where are the cell bodies for symp and parasym located?
both system has their cell bodies in the central nervous system
thoraco-lumbar region –> symp
cranial and sacral region –> parasymp
Sympathetic system (SNS) -pre and post synaptic neuron
short pre-ganglionic and long post-ganglionic
Parasympathetic system (PNS)
long pre-ganglionic neurons and short post ganglionic neuron
Transmitters of the ANS
- sympathetic pre-ganglionic neurons release Ach and post ganglionic neurons release Noradrenaline
- The presynaptic neurons release Ach to the adrenal medulla and adrenal medulla can release adrenaline and noradrenaline released in the circulation not tissue
- Parasympathetic system pre and post synaptic neuron release Ach
- the somatic neurons release Ach at target tissue
Sweat glands
sweat gland is part of the sympathetic NS –> sweat glands is part of the sympathetic –> cholinergic–>use Ach as neurotransmitter
co-transmitters in ANS
stored with and release with the main transmitter - have their own receptor - modulate activity
e.g. (ATP + NA) and (NO + ACh)
Does all part of the ANS use acetylcholine OR noradrenaline as the main neurotransmitter?
NO, in parts of the ANS the main transmitter is neither
acetylcholine OR noradrenaline…= NANC system (Non Adrenergic Non Cholinergic) e.g. nitric oxide (NO) involvement in erection - ) involvement in erection
ACh
sweat glans is part of the sympathetic cholinergic
stored with and release with the main transmitter - parasymp
Summary of the process of neurotransmission
1-start with the uptake of transmitter precursor entering the nerve terminal via an active transport
2-precursor is activated by metabolized enzyme
to form the neurotransmitter
3-neurotransmitter is stored within the storage system
4-action potential arrives at axon terminal- causes influx of calcium and release of the neurotransmitter
6-intract with receptors on effector organs
final step = determination of the action of the transmitter either by
- inactivation of the transmitter
- by metabolism
- taken back by the neural tissue by active uptake
- or it might be taken up by non-neuronal tissue
response of the neurotransmitter depend on the
- response dependent on
- tissue type
- neurotransmitter release and the receptor type
effect of sympathetic NS
pupil dilation - contraction of radial muscle
Broncho-dilation -no direct intervention -adrenaline released can effect the lung
-increase in heart rate and force of contraction
- vasoconstriction
- increase in blood pressure and vasodilation
- decrease in GI motility
- sweating
Parasympathetic NS
pupil constriction bronchoconstriction decrease in heart rate no effect and change on blood vessles increase gasto-intestinal motility stimulate exocrine secretion
Receptors of the ANS
ACH - choline receptor - nicotinic - muscarinic Noradrenaline - adrenoreceptor alpha and beta both systems can have some effect- most effect by most dominant system
ANS Receptors in other part of the body
•Tissues may have receptors for both ACh & NA
Receptors may be present even if the nerves aren’t: e.g
- NA receptor in bronchial smooth muscle
- ACH receptor in blood vessels
- no physiological role - can be activated by drugs
autonomic receptors” may exist in other parts of the
body not associated with the ANS eg brain….
Nicotinic receptors
found on
- skeletal muscle –> contraction of muscle
- parasympathetic and sympathetic ganglion
found on the post -symp ganglion
Muscarinic Receptors
- Neuroeffector tissues of parasympathetic NS
-
What effects are seen when peripheral muscarinic receptors are stimulated?
- misosis (pupil constriction )
- stimulated saliva flow
- decreased heart rate
- bronchoconstriction
- stimulates peristalsis and secretion
- stimulate bile release
- bladder constriction
Adrenoceptors
classification based on rank order of potency of:
noradrenaline(NA), adrenaline (adr) & isoprenaline (iso)
classification based on rank order of potency of:
—Alpha: noradrenaline(NA)> adrenaline (adr) >isoprenaline (iso)
—-Beta: isoprenaline > adrenaline ≥ noradrenaline
What effects are seen when peripheral adrenoceptors are stimulated?
not clear which type of receptor Alpha or Beta is involved in each
- Mydriasis
- reduced saliva flow
- increased SV and HR
- Vasoconstriction
- reduced peristalsis and secretion
- glycogen –> glucose
- inhibition of bladder contraction
- adrenaline release
- bronchodilation —> not involved
α-adrenoceptors
noradrenaline ≥ adrenaline > isoprenaline
excitatory more involved in contraction
β-adrenoceptors
isoprenaline > adrenaline ≥ noradrenaline
inhibitory(except in the heart)
Relaxation - dilation
receptor involved with
- Mydriasis
- increased SV and HR
- Vasoconstriction
- -inhibition of bladder contraction
- Mydriasis –> Alpha
- increased SV and HR –> Beta
- Vasoconstriction –> Alpha
- reduced peristalsis and secretion –> Beta
- inhibition of bladder contraction –> Beta
Adrenoceptors
esponse of a tissue depends on:
predominate subtype of receptor activated
relative populations in the tissue
relative potency of the agonist (eg NA vs adr)
α and β- adrenoceptors can coexist on different tissues, so the response seen depends on the relative abundance of the subtypes and how well the ligand activates each subtype.
Alpha vs Beta
Alpha receptor are sitting behind the sympathetic Nerve so they are the one that are going to be
targeted by NA and initate a response
Beta receptor - sit further away- they are most likley to be activated by the adrenaline released
from the medulla.
Synthesis & storage of acetylcholine
1-choline comes from diet enters the axon terminal by active transport through choline transporter
2-choline to acetylcholine by choline acetyl transferase
3- Acetylcholine into vesicle-associated transporter
Exocytosis of ACh
- AP arrives at Axon termina
- Influx of calcium
- fusion of the vesicel to the termina membrane
and release of Ach
where drugs targeting the Ach-choline receptor effect ?
Sympathetic system - preganglionic and post ganglionic interaction and interaction with medulla
Parasymp system - will effect the transmission of neurotransmitter between the pre- and post synaptic neuron and the effector tissue
and somatic system
BOTOX- botulinum toxin
cause of some form of food poisoning inhibits Ach Release
Interferes with exocytosis release of Ach - by preventing the fusion of the membranes
Symptoms of botulism
blurred or double vision drooping eyelids slurred speech difficulty swallowing dry mouth progressive weakness with paralysis fixed or dilated pupils maybe constipation facial weakness on both sides of the face breathing difficulty that may lead to respiratory failure
If Botulinum toxin affects so many sites, can it
have a therapeutic use?i
injected directly to the target tissue
selectivity of action p- it’s not getting into the circulation
Therapeutic uses of Botox
mostly related to effects on skeletal muscle
neurotransmission e.g.
- bleopharospasm – uncontrolled contractions of eyelid
- relaxes those muscles and allows eyes to be kept open
-cerebral palsy (not an approved use)- reduce muscles rigidity and uncontrollable spasms - not approved used
hyperhidrosis
hyperhidrosis –
abnormal & excessive sweating
- injected directly into the sweat gland to cause reduction in the amount of Ach released to stimulate sweating
Termination of the action of ACh
acetylcholinesterasecholine breaks down ACh to choline + acetate
Choline which can be recycled
Acetylcholinesterase results in enhanced neurotransmitter transmission at all site where Ach
is released. Accounts for symptoms seen following poisoning with organophosphate which are
Achestrase inhibitors
Symptoms of organophosphate poisoning
1- Stimulation of muscarinic receptors—DUMBBELLS
2-2. Stimulation of nicotinic receptors - NMJ
Ganglion
3. CNS effects - Anxiety; restlessness
lethargy; confusion; pyschosis, coma; seizures
therapeutic use of anticholinesterases
myasthenia gravis (NMJ) - - autoimmune condition associated with decreased skeletal neuromuscular transmission of Ach Alzheimer’s disease (CNS)- given systematically
therapeutic use of anticholinesterases side effect
Side-effects
diarrhoea, urination, miosis, bradycardia, bronchoconstriction
emesis, lacrimation, (lethary), emesis….
Overtreatment
May lead to a cholinergic crisis with increased cholinergic
effects….
Summary of the process of transmission of NA at sympathetic nerve terminals
1-L-tyrosine from diet
2- metabolized to dopamine
3-in the vesicle the final stage of NA synthesis occurs
4- vesicles contain : NA, DA and ATP
5- -AP and Ca influx
6- interacts with A or B depending on the location
Termination
- uptake to the axon terminal (1)
- uptake by non-neural tissue (uptake 2)
How can drugs effect NA
Drugs can affect:
Synthesis
Storage
Release
Action
Inactivation
•overlap between endogenous transmitters
dopamine ⇒ noradrenaline ⇒ adrenaline
Any drug effecting one of these hormone will also effect the others
point of difference: receptor they interact with
dopamine interact with dopamine receptors in
the CNS
⇒ Maybe used for effects on the sympathetic NS effects
⇒ Maybe used for other effects – but their side effects
maybe related to actions on the sympathetic NS
Drugs affecting NA release
can
Block release
Cause release
Drugs targeting NA release - direct blockers
= Noradrenergic neuron blocking drugs
Abolish response to nerve stimulation
interfere with sympathetic NS responses & reflexes reduces
Mechanism of action?
reduces Particularly with cardiovascular system
- not very well understood
- requires the uptake of these drugs into the nerve terminal - happens by same neuronal uptake NA uses.
- once inside the nerve it interferes with the movement of AP in the nerve terminal and deplete the NA from the vesicles meaning there is less NA release to
interact with the receptors
Effect NA release from all site of the body
bretylium guanethidine
Noradrenergic neuron blocking drugs
used for treatment of hypertension
Bretylium inhibits norepinephrine release by depressing adrenergic nerve terminal excitability.
Drugs targeting NA release - releasers
eg amphetamine; ephedrine/pseudoephedrine (structurally related to NA weak direct action of NA
receptors)
Mechanism of action: = Indirectly acting sympathomimetics
- NA released independently of AP
- activation by indirect release of NA
Sympathomimetics
are substances that mimic or modify the actions of endogenous catecholamines of the sympathetic nervous system
Sympathomimetics modes of transmission
1- emphetamine ephedrine enter nerve terminal by uptake
2-once inside they are taken up into vesicles by exchange with NA
Indirectly acting sympathomimetics
mostly used for their effects within the CNS - release of dopamine in the reward pathway system
produce effect in the periphery which strongly resembles activation of symp NS - increase in Bp and HR
Pseudoephedrine
Pseudoephedrine
nasal decongestant
⇒ vasoconstriction of dilated nasal vessels via α-adrenoceptors
⇒ ↓ tissue swelling and nasal congestion
Amphetamine & related compounds
ADD (ADHD) / recreational use (DA effects)
Side-effects: tachycardia; hypertension…
Drugs affecting NA removal
Affect uptake
Affect NA metabolism
NA uptake major pathway of NA removal in the
periphery
- so drugs that interfere with this will increase
the amount of NA available to intract with the
receptors lead to sympathomimetic actions
Drugs & NA uptake
Inhibitors of Uptake 1
eg cocaine; used for effects in CNS - causing excitement
enhance sympathetic transmission
↑HR; ↑BP; (euphoria; excitement)
e.g. MAO-I
Monoamine Oxidase - main enzyme involved in metabolism of NA
⇒ increase releasable store of NA –> increase effects
Uptake is the main removal process in the ANS
Control the amount of NA and dopamine present in the Cytosol of Axon terminal
Uptake is the main removal process in the ANS
mainly used for their CNS effects ⇒ may cause side-effects related to ANS
MAO more involved in termination of the action of NA and DP in CNS
MAO inhibitors used for their action in CNS - maybe used as anti-depressant
MAO-B inhibitors
MAO-B inhibitors decrease the normal activity of an enzyme – monoamine oxidase – that breaks down dopamine after it completes its activity in the brain. These drugs allow available dopamine (made by remaining dopamine-producing cells or given via other medications) to function for a longer period of time
Advantage of targeting the receptor on tissue ?
Targeting receptors on the effector tissues is associated with fewer side effects than
drugs that target the transmitter synthesis, storage, release or removal of the transmitter
Targeting nicotinic receptors
Activation or blockade of nicotinic receptors…..
will affect ganglionic neurotransmission ( in Smp + parasym ganglion)
responses complicated by affecting both the
sympathetic and parasympathetic arms
better to use drugs that have narrow effect
Receptor interaction
agonists (- Stimulate receptors )
⇒ effects ≅ postganglionic nerve stim
= parasympathomimetic - mimicking the action of parasymp NS -sympathomimetics
antagonists - Block the action
⇒ effects ≅ postganglionic nerve inhibition
= parasympatholytics
sympatholytics
What effects will muscarinic AGONISTS cause?
drugs that will activate the muscarinic receptors in Smp + parasym ganglion pupil constriction stimulated saliva flow bronchoconstriction decrease in heart rate increase gasto-intestinal bladder contraction stimulate bile release
What effects will muscarinic ANTAGONISTS
cause?
pupil dilation
inhibit secretions
increase heart rate
relax bronchial smooth muscle (bronchodilation)
decrease gastric motility & gastric acid secretion
decreased bladder emptying
Can ACh be used clinically?
no a really viable therapy of option - very rapidly broken down
Drugs targeting muscarinic receptors….eye
Agonists : cause pupil constriction and decrease intraocular pressure (used on
glaucoma which is a condition with increased pressure in the eye .
Antagonists: cause pupil dilation (e.f. eye examination )
Drugs targeting muscarinic receptors: Lungs
->asthma / COPD
agonist - cause bronchoconstriction (no clinical need)
Antagonist - cause bronchodilation
e.g. chronic obstructive pulmonary disease
anaesthetic premedication (dry secretions)
- musacrinic agonist = associated with exocrine secretion- primarily these secrestion can be stimulated in respiratory tract
Agonist - cause secrestion
Antagonist = inhibit secretion (eg. during surgery)
Drugs targeting muscarinic receptors ….GIT
GI motility
muscarininc agonists will increase motility
(may be useful to treat constipation)
muscarinic antagonists will decrease motility
(use to treat diarrhoea)
Drugs & adrenoceptors
effects we see depends on whether the drug effect the alpha or Beta receptors or both
pupil dilation - contraction of radial muscle (alpha)
Broncho-dilation -no direct intervention -adrenaline released can effect the lung
-increase in heart rate and force of contraction (beta)
- vasoconstriction (alpha)
- increase in blood pressure and vasodilation
- reduced peristalsis and secretion (alpha/beta)
- decrease in GI motility
- sweating
- glycogen –> glucose (beta)
- inhibition of bladder contraction (beta)
Therapeutic use of adrenaline?
vasoconstriction (α) / vasodilatation (β)
increase HR & force of contraction (β)
bronchodilation (β)
treatment for anaphylaxis- severe allergic reaction
rapidly broken down has to be give via IM injcetion
causes : decreased BP, HR bronchoconstriction
Adrenaline opposes these symptoms
levophed
vasoconstriction (α) ⇒ increases BP
used in life-theatening hypotension
often used during of after CPR
for rapid reponse it is given intravenously
Therapeutic uses of drugs targeting adrenoceptors?
we have much better drugs for agonist and antagonist that show better selectivity for alpha and beta receptors
Drugs targeting adrenoceptors - eyes
α- agonists cause pupil dilation
- useful in eye examination and surgery
- there’s also a related effect on the blood
vessels - drugs that activate alpha receptors
cause vaso-constriction and produce
decrease redning in the eye
Drugs targeting adrenoceptors – blood vessels
α-agonists - cause vasoconstriction
nasal decongestants and ocular decongestants
α-antagonists - inhibit vasoconstriction
LOWER blood pressure (eg in hypertension)
Drugs targeting β-adrenoceptors – bronchi
β-agonists - cause bronchodilation
useful in treatment of asthma main treatment for acute asthma attacks
• β - antagonists - ??ult
• β-antagonists are CONTRAINDICATED in asthmatics
