Lecture on Autonomic Nervous System Pharmacology PDF - Medical Study

AUTONOMIC NERVOUS SYSTEM PHARMACOLOGY JENNIFER Hofmann DMSc.,PA-C, MS  Objectives ◦ a. Describe the basic anatomy and physiology of the ANS; sympathetic and parasympathetic arms ◦ Classify cholinergic and adrenergic receptors and their subtypes. ◦ b...

AUTONOMIC NERVOUS SYSTEM PHARMACOLOGY JENNIFER Hofmann DMSc.,PA-C, MS  Objectives ◦ a. Describe the basic anatomy and physiology of the ANS; sympathetic and parasympathetic arms ◦ Classify cholinergic and adrenergic receptors and their subtypes. ◦ b. Distinguish between muscarinic and nicotinic cholinergic effects. ◦ c. Describe the mechanism of action, pharmacologic effects, adverse effects and therapeutic uses of representative cholinergic agonists and antagonists. ◦ d. Discuss the pharmacologic properties and toxicological actions of the reversible and irreversible cholinesterase inhibitors. ◦ e. Discuss the mechanisms of action, pharmacologic effects and therapeutic uses of neuromuscular blockers and ganglionic blocking agents. ◦ f. Differentiate the subclassification of adrenergic receptors and explain the effects of blocking or stimulating these receptors. ◦ g. Explain the mechanism of action, pharmacologic effects and therapeutic uses of selective and nonselective adrenergic agonists and antagonists. ◦ h. List the commonly used adrenergic agonists and antagonists and describe their therapeutic applications and adverse effects.  Links to Videos and Flashcards ◦ https://www.youtube.com/watch?v=71pCilo8k4M ◦ https://www.youtube.com/watch?v=0IDgBlCHVsA ◦ https://www.youtube.com/watch?v=qqU-VjqjczE ◦ Links to Flashcards (please review) ◦ https://quizlet.com/jhofmannpa1/folders/autonomic-nervous-system-pharm-and-physio- review/sets  Basics of ANS ◦ Overall, the autonomic nervous system is not under voluntary control (direct conscious control) ◦ Maintaining homeostasis cardiac output, blood flow, digestion and other necessary life functions. ◦ Effector tissues and organs / receptors refer to where actions of ANS and its neurotransmitters take place.  Physiology Basics 1. ANS: central part of ANS refers to nuclei in the hypothalamus and nucleus tractus solitarii 2. Receive and integrate information (afferent or sensory arm going toward the CNS) from afferent autonomic nerves such as the vagus and splanchnic nerves. ◦ Types of info: 1.Pain 2.Respiratory reflexes 3.Vasomotor reflexes (peripheral vascular resistance) ◦ baroreceptors in carotid sinus and aortic arch sense changes in mean arterial pressure or MAP decreased pressure  vasomotor center in brain leading to  decreased sympathetic outflow and increase parasympathetic vagal tone to lower heart rate ◦ ( if the MAP is low, sympathetic tone is increased to increase heart rate, increase peripheral vascular resistance 4.Viscerosomatic reflexes (i.e. gastric or colon fullness)  Basics ◦ After integration in the CNS efferent preganglionic autonomic nerve fibers exit from brain stem or spinal cord and terminate in autonomic ganglia where they synapse with postganglionic fibers that carry nerves and neurotransmitters to the effector organs where activity / receptor neurotransmitter interaction occurs  Two Arms of ANS ◦ Sympathetic – preganglionic fibers exit Parasympathetic – preganglionic the spinal cord and terminate in ganglia fibers leave thru cranial nerves located in “paravertebral chains” along the thoracolumbar spinal and sacral nerves and terminate cord [ ] postganglionic fibers sent to in ganglia in or near effector effector organs; more diffuse networks for organs “craniosacral”- the primary a full response in emergency situations neurotransmitter is acetylcholine ◦ Neurotransmitters are Norepinephrine, epinephrine ◦ Receptors: ◦ Muscarinic (M) receptors at end ◦ Alpha receptors organs ◦ Beta receptors  Roles of Each Arm of ANS ◦ Parasympathetic is rest and digest ◦ Sympathetic is fight or flight ◦ Slows heart rate ◦ Heart rate and blood pressure ◦ Pupils are constricted increases ◦ Blood is shunted to skeletal muscles ◦ Empties bowel and bladder ◦ Blood glucose increase ◦ Increases GI motility and secretions ◦ Bronchioles dilate ◦ Promotes absorption of nutrients ◦ Pupils dilate ◦ Erection (Point and Shoot) ◦ Ejaculation  Neurotransmitters Acetylcholine (Ach)[ ] cholinergic Adrenergic transmission: norepinephrine nerve fibers synthesize and (NE) and epinephrine release Ach ◦ ALL autonomic preganglionic fibers and ◦ NE--> synthesized from tyrosine all PARAsympathetic postganglionic fiber dopa (rate limiting step)  s also somatic motor nerves, which dopamine  into innervate skeletal muscle vesicles converted into NE by dopamine beta hydroxylase; ◦ Cholinergic fibers from CNS (presynaptic)- synapse at autonomic ganglia and ◦ release of NE occurs when release Ach which binds to N receptors on Action potential opens Ca++ channels and vesicles fuse to ◦ postganglionic cholinergic nerves  terminal membrane [ ] release Ach released at effector organs which NE that bind to adrenoceptors contain M (MUSCARINIC) receptors and on effector tissues (beta or this mediates parasympathetic activity alpha adrenoceptors)  Receptors (Parasympathetic) Acetylcholine (M receptors) ◦ Muscarinic (M) Receptors (Ach binds to M receptors on each end organ and cause muscarinic effects ◦ Muscarinic receptors are found on the effector organs ◦ M1 found in CNS, and in autonomic ganglia on exiting postganglionic neurons ◦ Depolarization at exiting cholinergic neurons ◦ M2 myocardium, smooth muscle, some presynaptic nerves ◦ Slows heart rate and conduction, slight decrease in contractile force ◦ M3 exocrine glands, blood vessels ◦ Dilates blood vessels (indirect and not a major effect) ◦ Increases secretion of glands in respiratory tract, GI tract, salivation, pancreatic acinar cells secretions ◦ Contracts bladder smooth muscle and relaxes bladder sphincter muscles (urination) ◦ Increases GI tone and motility (digestion and elimination); contracts gallbladder ducts and gallbladder ◦ Miosis via contraction of sphincter muscle in iris causing pupil to constrict; ◦ contracts ciliary muscle and lens shortens for near vision Sympathetic NS- NE, Epi (alpha and beta receptors and effects at organs) ◦ Alpha receptors *Beta receptors ◦ Alpha 1 ◦ Vasoconstriction arteries, veins vascular ◦ Beta 1 found on cardiac tissues (electrical smooth muscle increases BP and muscles) ◦ Contraction of pupil sphincter muscle ◦ Cardiac stimulant, [positive inotropic, (mydriasis, pupil dilates) chronotropic and dromotropic) ◦ Contraction of smooth muscle at bladder ◦ Increase renin release sphincter trigine ◦ Ejaculation ◦ Piloerection and sweaty palms/soles ◦ Beta 2 ◦ Bronchodilation (smooth muscle relaxation) ◦ Uterine relaxation ◦ ALPHA 2 (wild card) INHIBITORY and ◦ Increase blood blood and contractility of inhibits NE release from adrenergic skeletal muscles (large muscles) neurons (shut off switch) ◦ Increase glucose (liver) Drugs Affecting the Parasympathetic NS (Ach and M receptors) ◦ CHOLINOMIMETIC drugs (include DIRECT and INDIRECT acting drugs) ◦ Have acetylcholine like effects (PSYMP) ◦ Direct acting *cholinomimetic (these are muscarinic agonists at M receptors) ◦ Therapeutic muscarinic agonists ◦ Prototype : PILOCARPINE (mostly muscarinic effects) rarely used for glaucoma ◦ Pilocarpine ophthalmic drops recently approved for presbyopia ◦ Bethanechol- used for urinary retention or gastric atony after surgery (post op) tabs or injection ◦ Cevimeline selective for dry mouth sicca conditions ◦ Indirect acting (affect breakdown of Ach by inhibiting the enzyme acetylcholinesterase) increase ACH by blocking / inhibiting Achesterase leading to more ACH in synaptic cleft (NEXT slide)  Indirect acting CHOLINOMIMETIC drugs ◦ MOA: Inhibit Achesterase and increase ACh / cholinomimetic (rest and digest effects) ◦ Drugs: ◦ Short acting- edrophonium was used to diagnose Myasthenia Gravis (MG)onset 45 seconds and lasts minutes ◦ Not available in USA ◦ Longer acting neostigmine used for acute colonic pseudo-obstruction ◦ Pyridostigmine = myasthenia gravis tx ◦ Physostigmine= rarely anticholinergic OD ◦ Alzheimer's meds-oral rivastigmine, galantamine oral and patch, DOnepezil Irreversible acetylcholinesterase inhibitors ◦ Irreversible acetylcholinesterase inhibitors ◦ Toxic – organophosphates, pesticides malathion, parathion (irreversible over time b/c bonds are irreversible and stable over time) ◦ Saran and soman nerve gases ◦ Treatment of poisoning – (moderate to severe cholinergic toxicity) ◦ Atropine and ◦ Pralidoxime, which is an acetylcholinesterase regenerator ◦ (must treat within 36 hours) **ATNAA; Duodote Review Clinical uses of Acetylcholinesterase Inhibitors ◦ ALZHEIMER’s DISEASE ◦ Names of meds: donepezil, galantamine, or rivastigmine ◦ Post op colonic pseudoobstruction  Neostigmine ◦ Myasthenia gravis tx= pyridostigmine) ◦ Physostigmine may occasionally be useful to treat anticholinergic OD  **Atropine REVERSES Effects of CHOLINOMIMETIC drugs cholinergic effects ◦ Overall s/s ◦ SLUDGE/BBB ◦ Neck and proximal Muscle weakness, fasciculations ◦ Salivation, Lacrimation, ◦ Depressed DTRs ◦ Respiratory insufficiency Urination, Defecation, Gastric ◦ GI increased motility, Emesis, Bronchorrhea, secretions >>diarrhea Bronchospasm, Bradycardia ◦ Urinary>> urination ◦ PLUS neuro symptoms  ◦ Eye: miosis ◦ Cardiac bradycardia ◦ Resp: increased secretions and bronchoconstriction EYE AND ANS Ciliary Muscle and Lens is PARAsympathetic Control  Parasympatholytic (PSYMP) Drugs – Class: Antimuscarinic agents ◦ Prevent/blocks the effects of Ach at the muscarinic receptor by blocking M receptors ◦ Atropine and scopolamine are naturally occurring belladonna alkaloids ◦ Atropine used for cycloplegia; symptomatic bradycardia to block vagal stimulation ◦ Scopolamine used for motion sickness prevention (patch lasts 72 hours) ◦ Quaternary (do not cross BBB) ◦ Ipratropium bromide (Atrovent)used as bronchodilator in COPD ◦ Homatropine methylbromide (used for eye procedures to dilate pupil and relax ciliary muscle ◦ Glycopyrrolate ◦ Topical glycopyrronium inhibits sweating through inhibiting the action of acetylcholine on sweat glands. ◦ Glycopyrrolate IM or SC for reducing airway secretions prior to surgery or palliative care  PSYMP Drugs –Anti-muscarinic agents ◦ Tertiary drugs gain access to CNS ◦ Drugs by organ system ◦ EYE ◦ Cyclopentolate eye (drops) ◦ Tropicamide which are used as mydriatics (block M receptors cause mydriasis and cycloplegia) ◦ Neuro/psych : Benzotropine (Cogentin) and trihexyphenidyl (Artane) used to treat EP effects w/ antipsychotics and Parkinson’s disease ◦ GI ◦ Dicyclomine (Bentyl) and hycosamine sulfate (IB stat and Levsin) – antispasmotic in GI tract (for IBS) ◦ GU: urge incontinence meds ◦ Oxybutynin (Ditropan) used to treat URGE type urinary incontinence from overactive detrusor muscles ◦ Tolteridine (Detrol) ◦ Darifenacin ◦ Trospium Effects and Toxicity of Antimuscarinics agents  AE/ Toxic Effects and C/I of Antimuscarinic Agents ◦ Adverse effects of anticholinergics: ◦ Dry mouth, Dry eyes ◦ Constipation ◦ Tachycardia, ◦ Urinary retention esp. in BPH, ◦ Blurred vision, worsening of glaucoma ◦ Sedation and in high doses confusion and delirium ◦ (think about effects of blocking Ach at effector organs) ◦ Avoid IN ◦ GLAUCOMA ◦ GI AND GU OBSTRUCTION!! SYMPATHETIC DRUGS  Terms ◦ Inotropic: affects force and strength of contractions ◦ Chronotropic affects rate ◦ Dromotropic: affects velocity of conduction of impulses ◦ Epinephrine –released from adrenal medulla when stimulated by nicotinic preganglionic fibers (potent alpha and beta agonism more potent beta 2 effects) ◦ Effects include increased systolic BP, increased heart rate, stroke volume, cardiac output, arrhythmias, bronchodilation, increased glucose, hypokalemia ◦ Used for anaphylaxis, cardiac arrest, with local anesthesia ◦ Norepinephrine ( more alpha effects and little beta 2 otherwise similar to epinephrine) ◦ Effectsà increased DBP and SBP, increased peripheral resistance which stimulates baroreceptors à vagal response and slowing of heart rate à no vasodilation unlike epi ◦ Occasionally used to treat shock ◦ Dopamine ◦ Works on vascular DA receptors; Beta one agonist effects and causes positive inotropic effects; ◦ low doses increase renal blood flow, but high doses activate alpha 1 and cause vasoconstriction Adrenergic Agents: Beta agonists ◦ Concept: selective vs nonselective ◦ AGONISTS Act like or mimic effects of NE/Epi at Beta receptors ◦ Beta nonselective agents- isoproterenol ◦ Another Beta agonists: Dobutamine but has other effects including some alpha-1agonist and beta1>> beta-2 agonist effects ◦ Beta 2 agonists (beta 2 selective effect ) ◦ Bronchodilators ◦ Names: ALBUTEROL, levalbuterol, salmeterol, formoterol, indacaterol, vilanterol ◦ Used for asthma and COPD to relax smooth muscle of bronchi ◦ Terbutaline can be used for preterm labor bc it relaxes uterine smooth muscle ◦ Side effects ◦ Tremor, tachycardia, hyper, rarely hypoKALEMIA ◦ Beta- 3 agonists ◦ stimulating B-3 receptors in the bladder detrusor muscle  smooth muscle relaxation to relax bladder ◦ Names: Mirabegron and Vibegron  Beta Antagonists(blockers) ◦ Drugs that act as antagonists at beta receptors, block effects of NE, epi ◦ Nonselective will block beta 1 and beta 2 receptors ◦ Nonselective Beta blockers: ◦ Propanolol (most common) ◦ Timolol (for glaucoma) ◦ Pindolol ISA (intrinsic sympathomimetic activity) ◦ Nadolol (long half life) ◦ These agents block renin release, slow heart rate and decrease contractility; reduce conduction in AV nodes and atria, decrease firing or ectopic pacemakers ◦ CAUTION with BETA blockers and lung disease esp ASTHMA ◦ CANNOT use with heart blocks (in most cases) ◦ Can cause peripheral vasoconstriction ◦ Caution with Type 1 or insulin dependent DM  Class:Beta antagonists ◦ Beta one selective Beta blockers ◦ Metoprolol, Bisoprolol, Atenolol, esmolol ◦ More cardiac effects and less AE ◦ Negative inotropes, negative chronotropic and negative dromotropic effects ◦ AE: Bradycardia, heart block , fatigue, ED, cold extremities but less LUNG effects because these drugs are more CARDIO (beta 1) selective  Beta-blockers ◦ Names: LABETALOL and CARVEDILOL which are nonselective beta blockers AND alpha -1receptor blockers used for HTN and heart failure ◦ Labetalol also used for HTN in pregnancy and HTN emergencies Other Properties of Beta-Antagonists ◦ Membrane stabilizing action (may stabilize Na+ channels like local anesthetics, but not at usual dosages ◦ Intrinsic sympathomimetic activity (ISA) – may have partial agonist effects  low- grade beta stimulation at rest but acting as typical beta blockers when sympathetic activity is high ◦ Pindolol and acebutolol  Beta Blockers- overall ◦ Beta blockers are used for: heart failure, HTN, angina , migraines, stage fright, hyperthyroidism ◦ Beta one selective (heart) beta blockers have less diverse AE Alpha receptor agonists (SYMP) ◦ Alpha one agonists – act as NE /epi at alpha 1 receptors in smooth muscle  vasoconstriction/ smooth muscle contraction ◦ Drugs: phenylephrine (oral and nasal topical spray) used as nasal decongestant ◦ Decreases swelling in inflamed nasal mucosa ◦ Can increase BP if oral or systemic route  Alpha 2 agonists (shut off switch) ◦ Alpha 2 agonist act as alpha 2 receptors cause a decrease in NE output and lower blood pressure (BP)  Alpha 2 agonists ◦ Act as NE at alpha 2 receptors leading to a decrease in NE and lower BP ◦ Drugs: ◦ Clonidine ◦ Guanfacine ◦ Guanabenz ◦ Methyldopa (can be used for HTN in pregnancy) ◦ Effects: Used for treating HTN, ADHD, hot flashes ◦ AE: sedation, dry mouth ◦ MUST TAPER OFF no stopping “cold turkey” or rebound elevation in BP  Alpha one antagonists ◦ USED for: BPH and HTN treatment ◦ Drug names: ◦ Prazosin, terazosin, doxazocin used to treat HTN and BPH ◦ Alpha1a selective agents such as Tamsulosin are used to treat BPH with little effect on BP ◦ Effects and AE: ◦ Blocks alpha 1 receptors leading to vasodilation and relaxation or smooth muscle at bladder neck to facilitate urine flow ◦ Must give initial dose at night to prevent first dose syncope ◦ o Adverse effects - first dose phenomenon, HA, dizziness  Nonselective alpha blockers: ◦ § Phentolamine- alpha 1 and alpha2 blocker many side effects and rarely used (activates sympathetic reflexes and cardiac stimulation) affects many other receptors ◦ Indications - Perioperative hypertensive episodes associated with pheochromocytoma, prevention and management: ◦ § Phenoxybenzamine à covalent irreversible blockade of alpha 1>> alpha2 –long half life and used for pheochromocytoma * ◦ § Adverse effects ◦ first dose phenomenon (syncope), HA, dizziness Miscellaneous SYMP like Meds ◦ “STIMULANTS “ ◦ Amphetamines (Dextroamphetamine/amphetamine=Adderall, Lisdexamfetamine= Vyvanse etc.) for tx of ADHD, Narcolepsy ◦ Block reuptake of monoamines INCREASE DA, NE ◦ Methylphenidate (Ritalin) ADHD ◦ Methylphenidate primarily acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). ◦ Phentermine for obesity tx ◦ Pseudoephedrine (Sudafed) ◦ Pseudoephedrine acts on α- and β2-adrenergic receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi, respectively ◦ Nasal decongestant