Drugs and the peripheral nervous system Flashcards
Example of peripheral nervous system - afferent system
Input stimulus detected by sensory neurone.
Example of peripheral nervous system - efferent system
The effect of a muscle/glad to create an output
What is the PNS efferent pathway?
Autonomic nervous system.
Smooth muscle outside the influence of voluntary control.
What are the 2 types of autonomic NS?
Sympathetic and Parasympathetic
Sympathetic, autonomic NS
Pupils dilate. Lens of eye adjusts for far away vision. Airways in the lungs dilate. Respiratory rate increases. HR increases. Blood vessels to limb muscles dilate. Blood vessels to visceral organs constrict. Salivary secretions reduced. Brain activity general alertness.
Parasympathetic, autonomic NS
Pupils constrict. Lens of eye readjusts for closer vision. Airways in the lungs constrict. Respiratory rate decreases. HR decreases. Blood vessels to limb muscles constrict. Blood vessels to visceral organs dilate. Salivary secretions normalise. Brain activity normalise.
Somatic NS
Motor innervation of skeletal muscles.
Organisation of Sympathetic system
Short pre-ganglionic fibre (Ach)
Long post-ganglionic fibre (NA)
Organisation of Parasympathetic system
Long pre-ganglionic fibre (Ach)
Short post-ganglionic fibre (Ach)
Organisation of Somatic efferent system
Only one fibre (Ach and NMT)
Sympatheric system exceptions
Sweat glands (Ach - Pre and Post-ganglionic fibre) Adrenal glands -> Adrenaline (Ach - one fibre)
PNS: Acetylcholine pharmacology
Synthesis - Choline/Choline acetyl transferase.
Storage - Vesicles.
Release - Exocytotic.
Receptor interactions - Muscarinic/Nicotinic.
Termination - In synapse by Ach esterase.
Muscarinic receptors (mAch)
Slow response.
M1,2,3
Located at postganglionic parasympathetic synapses.
G-protein coupled receptor (or metabolic receptor)
Nicotinic receptors (nAch)
Fast response
Neuronal type - Brain and autonomic ganglia (excitatory).
Muscle type - Neuromuscular junction (NMJ) (excitatory).
Ligand-gated ion channels (or ionotropic receptors)
Made up of 4/5 subunits.
Coupled directly to an ion channel.
Time scale - fast (ms)
Effect of muscarinic agonists
Increases pupil constriction. Decrease focal length of the lens. Bronchoconstriction. Decrease cardiac output. Increase GI motility. Increase exocrine gland secretion. PARASMYMPATHOMIMETICS
Effect of muscarinic antagonists
Pupil dilate. Increase focal length of the lens. Bronchodilation Increase cardiac output. Decrease GI motility. Exocrine gland secretion decreased. PARASYMPATHOLYTIC.
Muscarinic receptor agonists
Pilocarpine - Glaucoma and xerostomia
Carbachol
Clinical uses of Pilocarpine
Used to treat Glaucoma.
Local application causes ciliary muscle contraction.
Focus on near vision.
Allows increase drainage of aqueous humour.
Contraction of sphincter muscle causes pupil constriction.
Stimulates saliva secretion.
Taken systemically.
Side effects of Pilocarpine
Muscarinic
Sweating, nausea, minimal cardiovascular side effect (due to low dose).
Clinical uses of muscarinic receptor antagonist (Atropine like drugs)
Pupil dilation in eye surgery, causes pupil dilation (Tropicamide - duration 2-6 hours compared to 6 days for atropine).
Decrease oral/respiratory secretions before ora procedures and as an adjunct to anaesthesia (atropine - belladonna, deadly nightshade - Glycopyrronium).
Resuscitation in bradycardia - causes increase in HR (Atropine).
Atropa belladonna (deadly nightshade). Used cosmetically over 2000 years ago. Pupils dilate.
Asthma (causes bronchodilation) - Ipratropium by inhalation.
Motion sickness - orally decreases gastric motility (Hyoscine).
Muscarinic receptor antagonists
Atropine - Bradycardia
Tropicamide- Pupil dilation
Ipratropium - Asthma
Hyoscine - decrease GI motility and motion sickness.
Neuronal type, nicotinic receptor.
Located on both sympathetic and parasympathetic ganglia.
Agonist (nicotine) activates both systems.
Sympathetic - Vasoconstriction, Tachycardia, hypertension.
Parasympathetic - Bradycardia, hypotension, Increase GIT motility, Increase secretions.
Autonomic confusion.
Antagonists = hexamethonium
Muscle type, nicotinic receptor.
Located at NMJ
Stimulation of these receptors by Ach causes depolarisation (in muscle fibre this is known as an end plate potential (EPP)) and contraction of the skeletal muscle fibre.
Antagonist - Tubocurarine.
Agonist - Suxemethonium.
Effect of nicotinic agonist at NMJ
Suxemethonium.
Initial depolarisation/EPP and muscle fibre contraction (muscle twitch).
Synthetic agonist isn’t metabolised rapidly by Achase, the fibre is persistantly depolarised resulting in loss of further electrical excitability - known as depolarising block.
Paralysis/Muscle relaxation (for surgery).
Depolarizing block.
Effect of nicotinic antagonist at NMJ
Tubocurarine. Hyperpolarisation, inhibition of EPPs. Muscle fibre relaxation. Paralysis (for surgery). Non-depolarising blocker.
Hemicholinium
Blocks choline uptake, inhibits synthesis and block Ach transmission.
Botulinum toxin
Inhibits Ach release.
Causes parasympathetic and motor paralysis if ingested.
Injected locally.
Used to treat muscle spasm and in plastic surgery (BOTOX)
Bungarotoxin
Inhibits release of Ach.
Causes parasympathetic and motor paralysis if ingested.
Acetylcholinesterase
The enzyme responsible for the metabolism of Ach and termination of the action of Ach.
Can be inhibited by anticholinesterases.
This will increase Ach transmission.
Effects of anticholinesterase on autonomic NS
EG Neostigmine, Organophosphates.
Reflect increased transmission at parasympathetic post ganglionic synapses - increase secretions, bradycardia, hypotension, pupil constriction.
Effects of anticholinesterase on neuromuscular junctions.
Increased muscle tension and twitching at large doses, can cause a depolarisation block.
Neostigmine used to treat myasthenia gravis (autoimmune disease, circulating antibodies against muscle nicotinic receptors)
Hemicholinium
Precursor uptake/synthesis inhibited by hemicholinium.
Noradrenergic receptors
The actions of NA are mediated via 2 main classes of NA receptors (α-receptors and β-receptors)
α-NA receptors
α1,2
Located in effector tissues/targets of sympathetic system.
G-protein coupled receptors (or metabotropic receptors)
Slow (seconds) response
β-NA receptors
β1,2,3
Located in effector tissue/targets of sympathetic system.
G-protein coupled receptors (or metabotropic receptors)
Slow (seconds) responses
α1-receptors
Smooth muscle and vasoconstriction.
Pupils dilate.
Blood vessels to visceral organs and skin constricts.
Brain activity general alertness.
α2-receptors
Inhibition of neurotransmitter release.
Presynaptic receptors.
Inhibits both NA, Ach and other neurotransmitters)
β1-receptors
Increases cardiac rate and force
β2-receptors
Bronchodilation, ciliary muscle relaxation.
Lens of eye adjust for far vision.
Airways in lungs dilate
Blood vessels to limb muscles dilate
β3-receptors
Lipolysis/increased metabolism.
Breakdown of fatty acids
Noradrenergic agonists
Adrenaline Clonidine Dobutamine Salbutamol Clenbuterol
Adrenaline
Agonist at all NA receptors.
Destroyed in the gut so has to be given by injection.
Two main uses:
1. Given subcutaneously (locally) adrenaline can prolong and isolate local anesthesia. α1-mediated vasoconstriction.
2. Given intramuscularly, adrenaline is used to treat anaphylactic shock. α1-mediated smooth muscle contraction (vasoconstriction). β1-mediated cardiac stimulation. β2-mediated bronchiole smooth muscle relaxation.
Clonidine
α2 agonists.
α2-receptor: presynaptic autoreceptors regulate release, agonist inhibits NA release.
Used for hypertension: decrease NA release, dampen down overall sympathetic system.
Mechanism is thought to also involve a central effect (nucleus tractus solitarius) which results in decrease in sympathetic outflow.
Also used to treat withdrawal symptoms (EG morphine)
Dobutamine
Selective β1 agonist.
β1-receptors: increased cardiac rate and force.
Used to treat heart failure.
β1-mediated cardiac stimulation (increased firing rate and increased contractive force)
Salbutamol
Selective β2 agonist.
β2-receptors: bronchodilation.
Used to treat asthma.
β2-mediated bronchiol smooth muscle relaxation
Clenbuterol
β2/β3 agonist.
β2-receptors: bronchodilation.
β3-receptors: lipolysis/increased metabolism (weight loss, muscle gain).
Used to treat asthma (β2)
Increases muscle bulk in athletes etc (β3)
Noradrenergic antagonists
Prazosin Tamsulson Propranolol Atenolol Timolol
Prazosin
Selective α1-antagonist.
Blocks α1-mediated smooth muscle and vasoconstriction.
Used to treat hypertension α1-antagonism vasodilation and decreased vascular resistance.
Side effects: Orthostatic or postural hypotension due to some loss in sympathetic reflex.
Tamsulson
Selective α1-antagonist.
Blocks α1-mediated smooth muscle and vasoconstriction.
Used to treat urination problems in prostate hyperplasia.
α1-antagonism: relaxation of smooth muscle in bladder neck, ease of urinary flow.
Side effects: Orthostatic or postural hypotension due to some loss in sympathetic reflex.
Propranolol
β1/β2 antagonists.
β1-receptors meditate increased cardiac rate and force.
β2-receptors mediated bronchodilation.
Used to treat hypertension and angina.
Blocking β1-receptors decreases cardiac output and also decreases oxygen demand.
However, blocking β2-receptors causes bronchoconstriction. Therefore contraindicative in asthmatics.
Atenolol
Selective β1 antagonist.
β1-receptors mediate increase cardiac rate and force.
Used to treat hypertension and angina.
Blocking β1 decreases cardiac output and also decreases oxygen demand.
Side effects: Can cause rebound hypertension/angina on abrupt withdrawal probability due to β1-receptor supersensitivity.
Timolol
Selectivity β2 antagonist.
β2-receptors mediate ciliary muscle/lens of eye relaxation.
Used to treat glaucoma, antagonism of β2-receptors cause ciliary contraction and decreased intraocular pressure.
Drugs affecting NA storage
NA stored in synaptic vesicles.
Reserpine disrupts storage of NA in synaptic vesicles.
Overall decrease in NA neurotransmission.
Used to treat hypertension
Drugs affecting NA release
NA release is subject to autoinhibitory control via presynaptic α2-autoreceptor.
Clonidine (α2-agonist) causes inhibitory of NA release.
Overall decrease in NA neutrotransmission.
Used to treat hypertension
Drugs affecting NA reuptake
The main mechanism terminating the action of NA is reuptake.
NA uptake can be blocked by NA reuptake inhibitors.
This will prolong the action of NA in the synapse.
Desipramine tricyclic antidepressants.
Reboxetine selective noradrenaline reuptake inhibitors.
Drugs affecting NA metabolism
After reuptake NA is metabolised by the enzymes monoamine oxidase (MAO) and catecholamine transferase (COMT).
By blocking these enzymes the amount of NA available for release is increased.
Tranylcypromine blocks MAO and allows more NA to be recycled so increases so increases NA neurotransmission.
Cheese reaction
Tranylcypromine and other MAOIs not only block the metabolism of dietary amines (Commonly found in cheese and marmite) and accumulation of dietary amines can have a sympathomimetic effect and result in hypertension.
Drugs affecting NA synthesis (by vesicular enzyme)
Inhibit enzymatic activity and synthesis with a false substrate.
Mathyldopa acts as a false substrate for DOPA decarboxylase.
Decreases overall noradrenergic synthesis neurotransmission.
Final product methylnoradrenaline also has α2 agonist (decreases NA release).
Used in the treatment of hypertension.
