Lecture 15- ANS (2) Flashcards
neurotransmission is a
common site of drug action
basic steps in NT
- Uptake of precursors
- Synthesis of transmitter
- Vesicular storage of transmitter
- Degradation of transmitter
- Depolarisation by propagated AP
- Depolarisation-dependent influx of Ca2+
- Exocytotic release of transmitter
- Diffusion to post-synaptic membrane
- Interaction with post-synaptic receptors
- Inactivation of transmitter
- Re-uptake of transmitter
- Interaction with pre-synaptic receptors
cholinergic system is used in both
sympathetic and parasympathetic (preganglionic- nicotinic receptors)
Messenger post ganglionically in the parasympathetic NS
synthesis of acetyl choline by
acetylcholinetransferase
acetylcholine degradation by
acetylcholinesterase
diet supplies us with an adequare supply of
choline
acetyl coA
key intermeidate of metabolism
choline is…..
recycled
Nicotinic AChRs at autonomic ganglia and the NMJ
differ in structure
some drugs have actions that act selectively at autonomic ganglia e.g.
Ganglion-blocking drugs
ganglion blocking drug e.g.
trimethaphan
trimethaphan
used in hypertensive emergencies and to produce controlled hypotension during surgery (not used regularly anymore)
few subtype selective … agonists or antagonists are available
mACHr
mACHr antagonist tolterodine (one of the few and newer agents which show tissue selectivity( used to treat)
overactive bladder
action of endgenous rleeased ACh can also be released by
AChE inhibitors
e. g. Pyridostigmine
e. g. donepezil
e.g. Pyridostigmine
treats myasthenia gravis
e.g. donepezil
alzheimers treatment
A relative lack of selectivity of cholinerrgic drugs means that
unwanted side-effects often limit their usages
e.g. non-selective, mACH receptors agonists is likely to cause autonomic side effects
- Heart rate and cardiac output decrease
- Smooth muscle: increase bronchoconstriction and GI tract peristalsis
- Exocrine glands: increase sweating and salvation
SLUDGE syndrome
a mneumonic for the pathoglogical effects indicative of paraysmpathetic nervous system
outline SLUDGE
SLUDGE is encoutnered in cases of
- Drug overdose
- Ingestion of magic mushrooms
- Organophosphorus insecticides (parathion) or nerve fades (sarin)
*
Sarin and parathion action
covalently modify ACHesterase to irreversibly deactivate the enzyme and raise acetylcholine levels
SLUDGE caused by
chronic stimulation of muscarinic acetylcholine receptors, in organs and muscle innervated by the parasympathetic NS
SLUDGE can be treated with
Atropine
Pralidoxime
Anti-cholinergic agents
mAChR agonists examples
Pilocarpine- treat glaucoma
Bethanechol- stimulate bladder emptying
mAChR antagonists
- Ipratropium and tiotropium are used to treat some forms of asthma and COPD
- Tolterodine, darifenacin and oxybutynin used to treat overactive bladder
Vast majority of post ganglionic sympathetic neurones are
adrenergic- utilising noradrenaline as chemical transmitter
Post-ganglionic sympathetic neurones
possess a highly branching atonal network with numerous varicosities, each of which is a specialised site for calcium dependent NA release
synthesis of noradrenaline occurs where
Synthesised within the adrenal medulla
synthesis of noradrenaline
Precursor- tyrosine—> DOPA —> dopamine (taken up by vesicles and then conversion) —> NA
how is noradrenline converted to adrenaline
by phenylethanolamine N- methyltransferase
90% of NA rleeased at cleft is
repacked and recycle (sodium/ NA cotransporter)
noradrengeric transmission
- NA diffuses across the synaptic cleft and interacts with adrenoreceptors in the post-synaptic membrane to initiate signalling in the effector tissue
- NA interacts with presynaptic adrenoreceptors to regulate processes within nerve terminal e.g. NA release
- NA has only a very limited time in which to influence pre and post synaptic adrenoreceptors as it rapidly removed from the synaptic cleft by NA transporter proteins
noradrenergic transmission termination
Uptake 1: NA actions are terminated by re-uptake into the pre-synaptic terminal by Na+ dependent, high affinity transporter
Uptake 2: NA not re-captured by Uptake 1 is taken up by a lower affinity, non-neuronal mechanism
metabolism of NA not reuptaken by vesicles in the pre-synaptic terminal
Within the pre-synaptic terminal NA not taken up into vesicles is susceptible to metabolism by two enzymes
- Monoamine oxidase (MAO)
- Catechol-O-methyltransferase (COMPT)
subtype selctive adrenorecptor agonists and antagonists are
used clinically
B2-adrenoreceptor-selective agonists (salbutamol) used in
asthma to oppose bronchoconstriction
why is B-adrenoreceptor selectivity of salbutamol important
limits possible CVD side-effects (e.g. positive inotropic and chronotropic actions)
