Cholinergic Transmission PDF
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Summary
These notes cover cholinergic transmission, including synthesis, storage, release, and termination. It discusses muscarinic receptors and their effects on various organ systems, such as cardiovascular and respiratory. The document also highlights the effects of nicotine using specific terms.
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I. INTRODUCTION Cholinergic Transmission I. Synthesis Acetyl coA (from mitochondria) + choline -> ACh ○ Using choline acetyltransferase Blocked by: Hemicholinuims Location: Cytoplasm II. torage S C...
I. INTRODUCTION Cholinergic Transmission I. Synthesis Acetyl coA (from mitochondria) + choline -> ACh ○ Using choline acetyltransferase Blocked by: Hemicholinuims Location: Cytoplasm II. torage S Cytoplasm to vesicle using VAT Blocked by: vesamicol III. Release Vesicle to synapse ○ Action potential of Ca2+ Fuses with the membrane Blocked by: botulinum toxin IV. Termination ACh to acetate and choline ○ Acetylcholinesterase Muscarinic Receptors *M3 has vasodilating effect but required intact endothelium, leads also to release of nitric oxide a vasodilator 1, M3, M5 - IP3/DAG(Gq) M M2, M4 - decrease cAMP/cyclic(Gi) M = GPCR, N= ion channel CNS Organ System Effects - Muscarinic M 1 abundant in brain areas involved in cognition N are less abundant but have significant function ○ ACh and Nicotine -> regulates 5-HT, GABA, DA, NE ○ Nicotine addiction ○ Exposure to nicotine: activation (depolarization) & desensitization ○ Nicotine action is same for para and sympha ganglia EYES Cardiovascular System Respiratory System Effects: M2 Effects Miosis B radycardia(↓heart rate) Bronchoconstriction ○ Contraction of iris sphincter Decreases contractility & conduction Secretions ○ Opposite: mydriasis Reflex tachycardia Stimulation of glands (salivary& ○ Pupil Constriction gastric) Accommodation M3 ○ Contraction of ciliary muscle V asodilatingeffect but requires intact ○ Near vision endothelium Release of NO (vasodilator) Indications: Hypotension Glaucoma Contraindications ○ Increased IO Asthma ○ Give cholinergic Note/s NIcotine action -> tachycardia DRUG:Pilocarpine Gastrointestinal Genitourinary Other glands M3 M2 & M3 S weat Smooth muscle contraction Bladder muscle relaxation (sphincter) Tears Urination Nasopharyngeal M2 Reduces cAMP formation Peristalsis + Sphincter relaxation ○ Increase leads to higher movement of gut Note/s Secretions (saliva, gastric) Nicotine action in GI and GU ○ Nausea, vomiting, diarrhea urination Note/s Nicotine action in GI and GU ○ Nausea, vomiting, diarrhea urination RUG/S D Bethanechol, Neostigmine NICOTINIC EFFECTS - ocated at autonomic ganglia L - Depolarization -> contraction - Neuromuscular junction = neuron & skeletal muscle connection - Action potential leads to release of ACh\ - Fasciculations - Muscle weakening(myasthenia gravis) - Paralysis - SIDE EFFECTS-CNS - CNS depression - ethargy L - Seizures Coma Indications: 1. Myasthenia gravis - Indirect agents RUG: D Edrophonium (diagnostics) Pyridostigmine(long-term treatment) 2. Anesthetic Management DRUG:Neostigmine(reverse paralysis) II. CHOLINERGIC DRUGS I. DIRECT-ACTING CHOLINERGICS MOA:direct bindingtoMandN receptors Indications: - Open angle glaucoma - Xerostomia (oral dryness) - Urinary retention and postoperative ileus - Miosis - Bronchoprovocation testing A. Choline Esters (quaternary amines, lipid-insoluble, can't cross BBB) - uaternary amines Q - Hydrophilic - Poorly absorbed; Poorly distributed to the CNS - Cannot cross BBB - All Choline Esters have similar action to ACh(differenceonly in potency and duration of action) - Low doses for all except ACh Drug Receptor / MOA Effects Indications / Contraindications Onset/Administration 1. Ach M & N ecrease cardiac output, heart D Nonspecific cholinergic effect rate, blood pressure Nonspecific Increases GI activity maller dose: vasodilation with reflex S tachycardia Miosis apidly inactivated R by ACE Heart and GI? Larger dose: bradycardia 2. Bethanechol M3 Increase in GI motility BOWEL BLADDER Short acting Bowel ost resistantto M Bladder emptying ACE Urinary and GI 3. Methacholine M3 ronchoconstriction B sthma A LUNGS Bronchoprovocation testing (alt: More resistant to GI and Urinary Tract* Mannitrol) hydrolysis Contraindication/s: Asthma ○ Hyperreactivity 4. Carbachol M and N iosisduring surgery M For the treatment ofGlaucoma Long acting Decreases ocular pressure ost resistant to M EYES ACE B. Alkaloids (Well absorbed and Lipid soluble) Drug Receptor / MOA Effects Indications/Contraindications Onset/Administration 1. Pilocarpine M1and N iosis M reatment ofacute glaucoma/ T Short acting Decreases ocular pressure open-angle glaucoma (alternative) Administration: IV May cause brief hypotension and hypertension 2. Nicotine A4B2 Increased craving Implication forsmoking cessation hronic exposure to nicotine -> activation C (depolarization) & desensitization Densensitization after 1 stick Cardiovascular Tachycardia GI and GU Nausea, vomiting, diarrhea, urination 3. Muscarine II. INDIRECT-ACTING CHOLINERGICS MOA:targetAcetylcholinesterase enzyme Same pharmacodynamic properties but different pharmacokinetic properties 3 groups: - Simple alcohols (4 amine)e.g. edrophonium - Carbamates(5 ammonium) e.g. neostigmine - Organophosphate Indirect Agonist (Reversible) Indications: - MG (carbamates) - Dementia (AChEIs) - eversal of nicotinic muscular blockade (Nm) (carbamates) R A. QUATERNARY CARBAMATES(Reversible) Drug Receptor / MOA Effects Indications / Contraindications Onset/Administration 1. Edrophonium OA: Inhibition of M apid increase in muscle R yasthenia gravis M Short acting Cholinesterase strength (diagnostics) (2-10 mins) bon oor absorption P ut no longer use bcs offalse positives B (needs larger doses) in MG egligible N distribution to CNS A. Carbamates(Reversible) - Stable in aq. Soln - Better inhibitor, longer effects Drug Receptor / MOA Effects Indications / Contraindications Onset/Administration 1. Physostigmine OA: Inhibition of M Can be used topically in the oroverdosesof F Short acting Cholinesterase ye (+-) e anticholinergic drugssuch as Tertiary Atropine 30 mins to 6 hours N and M Antimuscarinic toxicity Can cross BB PNS and CNSAnticholinergic poisoning ertiary amines T (moretoxic,more lipid soluble, better absorbed) 2. Neostigmine ladder and GI tract B G M Short OA: Inhibition of M Reverse the effects of Postoperative ileus Cholinesterase anesthesiafrom neuromuscular Paralysisfor general 30 mins to 6 hours blocking agents anesthesia Cannot cross BBB Can be used topically in the eye Neuromuscular blockers (depolarized Nm agonists) ertiary amines T (more toxic) 3. Pyridostigmine ame with neostigmine S MG(long-term) Long-term Cannot cross BBB Bladder and GI B. Central Acetylcholinesterase Inhibitors (Cannot stop progression ofAlzheimerjust ease) Drug Receptor / MOA Effects Indications / Contraindications Onset/Administration 1. Donepezil OA: Inhibition of M ase the symptoms of E lzheimer’s disease A Long-acting Cholinesterase Alzheimer's disease Dementia with Lewy bodies Tertiary amine can cross BBB 100% bioavailability Reversible Contraindications: Metabolized by liver, exreted in Hypersensitivity almost 100% the urine ioavailability; b Interactions: metabolized by liver AVOID ANTICHOLINERGICS enzymes, excreted by the urine 2. Rivastigmine OA: Inhibition of M ase the symptoms of E lzheimer’s disease A Intermediate-acting Cholinesterase Alzheimer's disease Dementia with Lewy bodies Tertiary amine seudoirreversible P Contraindications: Interactions: AVOID (self reversing over Hypersensitivity hrs) ANTICHOLINERGICS If stopped >3 days ○ Vomiting with ay release GFs interfere with amyloid M esophageal rupture deposition Interactions: AVOID ANTICHOLINERGICS 3. Galantamine ase the symptoms of E lzheimer’s disease A Alzheimer's disease Dementia C. Organophosphates(Irreversible) Highly lipid soluble ○ Can enter BBB Well absorbed from skin, lung, gut, conjunctiva Distributed toall parts of the body Toxic and not used as drugs High absorption = more toxicity = not used as drugs Less stable in aqueous solution vs carbamates Echothiophate - highly polar, more stable Non-medical uses: ○ Insecticide Stable, aging process ANTIDOTE:Pralidoxime Drug Receptor / MOA Effects Indications / Contraindications Onset/Administration 1. Echothiophate ot well absorbed? N Open angle glaucoma ONLY Irreversible Rarely used for its side effects Highly POLAR More stablethan other organophosphates 2. P arathion, Malathion ll organophosphatesexcept A (thiphosphates echothiophatearedistributed to all insecticides) parts of the body (CNS toxicity) bsorbed in all routes A Lipid-soluble Indications: Insecticides III. DUMBBELLS SIDE EFFECTS - NICOTINIC EFFECTS - Neuromuscular junction (depolarize) - Fasciculations - Muscle weakening (myasthenia gravis) - Paralysis SIDE EFFECTS - CNS - CNS depression - Lethargy - Seizures - Coma Gi and Bladder Bethanechol, Neostigmine, Pyridostigmine Asthma Bronchial LUNGS Methacholine Eyes Pilocarpine, Carbachol, +- Physostigmine Increase lacrimation, Increased salivation Pilocarpine + Carbachol MG locks nicotinic receptors ligand site and ACh cannot bind B Causesweakness Improve weakness thru Inhibit acetylcholinesterase Drugs:Edrophonium (short lived), Neostigmine (lesslasting), Pyridostigmine (long lasting for chronic) DON'T USE PHYSOSTIGMINE!CNS toxicity III. ANTICHOLINERGIC / ANTIMUSCARINIC / PARASYMPHOLITICS I. DIRECT ACTING OA: reversible inverse agonism M (most; atropine, pirenzepine, trihexyphenidyl, tio/ipratropium, glycopyrronium, dicycloverine, methscopolamine) or antagonism Effects:Opposite of DUMBBELSandCNS ACh effects - Constipation - Urinary retention - Mydriasis - Tachycardia - Bronchodilation - Anti-Emetic - Dry mouth - Decreased secretions A. Tertiary Amines (Tertiary amines have good absorption and cross BBB than quaternary) Drug Onset MOA / Receptor Indications Use/Effects 1. Atropine Long duration on-selectivemuscarinic ACh receptor N st line Symptomatic bradycardia 1 Eye antagonist (IM/IV) ydriasis M ○ Resuscitation Cycloplegia M3 and M2 (higher doses) ○ Inability to focus visually M2 Unresponsiveness to light nti-arrhythmic A Increases IO, blurred vision Vagolytic effect (improved conduction in sinoatrial node) GI tract Increased HR Reduced GI motility Anesthesia adjuvant Heart *tertiary amine alkaloid esters ○ prevent bronchoconstriction tachycardia nd reduce salivation + a Salivary, Sweat, Lacrimal(all decreases) respiratory secretions Dry mouth Dry skin High body temp M3 educed secretions->improved R efficacy topical anesthetics and improved laryngoscopy imaging Cholinergic crisis (?) Corneal abrasions, 2nd line for strabismus and ambluopia (poor vision) Mydriasis Cycloplegia M1 hemoreceptor trigger zone C blocked ○ Less nausea vs Glycopyrronium 2. iperiden,Benztropine, B on-selectiveCNSM1-5ACh receptor N ystonia D Increase dopamine release, used for movement Trihexyphenidyl antagonist,promotes dopamine release Pseudoparkinsonism(antipsychotic-induced), disorders such as Parkinson's or drug-induced tremors. tremors in Parkinson's disease Blocks the blockade of DA release Ineffective for akathisia(inability to remain stilll) 3. Hyoscine/Scopolamine on-selectivemuscarinic ACh receptor N otion sickness, M Primarily used for motion sickness(M1 antagonist). antagonist, blocksM1 receptorsin genitourinary spasms - Brainstem blocked oisonous plant P brainstem (dysmenorrhea), Reduces GI motility and spasm. L isomers more potent irritable bowel syndrome (IBS), hypersalivation/sialorrhea reater effect onCNS G Motion sickness Postoperative nausea and vomiting 4. icycloverine/Dicyclomi D on-selectivemuscarinic ACh receptor N Indication: sed mainly forGI conditionslike IBS, rather than U ne antagonist,reduces GI motility Irritable Bowel Syndrome (IBS), broader systemic effects. chronic obstructive pulmonary Reduced GI motility diseases(COPD) 5. Solifenacin, Darifenacin lightly prefers M3ACh receptor S Indication Less urination antagonist (Darifenacin more selective) Alternative over M1 and M2 Hyperhidrosis arifenacin is more M3 selective,reducing side effects; D Overactive bladder Solifenacin has broader muscarinic receptor blocking. (Solifenacin: CYP3A4substrate,Darifenacin: CYP2D6inhibitor) 6. Oxybutynin uscarinic ACh receptor blocker M veractive bladder, O ore likely to causeCNS effectsdue to M1/M4 affinity. M (M1/M3/M4 preference) Alternative, hyperhidrosis Also used forhyperhidrosisdue to M3 receptor blockade. ess urination L Decrease bladder tone Sphincter contracted 7. ropicamide, T ast effects for L on-selectivemuscarinic ACh receptor N Overactive bladder* ydriasis M Cyclopentolate, hours antagonists Eye exams Blopegia Homatropine corneal abrasions 2nd line for strabismus(crossed rimarily used inophthalmologyfor pupil dilation P eye), (mydriasis) and to paralyze accommodation (cycloplegia). mblyopia(lazy eye) (cause a GI tract* (?) mydriasis, cycloplegia) B. Quaternary Amines Drug Onset MOA / Receptor Indications Use/Effects 1. iotropium, T Long acting 3 ACh receptor-selective antagonist, M OPD(multiple C ong-acting bronchodilators, L Umeclidinium withkinetic selectivity(long-acting) in symptoms/exacerbations) Decreased contractility of smooth muscle in the lungs Once daily Asthma Umeclidinium = inhaler LUNGSlong acting Rhinorrhea Reduction of mucus 2. Ipratropium Short acting on-selectivemuscarinic ACh receptor N OPD, C hort-acting bronchodilator(compared to Tiotropium). S antagonist(M1/M2/M3) sialorrhea May causetransient bronchoconstrictiondue to M2 4x daily Hypersalivation blockade. LUNGSshort acting sialorrhea Rhinorrhea 3. lycopyrronium/Glycop G Short acting lightly selective M3 AChreceptor S nesthesia adjuvant(prevent A ess effect on heart rate compared to Atropine, fewer L yrrolate antagonist(NO kinetic selectivity) bradycardia, bronchoconstriction, and CNS effects (doesn't cross blood-brain barrier easily). reduce secretions), Hypersalivation / Sialorrhea Hyperhidrosis(excessive sweat) COPD 4. Trospium ANTICHOLINERGIC ADRS ABCD Agitation Blurred vision Constipation and Confusion Dry mouth Stasis of urine and sweating Other side effects Cholinergic rebound: Nausea, diaphoresis (sweating),hypotension, dizziness, drowsiness, fatigue Anticholinergic Toxicity Too much antimuscarinic agent First gen antihistamine Antidepressants Antipsychotics Belladonna plant Interactions Additive – Anticholinergics, CNS depressants, tachycardics Physiologic antagonism – Drugs with opposite physiologic effects – (ex. prokinetcs, opioids, etc) K+ salts (oral)– Strong anticholinergics mayenhanceulcerogenic effect of K+ salts Nitroglycerin– Anticholinergics maydecrease dissolutionof sublingual tablets Thiazide diuretics – Anticholinergics may increase their concentration Topiramate– Anticholinergics may increase Topiramate’shyperthermia risk II. Indirect-Acting Anticholinergics Drug MOA Indication Side Effects Use 1. Botulinum Toxin Type A inc endopeptidase from Z - Cosmetic:Glabellar lines - Injection site swelling/bruising sed in bothcosmeticandmedical U Clostridium botulinum. (frown lines), forehead lines, - Headache conditions for muscle relaxation and nabotulinumtoxin A O Cleaves proteins involved crow’s feet - Flu-like symptoms reduced secretion. Abobotulinumtoxin A in vesicle fusion to stop - Medical: Cervical dystonia, - Hoarseness Incobotulinumtoxin A them, blocking ACh focal tardive dystonia, - Urinary tract infection (UTI) Prabotulinumtoxin A release from presenaptic severe hyperhidrosis, - Urinary retention neuron in neuromuscular overactive bladder, localized - Dry mouth junction tics (Tourette’s), anal - Muscle weakness (away from Causesflaccid paralysis fissures, migraine, injection site) by inhibiting sialorrhea. Ca²⁺-induced neurotransmitter release. A. Ganglionic Blocker Drug MOA Indication Side Effects Use 1. Hexamethonium ompetitive nicotinic ganglionic C arely used today. R - Excessive hypotension irst drug forhypertension, now F blocker. Blocks nicotinic Historically used for - Severe autonomic effects (dry obsolete due to its non-specific and acetylcholine receptors at hypertension(1st drug). mouth, constipation, urinary severe effects. autonomic ganglia, preventing No longer in practice due to retention) transmission of nerve impulses and better alternatives. - Visual disturbances causing relaxation of blood vessels. 2. Trimethaphan ompetitive nicotinic ganglionic C ypertensive H imilar to hexamethonium: S nly used in specifichypertensive O blocker. Blocks nicotinic emergencies(e.g., aortic autonomic side effects, hypotension, emergencies, rarely in practice today. acetylcholine receptors at aneurysm dissection, dry mouth, constipation autonomic ganglia, preventing pulmonary edema). transmission of nerve impulses and Blood relaxation in blood vessels causing relaxation of blood vessels. oderately severe to M severe hypertension. (Mecamyline) arely used more good R drugs for others 3. Nicotine Nonselective It stimulates and later Increased release of epresses the autonomic d eurotransmitters such as D n icotine use disorder treatment: N ganglia Serotonin NE Bupropion It stimulates CNS higher doses Varenicline convulsions, but lower respiratory paralysis StimulatesBP and high HR but at higher doses it can cause lower BP GI ○ Increases motility ○ Nausea vomiting CNS stimulation Addiction Not very useful in clinical practice
