N27 - Autonomic pharmacology 2 Flashcards
Give an overview of neurochemical transmission in the ANS.
1.Uptake of precursor
2. Synthesis of transmitter (T) or intermediate
3. Storage of transmitter (T) or intermediate
4. Depolarization by action potential
5. Ca2+ entry via voltage -activated Ca2+ channels
6. Ca2+ induced release of transmitter (exocytosis)
7. Receptor activation
8.Enzyme-mediated inactivation of transmitter (cholinergic)
OR
9. Reupatke of transmitter (adrenergic)
what are all these steps a target for?
drug target (often clinical significance)
What are the general features of cholinergic transmission.
- Uptake of choline via transporter (CHT). Rate limiting in synthesis of ACh
- Synthesis of ACh by choline acetyltransferase (ChAT). Acetyl coenzyme A (AcCoA) synthesised by mitochondria
- Storage of ACh within vesicle via transporter (VAChT). ATP and other anions are co-stored
- Depolarization of terminal by action potential
- Ca2+ influx through voltage-activated Ca2+ channels
- Ca2+- induced release of ACh from vesicles (exocytosis)
- Activation of ACh receptors (nicotinic, or muscarinic) causing cellular response
- Degradation of ACh to choline and acetate by acetylcholinesterase (AChE) – terminates transmission
- Reuptake and reuse of choline
what does the nicotinic acetylcholine (ACh) receptors consist of?
five glycoprotein subunits that form a central, cation conducting (Na+, K+ and Ca2+), channel
what is nicotinic acetylcholine receptors assembled from?
diverse range of subunits
what do nicotinic acetylcholine exist as?
numerous subtypes (dozens) that are structurally, functionally and pharmacologically distinct (4 well characterised subtypes)
what are the 4 subtypes?
peripheral: -skeletal muscle (alpha12bye) -Ganglionic (alpha3b4) CNS: -alpha4b2 -alpha 7
what is the primary event?
cholinergic transmission at ganglia
what were drugs that block the autonomic ganglia once used for?
to control hypertension
what are the effects of autonomic ganglion blockade on tissues (site, predominant tone, effects of blockade)?
- Arterioles -Sympathetic (adrenergic)-Vasodilatation; ↑ peripheral blood flow; hypotension
- Veins- Sympathetic (adrenergic) -Vasodilatation; ↑ pooling of blood; ↓ venous return; ↓ cardiac output
- Heart -Parasympathetic (cholinergic) - Tachycardia
- Iris-Parasympathetic (cholinergic)-Mydriasis (pupil constriction)
- Ciliary muscle -Parasympathetic (cholinergic) -Cycloplegia (focussed for far vision)
- G.I. tract -Parasympathetic (cholinergic) -↓ Tone and motility; constipation; ↓ secretions
- Urinary bladder -Parasympathetic (cholinergic) - Urinary retention
- Salivary glands -Parasympathetic (cholinergic) -Xerostomia (dry mouth)
- Sweat glands-Sympathetic (cholinergic)-Anhidrosis (absence of sweating)
what can blockade be achieved by?
- depolarization block by high concentrations of agonists (e.g. nicotine)
- competitive antagonism (e.g. trimetaphan)
- Non-competitive antagonism
what is all ganglionic transmission (sympathetic and parasympathetic) selectively blocked by?
hexamethonium which illustrates an interesting molecular mechanism – open channel block – a form of non-competitive antagonism
Describe the stages of cholinergic transmission at parasympathetic neuroeffector junction?
Synthesis and storage of Each as previously described
- Depolarization by action potential
- Ca2+ influx through voltage-activated Ca2+ channels
- Ca2+- induced release of ACh (exocytosis)
- Activation of muscarinic ACh receptors subtypes (M1-M3) causing cellular response (tissue dependent)
- Degradation of ACh to choline and acetate by acetylcholinesterase (AChE) – terminates transmission
- Reuptake and reuse of choline
what is cholinergic transmission at parasympathetic neuroeffector junctions between?
varicosity of post ganglion neurone and effector cell. (e.g smooth muscle cell, gland cell)
what does M1 and Gq result in (G-Protein Coupled Muscarinic ACh Receptor Subtypes at Parasympathetic Neuroeffector Junctions)?
- stimulation of phospholipase C
- increased acid secretion
what does M2 and Gi result in (G-Protein Coupled Muscarinic ACh Receptor Subtypes at Parasympathetic Neuroeffector Junctions)?
- inhibition of adenylyl cyclase: opening of K channels
- decreased heart rate
what does M3 and Gq result in (G-Protein Coupled Muscarinic ACh Receptor Subtypes at Parasympathetic Neuroeffector Junctions)?
- stimulation of phospholipase C
- increased secretion (salivary)
what is increased vascular smooth muscle indirectly relaxed by?
M3 receptor activation via NO
What are the stages of noradrenergic transmission at sympathetic nueroeffector junctions?
- Synthesis of NA (multiple steps)
- Storage of NA by transporter (concentrates)
- Depolarization by action potential
- Ca2+ influx through voltage-activated Ca2+ channels
- Ca2+-induced release of NA
- Activation of adrenoceptor subtypes causing cellular response (tissue dependent)
- Reuptake of NA by transporters uptake 1 (U1) and uptake 2 (U2)
- Metabolism of NA by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)
What is noradrenergic transmission at sympathetic nueroeffector junctions between?
Between nerve terminal of post-ganglionic neurone and effector cell (e.g cardiac and smooth muscle cell)
what does B1 and Gs result in (G-Protein Coupled Adrenoceptor Subtypes at Sympathetic Neuroeffector Junctions)?
- stimulation of adenylyl cyclase
- increased heart rate and force
what does B2 and Gs result in (G-Protein Coupled Adrenoceptor Subtypes at Sympathetic Neuroeffector Junctions)?
- stimulation of adenylyl cyclase
- relaxtation of bronchial and vascular smooth muscle
what does alpha1 and Gq result in (G-Protein Coupled Adrenoceptor Subtypes at Sympathetic Neuroeffector Junctions)?
- stimulation of phospholipase C
- contraction of vascular smooth muscle
what does alpha2 and Gi result in (G-Protein Coupled Adrenoceptor Subtypes at Sympathetic Neuroeffector Junctions)?
- inhibition of adenylyl cyclase
- inhibition of NA release
what modulates the release of neurotransmitters?
presynaptic autoreceptors
how does presynaptic auto receptor mediate negative feedback of transmitter release?
Agonists decrease release, antagonists increase release
What is the effect of cocaine in the autonomic nervous system?
- Cocaine Blocks U1 , increasing the concentration of NA in the synaptic cleft resulting in increased adrenoceptor stimulation
- Peripheral actions cause vasoconstriction [alpha1 stimulation and cardiac arrhythmias [beeta 1 stimulation]
What is the effect of amphetamine in the autonomic nervous system?
- Amphetamine Is a substrate for U1 and enters the noradrenergic terminal where it inhibits MAO , enters the synaptic vesicle and displaces noradrenaline into the cytoplasm . Noradrenaline exits the terminal on U1 ‘running backwards’ and accumulates in the synaptic cleft causing increased adrenoceptor stimulation
- Peripheral actions cause vasoconstriction (alpha1 stimulation) and cardiac arrhythmias (beta 1 stimulation)
Describe the actions of prazosin in the autonomic nervous system.
Selective, competitive, antagonist of alpha 1. Does not block alpha2 ,beta 1 or beta 2 Vasodilator used as an anti-hypertensive agent
Describe the actions of atenolol in the autonomic nervous system.
Selective, competitive, antagonist of beta 1. Does not block beta2,alph1 or alpha 2. Used as an anti-anginal and anti hypertensive agent
Describe the actions of salbutamol in the autonomic nervous system.
Selective agonist at Beta 2. Does not activate beta1, alpha 1 or alpha 2. Used as a bronchodilator in asthma
Describe the actions of atropine in the autonomic nervous system.
Competitive antagonist of muscarinic ACh receptors, does not block nicotinic ACh receptors. Blocks all muscarinic ACh receptors with equal affinity (1,2,3) - exerts widespread effects by blockade of the parasympathetic division of the ANS
(used to reverse bradycardia following MI and in anti cholinesterase poisoning )
