Autonomic Pharmacology Flashcards

1
Q

what are the types of transmission that drugs target?

A

Most drugs target synaptic or junctional transmission.
Anything that targets axon transmission won’t be specific to the autonomic NS.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what are the main NT and receptors used in the ANS?
how does this relate to drug targeting?

A

Ach and NAd are the main NT released
Nicotinic and muscarinic are the main receptors present
If nAChRs targeted there would be no specificity between the sympathetic and parasympathetic nervous system.
So instead muscarinic and adrenergic receptors are targeted

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

explain the process of ACh synthesis and release

A

ACh release in the sympathetic and parasympathetic NS is the same as what happens at the skeletal NMJ
Currently there are no clinically used drugs to target nAChR in ganglia
Choline enters the presynaptic neurone via the choline transporter.
ACh is synthesised from choline by choline acetyl transferase
A transport mechanism packages up ACh into vesicles
Exocytosis of ACh
ACh acts on its receptors
ACh broken down by AChE into choline and acetate.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what is the structure of the nAChr?

A

Ligand-gated Na+ ion channels
Made up of 5 subunits
When ACh binds a pore opens to allow Na+ and Ca2+ to enter
This causes depolarisation and potentially an action potential firing
nAChRs have different α-subunits
skeletal NMJ has α1-subunit
Autonomic nAChRs have anywhere between α2- α7 subunits.
This is a benefits for pharmacology as it means we can target nAChRs only in the autonomic NS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what drug was used historically as an anatgonist for the nAChr?

A

Hexamethonium
It is a non-competitive antagonist for the neuronal sub-type of nAChR (doesn’t work at NMJ)
Won’t cause paralysis because it doesn’t affect the skeletal muscular NMJ.
Non-competitive - doesn’t bind to same site as Ach
It is a pore blocker to stop Na+ and Ca2+ moving though
It blocks ALL the effects of autonomic stimulation at pre-ganglionic level (bc they all have nAChr including ENS)
Works on both sympathetic and parasympathetic NS (as they share nAChRs). This is not useful as they oppose each other.
Was used as an anti-hypertensive, lowered blood pressure by blocking all autonomic function.
Had lots of -ve side effect so was stopped when better drugs were found

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is the structure of a mAChr?

A

It is a GPCR with 7 transmembrane domains
Involved in parasympathetic postganglionic transmission
There are 5 different subtypes of muscarinic receptors, of which the first 3 (m1-m3) are particularly important in the periphery
M1 – location = stomach & salivary glands
M2 – location = cardiac muscle
M3 – location = smooth muscle & exocrine glands
SSCES
Because there are different receptor subtypes in different organs, you can target specific organs directly
Parasympathetic NS targets cardiac & smooth muscle and glands

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what drugs could be given to target muscarinic receptors?
what would the effects of the drug be?

A

Muscarinic agonists e.g. muscarine (obtained initially from fungi) - mimic the effects of Parasympathetic NS by binding to muscarinic receptors
due to this often described as Parasympathomimetics

Effects (same as ParaNS):
1. Cardiac muscle
- Decreased heart rate & cardiac output
- Can also cause bradycardia –> lead to death
2. Smooth muscle
- smooth muscle contraction especially in the gut which can cause nausea and vomiting due to increase GI activity.
- In contrast vascular smooth muscle (e.g. blood vessels) have endothelial cell lining with muscarinic receptors. When bound with agonist they release EDRF (endothelium-derived relaxing factor). This is called nitric oxide (NO). This causes vascular smooth muscle to relax causing dilation.
3. Exocrine gland secretion:
- Sweating
- lacrimation (tears)
- salivation
- bronchial secretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what causes muscarinic poisoning?
what are the effects?
treatment?

A

By muscarinic agonists
Source: mushrooms

Adverse effects:
CV: bradycardia & vasodilation –> leads to falling Blood pressure
Smooth muscle:
increased gut motility (colicky pain)
bronchoconstriction
abnormal pupillary constriction (miosis)
Exocrine: salivation, lacrimation, airway secretions

Treatment is a competitive antagonist e.g. atropine.
It binds to the receptor and blocks the function of the muscarinic agonist.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what is another muscarinic agonist?
what is it used to treat?

A

Pilocarpine
If muscarinic agonists are given systemically (all over the body) it can cause a lot of unwanted effects.
Pilocarpine is given locally –> used to treat glaucoma
Glaucoma causes an increase in pressure in the anterior compartment of the eye
Pilocarpine is administered topically to eye (i.e. eyedrops)
Its action takes place by binding to the M3 receptors on ciliary muscles –> muscles contract –> lens fattens –> improving aqueous humor drainage –> dropping intraocular pressure

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what type of muscarinic antagonists are used?

A

Less specific antagonists are atropine (from Belladonna), hyoscine, cyclopentolate
They bind to multiple M receptors
more specific ones that act on sub types of receptors haven’t been looked out for clinical use

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what is the clinical uses of antimuscarinic drugs (Antagonists) in the PNS?

A

Asthma is caused due to a narrowing of airways.
This is due to the ParaNS
By inhaling ipratropium drug - dilate the airways (counter PNS action) so treat asthma
Bradycardia is a ParaNS action giving atropine opposes ParaNS so speed up heart rate.
During operations an anaesthetist may give you something to paralyse you. After they may give an AChE inhibitor to amplify amount of Ach to unparalyse you. But AChE inhibitors also amplifies ParaNS transmission. This causes a lot of problems such as airway secretions and bronchoconstriction which inhibits ventilation of patient. So, atropine is given to block muscarinic receptors to stop PaNS side effects.
Tropicamide can be given topically to eye which opposes the ParaNS action of pupillary constriction which result in pupil dilation
Urinary incontinence is caused by bladder spasm (excessive contraction – ParaNS) so you can give oxybutynin or tolterodine.
Hyoscine treats motion sickness

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

explain pharmacology of adrenergic transmission (Sympathetic NS)

A

Post ganglionic neurones in SympaNS release NAd as their NT
1. α-adrenoceptor agonists & antagonists
2. β-adrenoceptor agonists & antagonists
3. noradrenaline transporter blockers
4. monoamine oxidase inhibitors
5. indirectly-acting sympathomimetic amines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what are the 5 main adrenoceptors?

A

5 main subtypes: by looking at their location you can determine the effect of an agonist.
α1: activation causes contraction of smooth muscle in blood vessels (i.e. vasoconstriction)
α2 (CNS):
found on vascular prejunctional terminals. Activation causes inhibition of the release of noradrenaline in a form of negative feedback.
Its activation also causes central inhibition of sympathetic outflow
Its activation also causes direct vasoconstriction
β1: activation causes increase in heart rate & contractility (B1 found in heart)
β2: activation causes relax smooth muscle 🡪 bronchodilation, vasodilation (B2 found in lungs, and some BV)
β3: activation causes relax of smooth muscle in the bladder (prevent urination); stimulate lipolysis & thermogenesis in brown adipose tissue

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is a α1 Adrenoceptor?

A

A GPCR (Gq subtype) coupled to phospholipase C-beta
Binding of NAd activates the G protein which activates the Phospholipase C.
This enzyme produces signalling molecules e.g. DAG and IP3.
IP3 binds to receptors on endoplasmic/sarcoplasmic reticulum causing release of calcium.
Increase in calcium cause an effect. E.g. causing contraction of smooth muscle.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what are signal transduction mechanisms for autonomic receptors?

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what is the main uses of α-adrenoceptor agonists?

A

Vasoconstrictors (act on α1) are mixed with local anaesthetics.
This is are used to keep anaesthetic action local.
If the anaesthetic was absorbed systemically it would be lost from the site of action and can cause heart problems.
Example of vasoconstrictors - adrenaline, noradrenaline
Nasal decongestants e.g. phenylephrine (bind to mainly α1)
Hypertension treatment (act on central α2)
Facial erythema (facial treatment) in rosacea treatment
brimonidine binds to α2 🡪 direct vasoconstriction)

17
Q

what is the main uses of α-adrenoceptor antagonists?

A

Treat hypertension e.g. doxazosin by binding to α1.
Causes a drop in blood pressure causing peripheral dilation.
SympaNS normally causes blood vessels to contract so antagonist stops this and causes dilation.
α1 found on the prostate gland.
A benign prostatic hyperplasia causes difficulty urinating
tamsulosin binding to α1 causes prostate to relax allowing easier urination.

18
Q

what is the main uses of β-adrenoceptor agonists?

A

Cardiogenic shock (acute onset where heart cannot pump enough blood around body)
adrenaline or dobutamine binding to β1 receptor which increases cardiac output
Anaphylactic shock is an acute allergic reaction which causes blood pressure to drop.
So an EpiPen contains epinephrin (adrenaline) which binds to (α/β) receptors on heart increasing contractility and increasing cardiac output.
Asthma
Salbutamol can be inhaled and binds to β2 receptor to relive asthma.
Salbutamol can be given by IV used to delay premature labour (relaxes uterine smooth muscle)

19
Q

what is the main uses of β-adrenoceptor antagonists i.e. metoprolol (β1)?

A

They can be used to treat
Angina
Cardiac arrhythmias
Hypertension
Anxiety states
(chronic) heart failure
Locally used for glaucoma (timolol) (topically on eyes)

20
Q

how do drugs effect sympathetic transmission?

A

To alter sympathetic transmission the drug must be able to either interfere with the processes involved in the synthesis of noradrenaline, the exocytosis of NA or the termination of noradrenaline signalling
1. Instead of noradrenaline being broken down in the intracellular space like ACh is, it is instead taken back into the nerve terminal, through the noradrenaline transporter (NAT)
2. This terminates its action –> It is recycled.
3. It is repackaged into vesicles, or if it is not needed again it is broken down by Monoamine Oxidase (MAO).
4. NAd action can also be terminated by being taken up by other cells where it can be broken down by other enzymes.

21
Q

explain the process: 1. Uptake of catecholamines

A

Neuronal uptake is due to the secondary active transporter NAT
It is the main mechanism for terminating actions of NA
NAT cotransports Na+, Cl- & catecholamine
NAT is inhibited by cocaine and tricyclic antidepressants (desipramine)
NAT inhibitors enhance SympaNS activity
NAT is closely related to dopamine & serotonin transporters. Therefore, cocaine can inhibit all these transporters, causing the accumulation of dopamine and serotonin in the brain, causing psychiatric effects on the brain.
Desipramine (tricyclic antidepressant)
major action in CNS
adverse effects: tachycardia, dysrhythmia
cocaine
euphoria & excitement (CNS action);
Can cause tachycardia & increased peripheral BP 🡪 NAd that is released stays in the intracellular space for longer (as cocaine blocks NAT) and so activates receptors for longer amplifying its effects of sympathetic action
It is also a local anaesthetic, Na+ ion channel inhibition.

22
Q

explain the process: 2. Mono-amine oxidase inhibitors

A

Used clinically as antidepressants
Most irreversibly block MAOs
You get increased levels of NA, dopamine & 5-HT (serotonin) in brain & peripheral tissues as MAO enzyme is blocked
This increases levels of NAd in periphery as well
adverse effects 🡪 postural hypotension, weight gain, insomnia, cheese reaction (hypertensive episode following ingestion of tyramine-containing food, i.e. cheese & red wine), flushing
Example MAO inhibitors include phenelzine, tranylcypromine, iproniazid, moclobemide (reversible, competitive inhibitor)

23
Q

what are indirectly-acting sympathetic amines and what do they do?

A

E.g. amphetamines, ephedrine, tyramine
structurally related to NA
Transported into nerve terminal by NAT and into vesicles by VMAT
They move into the cell and displace NA 🡪 leaks out via NAT
They have a similar effect on dopamine & 5-HT in CNS
They have long-lasting effects that mimic those of NA – bronchodilation, vasoconstriction, +ve inotropy (increase strength of muscular contraction), raised BP
CNS effects underlie their use as substances of abuse

Tyrosine from diet is usually broken down by MAO in our gut
Hence eating cheese, whilst taking monoamine oxidase inhibitors causes sympathetic nervous stimulation