PHID1502 Integrated Sequence 2 Pharm Cholinergic agonists antagonists Winter 2024-2025 PDF

Winter quarter 2024-2025 [email protected] 4 Integrated Sequence 2 – PHID1502 – Winter 2024-2025 Pharmacology of Cholinergic agonists & antagonists Required reading: Foye’s, Sixth Edition – Chapter 12, pages 361 – 391, Fifth Edition Online –...

Winter quarter 2024-2025 [email protected] 4 Integrated Sequence 2 – PHID1502 – Winter 2024-2025 Pharmacology of Cholinergic agonists & antagonists Required reading: Foye’s, Sixth Edition – Chapter 12, pages 361 – 391, Fifth Edition Online – Chapter 9 Recommended: Katzung, Eleventh Edition - Chapter 7, pages 95 – 112, Chapter 8, pages 113-126. Oliver Grundmann, Ph.D. Adjunct Assistant Professor (MWU) Clinical Professor (UF) Phone: 352-246-4994 [email protected] Winter quarter 2024-2025 [email protected] 5 Definitions Cholinergic: pertaining to effects of acetylcholine on nicotinic and muscarinic receptors Parasympatholytic: a drug that competitively inhibits the action of acetylcholine at its receptors Direct agonist: directly binds to and activates the receptor to cause the agonist effect Indirect agonist: brings about receptor activation by binding to some other molecule, e.g., a reuptake carrier or enzyme, causing an increase in the synaptic concentration of the normal neurotransmitter Winter quarter 2024-2025 [email protected] 6 Definitions Miotic: a drug that causes constriction of the pupil; opposite of mydriatic Muscarinic: drugs that act on muscarinic acetylcholine receptors. Nicotinic: drugs that act on nicotinic acetylcholine receptors. Parasympathomimetic: a drug that mimics stimulation of the parasympathetic autonomic nervous system (PNS) when applied Winter quarter 2024-2025 [email protected] 7 Parasympathomimetic drugs/cholinergic agonists - spectrum of action Pilocarpine Physostigmine Carbachol Echothiophate Winter quarter 2024-2025 [email protected] 8 Organ system effect – comparison sympathetic & parasympathetic ANS  Winter quarter 2024-2025 [email protected] 9 Parasympathetic system effects “Rest and digest” principles Reduction of heart rate & blood pressure (M2) Constriction of bronchioles (M3) Miosis (M3) Vasodilation (M3) Increased GI motility (M3) Decreased bladder sphincter tone (M3)  Winter quarter 2024-2025 [email protected] 10 Direct, indirect, and mixed modes of action for parasympathomimetic drugs Direct Bind and activate cholinergic receptors directly Indirect Prolong action of acetylcholine through inhibition of degradation Winter quarter 2024-2025 [email protected] 11 Organ system effect – receptor specificity Winter quarter 2024-2025 [email protected] 12 Actions of direct & indirect parasympathomimetics Winter quarter 2024-2025 [email protected] 13 Effects of parasympathomimetics on different organ systems Winter quarter 2024-2025 [email protected] 14 Cardiovascular system effects Blood vessels Vasodilation mediated indirectly through release of NO (secondary messenger pathway (Gq – PLC-IP3) and Ca2+ - dependent activation of NO synthase) M3 receptors do not directly innervate vasculature Reflex tachycardia due to uncompensated response Heart → M2 receptors Activation of K+ current → decrease in L-type Ca2+ channels with subsequent decrease in cardiac pacemaker Negative chronotropic & inotropic effects Counteracts effects mediated through β1 receptors Inhibition of NE and Epi release from adrenergic terminals ↓ Heart rate Conduction velocity of SA node is decreased, hyperpolarization of atrial cells Winter quarter 2024-2025 [email protected] 15 Cardiovascular system effects Parasympathomimetic Parasympatholytic Winter quarter 2024-2025 [email protected] 16 Visual system effects Eye → M3 receptors Activates secondary messenger pathway inositoltriphosphate (IP3) and increase in phospholipase C activity Opening on Ca2+ channels leads to increased intracellular Ca2+ concentrations Increased tone due to increased muscle contrations Winter quarter 2024-2025 [email protected] 17 Visual system Parasympathomimetic Parasympatholytic Winter quarter 2024-2025 [email protected] 18 Respiratory system effects Respiratory tract → M3 receptors Similar second messenger cascade to visual system effects Constriction of smooth muscles in the bronchioles and bronchi due to increased Ca2+ in the cytosol Increased bronchial secretion  Winter quarter 2024-2025 [email protected] 19 Respiratory system effects Parasympathomimetic Parasympatholytic Winter quarter 2024-2025 [email protected] 20 Gastrointestinal, glandular & genitourinary effects Gastrointestinal M2 & M3 → increase in motility & tone M3 → decrease in sphincter contraction M3 → increase in secretion of gastric, pancreatic, salivary, and intestinal fluids Genitourinary M3>M2 → increase in detrusor contraction M3>M2 → relaxation of trigone and sphincter Male sex organs M3 → Erection Winter quarter 2024-2025 [email protected] 21 Gastrointestinal, glandular & genitourinary effects Parasympathomimetic Winter quarter 2024-2025 [email protected] 22 Central Nervous System Effects vary significantly with ability to pass BBB All preganglionic nerve transmission is cholinergic with acetylcholine as the neurotransmitter Diverse functions Regulation of cortical excitability Memory and learning (Alzheimer) Pain processing Brainstem motor control (Parkinson) Parasympatholytic Winter quarter 2024-2025 [email protected] 23 Cholinergic nerve transmission Winter quarter 2024-2025 [email protected] 24 Cholinergic nerve transmission Winter quarter 2024-2025 [email protected] 25 Dominant effects of cholinergic drugs Blood vessels: indirect vasodilation through M3 receptors and release of nitric oxide Heart: negative chronotropic and inotropic effects mediated by M2 receptors Bronchial Smooth Muscle: Smooth muscle contraction mediated through M3 receptors Gastrointestinal & endocrine: increased secretion through M3 receptors CNS: varied effects Winter quarter 2024-2025 [email protected] 26 Muscarinic and nicotinic receptors Muscarinic cholinergic receptors are all GPCR receptors Second messenger cascade takes longer for activation, but also prolonged effect Muscarinic receptors (M1, M2, and M3) both in the CNS and periphery, M4 and M5 exclusively in the CNS Nicotinic cholinergic receptors are all ch11f7a ion channels Consists of 5 subdomains (α, β, γ, δ, and ε) Present on all presynaptic ganglions in the CNS (NN) Also on adrenal medulla (NN) and skeletal muscle (NM) Winter quarter 2024-2025 [email protected] 27 Potential drug targets for cholinergic nerve transmission Synthesis of acetylcholine (hemicholinum) Storage of acetylcholine in intracellular vesicles (vesamicol) Release of acetylcholine (botulinum toxin) Action on postsynaptic receptors (direct muscarinic and nicotinic agonists & antagonists) Degradation of acetylcholine (acetylcholine esterase inhibitors)  Winter quarter 2024-2025 [email protected] 28 Synthesis of acetylcholine Inhibition of acetylcholine synthesis by hemicholinum Uptake of choline from the synaptic cleft after breakdown of acetylcholine by acetylcholine esterase is the rate-limiting step in the Serine Hemicholinum resynthesis of acetylcholine Serine in the presynaptic terminal decarboxylase Hemicholinum inhibits reuptake transporter for choline Synthesis of acetylcholine is from Choline-N-methyl acetyl-coenzyme A and choline in transferase the presynaptic terminal Choline synthesized from amino acid serine Choline-acetyl transferase Choline No therapeutic or clinical applications for hemicholinum Acetylcholine Winter quarter 2024-2025 [email protected] 29 Storage of acetylcholine Inhibition of acetylcholine storage by vesamicol Decreased storage and release of acetylcholine into the synaptic cleft upon activation of the presynaptic neuron No clinical applications, depletion of acetylcholine stores leads to loss of parasympathetic stimulation Vesamicol Winter quarter 2024-2025 [email protected] 30 Release of stored acetylcholine Inhibition of acetylcholine release by botulinum toxin Protein found in anaerobic soil bacterium Clostridium botulinum One of the most potent toxins in the world Prevents fusion of the acetylcholine vesicle proteins (synaptobrevins) with the preganglionic nerve cell membrane via protease activity Toxic after all routes of administration Therapeutic uses: migraine headaches through long-term relaxation of forehead muscles, fascial and other muscle spasms, cosmetic corrections (temporary removal of wrinkles), excessive sweating, cervical dystonia Injections necessary every 2-3 months, duration based on resynthesis of axon proteins and removal of botulinum toxin Winter quarter 2024-2025 [email protected] 32 Direct muscarinic agonists Winter quarter 2024-2025 [email protected] 33 Direct muscarinic agonists Winter quarter 2024-2025 [email protected] 34 Direct muscarinic agonists Used for the treatment of Urinary bladder disorders (bethanechol, urecholine®) Treatment of inadequate emptying of the bladder Postoperative urinary retention Chronic hypotonic, myogenic, or neurogenic bladder Gastrointestinal disorders (bethanechol) Stimulation of peristalsis, motility, and lower esophageal sphincter pressure Formerly used to treat postoperative abdominal distension, gastroparesis, adynamic ileus; but now more efficacious therapies available (mainly affecting serotonin system) Winter quarter 2024-2025 [email protected] 35 Direct muscarinic agonists Used for the treatment of Xerostomia (primary or secondary salivary gland dysfunction) (pilocarpine (Salagen®) & cevimeline) Increase mucus production in salivary glands with increased quality of life for patients after irradiation therapy for head & neck cancers and patients with Sjögren’s syndrome (genetic disorder with reduced salivary gland function) Glaucoma (carbachol, pilocarpine) Increased outflow of aqueous humor Reduction in intraocular pressure Also used as miotic agents in diagnostic procedures Diagnosis of bronchial hyperreactivity (methacholine) Differential diagnosis of asthma since asthmatic patients present with hyperreactivity to muscarinic agonists Winter quarter 2024-2025 [email protected] 36 Side effects of muscarinic agonists Extension of pharmacological effects Peripheral side effects Sweating, flushing Diarrhea Hypotension, bradycardia Bronchoconstriction Urinary bladder contraction CNS Parkinsonism, hallucinations Nausea & vomiting (both peripheral and CNS) Winter quarter 2024-2025 [email protected] 37 Nicotinic agonists Mainly used in the treatment of addiction Nicotine, natural alkaloid: stimulates all nicotinic receptors, nicotine patches indicated for smoking cessation Cytisine, natural alkaloid: potential application for smoking cessation, not approved by FDA but EMA (Europe) Varenicline (Chantix®): synthetic derivative approved for smoking cessation, may also have benefits in treatment of drug addiction; but side effects include suicidal thoughts, headache, nausea and vomiting, insomnia, taste alteration  Winter quarter 2024-2025 [email protected] 38 Indirect muscarinic agonists Direct acting agonists bind to postsynaptic muscarinic or nicotinic receptors Activation of receptor results in second messenger cascade Indirect acting agonists prevent degradation of acetylcholine, thereby prolong the action of acetylcholine in the synaptic cleft Indirect agonists can affect both muscarinic and nicotinic receptors All indirect acting agonists are acetylcholine esterase inhibitors (AChEI)  Winter quarter 2024-2025 [email protected] 39 Indirect cholinergic agonists Two groups of indirect acting cholinergic agonists that inhibit the degrading enzyme acetylcholine esterase Reversible acetylcholine esterase inhibitors, a.k.a reversible carbamate inhibitors Inhibit the enzyme for hours, depending on CNS penetrability may exert only peripheral (neostigmine and pyridostigmine) or both peripheral and central effects (physostigmine, rivastigmine, tacrine, donepezil, galantamine) Irreversible acetylcholine esterase inhibitors, a.k.a pesticides and warfare agents Inhibit enzyme for weeks or months, specificity towards enzyme determines use, pesticides more specific for insect acetylcholine esterase, warfare agents target human acetylcholine esterase Winter quarter 2024-2025 [email protected] 40 Reversible acetylcholine esterase inhibitors Pharmacological effects Stimulation of muscarinic receptor responses at autonomic effector organs Stimulation, followed by depression and paralysis, of all autonomic ganglia and skeletal muscles (nicotinic actions) Stimulation, with occasional subsequent depression, of cholinergic receptors in the CNS Winter quarter 2024-2025 [email protected] 41 Indirect cholinergic agents Therapeutic use of reversible acetylcholine esterase inhibitors Improvement of muscle strength in Myasthenia gravis patients (neostigmine, pyridostigmine) Open-angle glaucoma to reduce intraocular pressure (physostigmine) Treatment of anticholinergic toxidrome (physostigmine) Treatment of Alzheimer’s disease (tacrine (Cognex®), donepezil, rivastigmine, galantamine) Reversal of neuromuscular blocking agents during and after surgery (pyridostigmine, neostigmine, carbaryl, edrophonium) Edrophonium also used to differentiate myasthenia gravis from cholinergic crisis through blocking the enzyme acetylcholine esterase (Tensilon® test) Winter quarter 2024-2025 [email protected] 42 Irreversible acetylcholine esterase inhibitors - toxicity Only irreversible AChE inhibitor used is echothiophate for glaucoma and ocular hypertension Organophosphate insecticides and warfare agents pose a significant toxic risk Long-term inhibition of acetylcholine esterase action manifests as: Marked miosis, ocular pain, diminished vision, ciliary spasm Hypotension, rhinorrhea, hyperemia Tightness of chest, wheezing, bronchoconstriction and increased bronchial secretion GI symptoms: anorexia, nausea, vomiting, abdominal cramps, diarrhea Sweating and muscle fasciculations Severe intoxications lead to sweating, salivation, involuntary defecation and urination, lacrimation, penile erection, bradycardia, and hypotension Potential for lethality mainly based on paralysis of respiratory (muscarinic) and skeletal (nicotinic) muscles Winter quarter 2024-2025 [email protected] 43 Irreversible acetylcholine esterase inhibitors – treatment of poisoned patient Less severe with insecticides (parathion, malathion, diazinon, chlorpyrifos), mainly supportive care, removal of exposure (clothes and skin), maintenance of airway, treatment of shock Treatment of warfare agent (tabun, sarin, soman, DFP) poisoning: Immediate care necessary to preserve airway function, intubation Administration of anticholinergic (parasympatholytic agent, atropine) agent necessary to reduce cholinergic toxidrome effects Administration of cholinesterase reactivator pralidoxime as soon as possible to preserve and restore AChE function and prevent “aging” of the bond between phosphate group and enzyme Winter quarter 2024-2025 [email protected] 44 Cholinergic antagonists (parasympatholytics) Categorized into muscarinic and nicotinic antagonists Muscarinic antagonists Eye: cause mydriasis, used for eye diagnosis (as eye drops) Bladder: reduction in contraction (p.o.) Lungs: widening of lungs, treatment of asthma and COPD (mostly inhaled) Brain stem: prevention of nausea and vomiting (via patch) GI and genitourinary: relaxation of smooth muscles Nicotinic antagonists: Neuromuscular junction: blocking of muscle contractions, used during surgery Winter quarter 2024-2025 [email protected] 45 Muscarinic antagonists Categorized into central and peripheral competitive antagonists Central (uncharged): atropine, scopolamine, homatropine, pirenzepine Peripheral (charged): ipratropium, tiotropium (Spiriva®) Effects on organ systems: Heart: increase in heart rate, tachycardia, removal of vagal tone for autonomous cardiac activity Circulation: no significant effect if given alone, but counteracts effects of muscarinic agonists Respiratory system: bronchodilation and reduction in bronchial secretion, effective in both asthma and COPD Eye: mydriasis without reflex to light, used during diagnosis GI & Genitourinary tract: reduction in motility, contraction & secretion, used for spasms and overactive bladder Winter quarter 2024-2025 [email protected] 46 Muscarinic antagonists – clinical applications Asthma & COPD – tiotropium & ipratropium Semi-synthetic derivatives of atropine, permanent quaternary nitrogen charge prevents CNS penetration Overactive bladder – oxybutynin (Ditropan®), tolterodine, trospium, solifenacin, darifenacin Reduction in contractions, altered bladder sensation during filling, increase bladder capacity in spastic paraplegia Peptic ulcer (historic) – pirenzepine Reduce gastric motility and gastric acid secretion, but many side effects and other treatment options now available Motion sickness – scopolamine, homatropine Prophylaxis much more effective, not effective in chemotherapy- induced nausea and vomiting Winter quarter 2024-2025 [email protected] 47 Parasympatholytics - mnemonic Hot as a hare: increased body temperature Dry as a bone: dry mouth, dry eyes, decreased sweat Blind as a bat: mydriasis (dilated pupils) Red as a beet: flushed face, vasodilation Mad as a hatter: delirium, hallucinations (CNS) Winter quarter 2024-2025 [email protected] 48 Nicotinic antagonists Neuromuscular blocking agents Depolarizing and non-depolarizing agents Depolarizing agents (succinylcholine, decamethonium) cause consistent depolarization of the plasma membrane on the muscle fiber and prevent the actions of acetylcholine binding → permanent muscle rigidity; has to be short-acting (5-10 min.) Non-depolarizing agents (mivacurium, atracurium, vecuronium, pancuronium, tubocurarine) are competitive antagonists at the postsynaptic nicotinic receptors, blocking the binding of acetylcholine and activation of the ion channel; most common side effects are hypotension and reflex tachycardia; can be short, intermediate, or long acting depending on surgical procedures Winter quarter 2024-2025 [email protected] 49 Neuromuscular junction Winter quarter 2024-2025 [email protected] 50 Nicotinic antagonists at the neuromuscular junction The effects of the administration of non-depolarizing (competitive) and depolarizing neuromuscular blocking agents can cause antagonistic effects if given in conjunction Effects of depolarizing neuromuscular blocking agents cannot be reversed by AChE inhibitors Depolarizing agents may cause significant muscle rigidity and accompanying pain after surgical procedure