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  • 1. AUTONOMIC PHARMACOLOGY Enrico Ian L. Deliso, MD XU-JPRSM
  • 2. Autonomic Nervous System (ANS) • Sympathetic (thoracolumbar) division • Parasympathetic (craniosacral) division
  • 3. Organization of the ANS Characteristic Sympathetic Parasympathetic Origin of preganglionic T1 – T12; L1-L3 CN III, VII, IX, X; S2 – S4 Length of pre-ganglionic axon Short Long Neurotransmitter in the Gaglion ACh ACh Receptor in ganglion Nicotinic Nicotinic Length of post-ganglionic axon Long Short Neurotransmitter in effector organ Norepinephrine (except sweat glands-Ach) Ach Receptor in effector organs α1,α2,β1,β2,β3 Muscarinic
  • 4. Enteric Nervous Sytem • is a large and highly organized collection of neurons located in the walls of the gastrointestinal system • it is sometimes considered a third division of the ANS • Consist of – Myenteric plexus (Auerbach) – Submucous Plexus (Meissner)
  • 5. Uninnervated Receptors • Respond to autonomic transmitters and drugs but receive no innervation • Examples: – Muscarinic receptors on endothelium of blood vessels
  • 6. Cotransmitters • In the nerve terminals, autonomic nerves has vesicles that contain other transmitter molecules in addition to the main agents • Involves in the modulation of the synaptic transmission • Examples: – ATP, enkephalin, VIP
  • 7. CHOLINERGIC PHARMACOLOGY
  • 8. Acetylcholine (Ach) • Primary transmitter in all the automonic ganglia and at the synapses between parasympathetic postganglionic neurons and the effector cells • Primary transmitter at the somatic system (NMJ)
  • 9. Cholinergic Drug Effects • Not very useful, because their effects are not sufficiently selective • Botulinum toxin, a very large molecule that diffuses slowly, for relatively selective drug effect
  • 10. Receptor Name Typical Locations Result of Ligand Binding Muscarinic M1 CNS neurons, sympathetic postganglionic neurons, some presynaptic sites Formation of IP3 and DAG, increased intracellular calcium Muscarinic M2 Myocardium, smooth muscle, some presynaptic sites; CNS neurons Opening of potassium channels, inhibition of adenylyl cyclase Muscarinic M3 Exocrine glands, vessels (smooth muscle and endothelium); CNS neurons Like M1 receptor-ligand binding Muscarinic M4
 CNS neurons; possibly vagal nerve endings Like M2 receptor-ligand binding
 Muscarinic M5 Vascular endothelium, especially cerebral vessels; CNS neurons 
 Like M1 receptor-ligand binding Nicotinic NN Postganglionic neurons, some presynaptic cholinergic terminals Opening of Na+, K+ channels, depolarization
  • 11. Organ Response EYES Sphincter muscle of iris Contraction (miosis) Ciliary muscle Contraction for near vision HEART Sinoatrial node Decrease in rate (negative chronotropy) Atria Decrease in contractile strength (negative inotropy). Decrease in refractory period AV node Decrease in conduction velocity (negative dromotropy). Increase in refractory period Ventricles Small decrease in contractile strength BLOOD VESSELS Arteries Dilation (via EDRF). Constriction (high-dose direct effect)
  • 12. LUNG Bronchial muscle Contraction Bronchial gland Stimulation GI Motility Increase Sphincters Relaxation Secretion Stimulation URINARY BLADDER Detrussor contraction Trigone and sphincter relaxation GLANDS Sweat, salivary, lacrimal, nasopharyngeal secretion
  • 13. CHOLINOCEPTOR-ACTIVATING & CHOLINESTERASE- INHIBITING DRUGS
  • 14. Cholinomimetic Drugs • Indirect-acting – Edrophomium (short acting) – Carbamates (intermediate to long-acting) – Organophosphates (very long acting) • Direct-acting – Muscarinic • Choline Esters • Alkaloids – Nicotinic
  • 15. DIRECT ACTING CHOLINOMIMETICS
  • 16. Direct acting Cholinomimetics, MUSCARINIC DRUG CLINICAL USE TOXICITIES CHOLINE ESTERS Acetylcholine NONE All parasympathomimetic effects: diarrhea, urinary urgency Bethanechol Bladder and bowel atony Pilocarpine Sjogren’s Syndrome Glaucome ALKALOIDS Muscarine Alkaloid in mushroom Mushroom poisoning
  • 17. Direct acting Cholinomimetics, NICOTINIC DRUG CLINICAL USE TOXICITIES NICOTINE (full Nn agonist) Smoking cessation Insecticide Generalized ganglionic stimulation: hypertension, tachycardia, nausea, vomiting, diarrhea MAJOR overdose: convulsions, paralysis, coma VARENICLINE (partial Nn agonist) Smoking cessation HPN, sweating, sensory disturbance, diarrhea, polyuria, menstrual disturbance SUCCINYLCHOLINE (selective Nm agonist) Neuromuscular Relaxation Initial Muscle spasms and postoperative pain
  • 18. Muscarinic Toxicity • CNS stimulation • EYE: miosis • LUNGS: bronchoconstriction • GIT/GUT: excessive smooth muscle activity • Increase secretory activity of glands • vasodilation
  • 19. Reflex compensation for muscarinic toxicity • Transient bradycardia followed by reflex tachycardia if administered by IV • Reflex tachycardia for all other routes
  • 20. Nicotinic Toxicity • Ganglionic stimulation • Blockade of the Neuromuscular end plate depolarization – leading to paralysis • CNS toxicity: stimulation (convulsions) followed by CNS depression
  • 21. INDIRECT ACTING CHOLINOMIMETICS
  • 22. MOA of indirect acting cholinomimetics • Bind to the cholinesterase and undergo prompt hydrolysis • Amplify Ach effects wherever it is released • No significant actions at uninnervated sites where Ach is not normally released
  • 23. Indirect acting cholinomimetics DRUG CLINICAL USE TOXICITIES ALCOHOLS Edrophonium Reversal of nondepolarizing neuromuscular blockade; Diagnosis of Myasthenia; Differentiate myasthenic and cholinergic crisis Increased parasympathetic effects, nausea, vomiting, diarrhea, urinary urgency CARBAMATES Neostigmine Reversal of nondepolarizing neuromuscular blockade; Treatment of MG; Bladder atony Like edrophonium but longer duration Pyridostigmine Treatment of MG Physostigmine Antidote to atropine Glaucoma Like edrophonium but longer duration plus CNS effects
  • 24. Myasthenia Gravis • Autoimmune destruction of nicotinic Ach receptors – Fluctuating muscle weakness – Ocular symptoms – Bulbar symptoms – Proximal muscle weakness • Myasthenic crisis – Worsening of symptoms – EDROPHONIUM improves muscle strength • Cholinergic crisis – Excessive activation of cholinoreceptors – EDROPHONIUM weakens muscle strength
  • 25. Indirect acting cholinomimetics DRUG CLINICAL USE TOXICITIES SPECIAL CARBAMATES Rivastigmine Galantamine Donepezil Tacrine Alzheimer’s disease Nausea and Vomiting ORGANOPHOSPHATES Parathion Insectecide only Highly Dangerous; ALL parasympathetic effects plus muscle paralysis and coma Malathion Insecticide and scabicide Safer than parathion Sarin Tabun Nerve gas Terrorist threat Rapidly lethal
  • 26. CHOLINORECEPTOR BLOCKERS AND CHOLINESTERASE REGENERATORS
  • 27. Anticholinergic Drugs • Antimuscarinic – M1-Selective (Pirenzepine) – Non-selective (Atropine) • Antinicotinic – Ganglion Blockers (Hexamethomium) – Neuromuscular Blockers (Tubucurarine) • Cholinesterase regenerators – Oximes (Pralidoxime)
  • 28. Nonselective Muscarinic Antagonist Drug Clinical Use Toxicities Atropine Cyclopentolate Tropicamide Mydriatic Cycloplegic Antidote for cholinesterase inhibitor toxicity All Parasympathetic effects plus sedation, delirium, hyperthermia and flushing Scopolamine Motion sickness Benztropine Biperiden Trihexyphenidyl Anti-Parkinsonism Acute dystonia Ipratropium Tiotropium COPD Oxybutynin Urinary Urgency Postoperative bladder spasms Glycopyrrolate Dicyclomine Antispasmodic Transient Hypermotility
  • 29. Selective Muscarinic Antagonist DRUG CLINICAL USE TOXICITIES M1 Selective Pirenzepine Telenzepine PUD Excessive Parasympathetic Effects M2 Selective Tolterodine Darifenacin Fesoterodine Solifenacin Urinary Urgency Stress incontinence Excessive Parasympathetic Effects
  • 30. Contraindications to Muscarinic Blockers • Infants • Hyperthermia due to decrease sweating • Acute angle closure glaucoma • BPH
  • 31. Ganglion Blockers • Competitive pharmacologic antagonists at the nicotinic Ach receptors • First successful agents for the treatment of HPN but were abandoned because its adverse effects are so severe
  • 32. Ganglion Blockers DRUG CLINICAL USE TOXICITIES Hexamethonium Hypertension (not used) Complete blockade of ALL autonomic effects: Postural Hypotension Dry mouth Blurred vision Constipation Severe sexual dysfunction Trimethaphan Hypertensive urgencies Controlled Hypotension Mecamylamine Smoking cessation Tourette’s syndrome
  • 33. Neuromuscular Blockers • Important for producing complete skeletal muscle relaxation in surgery • Classification: – NONDEPOLARIZING (Tubocurarine, Pancuronium, Atracurium, Vecur onium) – DEPOLARIZING (Succinylcholine)
  • 34. ADRENERGIC PHARMACOLOGY
  • 35. Norepinephrine • Primary transmitter at the sympathetic postganglionic neuron-effector cell synapses in most tissues • Except: – Sweat glands – Ach
  • 36. Sites of Autonomic Drug Actions STEPS INHIBITORS CHOLINERGIC ADRENERGIC Synthesis Hemicholinium Metyrosine Storage Vesamicol Reserpine Release Botulinum Guanethidine Termination Metabolism Neostigmine MAOI’s, COMTIs Reuptake NONE Cocaine, TCAs
  • 37. Drug effects on Adrenergic Transmission • Other drugs promote catecholamine release • Used in treatment of several diseases (Pheochromocytoma, Hypertension) – Block sympathetic but NOT parasympathetic functions
  • 38. SYMPATHOMIMETICS
  • 39. ADRENERGIC AGONIST • DIRECT ACTING – ALPHA AGONIST • NONSELECTIVE • ALPHA 1 SELECTIVE • ALPHA 2 SELECTIVE – BETA AGONIST • NONSELECTIVE • BETA 1 SELECTIVE • BETA 2 SELECTIVE • INDIRECT ACTING – RELEASERS – REUPTAKE INHIBITORS
  • 40. MOA OF SYMPATHOMIMETICS • Direct activation of adrenoceptors • Indirect activation by increasing concentration of available catecholamines in the synapse – Release of stored catecholamines – Inhibits the reuptake process
  • 41. Nonselective Direct Acting Catecholamines DRUG ACTIVITY CLINICAL USE TOXICITIES Epinephrine α1,α2,β1,β2,β3 Anaphylaxis Hemostasis Excessive sympathomimetic effects: HPN, arrythmia, stroke, MI, pulmonary edema Norepinephrine α1,α2,β1 Neurogenic Shock Last resort in shock Extreme vasospasm, tissue necrosis, excessive BP increase, arrythmia and infarction Dopamine D1, D2 α1,α2,β1,β2,β3 Shock, Heart Failure Cardiovascular disturbance, arrythmias Isoproterenol β1,β2,β3 Acute asthma
  • 42. Selective α1 Agonist DRUG CLINICAL USE TOXICITIES Phenylephrine Decongestant Mydriatic Neurogenic Hypotension HPN Stroke MI Methoxamine Paroxysmal atrial tachycardia Midodrine Chronic orthostatic hypotension
  • 43. Selective α2 Agonist DRUG CLINICAL USE TOXICITIES Clonidine Hypertension Rebound hypertension Sedation Methyldopa Pre-eclampsia Hemolyttic Anemia Sedation Apraclonidine Brimonidine Glaucoma
  • 44. Selective β1 Agonist DRUG CLINICAL USE TOXICITIES Dobutamine Heart failure Shock Cardiac stress testing Tachycardia Arrythmia Tachyphylaxis
  • 45. Selective β2 Agonist DRUG CLINICAL USE TOXICITIES Albuterol Metaproterenol Terbutaline Acute Bronchospasm Asthma RELIEVER Tachycardia Tremors Salmeterol Formoterol Asthma CONTROLLER Ritodrine Premature Labor
  • 46. Dopamine • Low Dose (1-5 mcg/kg/min) – Vasodilation in the splanchnic and renal vascular beds via D1 receptors • Medium Dose (5-15 mcg/kg/min) – Increased renal blood flow, hear rate, cardiac contractility and cardiac output via βreceptors • High Dose (>15 mcg/kg/min) – Increased BP and vasoconstriction viaαreceptors
  • 47. Indirect Acting Sympathomimetics DRUG CLINICAL USE TOXICITIES Amphetamine Methamphetamine Anorexiant Weight reduction ADHD Narcolepsy Addiction Paranoia Aggresion Insomnia Arrythmia HPN Convulsions Ephedrine Narcolepsy Idiopathic postural hypotension Enuresis Tachycardia Hypertension Pseudoephedrine decongestant
  • 48. Indirect Acting Sympathomimetics DRUG CLINICAL USE TOXICITIES Cocaine Local Anesthetic Intrinsic Hemostatic Action Addiction HPN Arrythmias Seizures Tyramine Found in fermented Foods (cheese) Hypertensive Crisis when taken together Phenelzine Tranycypromine Mood Disorders
  • 49. ADRENORECEPTOR BLOCKERS
  • 50. Adrenoreceptor Antagonists • Alpha blockers – Nonselective • Irreversible (Phenoxybenzamine) • Reversible (Phentolamine) – Alpha 1 selective (Prazosin) – Alpha 2 selective (Yohimbine) • Beta Blockers – Nonselective (propranolol) – Beta 1 Selective (Atenolol) – Beta 2 Selective (Butoxamine)
  • 51. Nonselective Alpha Blockers DRUG CLINICAL USE TOXICITIES Phenoxybenzamine (irreversible and long acting) Pheochromocytoma, carcinoid, mastocytosis, Raynaud’s phenomenon Orthostatic Hypotension, Reflex Tachycardia GI irritation Phentolamine (reversible, short acting) Pheochromocytoma, antidote to alpha 1 agonist overdose, local vasoconstrictor, rebound HPN ED
  • 52. Selective Alpha 1 Blockers DRUG CLINICAL USE TOXICITIES Prazosin Doxazosin Terazosin HPN BPH First Dose orthostatic Hypotension, Little reflex tachycardia Tamsulosin Silodosin Urinary Hesitancy Urinary Retention BPH
  • 53. Selective Alpha 2 Blockers DRUG CLINICAL USE TOXICITIES Yohimbine Rauwolscine Research application ED (obsolete) Tachycardia GI upset Mirtazapine Depression Somnolence Hypercholesterolemia Increase appetite
  • 54. Nonselective Beta Blockers DRUG CLINICAL USE TOXICITIES Propranolol Angina Arrythmia HPN, Essential Tremors, Migraine prophylaxis, Variceal Bleeding Excessive beta blockade: Bronchospasm AV block Heart failure, CNS sedation, masks hypoglycemia in DM patients, EDNadolol Longest half life Pindolol Partial agonist activity Timolol Galucoma Lacks anesthetic effect Labetalol Partial agonist activity HPN (pre-ec) Pheochromocytoma Combined alpha and beta blockade Carvedilol Heart Failure
  • 55. Selective Beta 1 Blockers DRUG CLINICAL USE TOXICITIES Atenolol HPN Angina Arrythmia Like Propranolol Less danger of bronchospasm Betaxolol Glaucoma Esmolol Shortest half life SVT, Thyrotoxicosis Acebutolol Partial Agonist activity, SVT Metoprolol Arrythmia, heart failure Nebivolol Like atenolol Vasodilation
  • 56. Selective Beta 2 Blockers DRUG CLINICAL USE TOXICITIES Butoxamine Research application bronchospasm
  • 57. ORGAN EFFECT SYMPATHETIC PARASYMPATHETIC Pupils Mydriasis Miosis Heart rate Tachycardia Bradycardia Heart Contractility Increased Decreased Blood Vessels Skin, Splanchnic Vasoconstriction No effect Skeletal Vasodilation No Effect GI Motility Decreased Increased Secretion Decreased Increased Bladder Relaxation Contraction Uterus Relaxation (beta 2) Contraction (alpha 1) Contraction (M3) Penis Ejaculation erection
  • 58. ORGAN EFFECT SYMPATHETIC PARASYMPATHETIC Sweat glands Increase sweating (Ach) No effect Liver Gluconeogenesis Glycogenolysis No effect Fat cells Lipolysis No effect Kidney Increase renin release No effect