Autonomic Pharmacology Flashcards
The first neuron in efferent autonomic pathways uses which receptor?
nACh
Which sympathetic pathway only has 1 neuron instead of 2?
The chain to the adrenal medulla
Which spinal segments do parasympathetic nerves arise from?
Cranial and sacral
Which spinal segments to sympathetic nerves arise from?
Thoracic and lumbar
Where are the sympathetic ganglia found?
In the sympathetic chain close to the spine
Where are the parasympathetic ganglia found?
Close to the target organ rather than the spinal cord
When are the sympathetic and parasympathetic NS not working in opposition?
1) When only one of them innervates a tissue
2) They induce complimentary effects such as ejaculation and erection
3) They have a similar effect, only to different extents
What type of receptors are nicotinic?
ionotropic
Are nicotinic receptors the same everywhere?
No, there are different variations at the neuromuscular junction (Nm) and in nerves (Nn)
What type of receptors is muscarinic?
Metabotropic
Where are only M1 subtype receptors found?
Autonomic ganglia
Where are only M2 subtype receptors found?
Heart
Where are only M3 subtype receptors found?
Smooth muscle and secretory glands
Where are M1,2,3,4 and 5 subtype receptors found?
In the CNS
Which second messenger do M1,3 and 5 use?
Gq GPCR which activates PLC which activates IP3 and DAG
Which second messenger do M2 and 4 use?
Gi GPCR which inhibits Adenylyl cyclase
What is the pathway from Tyrosine to Adrenaline?
Tyrosine> DOPA> Dopamine> Noradrenaline> Adrenaline
What effect does DOPA have on tyrosine?
Inhibitory effect as a part of the negative feedback loop
What is the rate-limiting step in adrenaline synthesis?
Tyrosine concentration
Which enzyme catalyses tyrosine to DOPA?
Tyrosine hydroxylase
Which enzyme catalyses DOPA to dopamine?
DOPA decarboxylase
Which enzyme catalyses dopamine to noradrenaline?
Dopamine beta-hydroxylase
Which enzyme catalyses noradrenaline to adrenaline?
Phenylethanolamine N-methyltransferase (PNMT)
In order for a cell to produce only noradrenaline and not adrenaline what must it do?
Not express PNMT
Where is PNMT expressed?
In the adrenal medulla
Where is PNMT NOT expressed?
Adrenergic neurons
What is the first method of noradrenaline uptake?
Uptake 1- Presynaptic uptake
What are the characteristics of presynaptic uptake of NA
Monoamine oxidase has a HIGH affinity but a low maximal rate of reabsorption
What is the second method of noradrenaline uptake?
Uptake 2- Postsynaptic uptake
What are the characteristics of postsynaptic uptake?
COMT has a LOW affinity but a HIGH maximal rate of reabsorption
With regards to NA uptake, what are good drug targets?
COMT and MOA
Where are beta 1 receptors found?
The heart
Where are beta 2 receptors found?
Smooth muscle
Which second messenger are beta receptors linked to?
Gs GPCR linked meaning they activate adenylyl cyclase
Which side of the synapse are alpha-1 receptors found?
Post junctional
Which second messenger do alpha-1 receptors use?
Gq GPCR which activates PLC
Which side of the synapse are alpha-2 receptors found?
Pre and post junctionally
Which second messenger do alpha-2 receptors use?
Gi GPCR which inhibits adenylyl cyclase
NA is stored presynaptically in vesicles. What else is stored in these vesicles with NA?
Chromogranin and ATP
What is the function of chromogranin?
Stabilises noradrenaline and prevents it from leaking out of the vesicles
What is the function of ATP in the vesicles?
Assists in signalling (mechanism uncertain)
What is the purpose of presynaptic alpha-2 receptors?
They detect critically high levels of NA and inhibit its release. Gi inhibits AC which prevents cAMP synthesis and subsequent PKC activation. This prevents the activation of Ca2+ pumps on vesicles which release NA
Why do adrenergic neurons express ACh receptors?
So that the sympathetic neurons (adrenergic) can be inhibited by parasympathetic neurons (cholinergic)
Why do cholinergic neurons express adrenoceptors?
So that the parasympathetic neurons (cholinergic) can be inhibited by sympathetic (adrenergic) neurons
What can muscle prostaglandins (PG) do to adrenergic neurons?
Inhibit them
What effect does nitrous oxide have on cholinergic neurons?
It can inhibit and activate them
What is pre-synaptic inhibition?
When the neuron inhibits itself
What is heterotrophic inhibition?
When one neuron inhibits another
What is post-synaptic synergism?
When neurotransmitters released from the same presynaptic membrane have a synergistic response (enhance each other’s effects)
What is the purpose of neuromuscular blockers?
To prevent signal transmission at the neuromuscular junction
Are depolarising NM blockers agonists or antagonists?
Agonists
Are non-depolarising NM blockers agonists or antagonists?
Antagonists
What is the naturally occurring example of a non-depolarising NM blocker?
Tubocurarine
Name 3 synthetic non-depolarising NM blockers.
Gallamine, Pancuronium and Atracurium
What do most synthetic non-depolarising blockers have in common?
They have a quarternary ammonium group that mimics that of acetylcholine
Which ACh receptor type does tubocurarine block?
nicotinic
How many receptors on a given neuron are required to be inhibited before it is functionally inhibited and what is the purpose of this?
> 90% of ACh receptors need to be blocked before the neuron cannot function. This significant redundancy prevents neurons from being easily blocked by a toxin
Typically, with non-depolarising Nm blockers, what are the first and last muscles to be affected?
The eyelids first and the respiratory muscles last
Do non-depolarising NM blockers have effects anywhere other than at the motor end plate?
Yes. Nicotinic receptors are expressed in autonomic ganglia and, therefore, it can inhibit certain autonomic functions
Typically, do non-depolarising or depolarising NM blockers have a shorter active period?
Non-depolarising Nm blockers do not typically display effects for as long as depolarising ones
Name some depolarising NM blockers.
Decamethonium, suxamethonium and succinylcholine
How do depolarising NM blockers work?
They bind to ACh N receptors at the NMJ and act as ‘hyper’ agonists, inducing receptor activity and depolarisation so much that the receptors cannot return to their ground state; the voltage-sensitive Na+ gates are inactivated. This means that it cannot then fire again.
As a result of the initial depolarisation with depolarising NM blockers, what happens to the muscles of some species?
It causes an initial muscle spasm before the paralysis kicks in
What is Phase I of depolarising NM blocker action?
The depolarising ‘spasm’ stage
What is Phase II of depolarising NM blocker action?
The receptors are desensitised preventing further depolarisation
Why do humans not display the same ‘spasm’ as some other species?
Species, such as chickens, have several neurons arriving at the motor end plate for each fibre whereas humans only have 1 neuron per fibre. This means the extent of depolarisation and electrical activity is much greater in chickens than in humans
Due to the increased permeability to ions caused by the depolarising NM blocker, what happens with respect to K+ ions?
They increase in concentration in the extracellular fluid and subsequent plasma
Does increased potassium permeability matter?
In healthy individuals, this change can easily be compensated by endogenous mechanisms. However, individuals who have a decreased sensitivity to potassium ions due to burns or trauma are at risk.
What does muscle denervation do to ACh receptors?
It causes ACh n receptors on muscles to spread at and away from the motor end plate making a larger surface area of the muscle susceptible to suxamethonium. This significantly increases the individuals sensitivity to the drug.
Name one disorder for which depolarising NM are ineffective for
Myasthenia Gravis. Antibodies bind to ACh n receptors preventing them from being used for neurotransmission.
Individuals with myasthenia gravis become more or less sensitive to non-depolarising NM blockers
Significantly more sensitive as they have a reduced number of functional ACh n receptors and, therefore, do not require as much of the drug to achieve >90% block.
Which reversal agents work for non-depolarising blockers?
AChease blockers. This allows ACh concentration to build up and competitively outcompete the non-depolarising NM blocker as the ligand.
What happens with AChease blockers and depolarising NM blockers?
They increase ACh concentration which can increase the effectiveness of the depolarising blockers (ACh is a also depolarising agent)
What is mutual antagonism?
A depolarising agent works as a reversal agent for non-depolarising NMB and non-depolarising NMB work as a reversal agent for depolarising NMB. (They have inverse effects).
Suxamethonium and decamethonium are selective for NMJ ACh Nm receptors, which drugs are not?
Nicotine and lobeline are agonists to nicotinic receptors in the autonomic ganglia as well as at the NMJ
Can AChease degrade synthetic ligands?
Yes, but very slowly
Does the length of the carbon backbone of a drug affect its selectivity to a receptor?
Yes
What is the selectivity of a 6-carbon backbone drug (in the context of ACh receptors)?
They have a greater affinity for the receptors found in the autonomic ganglia (Nn)
What is the selectivity of a > 10-carbon backbone drug (in the context of ACh receptors)?
They have a greater affinity for the NMJ receptors (Nm)
What does hexamethonium block?
It selectively blocks ACh receptor channels.
What do trimetaphan and mecamylamine block?
They selectively block ACh receptors (antagonist)
What happens if you block autonomic ganglia with ACh blockers?
1) Decreased heart rate
2) Decreased gut motility
3) Increased bladder emptying
If parasympathetic and sympathetic inhibition is in equilibrium, what will change in the body?
Nothing largely will change, however, postural reflexes in heart rate will not occur.
Do drugs binding to ACh receptors need to ‘look’ like ACh?
No, Pilocarpine is structurally very different
Where is oxotremorine most effective?
The CNS. It is not very effective in the PNS
Name two drugs that block choline transport into the nerve terminal
Hemicholinium and triethylcholine
How does hemicholinium block choline uptake?
Competitively inhibits it
How does triethylcholine block choline to acetylcholine?
It is uptaken, acetylated, stored and released as a false neurotransmission instead of choline
Comment on choline transport blocker onset
Slow but dependent on frequency of use of neuron
Can choline transport blockers be reversed?
Yes, easily
Which ion affects calcium ion channels in the nerve terminal?
Mg2+ competes for and blocks Ca2+ channels
Which antibiotic affects calcium ion channels in the nerve terminal?
Aminoglycoside
Where do calcium channel blockers exert their greatest effect?
The heart
How does botulinum toxin produce an effect?
Deactivates molecules required for vesicles to duse with presynaptic membrane
Which toxin works in a similar way to botulinum toxin?
Bungarotoxin
Are nerve blocks still possible when AChE is inhibited?
Yes, a depolarising block is possible with the use of drugs such as suxamethonium
Which functional group do all AChE inhibitors share?
Quarternary ammonium group
The quarternary ammonium group of ACh and AChE inhibitors are attracted to which part of the AChE?
The anionic esteratic site
What does the esteratic site do
Cleaves ACh to acetate and choline
What are the three classes of AChE inhibitors?
Short-acting, medium-acting and irreversible
Name a short-acting AChE inhibitor
Edrophonium
Which type of bond do short-acting AChE inhibitors have?
Ionic
When are short-acting AChE inhibitors used clinically?
Diagnostically, such as in the diagnosis for myasthenia gravis
Name three medium-acting AChE inhibitors
Neostigmine, pyridostigmine and physostigmine
What do medium-acting AChE inhibitors have instead of acetyl?
Carbamyl
What makes medium-acting AChE inhibitors medium-acting?
The carbamyl takes longer to be broken down than the acetyl group, although it can be broken down eventually
Which common chemical structure is found in irreversible AChE inhibitors?
Pentavalent phosphate
What is a labile group?
A highly reactive and changeable group on a chemical
What are examples of labile groups in irreversible AChE inhibitors?
Fluoride (Dyflos), parathion and ecothiapane (organic)
How are AChE inhibitors usually administered?
Topically, to avoid systemic effects
What central effects do organophosphates have?
Depressive effects
What is the effect of organophosphates on the NMJ
Convulsive effects
What is the general effect of organophosphates on the body?
Initial muscular convulsions followed by physical ssytemic depressive effects
Can non-polar organophosphates cross the BBB?
Yes, this property allows them to be particularly effective in the CNS
What longer-term effect do organophosphates have?
They can cause demyelination of nerves and the issues associated with that
Which two drugs can be used in the treatment of organophosphate poisoning?
Atropine and pralidoxime
Can atropine and pralidoxime cross the BBB?
Atropine can, pralidoxime cannot
How does atropine help in organophosphate poisoning?
It antagonises the muscarinic receptors, preventing them from being overloaded by acetylcholine
How does pralidoxime help in organophosphate poisoning?
It binds to the organophosphate residue in the esteratic site, substituting itself in so the AChE can be free
Name 3 drugs that inhibit noradrenaline synthesis
Carbidopa, alpha-methyltyrosine and 6-hydroxydopamine
How does carbidopa inhibit NA synthesis?
Blocking DOPA decarboxylase, blocking formation of NA precursor
Can carbidopa cross the BBB?
no
How does α-methyltyrosine inhibit NA synthesis?
It inhibits tyrosine hydroxylase from converting tyrosine to DOPA. α-methyltyrosine is converted to α-methyl DOPA then α-methyl NA
What happens to α-methyl NA when it is released at the presynaptic membrane instead of NA?
It binds to and activates only the presynaptic α-2 receptors, initiating the negative feedback loop that ultimately inhibits NA signal transmission
What does 6-hydroxydopamine do to dopaminergic and adrenergic neurons?
Gradually destroys the nerves of the sympathetic nervous system
What is 6-hydroxydopamine used for?
Chemical sympathectomy
Name a drug that affects noradrenaline storage
Reserpine
How does reserpine prevent NA storage?
It blocks vesicles from accumulating NA
Can reserpine cross the BBB?
Yes
Comment on the selectivity of reserpine
It is highly unselective and can prevent the vesicular uptake of a number of neurotransmitters
Name 2 adrenergic neuron blocking drugs
Guanethidine and bretyllium
How fast do adrenergic neuron blockers act?
Slowly, they need to be uptaken to the vesicles and deplete NA stores. This means it is also slow to reverse them
How do adrenergic neuron blockers act?
Prevent the NA vesicles from fusing with the presynaptic membrane
Name 3 indirectly acting sympathomimetic amines (IDAS)
Tyramine, amphetamine and ephedrine
Are IDAS specific?
They are highly unspecific
How do IDAS have an effect?
They are uptaken by route 1 and replace NA in the storage vesicles.
Name drugs which block uptake 1 of NA
Cocaine and tri-cyclic anit-depressants
Name drugs which reduce uptake 1 of NA
Amphetamine, phenoxybenzamine and guanethidine
Name drugs that block uptake 2
Phenoxybenzamine and corticosteroids
What is structure activity function?
The concept of the structure of a molecule being used to predict its activity with regards to how it may bind to a receptor
On a catecholamine, what is the effect of ‘bulking up’ the nitrogen atom?
It will become a β-agonist that is susceptible to MAO but resistant to uptake 1
On a catecholamine, what is the effect of adding a methyl group?
It will become α-2 selective agonist that is resistant to MAO but susceptible to uptake 1
On a catecholamine, what is the effect of removing OH groups?
It decreases its adrenergic action and moves it structurally closer to becoming dopamine
On a catecholamine, what is the effect of modifying the catechol OH?
It will become a β-agonist and resistant to COMT and uptake 1
On a catecholamine, what is the effect of adding an alkyl side chain extension, N - atom extensions and a catechol OH extension?
It will become a β-agonist
On a catecholamine, what is the effect of removing all OH groups?
It will have no adrenergic receptor affinity, but it will be susceptible to uptake 1
Name two β-agonists
Isoprenaline and salbutamol
What is isoprenaline selective for
?
β-1 and 2
What is salbutamol selective for
?
β-2 only
Why is salbutamol still functional at lower doses?
It is resistant to COMT degradation
Name three β-antagonists and one partial β-antagonist
Propranolol, atenolol and metoprolol
Oxorpenolol is the partial antagonist
What is propranolol selective for?
β-1 and 2
What are atenolol and metoprolol selective for?
β-1 only
What is another term for β-1 selective antagonists?
Cardio selective β blockers
When does oxprenolol act as an agonist and antagonist?
At rest, it acts as an agonist and during exercise, it acts as an antagonist
What are β blockers used to treat?
Anxiety, tremor, migraine and angina
What are some potential side effects of β blockers?
Bradycardia and bronchoconstriction
Name two α-1 selective agonists
Methoxamine and phenylephrine
What do α-1 selective agonists cause?
Vasoconstriction
Name two α-2 selective agonists.
Clonidine and methylnoradrenaline
What do α-2 selective agonists cause?
Reduce hypertension by reducing NA release
What is the secondary mechanism of action of clonidine?
It prevents other agonists from binding to α receptors
Comment on how structure-activity relationship applies to α antagonists
It does not apply as cleanly here, some molecules antagonise receptors despite not being structurally similar to the endogenous ligand
What are the 4 heterogeneous classes of α antagonists
Ergot alkaloids, halo alkylamines, yohimbines and miscellaneous synthetic chemicals
Where are ergot alkaloids naturally found?
Fungi
What is St. Anthony’s fire?
The intense peripheral vasoconstriction caused by ergot alkaloids
Name an ergot alkaloid that is an α-antagonist and one that is a partial agonist
Dihydroergotamine is an antagonist and ergotamine is a partial agonist
What are some functions of ergot alkaloids?
They act as adrenaline reversal agents as they suppress the pressor response
Name a halo alkylamine α antagonist
Phenoxybenzamine
What is special about one of the functional groups on PBZ?
It has a highly unstable chloroethyl group, which easily covalently binds to substrates
Comment on the specificity of halo alkylamines
They are not selective antagonists for only α receptors; they show effects at histamine, serotonin and cholinergic receptor sites
What systemic effects can halo alkylamines cause?
A drop in arterial blood pressure
What is yohimbine selective for?
It is a selective α-2 antagonist
How does it exert its effect?
It binds to presynaptic α-2 receptors and thus blocks the mechanism that decreases NA release
What is the systemic effect of yohimbine?
The increased NA release causes vasodilation
Phentolamine is a miscellaneous synthetic α antagonist, comment on its selectivity
It is selective for both α- 1 and 2
What is phentolamine structurally similar to?
PBZ, except it binds reversibly
Prazosin and indoramide are also miscellaneous synthetic α antagonists, comment on their specificity
They are α-1 selective only
Comment on the specificity of labetalol
It is a mixed α and β antagonist (blocker)
Why are sympathetic blockers not commonly used clinically?
They are not particularly effective at reducing B.P and come with the side effect of increasing gut motility (leading to diarrhoea)
