PHAR232 - Cholergic & Adrenergic Pharmacology Flashcards
What are the key receptors that ACh bind to?
Nicotinic
Muscarinic
How is acetylcholine synthesised?
Choline acetyltransferase (CAT or ChAT) transfers an acetyl group from CoA and binds to choline
REVIEW
REVIEW
REVIEW
REVIEW
REVIEW
REVIEW
REVIEW
rREVIEW
Does choline cross the BBB?
No
REVIEW AND DRAW OUT??
What enzyme breaks DOWN ACh to choline?
Acetylcholinesterase (AChE)
What do the autoreceptors (Muscurininc e.g. mAChRs) do?
- Modulate how much ACh is in synaptic cleft
- act as ‘eyes’ of synapse
Allow pre-synpatic terminal to know how much ACh is being released
What does the activation of autoreceptors on the presynaptic membrane do?
- INHIBIT ACh release
- Prevents over-excitation of synapse
- = feedback regulation
- Reduces Ca2+ release
NOT ALL PRE-SYNAPTIC NEURONS HAVE MUSCURINIC AUTORECEPTORS ON THEM
BOTOX BOTULINUM TOXINS
LEARN AND EVALUATE SUMMARY AT A SYNAPSE
If a neuron is using ACh as a NT what is it referred to as?
Cholinergic nerve/neuron
How many subtypes of Muscarinic ACh receptors (mAChRs) are there?
5
What is M1, M3 and M5 mAChRs for?
M1 = Neurons
M3 = gands/smooth muscle
M5 - CNS, salivary glands
Are all muscarinic Ach Receptors metabotropic?
yes all of them
What is the GPCR subtype for and the mechanism of actions of M1, M3 and M5 mAChRs?
GPCR subtype = Gq
Gq = PLC-IP3-DAG pathway
– activate phospholipase C (PLC)
– increase IP3 & DAG
– increase IP3-mediated liberation of SR
store Ca+2
– increase DAG-mediated activation of
protein kinase C (PKC)
– excite neurons, increase glandular
secretions, cause smooth muscle
contraction
Where are M2 and M4 receptors ?
M2 = cardiac
M4 = CNS
What is the GPCR subtype and mechanism of action for M2 and M4 mAChRs?
Subtype: Gi
– inhibit AdCy
– decrease cAMP
– decrease PKA
– close Ca+2 channels
- Increase K+ in SA and AV nodes
= Decrease HR
= Decrease contraction force
= Decrease CO
= Increase PNS
What is the mechanism of action of M1 stimulation?
= Gq protein of PNS
= Increase IP3 and DAG
= IP3 = increase Ca++
= Increase Ca++ = increased cell excitability
= Increase excitabilty
= decreased K+ conductance
= Reduced repolarisation
= Increased depolarisation of PNS neurons
= Promote relaxation
= promote memory and cognition
» M1 inhibits K+ conductance = PROMOTES RELXATION (PNS)
Specifically M2 does what?
» M2 increases K+ conductance
(important in SA, AV nodes)
Specifically M3 does what?
» M3 increases Ca+2 conductance
= Bronchoconstriction
Muscarinic Receptor Effects on the * cardiovascular sys?
- primary parasympathetic mediator
- slows HR, decrease CO, causes vasodilation
Muscarinic Receptor Effects on smooth muscle (not including blood vessels) do what action?
- increase GI ‘rest and digest’,
** bronchoconstriction
Muscarinic Receptor Effects on secretions?
- promotes sweating, lacrimation, salivation,
bronchial secretion - stimulation of exocrine glands
Muscarinic Receptor Effects - eye
- constricts pupillae & ciliary muscles
Are nicotinic receptors metabotropic or ionotropic?
Ionotropic
REVIEW NICOTINIC RECEPTORS
What is the primary ion the Nicoinic ACh receptors cause for influx?
Na+
Is a muscinaric receptor primarily PNS or SNS?
PNS
Parasympathomimetics
Muscarinic receptor agonists
Muscarinic receptor agonists M1 vs M2
- PNS agonist
Muscarinic antagonists - aka parasympatholytic
What does atropine do?
Inrease AV node transmission
What do muscarinic antagonists do?
- Blocks PNS
- Increases SNS
- Inhibits glandular secretions
- Reduces saliva
- Increase HR = Increase AV node transmission
- TACHYCARDIA (high dose)
= BRADYCARDIA (low dose)
M1 & M2 LEARN
M1 & M2 LEARN
learn
Cholinergic antagonist effects
NORADRENALINE (NA) AND ADRENALINE structure
LEARN Catecholamine biosynthesis
Differences of adrenergic receptors
- Structure of the receptors will alter how the GPCR work
- How they are all regulated is difference
Is adrenaline defined more as a hormone or NT?
Hormone
Is Noradrenaline defined more as a hormone or NT?
NT
Relies a lot on co-factors
LEARN NORADRENERGIC SYNAPSE
- NET inhibitors are the ‘vacuum’ to put NA back into the presynaptic cell
- EMT is the minor inhibitor ‘vaccum’ for post synaptic cell
Do adrenergic receptors also have autoreceptors?
Yes
LEARN - Noradreneric synapse
Does alpha or beta noradrenergic receptors like NA more?
alphas like noradrenaline better
Remember that _________ receptors = autoreceptors
alpha 2
what does a sympathomimetic drug do?
mimic sympathic activity
What does a sympatholytic drug do?
Opposes or blocks sympathetic activity
lysis = breakdown
LEARN ADRENERGIC AGONIST EFFECTS
- Adrenalin use in anaphylaxis
- Adjunct to local anathsethic due to vasoconstriction
- Low BP due to shock
The main controller of all blood vessels for vasoconstriction is the ________ hormone acting on ________ receptors.
Adrenaline
alpha 1 receptors
What receptors on key blood vessels regulate vasodilation?
beta 2 receptors (but not a major role)
What is an ANTAGONIST of anaphylaxis creating bronchodilation and vasoconstriction?
Adrenalin
What does histamine do to the airways?
constriction and widespread vasodilation
Is noradrenaline (NA) a hormone or NT?
NT
What is an Indirect-acting sympathomimetic?
- MAO in the gut destroys tyramine
- If someone is taking MAO- inhibitor will reduce MAO that would breakdown tyramine = parasympathomimetic
- what else does an MAO disinhibit in the gut??
Would ALPHA 1 ADRENERGIC AGONISTS in SNS or PNS pathways?
Increase SNS
LEARN AND DRAW OUT - Adrenergic agonist effects
Beta 1 adrenergic agonists flow chart
The physiological effects of B1 adrenergic agonists
The effects of beta 2 agonists
The sweat glands and MOST blood vessels only have _____________ innovation
sympathetic
Bronchial smooth muscle only has a ___________________ constrictor innervation. (however, it’s tone is sensitive to circulating adrenaline)
PARASYMPATHETIC
Resistance artieries have a ____________ vasoconstriction innervation but NO _________________ innervation. Instead, the constrictor tone is opposed by a background release of NO from the endothelial cells
sympathetic
parasympathetic
What is he sympathetic adrenoreceptor type on the heart?
Beta 1 adrenergic receptors
What is the PNS cholinergic receptor in the heart?
Muscarinic (M2)
What does the increase in SNS do in the heart?
- Increase HR
- Increase contraction force
In the large coronary blood vessels - what adrenoreceptors in the SNS stimulate vasoconstriction?
Alpha 1 and 2
What do the small coronary blood vessels and muscle SNS receptors use to stimulate vasodilation?
SNS effect = beta 2 adrenoreceptors
What adrenoreceptors do the SNS have on the viscera, skin and brain blood vessels?
Alpha 1 adrenoreceptors
What does SNS alpha 1 receptor stimulation on viscera, skin and brain in blood vessels cause?
Vasoconstriction
The PNS has NO EFFECT on the blood vessel arterioles, except for?
Cholingeric vasodilation at M3 receptors
What is the cholinergic PNS receptor subtype in the heart?
M2 cholinergic receptors
Does smooth muscle bronchi viscera have sympathetic fibre innervation?
no
How is smooth muscle in the lungs dilated?
By circulating adrenaline (epinephrine)
and NA activating beta 2 receptors
What is the receptor subtype in the lungs innervated by adrenaline?
Beta 2
Does the SNS or PNS cause vasoconstriction in the lungs?
PNS
What receptor in the lungs causes vasoconstriction by the PNS?
M3 muscarinic - ACh
What are the 3 adrenergic receptors that are innervated by the GI tract?
Alpha 1 & 2
Beta 2
Cholinergic Receptors (Muscarinic):
What GPCR subtypes are:
M1, M3, M5: ___
M2, M4: ___
Gq.
Gi
What type of cholinergic receptors is the PNS GI tract innervated by?
Muscarinic ACh Rs
Does the SNS or PNS cause relaxation in the uterus?
SNS
What are the SNS receptors in the uterus?
Beta 2 adrenergic receptors
Does the SNS dilate or constrict the eye pupil?
dilate
What is the eye adrenergic receptors that cause dilation by the SNS?
alpha 1
If the SNS dilates the eye, what is the vasoconstriction cholinergic receptor in the eye?
M3 muscarinic ACh
What receptor innervation causes renin secretion from the kidneys by the adrenergic SNS ?
beta 1
Pre-ganglionic neurons are cholinergic or noradrenergic?
cholinergic ACh neurons
Preganglionic neurons are USUALLY always transmitted via _____ ___ ________
Nicotinic ACh receptors
Post-ganglionic PNS neurons are _________ and act on _________ receptors in target organs
cholinergic
muscarinic
Postganglionic SNS are mainly ___________ but have ___________ in the sweat glands
noradrenergic
cholinergic
NT release is inhibited when _____ channel opening is inhibited or when ____ channel opening is increased.
Ca++
K+
Presynaptic regulation by receptors linked are by _____ channels
Ion
The noradrenergic and cholinergic neurons are regulated by ____________ feedback
autoinhibitory
A cholinergic synapses ACh is rapidly inactivated by _______________
acetylcholinesterase
Is A
DRAW THIS OUT
Co-transmission and neuromodulation
Muscarinic actions closely resemble the effects of __________________ stimulation
parasympathetic
After the muscarinic effects have been blocked by __________, larger doses of ACh produce nicotine-like effects, including:
- stimulation of all autonomic ganglia
- stimulation of voluntary muscle
- Secretion of adrenaline from the adrenal medulla
Atropine
ACh causes generalised ________________, even though most blood vessels have no _______________ innervation
vasodilation
Parasympathetic
How does ACh indirectly act on vascular endothelial cells?
Increases NO
= relaxes smooth muscle
Is ACh cholingeric secretion from sweat glands innovated by the PNS or the SNS?
SNS
Nicotinic receptor subtypes
Muscarinic receptor subtypes
What type of muscarinic receptor subtype is found in the salivary glands, smooth muscle, GI tract, airway, bladder and blood vessel endothelium?
M3
What is the cellular response of stimulating M3 receptors?
- Increased IP3
= Increased Ca++
What is the cellular response of M2 receptors in the cardiac tissue?
- Decreased cAMP inhibition
= Increased cAMP
= Decreased Ca++
-=Increase K+
= PNS relaxation
= CHOLINERGIC INHIBITION OF THE HEART AND CNS AND PERIPHERY
What is the cellular response of M1 receptors on neuronal ganglia?
- Increased IP3
- Increased DAG
- Depolarisation
- Slow EPSP
- Reduce K+ conductance
What is a key non-selective antagonist for muscarinic receptors?
Atropine
Where are M2 receptors found?
Cardiac tissue
Where are M3 receptors usually found?
gandular/smooth muscle tissue
What is the primary stimulation of M3 receptors? Excitatory or inhibitory?
Excitatory e.g. increased salivation
- Increased bronchial contraction
- Increased sweat
mAChRs are GPCRs causing what key 3 things?
- Increased PLC
- Increase IP3
- Increased DAG
- Inhibition of Ad Cy
- Increased K+
- Inhibition of Ca++
= PNS STIMULATION
CHECK THIS QUESTION WITH ANNA MARIE - IS IT INHIBITORY OR NOT??? - TEXTBOOK PAGE 178 SAYS THE ABOVE
Free choline within the nerve terminal is acetylated by a cytosolic enzyme __________ __________. Which transfers the acetyl group from acetyl Co-enzyme A.
choline acetyltransferase (CAT)
_________________ is an enzyme present in the presynaptic nerve terminals to hydrolysed ACh into choline + acetate.
Acetylcholinesterase
Inhibition of cholinesterase causes the accumulation of ______ in the cytosol
ACh
Where does ACh leak out from the cytosol into the synaptic cleft?
via the Choline carrier
What enzyme breaks down ACh?
Acetylcholine esterase (AChE)
Catecholamine Biosynthesis - REVIEW
Structure of Adrenergic Receptors
Is noradrenaline a NT or hormone?
NT
Is adrenaline a hormone or NT?
hormone
noradrenaline & adrenaline best recognised for effects on heart and lungs. What beta receptors are associated with an increased HR, increased force of contraction ?
beta 1 receptors
What receptor is associated with vasoconstriction by noradrenaline and adrenaline?
Alpha 1
What receptor is associated with bronchodilation by noradrenaline and adrenaline?
beta 2
precursor for both noradrenaline & dopamine =
tyrosine
Noradrenergic Synapse
5 steps associated with adrenergic and cholinergic synapses:
- synthesis
- packaging
- release
- signal termination
5 control of NT release
Noradrenergic Synapse -
* synthesis = multistep process
like ACh, synaptic vesicles containing NA triggered to move by incoming AP from axon
& absolutely controlled by_____ influx
calcium
unlike ACh, NA signal termination does NOT use an_______
enzyme
What do Noradrenergic synapses use for NA signal termination?
(NET)
- Norepinephrine transporter
What does NET do to stop NA signalling?
acts like vacuum cleaner to remove all NA from the synapse to stop NA signalling
Activation of ___________ receptors stop NA release in noradrenergic synapses?
Autoreceptors at NA synapse
What type of receptors are the NA autoreceptors?
A2 adrenergic receptors
Noradrenergic Synapse - review
built-in neuromodulator of NA
signalling
Catecholamines what are some effects mediated by adrenergic receptors:
dilate pupil (a1) or relax ciliary muscle of eye (b2)
* constrict blood vessels (a1)
* dilate blood vessels (a2 & b2)
* inhibit histamine release from mast cells in lungs
(b2)
* decrease gut motility (a1)
* sweating (a1) – note that primary effect = ACh
* goosebumps (a1)
* monitor adrenergic neurotransmitter release (a2
receptors decrease release; b2 receptors increase
release)
» Remember: a2 receptors = autoreceptors
Are a2 receptors autoreceptors?
Yes
What is sympathomimetic?
mimics sympathetic
(adrenergic)
What is sympatholytic?
oppose/block sympathetic
ADRENERGIC AGONIST EFFECTS - DRAW OUT
what does agonist activation of a1 adrenergic receptors do?
= Increase SNS
= Vasoconstriction
= Pupil dilation
= Decreased GIT
= Increase B glucose
= Sweating
= Goosebumps
what does agonist activation of beta-1 adrenergic receptors do?
= INCREASE SNS
= Increased cardiac acceleration
= Increase HR
= Increase SV
= Increase CO
= Decrease GIT
= Lipolysis
= Increase renin = increase BP
what does agonist activation of beta-2 adrenergic receptors do?
= Increase PNS
= Bronchodilation
= Vasodilation
= Increase blood glucose
= Pregnant uterus relaxation
= Mast cell stabilisation
= RELAXATION
activation of the adrenal medulla is by ACh acting on________ but as part of
sympathetic 2-neuron chain
nAChRs
What receptors does adrenaline stimulate?
a1, a2, b1, b2
- stimulates all subtypes of adrenergic receptors
- therefore causes all major effects when SNS is activated
REMEMBER: Adrenaline: net direct effect on BP from blood vessel changes is________ because of
balance between constriction/dilation
small
What are the effects of adrenaline on the cardiovascular system?
increase HR and contraction force = b1 receptor
- vasoconstriction of majority of blood vessels =
a1 receptor - vasodilation of other key blood vessels = b2
receptors - promote renin release from kidneys, increasing
BP indirectly = b1 receptors
Is adrenaline a physiological antagonist or agonist of anaphylaxis?
Physiological ANTAGONIST
= Increased bronchodilation
= Increased vasoconstriction
What are the side effects of too much adrenaline?
SERIOUS CARDIOVASCULAR EFFECTS
- Tachycardia
- Increased BP
- Increased vasoconstriction
- Potential ischaemia/necrosis
What is they key difference between adrenaline and NA?
= receptors with which they interact
- noradrenaline has small effect on b2 receptors
vs other adrenergic receptors
» since b2 receptors responsible for
vasodilation, NA only really
vasoconstricts
KNOW AND REVISE
Indirect-acting Sympathomimetics
How do Indirect-acting Sympathomimetics work?
compete with NA at uptake proteins and
vesicle transporters
- outcompete NA at uptake 1 to prolong its
effects at synapse - once inside presynaptic cell, outcompete NA
for transport into vesicles
» leads to passive, regular release of NA
from cell
- classic agents are for indirect-acting sympathomimetics are ________ and ________
amphetamine, tyramine
KNOW AND DRAW OUT
Think of alpha 1 receptors as INCREASED SNS
What happens when you’re on amphetamines
The effects of alpha-1 agonists
KNOW AND DRAW OUT
The effects of alpha-2 agonists
What is a rate-limiting step at a synapse?
The rate-limiting step in a process or reaction is the slowest step, which determines the overall rate or speed of the entire process.
wha are the 4 key summary steps for a synapse?
- dedicated synthesis
- rate-limiting step for control of synaptic control
- method of rapid termination of signal
- means of feedback regulation (=autoreceptors)
Muscarinic ACh Receptors (mAChRs) mechanism of action
= activate PLC
= increase IP3 and DAG
= Increase IP3 - mediated liberation of SR store Ca++
= Increase DAG-mediated activation of PKC
= Excite neurons
= Increase glandular secretions, cause smooth muscle contraction
M1 ACh neurons associated with?
M1 (neurons)
M3 ACh neurons associated with?
glands/smooth muscle
M5 ACh neurons associated with?
CNS, salivary glands
M2 ACh neurons associated with?
Cardiac
M4 ACh neurons associated with?
CNS
What do M2 (cardiac) and M4 (CNS) use Gi type GPCRs to INHIBIT ____ for cell inhibition
Ad Cy
What do Gi GPCR do on M2 and M4 cells?
INHIBITION
= Inhibit Ad Cy
= Decrease cAMP
= decrease PKA
= Close Ca++ channels
What additionally happens upon Gi GPCR to inhibit M1 cells
ADDITIONAL: Inibits K+ conductance
INHIBITION
= Inhibit Ad Cy
= Decrease cAMP
= decrease PKA
= Close Ca++ channels
What additionally happens upon Gi GPCR to inhibit M2 CARDIAC cells
ADDITIONAL: Increase K+ conductance (important in SA and AV nodes)
INHIBITION
= Inhibit Ad Cy
= Decrease cAMP
= decrease PKA
= Close Ca++ channels
What mAChR effects have on the cardiovascular system?
- PRIMARY SNS MEDIATOR
- Slows HR
- Decrease CO
- Causes VASODILATION
What mAChR effects have on the smooth muscle system? (not including blood vessels)
- INCREASE SNS
- Increase parastalsis
- BRONCHOCONSTRICTION
What mAChR effects have on the secretions?
- Promotes sweating
- Lacrimation (tears)
- Salivation
- Bronchial secretion
- Exocrine gland stimulation
What mAChR effects have on the eyes?
- CONSTRICTS pupils
Nicotinic ACh Receptors
How many alpha subunits are on nAChRs?
2
How many ACh bind to nAChRs for activation?
2
What would be clinical uses for parasympathomimetics?
- Treat glaucoma
- Slow HR
- Stop atrial tachycardia
- Stimulate bladder emptying
- Stimulate GI activity
What receptors are used on the target organ of PNS?
mAChRs
Sympathomimetic effects (muscarinic receptor AGONIST EFFECTS)
MUSCARINIC RECEPTOR AGONIST FLOW CHART -DRAW OUT
MUSCARINIC RECEPTOR AGONIST FLOW CHART -DRAW OUT
Could AChE inhibitors be classified as parasympathomimetics?
yes
What is the MAIN mAChR ANTAGONIST?
atropine
What is another term for mAChR antagonist?
parasympatholytic
Is choline readily transported across the BBB?
no
How does the brain gets major source of choline?
By recycled ACh
Catabolism *(breakdown) of phosphatidyl-choline
What is the rate limiting step in ACh signalling?
Availability of choline at synapse
What does the activation of autoreceptors do at the ACh synapse?
Inhibit ACh release
= feedback regulation
What do botulinum toxins do to ACh in the presynaptic synapse?
Destroy proteins involved in vesicle mobilisation *enzymes
- Stop/reduce ACh release
Does M3 increase or decrease Ca+ conductance upon AChR activation?
Increases Ca++ Conductance
blocking parasympathetic activity results 3 key things:
- Dilates pupil & impairs near vision
- Inhibits GI motility
- Relaxes smooth muscle INCLUDING
- BRONCHIOL RELAXATION
- BLADDER relaxation (retention)
M1 and M2 muscarinic ANTAGONISTS - DRAW THIS OUT
M1 and M2 muscarinic ANTAGONISTS - DRAW THIS OUT
Why would a muscarinic antagonist be used as a pre-op medication for surgery?
- reduce bronchial & salivary secretions
- Prevent reflex bronchoconstriction
Why would a muscarinic antagonist (atropine) be used as an antidote for toxicity?
Toxins often have AChE inhibitors
youtube
CHOLINERGIC ANTAGONISTIC EFFECTS at muscarinic receptors - KNOW AND DRAW OUT
What synthesises ACh?
choline acetyltransferase (CAT or ChAT)
transfers acetyl group from
coenzyme A (CoA)
What is the vesicular ACh transporter (VAChT) doing?
= H+-ATPase pump
What is the rate limiting step of ACh?
Na+-dependent high affinity
choline uptake
What would anticholinesterases e.g. neostigmine o to ACh?
= Increase ACh
= Inhibit the activity of acetylcholinesterase (AChE)
= Increase ACh in synaptic cleft
- = reveral of non-depolarising muscle relaxants during anaesthesia
What are 6 KEY AREAS to focus on for synaptic drug targeting
- NT Synthesis
- Vesicular packaging
- Release
- Post-synaptic action
- Autoreceptor monitoring
- Signal Termination
- Ca++ VG channels
