PHA 300 Pharmacology I: The Autonomic and Somatic Motor Nervous System PDF

PHA 300 Pharmacology I The Autonomic and Somatic Motor Nervous System Rana A. Alaaeddine, RPh, PhD Assistant Professor of Pharmacology College of Pharmacy Overview of the Nervous System The nervous system i...

PHA 300 Pharmacology I The Autonomic and Somatic Motor Nervous System Rana A. Alaaeddine, RPh, PhD Assistant Professor of Pharmacology College of Pharmacy Overview of the Nervous System The nervous system is composed of central and peripheral components. The central nervous system (CNS) consists of the brain and spinal cord The peripheral nervous system (PNS) comprises the autonomic and somatic nerves that innervate muscles and tissues throughout the body. Both originate in and are controlled by the CNS. Pharmacology I - Dr. Rana Alaaeddine 2  Somatic Nervous System Activates skeletal muscle contraction, enabling voluntary body movements. The somatic nervous system is activated by corticospinal tracts, which originate in the cerebral motor cortex, and by spinal reflexes. Pharmacology I - Dr. Rana Alaaeddine 3  Autonomic Nervous System (ANS) Regulates autonomic functions that occur without conscious control. Includes the (1) sympathetic, (2) parasympathetic, and (3) enteric nervous systems. Pharmacology I - Dr. Rana Alaaeddine 4  Sympathetic vs Parasympathetic NS 1. Sympathetic Nervous System (SNS): “Fight or flight” response Support survival during times of stress 2. Parasympathetic Nervous System (PNS): “Rest and Digest” Response Opposite effects of SNS Pharmacology I - Dr. Rana Alaaeddine 5 Pharmacology I - Dr. Rana Alaaeddine 6  Enteric Nervous System (ENS) Consists of a network of nerves located in the gut wall that regulates gastrointestinal motility and secretion. Innervated by the sympathetic and parasympathetic nervous systems. ENS integrates autonomic input with localized reflexes so as to synchronize propulsive contractions of gut muscle (peristalsis) and regulate glandular secretion. Parasympathetic stimulation activates the ENS, whereas sympathetic stimulation inhibits the ENS. Unlike the sympathetic and parasympathetic systems, the ENS can function independently of the CNS after autonomic denervation. Pharmacology I - Dr. Rana Alaaeddine 7  ANS Anatomy 1. Sympathetic Nervous System (SNS): Arise from the thoracic and lumbar spinal cord 2. Parasympathetic Nervous System (PNS): Includes portions of cranial nerves III, VII, IX, and X (the oculomotor, facial, glossopharyngeal, and vagus nerves, respectively), as well as some nerves originating from the sacral spinal cord: craniosacral distribution Vagus nerve (X) is the most important Pharmacology I - Dr. Rana Alaaeddine 8  Ganglia Efferent path consists of a two-neuron chain with a synapse interposed between the central nervous system (CNS) and the effector cells Function of the ganglia is to transfer (and sometimes modify) the signals from the presynaptic neuron to the postsynaptic neuron Pharmacology I - Dr. Rana Alaaeddine 9  Ganglia 1. Sympathetic Nervous System (SNS): Have a short preganglionic fiber and a long postganglionic fiber. Preganglionic is a sympathetic neuron synapse with a large number of postganglionic neurons → widespread activation of the organs during sympathetic stimulation. 2. Parasympathetic Nervous System (PNS): The parasympathetic nerves have long preganglionic fibers and short postganglionic fibers, with the ganglia often located in the innervated organs. Low ratio of postganglionic fibers to preganglionic fibers in the parasympathetic system → More controlled regulation Pharmacology I - Dr. Rana Alaaeddine 10  Neurotransmitters Primary neurotransmitters: 1. Acetylcholine (cholinergic receptors) 2. Norepinephrine/noradrenaline (adrenergic receptors) Pharmacology I - Dr. Rana Alaaeddine 11  Neurotransmitters 1. Norepinephrine: Sympathetic postganglionic neuroeffector junctions 2. Acetylcholine: Parasympathetic neuroeffector junctions Autonomic Ganglia Somatic neuromuscular junctions (motor neuron) Sympathetic innervation of the adrenal gland (adrenal gland functions as a special form of ganglion that secretes epinephrine directly into the bloodstream) Sweat glands: sympathetically innervated, but the postsynaptic nerve releases ACh instead of NE Pharmacology I - Dr. Rana Alaaeddine 12 Comparative features of nerves of the autonomic nervous system. Pharmacology I - Dr. Rana Alaaeddine 13  Cholinergic Receptors Muscarinic (M) receptors: On organs that receive parasympathetic innervations. Subtypes include M1,M2,M3,M4,M5. Nicotinic (N) receptors: Muscle type (Nm), found in the vertebrate skeletal muscle, where they mediate transmission at the NMJ. Neuronal type (Nn), found mainly at autonomic ganglia and on adrenal glands. Pharmacology I - Dr. Rana Alaaeddine 14  Adrenergic Receptors Alpha (α) receptors Subtypes: α1 (α1A, α1B, α1D) and α2 (α2A, α2B, and α2C) Beta receptors (β) Subtypes: β1, β2, β3 Pharmacology I - Dr. Rana Alaaeddine 15 Pharmacology I - Dr. Rana Alaaeddine 16 Responses of Effector Organs To Autonomic Nerve Impulses Pharmacology I - Dr. Rana Alaaeddine 18 Pharmacology I - Dr. Rana Alaaeddine 19 Pharmacology I - Dr. Rana Alaaeddine 20 Pharmacology I - Dr. Rana Alaaeddine 21 Pharmacology I - Dr. Rana Alaaeddine 22 Pharmacology I - Dr. Rana Alaaeddine 23  Cholinergic Neurotransmission Synthesis The availability of choline is critical to the synthesis of ACh. Uptake of choline into presynaptic nerve terminal via a sodium-dependent choline transporter (CHT) (inhibited by hemicholinium) Choline acetyl transferase catalyzes the synthesis of ACh from choline and the acetyl moiety of acetyl CoA Pharmacology I - Dr. Rana Alaaeddine 24  Cholinergic Neurotransmission Storage ACh is transported into the storage vesicle by vesicular ACh transporter (VAChT) (inhibited by vesamicol). Driven by proton efflux Using the potential energy of a proton electrochemical gradient Co-transmitters (ATP and peptides) are also present Pharmacology I - Dr. Rana Alaaeddine 25  Cholinergic Neurotransmission Release Release of ACh and any co-transmitters occurs via exocytosis triggered by calcium entry via a voltage-sensitive calcium channel in response to membrane depolarization Fusion of the vesicular membrane with the plasma membrane, allowing exocytosis to occur Pharmacology I - Dr. Rana Alaaeddine 26  Cholinergic Neurotransmission Release Botulinum toxin blocks ACh release by interfering with the machinery of transmitter release. The active fragments of botulinum toxins are endopeptidases → cleaving a specific site on fusion proteins. Pharmacology I - Dr. Rana Alaaeddine 27  Cholinergic Neurotransmission Pharmacology I - Dr. Rana Alaaeddine 28  Cholinergic Neurotransmission Termination of action ACh molecules bind to and activate cholinergic receptors. Immediate hydrolysis of ACh by acetylcholine esterase (AChE) reduces lateral diffusion of the transmitter → rapid control of responses AChE is found in cholinergic neurons and is highly concentrated at the postsynaptic end plate of the NMJ. The time required for hydrolysis of ACh at the NMJ is less than a millisecond. Pharmacology I - Dr. Rana Alaaeddine 29  Cholinergic Neurotransmission Remarks Drugs that block the synthesis of acetylcholine (e.g., hemicholinium), its storage (e.g., vesamicol), or its release (e.g., botulinum toxin) are not very useful for systemic therapy their effects are not sufficiently selective (ie, PANS and SANS ganglia and somatic neuromuscular junctions all may be blocked) Botulinum toxin is a very large molecule and diffuses very slowly, it can be used by injection for relatively selective local effects Pharmacology I - Dr. Rana Alaaeddine 30 Adrenergic Neurotransmission Synthesis Catecholamines: Norepinephrine: sympathetic postganglionic fibers Epinephrine: major hormone of the adrenal medulla Dopamine: CNS Common precursor amino acid: Tyrosine Synthesis terminates where needed Tyrosine is transported into the noradrenergic ending or varicosity by a sodium-dependent carrier. Pharmacology I - Dr. Rana Alaaeddine 31  Adrenergic Neurotransmission Storage The vesicular monoamine transporter (VMAT) 2, a vesicular membrane protein, moves catecholamines from the cytosol into neuronal storage vesicles. VMAT can be blocked by reserpine (irreversible agent). Pharmacology I - Dr. Rana Alaaeddine 32  Adrenergic Neurotransmission Pharmacology I - Dr. Rana Alaaeddine 33  Adrenergic Neurotransmission Release Release of the vesicular transmitter store from noradrenergic nerve endings is similar to the calcium-dependent process for cholinergic terminals Following its release from a sympathetic nerve varicosity, NE interacts with receptors. Adrenergic fibers can sustain the output of NE during prolonged periods of stimulation without exhausting their supply. Pharmacology I - Dr. Rana Alaaeddine 34  Adrenergic Neurotransmission Termination of Action The actions of catecholamines are terminated by reuptake into the nerve (NE transporter/NET) and postjunctional cells (Extraneuronal transporter/ENT) and to a smaller extent by diffusion out of the synaptic cleft. NET can be blocked by cocaine and tricyclic antidepressants Regulatory receptors are present on the presynaptic terminal. Following uptake, catecholamines can be metabolized (in neuronal and nonneuronal cells) or re-stored in vesicles (in neurons). Metabolism of Catecholamines: 1. Mono-amine oxidase/MAO: Sympathetic nerves, adrenal medulla 2. Catechol-O-methyltransferase/COMT: adrenal medulla, liver Pharmacology I - Dr. Rana Alaaeddine 35  Adrenergic Neurotransmission Applications Indirectly acting and mixed Sympathomimetics, eg, tyramine, amphetamines, and ephedrine, are capable of releasing stored transmitter from noradrenergic nerve endings by a calcium-independent process. Poor agonists (some are inactive) at adrenoceptor They are excellent substrates for monoamine transporters As a result, they are avidly taken up into noradrenergic nerve endings In the nerve ending, they are then transported by VMAT into the vesicles, displacing norepinephrine, which is subsequently expelled into the synaptic space by reverse transport. Their action does not require vesicle exocytosis. Amphetamines also inhibit monoamine oxidase and have other effects that result in increased norepinephrine activity in the synapse. Pharmacology I - Dr. Rana Alaaeddine 36