Lecture 16 - (ANS) Neurochemistry And Pharmocology Flashcards
What points of neurotransmission can we have drugs interfere with the process?
The degradation of the neurotransmitter
Interaction of NT with post-synaptic receptors
Transmitter inactivation
Re-uptake of transmitter
How is acetylcholine synthesised?
Acetyl CoA + Choline
What enzyme is necessary to produce ACh from acetyl CoA and choline?
Choline acetyltransferase (CAT)
What enzyme is needed to degrade acetylcholine?
Acetylcholineesterase
Where is acetylcholineesterase located?
Surfaces of the synapse
What do nAChr antagonist drugs do?
Block transmission between the 2 neurones in the ANS
Why is it important to use selectively blocking nAChr drugs that are specific to autonomic ganglia?
Neuromuscular junctions have nAChrs
Any non selective nAChr antagonist would therefore lead to paralysis
What is a ganglion blocking drug (nACHr antagonist) that is used in hypertensive surgical emergencies?
Trimethaphan
What is the method of action of a cholinesterase inhibitor?
Inhibits the action of acetylcholine esterase
Means ACh doesn’t get degraded as easily so builds up in the synaptic cleft
What cholinesterase inhibitor is used to treat myasthenia gravis?
Pyridostigmine
What cholinesterase inhibitor is used to treat Alzheimer’s disease?
Donepezil
What side effects are non selective muscarinic ACh receptor agonists likely to cause?
Decreased Heart rate so less cardiac output
Bronchoconstriction
GI tract peristalsis
Increased Sweating and salivation
What is SLUDGE Syndrome?
The pneumonic for the pathological effects that are indicitive of a massive discharge of the parasympathetic nervous system/over stimulation of muscarinic ACh receptors
What does the SLUDGE pneumonic stand for?
Salivation
Lacrimal
Urination
Defecation
Gastrointestinal upset
Emesis
What is lacrimation?
The flow of tears from the lacrimal glands
What is Emesis?
Vomiting
When do you normally get SLUDGE syndrome?
Drug overdose
Magic mushrooms
Exposure to nerve agents and organophosphorus
How do nerve agents increase acetylcholine levels?
Covalently modify acetylcholineesterase deactivating it
What causes the symptoms of SLUDGE?
Prolonged stimulation of Muscarinic acetylcholine receptors
Overstimulates the organs supplied by M receptors
What are the 2 anti cholinergic agents used to treat SLUDGE syndrome?
Atropine
Pralidoxime
How does Pralidoxime act to treat SLUDGE syndrome?
How does Atropine act to treat SLUDGE syndrome?
Pralidoxime = Reverses covalent modification of acetylcholine esterase
Atropine = Competitive antagonist to the Muscarinic Receptors
What are 2 Muscarinic ACh receptor agonists that treat glaucoma?
Pilocarpine
Bethanechol
What are 2 Muscarinic ACh receptor antagonists used to treat some forms of asthma and COPD?
Ipratropium
Tiotropium
What are 3 Muscarinic ACh receptor antagonists used to treat overactive bladder?
Tolterdine
Darifenacin
Oxybutynin
What is a Muscarinic ACh receptor antagonist used to treat Irritable Bowel Syndrome?
Hyoscine
What structures do postganglionic sympathetic neurones (noradrenaline) form on smooth muscles?
Highly branching atonal network with many Varicosities
What are varicosities?
Bulges along the axons
They are specialised zones that release neurotransmitter
What is released from varicosities of smooth muscles?
Noradrenaline
(Ca2+ dependant vesicular noradrenaline release)
What is released from varicosities of smooth muscles?
Noradrenaline
(Ca2+ dependant vesicular noradrenaline release)
What is the precursor molecule to synthesise noradrenaline?
Tyrosine
What are the steps to produce noradrenaline?
Tyrosine ——> DOPA ——> Dopamine ——> Noradrenaline
What stimulates the release of the noradrenaline from the noradrenergic varicosities?
Ca2+ dependant exocytosis
Needs a Ca2+ influx
How is Noradrenaline removed from the synaptic cleft?
Not broken down in cleft but re taken back up by NET (norepinephrine) cotransporter
What can happen when noradrenaline has been re taken back up into the varicosities?
Repacked back into a vesicle
Metabolised or broken down
How do the noradrenaline filled vesicles have a high concentration of noradrenaline?
H+ ATPase pumps protons into the vesicle, this acidic nature drives noradrenaline into the vesicles
What structure rapidly re takes up noradrenaline from the synaptic cleft making it so NA doesn’t have a long time to act on postsynaptic adrenoceptors?
Why is it removed quickly?
Noradrenaline/norepinephrine Transporters (NET)
NET has a high affinity for NA
Na taken back into varicosity with NA
What are the 2 ways by which noradrenergic transmission can be terminated?
Reuptake into presynaptic terminal by Na+ dependant high affinty transporter (NET)
Remaining NA taken up by low affinty non-neuronal mechanism
What is a B2- adrenoceptor-selective agonist to treat asthma/oppose bronchoconstriction?
Salbutamol
Why is it important when treating an asthmatic that the drug is selective to only be an agonist to B2 adrenoceptors?
To only affect bronchiole smooth muscle and not have cardiovascular effects (like +ve inotropy and +ve chronotropy)
What can propranolol and atenolol be used to treat?
Hypertension
What is the difference between propranolol and atenolol?
Atenolol is selective for B1 so only acts on the heart which is good
Propranolol is non selective so could affect B2 as well as B1, this is bad since it causes bronchoconstriction.
What is an a1-adrenoceptor-selective antagonist that treats cardiovascular disorders like hypertension?
Doxazosin
What is an B1-adrenoceptor-selective antagonist that treats cardiovascular disorders like hypertension?
Atenolol
What is the problem with drugs using anti cholinergic drugs?
Drugs can exert actions both autonomic and CNS:
Systemic symptoms
CNS symptoms
