What does Acetylcholine interact with?
- The transmitter ACETYLCHOLINE interacts with distinct subclasses of cholinoceptors at different cholinergic synapses.
- This specificity of distinct cholinoceptors allows for selective pharmacological interventions.
ACh (acetylcholine) serves as the mediator at which terminals of…?
- All postganglionic parasympathetic nerve fibres
- Preganglionic synapses within both the sympathetic & parasympathetic ANS
- Neuromuscular junction of skeletal muscle
What inactivates acetylcholine?
- Neurotransmitter ACh is usually very quickly hydrolyzed and inactivated by the highly active enzyme acetylcholinesterase AChE.
- Thus, ACh is not suitable as a drug.
- Several pharmacologically active substances exist that mimic the action of ACh
What are the 2 main groups of Cholinomimetics?
- Direct acting agonists
- Indirect acting enzyme inhibitors
Name a direct acting agonist
(one of the main groups of cholinomimetics)
Muscarinic agonist: PILOCARPINE
* Pilocarpine-containing eye drops for the treatment of glaucoma, a group of ocular diseases with abnormally high intraocular pressure.
* Reduction of IOP is achieved by contracting the ciliary muscle which increases aqueous outflow.
Name an indirect acting enzyme inhibitor
(one of the main groups of cholinomimetics)
Enzyme inhibitor: NEOSTIGMINE
* Anticholinesterase drug neostigmine is used in the treatment of myasthenia gravis, an autoimmune disease in which neuromuscular transmission is defective due to the loss of functional nACh receptors in skeletal muscle.
* Anti-AChE drugs increase the amount of ACh available in the synaptic cleft, thus counteracting MG.
Name the 7 groups that cholinergic drugs can be subdivided into
- Muscarinic Agonists
- Muscarinic Antagonists
- Ganglion - stimulating Nicotinic Agonists
- Ganglion - blocking Drugs
- Anti-Cholinesterases
- Non-depolarizing Neuromuscular Blockers
- Depolarizing Neuromuscular Blockers
Slide 6
Nicotine
Alkaloid (from the tobacco plant Nicotiana tabacum) which activates a specific subclass of ACh receptors
— nAChR
see slide 7
Muscarine
Alkaloid (from the poisonous mushroom Amanita muscaria) which activates a specific subclass of ACh receptors —> mAChR
see slide 7
What are the divisions in the Autonomic Nervous System and drug action
- The ANS has sympathetic and parasympathetic divisions consisting of both efferent and afferent nerves.
- Both branches of the ANS serve their own physiological functions and are thus more or less active in a particular tissue according to the specific need of the body at that given moment.
Rest: ‘Housekeeping’ during inactivity
Parasympathetic NS: + Sympathetic NS: -
Stress: Mobilization during activity
Parasympathetic NS: - Sympathetic NS: +
Where is the neurotransmitter Acetylcholine released from?
- ACh is release from the synapse into the synaptic cleft and acts post-synaptically on a nicotinic ACh receptor complex that intrinsically controls the physiological activity of a cation channel. (e.g at the neuromuscular junction or ganglionic synapses)
Muscarinic Acetylcholine Receptor
- M-AChRare activated by agonist ACh
- Pharmacologically type 2 class of metabotropic receptors
- G-protein coupled class of receptors N
- ACh effects at postganglionic parasympathetic synapses are mediated via m-AChR: Hear, Smooth muscle, Glands
What activates mAChRs?
- Activated by acetylcholine
What blocks mAChRs?
- Blocked by atropine
Muscarinic AChRs are G-protein-coupled receptors causing..?
- Activation of phospholipase C, triggering production of second messengers:
Formation of inositol trisphosphate
Diacylglycerol - Inhibition of adenylyl cyclase
- Activation of potassium channels
- Inhibition of calcium channels
M-AChR second messenger cascade:
- Heart pacemaker cell M2 receptor
K+ channel activation - slows depolarizaton - reduced
heart rate - Smooth muscle M3 receptor
Phospholipase C activation - increased cytosolic Ca2+- increased muscle tone
- Secretory cell M3 receptor
Phospholipase C activation - increased cytosolic Ca2+
- increased secretion
How many subtypes can mAchR be divided into?
- Can be divided into 5 main subtypes (M1 to M5) according to their biochemical and physiological properties
- Pharmacologically the most important receptors are the classes M1, M2 and M3.
M1 ‘Neural’ mAChR
- Mostly found in cerebral cortex, autonomic ganglia, gastric glands, salivary glands
- Functional response: CNS excitation, gastric secretion
- Selective M1 antagonist is the blocker Pirenze (treatment of peptic ulcers)
M2 ‘Caridiac’ mAChR
- Mostly found in the heart and presynaptic terminals of peripheral and central neurons
- Functional response: Cardiac inhibition, neural inhibition
- Selective blocker Gallamine (obsolete muscle relaxant with unwanted cardiac effects - tachycardia)
M3 ‘GLANDULAR’ mAChR
- Mostly found in glands and smooth muscle
- Functional response: Gastric secretion, salivary secretion, smooth muscle contraction
- Selective blocker Darifenancin (treatment of urinary incontinence)
What are some of the main effects of muscarinic cholinomimetics which resembles that of parasympathetic stimulation?
- Vasodilation
- Decreased heart rate
- Decreased blood pressure
- Contraction of gut smooth muscle
- exocrine secretions
Where are muscarinic agonists poorly absorbed from?
Muscarinic agonists are poorly absorbed from the GI-tract and furthermore exhibit considerable side effects which excludes many pharmacological applications.
