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Part 2 autonomic.pptx
- 1. Pharmacology of the AutonomicNervous System Part 2 Thomas E. Tenner, Jr., Ph.D. Dept. of Medical Education Dept. Pharmacology & Neuroscience tom.tenner@ttuhsc.edu 743-7169 1
- 2. Recommended Background Reading: Chapters 7, 8, 9, and 10 Basic and Clinical Pharmacology Bertram Katzung (13th Edition) 2
- 3. Learning Objectives: 1) Listand describe the mechanism of action, therapeutic indications, and adverse effects of cholinergic agonists and cholinesterase inhibitors. 2) List and describe the mechanism of action, therapeutic indications, and adverse effects of muscarinic and nicotinic receptor antagonists. 3) List and describe the mechanism of action, therapeutic indications, and adverse effects of direct, indirect, and mixed acting adrenergic agonists. 4) List and describe the mechanism of action, therapeutic indications, and adverse effects of adrenergic and - adrenergic blocking agents. 3
- 4.
- 5. PARASYMPATHOMIMETICS (CHOLINOMIMETICS): Drugs that facilitateor mimic some or all of the actions of the parasympathetic nervous system. Muscarinic receptor agonists Anticholinesterases 5 Reversible Indirect Acting Irreversible Direct Acting Nicotinic receptor agonists
- 6. 6 Direct Acting Cholinergic Agonists •Acetylcholine *not used therapeutically – N/M • Carbachol * (Miostat) – N/M • Bethanechol * (Urecholine) – M • Pilocarpine (Pilocar, Ocusert) – M • Indications – Urinary retention after surgery or postpartum, Glaucoma • Adverse effects – – Muscarinic (M): salivation, flushing, bronchospasm, sweating, nausea, abdominal pain – acid indigestion and GI cramping, diarrhea, and possibly, decreased blood pressure. – Nicotinic (N)- Fasciculations, respiratory arrest
- 7. 7 Direct Acting Cholinergic NicotinicAgonists • Nicotine – MOA**- Low doses – ganglionic stimulation causing euphoria and arousal. CNS effects cause relaxation and improves attention (Acute) – Indications – None – Adverse effects – Vomiting, convulsions, hypertension, cardiac arrhythmias, Respiratory arrest – (depolarizing blockade), Muscarinic effects - PNS ganglia stimulation. • Succinylcholine *: – MOA - Overstimulation results in depolarizing blockade – Indications – muscle relaxation/paralysis associated with intubation, other procedures – Adverse effects – Fasciculations, respiratory arrest, malignant hyperthermia
- 8. 8 Indirect Acting Cholinergic Agonists- Reversible • Edrophonium *(Tensilon) • Neostigmine * • Pyridostigmine* (Mestinon,) • Physostigmine • MOA - Prolongs duration of acetylcholine by binding with and blocking acetylcholinesterase. • Therefore both Nicotinic(N) and Muscarinic(M) effects! • Indications – Myasthenia Gravis, Glaucoma, Atropine Poisoning • Adverse effects –salivation, flushing, bradycardia, bronchospasm, sweating, nausea, abdominal pain, diarrhea, decreased blood pressure, muscle fasciculations (N), and respiratory arrest (N).
- 9. 9 Indirect Acting Cholinergic Agonists– Reversible - CNS • Used in Alzheimer’s : • Donepezil (Aricept, Aricept ODT) • Galantamine (Razadyne, Razadyne ER) • Rivastigmine (Exelon) – tertiary amine • Mechanism of action – Increase cerebral concentrations of acetylcholine by inhibiting acetylcholinesterase • Adverse effects –Same as other reversible ACHase Inhibitors
- 10. 10 Indirect Acting Cholinergic Agonists- Irreversible • Echothiophate* (Phospholine) • MOA- Prolongs duration of acetylcholine by permanently inactivating acetylcholinesterase. • Therefore both Nicotinic(N) and Muscarinic(M) effects! • Indications – Glaucoma • Adverse effects –salivation, flushing, bradycardia, bronchospasm, sweating, nausea, abdominal pain, diarrhea, decreased blood pressure, muscle fasciculations (N), and respiratory arrest (N).
- 11. “SLUDWARMF” • Sweating • Lacrimation •Urination • Diarrhea • Wheezing • Accommodation • Rhinorrhea • Miosis • Fasciculations 11 Muscarinic Nicotinic
- 12. PARASYMPATHOLYTICS (ANTICHOLINERGICS): Drugs that reduceor inhibit some or all of the actions of the parasympathetic nervous system. Muscarinic receptor antagonists Ganglionic blocking drugs (Nn) 12 Neuromuscular blocking drugs (Nm) Nicotinic receptor antagonists
- 13. 13 Parasympatholytics Muscarinic receptor antagonists •MOA- Block muscarinic receptors on the effector organs of the parasympathetic nervous system and on the sweat glands • Indications – Varied - specificity for muscarinic receptors is a key reason behind their usefulness. • Adverse effects – – Autonomic • PNS - dry mouth, blurred vision, tachycardia, urinary retention, and constipation • SAS - Inhibition of sweating – CNS - restlessness, confusion, and hallucinations • Common mnemonic : “hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter"
- 14. 14 Parasympatholytics Muscarinic receptor antagonists •Atropine Sulfate – Cholinesterase poisoning, – ACLS: Bradycardia, Pulseless Electrical Activity and Asystole • Benztropine (Cogentin) – Parkinsonism • Dicyclomine (Bentyl) – Irritable Bowel Syndrome • Ipratropium *(Atrovent) – COPD, Rhinorrhea • Tiotropium * (Spiriva) – COPD, Rhinorrhea • Oxybutynin (Ditropan) – Overactive bladder • Tolterodine (Detrol) – Overactive bladder • Tropicamide (Mydriacyl) - Mydriasis (short duration) • Scopolamine - Motion Sickness, Amnesia
- 15. 15 Parasympatholytics Nicotinic receptor antagonists- GanglionicBlockers (NN) • Mecamylamine – Non-depolarizing, competitive blocker • Nicotine – Depolarizing blocker – High doses – ganglionic blockade causing respiratory paralysis and hypotension • No selectivity - block receptors on both the parasympathetic and sympathetic ganglia • Adverse Effects – Intolerable – Hypotension, Orthostatic Hypotension, atony of bladder and GI Tract, cycloplegia, xerostomia, sexual dysfunction, hyperthermia • Rarely used therapeutically
- 16. 16 Parasympatholytics Nicotinic receptor antagonists- NeuromuscularBlockers (NM) • Tubocurarine* - Prototype • Atracurium* • Pancuronium * • Rocuronium* • Vecuronium* • Indications – muscle relaxation/paralysis associated with intubation, other procedures • MOA - Competitive blocker - action can be reversed by increasing concentration of Ach** • Adverse Effects – Respiratory arrest.
- 17.
- 18. Raymond Ahlquist (1948)on Adrenergic receptor function • “Alpha receptors are excitatory everywhere but the gut” • “Beta receptors are inhibitory everywhere but the heart” 18
- 19. 19 Adrenergic Agonists • Catecholamines- Name is based on their chemical structure (hydroxyl groups at the 3 and 4 position of a benzene ring): – High potency - activate both alpha and beta receptors – Rapid inactivation - Destroyed by COMT (Catechol O- methyltransferase) and by MAO (Monoamine oxidase) which are both located at the neuron and in the gut wall. Catecholamines are not effective when given orally – Poor CNS penetration - They are polar but they still may cause some CNS effects – 5 catecholamines - epinephrine, norepinephrine, dopamine, dobutamine, and isoproterenol
- 20. 20 Epinephrine: Basic Catecholamine Structure HO HO CHCH2 N H CH3 OH 1 3 4
- 21. 25 Adrenergic agonists Cont. •Non-catecholamines - – Not destroyed by COMT and MAO deactivation is limited, so they have longer half lives – Better CNS penetration due to increased lipid solubility
- 22. SYMPATHOMIMETICS: Drugs that facilitateor mimic some or all of the actions of the sympathetic nervous system. 26 Indirect Acting Direct Acting Drugs that facilitate NE release α-adrenergic agonists β-adrenergic agonists Drugs that block NE uptake Mixed Acting Both Direct and Indirect Actions Drugs that inhibit enzymatic breakdown of NE
- 23. Mechanism of actionof adrenergic agonists • Direct-Acting Agonists - Mimic NE and EPI. They bind to the adrenergic receptors without interacting with the prejunctional neuron. • (EPI, NE, ISO and Phenylephrine) • Indirect-Acting Agonists: • Displace norepinephrine from storage sites (Amphetamine, hydroxyamphetamine, and tyramine) • Block the uptake of norepinephrine at storage sites (Cocaine, Tricylic Antidepressants, SNRI) • Inhibit enzymatic breakdown of norepinephrine (Monoamine Oxidase Inhibitors, i.e., phenelzine) • Mixed-action agonists - Both stimulate receptors and displace NE from storage sites. • (Ephedrine, pseudoephedrine)
- 24. Catecholamines: Rank Order ofPotency – Isoproterenol: β 1 = β 2 = β 3 >>>> α1 = α2 – Norepinephrine : α1 = α2 = β 1 = β 3 >>>> β 2 – Epinephrine: α1 = α2 = β 1 = β 2 = β 3 – Dopamine : DA 1> β 1> α1 28
- 25. Adrenergic Receptor Subtypes α-adrenergicreceptors (Epinephrine > Isoproterenol) β-adrenergic receptors (Isoproterenol > Epinephrine) α 1-adrenergic receptors (Phenylephrine > Clonidine) α 2-adrenergic receptors (Clonidine > Phenylephrine) β 1-adrenergic receptors (EPI = NE) β 2-adrenergic receptors (EPI>NE) β 3-adrenergic receptors (NE>EPI) 29
- 26. 30 Direct Acting Alpha1- Adrenergic Agonists • Phenylephrine (Neo-Synephrine) • Oxymetazoline ( Afrin, Visine L.R.) • Indications – Nasal decongestant, mydriatic, and systemically as a vasopressor for hypotension to raise BP. • Adverse effects – Hypertension, Nervousness, Headaches
- 27. 31 Direct Acting Alpha2 - Adrenergic Agonists • Clonidine (Catapres) • Apraclonidine a (Lopidine) • Brimonidine a (Alphagan P) • Indications : – Hypertension - produces inhibition of sympathetic vasomotor centers, reducing blood pressure. – ADHD and impulsive behavior – Glaucoma a • Adverse effects – Bradycardia, Hypotension, Headaches, Sedation, Depression, • Caution for Withdrawal Supersensitivity with Chronic use
- 28. 32 Direct Acting Beta1- Adrenergic Agonists • Dobutamine (Dobutrex) • Mechanism of Action – Primarily a beta 1 agonist. Increases cardiac output with few heart rate or vascular effects • Indication - Congestive heart failure • Adverse actions – tachycardia, palpitations, severe hypotension (alpha antagonist effect). Can increase ventricular rate in atrial fibrillation
- 29. 33 Direct Acting Beta2- Adrenergic Agonists • Albuterol (Proventil, Ventolin) • Terbutaline (Brethine, Bricanyl) • Metaproterenol (Alupent) • Long Acting Beta Agonists (LABA) – Salmeterol (Serevent) – Formoterol (Perforomist) • Indications : Bronchodilator, Asthma; LABA only in COPD. • Adverse effects – Nervousness, muscle tremors, tachycardia. • Systemic route: Hypokalemia and hyperglycemia
- 30. 34 Indirect Acting Adrenergic Agonists •Amphetaminea • Hydroxyamphetamine • Cocaine • TCA’s, SNRI’sb • MAOI’sb • Indications : – Attention Deficit Disorder (ADD) a – Narcolepsya – Depressioni/Neuropathic painb • Adverse effects – Similar to direct acting Adrenomimetic drugs. (See next slides).
- 31. Amphetamines - Adverse Effects: •CNS confusion insomnia irritability weakness vertigo/dizziness tremor hyperactive reflexes delirium panic suicide amphetamine psychosis •CVS palpitations arrhythmias hypertension angina circulatory collapse headache chills sweating •GI anorexia nausea, vomitinmg & diarrhea abdominal cramping
- 32. Adverse Effects: 1) Anxiety*reaction (hypertension, tachycardia, sweating & paranoia) 2) Depression 3) Agitation* 4) Cardiac Arrhythmias 5) Seizures* 6) Incidence of MI unrelated to dose, duration of use or route of administration (no marker) * Can be treated with Benzodiazepines-Diazepam Cocaine
- 33. SYMPATHOLYTICS: Drugs that reduceor inhibit some or all of the actions of the sympathetic nervous system. β-adrenergic antagonists Adrenergic neuronal blocking drugs Ganglionic blocking drugs α-adrenergic antagonists
- 34. 38 Adrenergic Neuronal Blocking Drug •Reserpine – Discontinued in US • MOA: Prevents uptake of biogenic amines (DA, NE, EPI, 5HT) in both central and peripheral neurons (also adrenal chromaffin granules) Results in Biogenic amine depletion - denervation • Indications : Hypertension . • Adverse effects – Diarrhea, cramps, GI acid secretion, postural hypotension, bradycardia, sexual dysfunction, sedation, depression (suicide). • Caution for Supersensitivity with Chronic use.
- 35. 39 Nonselective Alpha Adrenergic BlockingAgents • Phentolaminea (Regitine) – reversible and competitive • Phenoxybenzamineb (Dibenzyline) – irreversible and non-competitive • MOA – block both Alpha1 and Alpha2 • Indications : Diagnosisa and Treatmentb of Pheochromocytoma • Adverse effects – Orthostatic hypotension, exaggerated reflex tachycardia (why), nasal stuffiness, ejaculatory dysfunction
- 36. 40 Alpha-1 Selective Adrenergic BlockingAgents • Prazosin (Minipress) - Prototype • Doxazosin (Cardura) • Terazosin (Hytrin) • Tamsulosin (Flomax) – Selective for Alpha 1Aa • Indications: – Hypertension – not monotherapy – Benign Prostatic Hypertrophya - relaxes bladder neck and prostate smooth muscle
- 37. 41 Alpha-1 Selective Adrenergic BlockingAgents • Adverse effects : • First Dose Effect - Exaggerated hypotension that can lead to syncope especially when patient stands after sitting or lying down (orthostatic hypotension) – less reflex tachycardia (why) – sodium and water retention (prazosin) (limits use in high blood pressure) – nasal stuffiness – ejaculatory dysfunction
- 38. 42 Beta Adrenergic Blocking Agents •Propranolol a (Inderal) • Timolol a (Timoptic) • Nadolol a (Corgard) • Atenolol b (Tenormin) • Metoprolol b (Lopressor) • Esmolol b (Brevibloc) • MOA : a Nonselective - both beta-1 and 2 b “Cardioselective” Beta-1 specific
- 39. 43 Beta Blockers Indicationscont. • Indications : – Prevention of migraines - May prevent catecholamine vasodilation in the brain vasculature (Beta-2?) – Hyperthyroidism – Thyroid storm – Glaucoma – (Timolol) – Arrhythmias, Angina pectoris, Myocardial Infarction, Heart failure – Protective effect against sympathetic overstimulation – improved survival !! • Adverse reactions – Bradycardia, Heart block, Heart failure, Raynaud’s (peripheral vasospasm), Vivid dreams, depression, Bronchoconstriction in asthmatics/COPD, Sexual dysfunction, Decreased glycogenolysis and glucagon secretion • Caution for Withdrawal Supersensitivity with Chronic use
- 40. 44 Alpha and BetaAdrenergic Blocking Agents • Labetalol a(Trandate, Normodyne) • Carvedilol b(Coreg) • MOA – block both Alpha1 and Beta Adrenoceptors. – Result in peripheral vasodilation that lowers blood pressure with reduced cardiac rate and contraction • Indications : Hypertension a and Congestive heart failure b • Adverse effects – Combines BOTH Alpha and Beta adrenoceptor blocker adverse effects.
- 41. 45 Process Affected DrugExample Site Action Receptor Activation or Blockade Bethanechol, Pilocarpine Muscarinic Receptor Activation Parasympatho- mimetic, Atropine Muscarinic Receptor Blockade Parasympatholytic Nicotine Nicotinic Receptor Activation Skeletal muscle activation Tubocurarine Nicotinic Receptor Blockade Muscle paralysis, respiratory arrest Epinephrine α1, α2, β1, β2, β3 Receptor Activation Sympathomimetic Norepinephrine α1, α2, β1, Receptor Activation Sympathomimetic Phenylephrine α1 Receptor Activation Sympathomimetic Phentolamine α1, α2, Receptor Blockade Sympatholytic Prazosin α1 Receptor Blockade Sympatholytic Isoproterenol β1, β2, β3 Receptor Activation Sympathomimetic Propranolol β1, β2, β3 Receptor Blockade Sympatholytic
- 42. Target Organ Responses Adrenergicand Cholinergic Receptors 46 Adrenergic Cholinergic Subtype: 1 2 1 2 M N Agonist Antagonist Location Importance
- 43.
- 44. 48 Control of BloodPressure CF VR mABP = CO x TPR HR SV Cardiac - Chronotropy Venous – Preload Arterial - Afterload Cardiac - Inotropy
Editor's Notes
- #7 * Quaternary ammonium compounds ** N = Nicotinic, M = Muscarinic
- #8 *Quaternary ammonium compounds ** MOA – Mechanism of actino
- #9 * Quaternary ammonium compounds
- #10 a Rivastigmine, but not its competitors, inhibits both acetylcholinesterase and butyrylcholinesterase by covalently binding to active sites on these enzymes, blocking their function. Breaking of these covalent bonds is the first and most important step in the degradation of rivastigmine, which is not metabolized in the liver
- #11 * Quaternary ammonium compounds
- #15 Atropine Sulfate – Prototype ACLS - Advanced Cardiac Life Support. *quaternary ammonium
- #17 Quaternary ammonium compounds **Competitive blocker - action can be reversed by increasing concentration of acetylcholine with cholinesterase inhibitors (edrophonium, neostigmine, and pyridostigmine)
- #21 Epi – Methylated NE NE – lose the amino CH3 Dopamine – lose the Beta hydroxy from NE ISO – Add isopropyl group on Nitrogen Amphetamine – phenylisopropylamine
- #22 Epi – Methylated NE NE – lose the amino CH3 Dopamine – lose the Beta hydroxy from NE ISO – Add isopropyl group on Nitrogen Amphetamine – phenylisopropylamine
- #23 Epi – Methylated NE NE – lose the amino CH3 Dopamine – lose the Beta hydroxy from NE ISO – Add isopropyl group on Nitrogen Amphetamine – phenylisopropylamine
- #24 Epi – Methylated NE NE – lose the amino CH3 Dopamine – lose the Beta hydroxy from NE ISO – Add isopropyl group on Nitrogen Amphetamine – phenylisopropylamine
- #25 Epi – Methylated NE NE – lose the amino CH3 Dopamine – lose the Beta hydroxy from NE ISO – Add isopropyl group on Nitrogen Amphetamine – phenylisopropylamine
- #28 EPI= Epinephrine NE=Norepinephrine ISO=Isoproterenol
- #32 ADHD = Attention-deficit/hyperactivity disorder
- #34 COPD- Chronic Obstructive Pulmonary Disease
- #35 COPD- Chronic Obstructive Pulmonary Disease
- #45 No reflex tachycardia as seen with alpha blockade, no reflex increased total peripheral resistance as seen with beta blockers.
- #46 Alpha latrotoxin- black widow spider venom Fig 6-1, Katzung, 2007
- #47 Study aid – fill in appropriate information
- #48 Study aid – fill in appropriate information