Autonomic Drugs Notes - Pharm L13 Drug, PDF

CM 109: INTEGRATED BASIC SCIENCES II (PHARMACOLOGY) AUTONOMIC DRUGS DR. MARY ANN ROA | 17 NOVEMBER 2024 TABLE OF CONTENTS o​ Somatic System...

CM 109: INTEGRATED BASIC SCIENCES II (PHARMACOLOGY) AUTONOMIC DRUGS DR. MARY ANN ROA | 17 NOVEMBER 2024 TABLE OF CONTENTS o​ Somatic System =​ Involved in a voluntary control of functions such as I. OVERVIEW OF THE AUTONOMIC NERVOUS SYSTEM (ANS)​ contraction of skeletal muscle which is essential 1 for locomotion. A. ORGANIZATION OF THE NERVOUS SYSTEM​ 1 −​ Afferent Division ​ B. EFFECTOR NEURONS OF ANS​ 1 o​ Afferent neurons bringing information from the periphery to the CNS C. AUTONOMIC RECEPTORS​ 2 o​ Provide sensory input to modulate the function of the II. DRUGS AFFECTING THE ANS​ 5 efferent division through reflex arcs or neural III. CHOLINERGIC DRUGS​ 5 pathways that mediate a reflex action. A. CHOLINERGIC AGONISTS​ 5 Table 1. Somatic Nervous System vs. Autonomic Nervous System B. CHOLINERGIC ANTAGONISTS​ 8 Somatic Autonomic IV. NEUROMUSCULAR BLOCKING AGENTS​ 9 Voluntary (motor) control Involuntary control → visceral A. NONDEPOLARIZING (COMPETITIVE) BLOCKERS​ 9 organs B. DEPOLARIZING AGENTS​ 10 Single motor neuron + skeletal Preganglionic & postganglionic V. ADRENERGIC DRUGS​ 10 muscle neurons A. ADRENERGIC AGONISTS​ 10 Cell body: in CNS Cell body: in CNS B. ADRENERGIC ANTAGONISTS​ 12 VI. REFERENCES​ 13 Axon synapses on skeletal Preganglionic axons synapse on muscle cell bodies of postganglionic I. OVERVIEW OF THE AUTONOMIC NERVOUS SYSTEM (ANS) neuron → synapse on visceral effector organs A. ORGANIZATION OF THE NERVOUS SYSTEM Ach neurotransmitter → All preganglionic neurons: Nicotinic receptors release Ach Postganglionic neurons: Ach or NE or neuropeptides B. EFFECTOR NEURONS OF ANS Figure 1. Organization of the Nervous System Figure 2. Effector Neurons of ANS Retrieved from Doc Roa’s PPT (2024). Retrieved from Doc Roa’s PPT (2024). PRECEPTOR NOTES PRECEPTOR NOTES Organization of the Nervous System Effector Neurons of ANS ​ The Nervous System is divided into two anatomical division ​ Preganglionic Neuron →​Central Nervous System (CNS) →​The cell body is in the brainstem or the spinal cord ▪​ Composed of the brain and the spinal cord →​Releases Acetylcholine as a neurotransmitter → →​Peripheral Nervous System (PNS) postganglionic neuron ▪​ Composed of neurons located in the brain and in the spinal ​ Postganglionic neuron - cord. →​Release a neuroeffector transmitter either Acetylcholine or ▪​ Further divided into Norepinephrine or Adrenaline/Noradrenaline which will bind to −​ Efferent Division effector organs o​ Carries signals away from the brain and the spinal cord to the peripheral tissues. o​ Autonomic System =​ Regulates everyday requirements of vital body functions without conscious participation of the mind (Involuntary nature of function) =​ Also known as the visceral, vegetative or involuntary nervous system. =​ Composed of efferent neurons that innervate smooth muscles, the viscera, cardiac muscle, vasculature and the exocrine glands. =​ Control digestion, cardiac output, blood flow and glandular secretions. =​ 3 Divisions ​ Enteric - located in the plexus in the gastrointestinal tract. ​ Parasympathetic ​ Sympathetic Figure 3.Organization of SNS vs ANS Retrieved from Doc Roa’s PPT (2024). Trans 13 SGD4: Abagatnan, Albus, Asubar, Beato, Britanico, Buenaflor, Condes, Dacuno, Gerente, Guantero, Guerrero, Jubilla 1 of 17 PRECEPTOR NOTES ​ Receptor types in effector organs for sympathetic division is a ​ Somatic Nervous System little complicated because of the different receptor sites, the α1, →​A single motor neuron, which connects directly to the effector α2, β1, β2. organ, skeletal muscle →​Neurotransmitter: releases acetylcholine (Ach) →​Receptor: contains the nicotinic receptor →​The resulting effect of the Ach-Nicotinic receptor binding would be contraction of skeletal muscle. ​ Autonomic Nervous System →​Sympathetic innervation of the adrenal medulla ▪​ The preganglionic neuron will release Ach ▪​ But the neuroeffector transmitter would either be epinephrine and norepinephrine released into the blood ▪​ This will bind to the adrenergic receptor in the different effector organs. →​Other Sympathetic Ganglia ▪​ The Ach is released from the preganglionic neuron, ▪​ The initial receptor that would receive the Ach in the postganglionic neuron will be the nicotinic receptor, which Figure 4.Schematic Diagram of ANS is the same with the adrenal medulla. Retrieved from Doc Roa’s PPT (2024) ▪​ The postganglionic neuron will release the norepinephrine or noradrenaline which binds to the adrenergic receptor in PRECEPTOR NOTES specific effector organs. ​ Schematic view of the Autonomic Nervous System −​ For Adrenal Medulla →​The pre and post ganglions of the sympathetic and o​ Specifically would release norepinephrine and parasympathetic divisions epinephrine. →​Sympathetic Division: Green −​ For other Sympathetic Ganglia ▪​ Preganglionic fibers - Longer o​ The only neurotransmitter will be norepinephrine ▪​ Postganglionic fibers - Shorter o​ Because the ganglions and neurons do not contain a →​Parasympathetic Division: Peach specific enzyme that would convert the ▪​ Preganglionic fibers - Shorter norepinephrine to epinephrine, that particular ▪​ Postganglionic fibers - Longer, because they are enzyme is only present in the adrenal medulla. innervating remote areas/organs. →​Parasympathetic NS ▪​ Preganglionic neurons release Ach and will bind to nicotinic receptors in the postganglionic neuron which will also release Ach. ▪​ In contrast to the somatic nervous system, it binds to muscarinic receptors in the effector organ. Table 2. Sympathetic Division vs Parasympathetic Division Characteristics Sympathetic Parasympathetic Division Division Origin of the Spinal cord: T1-L3 Nuclei of CN III, VII, IX, X preganglionic (thoracolumbar) Spinal cord: S2-S4 neurons (craniosacral) Location of Paravertebral and In or near effector organs autonomic prevertebral ganglia Length of Short Long Figure 5. ANS Innervation on different Effector Organs preganglionic Retrieved from Doc Roa’s PPT (2024) Length of Long Short PRECEPTOR NOTES postganglionic ​ The different effector organs that the Autonomic Nervous System axons innervates or initiates their actions. ​ Sympathetic Actions - Red Effector Smooth muscle; cardiac muscle; glands →​Most actions are stimulatory and would produce certain organs activity on the visceral organs. →​Increase contractility and increase heart rate. Neuroeffector Diffuse, branching; receptors not concentrated in ​ Parasympathetic Actions - Blue junctions one region →​More of inhibitory or relaxation. →​Decrease heart rate and decrease contractility Neurotransmitt ACh/Nicotinic Receptor ​ Exception: Male Genitalia in sympathetic and parasympathetic er and are both stimulatory and can stimulate different events like: receptor type →​For sympathetic - Male ejaculation in ganglion →​For parasympathetic - Male erection Neurotransmitt NE (except sweat ACh C. AUTONOMIC RECEPTORS er in effector glands) ​ Present at →​Neuromuscular junction organs →​Cell bodies of postganglionic neurons Receptor types α1, α2, β1, β2 Muscarinic →​Effector organs ​ G protein-linked receptors in effector ​ Heterotrimeric organs →​With 3 subunits: α, β, and γ →​Activity resides in a subunit PRECEPTOR NOTES ▪​ GDP binding → inactive ​ The different characteristics of Autonomic Nervous System ▪​ GTP binding → active →​Sympathetic ​ Type and its mechanism of action → determine physiologic →​Parasympathetic response ​ Neuroeffector junctions →​Tissue specific →​Similar to neuromuscular junctions in the somatic nervous →​Cell type specific system ▪​ β1 receptor in SA node (heart) - ↑ heart rate →​Found between postganglionic neurons and the effectors or ▪​ β1 receptor in ventricular muscle (heart) - ↑ cardiac their target tissues. contractility (no effect on heart rate) ​ Both divisions have diffuse and branching patterns allowing them to innervate many effector organs. PRECEPTOR NOTES ​ Actions in effector organs need to have specific neurotransmitter binding to a specific receptor. CM 109 Autonomic Drugs 2 of 17 ​ Most of these autonomic receptors are G protein-linked receptors ​ Heterotrimeric, with 3 subunits →​Most of them would have similar structures for their subunits but they would have different types of the alpha subunit ​ Alpha (α) subunit →​The one which determines receptor specificity →​Where activity of receptor is located →​This is where guanosine diphosphate binds and render the receptor inactive →​Binding to guanosine triphosphate and render receptor active ​ Type and mechanism of action determine physiologic response →​Depends on what binds and to neurotransmitter-hormone interaction Figure 8. Metabotropic Receptor Coupled to Diacylglycerol and Inositol ​ Physiologic response triphosphate. Retrieved from Doc Roa’s PPT (2024). →​Binding could result in stimulation or agonistic response or inhibition or antagonistic response. PRECEPTOR NOTES ​ Specificity is very important, ​ Third prototype: another Metabotropic receptor →​Receptors are not allowed to bind to any neurotransmitter or →​Receptor coupled to diacylglycerol and inositol triphosphate hormone →​Initiates a different type of reaction within the cell →​Disruption lead to disarray of the physiologic response ​ Binding of similar hormone to β1 receptors located in different Mechanism of Action of α1 adrenoreceptors cell types would result to totally different actions Mechanisms Whereby Binding of a Neurotransmitter Leads to a Cellular Effect Figure 6. Ionotropic Receptor Coupled to Ion Channels Retrieved from Doc Roa’s PPT (2024). PRECEPTOR NOTES Figure 9. Mechanism of Action of α1 Adrenoreceptors ​ First Prototype: Ionotropic Receptors Retrieved from Doc Roa’s PPT (2024). →​Receptors coupled to ion channels →​Binding of a neurotransmitter to the ionotropic receptor PRECEPTOR NOTES causes movement of charged ions in the cell membrane. α1 adrenoceptors ▪​ Change in the conformation of the cell membrane and the ​ Coupled with Gq protein membrane potential and/or the ionic concentration within →​In inactive state the cell ▪​ αq subunit of Gq protein is bound to GDP ▪​ Binding initiates actions of neurotransmitter to effector cell →​In active State or effector organ ▪​ αq subunit of Gq protein is bound to GTP ​ Embedded in the cell membranes, coupled via Gq protein to phospholipase C ​ Norepinephrine →​Agonist →​Sympathetic neurotransmitter ​ Activation Process →​1st step: Norepinephrine binds to the α1 receptor, causing conformational change →​2nd Step: GDP is released from the αq subunit, and will be replaced by GTP in binding α1 or αq subunit of Gq protein →​3rd Step: αq - GTP complex will migrate within the cell membrane and binds to and activates phospholipase C ​ Intrinsic GTPase activity Figure 7. Metabotropic Receptor Coupled to Adenylyl Cyclase →​Converts GTP back to GDP and the αq subunit returns to Retrieved from Doc Roa’s PPT (2024). inactive state ​ Activated Phospholipase C PRECEPTOR NOTES →​Catalyzes the liberation of Diacylglycerol (DAG) and Inositol ​ Second Prototype: Metabotropic receptor triphosphate (IP3) of the phosphatidyl inositol diphosphate →​Receptors coupled to adenylyl cyclase →​DAG activates protein kinase C →​Metabolic receptor →​IP3 causes the release of calcium from the intracellular stores →​Coupled to ATP in the ER or SR, increasing intracellular calcium levels →​Binding of a specific hormone or neurotransmitter to this ​ Elevated Ca + activated protein kinase C receptor would cause changes linked to adenylyl cyclase →​Phosphorylate proteins executing the final physiologic action activity and produce protein phosphorylation in the cellular of this hormone receptor binding cytoplasm →​Example: Contraction of the smooth muscle ​ In the first prototype, would result in the change in the membrane potential of the ionic concentration CM 109 Autonomic Drugs 3 of 17  Mechanism of Action of β adrenoreceptors ​ In the figure: →​Binding of acetylcholine to the muscarinic receptor (M2) →​Dissociation of the α subunit of the receptor (G protein) →​Activate the phospholipase C and generate the inositol triphosphate (IP3) and diacylglycerol (DAG) →​Similar to the α adrenoceptor activation ​ In other muscarinic receptors, ex. M4: →​Act to inhibit adenylyl cyclase →​α subunit in muscarinic receptor being released binds to adenylyl cyclase and inhibits it →​Could decrease intracellular cAMP levels →​Cause inhibition or decrease in the activity of sinoatrial node ▪​ In some cases, decrease in cAMP would also decrease PKA enzyme which would also decrease ATP production ▪​ Therefore, this would inhibit the ionic changes in some of the ion channels in the cell membrane ▪​ Inhibiting the activity of the particular cell ▪​ Inhibiting the sinoatrial node also decreases or slows down heart rate Muscarinic Transmission to the SA Node in Heart Figure 10. Mechanism of Action of β Adrenoceptors Retrieved from Dr. Roa’s PPT (2024). PRECEPTOR NOTES β adrenoceptors ​ Coupled with Gs protein and adenylyl cyclase →​Similar to alpha receptor, during inactive state ▪​ αs subunit of Gs protein is bound to GDP ​ Activation Process →​1st Step: Once norepinephrine binds to β receptors, GDP would be released from the Gs protein and be replaced by GTP. →​2nd Step: Binding would cause conformational changes and would activate adenylyl cyclase and act on ATP →​3rd Step: Adenylyl cyclase will convert ATP to cAMP which now serves as the second messenger via steps involving activation of protein kinases and initiate the final physiologic actions ​ Physiologic actions →​Tissue specific Figure 12. Nicotinic Transmission at the Skeletal Neuromuscular Junction →​Cell type specific Retrieved from Dr. Roa’s PPT (2024). ​ Example: PRECEPTOR NOTES →​If β1 receptor is activated in the SA node of the heart, this ​ Nicotinic - somatic would cause increased HR. ​ Acetylcholine as neurotransmitter released from the motor →​If β1 receptor is activated located in the ventricular muscle, nerve terminal and would interact with the subunit of the this would cause increase contractility of cardiac muscle pentameric nicotinic receptor to open it ​ Different receptors specific to the different cells or tissues would ​ Would allow the sodium influx result to different effects →​Sodium enters intracellularly to produce an excitatory →​ Β1 receptors located in the salivary gland would increase postsynaptic potential (EPSP) secretions →​EPSP would depolarize the muscle membrane and generate →​ β1 receptors in the kidney would cause renin secretion an action potential Muscarinic Transmission to the SA Node in Heart →​thereby triggering the conjunction of the skeletal muscle ​ Acetylcholine is hydrolyzed by enzyme acetylcholinesterase →​Very good venue to either inhibit or stimulate the production or action of acetylcholine →​The absence or presence of acetylcholinesterase would either ▪​ Increase or prolong the action of acetylcholine, ▪​ Decrease or inhibit the action of acetylcholine in the postsynaptic area Table 3. Location and Mechanism of Action of AN Receptors Receptor Target Tissue Mechanism of Action Adrenoceptors α1 Vascular smooth Inositol (IP3), muscle, skin, renal, and ↑ intracellular Ca++ splanchnic GIT sphincters, bladder sphincter, radial muscle of iris α2 GIT wall; presynaptic (-) adenylyl cyclase, Figure 11. Muscarinic Transmission to the Sinoatrial Node in Heart adrenergic neurons ↓ cAMP Retrieved from Dr. Roa’s PPT (2024). β1 Heart, salivary glands, (+) adenylyl cyclase, PRECEPTOR NOTES ​ Muscarinic - parasympathetic innervation adipose tissue, and ↑ cAMP ​ Different muscarinic receptors kidney →​M1, M2, M3, M5 →​Some could have the same mechanism of action as the α1 adrenoreceptors: β2 Vascular smooth (+) adenylyl cyclase, ▪​ The binding of acetylcholine to the muscarinic receptor (skeletal) muscle, GIT ↑ cAMP would cause dissociation of the α subunit of the G protein wall, bladder wall, bronchioles CM 109 Autonomic Drugs 4 of 17  Receptor Target Tissue Mechanism of Action PRECEPTOR NOTES STEP 1: SYNTHESIS OF ACETYLCHOLINE Cholinoceptors ​ Acetylcholine is synthesized using choline transported together Nicotinic (N) Skeletal muscle (motor Opening Na+ and K+ with sodium from the extracellular fluid into the cytoplasm of the cholinergic neuron endplate N1), channels (depolarization) →​energy-dependent carrier system (sodium is cotransporter of postganglionic neurons, choline) SNS and PNS (N2), →​can be inhibited by certain drugs (eg. hemicholinium) adrenal medulla (N2) (rate-limiting step) ​ can already inhibit cholinergic action by inhibiting the first step in Muscarinic All effector organs ↑ intracellular Ca++ (M1, the synthesis of acetylcholine (movement or recruitment) (M) (PNS) M3, M5) ​ choline catalyzed by a specific enzyme (choline Sweat glands (SNS) ↓ Adenylyl cyclase, ↓ cAMP acetyltransferase) (M2, M4) STEP 2: UPTAKE INTO STORAGE VESICLES ​ choline and acetyl-CoA combine to form acetylcholine: PRECEPTOR NOTES →​Stored or packaged in vesicles in the presynaptic area to be ​ AN receptors NOT neurotransmitters and hormones protected from degradation ​ Tissue and cell-specific STEP 3: RELEASE OF NEUROTRANSMITTER ​ Cholinoceptors - receptors for acetylcholine ​ Released when the action potential propagated by the voltage sensitive sodium channels arrive at the nerve ending II. DRUGS AFFECTING THE ANS ​ Voltage sensitive calcium channels in the presynaptic membrane would open causing an increase in concentration of the Cholinergic Drugs intracellular calcium ​ Act on receptors that are activated by acetylcholine →​calcium causes release of acetylcholine from synaptic ​ Cholinergic Agonists vesicles →​Direct acting ▪​ can be blocked by botulinum toxin (one mechanism of →​Indirect acting (reversible) inhibiting the action of acetylcholine transmission) →​Indirect acting (irreversible) ▪​ toxin in black widow spider venom causes all the ​ Cholinergic Antagonists acetylcholine stored in the synaptic vesicles to empty into →​Antimuscarinic agents the synaptic gap (increasing the action of the →​Ganglionic blockers neurotransmitter) →​Neuromuscular blockers →​released acetylcholine diffuse across the synaptic space and Adrenergic Drugs ▪​ bind to the postsynaptic receptors on the target cell ​ Act on receptors stimulated by norepinephrine or epinephrine ▪​ bind to the presynaptic receptor of the membrane of the ​ Adrenergic Agonists neuron that release acetylcholine or to the other targeted →​Direct-acting presynaptic receptors →​Indirect-acting ​ Postsynaptic cholinergic receptors on the surface of the effector →​Mixed action organ may be divided into two classes: ​ Adrenergic Antagonists →​Muscarinic →​ α-blockers →​Nicotinic →​ β-blockers STEP 4: BINDING TO THE RECEPTOR →​Drugs affecting neurotransmitter uptake or release ​ Binding to a receptor by acetylcholine lead to a biologic response within the cell, e.g,: PRECEPTOR NOTES →​initiation of a nerve impulse in the postganglionic fiber ​ Cholinergic Agonists →​possible activation of specific enzymes in the effector cells as →​Drugs that increase the effect of acetylcholine or acetylcholine mediated by second messenger molecules receptor binding ​ Acetylcholine which may not bind to a specific receptor will ​ Cholinergic Antagonists undergo degradation →​Drugs that inhibit the effect of acetylcholine on the receptor →​only a specific number of receptors is available in the effector ​ Adrenergic Antagonist organs →​ α or β-blockers depending on the receptor antagonized or STEP 5: DEGRADATION OF ACETYLCHOLINE blocked ​ Unbound acetylcholine is degraded by the enzyme acetylcholinesterase: →​Can also act on the neurotransmitter itself and not the →​cleaves acetylcholine to choline and acetate in synaptic cleft receptor STEP 6: RECYCLING OF CHOLINE ​ In general, the drugs may produce their primary therapeutic ​ Choline is recycled and recaptured by a sodium coupled high effect by mimicking or altering the functions of the ANS affinity active system that transports this molecule back into the →​aka Autonomic Drugs neuron →​autonomic agents may act either: ​ Once in the extracellular fluid then the active transporter coupled ▪​ by stimulating (agonist) portions of the ANS with sodium would put it back inside the cell ▪​ by blocking (antagonist) the action of the ANS ​ A means to conserve choline which was degraded from III. CHOLINERGIC DRUGS acetylcholine that has not been used or was not able to bind to the particular receptor in the effector organs See Appendix for Table 4. Subtypes and Characteristics of Cholinoceptors A. CHOLINERGIC AGONISTS Direct-Acting Cholinergic Agonist ​ Mimic ACh effects by binding directly to cholinoceptors (M or N) ​ Longer duration of action than ACh ​ Classification: →​Endogenous choline esters ▪​ Acetylcholine ▪​ Synthetic esters of choline (carbachol, bethanechol) →​Naturally occurring alkaloids ▪​ Nicotine ▪​ Pilocarpine ​ Little specificity → limited clinical use →​Pilocarpine and bethanechol → muscarinic agents (therapeutically useful) PRECEPTOR NOTES ​ Cholinoceptors can be muscarinic (M) or nicotinic (N) ​ Since it mimics the ACh, the improvement in the action of these Figure 13. Neurotransmission at Cholinergic Neurons direct cholinergics, is that they have a longer duration of action Retrieved from Dr. Roa’s PPT (2024). compared to the ACh ​ Pilocarpine and bethanechol are exceptions →​These are muscarinic agonists exhibiting therapeutic use CM 109 Autonomic Drugs 5 of 17 Table 5. Effects of Direct-Acting Cholinoceptor Stimulants. Retrieved from Katzung’s Basic and Clinical Pharmacology, 14E (2017). Organ Response Eye Sphincter muscle of iris Contraction (miosis) Ciliary muscle Contraction for near vision (accommodation) Heart Sinoatrial node Decrease in rate (negative chronotropy) Atria Decrease in contractile strength (negative inotropy) Decrease in refractory period Atrioventricular node Decrease in conduction velocity (negative dromotropy) Increase in refractory period Ventricles Small decrease in contractile strength Blood vessels Arteries, veins Dilation (via EDRF) Constriction (high-dose direct effect) Figure 14. Molecular Structures of Four Choline Esters. Retrieved from Lung Katzung’s Basic and Clinical Pharmacology, 14E (2017). Bronchial muscle Contraction Note: Information was directly taken from Katzung's Basic and (bronchoconstriction) Clinical Pharmacology, 14E (2017). Bronchial glands Secretion ​ Acetylcholine and methacholine are acetic acid esters of choline and β-methylcholine, respectively. Gastrointestinal tract ​ Carbachol and bethanechol are carbamic acid esters of the same alcohols. Motility Increase Sphincters Relaxation PRECEPTOR NOTES ​ The four types of choline esters are typified by direct-acting Secretion Stimulation cholinoceptor agonists. Urinary bladder Table 6. Properties of Choline Esters. Retrieved from Katzung’s Basic Detrusor Contraction and Clinical Pharmacology, 14E (2017). Choline Ester Susceptibility Muscarinic Nicotinic Trigone and sphincter Relaxation to Action Action Glands Cholinesterase Sweat, salivary, lacrimal, Secretion Acetylcholine ++++ +++ +++ nasopharyngeal chloride Methacholine + ++++ None Note: Information was directly taken from Katzung’s Basic and chloride Clinical Pharmacology, 14E (2017). ​ Only the direct effects are indicated; homeostatic responses to Carbachol Negligible ++ +++ these direct actions may be important (see text). chloride ​ EDRF - endothelium-derived relaxing factor Bethanechol Negligible ++ None chloride PRECEPTOR NOTES ​ Direct-acting cholinoceptor stimulants →​More of the parasympathetic PRECEPTOR NOTES →​Despite being a stimulant, some of the actions of these ​ Acetylcholine Chloride agonists are inhibitory →​Increased susceptibility to cholinesterase (++++) →​Example: ▪​ Easily degraded by cholinesterase ▪​ Gastrointestinal tract → sphincter relaxation ▪​ Shorter duration of action ▪​ Urinary bladder → trigone and sphincter relaxation ​ Carbachol Chloride and Bethanechol Chloride ▪​ Glands → secretion →​Decreased or negligible susceptibility to cholinesterase → ▪​ AV node → decrease in conduction velocity longer duration of action ▪​ SA node → decrease in rate (negative chronotropy) →​High muscarinic action ​ Carbachol Chloride →​Both muscarinic and nicotinic actions ​ Bethanechol Chloride →​More specific for muscarinic receptor/agonist See Appendix for Table 7. Characteristics of Cholinergic Agonists PRECEPTOR NOTES ​ Pilocarpine →​Clinically used for the treatment of: ▪​ Glaucoma ▪​ Xerostomia ▪​ Sjögren syndrome →​Adverse Effects ▪​ Blurred vision ▪​ Night blindness ▪​ Brow ache ▪​ Diaphoresis ▪​ Salivation −​ In relation to its action as cholinergic agonists CM 109 Autonomic Drugs 6 of 17  Anticholinesterases (Indirect-Acting/Reversible) ​ Adverse effect of bradycardia is because of its effect on the SA ​ Acetylcholinesterase node as well as the AV node →​Enzyme that cleaves ACh → acetate + choline ​ Paralysis of skeletal muscles is if your acetylcholine accumulates →​Membrane-bound in the skeletal neuromuscular junction →​Found in pre- and post-synaptic nerve terminals ​ Acetylcholinesterase Inhibitors Neostigmine →​Prolong lifetime of ACh at cholinergic nerve endings → ACh ​ A synthetic compound and a carbamic acid ester accumulates in synaptic space ​ Has a quaternary nitrogen ➜ more polar, absorbed poorly from →​Provoke response of all cholinoceptors in the body the GIT ​ Does not enter the CNS PRECEPTOR NOTES ​ Intermediate duration of action: ~30 minutes to 2 hours ​ Anticholinesterases are indirect-acting or reversible ​ Therapeutic uses: →​Not act as a direct mimic of the neurotransmitter (ACh) →​Stimulate bladder and GIT →​Act by inhibiting acetylcholinesterase enzyme which degrades →​Antidote for competitive neuromuscular blocking agents ACh →​Treat symptoms of Myasthenia Gravis →​ACh accumulation in the synaptic space ​ Adverse effects: ▪​ Increases the amount of acetylcholine available for binding →​Generalized cholinergic stimulation ➜ salivation, flushing, to specific muscarinic and nicotinic receptors decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm ​ Contraindicated in intestinal or urinary bladder obstruction PRECEPTOR NOTES ​ Contraindication is because giving neostigmine to patients with intestinal or urinary bladder obstruction causes further abdominal pain to these patients Edrophonium ​ Quaternary amine ​ Prototype short-acting AChE inhibitor ➜ prevents hydrolysis of Ach ​ Rapidly absorbed ​ Short duration of action (~10 to 20 minutes) due to rapid renal elimination ​ Used in the diagnosing myasthenia gravis (differentiate cholinergic from myasthenia crises) ​ Used to reverse effect of neuromuscular blockers after surgery Pyridostigmine and ambenonium ​ Chronic management of myasthenia gravis ​ Intermediate duration of action (3-6 hours; 4 to 8 hours) Tacrine, donepezil, rivastigmine, and galantamine Figure 15. Mechanisms of Action of Indirect-Acting Cholinergic Agonists: Anticholinesterase Agents (Reversible). Retrieved from Lippincott ​ Delay the progression of Alzheimer’s disease Illustrated Reviews Pharmacology, 7E (2018). ​ Adverse effects: GI distress PRECEPTOR NOTES PRECEPTOR NOTES ​ Release of ACh from the presynaptic neuron ​ Donepezil is available in the Philippines and is commonly given ​ Through the action of acetylcholinesterase enzyme (AChE): to patients with dementia, as well as for those with vascular →​ACh is degraded to acetate and choline damage →​Choline goes back to reservoir for it to be use again in ACh Anticholinesterases (Indirect-Acting/Irreversible) synthesis ​ Synthetic organophosphate compounds can bind covalently to →​Enzyme shortens the action of ACh in the synaptic cleft AChE ▪​ Treatment: administration of anticholinesterases →​Long-lasting increase in ACh at all release sites −​ Inhibits AChE that degrades ACh ​ Extremely toxic ➜ developed by the military as nerve agents ▪​ Improve ACh action ​ Parathion and malathion ➜ used as insecticides −​ Gives more time for ACh to interact with the receptors in ​ Echothiophate both presynaptic and postsynaptic areas of the effector →​Organophosphate organs. →​Covalently binds (via its phosphate group) at the active site of Physostigmine AChE ​ Alkaloid and tertiary amine ▪​ Permanently inactivates enzyme ​ Serves as substrate for acetylcholinesterases (AChE) ➜ stable →​Generalized cholinergic stimulation, paralysis of motor function enzyme-substrate intermediate ➜ reversibly inactivates AChE (causing breathing difficulties), and convulsions ​ (+) nicotinic and muscarinic receptors of ANS →​Produces intense miosis ➜ treatment of open-angle glaucoma ​ (+) nicotinic receptors of NMJ (but can induce risk of cataract formation) ​ Can enter and stimulate CNS PRECEPTOR NOTES ​ Duration of action: 2-4 hours ​ Some psychiatric patients have used these agents as poisons ​ Therapeutic uses: and in suicidal attempts →​Contraction of visceral smooth muscle ➜ atony of bladder & GIT →​Antidote for Atropine (anticholinergic) Table 8. Therapeutic Uses and Duration of Action of Cholinesterase ​ Adverse effects: Inhibitors →​Miosis Uses Approximate →​Hypotension Duration of Action →​Bradycardia →​Paralysis of skeletal muscles Alcohols →​Convulsions Edrophonium Myasthenia gravis, ileus, 5-15 minutes arrhythmias Carbamates and related agents Neostigmine Myasthenia gravis, ileus 0.5-2 hours Pyridostigmine Myasthenia gravis 3-6 hours Figure 16. Miosis Retrieved from Dr. Roa’s PPT (2024). Physostigmine Glaucoma 0.5-2 hours PRECEPTOR NOTES ​ Inhibits acetylcholinesterase, increasing the effect of Ambenonium Myasthenia gravis 4-8 hours acetylcholine, therefore inhibiting parasympathetics of bladder and gastrointestinal tract (relaxes muscles), causing contraction Demecarium Glaucoma 4-6 hours of visceral smooth muscle instead CM 109 Autonomic Drugs 7 of 17  Uses Approximate B. CHOLINERGIC ANTAGONISTS Duration of Action ​ Agents that bind to cholinoceptors (muscarinic or nicotinic) →​Prevent effects of ACh and other cholinergic agonists Organophosphates Echothiophate Glaucoma 100 hours Antidote for Toxicity from Anticholinesterase Agents ​ Pralidoxime (2-PAM) →​Can reactivate inhibited AChE →​Unable to penetrate into the CNS ➜ not useful in treating CNS effects of organophosphates →​A weak AChE inhibitor ➜ (at higher doses) may cause side effects similar to other AChE inhibitors →​Cannot overcome toxicity of reversible AChE inhibitors ​ Atropine →​Prevent muscarinic side effects (increased bronchial and salivary secretion, bronchoconstriction, and bradycardia) ​ Diazepam →​Reduce persistent convulsion PRECEPTOR NOTES ​ Atropine is the common antidote for an anticholinesterase agent’s toxicity; given to symptomatic patients with cardiac rates less than 40 beats per minute to increase the heart rate See Appendix for Table 9. Summary of Drugs Used for Figure 17. Cholinergic Antagonists Cholinomimetic Effects Retrieved from Dr. Roa’s PPT (2024). Table 10. Summary of Actions of Some Cholinergic Agonists PRECEPTOR NOTES Drug Actions and Uses ​ Ipratropium →​Inhalational drug for patients with COPD Bethanechol ​ Used in the treatment of urinary ​ Figure 17 shows the common brandings in red retention ​ Ganglionic blockers ​ Binds preferentially at muscarinic →​Typified by nicotine (e.g. cigarette is a ganglionic blocker) receptors ​ Neuromuscular blocker Physostigmine ​ Increases intestinal and bladder →​Pancuronium, Succinylcholine, and Vecuronium are used in motility anesthesia ​ Reverses CNS and cardiac effects of tricyclic antidepressants ​ Reverses CNS effects of atropine ​ Uncharged, tertiary amine that can penetrate the CNS Rivastigmine ​ Used as first-line treatments for Galantamine Alzheimer's disease, though with Donepezil modest benefit ​ Do not reduce healthcare costs or delay institutionalization ​ Can be used with memantine (N-methyl-D-aspartate antagonist) for moderate to severe disease Carbachol ​ Produces miosis during ocular surgery ​ Used topically to reduce intraocular pressure in open-angle or narrow-angle glaucoma, especially in patients who are tolerant to pilocarpine ​ Uncharged, tertiary amine that can penetrate the CNS Figure 18. Sites of Actions of Cholinergic Antagonists Neostigmine ​ Prevents postoperative abdominal Retrieved from Dr. Roa’s PPT (2024). distention and urinary retention PRECEPTOR NOTES ​ Used in treatment of myasthenia ​ The actions of cholinergic antagonists happen in gravis →​Presynaptic terminals (nicotinic receptor), ​ Serves as an antidote for competitive post-synaptic(muscarinic receptor) in the effector organs, and neuromuscular blockers nicotinic receptors in skeletal muscles ​ Has intermediate duration of action (0.5 to 2 hours) Antimuscarinic Agents Echothiophate ​ Used in the treatment of open-angle Atropine glaucoma ​ Has a long duration of action (100 ​ Tertiary amine belladonna alkaloid hours) ​ (+) high affinity for muscarinic receptors ​ Binds competitively Pilocarpine ​ Reduces intraocular pressure in ​ Readily absorbed, partially metabolized by the liver, and open-angle and narrow-angle eliminated primarily in urine glaucoma ​ Half-life: ~4 hours ​ Binds preferentially at muscarinic receptors Actions of Atropine ​ Uncharged, tertiary amine that can ​ Eye penetrate the CNS →​mydriasis(dilation of the pupil) Edrophonium ​ Used for diagnosis of myasthenia →​unresponsiveness to light gravis →​cycloplegia (inability to focus for near vision) ​ Serves as an antidote for competitive ​ GIT neuromuscular blockers →​Antispasmodic (HCL production not affected) ​ Has a short duration of action (10 to ​ Secretions 20 minutes) →​Dryness of the mouth (xerostomia) Acetylcholine ​ Used to produce miosis in ophthalmic surgery CM 109 Autonomic Drugs 8 of 17 ​ Cardiovascular PRECEPTOR NOTES →​(+) divergent effects depending on the dose ​ This is in relation to receptor occupancy. At low doses, even if ▪​ Low doses: slight decrease in heart rate due to blockade of the drug has high affinity for muscarinic receptors, the effect of the M1 receptors on the inhibitory prejunctional (or acetylcholine will dominate because there is more acetylcholine presynaptic) neurons -> increased ACh release available, allowing it to saturate the receptors. At higher doses, ▪​ Higher doses: progressive increase in heart rate by more of the drug will be present, leading to greater receptor blocking the M2 receptors on the sinoatrial node occupancy by the drug. Scopolamine ​ Longer duration of action ​ Greater action on the CNS ​ Blocking short-term memory ​ Produces sedation →​At higher doses ▪​ Produce excitement ​ May produce euphoria →​ susceptible to abuse Ipratropium and Tiotropium ​ Do not enter the systemic circulation or the CNS →​Isolating effects to the pulmonary system PRECEPTOR NOTES ​ Scopolamine is usually used in anesthesia ​ Ipratropium and tiotropium is used to patients with pulmonary problems like asthma or COPD Side Effects of Antimuscarinic Agents ​ Blurred vision ​ Confusion ​ Mydriasis Figure 19. Varying Effects of the Dose of Atropine ​ Constipation Retrieved from Dr. Roa’s PPT (2024). Ganglionic Blockers ​ Specifically act on the nicotinic receptors of both PRECEPTOR NOTES parasympathetic and sympathetic autonomic ganglia ​ The dose of atropine can have varying effects in the ​ No selectivity cardiovascular system orin the heart in particular. →​Block the entire output of the autonomic nervous system at the ​ Low dose nicotinic receptor →​0.5-2mg ​ Not effective as neuromuscular antagonists ​ If you increase the dose to 5 ​ Rarely used therapeutically →​Increase in heart rate ​ Often serves as a tool in experimental pharmacology ​ If you further increase the dose to 10mg →​It can already cause hallucinations, delirium, and coma Nicotine ​ Depolarizes autonomic ganglia, resulting first in stimulation and then in paralysis of all ganglia ​ Without therapeutic benefit ​ Deleterious to health PRECEPTOR NOTES ​ This means all the action takes place at the presynaptic level. ​ This explains why nicotine has such a harmful effect on our system. ​ It can influence various hormones in the body, leading to a wide range of effects. Effect of Nicotine on Hormones ​ Dopamine →​Pleasure, appetite suppression ​ Norepinephrine →​Arousal, appetite suppression ​ Acetylcholine →​Arousal, cognitive enhancement ​ Glutamate →​Learning, memory enhancement Figure 20. Effects of Increasing Doses of Atropine on Heart Rate ​ Serotonin Retrieved from Dr. Roa’s PPT (2024). →​Mood modulation, appetite suppression ​ B-Endorphin →​Reduction of anxiety and tension ​ GABA →​Reduction of anxiety and tension Figure 21. Effects of Increasing Doses of Atropine on Salivary Flow Retrieved from Dr. Roa’s PPT (2024). CM 109 Autonomic Drugs 9 of 17 Table 11. Common Cholinergic Antagonists and their Uses DRUG THERAPEUTIC USES Muscarinic Blockers ​ Trihexyphenidyl →Treatment of Parkinson's disease ​ Benztropine ​ Darifenacin Fesoterodine →Treatment of overactive urinary ​ Oxybutynin bladder ​ Solifenacin Tolterodine ​ Trospium ​ Cyclopentolate → In ophthalmology, to produce ​ Tropicamide mydriasis and cycloplegia prior to ​ Atropine* refraction ​ Atropine* → To treat spastic disorders of the GI tract ​ To treat organophosphate poisoning ​ To suppress respiratory secretions prior to surgery ​ To treat bradycardia ​ Scopolamine → To prevent motion sickness ​ Ipratropium → Treatment of COPD Figure 23. Mechanism of Action of Depolarizing Neuromuscular-Blocking ​ Tiotropium Drugs (Phase I and II). Retrieved from Dr. Roa’s PPT (2024). Ganglionic Blockers PRECEPTOR NOTES ​ Nicotine → Smoking cessation ​ Phase I (Depolarization) →​Example: Succinylcholine IV. NEUROMUSCULAR BLOCKING AGENTS ▪​ Once it binds to receptor (displacing ACh) → ​ Block cholinergic transmission between motor nerve endings and depolarization of cellular membrane → initial discharge → the nicotinic receptors on the skeletal muscle fasciculations → flaccid paralysis ​ Possess some chemical similarities to ACh ​ Phase II (Repolarization) ​ Useful during surgery to facilitate tracheal intubation and provide →​Receptor is desensitized to ACh effect, so either: complete muscle relaxation at lower anesthetic doses ▪​ ACh binds → no response elicited; or →​allow more rapid recovery from anesthesia and reducing ▪​ ACh cannot bind (not accepted by receptor) ​ Postoperative respiratory depression V. ADRENERGIC DRUGS PRECEPTOR NOTES A. ADRENERGIC AGONISTS ​ Meaning they have a shorter duration of action. ​ One example here and what is the only depolarizing muscle Neurotransmission at Adrenergic Neurons relaxant that is used today is succinylcholine ​ Closely resembles that for cholinergic neurons ​ Except for its neurotransmitter: Norepinephrine (NE) instead of A. NONDEPOLARIZING (COMPETITIVE) BLOCKERS Acetylcholine (ACh) ​ Curare – 1st drug known to block skeletal NMJ (neuromuscular ​ Synthesis and release of NE from adrenergic neuron junction) ​ Injected IV or occasionally IM PRECEPTOR NOTES ​ Examples: cisatracurium, pancuronium, rocuronium, and ​ Each of these main receptor type has a no. of specific receptor vecuronium subtypes ​ Alterations in primary structure of these receptors can influence their affinity for various agents ​ Example: →​α Receptors ▪​ Rank order of potency and affinity for E, NE, and Isoproterenol (Isoproterenol > NE > E) Figure 22. Mechanism of Action of Competitive Neuromuscular-Blocking Drugs. Retrieved from Dr. Roa’s PPT (2024). PRECEPTOR NOTES ​ Neuromuscular-Blocking Drugs →​Has a greater affinity to nicotinic receptors →​Can displace Acetylcholine (ACh) in receptor site and bind to receptor instead B. DEPOLARIZING AGENTS ​ Depolarizing plasma membrane of muscle fiber ​ Similar to ACh action ​ More resistant to degradation by AChE (ACh Enzyme) ​ Succinylcholine →​Adverse effects: ▪​ Hyperthermia ▪​ Apnea ▪​ Hyperkalemia Figure 24. Synthesis and Release of NE from the Adrenergic Neuron PRECEPTOR NOTES Retrieved from Dr. Roa’s PPT (2024). ​ Succinylcholine →​Used as muscle relaxant during anesthesia CM 109 Autonomic Drugs 10 of 17 PRECEPTOR NOTES Type Tissue Actions 1. Synthesis of NE ​ Adrenergic & cholinergic → Inhibits transmitter →​Tyrosine – NE’s very important amino acid nerve terminals release ▪​ Transported by a carrier into adrenergic neuron → Hydroxylated to dihydroxyphenylalanine or DOPA ​ Some vascular smooth → Contraction ▪​ Tyrosine from extracellular fluid → taken up by another muscle process of active transport using Na (co-transporter) → goes inside → synthesized thru hydroxylation ​ Fat cells → Inhibits lipolysis (rate-limiting step) → DOPA β1 ​ Heart, Juxtaglomerular → Increases force and rate 2. Uptake into Storage Vesicles cells of contraction →​DOPA is decarboxylated by enzyme aromatic 1 amino acid → Increases renin release decarboxylase → forms Dopamine in presynaptic neuron → transported into synaptic vesicles by an mine transporter ​ Respiratory, uterine, and → Promotes smooth system vascular smooth muscle muscle relaxation →​Vesicles block effects of NE ▪​ Example: Reserpine – affect carrier system and block β2 ​ Skeletal muscle → Promotes potassium effect NE uptake 3. Release of Neurotransmitter ​ Human liver → Activates glycogenolysis →​Influx of Ca (second messenger) → fusion of vesicle with cell membrane (exocytosis) → NE will be released in synaptic β3 ​ Fat cells → Activates lipolysis space →​Guanethidine D1 ​ Smooth muscle → Dilates renal blood ▪​ drug that can block this step vessels ▪​ effect on neuroeffector organ will not proceed D2 ​ Nerve endings → Modulates transmitter 4. Binding to Receptor release →​Released NE will bind to: ▪​ Postsynaptic receptors on effector organ; or Major Effects Mediated by α- and β- Adrenoceptors ▪​ Presynaptic receptor on nerve ending ​ α1 adrenoreceptors →​Triggers cascade of events within cell → formation of →​Vasoconstriction intracellular second messengers → will act as links in →​Increased peripheral resistance communication between: →​Increased blood pressure ▪​ Neurotransmitter; and →​Mydriasis ▪​ Action generated with effector cell →​Increased closure of internal sphincter of the bladder →​Adrenergic receptors use both of these (as second ​ α2 adrenoreceptors messenger system) to transduce signal into an effect: →​Inhibition of norepinephrine release ▪​ Cyclic Adenosine Monophosphate (CAM) →​Inhibition of acetylcholine release ▪​ Phosphatidylinositol (Pi) →​Inhibition of insulin release 5. Removal of NE ​ β1 adrenoreceptors →​NE may diffuse out of synaptic space → enter systemic →​Tachycardia circulation →​Increased lipolysis 6. Metabolism →​Increased myocardial contractility →​Metabolize inactive metabolites by specific enzyme →​Increased release of renin (Catechol-O-methyltransferase) in synaptic space ​ β2 adrenoreceptors →​May undergo reuptake back into neuron involving →​Vasodilation NaCl-dependent NE transporter →​Decreased peripheral resistance ▪​ Can be inhibited by: →​Bronchodilation −​ Tricyclic antidepressants (Imipramine) →​Increased muscle and liver glycogenolysis −​ Serotonin NE reuptake inhibitors (Duloxetine or →​Increased release of glucagon Cocaine) →​Relaxed uterine smooth muscle →​Reuptake can be potential target of some of these neuroblocking drugs Adrenergic Receptors (Adrenoreceptors) ​ 2 main families of receptors (α and β) classified on basis of their responses to adrenergic agonists epinephrine (E), NE, and isoproterenol →​α-Adrenoreceptors: E ≥ NE >> isoproterenol ▪​ α1 Receptors (postsynaptic) −​ Mediate many of classic effects of α-adrenergic (e.g. constriction of smooth muscle) Figure 25. Major Effects mediated by α- and β- adrenoceptors ▪​ α2 Receptors (sympathetic presynaptic) Retrieved from Doc Roa’s PPT (2024). −​ control release of NE →​β-Adrenoreceptors: isoproterenol > E > NE Characteristics of Adrenergic Agonists ▪​ β1, β2, and β3 Catecholamines −​ Based on affinities for adrenergic agonists and ​ Epinephrine, norepinephrine, isoproterenol, and dopamine antagonists ​ Sympathomimetic amines containing the 3.4-dihydroxybenzene ▪​ β1 (E = NE) group ▪​ β2 (E > NE) ​ Highest potency in directly activating α or β receptors ▪​ β3 – Lipolysis have effects on detrusor muscle of bladder ​ Rapid inactivation by COMT and MAO Table 12. Distribution of Adrenoceptor Subtypes →​Only a brief period of action parenterally, and inactivated orally Type Tissue Actions ​ Poor penetration into the CNS Noncatecholamines ​ Most vascular smooth → Contraction ​ Phenylephrine, ephedrine, and amphetamine muscle (innervated) ​ Lack catechol hydroxyl groups ​ Pupillary dilator muscle → Contraction (dilates ​ Have longer half-lives (not inactivated by COMT) pupil) ​ Increased lipid solubility → greater access to the CNS α1 ​ Pilomotor smooth → Erects hair PRECEPTOR NOTES muscle ​ Phenylephrine → used as a decongestant ​ COMT → Catechol-O-Methyltransferase ​ Prostate → Contraction ​ MAO → Monoamine Oxidase ​ Heart → Increases force of Mechanism of Action of Adrenergic Agonists contraction Direct-acting agonists ​ Postsynaptic CNS → Probably multiple ​ Epinephrine, Norepinephrine, Isoproterenol, Phenylephrine neurons ​ Act directly on α or β receptors ​ Platelets → Aggregation Indirect-acting agonists α2 ​ Cocaine →​Block reuptake of norepinephrine (NE) CM 109 Autonomic Drugs 11 of 17 ​ Amphetamines Table 16. Blocking Agents and Drug affecting Neurotransmitter →​Release NE from the cytoplasmic pools or vesicles of the Uptake/Release adrenergic neuron DRUGS Mixed-action agonists ​ Alfuzosin UROXATRAL ​ Ephedrine and its stereoisomer and its stereoisomer, ​ Doxazosin CARDURA pseudoephedrine ​ Stimulate adrenoceptors directly and release norepinephrine from ​ Phenoxybenzamine DIBENZYLINE the adrenergic neuron ​ Phentolamine REGITINE ​ Prazosin MINIPRESS ​ Tamsulosin FLOMAX ​ Terazosin HYTRIN ​ Yohimbine YOCON ​ Acebutolol SECTRAL ​ Atenolol TENORMIN ​ Betaxolo/ BETOPTIC-S, KERLONE ​ Bisoprolol ZEBETA ​ Carteolol CARTROL ​ Carvedilol COREG, COREG CR ​ Esmolol BREVIBLOC ​ Labetalol TRANDATE ​ Metoprolol I OPRESSOR, TOPROL -XI ​ Nadolol CORGARD ​ Nebivolol BYSTOLIC ​ Penbutolol LEVATOL ​ Pindolo/ VISKEN ​ Propranolol INDERAL LA, INNOPRAN XL Figure 26. Sites of Action of Adrenergic Agonists Retrieved from Doc Roa’s PPT (2024). ​ Timolol BETIMOL, ISTALOL, TIMOPTIC ​ Drugs affecting neurotransmitter uptake or PRECEPTOR NOTES ​ Direct action release →​Enhances the binding of neurotransmitter NE to the receptor →​Reserpine SERPASIL ​ Indirect action →​Enhances the release of NE from vesicles ​ Mixed action →​Both acting directly on the receptor itself or indirectly enhancing the release of NE at the neuromuscular junction. Table 13. Relative Receptor Affinities Relative Drugs Receptor Affinity Alpha agonists Phenylephrine, methoxamine α1 > α2 >>>>> β Clonidine, methylnorepinephrine α2 > α1 >>>>> β Mixed alpha and beta agonists Norepinephrine α1 = α2; β1 >> β2 Epinephrine α1 = α2; β1 = β2 Beta antagonists Dobutamine β1 > β2 >>>> α Isoproterenol β1 = β2 >>>> α Figure 27. Covalent Inactivation of α1 Adrenoreceptor Retrieved from Dr. Roa’s PPT (2024). Albuterol, terbutaline, PRECEPTOR NOTES metaproterenol, ritodrine β2 >> β1 >>>> α ​ Phenoxybenzamine (blocking agent example) binds rapidly to α1 adrenoreceptor since it binds rapidly through covalent binding, Dopamine agonists therefore, it has stronger affinity/binding to the receptor and it renders the α1 adrenoreceptor inactive. Dopamine D1 = D2 >> β >> α Fenoldopam D1 >> D2 See Appendix for: ​ Table 14. Cardiovascular Responses to Sympathomimetic Amines ​ Table 15. Summary of Sympathomimetic Drugs B. ADRENERGIC ANTAGONISTS ​ Reversibly or irreversibly attaching to the adrenoceptors →​Prevent activation by endogenous catecholamines ​ Classified according to relative affinities for α or β receptors in SNS →​α-adrenergic blocking agents ▪​ Profoundly affect blood pressure - ( reduce sympathetic tone of the blood vessels→ decreased PVR, reflex tachycardia) →​β-adrenergic blocking agents ▪​ Competitive antagonist ▪​ Lower blood pressure, but do not induce postural hypotension(α adrenoceptors remain functional) ▪​ Treatment of hypertension, angina, cardiac arrhythmias , myocardial infarction, heart failure, hyperthyroidism, glaucoma, prophylaxis of migraine headaches CM 109 Autonomic Drugs 12 of 17 Table 17. Relative Selectivity Of Agonists For Your Adrenoceptors. Receptor Agonists Antagonist Drugs Receptor Affinity β2 Epinephrine, Propranolol, Alpha antagonists Norepinephrine, Butoxamine Prazosin, terazosin, doxazosin α₁ >>> α₂ Isoproterenol, Albuterol Phenoxybenzamine α₁ > α₂ Cholinoceptors Phentolamine α₁ = α₂ Nicotinic (N) ACh, Nicotine Curare (blocks Yohimbine, tolazoline α₂ >> α₁ neuromuscular N1 Mixed antagonists receptors), Hexamethonium (blocks Labetalol, carvedilol β₁ = β₂ ≥ α₁ > α₂ ganglionic N2 receptors) Beta antagonists Muscarinic (M) ACh, Muscarine Atropine Metoprolol, acebutolol, alprenolol, β₁ >>> β₂ atenolol, betaxolol, celiprolol, esmolol, nebivolol PRECEPTOR NOTES ​ Have at least an idea of different drugs that act on ANS Propranolol, carteolol, nadolol, β₁ = β₂ ​ Have basic knowledge of physiology to understand the effect of penbutolol, pindolol, timolol these drugs. →​E.g. neurotransmitter hormone receptor binding physiology. Butoxamine β₂ >>> β₁ ​ Neurotransmitter receptor binding →​is an area where ANS drugs are designed to act on. See Appendix for Table 18. Summary of Sympathetic Antagonists ​ In general, ANS Drugs influences the ff: →​Neurotransmitter synthesis Drugs Affecting Neurotransmitter Release or Uptake →​Receptor binding ​ Reserpine ​ Agonist Drugs: →​A plant alkaloid →​Mimic the effect of neurotransmitters →​Mechanism of Action: →​Enhance half life of neurotransmitters ▪​ Blocks the Mg²⁺/adenosine triphosphate-dependent →​Increase the release of neurotransmitters transport of biogenic amines from the cytoplasm into ​ Antagonistic Drugs: storage vesicles in the adrenergic nerve terminals in all body →​Act on decreasing the degradation of neurotransmitters at the tissues neuro-effector junc