Autonomic Drugs Chapter 5.pptx

Autonomic Drugs UNIT 2- DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHAPTERS 3, 4, 5, 6, & 7 © 2022-2024, Dr. Susan Wrenn, All rights reserved Whalen, K., Lerchenfeldt, S., Giordano, C. (2023). Lippincott  Chapter 5 CHOLINERGIC ANTAGONISTS ...

Autonomic Drugs UNIT 2- DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHAPTERS 3, 4, 5, 6, & 7 © 2022-2024, Dr. Susan Wrenn, All rights reserved Whalen, K., Lerchenfeldt, S., Giordano, C. (2023). Lippincott  Chapter 5 CHOLINERGIC ANTAGONISTS  Cholinergic antagonist- general term for agents that bind to cholinoceptors (muscarinic or nicotinic) and prevent the effects of ACh and other cholinergic Overview agonists 3 groups: Muscarinic blockers = anticholinergic agents = antimuscarinic agents = parasympatholytics Block parasympathetic activity, leave sympathetic activity unopposed Ganglionic blockers Show preference for nicotinic receptors at sympathetic and parasympathetic ganglia Neuromuscular blocking agents Antimuscari nic Agents Commonly known as anticholinergic drugs- block muscarinic receptors, including the few sympathetic cholinergic neurons (for sweating and salivation) Do not block nicotinic receptors and have no activity at the NMJ Antimuscarinic Agents Atropine ◦ Tertiary amine extracted from belladonna alkaloid ◦ High affinity for muscarinic receptors- prevents ACh from binding ◦ Acts both centrally and peripherally- crosses BBB ◦ General actions last 4 hours, ocular effects may persist for days ◦ Neuroeffector organs vary in sensitivity- greatest effects seen in bronchial tissue, salivary and sweat glands, and the heart Antimuscarinic Agents Atropine – Ophthalmic and injection ◦ Actions / Therapeutic Uses ◦ Eye: mydriasis and may cause dangerous elevation in intraocular pressure for patients with glaucoma / Can be used for mydriatic effects, but generally replaced by other agents- allow measurement of refractive errors without interference by accommodative capacity of the eye ◦ GI: antispasmodic to reduce activity of GI tract / used to relax the GI tract ◦ Cardiovascular: divergent effects depending on dose- at low doses, effect is a slight decrease in heart rate, at higher doses increases heart rate / Used to treat bradycardia ◦ Secretions: blocks muscarinic receptors on salivary glands, producing dry mouth. Similar effects on tear production and sweat / Can be used to block secretions in respiratory tract prior to surgery ◦ Antidote for cholinergic agonists- used for treatment of organophosphate poisoning, anticholinesterase overdose, and some types of mushroom poisoning- CNS activity** Antimuscarinic Agents Atropine ◦ Pharmacokinetics ◦ Readily absorbed, half-life of about 4 hours ◦ Adverse Effects ◦ Dose dependent; can cause dry mouth, blurred vision, sandy eyes, tachycardia, urinary retention, constipation. CNS effects include restlessness, confusion, hallucination and delirium ◦ Low doses of cholinesterase inhibitors can be used to overcome toxicity ◦ Geriatric patients are at high risk of confusion, disorientation, and depressed cognitive function. ◦ Dangerous in children- sensitive to rapid increases in body temperature (occurs with decreased sweating) Antimuscarinic Agents Scopolamine - patch ◦ Tertiary amine plant alkaloid ◦ Peripheral effects similar to atropine, has greater CNS effects ◦ Longer duration of action ◦ Actions / Therapeutic Uses ◦ Effective for motion sickness / Used for prevention of motion sickness and postoperative nausea and vomiting (PONV) ◦ Blocks short term memory ◦ Causes sedation but at high doses can produce excitement and euphoria- susceptible to abuse Antimuscarinic Agents Aclidinium, glycopyrrolate, ipratropium, umeclidinium, and tiotropium-inhaled agents ◦ Ipratropium- short-acting muscarinic antagonist (SAMA) ◦ Aclidinium, glycopyrrolate, umeclidinium, and tiotropium- long-acting muscarinic antagonists (LAMAs) ◦ Used as bronchodilators and for maintenance treatment of bronchospasm associated with COPD ◦ Ipratropium is used in the acute management of bronchospasm in asthma ◦ Tiotropium is used in the chronic management of bronchospasm in asthma ◦ All agents are delivered via inhalation where effects are restricted to the pulmonary system, and they do not enter the systemic circulation or the CNS ◦ Glycopyrrolate has some systemic uses as well - given as injection Tropicamide and cyclopentolate ◦ These agents are used as ophthalmic solutions for mydriasis and cycloplegia ◦ Duration of action is shorter than atropine. Tropicamide produces mydriasis for 6 hours and cyclopentolate for 24 hours. Antimuscarinic Agents Benztropine and trihexyphenidyl- oral ◦ Useful as adjuncts with other antiparkinson agents to treat Parkinson disease and antipsychotic-induced extrapyramidal symptoms Oxybutynin and other antimuscarinic agents for overactive bladder- oral ◦ Oxybutynin, darifenacin, fesoterodine, solifenacin, tolterodine, and trospium ◦ Actions: By competitively blocking muscarinic (M3) receptors in the bladder, intravesical pressure is lowered, bladder capacity is increased, and the frequency of bladder contractions is reduced. Antimuscarinic actions in the GI tract, salivary glands, CNS, and eye may cause adverse effects. Darifenacin and solifenacin are relatively more selective M3 muscarinic receptor antagonists; however, the other drugs are mainly nonselective muscarinic antagonists, and binding to other muscarinic receptor subtypes may contribute to adverse effects. ◦ Therapeutic uses: These agents are used for management of overactive bladder and urinary incontinence. Oxybutynin is also used in patients with neurogenic bladder. Antimuscarinic Agents Oxybutynin and other antimuscarinic agents for overactive bladder ◦ Oxybutynin, darifenacin, fesoterodine, solifenacin, tolterodine, and trospium ◦ Pharmacokinetics: oral dosage forms, long-half life ◦ Adverse Effects: dry mouth, constipation, blurred vision limit tolerability ◦ Trospium is preferred in geriatric patients, especially those at risk of cognitive dysfunction, due to fewer CNS effects- minimally crosses BBB Ganglionic Blockers Most agents are used for research- have no therapeutic use Nicotine- covered in Chapter 15 (CNS) ◦ Has effects on both sympathetic and parasympathetic ganglia ◦ Used for smoking cessation Summary of cholinergic antagonists Neuromuscular Blocking Agents ◦ Block cholinergic transmission between motor nerve endings and nicotinic receptors on skeletal muscle ◦ Have some similarities to ACh and act as antagonists (nondepolarizing) or as agonists (depolarizing) at receptors at the NMJ ◦ Used to facilitate rapid intubation (RSI) and as adjuvant therapy to mechanical ventilation ◦ Used in surgery to facilitate endotracheal intubation and provide complete muscle relaxation at lower anesthetic doses Neuromuscular Blocking Agents Nondepolarizing (competitive) blockers (antagonists) Cisatracurium, mivacurium, pancuronium, rocuronium, and vecuronium- injections ◦ Mechanism of Action ◦ Low doses ◦ Competitively block ACh at the nicotinic receptors without stimulating the receptor, thus preventing depolarization of the muscle cell membrane and inhibiting muscular contraction ◦ Effects can be overcome by administration of AChE inhibitors ◦ Muscle is still able to respond to electrical stimulation ◦ High doses ◦ AChE inhibitors are less effective at reversing effects ◦ Muscle dose not respond to electrical stimulation Neuromuscular Blocking Agents Nondepolarizing (competitive) blockers (antagonists) Cisatracurium, mivacurium, pancuronium, rocuronium, and vecuronium ◦ Actions ◦ Muscles have differing sensitivity to blockade ◦ Small, rapidly contracting muscles of the face and eyes are most susceptible and are paralyzed first, followed by the fingers, limbs, neck, and trunk muscles and lastly the diaphragm ◦ The muscles recover in the reverse order ◦ Pharmacokinetics ◦ Given as IV or occasionally IM ◦ Do not enter cells or cross the BBB ◦ Each have different methods of metabolism Neuromuscular Blocking Agents Nondepolarizing (competitive) blockers (antagonists) Cisatracurium, mivacurium, pancuronium, rocuronium, and vecuronium ◦ Drug interactions ◦ Cholinesterase inhibitors- can overcome effects of nondepolarizing blockers, but at high doses can cause depolarizing blockade ◦ Halogenated hydrocarbon anesthetics- enhance neuromuscular blockade by sensitizing the NMJ to the effects of NMBs ◦ Aminoglycoside antibiotics-inhibit ACh release from cholinergic nerves and synergize with competitive blockers, enhancing neuromuscular blockade ◦ Calcium channel blockers- increase the neuromuscular blockade of competitive blockers Neuromuscular Blocking Agents Depolarizing blockers (agonists) Succinylcholine ◦ Depolarize the plasma membrane of the muscle fiber, similar to ACh ◦ Resist degradation by AChE and can more persistently depolarize the muscle fibers ◦ The receptor is depolarized until the receptor is incapable of transmitting further impulses ◦ This is process causes transient twitching (fasciculations) and later paralysis ◦ Phase I- Receptor membrane depolarizes, producing transient fasciculations followed by flacid paralysis ◦ Phase II- membrane repolarizes, but the receptor is desensitized to the effect of acetylcholine- sustained paralysis ◦ Actions: ◦ As with other agents, respiratory muscles are paralyzed last ◦ Brief muscle fasciculations result in severe muscle soreness Neuromuscular Blocking Agents Depolarizing blockers (agonists) Succinylcholine ◦ Therapeutic Uses ◦ Rapid endotracheal intubation (RSI) ◦ Used during electroconvulsive shock treatment ◦ Pharmacokinetics ◦ Short duration of action due to plasma cholinesterase ◦ Adverse Effects ◦ Hyperthermia- can induce malignant hyperthermia (Chapter 20) ◦ Prolonged muscular weakness- may experience prolonged paralysis in patients who are deficient in plasma cholinesterase or have an atypical form of the enzyme. ◦ Hyperkalemia- increases potassium release from intracellular stores- avoid in burn patients and patients with renal failure- can lead to cardiac arrythmias or cardiac arrest https://www.ismp.org/resources/safety-enhancements-every-hospital-must-consider-wake-another-tragic-neuro muscular