Autonomic Pharmacology II Flashcards
Structure of Nicotinic Acetylcholine (ACh) receptors?
Consist of 5 glycoprotein subunits that form a central, cation conducting channel and they can be assembled from a diverse range of subunits (α1-10, β1-4, γ, δ, ε)
Exist as numerous subtypes that are structurally, functionally and PHARMACOLOGICALLY distinct
Four subtypes of nicotinic acetylcholine (ACh) receptors?
Peripheral:
Skeletal muscle - (α1)2βγε
Ganglionic - α3β4
CNS:
α4β2 - nicotine receptor
α7 - 5 α7 subunits
How does cholinergic transmission work?
- Uptake of choline via transporter
- Synthesis of ACh via choline acetyltransferase (CAT)
- Storage of ACh via trasnporter (concentrates the ACh)
- Depolarisation by action potential
- Ca2+ influx through voltage-activated Ca2+ channels
- Ca2+ induced release of ACh (exocytosis)
- Activation of ACh receptors (nicotinic or muscarinic) causing a cellular response
- Degradation of ACh to choline and acetate by actylcholinesterase (AChE) - terminates transmission
- Reuptake and reuse of choline
Describe how depolarisation occurs in cholinergic transmission
Opening of ion channel causes Na+ to move into cell so depolarisation of cell body of post-ganglionic neurone occur
This is a GRADED EVENT - more ACh is released and so greater depolarisation of cell body (EPSP - Excitatory Post-Synaptic Potential)
Action potential is an “all or none” event - as long as EPSP is at sufficient amplitude, ion channel will open
Drugs that affect cholinergic transmission at ganglia?
Little clinical significance (except nicotine)
Hexamethonium - antihypertensive that selectively blocks ganglionic transmission . Now obsolete but worked by open channel block (form of non-competitive antagonism) that can only work when channel is open
Describe cholinergic transmission at parasympathetic neuroeffector junctions
- Uptake of choline via transporter
- Synthesis of ACh via choline acetyltransferase (CAT)
- Storage of ACh via transporter (concentrates)
- Depolarisation by action potential
- Ca2+ influx through voltage-activated channels
- Ca2+ induced release of ACh (exocytosis)
- Activation of muscarinic ACH receptor 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
Receptors in effector cells?
Always muscarinic
G-protein coupled muscarinic ACh receptor subtypes at parasympathetic neuroeffector junctions?
M1 with Gq leads to stimulation of phospholipase C and increased acid secretion
M2 with Gi leads to inhibition of adenylyl cyclase and opening of K+ channels and thus decreased heart rate
M3 with Gq leads to stimulation of phospholipase C and contraction of visceral smooth muscle (vascular smooth muscle is indirectly relaxed by M3 receptor activation)
Describe noradrenergic transmission at sympathetic neuroeffector junctions
- Synthesis of noradrenaline (precursor is dopamine)
- Storage of noradrenaline by transporter (concentrates)
- Depolarisation by action potential
- Ca2+ influx through voltage-activated Ca2+ channels
- Ca2+ induced release of noradrenaline
- Activation of adrenoceptor subtypes causing cellular response (tissue dependent)
- Reuptake of noradrenaline by transporters uptake 1 (U1 - pre-synpatic) and uptake 2 (U2 - post-synaptic)
- Metabolism of Na by monoamine oxidase (MAO - pre-synaptic) and catechol-O-methyltransferase (COMT - post-synaptic)
G-protein coupled adrenoceptor subtypes at sympathetic neuroeffector junctions (noradrenaline)?
All adrenoceptors are G-protein coupled receptors (none are ligand-gated)
β1 with Gs leads to stimulation of adenylyl cyclase and increased heart rate and force
β2 with Gs leads to stimulation of adenylyl cyclase and relaxation of bronchial and vascular smooth muscle
α1 with Gq leads to stimulation of phospholipase C and contraction of vascular smooth muscle
α2 with Gi leads to inhibition of adenylyl cyclase and inhibition of noradrenaline release
How do pre-synaptic neurones modulate release of neurotransmitters?
Via pre-synaptic autoreceptors, which mediate negative feedback inhibition of transmitter release (M2 and α2 activation, by reuptaken molecules, inhibits Ca2+ entry so less transmitter is released)
Agonists decrease release and antagonists increase release
How does cocaine affect the ANS?
Blocks U1 thus increasing conc. of noradrenaline in the synaptic cleft, so there is increased adrenoceptor stimulation
Peripheral actions cause vasoconstriction (α1 stimulation) and cardiac arrhythmias (β1 stimulation)
How does amphetamine affect the ANS?
It is a substrate for U1 and enters the noradrenergic terminal, where it inhibits MAO; it enters the synaptic vesicle and displaces noradrenaline into the cytocplasm.
Noradrenaline exits the terminal on U1 (“running backwards”) and accumulates in the synaptic cleft, causing increased adrenoceptor stimulation
Peripheral actions are largely the same as for cocaine
How does Prazosin affect the ANS?
Selective, competitive ANTAGONIST of α1 receptors
Vasodilator used as an anti-hypertensive agent
How does Atenolol affect the ANS?
Selective, competitive ANTAGONIST of β1; it does not block β2, α1 or α2
Used as an anti-anginal and anti-hypertensive agent
