intro autonomics + somatic + cholin adrenergic.pdf

Introduction to Autonomic Pharmacology and Somatic Pharmacology  Intro:  PNS: Two divisions ANS, sensory, somatic, ENS  Wiring and receptor locations  Reflexes  Principles of cholinergic and adrenergic transmission  Physiological responses T...

Introduction to Autonomic Pharmacology and Somatic Pharmacology  Intro:  PNS: Two divisions ANS, sensory, somatic, ENS  Wiring and receptor locations  Reflexes  Principles of cholinergic and adrenergic transmission  Physiological responses Think about the reasons we have them  Examples of cholinergic/adrenergic agonists and antagonists  Endocrine vs. Nervous  Endocrine system: slower, adaptations  Chemical transmitters (hormones) are released into the circulation where they find and bind to receptors on the effector tissues.  Nervous system: rapid  Chemical transmitters (Neurotransmitters) at Synapses  Neurons—Neurons---tissue:  Neurotransmitters are released from presynaptic neuron terminals where they diffuse across the synaptic cleft and bind to receptors on the postsynaptic cell either activating or inhibiting the activity of that cell.  Drugs that mimic or block the effects of transmitters can modify function throughout the body.  Nervous system  Central nervous system  Brain and spinal cord  Nervous system  Central nervous system  Brain and spinal cord  Peripheral nervous system  Everything else Efferent (motor) out to tissue  Autonomic and Somatic Afferent (sensory) in to CNS  Reflex arcs  Nervous system Central Nervous system Peripheral nervous system  Nervous system Central Nervous system Peripheral nervous system Somatic Autonomic  Somatic nervous system  Consciously controlled functions  Movement  Respiration  Posture  Cell bodies within the cerebrospinal axis result in spinal efferent nerves  In the periphery it consists of  Nerves (myelinated)  No ganglia with peripheral synapses occurring on skeletal muscle  Neuromuscular junction  Paralysis and atrophy after transection Motor neuron  Drugs can modify function at the NMJ  Neuromuscular junction Feng et al. Neuron 2000 Innervated muscle fibers. Nerve bundles visualized with yellow fluorescent protein. Postsynaptic nicotinic acetylcholine receptors are visualized with alpha-bungarotoxin.  Nervous system Central Nervous system Peripheral nervous system Somatic Autonomic NMJs on muscle Voluntary movement  Nervous system Central Nervous system Peripheral nervous system Somatic Autonomic NMJs on muscle Voluntary movement  Autonomic nervous system  Regulates autonomic functions without direct conscious control  Cardiac Muscle: Heart  Exocrine Glands: saliva  Smooth muscle: vessels, intestine  Nerves and endothelium  Autonomic nervous system  In the periphery it consists of two neurons  Spinal efferents form synapses in peripheral ganglia  Ganglia Preganglionic nerves Postganglionic nerves (generally non-myelinated) Plexuses (complex networks of synapses) Presynaptic vs preganglionic  Some spontaneous activity independent of intact innervation  2 efferent neurons pre and post ganglionic  Preganglionic: all are cholinergic (bind to neuronal nicotinic rcptrs Nn)  Postganglionic: Cholinergic or Adrenergic (bind muscarinic or adrenergic)  Sensory Neurons  Sensory afferents  Both the Somatic and Autonomic receive input  Cell bodies are in ganglia  Dendrites to tissue Feng et al. Neuron 2000  Axons to CNS CNS inputs from viscera  Respiratory control in the medulla oblongata  Hypothalamus and STN are also loci of integration reflex arcs  Nervous system Central Nervous system Peripheral nervous system Somatic Autonomic Sympathetic Parasympathetic 2 anatomic divisions  The Peripheral Nervous System Parasympathetic “Craniosacral” Efferents arise from either Cranial nerves (III, VII, IX, or X) or the sacral spinal roots Sacral spinal likely Sympathetic not Parasympathetic So nomenclature may change to “Cranial autonomic”  Sympathetic “Thoracolumbar” Nerves exit the CNS through the thoracic and lumbar nerves  Two neuron systems. Preganglionic + Postganglionic  Two neuron systems. Sympathetic: 1. Short preganglionic neurons 2. Highly connected ganglia in paravertebral chain (22 pairs), prevertebral ganglia (celiac, mesenteric etc.) and the terminal ganglia (cervical) 3. Adrenal medulla releases to circulation Rapid full activation  Two neuron systems. Parasympathetic: 1. Ganglia on or near effector tissue 2. Not much interconnectedness. Slow deliberate activation of specific tissues Preganglionic efferents of both divisions synapse in ganglia and all secrete acetylcholine (ACh). Neurons that release ACh are referred to as cholinergic. Basic and Clinical Pharmacology, 9th edition, The McGraw Hill Companies, 2004. Preganglionic efferents synapse in ganglia and all secrete acetylcholine (ACh). Neurons that release ACh are referred to as cholinergic. Somatic nerves are also cholinergic ACh binds to receptors on the postganglionic neuron or muscle fiber called nicotinic acetylcholine receptors. This activates the postganglionic neuron or stimulates the muscle. Nicotinic receptors come in 2 flavors: neuronal or muscle. Postganglionic neurons send axonal projections to the effector tissues. Postganglionic parasympathetic neurons are mostly: Cholinergic ACh binds to muscarinic acetylcholine receptors expressed in the effector tissues. Basic and Clinical Pharmacology, 9th edition, The McGraw Hill Companies, 2004. Postganglionic sympathetic neurons can be: Adrenergic Most; release norepinephrine. Postganglionic sympathetic neurons can be: Adrenergic Most; release norepinephrine. Cholinergic sweat glands Postganglionic sympathetic neurons can be: Adrenergic majority; release norepinephrine. Cholinergic sweat glands Dopaminergic Release dopamine on the kidney  Adrenal medulla The adrenal medulla is a modified sympathetic ganglion. Sympathetic Cholinergic nerves synapse on adrenal chromaffin cells in the adrenal medulla. ACh binds to nicotinic ACh receptors like those found in ganglia Neuronal nAchR  Adrenal medulla The adrenal medulla is a modified sympathetic ganglion. This stimulates adrenal chromaffin cells to release epinephrine (80%) and norepinephrine (20%) into the circulation. This can bind to adrenergic receptors at many locations in the body.  Reflex arcs  Somatic Reflex  Autonomic Reflex Baroreceptors Modify Autonomic output  Drugs can stimulate this response Function of the ANS divisions  Parasympathetic  “Rest and digest”  Sympathetic “fight or flight” response to stress/fear Like being attacked by a lion…or... Function of the ANS divisions  Parasympathetic  Rest and digest  Sympathetic “fight or flight” response to stress/fear Like : Function of the ANS divisions  Parasympathetic  Rest and digest  Sympathetic “fight or flight response” response to stress Function of the ANS divisions  Parasympathetic  Rest and digest  Sympathetic “fight or flight response” response to stress Tone. Always some sympathetic tone normally allows for rapid environmental adjustments but parasympathetic dominates at rest  Sympathetic activation  Continuous tone for quick adjustments  Not absolutely necessary for life  CNS perceives threat activates entire sympathetic system at once and is designed to cope with stressful situations. (exercise, hypoglycemia, trauma etc)  NE in locus coeruleus increases sympathetic outflow  Results in:  Increases blood pressure, heart rate, respiration  Increases blood supply to skeletal muscle, brain, lungs and heart  Decreased blood supply to viscera (GI, kidneys), skin  Decreased peristalsis and contraction of sphincters  Pupil dilation  Bronchiole dilation  Piloerection  Energy: stimulation of glycogenolysis (liver) and lipolysis (adipose)  Sweat production (cholinergic)  Parasympathetic activation  Rest and recovery; Parasympathetic tone dominates at rest  necessary for life  It operates in part not in whole and generally opposite the sympathetic system.  Parasympathetic activation would result in: Lowers blood pressure Lowers heart rate Diverts blood to skin, GI and kidneys Contracts pupils and bronchioles Increases peristalsis Empties bladder and rectum Increases salivary gland secretion  Each division innervates many tissues in the body and regulates the function of that tissue.  The functional output after activation or inhibition of each division of the ANS is dependent on:  innervation of the tissue (both or one division) Dominant tone  receptors present in that tissue.  Muscarinic receptors M1, M2 , M3 M4  Adrenergic receptors α1, α2, β1, β2, β3  Dopaminergic Receptors D1, D2  Drugs can distinguish between receptors and isolate specific responses Receptors in the PNS  Cholinergic Transmission A B C E D  Cholinomimetics  Drugsthat activate or mimic cholinergic transmission  Cholinergic receptor Agonists:  Acetylcholine, Nicotine, Pilocarpine, Varenecline Main uses: Ocular, GI, Genitourinary, smoking cessation  Cholinesterase inhibitors  Neostigmine, Soman, Malathion, Edrophonium Main uses: myasthenia, Dementia, poisons  Cholinergic Agonist Ocular indications  Agonists bind to muscarinic receptors  M3 contracts circular muscle (miosis) and ciliary muscle (accomodation), both IOP (Glaucoma)  Ach: prevent intraoperative s in IOP  Pilocarpine: muscarinic- reduce IOP  Reverse mydriasis (eye exams) Genitourinary and GI  Bethanechol: M rcptrs smooth muscle tone for NON- obstructive GI and Urinary retention.  Other  Methacholine: M3 Respiratory:  assess airway sensitivity in asthma  Pilocarpine, Cevimiline: M3 for Xerostomia Cholinergic toxicity Alexey Navalny D Diarrhea, Diaphoresis U Urination M Miosis B Bradycardia B Bronchoconstriction E Emesis L Lacrimation, Lethargy S Salivation Treat: Decon, Atropine, 2-PAM, BZ, support Cholinergic antagonists  Muscarinic: motion sickness, excessive bradycardia, COPD, incontinence, IBS, Parkinson disease, AChE inhibitor poisoning  Atropine: Too much Vagus, decrease GI spacticity …  Scopolamine (Transderm Scop): motion sickness  Ipratropium (Atrovent): COPD  Benztropine (Cogentin): parkinson symptoms  Oxybutynin (Ditropan): Over active bladder  Tropicamide (Mydriacyl): Mydriasis and Cycloplegia for eye exams.  Many drugs have anticholinergic activity so there is a possibility of polypharmacy contributing to S.E.  BOTOX  Botulinum Toxin  Produced by Clostridium Botulinum  8 serotypes A-G  Very potent 1 ng/kg is lethal dose  Type A used clinically, reconstituted powder Cosmetic, neurology, ophthalmology, ANS dysfunction pain etc. Lasts for 2-3 months, reversible  Adverse effects Diffusion to other unintended sites Ptosis, muscle weakness, respiratory muscle weakness, dysphagia, anaphylaxis Anticholinergic Toxicity Treat by increasing ACh  Adrenergic Transmission B A C D E F H G Sympathomimetics  Drugs that mimic the actions of catecholamines at adrenergic terminals  Agonists (albuterol)  Structural analogs reverse transporters (Tyramine and amphetamine)  Enzyme inhibitors (tranylcypromine)  Uptake inhibitors (cocaine and TCAs) Adrenergic Receptor Function  Alpha Receptors:  α1: Contraction of vascular and genitourinary smooth muscle.  α2: Decrease sympathetic outflow, contraction of vascular smooth muscle; decreased insulin secretion; aggregation of platelets; pre-synaptic inhibition of NE.  Beta Receptors:  β 1: Positive inotropic and chronotropic effects on the heart.  Post synaptic  β2: Relaxes vascular, bronchial, gastrointestinal and genitourinary smooth muscle; stimulates glyconenolysis and gluconeogenesis in the liver. Extrajunctional  β3: Lipolysis in adipose tissue. Bladder relaxation  Direct Adrenergic Agonists  Epinephrine: α1=α2; β 1=β 2  endogenous released from Adrenal medulla so non synaptic activity targets extrasynaptic recptrs Mixed receptor activity: Potent vasoconstrictor (alpha 1), vasodilation (beta 2), cardiac stimulant (beta 1)  Uses: Anaphylaxis (opposes histamine) SubQ to reduce absorption of local anesthetic (a1 mediated vasoconstriction) Cardiac stimulant  Norepinephrine: α1=α2; β 1>>β 2 strong α1, β1  Increases heart rate (Baroreflex reduces), force of contraction and peripheral resistance by α1 vasoconstriction.  Therapeutic use:  Increase BP in acute hypotension (Shock)  Metabolized by COMT and MAO so short  Adrenergic Agonists  Dopamine: D1=D2 >> β >> α as dose increases activates other adrenergic rcptrs β then α  Low doses: Renal, coronary, mesenteric vasculature dilation  GFR, BF and Na+ excretion  Higher doses—β1 activation heart  At even higher doses α1 causes vasoconstriction (vasopressor dose) α1 on heart-arrythmias  Uses  IV only, titrated to effect Infusion rate is correlated to effect due to rapid degradation  Severe congestive heart failure  Approved for all shock but NE might have advantage in Cardiogenic  Adrenergic Agonists  Direct acting Selective  α1 : phenylephrine nasal decongestant, vasopressor, (Neo-synephrine) tachycardia (?)  α2: clonidine (Catapres) hypertension, withdrawal symptoms, pain  β1: Dobutamine (Dobutrex) Selective Cardiac stimulation  β2: Albuterol (Ventolin) Respiratory relaxation  β3: Mirabegron (Myrbetriq) Bladder relaxation  Indirect acting  These agents modify neurotransmitter reuptake at the terminals and increase the amount of neurotransmitter at the synapse.  ADHD Amphetamine/Dextroamphetamine (Adderall) Methylphenidate (Ritalin)  Cocaine blocks reuptake and Na channels Stimulant and local anesthetic but no clinical uses due to abuse  Decongestant:  Psuedoephedrine (Sudafed), ephedrine  Antidepressants + anxiety (5HT3/NE/DA)  Amitryptiline, Venlafaxine (Effexor), Bupropion (Wellbutrin, Zyban)  Adrenergic Antagonists  Alpha blockers: blocks NE induced vasoconstriction  So cause vasodilatation of veins and arteries  Selective alpha blockers Phentolamine (Regitine) α1 and α2: hypertensive crisis Prazocin (Minipres) α1 selective: BPH, hypertension Tamsulosin (Flomax) α1a and α1d: Benign prostatic hyperplasia Yohimbine- α2: no uses (sexual perform???)  Adverse effects: Postural hypotension, nasal stuffiness, tachycardia, miosis  Epinephrine reversal Exercise can potentiate hypotension. Why?  Adrenergic Antagonists  Beta blockers selective and non selective Propranolol-β1 and β2: Atenolol- β1 (Cardioselective):  Clinically β-blockers are widely used for:  Hypertension  Angina pectoris  Arrhythmias  Myocardial infarction  Glaucoma  Migraines  Adverse effects β-Blockers  Cardiac failure If output is dependent on sympathetic tone Extreme caution in CHF or MI Glucagon can reverse  Never withdraw abruptly Upregulated β-receptors so can cause dangerous ventricular arrhythmias, MI, severe hypertension  CNS:  Sedation, sleep disturbances, depression  Respiratory adverse effects:  Worsen bronchospasm in asthma and COPD and are contraindicated β1 selective if absolutely necessary  Diabetes  Diabetics with frequent hypoglycemic attacks β1 selective are preferred.  Sexual dysfunction  Some impaired sexual activity but mechanism is not fully understood (reduced Symp. and β2 block) Libido Impotence Might be psychosomatic “I heard this happens…..”