Sympathetic Nervous System PDF

Sympathetic nervous system Gillian Lewis & Dr Jane Jackson Where opportunity creates success Autonomic nervous system Fight or Flight response  Structure of the sympathetic nervous system SNS nerves originate in the thoracic and lumbar spinal cord (T1 to T12 and L1 to L3) DON’T TR...

Sympathetic nervous system Gillian Lewis & Dr Jane Jackson Where opportunity creates success Autonomic nervous system Fight or Flight response  Structure of the sympathetic nervous system SNS nerves originate in the thoracic and lumbar spinal cord (T1 to T12 and L1 to L3) DON’T TRAVEL DIRECTLY to the organs→ SYMPATHETIC GANGLIA 1. Para-ventral ganglia (sympathetic chain) 2. Prevertebral ganglia – celiac, superior mesenteric, and inferior mesenteric Sympathetic ganglia Located near the spinal cord (paravertebral ganglia and the prevertebral ganglia 1. Superior cervical ganglion→ eyes and the salivary glands 2. Celiac ganglion → stomach and the small intestine 3. Superior mesenteric ganglion → small and large intestine 4. Inferior mesenteric ganglion → lower large intestine, anus, bladder, and genitalia. Receptors and Neurotransmitters of SNS ADRENAL MEDULLA Thoracic spinal cord→ splanchnic nerve→ adrenal medulla → chromaffin cells Preganglionic neurons → cholinergic – Release Ach – Bind to Nicotinic receptors Activation of Nicotinic receptors – Release of adrenaline and noradrenaline – Circulatory system  Co-transmitters in the SNS Sympathetic postganglionic adrenergic nerves CN and non-CN – Small dense-core vesicle→ NA and ATP – Large dense-core vesicle→ Neuropeptide Y NA and ATP act together and for more intensity, release of NPY  Brain control of ANS HYPOTHALAMUS MIDBRAIN PONS MEDULLA  Classification Receptor Target Tissue Mechanism of Action Adrenoreceptors 2+ α1 Vascular smooth muscle, skin, renal, and IP 3 , ↑ intracellular [Ca ] G PROTEIN receptors splanchnic Gastrointestinal tract, sphincters 1. Extracellular domain→ NT’s Bladder, sphincter Radial muscle, iris binding α2 Gastrointestinal tract, wall Inhibition of adenylyl cyclase, ↓ cAMP 2. Intracellular domain→ G protein Presynaptic adrenergic neurons (α, β, and γ) β1 Heart Stimulation of adenylyl cyclase, ↑ cAMP 3. α subunit + GDP→ inactive Salivary glands Adipose tissue 4. α subunit + GTP→ active Kidney 5. Second messenger cAMP or IP 3 β2 Vascular smooth muscle of skeletal muscle Stimulation of adenylyl cyclase, ↑ cAMP or alters function ion channel Gastrointestinal tract, wall Bladder, wall Bronchioles Cholinoreceptors + + Nicotinic Skeletal muscle, motor end plate (N M ) Opening Na and K channels → Postganglionic neurons, SNS and PNS (N N ) depolarization Adrenal medulla (N N ) 2+ Muscarinic All effector organs, PNS IP 3 , ↑ intracellular [Ca ] (M 1 , M 3 , M 5 ) Sweat glands, SNS ↓ adenylyl cyclase, ↓ cAMP (M 2 , M 4 ) A bit of Pharma… Physiologic response – Neurotransmitters – Type of receptor – Mechanism of action – Tissue and cell specific Pharmacological effect – Drug (agonist, antagonist and many other variants) – Type of receptor – NO tissue or cell specific (side effects of the drug)  Adrenoreceptors Noradrenaline and adrenaline Receptors found in target organs TWO TYPES of adrenoreceptors 1. Alpha receptors - α1 - α2 2. Beta receptors - β1 - β2 - β3 α1 Adrenoreceptors Location Mechanism of Action - vascular smooth muscle of the skin 1. Inactive→ α q subunit is bound to GDP - skeletal muscle 2. Noradrenaline binds to the receptor→ - sphincters of the gastrointestinal tract and ACTIVATION bladder - α subunit binds to GTP - radial muscle of the iris - α subunit detaches from the rest of the G protein EFFECT after activation→ contraction 3. α-GTP complex migrates and binds to and activates phospholipase C 4. Activated phospholipase C → diacylglycerol and IP 3 5. IP 3 generated→ release of Ca 2+ 6. Ca 2+ and diacylglycerol→ protein kinase C α1 Adrenoreceptors Location Mechanism of Action - vascular smooth muscle of the skin 1. Inactive→ α q subunit is bound to GDP - skeletal muscle 2. Noradrenaline binds to the receptor→ - sphincters of the gastrointestinal tract and ACTIVATION bladder - α subunit binds to GTP - radial muscle of the iris - α subunit detaches from the rest of the G protein EFFECT after activation→ contraction 3. α-GTP complex migrates and binds to and activates phospholipase C 4. Activated phospholipase C → diacylglycerol and IP 3 5. IP 3 generated→ release of Ca 2+ 6. Ca 2+ and diacylglycerol→ protein kinase C α2 Adrenoreceptors Location – presynaptically and postsynaptically in neurons – Gastrointestinal tract EFFECT after activation→ Inhibitory Hetero and autoreceptors – SNS→ autoreceptors – PNS→ heteroreceptor Mechanism of action 1. Noradrenaline binds to the α 2 receptor→ ACTIVATION 2. G protein binds GTP, and the α subunit dissociates from the G protein complex. 3. Inhibits adenylyl cyclase β1 receptors Location – Heart→ heart rate contractibility – salivary glands→ secretion – adipose tissue – kidney → renin secretion Mechanism of action 1. NA binds to the receptor→ ACTIVATION - α subunit binds to GTP - α subunit detaches from the rest of the G protein 2. α-GTP complex migrates and binds to and adenylyl cyclase 3. Activated adenylyl cyclase → conversion of ATP to cAMP β2 receptors Location – vascular smooth muscle of skeletal muscle – walls of the gastrointestinal tract and bladder, and in the bronchioles Mechanism of action – Same than for β1 receptors  Cholinoreceptors Acetylcholine Location in SNS→ postganglionic and chromaffin cells TWO TYPES of cholinoreceptors 1. Nicotinic receptors 2. Muscarinic receptors Nicotinic receptors LOCATION – postganglionic neurons – chromaffin cells of the adrenal medulla – Ion channel MECHANISM OF ACTION 1. Ach detached→ inactive 2. Ach binds to the receptor→ ACTIVATION 3. Channels opens→ Na + and K + flow down electrochemical gradients 4. Membrane potential → depolarisation Muscarinic receptors (M3) Location – SNS→ sweat glands Mechanism of action 1. Inactive→ α q subunit is bound to GDP 2. Acetylcholine binds to the receptor→ ACTIVATION - α subunit binds to GTP - α subunit detaches from the rest of the G protein 3. α-GTP complex migrates and binds to and activates phospholipase C 4. Activated phospholipase C → diacylglycerol and IP 3 5. IP 3 generated→ release of Ca 2+ 6. Ca 2+ and diacylglycerol→ protein kinase C 1.4. Indirect-Acting Adrenoceptor Agonists Mechanism of action amphetamine-like or “displacers” inhibit the reuptake of released transmitter 1. Amphetamine – Release of DA and NA – use and misuse as a CNS stimulant→ stimulant effect on mood and alertness and a depressant effect on appetite 2. Cocaine – Blocks the DAT→ inhibiting reuptake of DA – Can be used as a local anaesthetic (Numbrino and Gopeltro)  Clinical applications of adrenoreceptor agonists 1. Cardiovascular Applications Acute hypotension – doesn’t require direct treatment – Shock→ agonists with both α and β activity→ sustained hypotension with evidence of tissue hypoperfusion – Noradrenaline Chronic Orthostatic Hypotension – Impairment of autonomic reflexes that regulate blood pressure – Midodrine→ α1 agonist Cardiac Applications – Cardiac arrest→ epinephrine Inducing local vasoconstriction – Haemostasis for surgery – Epinephrine and cocaine – Combination of α agonists with some local anesthetics 2. Pulmonary applications Asthma and chronic obstructive pulmonary disease (COPD) – β2 agonist (albuterol, metaproterenol, terbutaline) – Chronic asthma treatment → long-lasting β2 agonists (Indacaterol, olodaterol, and vilanterol) only in combination with steroids – COPD→ long-lasting β2 agonists 3. Anaphylaxis – Syndrome→ bronchospasm, mucous membrane congestion, angioedema, and severe hypotension – Epinephrine 4. Ophthalmic Applications – Examination of the retina→ Phenylephrine – Glaucoma→ α2-selective agonists (apraclonidine and brimonidine) and β- blocking agents (timolol and others) 5. Genitourinary Applications – suppress premature labour→ β2-selective agents (terbutaline) – overactive bladder→ selective β3 agonist (mirabegron) 6. Central Nervous System Applications – Narcolepsy→ amphetamines (Modafinil and armodafinil) – ADHD→ amphetamine substitute (methylphenidate), α2 agonists (clonidine and guanfacine) Clinical applications of alpha-receptor antagonists 1. Pheochromocytoma – tumor of the adrenal medulla or sympathetic ganglion cells – catecholamine excess, including intermittent or sustained hypertension, headaches, palpitations, and increased sweating 2. Hypertensive Emergencies 3. Chronic Hypertension 4. Urinary Obstruction 2.2. Beta-receptor antagonists drugs 1. Propranolol – Non selective β-blocking drug 2. Metoprolol, atenolol – β1-selective drugs – used with great caution in asthma patients – selected patients with COPD – diabetes or peripheral vascular disease when therapy with a β blocker is required 3. Levobunolol (nonselective) and betaxolol (β1-selective) – ophthalmic application in glaucoma Clinical applications 1. Hypertension – β-adrenoceptor antagonists→ no first choice of antihypertensive medications – Indicated in hypertension in special populations in whom “cardioprotection” is desirable 2. Ischemic Heart Disease – chronic stable angina→ decreased cardiac work, slowing and regularization of the heart rate, and reduction in oxygen demand – Metoprolol→ reduce infarct size and acute mortality when given early during acute myocardial infarction 3. Glaucoma – Timolol and related drugs – reduce intraocular pressure in patients – Betaxolol, carteolol, levobunolol, and metipranolol are also approved 4. Hyperthyroidism – Propranolol – reduce palpitations, tachycardia, tremulousness, and anxiety 5. Neurologic Diseases – Migraine→ Propranolol, metoprolol, and timolol→ reduce the frequency and intensity CNS control of the ANS Reflex mechanisms controlling blood pressure Both sympathetic and parasympathetic innervations SA node is the normal pacemaker of the heart → rate of depolarisation determines the heart rate Brain stem→ vasomotor centers 1. Blood pressure→ SNS / PNS 2. Blood pressure→ SNS/ PNS  Reflex mechanisms controlling micturition Voluntary control 1. Bladder filling- Sympathetic control- - Adrenergic receptors - Contraction 2. Bladder emptying – Parasympathetic control- - Muscarinic receptors - Relaxation Reflex mechanisms controlling pupillary diameter Size of the pupil 1. pupillary dilator muscle – Sympathetic innervation – α 1 receptors – constriction of the muscle→ causes dilation of the pupil 2. pupillary constrictor muscle – parasympathetic innervation – muscarinic receptors – constriction of the sphincter muscle→ causes constriction of the pupil