Lesson 9 - Cholinergic Transmission - 2024/25 PDF

Lesson 9 Cholinergic Transmission Parasympathetic and Somatic nervous system 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  Peripheral Nervous System Sympathetic...

Lesson 9 Cholinergic Transmission Parasympathetic and Somatic nervous system 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  Peripheral Nervous System Sympathetic Parasympathetic Somatic Preganglionic neuron Ach Ach Ganglion Postganglionic neuron Nicotinic Receptor Nicotinic Receptor N.A. Ach Ach Adrenergic Receptor Muscarinic Receptor Nicotinic Receptor (Skeletal muscle) Effector organs Summary 1. Cholinergic transmission. Acetylcholine, Synthesis, receptors (nicotinic and muscarinic) 2. Direct acting drugs (Muscarinic agonists). Clinical uses 3. Anticholinesterase drugs. Clinical uses 4. Muscarinic Antagonists 5. Somatic nervious system, Nicotinic agonists and antagonists. 6. Summary Important concepts: ACETYLCHOLINE (Ach) is released at the level of: Parasympathetic postganglionic fibers (muscarinic receptors) Neuromuscular plaque (somatic NS-nicotinic receptors) Preganglionic fibers from all over the ANS (nicotinic receptors)  ACETYLCHOLINE It is a neurotransmitter, the main neurotransmitter of the parasympathetic NS, which is why it is called the CHOLINERGIC SYSTEM Synthesis of Ach: In the neurons of the cholinergic system Acetyl CoA+ choline → Ach (acetylcholine)  cholinoacetyl transferase *choline syntetized in the liver from the aa serine  ACETYLCHOLINE Storage of Ach: In vesicles or granules of the presynaptic fiber. Release of Ach: Once the transmission of the electrical impulse occurs, by ↑ Ca+2 intracellular favors the release of Ach into the synaptic space. Degradación Ach: Ach → Acetyl Co A + choline  acetylcolinesterase (AchE) When AchE hydrolyzes Ach, choline is reuptaked by the pre-synaptic neuron for a new production of Ach.  ACETYLCHOLINE Synthesis, Storage, Release and Inactivation of Ach. Acetylcholine is inactivated by enzyme action: Acetilcolinesterase (AchE).  Classification of cholinergic receptors 1) Nicotinic: Ion channel-coupled receptors Nicotine 2) Muscarinic: G-protein-coupled receptors They are named for the similarity between the Muscarine observed effects of muscarine (amanita muscaria) and nicotine.  Cholinergic receptors 1) Nicotinic Receptors: nicotinic receptor on the skeletal muscle (somatic nervous system) - Inhibited by tubocuranine Nicotinic receptor in the post-ganglionar neuron. In vegetative nodes and chromaffin cells of the adrenal glands - Inhibited by trimetafan.  Cholinergic receptors The nicotinic actions correspond 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. 10 Cholinergic receptors 2) Muscarinic Receptors: M1: In neurons of the ANS and CNS. (Gq) M: In heart and CNS (Gi) M: In secretory cells and smooth muscle cells and CNS (Gq) M: vascular endothelial cells, and CNS. (Gi) M: In CNS neurons, eyes (Gq) - Inhibited by Atropine.  Cholinergic receptors Muscarinic receptors (mAChRs) are typical G protein- coupled receptors. – (M1, M3, M5) couple with Gq to activate the inositol phosphate pathway – (M2, M4) open potassium (KATP) channels causing membrane hyperpolarisation as well as acting through Gi to inhibit adenylyl cyclase and thus reduce intracellular cAMP. Both groups activate the MAP kinase pathway. 12  Cholinergic receptors Main physiological functions of ACh in the body. The muscarinic actions correspond to those of ACh released at postganglionic parasympathetic nerve endings, with two significant exceptions: 1. Acetylcholine causes generalised vasodilatation, even though most blood vessels have no parasympathetic innervation. This is an indirect effect: – ACh acts on vascular endothelial cells to release nitric oxide , which relaxes smooth muscle. 2. Acetylcholine evokes secretion from sweat glands, which are innervated by cholinergic fibres of the sympathetic nervous system Summary 1. Cholinergic transmission. Acetylcholine, Synthesis, receptors (nicotinic and muscarinic) 2. Direct acting drugs (Muscarinic agonists). Clinical uses 3. Anticholinesterase drugs. Clinical uses 4. Muscarinic Antagonists 5. Somatic nervious system, Nicotinic agonists and antagonists. 6. Summary Parasympathetic Nervous System PNS AGONIST drugs are called PARASYMPATHOMIMETICS Synonyms: Cholinergic Agonists Muscarinic Agonists  Fármacos Parasimpaticomiméticos D + They are divided into: 1) DIRECT AGONISTS (act directly on the receptor) 2) INDIRECT AGONISTS (increase Ach levels indirectly; e.g. ↑ its release or ↓metabolism)  Parasympathomimetic drugs 1) DIRECT AGONISTS 1. Choline esters: CARBACOL BETHANECHOL ACETYLCHOLIN / METHACHOLINE 2.Natural alkaloids:De MUSCARINE PILOCARPINE 3. Synthetic drugs: CEVIMELINE Betanechol, pilocarpine and cevimeline are the only ones used clinically.  Parasympathomimetic drugs 1) DIRECT AGONISTS FARMACOCINÉTICA: PHARMACOKINETICS: Choline esters are hydrophilic and all hydrolyze in the stomach. They are administered parenterally but also topically. Alkaloids are orally administered PHARMACOLOGICAL ACTIONS:They are the consequence of the activation of cholinergic receptors Cardiovascular:  cardiac rhythm and output, Generalized vasodilation( BP) Gastrointestinal system:  Secretions peristaltic activity, increased intestinal transit, cramping pain, diarrhea (bethanechol,and pilocarpine).  Parasympathomimetic drugs 1) DIRECT AGONISTS PHARMACOLOGICAL ACTIONS: Urinary tract: they stimulate the bladder sphincter, increase urination pressure promote urination (betanechol). Airways: bronchoconstriction. Secretions: of exocrine secretions. Eyes: Accommodation of near vision (Miosis). MIOSIS Ciliary muscle contraction producing, decrease intraocular pression (Treatment of glaucoma) CNS: Intravenous pilocarpine only, toxicity (tremor, ataxia...) Choline esters do not pass through the BBB.  Parasympathomimetic drugs 1) DIRECT AGONISTS ADRs: GI: nausea, vomiting, epigastric pain. Secretions: Hypersalivation. Headaches, bronchoconstriction, visual disturbances, hypotension... ABSOLUTE CONTRAINDICATIONS: In bronchial asthma Gastric ulcer. Coronary insufficiency.  Parasympathomimetic drugs 1) DIRECT AGONISTS THERAPEUTIC APPLICATIONS: ► Glaucoma treatment: Pilocarpine (collyrium). ► Intestinal or gastrointestinal atony, and urinary bladder (bethanechol). ►Abdominal distension after surgery(bethanechol). ►Xerostomia (pilocarpine, cevimeline) Acetylcholine and methacholine are not used in the clinic due to their rapid inactivation by AchE. Muscarine is not used because of its toxicity.  Parasympathomimetic drugs 1) DIRECT AGONISTS Pharmacological application of PILOCARPINE ► GLAUCOMA: is an ocular pathology caused by elevated intraocular pressure due to a deficiency of aqueous humour flow. It can be treated by increasing pupillary sphincter contraction (miosis) and facilitating the flow. Pharamocological action: – Activation of the constrictor pupillae muscle by muscarinic agonists: lowers the intraocular pressure, improving drainage – by realigning the connective tissue trabeculae through which the canal of Schlemm passes.  Parasympathomimetic drugs 1) DIRECT AGONISTS Pharmacological application of PILOCARPINE/ CEVIMELINE XEROSTOMIA/SJOGREN ‘S SYNDROME: Xerostomia is the medical term for dry mouth. It results from insufficient production by the salivary glands. Sjögren’s syndrome is an autoimmune desease. Pharamocological action: – increase salivation and lacrimal secretion in patients with dry mouth or dry eyes (e.g. following irradiation, autoimmune damage to the salivary or lacrimal glands as in Sjögren’s syndrome). Summary 1. Cholinergic transmission. Acetylcholine, Synthesis, receptors (nicotinic and muscarinic) 2. Direct acting drugs (Muscarinic agonists). Clinical uses 3. Anticholinesterase drugs. Clinical uses 4. Muscarinic Antagonists 5. Somatic nervious system, Nicotinic agonists and antagonists. 6. Summary  Parasympathomimetic drugs 2) INDIRECT AGONISTS Acetylcholinesterase inhibitors: Reversible: NEOSTIGMINE PHYSOSTIGMINE EDROPHONIUM AMBENONIUM Irreversible: ORGANOPHOSPHATES (ECOTHIOPHAT, PARATION)  Parasympathomimetic drugs 2) INDIRECT AGONISTS Acetylcholinesterase inhibitors Drugs that inhibit Ach metabolism by blocking AchE. They prolong the effect of Ach, and this depends on the binding of the drug to the enzyme: weak bond (H-bridges) reversible strong bond (covalent) irreversible* *Irreversible AchE inhibitors are commonly called organophosphates. Acute toxicity (SARIN gas) death for respiratory paralysis (action of Ach on the neuromuscular plaque) ANTIDOTE: PRALIDOXIME (2-PAM), can remove sarin from the active site only in the early stages of exposure.  Parasympathomimetic drugs 2) INDIRECT AGONISTS Acetylcholinesterase inhibitors Mechanism of action They block or inhibit acetylcholinesterase (AchE), so that Ach is not hydrolyzed increases the concentration of Ach in the intersynaptic space and prolongs its action on the receptor.  Parasympathomimetic drugs 2) INDIRECT AGONISTS Acetylcholinesterase inhibitors Pharmacokinetics: Edrophonium and neostigmine malabsorption orally, are poorly liposoluble. Subcutaneous and intravenous route of administration Physostigmine and ecothiophate very liposolubles. Topical conjunctival route (glaucoma) Pharmacological effects and adverse reactions: They are similar to those produced by direct-acting drugs.  Parasympathomimetic drugs 2) INDIRECT AGONISTS Acetylcholinesterase inhibitors THERAPEUTIC APPLICATIONS: Myasthenia gravis: is a neuromuscular junction disease of autoimmune etiology characterized by muscle weakness Neostigmine Neutralization: to reverse post-anaesthetic muscle paralysis from non-depolarizing muscle relaxants (Neostigmine). Glaucoma: Physostigmine (tópica). Atony of the digestive and urinary system:Neostigmine.  Parasympathomimetic drugs 2) INDIRECT AGONISTS Acetylcholinesterase inhibitors Pharmacological application of EDROPHONIUM Short-acting anticholinesterases Used for diagnostic purposes, because improvement of muscle strength by an anticholinesterase is characteristic of myasthenia gravis but does not occur when muscle weakness is due to other causes.  Parasympathomimetic drugs 2) INDIRECT AGONISTS Acetylcholinesterase inhibitors Pharmacological application of NEOSTIGMINE /PHYSOSTIGMINE/ PYRIDOSTIGMINE. Medium-duration anticholinesterases  Parasympathomimetic drugs 2) INDIRECT AGONISTS Acetylcholinesterase inhibitors Clinical Use: To reverse the action of non-depolarising neuromuscular- blocking drugs (neostigmine). Atropine must be given to limit parasympathomimetic effects. To treat myasthenia gravis (neostigmine or pyridostigmine). As a test for myasthenia gravis and to distinguish weakness caused by anticholinesterase overdosage (‘cholinergic crisis’) from the weakness of myasthenia itself (‘myasthenic crisis’): edrophonium Alzheimer’s disease (e.g. donepezil). Glaucoma (ecothiophate/phisostigmine eye drops). Summary 1. Cholinergic transmission. Acetylcholine, Synthesis, receptors (nicotinic and muscarinic) 2. Direct acting drugs (Muscarinic agonists). Clinical uses 3. Anticholinesterase drugs. Clinical uses 4. Muscarinic Antagonists 5. Somatic nervious system, Nicotinic agonists and antagonists. 6. Summary Parasympathetic Nervous System SNP ANTAGONIST drugs are called PARASYMPATHOLYTICS Synonym: Muscarinic antagonists  Parasympatholytic drugs D - MUSCARINIC ANTAGONISTS Drugs that competitively inhibit muscarinic receptors at usual doses. At high doses they also inhibit nicotinic receptors.  Parasympatholytic drugs Muscarinic antagonists They are divided into: 1. Natural alkaloids: Atropine Scopolamine Atropa belladonna Deadly Nightshade Hyoscyamus niger Black Henbane 2. Synthetic and semi-synthetic derivatives: A) Tertiary amines: Methylamphetamine, Benzatropin B) Quaternary derivatives: Methylscopolamine, Scopolamine butylbromide (Buscapina). Ipatropium (Atrovent) Tiotropium  Parasympatholytic drugs Muscarinic antagonists Pharmacokinetics Naturai alkaloids and tertiary amines are more liposoluble, so they are distributed to all tissues, including the BBB, placenta and breast milk They are well absorbed orally. Quaternary derivatives that, as they are not liposoluble, do not cross the barriers, the route of administration will be parenteral. Ipatropium: inhalation route They are metabolized in the liver and elimination is renal.  Parasympatholytic drugs Muscarinic antagonists Pharmacological effects Cardiovascular:  of heart rate and output. Respiratory: Bronchodilation.  of bronchial secretion. Digestive system:  of digestive secretions  of salivary secretions  of motility  of gastric emptying.  Bile duct motility (spasmolytic) Urinary system: They relax the bladder body, making it difficult to urination.  the urethral tone  Parasympatholytic drugs Muscarinic antagonists Pharmacological effects Eyes: Mydriasis, blurred vision and photophobia. cycloplegia(ciliary muscle paralisis). Increased intraocular pressure.(NO GLAUCOMA) Decreased tear secretion. Central nervous system: MIDRIASIS Anti-kinetic action (movement) Antiemetic action. Scopolamine, at therapeutic doses, produces sedation and drowsiness. Anti-Parkinsonian action (Decreased cholinergic activity of the extrapyramidal centers).  Parasympatholytic drugs Muscarinic antagonists ADRs: Peripheral : of secretions (dry mouth and mucous membranes). Bloating and constipation. Mydriasis, blurred vision, photophobia, increased intraocular pressure. Tachycardia. Urinary retention. In CNS: At very high doses: excitement, hallucination and delirium (scopolamine and atropine). Mood swings, gait disturbance, distraction, memory impairment...  Parasympatholytic drugs Muscarinic antagonists Therapeutic applications: Cardiovascular: Treatment of bradycardia (Atropine i.v.) (M2) Ophthalmic: Pupil dilation for eye exams (M5) Neurological: Preventing motion sickness (Scopolamine) Respiratory: Bronchial asthma (Ipratropium) (M3) Gastrointestinal: Antispasmodic. (scopolamine...) (M3) Overactive bladder: Oxibutinine, tolterodine (M3) Parkinson's disease (Benzotropin) (M4) Poisoning by organophosphates or cholinergic drugs. Muscarinic antagonists also affect the extrapyramidal system, reducing the involuntary movement and rigidity (M4) of patients with Parkinson’s disease and counteracting the extrapyramidal side effects of many antipsychotic drugs.  Parasympatholytic drugs Muscarinic antagonists The history of ‘’Deadly nightshade’’ ATROPA BELLADONNA In ancient Greece and later during the Renaissance, women used the juice of the belladonna berries to dilate their pupils, as dilated pupils were considered attractive and seductive The name "belladonna" literally means "beautiful woman" in Italian, reflecting this practice. It was believed that large, dark pupils made a woman's gaze more appealing. However, this cosmetic practice was dangerous because the plant contains atropine, a toxic substance. It is estimated that ingesting 2-5 berries can be fatal for a child, while for an adult, the lethal dose could be higher, around 10-20 berries. However, even lower doses can result in serious symptoms. what could be the antidote to atropine intoxication? PHYSOSTIGMINE  Parasympatholytic drugs Muscarinic antagonists Clinical use of ATROPIN Different effects depending on the dose  Parasympatholytic drugs Muscarinic antagonists Clinical use of ATROPIN The main effects of atropine are: Inhibition of secretions. – Salivary, lacrimal, bronchial and sweat glands – Mucociliary clearance in the bronchi is inhibited: secretions tend to accumulate in the lungs. Ipratropium lacks this effect. Effects on heart rate. – Tachycardia (80–90 beats/min in humans). most pronounced in young people (vagal tone is highest) – At very low doses: bradycardia  Parasympatholytic drugs Muscarinic antagonists Clinical use of ATROPIN Effects on the eye. – (mydriasis). – Intraocular pressure may rise – Effects on the gastrointestinal tract. – Decrease gastrointestinal motility. – Pirenzepine (M1 antagonist), inhibits gastric acid secretion Effects on other smooth muscle. – Relaxation of Bronchial, biliary and urinary tract smooth muscle. – Prevention of Reflex bronchoconstriction is prevented by atropine(e.g. during anaesthesia). – Urinary retention in elderly men with prostatic enlargement. – Reduction of Incontinence due to bladder overactivity. Summary 1. Cholinergic transmission. Acetylcholine, Synthesis, receptors (nicotinic and muscarinic) 2. Direct acting drugs (Muscarinic agonists). Clinical uses 3. Anticholinesterase drugs. Clinical uses 4. Muscarinic Antagonists 5. Somatic nervious system, Nicotinic agonists and antagonists. 6. Summary  Peripheral Nervous System Sympathetic Parasympathetic Somatic Preganglionic neuron Ach Ach Ganglion Postganglionic neuron Nicotinic Receptor Nicotinic Receptor N.A. Ach Ach Adrenergic Receptor Muscarinic Receptor Nicotinic Receptor (Skeletal muscle) Effector organs  Nicotinic Agonists Most agonists act on either neuronal nACh receptors or on striated muscle receptors, apart from nicotine and ACh, that act on both.  Nicotinic Agonists Ganglion-stimulating drugs nicotine, dimethylphenylpiperazinium (DMPP). – Both sympathetic and parasympathetic ganglia are stimulated: tachycardia and increase of blood pressure variable effects on gastrointestinal motility and secretions increased bronchial, salivary and sweat secretions. – Additional effects result from stimulation of other neuronal structures, including sensory and noradrenergic nerve terminals. Ganglion stimulation may be followed by depolarisation block. Nicotine also has important central nervous system effects. No therapeutic uses, except for nicotine to assist giving up smoking.  Neuromuscular Blockers Motor plate or neuromuscular plate: A specialized area of skeletal muscle fiber rich in cholinergic receptors that is part of the neuromuscular junction. Neuromuscular block is an important adjunct to anaesthesia , when artificial ventilation is available. – The drugs used for this purpose all work postsynaptically, either by blocking ACh receptors (non-depolarising agents) by activating ACh receptors and thus causing persistent depolarisation of the motor endplate (depolarising agents) Apart from suxamethonium all of the drugs used clinically are non-depolarising agents.  Neuromuscular Blockers Site of action: 56  Neuromuscular Blockers NICOTINIC ANTAGONISTS Non-Depolarizing agents They derive from curare, obtained from Chododendrum tomentosum Tubocurarine (d-tubocurarine). Mechanism of action: Competitive antagonists of the Ach. They block the nicotinic receptor so that Ach cannot reach the receptors, resulting in flaccid paralysis.  Neuromuscular Blockers NICOTINIC ANTAGONISTS Non-Depolarizing agents Pharmacokinetics: Administered IV They do not cross the placental barrier. The level of motor plate block depends on the dose and the individual sensitivity. The effects starts: 1º With an initial motor weakness, small muscles, eyes... 2º Neck, trunk, limbs. 3º Larger muscles and diaphragm Recovery is in reverse order ADRs: Respiratory paralysis Tubocuranin causes bronchospasm and hypotension Therapeutic applications: ✓ Induction and Maintenance of Muscle Relaxation in General Anesthesia ✓ Intubations.  Neuromuscular Blockers NICOTINIC ANTAGONISTS Non-Depolarizing agents Unwanted effects: fall in arterial pressure (tubocurarine) (M2 agonism) bronchospasm in sensitive individuals (atracurium and mivacurium ) (M3 agonism) Tachycardia: Pancuronium also blocks mAChRs, particularly in the heart.  Neuromuscular Blockers NICOTINIC ANTAGONISTS Depolarizing agents SUCCINYLCHOLINE (SUXAMETHONIUM) DECAMETONIUM Mechanism of action: They produce a depolarization of the motor plate and until succinylcholine is metabolized by the action of pseudocholinesterases, repolarization does not occur Complete muscle relaxation or flaccid paralysis  Neuromuscular Blockers NICOTINIC ANTAGONISTS Depolarizing agents SUCCINYLCHOLINE (SUXAMETHONIUM) – its action lasts only a few minutes, because it is quickly hydrolysed by plasma cholinesterase. – When given IV, however, its depolarising action lasts for long enough Suxamethonium has several adverse effects but remains in use because of the rapid recovery that follows its withdrawal.  Neuromuscular Blockers NICOTINIC ANTAGONISTS Depolarizing agents SUCCINYLCHOLINE (SUXAMETHONIUM) – Bradycardia: This is preventable by atropine and is due to a direct muscarinic action.(M2) – Potassium release.(M2): May cause ventricular dysrhythmia or even cardiac arrest. Increased intraocular pressure: important to avoid this if the eyeball has been injured.(blocks mAChr in the eye) Prolonged paralysis. Malignant hyperthermia (Muscle contraction and fever) – This is a rare inherited condition, due to a mutation of the Ca2+ release channel. – The condition carries a very high mortality (about 65%) and is treated by administration of dantrolene, a drug that inhibits muscle contraction by preventing Ca2+ release from the sarcoplasmic reticulum.  Neuromuscular Blockers NICOTINIC ANTAGONISTS Depolarizing ADRs: Serious: cardiac arrest, malignant hyperthermia, anaphylactic shock and prolonged paralysis. Other: Muscle pain, cardiac arrhythmias, increased intraocular pressure and bradycardia. Therapeutic applications: Situations in which intense relaxation of short duration is required (dislocations...) Intubación endotraqueal Terapia electroconvulsiva  Neuromuscular Blockers: Depolarizing Vs Non-Depolarizing Depolarizing Neuromuscular Blockers: Act as persistent agonists at nicotinic receptor, causing prolonged depolarization and subsequent muscle paralysis. Non-Depolarizing Neuromuscular Blockers: Act as competitive antagonists of nicotinic receptor, blocking the nerve signal transmission to the muscle without an initial depolarization phase. Both types of neuromuscular blockers are used in anesthesia and clinical settings to manage muscle paralysis needed during medical procedures. Summary 1. Cholinergic transmission. Acetylcholine, Synthesis, receptors (nicotinic and muscarinic) 2. Direct acting drugs (Muscarinic agonists). Clinical uses 3. Anticholinesterase drugs. Clinical uses 4. Muscarinic Antagonists 5. Somatic nervious system, Nicotinic agonists and antagonists. 6. Summary SUMMARY 68 Questions?????