2024-2025 Parasympathomimetics and parasympatholytics PDF

Phillip G Kopf, PhD Department of Pharmacology Midwestern University Muscarinic agonists Cholinesterase inhibitors  Acetylcholine (Miochol-E)  Reversible inhibitors  Physostigmine  Carbachol (Mios...

Phillip G Kopf, PhD Department of Pharmacology Midwestern University Muscarinic agonists Cholinesterase inhibitors  Acetylcholine (Miochol-E)  Reversible inhibitors  Physostigmine  Carbachol (Miostat)  Neostigmine (Bloxiverz)  Bethanechol  Pyridostigmine (Mestinon, Regonol)  Donepezil (Aricept)  Pilocarpine (systemic: Salagen, opthalamic:  Rivastigmine (Exelon) Isopto Carpine)  Galantamine (Razadyne ER)  Cevimeline (Evoxac)  Irreversible Inhibitors  Echothiophate (Phospholine Iodide)  Organophosphate insecticides  Malathion  Parathion  Nerve agents  Sarin  VX Cholinesterase reactivators  Pralidoxime (Protopam Chloride) Agents that block Muscarinic antagonists acetylcholine release  Atropine (systemic:  Botulinum toxin (BOTOX) AtroPen, opthalamic: Isopto Atropine)  Scopolamine (Transderm Scop)  Dicyclomine (Bentyl)  Ipratropium (Atrovent)  Tolterodine (Detrol)  Tropicamide (Mydriacyl) Muscarinic agonists Acetylcholinesterase inhibitors Botulinum toxin (Botox) Blocks acetylcholine vesicle release Muscarinic antagonists Muscarinic receptors Classic dose-response relationship Nicotinic receptors Tachyphylaxis at high concentrations  Activation of muscarinic receptors on endothelial cell results in NO/cGMP-mediated relaxation of vascular smooth muscle Muscarinic Receptors Smooth Muscle NO Ach cGMP PDE GMP Sildenafil Endothelium Edrophonium acetylcholinesterase inhibitor Atropine muscarinic antagonist Parasympathetic Innervation Circular pupillary constrictor muscle Miosis (constriction of pupil) Ciliary muscle Accommodation of focus for near vision Tension on trabecular meshwork / opening of pores Outflow of aqueous humor into the canal of Schlemm Reduces intraocular pressure  Acetylcholine (Miochol-E)  Carbachol (Miostat)  Bethanechol  Pilocarpine (systemic: Salagen, opthalamic: Isopto Carpine)  Cevimeline (Evoxac)  Increased GI motility and secretion  Decreased heart rate  Decreased blood pressure  Decreased cardiac output  Direct vasodilation  Contraction of bladder and relaxation of urinary sphincters  Miosis and decreased intraocular pressure  Stimulation of secretions (salivation, lacrimation, GI secretions, sweating, etc...)  Urinary and GI applications (bethanechol)  Stimulation of peristalsis and increased GI motility  Formerly used to treat postoperative abdominal distention, gastric atony, adynamic ileus, and GERD  More efficacious therapies are now available  Treatment of urinary retention and inadequate emptying of the bladder  Postoperative urinary retention  Diabetic autonomic neuropathy  Chronic hypotonic, myogenic, or neurogenic bladder  Ocular applications  Treatment of glaucoma (carbachol, pilocarpine)  Ophthalmic surgery (induction of miosis) (acetylcholine, carbachol, pilocarpine)  Treatment of salivary gland dysfunction (pilocarpine, cevimeline)  Xerostomia due to:  Head and neck radiation  Sjorgen syndrome  Autoimmune disorder where salivary and lacrimal secretions are compromised  Enhanced salivary secretion and ease of swallowing  Mainly the result of unwanted or excessive muscarinic stimulation  Hypotension  Bradycardia  Bronchoconstriction  Diarrhea  Cramping  Urinary incontinence  Excessive sweating  Salivation  Asthma  Cardiovascular  Bradycardia  Hypotension  Vasomotor instability  Coronary artery disease  Peptic ulcer disease  Weakened smooth muscle of the bladder or GI tract (such as after bladder surgery or intestinal anastomosis)  Urinary or intestinal obstruction  Acetylcholine  Limited use to ophthalmic surgery where rapid miosis is necessary  When it is administered systemically, it is very rapidly hydrolyzed by "pseudocholinesterase" in the plasma  Bethanechol  Analog of acetylcholine that is resistant to rapid hydrolysis  Direct muscarinic agonist with little effect at nicotinic receptors  Used to stimulate GI motility and treat urinary retention  Pilocarpine  Used in the treatment of glaucoma and xerostomia due to poor salivary secretion  Cevimeline  Used in the treatment of xerostomia due to poor salivary secretion  Reversible inhibitors  Physostigmine  Neostigmine (Bloxiverz)  Pyridostigmine (Mestinon, Regonol)  Donepezil (Aricept)  Rivastigmine (Exelon)  Galantamine (Razadyne ER)  Irreversible Inhibitors  Echothiophate (Phospholine Iodide)  Organophosphate insecticides  Malathion  Parathion  Nerve agents  Sarin  VX  Cholinesterase reactivators  Pralidoxime (Protopam Chloride)  Acetylcholine Choline Acetic Acid H3C CH2 O O H3C CH2 OH O O CH2 C CH2 C HO – C N N CH3 + CH3 + CH3 +H2O H3C CH3 H3C CH3 + + N H O N: O N: H O Enzyme-Substrate Acetylated Regenerated Intermediate Enzyme Enzyme Edrophonium H3 C N O–H + H3 C CH3.. N H–O Enzyme-Substrate Complex DFP Diisopropylphosphoric Acid F - O O HO O P HF P +H2O P H7C3O OC3H7 OC3H7 OC3H7 H7C3O H7C3O + + N H O N: O N: H O Enzyme-Inhibitor Phosphorylated Intermediate Enzyme  The cholinesterase inhibitors act by preventing the breakdown of acetylcholine in the synapse  Increased GI motility and secretion  Contraction of bladder and relaxation of sphincters  Bradycardia and hypotension  Increased secretions (salivation, lacrimation, sweating, etc...)  Decreased intraocular pressure  Stimulation of skeletal muscle (therapeutic doses) / paralysis of skeletal muscle (toxic doses)  Bronchoconstriction  Treatment of paralytic ileus and atony of the bladder (neostigmine)  Abdominal distention and acute colonic pseudo-obstruction from a variety of medical and surgical causes  Atony of the bladder detrusor muscle of the urinary bladder  Should not be used:  Intestine or bladder are obstructed  Peritonitis  Inflammatory bowel disease  Treatment of Alzheimer disease (donepezil, rivastigmine, and galantamine)  Patients with AD have reduced cerebral content of choline acetyltransferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function  Cholinesterase inhibitors increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft and provide modest symptomatic benefit in patients with AD  Treatment of myasthenia gravis (pyridostigmine) (neostigmine is less commonly used)  An autoimmune neuromuscular disorder characterized by fluctuating motor weakness involving ocular, bulbar, limb, and/or respiratory muscles  The weakness is due to an antibody-mediated, immunologic attack directed at proteins in the postsynaptic membrane of the neuromuscular junction (acetylcholine receptors or receptor-associated proteins)  Acetylcholinesterase inhibitors retard the degradation of ACh that occurs by enzymatic hydrolysis in the neuromuscular junction, resulting in a prolonged effect of ACh  Variable improvement in strength in patients with MG  Pyridostigmine provides marked improvement in some patients and little or none in others  Ophthalmologic use for treatment of glaucoma  A disease that is characterized by increased intraocular pressure  Pharmacologic options include:  Cholinergic agonists (carbachol and pilocarpine)  Cholinesterase inhibitors (echothiophate)  By contracting the ciliary muscle, these drugs put tension on the trabecular meshwork and increase the outflow of aqueous humor through the canal of Schlemm  Rarely used today  Ocular side effects such as fixed, small pupils, myopia, and increased subjective visual disturbance related to coexistent cataract  Treatment of poisoning with atropine or other antimuscarinic drugs (physostigmine)  Pyridostigmine is used by the military to protect personnel against nerve agents used in chemical warfare  This is referred to as “pre-exposure antidotal enhancement”  Toxic effects may be severe (cholinergic crisis) especially in overdose situations (organophosphate insecticide poisoning or nerve-gas poisoning)  SLUDGE (salivation, lacrimation, urination, defecation, GI distress, emesis)  Skeletal muscle fasciculation followed by paralysis  Bradycardia, hypotension, shock  Severe miosis  CNS stimulation and seizures followed by coma  Asthma  Cardiovascular  Bradycardia, hypotension, coronary artery disease  Peptic ulcer disease  Urinary or intestinal obstruction  Administer high doses of atropine (2-4 mg IV initially) followed by 2 mg IM every 10 minutes until symptoms disappear to block muscarinic receptors  Administer pralidoxime to reactivate enzyme (effective only with organophosphates)  Provide additional symptomatic treatment as needed.  Diazepam is useful for controlling seizures  Neostigmine and pyridostigmine  Reversible cholinesterase inhibitors  Quaternary ammonium compounds that don't enter the CNS  Uses:  Treatment of myasthenia gravis (both are longer acting)  Neostigmine is used to treat paralytic ileus and atony of the bladder  Pyridostigmine is also used by the military to protect troops against nerve agents used in chemical warfare  Donepezil, rivastigmine, and galantamine  Reversible cholinesterase inhibitor  Nonquaternary, so it can get into the CNS  Used in the treatment of mild to moderate Alzheimer disease  Physostigmine  Reversible cholinesterase inhibitor  Nonquaternary, so it can get into the CNS  Used in treating poisoning with atropine or other antimuscarinic agents  Organophosphate insecticides (parathion, malathion)  Parathion and malathion must be oxidized to active metabolites (paroxone and malaoxone)  The conversion occurs more rapidly in insects than humans.  In addition, most insects can not easily detoxify these metabolites  Basis for selective toxicity as an insecticide  However, they still can cause toxic effects in humans  Some agents (especially parathion) can be absorbed through the skin  Signs and symptoms of poisoning are typical of cholinesterase inhibitors  Treat poisoning with atropine, pralidoxime, and other symptomatic support  Nerve Gases (sarin, VX)  Very potent and toxic, irreversible cholinesterase inhibitors  Just a few droplets of sarin can kill an adult  Signs and symptoms are typical for cholinesterase inhibitors  Treat poisoning with atropine and pralidoxime  Pralidoxime/2-PAM (Protopam)  Cholinesterase reactivator  It chemically binds to the phosphate group that inhibits the enzyme and thereby regenerates the enzyme  Antidote for organophosphate poisoning  It must be used within 2 hours following exposure because the phosphorylated enzyme changes to a form that can not be regenerated  Toxin produced by Clostridium botulinum  Humans usually are exposed by ingesting canned foods that were not processed properly  Toxin prevents the release of acetylcholine from nerve endings  It affects both the autonomic nerve endings (classic anticholinergic effects) and the neuromuscular junction (paralysis)  Botulinum toxin is extremely potent  A dose of 0.5-1.0 g may be fatal  Death results from diaphragmatic paralysis  Treatment involves aggressive symptomatic support (especially of respiratory function) plus administration of antibodies to the toxin  Clinical uses as a locally injected neuromuscular blocker (sold under the brand name Botox)  Reduce the appearance of facial wrinkles  Excessive sweating (hyperhidrosis)  Overactive bladder  Lazy eye (an imbalance in the muscles responsible for positioning the eye)  Eye twitching  Prevention of chronic migraines  Atropine (systemic: AtroPen, opthalamic: Isopto Atropine)  Scopolamine (Transderm Scop)  Dicyclomine (Bentyl)  Ipratropium (Atrovent)  Tolterodine (Detrol)  Tropicamide (Mydriacyl)  Drying of secretions (lacrimal, salivary, respiratory, GI, sweat, etc.)  Decrease tone and motility of GI tract  Relaxation of the bladder and urine retention  Bronchodilation  Mydriasis (dilation of pupil) with cycloplegia (loss of accommodation) and pronounced increase in intraocular pressure  Increased heart rate  CNS  Sedation and amnesia at low doses  Excitation and seizures at toxic doses  Some of the agents are quaternary salts that do not produce these CNS effects  Treatment of GI disorders  Cramping, diarrhea, irritable bowel syndrome  Urology  Treatment of urinary incontinence  Ophthalmologic use as mydriatic agents  Do not use in patients with glaucoma  Antidote for poisoning with cholinesterase inhibitors or muscarinic agonists (e.g. some types of mushroom poisoning)  Prevention of motion sickness (scopolamine)  Cardiac stimulation in emergency situations (atropine)  Dry mouth  Dry, hot skin  Constipation  Urine retention  Visual disturbances, blurred vision, photophobia  CNS effects  Sedation, confusion, amnesia (especially in elderly patients)  Mainly extension of antimuscarinic action  Glaucoma  Prostatic hypertrophy  Cardiovascular instability  Severe ulcerative colitis  Anticholinergic syndrome  Symptoms include:  Dry, hot skin and hyperthermia  Severe mydriasis, blurring of vision, photophobia  CNS stimulation  Agitation, hallucinations, seizures progressing to coma and death  Cessation of GI motility (no bowel sounds)  Cardiovascular  Weak, rapid pulse, tachycardia and arrhythmias  Treatment:  Administration of physostigmine or other cholinesterase inhibitors  Benzodiazepines for the treatment of seizures  Ice baths to reduce hyperthermia  Keep patient in a dark, quiet area to prevent photophobia and excitement  Atropine  Prototypical antimuscarinic agent  A naturally-occurring belladonna alkaloid found in the plant Deadly Nightshade (Atropa belladonna) and Jimson weed  Clinical uses:  Bradycardia  Inhibition of salivation and secretions (preanesthesia)  Organophosphate or nerve agent poisoning  Scopolamine  A natural product found in the plant Hyoscyamus niger (Henbane)  Chemically similar to atropine  Clinical use:  Transdermal patch (Transderm Scop) is used for the prevention of motion- sickness and vertigo  Dicyclomine  Nonquaternary  Widely used as an intestinal antispasmodic for the treatment of irritable bowel syndrome  Ipratropium  Quaternary salt  Administered by inhalation for the treatment of asthma and COPD  Fewer systemic effects  Tolterodine  Used to treat urinary incontinence  Tropicamide  Widely used to dilate the pupil for ophthalmologic examination