Autonomic Drugs Chapter 4.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 4 CHOLINERGIC AGONISTS ...

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 4 CHOLINERGIC AGONISTS  Drugs affecting the ANS are divided into 2 groups: Cholinergic/anticholinergic drugs- act on receptors activated by Overview acetylcholine (ACh) Adrenergic drugs- act on receptors activated by norepinephrine or epinephrine Cholinergic and adrenergic drugs act by either stimulating or blocking receptors of the ANS The Cholinergic Neuron Where are they? ◦ Preganglionic fibers terminating in the adrenal medulla ◦ Parasympathetic and sympathetic ganglia (autonomic ganglia) ◦ Parasympathetic postganglionic fibers (all) ◦ Sympathetic postganglionic fibers of sweat glands (only) ◦ Skeletal muscle in the somatic system ◦ CNS See figure 4.2  The Cholinergic Neuron Neurotransmission at cholinergic neurons 6 sequential steps: 1. Synthesis of Ach 2. Storage 3. Release 4. Binding of ACh to the receptor 5. Degradation of ACh in the synaptic cleft 6. Recycling of choline The Cholinergic Neuron Neurotransmission at cholinergic neurons 1. Synthesis of acetylcholine (ACh) ◦ Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by an energy-dependent carrier system- can be inhibited by the drug hemicholinium. ◦ The uptake of choline is the rate-limiting step in ACh synthesis ◦ Choline acetyl-transferase catalyzes the reaction of choline + acetyl coenzyme A (CoA) to form ACh in the cytosol. The Cholinergic Neuron Neurotransmission at cholinergic neurons 2. Storage of acetylcholine in vesicles ◦ ACh is packaged and stored into presynaptic vesicles by an active transport process. ◦ The vesicle contains ACh and ATP (adenosine triphosphate) ◦ ATP is a cotransmitter that increases or decreases the effect of the primary neurotransmitter. The Cholinergic Neuron Neurotransmission at cholinergic neurons 3. Release of acetylcholine ◦ When an action potential propagated by voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. ◦ Elevated calcium levels promote the fusion of the synaptic vesicles with the cell membrane and the release of vesicular contents into the synaptic space. ◦ Release can be blocked by botulinum toxin ◦ Release can be accelerated by black widow spider venom The Cholinergic Neuron Neurotransmission at cholinergic neurons 4. Binding to the receptor ◦ ACh released from the synaptic vesicles diffuses across the synaptic space and binds to: ◦ Postsynaptic receptors on the target cell ◦ Presynaptic receptors on the membrane of the neuron that released ACh ◦ Other targeted presynaptic receptors ◦ Postsynaptic cholinergic receptors on the surface of effector organs are divided into two classes: ◦ Muscarinic ◦ Nicotinic ◦ Binding to a receptor leads to a biologic response within the cell The Cholinergic Neuron Neurotransmission at cholinergic neurons 5. Degradation of acetylcholine ◦ The signal at the postjunctional effector site is rapidly terminated because acetylcholinesterase (AChE) cleaves ACh to choline and acetate in the synaptic cleft. The Cholinergic Neuron Neurotransmission at cholinergic neurons 6. Recycling of choline ◦ Choline is recaptured by a sodium- coupled, high affinity uptake system that transports the molecule back into the neuron ◦ It is then available to be acetylated into ACh Cholinergic Receptors (Cholinoceptors) Muscarinic receptors ◦G-protein–coupled receptors (metabotropic receptors) ◦Bind to ACh but also recognize and bind to muscarine, an alkaloid found in certain poisonous mushrooms ◦5 subclasses- M1-M5, only some are understood ◦Locations ◦Autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands ◦M1 receptors are also found on gastric parietal cells ◦M2 receptors on cardiac cells and smooth muscle ◦M3 receptors on the lungs, bladder, exocrine glands, and smooth muscle ◦Mechanism ◦G-protein-coupled: involves second messenger systems and may result in either activation or inhibition of different chemicals ◦Drugs (Muscarinic agonists) ◦May bind and activate muscarinic receptors or may inhibit acetylcholinesterase (AChE) Cholinergic Receptors (Cholinoceptors) Nicotinic receptors ◦ Ligand-gated ion channel (ionotropic receptor) ◦ Bind to ACh but also recognize and bind to nicotine, an alkaloid found in tobacco and other plants ◦ The nicotinic receptor is composed of 5 subunits ◦ Locations ◦ CNS ◦ Adrenal medulla ◦ Autonomic ganglia ◦ Neuromuscular junction (NMJ) in skeletal muscles ◦ Mechanism ◦ Ligand-gated ion channel: binding of two ACh molecules elicits a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell ◦ Nicotine at low concentration stimulates the receptor, whereas nicotine at high concentration blocks the receptor Direct-acting Cholinergic Agonists ◦ Mimic the effects of ACh by binding directly to cholinoceptors (muscarinic or nicotinic) ◦ Broadly classified into two groups: 1) choline esters, which include endogenous ACh and synthetic esters of choline, such as carbachol and bethanechol, and 2) naturally occurring alkaloids, such as nicotine and pilocarpine, and their synthetic analogs ◦ All direct-acting cholinergic drugs have a longer duration of action than ACh. ◦ The more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. ◦ As a group, the direct-acting agonists show little specificity in their actions, which limits clinical usefulness. Direct-acting Cholinergic Agonists Acetylcholine- Intraocular ◦ Cannot penetrate membranes ◦ Lacks therapeutic importance due to diffuse effects* and deactivation by acetylcholinesterase ◦ Has both muscarinic and nicotinic activity ◦ Actions: ◦ Decrease in heart rate and cardiac output- reduces rate of firing at the sinoatrial (SA) node (mimics vagal stimulation) ◦ Decrease in blood pressure- causes vasodilation- no known activity due to lack of ACh in bloodstream ◦ Other actions- stimulates salivary secretions, increases gastric acid secretion, and stimulates intestinal secretions and motility. Also enhances bronchiolar secretions and causes bronchoconstriction. Causes urination and miosis (pupil constriction) ◦ Uses: ◦ ACh is used during eye surgery to produce miosis Direct-acting Cholinergic Agonists Bethanechol- Oral ◦ Is not hydrolyzed by AChE, but is inactivated by other esterases ◦ Has strong muscarinic activity ◦ 1-hour duration of activity ◦ Actions ◦ Stimulates urination and increases intestinal motility and tone ◦ Therapeutic Uses ◦ Used to stimulate the atonic bladder, particularly in postpartum or postoperative nonobstructive urinary retention ◦ Adverse Effects ◦ Generalized cholinergic stimulation: sweating, salivation, flushing, decreased blood pressure ◦ Atropine sulfate is used to overcome severe cardiovascular or bronchoconstrictor responses to this agent Direct-acting Cholinergic Agonists Carbachol (carbamylcholine) (Miostat)- Intraocular ◦ Has both muscarinic and nicotinic activity ◦ Is weakly hydrolyzed by AChE, and is slowly inactivated by other esterases ◦ Actions ◦ Profound effects on both the cardiovascular and GI systems because of its ganglion-stimulating activity, and it may first stimulate and then depress these systems ◦ Also causes miosis ◦ Therapeutic Uses ◦ Intraocular use during eye surgery and to lower intraocular pressure due to glaucoma ◦ Adverse Effects ◦ Ophthalmic use: few side effects due to lack of systemic penetration ◦ Otherwise rarely used due to high potency, receptor nonselectivity, and relatively long duration of action Direct-acting Cholinergic Agonists Pilocarpine- Ophthalmic and Oral ◦ Less potent but is uncharged and can penetrate the CNS at therapeutic doses ◦ Not hydrolyzed by AChE ◦ Has muscarinic activity ◦ Actions ◦ Causes rapid miosis ◦ Is one of the most potent stimulators of secretions such as sweat, tears, and saliva ◦ Therapeutic Uses ◦ Drug of choice for emergency lowering of intraocular pressure due to glaucoma ◦ Also used to treat glaucoma ◦ Action occurs within a few minutes and lasts 4-8 hours and can be repeated ◦ Also used to reverse mydriasis due to atropine ◦ Treats xerostomia (dry mouth) in patients with irradiation of head and neck- tablets ◦ Increases secretions (saliva and tears) in patients with Sjögren syndrome- tablets Direct-acting Cholinergic Agonists Pilocarpine ◦ Adverse Effects ◦ Ophthalmic use: blurred vision, night blindness, and brow ache ◦ Tablets- diffuse effects due to nonselectivity ◦ Poisoning causes diffuse parasympathetic activity and is treated with atropine (CNS activity) Indirect-Acting Cholinergic Agonists: Anticholinesterase Agents (Reversible) AChE is an enzyme that specifically cleaves ACh to acetate and choline and, thus, terminates its actions. It is located both pre- and postsynaptically in the nerve terminal where it is membrane bound. Inhibitors of AChE (anticholinesterase agents or cholinesterase inhibitors) indirectly provide cholinergic action by preventing the degradation of ACh. This results in an accumulation of ACh in the synaptic space Therefore, these drugs can provoke a response at all cholinoceptors, including both muscarinic and nicotinic receptors of the ANS, as well as at the NMJ and in the brain. The reversible AChE inhibitors can be broadly classified as short-acting or intermediate-acting agents. Reversible and irreversible agents Indirect-Acting Cholinergic Agonists: Anticholinesterase Agents (Reversible) Edrophonium ◦ Short-acting- 10-20 minutes, rapid renal elimination ◦ Quaternary amine- effects limited to periphery ◦ Used in the diagnosis of myasthenia gravis- not available and no longer used in the US per UpToDate Physostigmine- Injection ◦ Intermediate-acting- 30 minutes to 2 hours ◦ Tertiary amine found naturally in plants ◦ Substrate for AChE, occupies enzyme to allow ACh to exist longer- allows for potentiation of cholinergic activity throughout body ◦ Stimulates all cholinergic sites- muscarinic, nicotinic, and NMJ- results in contraction of GI smooth muscles, miosis, bradycardia, hypotension, skeletal muscle twitches and paralysis, and CNS activity ◦ Uses: treatment of overdoses of drugs with anticholinergic effects and reversal of NMBs ◦ Adverse effects occur more at higher doses Indirect-Acting Cholinergic Agonists: Anticholinesterase Agents (Reversible) Neostigmine- Injection ◦ Intermediate-acting- 30 minutes to 2 hours ◦ Synthetic ester, polar, does not cross CNS ◦ Substrate for AChE, occupies enzyme to allow ACh to exist longer- allows for potentiation of cholinergic activity throughout body ◦ Has greater effects on skeletal muscle than physostigmine and stimulates contractility prior to paralysis ◦ Uses: stimulation of bladder and GI tract, antidote for competitive NMBs, and management of symptoms of myasthenia gravis ◦ Adverse Effects- generalized cholinergic activity- salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, bronchospasm- no CNS effects ◦ Cannot be used to reverse central-acting antimuscarinic agents (like atropine) ◦ Contraindicated when intestinal or urinary bladder obstruction is present Indirect-Acting Cholinergic Agonists: Anticholinesterase Agents (Reversible) Pyridostigmine- Oral and Injection ◦ Intermediate-acting- 3-6 hours ◦ Uses: chronic management of myasthenia gravis ◦ Adverse effects- similar to neostigmine Tacrine, donepezil, rivastigmine, and galantamine – oral, topical (R) ◦ Used to delay the progression of Alzheimer’s disease related to deficiency of cholinergic neurons and lower levels of ACh in the CNS Indirect-Acting Cholinergic Agonists: Anticholinesterase Agents (Irreversible) Covalently bind to AChE- irreversible Results in long-lasting increase of ACh at all sites where it is released Extremely toxic- developed by the military as nerve agents Echothiophate (no longer used)- Intraocular ◦ Organophosphate ◦ Permanently inactivates AChE- restoration of AChE activity requires the synthesis of new enzyme molecules ◦ Actions include generalized cholinergic stimulation, paralysis of motor functions (causing breathing difficulties) and convulsions ◦ Causes intense miosis and can be used as ophthalmic preparation to reduce intraocular pressure ◦ High dose atropine can be used to reverse some effects Toxicology of Anticholinesterase Agents ◦ Irreversible AChE inhibitors (usually organophosphates) are commonly used as agricultural insecticides – has led to numerous cases of accidental poisoning, as well as suicides and homicides ◦ Organophosphate nerve gases are used as agents of warfare and chemical terrorism ◦ Toxicity presents as a cholinergic crisis ◦ Depending on the agent, effects may be peripheral or can affect the whole body ◦ Antidotes: ◦ Pralidoxime (2-PAM) can reactivate inhibited AChE but cannot cross the CNS and is unable to overcome the toxicity of reversible AChE inhibitors. Also, less useful with more rapidly acting agents. ◦ Atropine can be used to prevent muscarinic side effects. ◦ Diazepam is used to reduce convulsions