Cholinomimetics Flashcards
What are cholinomimetics
Drugs that mimic the actions of Ach in the nervous system.
Where is the enzyme choline acetyltransferase (CAT) exclusively found
In cholinergic nerve terminals.
Outline the synthesis of Ach
Ach is synthesised within the nerve terminal from choline, which is taken into the nerve terminal via a specific transporter (choline carrier)- this transporter is not important in terminating the action of Ach
Free choline within the nerve terminal is acetylated by a cytosolic enzyme, choline acetyltransferase (CAT), which transfers the acetyl group from acetyl coA to choline- forming acetylcholine.
The rate-limiting process in ACh synthesis appears to be choline transport, which is determined by the extracellular choline concentration and hence is linked to the rate at which Ach is being released.
Describe the action of cholinesterase
Present in the pre-synaptic nerve terminals, and ACh is continually being hydrolysed and resynthesized. Inhibition of the nerve terminal cholinesterase causes the accumulation of surplus ACh in the cytosol, which is not available for release by nerve impulses (although it is able to leak out via the choline carrier).
Most of the ACh synthesised, however, is packaged into synaptic vesicles, in which its concentration is extraordinarily high (about 100mmol/L), and from which its release occurs by exocytosis triggered by Ca2+ entry into the nerve terminal.
Describe the packaging of ACh into vesicles
Cholinergic vesicles accumulate ACh actively, by means of a specific transporter belonging to a family of amine transporters (ACh carrier).
Accumulation of ACh is coupled to the large electrochemical gradient for protons that exists between acidic intracellular organelles and the cytosol; it is blocked selectively by the experimental drug vesamicol.
Describe the release of ACh from the vesicles
Following its release, ACh diffuses across the synaptic cleft to combine with receptors on the postsynaptic cells.
Some of it succumbs on the way to hydrolysis by acetylcholinesterase, an enzyme that is bound to the basement membrane that lies between the pre- and postsynaptic membranes.
At fast cholinergic synapses (e.g the neuromuscular and ganglionic synapses), but not at slow ones (smooth muscle cells, glands, heart), the released ACh is hydrolysed very quickly so that it acts very rapidly.
What are the pharmacological actions of ACh distinguished by
Two types of activity:
muscarinic- mimicking the effects of muscarine (the active principle of the poisonous mushroom Amanita muscaria)
Nicotinic- mimicking the effects of nicotine.
Where do muscarine and nicotine originate from
Comes from amanita muscaria and nicotiana tabacum
Summarise muscarinic vs nicotinic effects
Muscarinic effects are those that can be replicated by muscarine, and can be abolished by low doses of the antagonist atropine
Muscarinic actions correspond to those of parasympathetic stimulation
After atropine blockade of muscarinic actions larger doses of acetylcholine can induce effects similar to those caused by nicotine
Compare some nicotinic and some muscarinic actions
Muscarinic effects- fall in BP (arteriolar vasodilation) and slowing of the heart
Nicotinic effects- initial rise in BP (stimulation of sympathetic ganglia and consequent vasoconstriction), and a secondary rise resulting from the release of adrenaline.
What do the muscarinic actions correspond to
The ACh released at postganglionic parasympathetic nerve endings, with two significant exceptions:
- ACh causes generalised vasodilation, even though most blood vessels have no parasympathetic innervation. This is an indirect effect: ACh (like many other mediators) acts on endothelial cells to release nitric oxide, which relaxes smooth muscle. The physiological function of this is uncertain. because ACh is not normally present in circulating blood.
- ACh evokes secretion from sweat glands, which are innervated by cholinergic fibres of the sympathetic nervous system.
What do the nicotinic actions correspond to
To those of ACh acting on autonomic ganglia of the sympathetic and parasympathetic systems, the motor endplate of voluntary muscle and the secretory cells of the adrenal medulla.
Summarise the muscarinic receptors
Muscarinic receptors (mAChRs) are typical G-protein coupled receptors, and five molecular subtypes (M1-M5) are known.
State where you would find the different types of muscarinic receptor.
M1: Salivary glands Stomach CNS M2: Heart M3: Salivary glands Bronchial/visceral SM Sweat glands Eye M4: CNS M5: CNS NOTE: muscarinic receptors are generally excitatory except for on the heart
Summarise the intracellular effects of the different muscarinic receptors
The odd-numbered members of the group (M1,M3,M5) couple with Gq to activate the inositol phosphate pathway
The even-numbered receptors (M2,M4) act through Gi to open potassium (Kir) channels causing membrane hyperpolarisation; they also inhibit adenylyl cyclase but intracellular cAMP is usually low.
Muscarinic agonists with either transduction mechanism also activate the mitogen-activated protein kinase pathway.
Describe the M1 receptors
Found mainly on CNS, peripheral neurons, gastric parietal cells and lacrimal and salivary glands
They mediate excitatory effects, for example, the slow muscarinic excitation (slow epsp) mediated by ACh in sympathetic ganglia and central neurons
This excitation is produced by a decrease in K+ conductance, which causes membrane depolarisation.
Deficiency of this kind of ACh-mediated effect in the brain is possibly associated with dementia, although transgenic M1-receptor knockout mice show only slight cognitive impairment.
M1 receptors are also involved in the increase of gastric acid secretion following vagal stimulation.
Describe the M3 receptors
Found in glandular and smooth muscle
produce mainly excitatory effects i.e stimulation of glandular secretions (salivary, bronchial, sweat etc) and contraction of visceral smooth muscle.
M3 receptor activation also causes relaxation of some smooth muscles (mainly vascular) via the release of nitric oxide from neighbouring endothelial cells.
M3 receptors also occur in specific locations in the CNS.
G.I smooth muscle contraction, ocular accommodation too
Rise in IP3 and Ca2+
Summarise the M4 and M5 receptors
Largely confined to the CNS, and their functional role is not well understood, although mice lacking these receptors do show behavioural changes.
No therapeutic uses currently.
M4 may be involved in enhanced locomotion
What is the difference in the G-protein receptors of M1, M3 and M5 compared to M2 and M4?
M1, M3 and M5 = Gq protein linked receptors – they stimulate PLC which increases IP3 and DAG
M2 and M4 = Gi protein linked receptors (inhibitory) – they decrease the production of cAMP
Essentially, what type of receptors are muscarinic receptors
GPCRs- their activation causing:
activation of PLC (hence formation of IP3 and DAG as secondary messengers)
inhibition of adenylyl cyclase- hence reducing the formation of cAMP.
activation of potassium channels and/or inhibition of calcium channels
Summarise potential new therapeutic roles for mAChR ligands
Cytokine secretion from lymphocytes and other cells is regulated by M1 and M3 receptors, while M2 and M4 receptors affect cell proliferation in various situations.
What happens in response to nicotinic receptor activation
Na+ influx- but also some K+ efflux.
Summarise the nicotinic receptors
Muscle receptors are confined to the skeletal NMJ; ganglionic receptors are responsible for fast transmission at sympathetic and parasympathetic ganglia; and CNS-type receptors are heterogenous with respect to their molecular composition and location.
Where are many of the CNS nicotinic receptors found
presynaptically and serve to facilitate or inhibit the release of other mediators, such as glutamate or dopamine.
Describe the structure of nicotinic receptors. What determines its ligand binding properties?
Nicotinic receptors consist of 5 subunits (alpha, beta, gamma, delta or epsilon)
The combination of subunits determines its ligand binding properties
Pentameric structures
The five subunits each possess four membrane-spanning helical domains and one of these helices from each subunit forms the central pore.
What are the two main types of nicotinic receptor? Describe their subunit composition.
Muscle and Ganglion
Muscle = 2 alpha + beta + delta + epsilon
Ganglion = 2 alpha + 3 beta CNS also 2 alpha + 3 beta- but different types of each one
How do the effects of acetylcholine on nicotinic receptors compare to its effects on muscarinic receptors?
The effects of acetylcholine are relatively weak on nicotinic compared to muscarinic
List the muscarinic cholinergic target systems
Eye Salivary glands Lungs Heart Vasculature Sweat Glands Gut Bladder
Summarise the end result of muscarinic effects
combined vasodilation, decreased HR and decreased CO = sharp BP drop
Describe the muscarinic effects on the heart
M2 AChR in
atria and nodes
Stimulation of these receptors- decreased cAMP
This results in:
Decreased Ca2+ entry and increased K+ efflux
Decreasing Q and HR respectively.
Negative inotropic and chronotropic effects
What is important to remember about blood vessels
Most blood vessels don’t have PSNS innervation.
However, they do express muscarinic receptors and so can be exploited by exogenous drugs
Describe the muscarinic effects on the vasculature
Most blood vessels do not have parasympathetic innervation
Acetylcholine acts on vascular endothelial cells to stimulate NO release via M3 AChR
NO induces vascular smooth muscle relaxation
Result is a decrease in TPR
When are the muscarinic effects on the vasculature more relevant
This is more relevant to the clinical use of cholinomimetics than normal physiology
Summarise the muscarinic effects on the cardiovascular system
Decreased heart rate (bradycardia)
Decreased cardiac output (due to decreased atrial contraction)
Vasodilatation (stimulation of NO production)
All of these combined can lead to a sharp drop in blood pressure
How do the muscarinic effects on non-vascular smooth muscle compare to that of vascular smooth muscle
Smooth muscle that does have parasympathetic innervation responds in the opposite way to vascular muscle – i.e. it contracts
Summarise the muscarinic effects on non-vascular smooth muscle
Lung: Bronchoconstriction
Gut: Increased peristalsis (motility)
Bladder: Increased bladder emptying
What is colicky G.I pain due to
Contraction of the smooth muscle in the gut
Summarise the muscarinic effects on the exocrine glands
Salivation
Increased bronchial secretions
Increased gastro-intestinal secretions (including gastric HCl production)
Increased sweating (SNS-mediated)
Summarise the muscarinic effects on the eye
Contraction of the ciliary muscle: accommodation for near vision
Contraction of the sphincter pupillae (circular muscle of the iris): Constricts pupil (miosis) and improves drainage of intraocular fluid
Lacrimation (tears)
What is the effect of contraction of the sphincter pupillae muscle on the drainage of intra-ocular fluid
Contraction of sphincter pupillae opens pathway for aqueous humour, allowing drainage via the canals of Schlemm and reducing intra-ocular pressure
Describe the contraction of the ciliary muscle
Allows the lens to bulge
Becomes more convex
Allowing us to accommodate for near vision- need a more powerful lens- as light rays are heading outwards- so we need two bring light rays back onto the retina quickly
How does the lens need to be when looking at distant objects
Flat- to collect all the light rays
Where is the aqueous humour produced
Ciliary body- epithelial cells cover it
Aquous humour flows forward into the anterior chambers of the eye
Bathes the lens and cornea- don’t have blood supply- so this supplies oxygen and nutrients to these regions
Drains into the margin of the eye- Canal of schlemm
Drains through these into the venous system
Continuous flow of aqueous humour.
Describe closed angle glaucoma
Angle of drainage into canal of schlemm changes- becoming more occluded
This results in a lower rate of drainage- raining the intraocular pressure- damaging the retina or optic nerve which can lead to blindness.
Summarise the effects of muscarinic receptor activation
Decreased heart rate
Decreased blood pressure
Increased sweating
Difficulty breathing
Bladder contraction
Gastrointestinal pain
Increased salivation and tears
