Autonomic Pharmacology Flashcards
At which points can drugs target autonomic transmission
Synapse
Along axon - not specific
At target organ
Where are Muscarinic receptors present?
At effector organs of parasympathetic ns
Where are nicotinic receptors present in sympathetic and para ns
In ganglion
Structure of nicotinic cholinergic receptor
Transmembrane
5 subunits
2 ACh molecules need to bind
What is hexamethonium
A methonium derivative
Selective antagonist for neuronal sub type of nicotinic receptor
Not competitive
Blocks all the effects of autonomic stimulation (all preganglionic fibres are cholinergic)
Why is hexamethonium not used anymore
Not specific enough
Has too many side effects
What NT is released on to muscarinic receptors
ACh
How many transmembrane segments do muscarinic receptors have
7
How many subtypes of muscarinic receptors
5
First 3 (M1-3) are important in the periphery
Why are muscarinic drugs described as “parasympathomimetic drugs”
Mimic the effects of parasympathetic NS activation
Where were muscarinic drugs found
In family of fungi
General Effects of parasympathomimetics
Cardiovascular - decreased HR
Smooth muscle - contracts
Exocrine glands - secrete eg. Sweat, salivation, bronchial secretion
Source of muscarinic poisoning
Muscarinic agonists in Many mushrooms
Adverse effects of poisoning by muscarinic agonists
Bradycardia so decreased BP
Increased gut motility
Bronchoconstriction
Pupillary constriction
Salivation
Lacrimation
Treatment of muscarinic poisoning
Muscarinic antagonist (atropine)
Example of muscarinic agonist tht treats glaucoma and how it works
Pilocarpine
Route of administration: Topical to the eye
Action: on M3 receptors on ciliary muscles, improving aqueous humour drainag, dropping intraocular pressure
Types of muscarinic antagonists and where they act
Antagonists specific to muscarinic receptor they act on
M1 - stomach and salivary glands
M2 - cardiac
M3 - smooth muscle
Less specific antagonists like are used more widely
Atropine
Hyoscine
Cyclopentolate
Clinical uses of antimuscarinic drugs
Stop parasympathetic NS
- Asthma (ipratropium)
- Treat bradycardia (atropine)
- During operations (atropine)
- Dilate pupils (tropicamide)
- Urinary incontinence (oxybutynin)
- Motion sickness
Why is atropin used in operations
Skeletal NMJ blocking agent given to cause paralysis
Stop cholinergic transmission
After operation need to reverse paralysis with acetylcholinesterase inhibitor
This increases ACh at NMJ
Excessive ACh in the lungs and heart
Atropine used to block muscarinic receptors in airways
5 main subtypes of adrenoceptors (sympathetic) and their role
Alpha 1 - contract smooth muscle
Alpha 2 - presynaptic auto inhibition, direct vasoconstriction, central inhibition of sympathetic outflow
Beta 1 - increases heart rate and contractility
Beta 2 - relax smooth muscle (bronchodilation, vasodilation)
Beta 3 - relax smooth muscle (bladder), lipolysis
Main uses of alpha adrenoceptor receptor agonists
- Vasoconstrictors (adrenaline/ noradrenaline) with local anaesthetic (keeps LA at target tissue). Alpha 1.
- Nasal decongestants (phenylephrine). Alpha 1
- Hypertension. Central alpha 2.
- Facial erythema in rosacea (brimonidine). Alpha 2.
How adrenoceptors produce intrinsic cascade
Receptor stimulated
Gq protein activated
Stimulates phospholipase C
Releases Ca from Intracellular stores
DAG activates and causes Intracellular cascade
Signal transduction mechanisms for alpha 1 adrenoceptor
G protein: Gq
Target: phospholipase C
Transduction effect: increase IP3/ DAG
What are some autonomic receptors
Nicotinic - ACh
Adrenoceptor - catecholamines
Muscarinic - ACh post ganglionic
Signal transduction mechanisms for alpha 2 adrenoceptors
Gi
Decreases adenylyl cyclase
Decrease cAMP
Signal transduction mechanism for all beta adrenoceptors
Gs
Increases AC
Increases cAMP
Signal transduction mechanism for M1/ M3 muscarinic agonists and antagonists
Gq
Phospholipase C
Increases IP3/ DAG
Signal transduction mechanism for M2 muscarinic agonists and antagonists
Gi
Decrease in Adenylyl cyclase
Decrease cAMP
Main uses of alpha-adrenoceptor 1 antagonists
Block sympathetic transmission
- Doxazosin alpha 1 - To lower hypertension
- Tamsulosin alpha 1 - Treat benign prostatic hyperplasia
Main uses of Beta adrenoceptor agonists
Stimulate sympathetic NS
- Cardiogenic shock (beta 1)
Adrenaline, dobutamine
- Anaphylactic shock (alpha/ beta)
Adrenaline
- Asthma (beta 2)
Salbutamol
Main uses of beta adrenoceptors antagonists
Block sympathetic NS
Cardiac arrhythmias
Hypertension, angina (metoprolol)
Anxiety states
Heart failure
Glaucoma (timolol)
3 ways Adrenergic transmission is continued
- Noradrenaline transporter blockers
- Monoamine oxidase inhibitors
- Indirectly acting sympathomimetic amines
How do “inhibitors of noradrenaline uptake” work
NAT inhibitors enhance the effects of sympathetic activity
By blocking NAT (transporter)
NAd stays in extracellular space
Promotes sympathetic transmission
What does NAT (noradrenaline transporter) transport
Cotransport Na+, Cl- and Catecholamine
What is the main way for terminating the actions of NAd
NAd uptaken by NAT
What drugs inhibit NAT (they enhance effects of sympathetic NS)
Cocaine
Tricyclic antidepressants (desipramine)
What other transporters are NAT closely related to
Dopamine transporters
Serotonin transporters
What is desipramine
Tricyclic antidepressant
NAT inhibitor
Major action is on CNS
Adverse effects: tachycardia, dsyrhythmia
What is cocaine and its effects
Euphoria and excitement CNS action
NAT inhibitor
Causes tachycardia and increased BP
Type of Local anaesthetic
How mono-amine oxidase inhibitors promote Adrenergic transmission
Most block MAO irreversibly
Used clinically as antidepressants
Increase levels of NAd, dopamine and 5-HT in brain and peripheral tissue
Adverse effects: postural hypotension, weight gain, restlessness, insomnia, cheese reaction
Examples of mono-oxidase inhibitors
Phenelzine
Tranylcypromine
Iproniazid
Moclobemide
How indirectly acting sympathetic amines promote Adrenergic transmission
They are structurally related to noradrenaline
Transported into nerve terminals (NAT) and into vesicles (VMAT)
Displace noradrenaline which leaks out via NAT
Long lasting effects that mimic those of NAd
Examples of indirectly acting sympathetic amines
Amphetamine
Ephedrine
Tyramine
What are some effects of NAd in the sympathetic NS
Bronchodilatation
Vasoconstriction
Raised BP
What are receptors of sympathetic and parasympathetic
SNS - nicotinic and adrenoceptors
PNS - nicotinic and muscarinic
