a direct cholinomimetic acting on muscarinic receptors. (activates them).
It thus causes vasodilation by acting directly on the vascular endothelium M3 receptors as it is not degraded by AchE.
Pilocarpine used for - what is it and how does it act?
Direct acting cholinomimetic: Used for glaucoma, topically applied, works on muscarinic receptors: Good lipid solubility
Muscarine (and what is the antidote?)
Directly acting cholinomimetic, toxin/poisining- results in salivation, lacrimation, stomach pain, BRADYcardia, HYPOtension, Miosis.
The antidote is ATROPINE
What is physostigmine. It is an antidote for?
Alkaloid against glaucoma by inhibiting AchE (indirect acting cholinomimetic). Uncharged, so can cross the BBB, absorbed orally. Can also be used in Atropine poisoning
What is Neostigmine
For myasthenia gravis (indirect acting cholinomimetic AchE inhibitor). It has a positive charge (doesn’t cross barriers) thus good for peripheral use, also used to get muscles to contract again after surgery where you have used nicotinic NMJ blockers.
Name 3 drugs used in Alzheimers disease and what do they do?
Donepezil, galantamine, rivastigmine (are all reversible AchE inhibitors). Increasing Ach improves cognitive function (symptomatic only).
Name 5 classes of irreversible AchE inhibitors
Organophosphates Insecticides Herbicides Nerve gases Ophthalmic agents
What is echothiopate and how does it work
Ophthalmic agent treating glaucoma (irreversible AchE inhibitor). It is a toxic compound (organophosphate) but acts locally giving a good effect = purely topical.
What does Sarin Gas do to you? How do we treat it?
Sarin (an organophosphate and nerve gas) blocks AchE (also pseudocholinesterase in blood). Atropine is the antidote (because it is an antagonist of muscarinic receptors!). But this does not work on NICOTINIC receptors so we give 2-PAM (pralidoxime) which can help stop the ageing of the bond (preventing covalent binding).
Effects at the Nicotinic sites:
- fasciculations
-respiratory paralysis
Effects at Muscarinic: (SLUDGE)
Salivation, lacrimation, urination, diaphoresis (sweating), GI upsets, Emesis as well as the killer B’s : bronchoconstriction and bronchorrhea
We also give benzodiazepine/scopolamine to avoid seizures/CNS symptoms.
What dose of atropine in AchE inhibitor poisoning like sarin?
2mg Iv repeated every 10 minutes until atropinisation signs occur (mydriasis, tachycardia)
What does 2-PAM do
binds to organophosphates prevents ageing of the chemical stabilisation of the phosphate bond to AchE - thus regenerates AchE.
What is atropine- what do we use it for clinically
Used in AchE inhibitor poisoning, as it blocks all muscarinic receptors.
it is an alkaloid from belladonna (used to have mydriasis = pupil dilation to appear pretty). Acts on:
Sphincter muscle - relaxation = dilation = mydriasis - used in opthalmological action
- reverses sinus bradycardia from excessive vagal tone
- counters muscarinic poisoning
- inhibits excessive salivation / mucus secretion during surgery
EYE refresher - what causes accommodation?
The effect of contraction radial muscle is to decrease the diameter of the ring of ciliary muscle causing relaxation of the zonule fibers, the lens becomes more spherical, increasing its power to refract light for near vision. CONTRACTION = causes relaxation and rounding of the lens = near vision. It is under the effect of ADRENERGIC FIBRES - ALPHA 1 receptors.
What is mydriasis
D for dilation - pupil dilation
2 effects of atropine on the eye.
Contraindications?
Mydriasis and cycloplegia (paralysis of radial muscles) loss of accommodation and near vision. It excessively blocks parasympathetic innervation and is contraindicated in narrow angle glaucoma.
Name three classes of cholinolytics (drugs that act like atropine!)
Muscarinic antagonists Ganglionic blockers (antagonists of Neural Nicotinic) Neuromuscular blockers (antagonists of Neural Nicotinic)
What is scopolamine and how is it used
Alkaloid, similar effects to atropine but more powerful on the CNS, used against motion sickness (plaster behind ear). Powerful antiemetic activity and sedation.
Side effects: drowsiness / dry mouth
What is Ipratropium
Cholinolytic: Used for asthma - it is a charged molecule (quaternary amine) so does not cross the membrane, can have inhalation causing bronchodilation locally.
Name two anticholinergic drugs and what they are used for ?
Benztropine & trihexphennidyl:
modest antiparkinson - improve tremor and rigidity, used in early stages of the disease or as adjunct to levodopa therapy
What is Pirenzepine and what is it used for?
Selective M1 antagonist in the smooth muscle of the GIT- helps patients with ulcer disease / gastric acid - reduces gastric acid secretion, it has fewer adverse effects than atropine or less selective agents.
What is a negative effect to remember when blocking Ach?
Cognitive problems - thus muscarinic antagonists are contraindicated in older people
What happens if you use a nicotinic agonist for a long time?
Desensitisation
What does a ganglionic blocker do
acts as antagonists at nicotine Ach receptors but are non selective for sympathetic / parasympathetic so mixed effects - so the predominant receptor will be seen.
What happens to the vessels if you use a ganglionic blocker? (trimetaphan)
since it is a nicotinic antagonist acting for both parasympathetic / sympathetic, the prevalent receptor function will be affected. We know that blood vessels do not have parasympathetic innervation, so if we block here, only sympathetic effects will be blocked = vasodilation
Ganglion blockers (trimetaphan) effect on intestine
Parasympathetic is prevalent in the GIT, thus if you block here you will have block of contraction resulting in constipation
Ganglion blockers (Trimetaphan) effect on the heart
In the heart parasympathetic nicotinic receptors are prevalent (normally decreasing the heart rate) so a block here will increase the heart rate = tachycardia
What is trimetaphan
Ganglionic blocker
Name the two kinds of neuromuscular blocker categories and give examples:
Depolarising - initially stimulates the nicotinic receptors (agonist) - Succinylcholine (not broken down by AchE but by pseudocholinesterase - need to give continuous IV, eventually desensitises. After surgery produces PAIN!
Non depolarising - antagonists that block receptor eg curare - no initial contraction so no pain. After administering this you give NEOstigmine, you block AchE, so Ach increases at junction and displaces competitive inhibitor so muscle can contract again.
If you use neuromuscular blockers, what do you need to be aware of in terms of patient care?
Patient can’t breathe - acts on striated muscle - diaphragm and intercostals. Need to be ventilated.
What is succinylcholine?
Depolarising neuromuscular blocker, initially stimulates the nicotinic receptors (agonist) - not broken down by AchE but by pseudocholinesterase (thus can only use for short surgeries), need to give continuous IV, eventually desensitises. If you give neostigmine (which blocks AchE) it will reduce contraction EVEN more. After surgery produces some pain. Remember it is a PARTIAL AGONIST that causes desensitisation, the muscle doesn’t fully contract but a fasciculation. Often used during tracheal intubation.
What is curare?
Non depolarising neuromuscular nicotinic receptor antagonist, that BLOCKS the receptor. If you give neostigmine (which blocks AchE) Ach increases in synapse and eventually you displace the competitive inhibitor so muscle contraction can start again.
Name 2 types of curare (non depolarising neuromuscular blockers)
Name a short acting version and two types:
Tubocurarine - prevents activation of NMJ (Nm) nicotinic receptors. natural alkaloid: skeletal muscle relaxant activity. It is charged quaternary ammonium so cannot cross BBB and thus only peripheral actions. (used to dart animals). We use analogs in surgery for muscle relaxation : coronium compounds and curium compounds
Curonium - derivative of curare alkaloids:
Pancuronium: fast onset - no hypotension /bronchoconstriction
Vercuronium/rocuronium - fast onset, less tachycardia.
Curium: short acting neuromuscular blocker:
Atracurium - short acting in acidic environment
Mivacurium - undergoes rapid hydrolysis by plasma choninesterases.
Does morphine release histamine
YES
What is vesamicol
Inhibits the transport of Ach into its vessicle by the Vessicle-Associated Transporter VAT
SNARE PROTEINS discuss
V snares: (vessicles): - Synaptobrevin, - synaptotagmin t-Snares: terminal membrane: - SNAP-25 - Syntaxin
They allow the docking of the vessicle and with Ca++ influx, the fusion and exocytosis.
Botuliium toxin enzymatically alters these proteins to prevent release.
Name drugs that do the following to Ach - block synthesis - bock storage - block release Why are they not good for systemic therapy
- block synthesis - hemicholinium
- bock storage - vesamicol
- block release - botulinum toxin
Not good for systemic therapy because effects are not selective, PANS and SANS ganglia and somatic NMJ may be locked. However botulinum is a large toxin and can be injected for local effects.
How is botulinum toxin taken up
By receptor mediated endocytosis, present only on cholinergic neurons not adrenergic neurons.
Discuss Uptake 1 system, what its called, what it does, what blocks it
NET = norepinephrine transporter, takes up NE normally, Cocaine and TCE (tricyclic antidepressants) block the reuptake.
What blocks the adrenergic conversion of tyrosine into DOPA?
Metyrosine
What blocks the docking of NE vessicle?
Guanethidine
NE is primary transmitter at sympathetic postganglionic EXCEPT WHERE?
Thermoregulatory sweat glands (eccrine) and vasodilator sympathetic fibres in skeletal muscle which release Ach!
Which two neurotransmitters act on renal blood vessels and what are their actions
Dopamine is a vasodilator at D1 receptors
NE is a vasoconstrictor of those vessels
What are the actions of MAO (monoamine oxidase in adrenergic neurons and what would blocking them cause?
Degrade some NE and Dopamine in cytoplasm.
Blocking can increase stores of these transmitters
What is responsible for the termination of action of cathecolamines
diffusion and reuptake by the NE transporter NET or dopamine transporter DAT.
They can also be metabolised by MAO and COMT
What is inhibition of COMT in the brain useful for
Parkinsons disease
Hexamethonium- what is it and action
Prevents activation of Nicotinic Neural (Nn) receptors. Also called a ganglion blocker as it blocks all ANS ganglia. Useful in blocking the ANS response to BP drop.
PREVENTS AUTONOMIC COMPENSATORY REFEXES.
Tetrodotoxin - how does it act
blocks sodium channels and limits transmission in all nerve fibres.
Varenicline - what is it and how does it act
Partial agonists at Nicotinic receptors, high lipid solubility. Used for reducing the cravings in tobacco smokers.
What is parathion
Organophosphate, VERY lipid soluble, more toxic than malathion, less persistent in environment than DDT, if treated early can be treated with Pralidoxine. Duration of action 7-30 days!
What is Edrophonium
Shortest acting cholinesterase inhibitor, useful for distinguishing between cholinergic / myasthenia crisis.
What is pyridostigmine
Like neostigmine, poor lipid solubility, but longer duration of action
M1/M3 activation
Gq protein couples M1/M3 receptors to phospholipase C, which leads to the release of the second messengers DAG and IP3.
DAG modulates action of Protein Kinase C, an enzyme important in secretion, where IP3 evokes the release of calcium from intracellular storage sites which in smooth muscle results in contraction.
M2 activation
M2 couple to adenylyl cyclase through inhibitory Gi coupling protein.
In the heart, M2 receptors via the B subunit of the G protein are coupled to potassium channels, opening these channels for depolarisation.
Which drug will cause eccrine thermoregulatory sweating?
Cholinomimetics - however this is a SYMPATHETIC cholinergic effect!
Injections of direct acting muscarinic cholinomimetics often cause?
Why?
Tachycardia.
Directly acting cholinomimetics will cause vasodilation mediated by UNINNERVATED muscarinic receptors on endothelial cell. The vasodilation is caused by EDRF endothelium derived relaxing factor and NO. The decrease in BP causes a strong compensatory sympathetic discharge to the heart - increasing HR.
Blood vessels are dominated by ____ innervation so nicotinic receptor activation results in _____. mediated by _____ ic _____ganglionic nerve discharge
Sympathetic innervation
Nicotinic results in vasoconstriction mediated by sympathetic postganglionic discharge.
What type of innervation is the gut dominated by ? What happens if you increase nicotinic drugs here
Parasympathetic control.
increase motility
What happens if we give direct acting drugs to NJM
Fasciculations and spasms, prolonged action = paralysis, a hazard of exposure to nicotine contenting and organophosphate pesticides.
In patients with COPD/asthma, what is mediated by vagal outflow
Bronchospasm
What is a therapeutic indication for anti-muscarinic agents?
COPD
Do AchE inhibitors cause vasodilation, and why?
NO. because the vascular endothelium is not PARASYMPATHETICALLY INNVERVATED thus blocking the degradation of Ach at the receptor will have no effect as Ach is not released at this site.
Are atrial fibrillations / arrhythmia responsive to antimuscarinics?
no
What is Cyclopentolate and how is it commonly used.
Cyclopentolate is a muscarinic antagonist. It is commonly used as an eye drop during pediatric eye examinations to dilate the eye and prevent the eye from focusing/accommodating
