PHARM Central and Peripheral Nervous Systems Michael Haines, MPH, RRT-NPS, AE-C

The Nervous System Two major control systems ▫Nervous system (hormones used to transmit signals) ▫Endocrine system (Chapter 11) (secretion of hormones) Both systems can be manipulated by drug therapy which either mimics or blocks the usual action of the control system (That’s all pharmacology is! We either mimic or block a natural hormone response)

The Nervous System Central nervous system ▫Brain ▫Spinal cord Peripheral nervous system ▫Sensory neurons ▫Somatic neurons ▫Autonomic neurons * Do not control  Parasympathetic branch (Acetylcholine receptors/ rest and digest reactions)  Sympathetic branch (Epinephrine receptors/fight or flight reactions)

Central and Peripheral Nervous System Figure 5-1 ​ Functional diagram of central and peripheral nervous systems, indicating the somatic branches (sensory, motor) and the autonomic branches (sympathetic, parasympathetic), with their neurotransmitters. Ach, Acetylcholine; NE, norepinephrine. afferent somatic :heat, light, pressure, pain :voluntary muscle control Autonomic nervous system: involuntary control

Autonomic Nervous System neurons synapse craniosacral thoracolumbar

Autonomic Nervous System Parasympathetic Stimulation ▫Good specificity because postganglionic fibers arise near the effector site. Sympathetic Stimulation ▫Because fibers innervate the adrenal medulla  when sympathetic activation occurs  there is a release of epinephrine into the bloodstream ▫causing a widespread reaction in the body.

Parasympathetic and Sympathetic Regulation Parasympathetic Nervous System ▫Essential to life ▫Finely regulated (good specificity) ▫Controls digestion, bladder, and rectal function Sympathetic Nervous System ▫General alarm system  “Fight or flight” response ▫Not essential to life ▫Increases HR and BP and causes blood flow to shift from the periphery to the core

Neutotransmitters Nerve impulses are transmitted by electrical and chemical means (neurotransmitters) Acetylcholine ▫Neuromuscular junction ▫Ganglia ▫Parasympathetic end sites ▫Sweat glands ▫Adrenal medulla Norepinephrine ▫Sympathetic end sites Everywhere, except

Neurotransmission Neuron: basic cell of the nervous system, provide instant method of cellular communication Don’t confuse nerve with neuron, nerve is a collection of neuron axon fibers The signals in nerves can run both ways ▫Efferent (out) ▫Afferent (in)

Neurotransmission Hormones such as epinephrine and AcH are stored in packets in the neuron; action potential causes these stored transmitters to release into organs, muscles… AcH: made by mitochondria as part of energy transfer (Kreb cycle) along with lecithin that contains choline. AcH is in the neuromuscular junction. Voluntary muscle movement, stimulated at nicotinic receptors to cause muscle contraction

Efferent and Afferent Nerve Fibers Efferent: signals that are transmitted from the brain and spinal cord ▫Autonomic Nervous System Afferent: signals that are transmitted to the brain and spinal cord ▫Chapter 7: drugs used to block parasympathetic impulses

Example of Neurotransmission Error Myasthenia Gravis antibodies block the nicotinic receptors in the neuromuscular junction from getting AcH. AcH is also used by the autonomic nervous system in the control of Parasympathetic smooth muscle movement (lungs, heart). The receptor here is called muscarinic

Neurotransmission AcH also found in the CNS, and affect brain and spinal cord transmissions. Catecholamines (Dopamine, norepinephrine, epinephrine): Made from the amino acid tyrosine. Located in the autonomic nervous system signals sympathetic smooth muscle movement and organ is epinephrine and norepinephrine. The receptors are alpha and beta

Neurotransmission AcH esterase breaks down AcH in the synapse. (cholinesterase) So, if we block AcH esterase, we end up with more AcH in the synapse MG patients are on cholinesterase inhibitors

Terminology Sympathomimetic = Adrenergic Sympatholytic = Antiadrenergic Parasympathomimetic = Cholinergic Parasympatholytic = Anticholinergic

Parasympathetic Branch Cholinergic Neurotransmitter Function Ach is synthesized from Catalyzed by Ach is concentrate in the presynaptic neuron Nerve Impulse Calcium triggers the secretion of Ach Ach attaches to receptors on the postsynaptic membrane and initiates an effect in the tissue or organ site Inactivates Ach through hydrolysis

Parasympathetic Branch Parasympathetic effects on the cardiopulmonary system: ▫Heart: slows rate (vagus) ▫Bronchial smooth muscle: constriction ▫Exocrine glands: increased secretion Drugs can be used to block or mimic action ▫Parasympatholytics ▫Parasympathomimetics

Parasympathetic Branch Muscarinic Effects ▫Musacrine stimulates Ach receptors at the parasympathetic terminal sites:  Exocrine glands: lacrimal, salivary, bronchial mucous glands  Cardiac muscle  Smooth muscle: gastrointestinal tract ▫Increase in airway secretions after the administration of Ach-like drugs

Parasympathetic Branch Subtypes of Muscarinic Receptors

Parasympathetic Branch Nicotinic Effects ▫Nicotine stimulates Ach receptors at:  Autonomic ganglia  Skeletal muscle sites ▫Effects:  Increase in blood pressure  Muscle tremor

Cholinergic Agents Cholinergic drugs mimic the action caused by Ach at the receptor sites in the parasympathetic system and neuromuscular junction A cholinergic drug can also activate muscarinic and nicotinic rceptors ▫Direct-Acting Cholinergic Agents ▫Indirect-Acting Cholinergic Agents

Cholinergic Agents Direct acting ▫Mimic acetylcholine  Methacholine – diagnostic, asthma Indirect acting ▫Inhibit cholinesterase enzyme  Neostigmine – reversal of nondepolarizing muscle relaxants  Tensilon – diagnostic, MG

Anticholinergic Agents Block acetylcholine receptors ▫Parasympatholytic (antimuscarinic) effects  Bronchodilation  Preoperative drying of secretions  Antidiarrheal agent  Prevention of bed-wetting in children (increase in urinary retention)  Treatment of peptic ulcer  Treatment of organophosphate poisoning  Treatment of mushroom (Amanita muscaria) ingestion  Treatment of bradycardia

Sympathetic Branch Adrenergic neurotransmitter function Is converted t0… NE is stored in the presynaptic neuron Nerve impulse Calcium triggers the secretion of NE NEattaches to receptors on the postsynaptic membrane and initiates an effect in the tissue or organ site 3 ways of inactivating NE

Sympathetic Branch Enzyme Inactivation ▫Catecholamines: chemicals structurally related to epinephrine ▫Two enzymes inactivate catecholamines:  catechol O-methyltransferase (COMT)  Monoamine oxidase (MAO) ▫Chapter 6

Sympathetic Branch Sympathetic effects on the cardiopulmonary system: ▫Increased heart rate and contractile force ▫Increased BP ▫Bronchodilation Drugs can be used to block or mimic action ▫Sympatholytics (antiadrenergic) ▫Sympathomimetics (antiadrenergic)

Sympathetic Branch Sympathetic (Adrenergic) Receptor Types

Sympathetic Branch α and β Receptors ▫α receptors: Vasoconstriction ▫β 1 receptors: Increase the rate and force of cardiac contraction ▫β 2 receptors: Relax bronchial smooth muscle  Chapter 6

Dopaminergic Receptors Because dopamine is chemically similar to epinephrine and stimulates α and β receptors, dopaminergic receptors are classified as a type of adrenergic receptor.

Receptors Adrenergics: ▫Beta 1 (heart, when stimulated cause contraction, increased HR)--- Isoperternal, Epinephrine ▫Beta 2 (lungs, when stimulated cause dilation)----Albuterol/Xopenex ▫Alpha 1 (blood vessels/brain/kidney, when stimulated cause vessel constriction)—Racemic Epinephrine ▫Alpha 2 (Sphincters, GI tract, inhibits insulin release; stimulation causes constriction) Stimulated by neurotransmitter Epinephrine/ norepinephrine *Stimulation of a receptor= agonist *Blocking of a receptor = antagonist

Receptors Cholinergic: ▫Nicotinic (found in the CNS and the peripheral nervous system. The neuromuscular receptors are found in the neuromuscular junctions of somatic muscles; stimulation of these receptors causes muscular contraction) Blocked with Nicotinic acetylcholine receptors can be blocked by curare; used for anesthesia and mechainical ventilation ▫Muscarinic (found primarily in lung; G-protein-coupled receptors that activate other ionic channels via a second messenger cascade. sub types; M1-M5) ▫responds to the binding neurotransmitter acetylcholine

Airway Receptors Adrenergic receptors ▫Also known as sympathetic and sympathomimetic receptors ▫Sympatholytics = block response ▫Stimulated by epinephrine or norepinephrine ▫Antiadrenergic drugs block receptors for norepinephrine or epinephrine (usually to slow the heart rate or decrease blood pressure)

Airway Receptors Cholinergic receptors ▫Also known as parasympathetic or parasympathomimetic receptors ▫Stimulated by acetylcholine ▫Blocked by ant-cholingergics ▫In airway anti-musacarinic (anti-cholinergic) = bronchodilation ▫Anti-nicotinics= neuromuscular paralysis

ACh Airway smooth-muscle cells are innervated by postganglionic parasympathetic nerves. Acetylcholine (ACh) release from these nerves triggers the contraction of airway smooth muscles. This activity is predominantly mediated by smooth-muscle M 3 receptors, but activation of postsynaptic M 2 receptors is also likely to contribute to this response / ACh also leads to the activation of pre-junctional M 2 muscarinic Ach receptor (mAChR) autoreceptors, which mediate the inhibition of ACh release M2 receptive for cholinersterase (we block all M receptors, so also the “good” M2)

Adrenergic Receptors The adrenergic receptors which subserve the responses of the sympathetic nervous system have been divided into two discrete subtypes: alpha adrenergic receptors (alpha receptors) and beta adrenergic receptors (beta receptors).

Adrenergic Receptors The mechanism of adrenergic receptors. Adrenaline or noradrenaline are receptor ligands to either α 1, α 2 or β-adrenergic receptors. Blood vessels: α 1 couples to G q, which results in increased intracellular Ca 2+ which results in smooth muscle contraction. α 2, on the other hand, couples to G i, which causes a decrease of cAMP activity, resulting in e.g. smooth muscle contraction. Heart/Lung: β receptors couple to G s, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.

Beta Receptors Beta Receptors Beta receptors have been further subdivided into beta 1 and beta 2 receptors. beta 3 and beta 4 receptors have recently been isolated, cloned and characterized. The beta 3 receptor may be involved in regulating the metabolism of fatty acids. This receptor could be the site of antiobesity drugs in the future. The functions of the beta 4 receptor remain to be discovered. The classification of beta receptors is based on the interaction of a series of drugs with these receptors.

Beta Receptors Beta Receptor Systems Most tissues express multiple receptors. However, the receptor mainly utilized by the sympathetic nervous system to affect myocardial function in the normal heart is the beta 1 receptor; while in vascular and nonvascular smooth muscle it is the beta 2 receptor.