SAR in the Peripheral Nervous System Flashcards
Peripheral nervous system
2 types:
Somatic efferent system:
- Innervates (supplies with nerves) skeletal muscle
- Voluntary, something we consciously take control of i.e. flexing a muscle, moving around
Autonomic system:
- Innervates smooth muscle e.g. blood vessels
- Involuntary
- Sub-types inc. sympathetic and parasympathetic (can work in same tissues to bring about opposite effects)
Neurotransmission in the Somatic Nervous System
- Transmission of electrical signals from central nervous system > neurone > skeletal muscle fibre
- Trigger release of neurotransmitters that act on receptors in skeletal muscle fibre
- Leads to innervation of (supplying of nerves to) skeletal muscle
Sympathetic nervous system
- Sympathetic nervous system signalling processes gather in the ganglion chain (tissue parallel to spinal chord) then come down into different tissues
- Lots of connections from ganglion chain can come down into one tissue e.g. blood vessels
- To manipulate system for particular outcome/benefit, need to target ganglia as there is a synaptic gap which electrical impulse can’t travel over (chemical mediator needs to be released into gap to act on receptors on other side)
FIGHT OR FLIGHT
Thoracic:
- Eye
- Salivary glands
- Heart
- Lungs
- Liver
Lumbar:
- GI tract
Sacral
- Bladder
- Blood vessels
Parasympathetic nervous system
- Similar organs/tissues innervated as in the sympathetic system
- Innervated from medulla and sacral region of CNS
- Longer fibres come down to a junction, lead to different tissues
- Electrical signals travel down fibres, reach ganglia then carry down into particular tissue to give desired effect
REST AND DIGEST
Medulla:
- Eye
- Lacrimal gland
- Salivary glands
- Heart
- Lungs
- Upper GI tract
Sacral:
- Lower GI tract
- Bladder
Somatic nervous system
- somatic nerves innervate skeletal (voluntary) muscles
- one single axon from the spinal cord to muscle (no ganglia)
- acetylcholine (ACh) is the neurotransmitter
- acts on nicotinic ACh receptors located on skeletal muscle membranes
- nicotinic receptors linked to Na+ ion channel
Autonomic nervous system
Parasympathetic:
- long pre-ganglionic nerve, short post-ganglionic nerve
- post-ganglionic nerves release ACh to act on muscarinic receptors on effector cells
Sympathetic:
- short pre-ganglionic nerve, long post-ganglionic nerve
- most post-ganglionic nerves release noradrenaline (NA) to act on α and β adrenoreceptors on effector cells
Both:
- pre-ganglionic nerves release ACh to act on nicotinic receptors on post-ganglionic nerve
Nicotinic agonists
Acetylcholine
Nicotine
Carbachol
Nicotinic antagonists
d-Tubocurarine
Pancuronium
Suxamethonium
Ganglia
- Relay station between neurones (not a synapse)
- Information enters ganglion, excites neurone then exits
- Give an opportunity to intervene pharmacologically
The Nicotinic Cholinergic Synapse (Ach)
- Acetyl CoA and choline combine to form ACh (choline acetyl transferase)
- ACh stored in vesicles
- Action potential release ACh
- ACh acts on nicotinic receptor, opening ion channel
- ACh action terminated by acetylcholinesterase enzyme
- Choline reclaimed by nerve ending (rate limiting step in ACh synthesis)
- Empty vesicles are refilled with ACh
Drugs that interfere with ACh process
Vesamicol
- Blocks transfer of ACh into vesicles
Botulinum toxin
- Blocks release of ACh from nerve endings
Anticholinesterases
- Prevent hydrolysis of ACh by the enzyme acetylcholinesterase
Hemicholinium
- Blocks uptake of choline by NMJ (slide7?)
Synthesis of Noradrenaline
Occurs in noradrenergic nerves
Tyrosine hydroxylase is rate limiting step
- Tyrosine > DOPA by tyrosine hydroxylase
- DOPA > dopamine by DOPA decarboxylase
- Dopamine > noradrenaline by dopamine β hydroxylase
NA in nerve terminals is contained in vesicles along with ATP and chromogranin A
ATP also has neurotransmitter function
Release of noradrenaline
- Ca2+ enters nerve ending and activates exocytosis of NA from storage vesicles
- Reduced by action of released NA on pre-synaptic α2-adrenoreceptors
Negative feedback inhibition of transmitter relase
Autoinhibitory feedback mechanism
Drugs affecting noradrenaline
Synthesis:
- Disulfiram (antabuse) inhibits dopamine β-hydroxylase, causing some depletion of NA stores
- mainly used for its action on metabolism of alcohol
Storage:
- Reserpine blocks mechanism that transports NA into vesicles
Release:
- Tyramine, amphetamine (indirectly acting sympathomimetics) increase release of NA from vesicles
-Nimodipine reduces release by blockade of Ca2+ channels in nerve terminals
- Any α_2 agonist
Actions of noradrenaline
- Effector cells innervated by sympathetic nerves have receptors for NA
- Some organs or tissues have only one type of adrenoreceptor, others have two or more
- Different subtypes can mediate similar or different responses
Locations of adrenoreceptor subtypes
α1:
- Blood vessels
- Gut smooth muscle
- Uterus
- Liver
α2:
- Blood vessels
- Gut smooth muscle
β1:
- Heart
β2:
- Blood vessels
- Lungs
- Gut smooth muscle
- Uterus
- Kidney
- Liver
α1 activation effects
- Contraction of smooth muscle generally (not gut) e.g. blood vessels, uterus
- Relaxation of gut smooth muscle
- Salivary secretion
- Hepatic glycogenolysis
α2 activation effects
- Inhibition of transmitter release
- Platelet aggregation
- Contraction of vascular smooth muscle
- Decrease in insulin release
β1, 2 and 3 activation effects
β1:
- Increased cardiac rate and force
β2:
- Bronchodilation
- Vasodilation
- Relaxation of gut smooth muscle
- Hepatic glycogenolysis
- Muscle tremor
β3:
- Lipolysis
Adrenaline receptor sites
α1, α2, β1, β2
Noradrenaline receptor sites
α1, α2, β1
Isoprenaline receptor sites
β1, β2
Adrenoreceptor agonists
α1:
- Phenlyephrine
α2:
- Clonidine (high blood pressure)
β1:
- Dobutamine (heart failure)
β2:
- Salbutamol, terbutaline (asthma)
Adrenoreceptor antagonists
α (non-selective):
- Phentolamine, phenoxybenzamine
α1:
- Prazosin (ant-hypertensive)
α2:
- Yohimbine
β (non-selective):
- Propranolol (cardiovasculae, glaucoma, thyrotoxicosis, tremor, migraine prophylaxis, anxiety) (beta-blocker)
β1:
- atenolol (cardiovascular, anti-hypertensive, antianginal, antiarrythmic)
β2:
- Butoxamine
Termination of noradrenaline action
- Noradrenaline rapidly removed from synapses by active transport mechanisms
Uptake 1 (neuronal re-uptake):
- relatively selective for noradrenaline (tyramine)
Uptake 2 (extraneuronal re-uptake):
- takes up noradrenaline, adrenaline, and isprenaline
Metabolism of noradrenaline
Endogenous and exogenous catecholamines are metabolised by two enzymes:
- monoamine oxidase (MAO)
- catechol-O-methyl transferase (COMT)
MAO is abundant in sympathetic nerve endings
COMT Is widely distributed in effector cells and also present in the extracellular space:
- more important for circulating adrenaline and some drugs e.g. isoprenaline
Drugs affecting uptake of noradrenaline
Uptake 1 blocked by:
- Cocaine, despiramine
Uptake 2 blocked by:
- Phenoxybenzamine, corticosterone (and other steroid hormones)
Drugs affecting metabolism of noradrenaline
MAO inhibited by:
- Tranylcypromine, iproniazid
MAOIs (?) used in treatment of depression
Drug binding
Drug - Receptor
Hormone - Receptor
Substrate - Enzyme
Drug - Enzyme
Antibody - Antigen
Stages of drug binding
1 - Chemical recognition
2 - Biological event:
- response (agonist)
- prevent response (antagonist)
- chemical change (substrate)
- prevent chemical change (inhibitor)
Optimize 1 & 2 for a specific effect
Chemical bonds in drug action
Covalent - 150-600 (kJ/mol) - -
Ion-ion - 20-40 - 1/d (relationship between strength and distance)
Ion-dipole - 8-20 - 1/d^2
Dipole-dipole - 3-15 - 1/d^3
Hydrogen - 5-25 - 1/d^4
VdW - 0.5-5 - 1/d^5-8
Hydrophobic bonds - 3.4 per ethylene group
Treatment of Myasthenia Gravis
- Disease characterized by progressive muscle weakness
- Antibodies against nicotinic receptors in the NMJ (neuromuscular junction)
1 - Increase ACh in the NMJ strengthens muscle contractions (anticholinesterases)
2 - Mimic the effect of of ACh at the NMJ (nicotinic agonists)
Anticholinesterase effects
Increase ACh at nicotinic (skeletal muscle) and muscarinic (heart, gut motility) receptors
Increased skeletal muscle tension
Decreased heart rate
Increased gut motility
Mimicking agonists and antagonists
Selectivity advantage:
- Nicotinic agonists for myasthenia gravis do not decrease heart rate
- Muscarinic antagonists reduce gut motility and don’t decrease skeletal tension
Equipotent molar ratio (EMR)
EC50 of test compound / EC50 of Acetylcholine
EMR < 1 = more potent
EMR > 1 = less potent
Can be used to compare effects of variant molecules
Assay of acetylcholine
Measure the response (%) of acetylcholine on a prepared tissue receptor (muscarinic or nicotinic) by measuring tension of contraction and compare to a test compound on the same tissue
Structure of acetylcholine
Ether oxygen essential for muscarinic receptors
Ester oxygen essential for nicotinic receptors
Rigid analogues of muscarinic receptors
Muscarine - 0.33 EMR
Methyl futrethonium - 0.34 EMR
Rigid analogues of nicotinic receptors
Nicotine - 8 EMR
Bisonium compounds
+N(CH3)3-(CH2)n-(CH3)3N+
n = 6 - ganglion blocker (hexamethonium)
n= 10 - neuromuscular blocker - decamethonium
Morphine SAR
- used to treat pain
- potentially lethal side effects
- mediated by μ-opioid receptors
- β-arrestin signalling (side effects)
- G-protein signalling (analgesia)
Anticholinesterase drug examples
Edrophonium
- short acting
- diagnostic only
Neostigmine
- long acting
- carbamyl ester
- used to treat muscle weakness and reverse paralysis after surgery
Dyflos
- irreversible
- non-selective, block other serine hydrolases
- insecticides, chemical warfare
Anticholinesterase as a treatment
- used in neurodegenerative diseases (alzheimer’s, parkinsons) (i.e. rivastigmine, donepezil, galantamine)
- loss of ACh producing cells leading to reduced cholinergic signalling in the brain
- can develop cholinergic crisis (overstimulation of acetylcholine receptor): SLUDGE
SLUDGE (cholinergic crisis)
- Salivation
- Lacrimation
- Urination
- Diaphoresis
- GI upset
- Emesis
Adverse effects of anticholinesterases
Cholinergic crisis:
- SLUDGE
- Prolonged muscle contraction
- Seizures
- Respiratory depression
Treatment of adverse effects of anticholinesterases (cholinergic crisis)
- Some elements can be reversed with antimuscarinic drugs (atropine, diphenhydramine) but the most dangerous, respiratory depression, cannot
- The NMJ (like the diaphragm) works by ACh activating nicotinic ACh receptors leading to a muscle contraction
- Atropine only blocks muscarinic receptors, so will not improve muscle strength and ability breathe during a cholinergic crisis
- Patient requires NM blocking drugs snd mechanical ventilation until crisis is resolved
- Brings into question their use, concerns over long term problems and minimal efficacy
Anticholinesterases, inhibitors of AChE, are used in treating Alzheimer’s disease but require careful monitoring and consideration for use. Describe the issues here in terms of the mechanisms of action of acetylcholine and its regulation (100 marks)
40-59%
- Simple descriptions of ACh synthesis, activity at nicotinic and muscarinic receptors, regulation of ACh activity by AChE, discussion of the cellular issues that AChE inhibitors could support
60-69%, as above but also:
- Discussion of how AChE could cause issues more broadly, a clear description of the receptor differences and their locations and interactions with comparisons, and discussion if how various AChEs can impact the enzyme (MoA(. Some evidence of critical evaluation
70%+, as above but also:
- Discuss the side effects of their use, what is know about AEs (adverse effects), how AEs may be treated, and what are the benefits vs. risks? Clear evidence of critical evaluation
Acetylcholinesterase
2 types:
- True cholinesterase
- Acetylcholinesterase found at nerve endings, skeletal muscle
- Pseudo cholinesterase
- Butyrylcholinesterase found in plasma, liver, instestine
Both hydrolyse ACh, true AChE has greatest affinity for ACh
AChE is a globular protein that resemble bunches of balloons tethered to the postsynaptic membrane
1 molecule of cholinesterase hydrolyses 5000 molecules of ACh per second
