Parasympathetic NS Flashcards
how do directly acting cholinomimmetic drugs produce their biological effect
exogenous agonists of specific ACh receptors
how do indirectly acting cholinomimmetic drugs produce their biological effect
inhibitions of Acetylcholinesterase- present in ALL cholinergic synapses,
this causes build up of Ash in synapse- therefore increasing its effect
why are directly acting cholinomimmetic drugs more selective in their actions than indirectly acting ones
because exogenous agonists only agonise specific receptors but anticholinesterases are found in all PNS synapses so bring about its effect in all of them
what is the structure of nicotinic receptors
Type 2- Ligand gated ion channels (fast)
Must have 2 alpha units and then a mix of 3 others (beta, delta, epsilon, gamma)
Ganglion (‘neuronal’) type: 2α 3β
what is the structure of muscarinic
+what are the 3 main subtypes
3 main types of receptors (5total) M1-salivary glands, CNS, stomach M2- HEART M3- Salivary/sweat glands+ bronchial/viceral SM+eye M4/M5: in CNS
ODD: Gq (PIP2–>IP3+DAG)-excitatory
EVEN: Gi (cAMP)-inhibitory
where are muscarinic and nicotinic receptors found
muscarinic- effector organs on the postsynaptic side (PNS) and also act on SNS sweat glands
Nicotinic- are found on the all ANS ganglions (PNS and SNS)
how do cholinomimmetics produce most of their effect on the PNS when SNS also has nicotinic receptors
Lower concentrations of ACh required to stimulate muscarinic receptors than nicotinic, so cholinomimetics bring about PNS effects.
what are the muscarinic receptor agonists (aka direct acting cholinomimmetics) and what are their uses and pharmacokinetic properties
Choline esters - BETHANECHOL - M3 selective-limited brain access- half life: 3-4h
Uses: Assist bladder emptying and gastric motility after surgery
Alkaloids - PILOCARPINE-non selective- good lipid solubility- half life- 3-4h
Uses: GLAUCOMA
what are the anti-cholinesterase drugs (aka indirect acting cholinomimmetics
Reversible:
- PHYSOSTIGMINE-Competes with ACh - half life 30mins
donates carbamyl group to enzyme- slowly removed
Uses: Glaucoma, Atropine poisoning
- Neostigmine:
Uses:-Reverse non-depolarising NM Block
-Treat Myaesthenia gravis
Irreversible:
- ECOTHIOPATE- eye drops
Organophosphate compounds Rapidly reacts with active site to leave a large phosphate blocking group-Stable and resistant to hydrolysis.–May require new enzymes (Days/weeks)
Uses: Glaucoma (Prolonged DofA)
how does pilocarpine (musc agonist) treat glaucoma
because the PNS mediates sphincter papillae contraction, giving a musc agonist causes Contraction of the sphincter pupillae –>opens a pathway for aqueous humour, allowing drainage via the Canals of Schlemm thus reducing IOP–in glaucoma this is impeded
whats the difference between closed and open angle glaucoma
open= caused by obstruction in trabecular meshwork or canals of schlemm closed= fluid can't drain out of the eye in the first place because iris is too close to lens
what effect do anticholinesterases have on the CNS
Non-polar anticholinesterases can cross the blood brain barrier:
Low doses–excitation with possibility of convulsions.
High doses–unconsciousness, respiratory
depression, death
what are the side effects of cholinomimmetics
Sweating Impaired/blurred vision Bradycardia Hypotension Respiratory difficulty/Arrest GI disturbance/pain
what are the effects of CHOLINOMIMETICS on the CVS
causes a DROP IN BP:
heart via M2:decrease HR (effect on nodes) and CO (via less atrial contraction)
Reduction of cAMP causes:
1.Decreased Ca2+ entry–>Decreased CO.
2.Increased K+efflux–> Decreased HR
Vasculature via M3: decrease in TPR due to SM relaxation
ACh acts on vascular endothelial cells to stimulate NO release viaM3 AChR–> NO acts on SM–> relaxation and reduction of TPR
(note: most blood vessels do not have PNS innervation)
what are the effects of CHOLINOMIMETICS on non vascular smooth muscle
causes contraction of non vascular smooth muscle:
Lung: Bronchoconstriction
Gut: Increased peristalsis (motility)
Bladder: Increased bladder emptying
(the last two are how BETHANECHOL has its effect)
what are the effects of CHOLINOMIMETICS on Exocrine Glands
Digestion:
Salivation
Increased gastro-intestinal secretions (HCl)
Increased bronchial secretions Increased sweating (SNS-mediated)- due to sweat glands having musc receptors
what are the signs and symptoms of anti cholinesterase poisoning
Low dose
– Enhanced muscarinic activity (see above)
Moderate dose
– Further enhancement of muscarinic activity
– Increased transmission at ALL autonomic ganglia (nAChRs)
– This is because the anticholinesterase increases the acetylcholine concentration at ALL cholinergic synapses, muscarinic and nicotinic
High dose (toxic) – Depolarising block at autonomic ganglia & NMJ – Nicotinic receptors get over stimulated -->SHUT DOWN
what are the treatments for anti cholinesterase poisoning
Treatment = IV-atropine, artificial respiration, IV-pralidoxime- this unblocks the acetylcholinesterase enzymes
explain how nicotinic receptor antagonists(ganglion blocking drugs, GBD’s) work
they affect ALL ANS ganglions (mostly PNS at rest and SNS during exercise)
MOA: Blocks receptor and/or channel pore Channel pore bloackage: Use-dependent block (↑ agonist present = more accessible channel) Incomplete block (ion leakage)
what effect do GBD have on body
depending on the situation they reduce activity of SNS or PNS
ie:
-At rest the reduce the PNS- , you would expect
to see an increased HR and bronchodilation after giving GBD
-During fight or flight they reduce the SNS
- CVS effects: ^HR but hypotension–blood vessel vasoconstriction inhibited (as weirdly SNS tone dominates at rest) kidney renin secretion inhibited (so no AngII)-also SNS .
- Smooth muscle effects: pupil dilation, decreased GI-tone, bladder dysfunction, bronchodilation.
- Exocrine secretions: decreased secretions
what are the main nicotinic receptor antagonists(ganglion blocking drugs, GBD’s) + toxins
- Hexamethonium= 1st Anti-hypertensive (Blocks receptor and channel)
- Trimetaphan = Hypotension during surgery, short acting (Blocks receptor only)
Toxin made by snake: alpha-bungarotoxin: irreversible, covalent block-Affects ANS + Skeletal muscles+Paralyses diaphragm and respiratory muscles
what are the main musc receptor antagonists
Mainly PNS antagonist except sweat glands (SNS)
Atropine:
Normal dose – Little effect
Toxic dose - Mild restlessness Agitation
(Less M1 selective)
Hyoscine:
Normal dose – Sedation, amnesia
Toxic dose – CNS depression or paradoxical CNS excitation (associated with pain)
(Greater permeation into CNS – more lipid soluble; more M1 selective)
Tropicamide: used for ophthalmic exam
what are the clinical uses of MR antagonists:
o Opthalmology: Retina examination
-Tropicamide blocks PNS constriction of pupils pupil dilation
o Pre-surgery:
-Blocks PNS bronchoconstriction – so anaesthetic has better access (as dilation takes place)
-Reduce saliva and GI secretions – prevent aspiration
Counteract HR decrease (many anaesthetics lower HR - dangerous)
-Sedation: Hyoscine
0 Motion sickness:
-Hyoscine patch: muscarinic receptors in the vomiting centre so the sensory mis-match cannot induce vomiting when suffering from motion sickness
o Parkinson’s Disease:
Muscarinic neurones inhibit dopamine release into striatum from alternative source (not SNc), therefore inhibiting the musc, prevents inhibition of dopamine release–>^dopamine in striatum
o Asthma/Obstructive airway disease
Blocks PNS bronchoconstriction–>bronchodilation(Atropine or Ipratropium Bromide)
o Irritable bowel syndrome (hyperactive gut)
Blocks (M3r-mediated) gut motility + tone, secretions
what are the side effects of musc receptor antagonists
Hot as hell - less sweating, thermoregulation
Dry as a bone - less secretions
Blind as a bat - cyclopegia- Paralysis of the ciliary
muscle of the eye, resulting in a loss of
accommodation.
Mad as a hatter - CNS disturbance
what are the signs and symptoms of atropine poisoning
Hot as hell - less sweating, thermoregulation
Dry as a bone - less secretions
Blind as a bat - cyclopegia- Paralysis of the ciliary
muscle of the eye, resulting in a loss of
accommodation.
Mad as a hatter - CNS disturbance
basically the side effects but worse
how can you treat atropine poisoning
Treat with Physostigmine- (Anticholinesterase)-Increases [Ach], which outcompetes antagonist
how does botulinum toxin work
Botulinum binds to the ACh vesicles and stops them
docking with the inner membrane.
Forms SNARE complexes—> no ACh released at NMJ—> paralysis
