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Reading assignments: Katzung’s Basic & Clinical Pharmacology, 13th Edi ,Ch-7 ,p105-132 ; II. Cholinoceptor-Activating and Cholinesterase-Inhibiting Drugs A. Spectrum of Action of Cholinomimetics Drugs + What are the major subtypes of cholinoceptors? + Know the differences between muscarinic and nicotinic receptors. —Where are they located? —With which signal transduction systems are they associated? B. Mode of Action of Cholinomimetic Drugs + What are the major differences between "direct" and "indirect" cholinoceptor agonists? C. Direct-Acting Cholinomimetics 1. Basic Pharmacology + How do choline esters differ from each other? —How are they similar? + Which choline esters are potentiated by the presence of anticholinesterase agents? + What cellular events occur when cholinoceptors are activated? + What are the physiological responses produced by muscarinic and nicotinic agonists? +What is EDRF? 2. Clinical Uses + GI and GU + Ophthalmology 3. Adverse Effects + salivation, sweating, colic, defecation, headache, loss of accommodation 4. Contraindications + peptic ulcer + asthma + coronary insufficiency +hyperthyroidism D. Indirect-acting Cholinomimetics 1. Basic Pharmacology + What are the major differences among the 3 groups of cholinesterase inhibitors? —How do these differences influence the pharmacokinetics of the drugs? —What is unique about parathion and malathion? + By what mechanisms can drugs inhibit acetylcholinesterase and/or butyrylcholinesterase? —Understand the importance of the mechanisms. + Understand differences between reversible and irreversible cholinesterase inhibitors. + What is "aging" as it relates to acetylcholinesterase inhibition? + Which organ systems are prominently affected by cholinesterase inhibitors? —What are the actions of acetylcholinesterase inhibitors on these systems? 2. Clinical Uses + GI and GU + Ophthalmology + Myasthenia gravis 3. Adverse Effects + Predictable based on excess acetylcholine and overstimulation of muscarinic and nicotinic receptors: miosis, salivation, sweating, bronchial constriction, vomiting and diarrhea, followed by peripheral nicotinic effects particularly manifest as neuromuscular blockade. III. Cholinoceptor-Blocking Drugs A. Muscarinic Receptor Antagonists 1. Basic Pharmacology + What is the original source of the prototypic antimuscarinic drugs? + What is the importance of their structures (tertiary vs. quaternary amines) as related to absorption and distribution? + What are the effects of antimuscarinic drugs on various organ systems? + Do all drugs affect each system similarly or is there some degree of organ selectivity? 2. Clinical Pharmacology + Gastric or intestinal hypersensitivity or secretion + Excessive salivation + To produce mydriasis and cycloplegia + Adjunct prior to general anesthesia + Asthma + Understand how antimuscarinics can be used to treat insecticide poisoning and exposure to nerve gas. + Understand the importance of "aging" as it relates to organophosphate poisoning and pralidoxime (2-PAM). 3. Adverse effects + Dry mouth (often seen at therapeutic doses with drugs used primarily for other properties) + Blurred vision + Others 4. Contraindications + Relative, not absolute B. Ganglion Blocking Drugs + What is the selectivity of ganglion-blocking drugs for sympathetic vs. parasympathetic nervous systems? + For nicotinic vs. muscarinic receptors? + For autonomic ganglia vs. neuromuscular junction? + Even though ganglion blockers are very effective in lowering blood pressure in patients with malignant hypertension, why are they used rarely today? Cholinoceptor-Activating & CholinesteraseInhibiting Drugs Drugs in this section mimic acetylcholine (cholinomimetic agents) NBME Cholinoceptor-Activating & CholinesteraseInhibiting Drugs Drugs in this section mimic acetylcholine (cholinomimetic agents) Agonists classified pharmacologically by receptor action • Muscarinic • Nicotinic Further classified by their mechanism of action • Direct-acting cholinomimetic agents • Directly bind and activate muscarinic or nicotinic receptors • Indirect-acting agents inhibit acetylcholinesterase • Reduce hydrolysis of acetylcholine • Increase endogenous acetylcholine concentration in synaptic clefts • Excess acetylcholine stimulates cholinoceptors to evoke increased responses • Drugs act primarily where acetylcholine is physiologically released Spectrum of Action of Cholinomimetic Drugs Cholinoceptors are either: G protein-linked (muscarinic) • Seven transmembrane domains • Third cytoplasmic loop is coupled to G proteins • Receptors are located • In CNS • In tissues targeted by PNS • In vascular endothelium (not innervated by PNS!) Ion channel (nicotinic) • Five subunits form cation-selective ion channels • Located on: • All ANS ganglionic cells (“neuronal” type) • Adrenal gland (“neuronal” type) • Muscles innervated by somatic motor fibers (“NMJ” type) • Some CNS neurons (“neuronal” type) C. Direct-Acting Cholinomimetics 1. Basic Pharmacology + How do choline esters differ from each other? —How are they similar? + Which choline esters are potentiated by the presence of anticholinesterase agents? + What cellular events occur when cholinoceptors are activated? + What are the physiological responses produced by muscarinic and nicotinic agonists? +What is EDRF? 2. Clinical Uses + GI and GU + Ophthalmology 3. Adverse Effects + salivation, sweating, colic, defecation, headache, loss of accommodation 4. Contraindications + peptic ulcer + asthma + coronary insufficiency +hyperthyroidism Basic Pharmacology of the Direct-Acting Cholinoceptor agonists Classified as either: • Esters of choline (including acetylcholine) • Alkaloids (such as muscarine and nicotine) NBME Many have effects on both receptor types • Acetylcholine is both the prototypical drug agent and endogenous transmitter • Some drugs are selective for the muscarinic or nicotinic receptors Choline esters Do not cross BBB NBME • Quaternary ammonium group renders them relatively insoluble in lipids • Acetylcholine - acetic acid ester of choline • Methacholine - acetic acid ester of methylcholine • Carbachol and bethanechol are carbamic acid esters of the same alcohols • Choline esters are poorly absorbed and poorly distributed into CNS • Marked differences in susceptibility to hydrolysis by cholinesterases • Acetylcholine is very rapidly hydrolyzed • Methacholine is more resistant to hydrolysis • Carbachol and bethanechol are very resistant to hydrolysis • correspondingly longer durations of action • Methyl group (methacholine, bethanechol) reduces potency at nicotinic receptors From: McGraw Hill’s AccessMedicine; Katzung; Table 7-2 Note methyl group blocks nicotinic activity Note carbamoyl group blocks hydrolysis Tertiary natural cholinomimetic alkaloids • Pilocarpine • Nicotine • Lobeline is a plant derivative similar to nicotine in action Muscarine - a quaternary amine • Source – Amantia muscaria Mushrooms NBME Pharmacodynamics / Mechanism of Action All muscarinic receptors are GPCR • Agonist binding: • Activates the IP3, DAG cascade (Gq) • Increases potassium flux (Gi) • In some tissues inhibits adenylyl cyclase activity (Gi) Nicotinic receptor activation • Results in electrical and ionic changes • Depolarization of the nerve cell or neuromuscular end plate membrane • Prolonged agonist occupancy • Abolishes the effector response • “Depolarizing blockade" • Can produce muscle paralysis Cholinergic Organ System Effects NBME Muscarinic cholinoceptor effects are predicted from: • Effects of parasympathetic nerve stimulation • Distribution of muscarinic receptors Nicotinic agonist effects are similarly predictable from: • Physiology of the autonomic ganglia and skeletal muscle motor end plate Eye: • Muscarinic agonists produce: • Contraction of the iris sphincter (miosis) • Contraction of ciliary muscle (accommodation) • Facilitates aqueous humor outflow •Useful in both open & closed angle glaucoma NBME Cholinergic Organ System Effects (continued) Cardiovascular System: • Muscarinic agonists: • Reduce peripheral vascular resistance • Direct effect is to slow heart rate • Intravenous infusions of ACh cause vasodilation and reduces blood pressure • Acetylcholine-induced vasodilation requires intact endothelium • Releases nitric oxide (EDRF) • NO relaxes smooth muscle • Note that muscarinic vasodilation evokes: • SNS reflex • Increase in heart rate • Larger ACh doses mask this reflex (direct bradycardia) • Cardiovascular effects of all choline esters are similar to ACh Cholinergic Organ System Effects (continued) NBME Respiratory System • Contracts the smooth muscle of the bronchial tree • Glands of mucosa are stimulated to secrete • Often exacerbates symptoms of asthma. Gastrointestinal Tract • Increases secretions (salivary, gastric, pancreatic, intestinal) • Increases peristaltic activity • Contraction of longitudinal muscle • Relaxation of sphincters Genitourinary Tract • Contracts detrusor muscle • Relaxes trigone and sphincter muscles • Promotes voiding (remember – micturition is it’s own reflex) Secretory Glands • Stimulation of secretion by thermoregulatory sweat glands Cholinergic Organ System Effects (continued) NBME Nicotinic agonists: • Autonomic ganglia are major site of action • Simultaneous SNS and PNS discharge • Predominant tone predicts activation of ganglia • SNS – vasculature • PNS – most other tissues • Nicotine has a somewhat greater affinity for neuronal than for skeletal muscle nicotinic receptors • Effects on Neuromuscular Junction • Produces muscle fasciculations • Subsequent development of depolarization blockade (flaccid paralysis) Succinylcholine >> the depolarizing neuromuscular blocker is a nicotinic agonist 22 Clinical uses of choline esteres and alkaloid Choline Ester Clinical uses Acetylcholine chloride. Short t1/2, no clinical use Methacholine chloride Dx-bronchial hyperreactivity Carbachol chloride Bethanechol chloride Rx-ileus (postop/neurogenic) , urinary retention Choline Alkaloid NBME Clinical uses Muscarine no clinical use, toxological importance Nicotine no clinical use, toxological importance Lobeline no clinical use, toxological importance Pilocarpine Rx-glaucoma (topical), xerostomia Some Terminology (Jargon) NBME “Low” Dose Acetylcholine Generally, only activates vascular muscarinic receptors (endothelium) • Evokes synthesis and release of NO • Produces vasodilation (decrease in BP) • Produces reflex tachycardia Effects that are blocked by atropine (muscarinic antagonist). In the presence of ganglionic blockade or other elimination of baroreceptor-mediated reflexes, a “low” dose ACh will now decrease both blood pressure and heart rate. Remember: Only direct effects on heart are observed when reflex is blocked by ganglionic blockade!! “High” Dose Acetylcholine plus atropine • Death occurs if muscarinic receptors are not blocked • Now, nicotinic receptors in both SNS & PSNS are activated but output from PSNS is blocked by atropine • Thus, only SNS effects are observed See illustrations of this phenomena later in slide presentation D. Indirect-acting Cholinomimetics 1. Basic Pharmacology + What are the major differences among the 3 groups of cholinesterase inhibitors? —How do these differences influence the pharmacokinetics of the drugs? —What is unique about parathion and malathion? + By what mechanisms can drugs inhibit acetylcholinesterase and/or butyrylcholinesterase? —Understand the importance of the mechanisms. + Understand differences between reversible and irreversible cholinesterase inhibitors. + What is "aging" as it relates to acetylcholinesterase inhibition? + Which organ systems are prominently affected by cholinesterase inhibitors? —What are the actions of acetylcholinesterase inhibitors on these systems? 2. Clinical Uses + GI and GU + Ophthalmology + Myasthenia gravis 3. Adverse Effects + Predictable based on excess acetylcholine and overstimulation of muscarinic and nicotinic receptors: miosis, salivation, sweating, bronchial constriction, vomiting and diarrhea, followed by peripheral nicotinic effects particularly manifest as neuromuscular blockade. Indirect-Acting Cholinomimetics: Basic Pharmacology NBME ACh effects terminated by Acetylcholinesterase Indirect-acting cholinomimetics inhibit this enzyme Cholinesterase inhibitors fall into three chemical groups: (1) Simple alcohols bearing a quaternary ammonium group (doesn’t enter CNS); compete for ACh at the enzyme Edrophonium (2) Carbamic acid esters of alcohols bearing quaternary (doesn’t enter CNS); or tertiary ammonium (enter CNS); groups (carbamates); carbamoylate the active site Neostigmine – quaternary Physostigmine – tertiary (crosses BBB) Carbaryl – high lipid solubility (rapid CNS effects); insecticide (3) Organic derivatives of phosphoric acid (organophosphates); phosporylate the active site Echothiophate; used for glaucoma Soman; nerve agent Sarin; nerve agent Malathion, parathion Bioactivated to give active phosphorylating agent used as insecticides. Indirect-Acting Cholinomimetics: Basic Pharmacology (Structures) Cholinesterase Inhibitors: Absorption, Distribution, and Metabolism Absorption of quaternary carbamates is predictably poor • Permanent charge renders them relatively insoluble in lipids The tertiary amine carbamates (physostigmine; carbaryl) are well absorbed • Distribute into the CNS (crossess BBB) • Duration of their effect is determined by stability of inhibitorenzyme complex Organophosphates (except for echothiophate) • Are well absorbed both topically and orally • Are distributed to all parts of the body, including the CNS Cholinesterase Inhibitors: Pharmacodynamics NBME Acetylcholinesterase is primary target Butyrylcholinesterase is also inhibited Quaternary alcohols (edrophonium) reversibly bind to the active site • Inhibition is short-lived (on the order of 2–10 minutes) Carbamate esters undergo a two-step hydrolysis • Covalent bond of the carbamoylated enzyme is slowly hydrolyzed (reactivated) • Inhibition is longer (on the order of 30 minutes to 6 hours) Organophosphates • Results in a phosphorylated AChE active site • Covalent phosphorus-enzyme bond is extremely stable • Inhibition lasts hundreds of hours • Lifetime of enzyme protein • “Aging” strengthens phosphorus-enzyme bond • Before aging, pralidoxime (2-PAM) can restore enzyme function (Reactivation) Cholinesterase Inhibitors: Organ System Effects Most prominent effects are on: • Cardiovascular and gastrointestinal systems • Eye and skeletal muscle Actions amplify the actions of endogenous acetylcholine Effects are similar to direct-acting cholinomimetics Little effect on vascular smooth muscle and on blood pressure • Remember PNS does not innervate peripheral vasculature!) NBME • At NMJ: • Low (therapeutic) concentrations increase force of contraction • Higher doses produce depolarizing neuromuscular blockade Cholinesterase Inhibitors: Clinical Uses Eye • Glaucoma (closed & open angle)-(Physiostigmine,Ecothiophate) • Reduce intraocular pressure • Contraction of the ciliary body NBME • Facilitates outflow of aqueous humor Gastrointestinal and Urinary Tracts (Neostigmine,pyridostigmine) • Clinical disorders related to inactivity of smooth muscle activity • Postoperative ileus • Congenital megacolon • Urinary retention • Neurogenic bladder • Reflux esophagitis NBME • Insufficient salivary secretion Reversal of Non-depolarizing Neuromuscilar blockers (Neostigmine ,pyridostigmine) NBME Cholinesterase Inhibitors: Clinical Uses (cont’d) Neuromuscular Junction (Dx-Edrophonium ); T/t: Neostigmine, pyridostigmine) • Myasthenia gravis • Autoimmune disease affecting NMJ NBME • Cholinesterase inhibitors are valuable therapy • Edrophonium (Tensilon test) – i.diagnostic test for MG (improvement in muscle strength after inj.) ii.differential diagnosis bet. MG & Cholinergic crisis. Cholinesterase Inhibitors: Clinical Uses (cont’d) Atropine intoxication (physostigmine) • Reversal of competitive blockade by cholinomimetics NBME • Physostigmine has tertiary structure so reverses both CNS and peripheral effects Central Nervous System (Tacrine & donepezil ) • Alzheimer’s disease • Tacrine & donepezil have anticholinesterase and cholinomimetic actions • Used in therapy for mild to moderate Alzheimer's disease NBME Cholinesterase Inhibitors: Acute Toxicity “SLUDGE” • Salivation • Lacrimation • Urinary incontinence • Diarrhea • Gastrointestinal cramps • Emesis DUMBBELSS Diarrhea Urination Miosis Bronchoconstriction Bradycardia Excitation; Emesis Lacrimation Salivation Sweating • Can be reversed by atropine (muscarinic antagonist) • Cholinesterase inhibitor poisoning also treated by: • Maintenance of vital signs (respiration) • Decontamination to prevent further absorption • Atropine parenterally in large doses • Therapy may also include treatment with pralidoxime to “rescue” un-aged inhibited enzyme; but pralidoxime contraindicated for carbamate intoxication NBME NBME Irreversibly acting Cholinomimetics These compounds phosphrylate the esteric site of AchE,at serine hydroxyl groups. 1.Phosphorylation-reversible by pralidoxime (2PAM) 2.Removal of part of organophosphate molecule (aging). Complex no longer reversible by 2PAM. R-leaving group P-organophosphate Nicotinic Toxicity: Usually produced by nicotine • Fatal dose is approximately 40 mg • Amount in two regular cigarettes • Most is destroyed by burning • Ingestion is usually followed by vomiting • Limits absorbed dose • Readily absorbed from the skin Toxic effects include: NBME • CNS stimulation – convulsions, coma, respiratory arrest • Skeletal muscle end plate depolarization - respiratory paralysis • Hypertension and cardiac arrhythmias Treatment is symptom-directed (Muscarinic antagonists and mechanical respiration) Most significant toxicity is due to chronic use (smoking) NBME Cholinergic agents: Direct muscarinic agonists: Choline esters: Acetylcholine Bethanechol Carbachol Alkaloids: Muscarine Pilocarpine Direct nicotinic agonists: Nicotine Lobeline Cholinesterase Inhibitors Indirect Parasympathomimetics Reversible inhibitors: Simple Alcohol ester: Edrophonium Alzheimer drugs: Donepezil Tacrine Rivastigmine Carbamates: (pseudo-reversible): Neostigmine Physostigmine Pyridostigmine Rivastigmine Ambenonium Demecarium Carbaryl Irreversible inhibitors: Organophosphates: Echothiophate Soman Sarin Parathion Malathion Isoflurophate Parasympathomimetics Resting Vegetative Cholinoceptor Agonists Eye GI Direct acting GU Indirect acting (cholinesterase inhibitors) Muscarinic Nicotinic Choline esters Alkaloids Ganglionic Neuromuscular Acetylcholine Bethanechol Carbachol Methacholine Muscarine Pilocarpine ACh Nicotine ACh Nicotine Succinylcholine Physostigmine crosses BBB Reversible Irreversible Neostigmine Physostigmine Edrophonium Pyridostigmine Tacrine Donepezil Sarin Parathion Malathion Echothiophate SLUDGE DUMBBELSS The administration of pralidoxime would be most useful in treating a 29-year-old man 2 hours after an excessive exposure to which to the following cholinergic poisons? A. Carbaryl B. Donepezil C. Parathion D. Pilocarpine E. Sarin Answer: C Only for organophosphates; Sarin ages to rapidly III. Cholinoceptor-Blocking Drugs A. Muscarinic Receptor Antagonists 1. Basic Pharmacology + What is the original source of the prototypic antimuscarinic drugs? + What is the importance of their structures (tertiary vs. quaternary amines) as related to absorption and distribution? + What are the effects of antimuscarinic drugs on various organ systems? + Do all drugs affect each system similarly or is there some degree of organ selectivity? 2. Clinical Pharmacology + Gastric or intestinal hypersensitivity or secretion + Excessive salivation + To produce mydriasis and cycloplegia + Adjunct prior to general anesthesia + Asthma + Understand how antimuscarinics can be used to treat insecticide poisoning and exposure to nerve gas. + Understand the importance of "aging" as it relates to organophosphate poisoning and pralidoxime (2-PAM). 3. Adverse effects + Dry mouth (often seen at therapeutic doses with drugs used primarily for other properties) + Blurred vision + Others 4. Contraindications + Relative, not absolute Cholinoceptor-Blocking Drugs Divided into muscarinic and nicotinic subgroups • Muscarinic antagonists • Nicotinic antagonists: • Ganglion-blockers • Neuromuscular junction blockers (paralytics) • Not discussed in this block Antimuscarinic drugs: • Tertiary compounds used for their effects in eye or CNS • Quaternary amines selectively produce peripheral effects • Prototypic drug is Atropine • Causes reversible (competitive) blockade • Not selective between M1, M2, and M3 subtypes NBME Cholinoceptor-Blocking Drugs: Organ System Effects Central Nervous System • Minimal stimulant effects on CNS • Toxic doses can cause agitation, hallucinations, and coma • Often used with dopamine precursor in Parkinson’s disease Eye • Muscarinic cholinoceptor activation constricts pupil • Blockade by topical atropine results in mydriasis • Belladonna ("beautiful lady") • Paralysis of the ciliary muscle, or cycloplegia (ophthalmic exam) • Cause acute glaucoma in patients with narrow anterior chamber angle Cardiovascular System • SA node under PNS tone - sensitive to muscarinic blockade • Atropine produces tachycardia • Few hemodynamic effects • Antimuscarinics can cause cutaneous vasodilation • Mechanism is unknown (atropine flush) Cholinoceptor-Blocking Drugs: Organ System Effects (cont’d) Respiratory System • Bronchodilation and reduction of secretion • Antimuscarinic drugs are not as useful as beta-adrenoceptor stimulants in the treatment of asthma Gastrointestinal Tract • Reduces motility and secretion in GI tract • Can be useful as preoperative adjuvant before abdominal surgery Genitourinary Tract • Can produce urinary retention, especially with BPH • Oxybutynin and tolterodine are used to treat overactive bladder Sweat Glands • Suppresses thermoregulatory sweating (Sympathetic!) • Body temperature can be elevated ("atropine fever") Cholinoceptor-Blocking Drugs (anti muscarinics): Therapeutic Applications Figure out Receptor subtypes for each indication Parkinson's Disease (benztropine, trihexphenidyl) Motion Sickness (scopolamine) Patch behind the ear NBME NBME Preoperative medication – prevents laryngospasm (glycopyrrolate); some are also amnestic (scopalamine) Relieves bronchodilation – asthma and COPD (ipratropium, tiotropium) NBME Relief of vagal syncope Traveler's diarrhea, mild GI hypermotility • Combined with an opioid antidiarrheal (abuse deterrent) Cholinoceptor-Blocking Drugs: Therapeutic Applications Urinary urgency, frequency, incontinence (Oxybutynin; Tolterodine – M3 selective) NBME Oxybutynin available as a patch Reversal of cholinergic poisoning • Requires a tertiary (not quaternary) drug • Large doses of atropine may be needed • Drug may have to be repeated NBME Ophthalmology (homatropine, cyclopentolate, tropcainamide, scoplolamine, atropine) NBME • Retinal examination • Prevention of synechiae after surgery Hyperhidrosis • Relief is incomplete at best • Understand ecccrine (cholinergic) vs. apocrine (adrenergic) glands Use of Atropine to Stimulate the Heart For the treatment of sinus bradycardia as with a vasovagal response For use in cardiopulmonary resuscitation (CPR) in accordance with the ACLS algorithm for cardiac arrest associated with ventricular asystole or slow pulseless electrical activity For pre-operative use to decrease secretions (i.e., aspiration prophylaxis) and block cardiovagal reflexes and/or succinylcholineinduced arrhythmias during surgery Non-anticholinergic drugs with Anticholinergic properties -H1 antihistaminics -TCAs -Antipsychotics -Quinidine -Amantidine -Meperidine -many others Cholinoceptor-Blocking Drugs: Adverse Effects Atropine poisoning • Dry mouth, mydriasis, tachycardia, flushed skin, delirium • “Dry as a bone, blind as a bat, red as a beet, mad as a hatter." • Can be treated with physostigmine or symptom management Contraindications are relative: • Glaucoma (especially narrow angle-closure glaucoma) • Prostatic hyperplasia • May increase gastric ulcer symptoms NBME Dose dependent effect of Atropine 49 B. Ganglion Blocking Drugs + What is the selectivity of ganglion-blocking drugs for sympathetic vs. parasympathetic nervous systems? + For nicotinic vs. muscarinic receptors? + For autonomic ganglia vs. neuromuscular junction? + Even though ganglion blockers are very effective in lowering blood pressure in patients with malignant hypertension, why are they used rarely today? Nicotinic Cholinoceptor-Blocking Drugs: Adverse Effects Block actions of ACh and other agonists at nicotinic receptors • Receptors located on both PNS and SNS autonomic ganglia Non-selectivity produces array of adverse effects All are synthetic amines First was tetraethylammonium (TEA) – short duration of action Ganglion-Blocking Drugs: Organ system effects Effects depend on predominant ANS tone at specific end-organ Quaternary amines, like trimethaphan or hexamethonium Lack central effects Mecamylamine readily enters CNS • Sedation, tremor, choreiform movements, mental aberrations Eye • Ciliary muscle (mostly PNS tone) – cycloplegia • Pupil (both PNS and SNS, but PNS dominates slightly) • Moderate dilation of the pupil Cardiovascular System • Blood vessels (SNS tone) • Decrease in arteriolar and venomotor tone • Reduced blood pressure • Orthostatic hypotension • Moderate tachycardia (removal of PNS tone at SA node) NBME Ganglion-Blocking Drugs: Organ system effects: (cont’d) Gastrointestinal Tract • Tone is PNS – reduced secretion and motility • Can produce constipation Genitourinary system • Hesitancy or urinary retention (esp. with prostatic hyperplasia) • Sexual function is impaired (requires both SNS and PNS) Blocks thermoregulatory sweating Responses to Autonomic Drugs are altered!! • Effector cell receptors are not blocked • End-organ effects are present • Homeostatic reflexes are absent! • Can dramatically alter responsiveness to drugs • Example – NE and heart rate Algorithm: Reflex control of Heart Rate Muscarinic antagonists Tertiary amines Atropine Scopolamine Homatropine Oxybutynin Pirenzepine (M1 selective) Anticholinergic Tropicamide Agents Tolterodine (M3 - bladder) Quaternary amines Atropine methyl nitrate Methscopolamine Ipratropium Tiotropium Propantheline Glycopyrrolate Ganglionic blocking drugs Hexamethonium Trimethaphan (lacks CNS effects) Mecamylamine Cholinesterase regenerator Pralidoxime (2-PAM) Parasympatholytics Eye GI GU Dry mouth Urinary retention constipation Cholinoceptor antagonists ACh release inhibitors Postsynaptic inhibitors Botulinus toxin Muscarinic Antagonists Atropine Scopolamine Ipratropium Glycopyrrolate Pirenzepine (M1 selective) Oxybutynin Tolterodine (M3) Nicotinic antagonists Ganglionic Hexamethonium Mecamylamine Trimethaphan Used for eye exams Homatropine Cyclopentolate Tropocainamide Neuromuscular (Muscle relaxants) Nondepolarizing Atracurium Pancuronium Tubocurarine Vecuronium Depolarizing Succinylcholine Dry as a bone Red as a beat Hot as a hare Mad as a hatter Tachycardia Histamine release Which of the following medications blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering nerve terminals, and inhibiting the release of acetylcholine and would be appropriate for the treatment of cervical dystonia in a 46-year-old woman? A. Botulinum toxin B. Hemicholinium C. Scopolamine D. Tetrodotoxin E. Vesamicol Answer: A LEARNING OBJECTIVES Neuromuscular Blocking Agents Competitive – nicotinic antagonists d-TUBOCURARINE potency altered by pH causes large increase in histamine release ATRACURIUM CISATRACURIUM MIVACURIUM PANCURONIUM ROCURONIUM Depolarizing – nicotinic agonists SUCCINYLCHOLINE short duration of action (<8 min) NBME Effects of Neuromuscular Blocking Agents NBME Competitive Depolarizing Antagonist Agonist Effect on motor end plate depolarization None Partial persistent depolarization Initial effect on striated muscle None Fasciculation Small muscles Skeletal muscle Respiratory muscles Respiratory muscles Effect of inhaled anesthetics Increase potency No or little effect Effect of antibiotics Increase potency No or little effect Action at receptor Muscles affected first Muscles affected last Neuromuscular Blocking Agents: Adverse Effects NBME Many paralytics cause histamine release leading to hypotension and bronchospasm Most pronounced with d-Tubocurarine. Neuromuscular Blocking Agents: Drug Interactions Numerous – alter potency of paralytics Opioids Local anesthetics - increases potency of both competitive and depolarizing agents Anticonvulsants Cardiovascular drugs Antibiotics, esp. aminoglycosides Inhalable anesthetics 63 Skeletal Muscle Relaxants Parasympatholytics Eye GI GU Dry mouth Urinary retention constipation Cholinoceptor antagonists ACh release inhibitors Postsynaptic inhibitors Botulinus toxin Muscarinic Antagonists Atropine Scopolamine Ipratropium Glycopyrrolate Pirenzepine (M1 selective) Oxybutynin Tolterodine (M3) Nicotinic antagonists Ganglionic Hexamethonium Mecamylamine Trimethaphan Used for eye exams Homatropine Cyclopentolate Tropocainamide Neuromuscular (Muscle relaxants) Nondepolarizing Atracurium Pancuronium Tubocurarine Vecuronium Depolarizing Succinylcholine Dry as a bone Red as a beat Hot as a hare Mad as a hatter Tachycardia Histamine release Which of the following medications blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering nerve terminals, and inhibiting the release of acetylcholine and would be appropriate for the treatment of cervical dystonia in a 46-year-old woman? A. Botulinum toxin B. Hemicholinium C. Scopolamine D. Tetrodotoxin E. Vesamicol Answer: A PowerPoint Slides Several of the PowerPoint slides are Copyright © 2002-04, the American Society for Pharmacology and Experimental Therapeutics (ASPET). All rights reserved. Some of slides in this session are from the above mentioned format and are free for use by members of ASPET. Some others are from various sources like text book, recommended books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA), Dr. S. Kacker (co-professor , Clinical Pharmacology & Therapeutics, MUA) Core concepts of various USMLE High yield review series like Kaplan ,BRS etc. are thoroughly explored & integrated whenever necessary