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SYMPATHETIC NERVOUS SYSTEM Lylah D. Reyes, MD FPOGS Associate Professor A, Department of Pharmacology Senior Consultant, Department of Obstetrics and Gynecology FEU-NRMF Institute of Medicine and Medical Center OBJECTIVES Describe the mechanism of action of the drugs acting on the sympathetic...

SYMPATHETIC NERVOUS SYSTEM Lylah D. Reyes, MD FPOGS Associate Professor A, Department of Pharmacology Senior Consultant, Department of Obstetrics and Gynecology FEU-NRMF Institute of Medicine and Medical Center OBJECTIVES Describe the mechanism of action of the drugs acting on the sympathetic nervous system Correlate the structure of the drugs with the following: action metabolism Identify the drugs acting on the sympathetic system according to the autonomic function or process affected OBJECTIVES Correlate the following with the mechanism of action of the drug - action -adverse effect -drug interaction -indication -contraindication or precaution Compare the difference in the pharmacologic action based on receptor affinity Parasympathetic/ Sympathetic / craniosacral Thoracolumbar SYMPATHETIC NERVOUS SYSTEM ADRENERGIC TRANSMISSION: SYNTHESIS, STORAGE, RELEASE, REGULATION, & METABOLISM NOREPINEPHRINE DOPAMINE EPINEPHRINE STORAGE SYNTHESIS STORAGE DOPAMINE STORAGE SYNTHESIS SYNTHESIS SYNTHESIS SYNTHESIS RELEASE RELEASE RELEASE PRESYNAPTIC REGULATION PRESYNAPTIC REGULATION PRESYNAPTIC REGULATION POSTSYNAPTIC REGULATION Up- and down-regulation Post-synaptic potential ▫ Excitatory (fast) ▫ Inhibitory (slow, longer-lasting) METABOLISM METABOLISM METABOLISM METABOLISM TERMINATION OF CATECHOLAMINE ACTION Reuptake into nerve terminals by NET ▫ DA > NE > E Dilution by diffusion out of the junctional cleft and uptake at extraneuronal sites by ▫ ENT = E >> NE > DA ▫ OCT1 = DA = E >> NE ▫ OCT2 = DA >> NE >> E Metabolic transformation by MAO and COMT RECEPTORS  ALPHA ADRENOCEPTORS RECEPTOR RECEPTOR SITE POSTRECEPTOR MECHANISM Alpha 1 Postsynpatic effector cell, Formation of IP3 and DAG, especially smooth muscles increased intracellular calcium Alpha 2 Presynaptic adrenergic Inhibition of adenylyl cyclase nerve terminals, platelets, Decreased cAMP lipocytes, smooth muscle ALPHA ADRENOCEPTORS  Alpha 2 adrenergic receptor ALPHA ADRENOCEPTORS α1 activation vasoconstriction  ↑ BP Dilation of radial pupillary dilator muscle (mydriasis) Increases outflow of aqueous humor Erects hair Prostate and bladder base contraction Increase cardiac force of contraction  ALPHA ADRENOCEPTORS RECEPTOR RECEPTOR SITE POSTRECEPTOR MECHANISM Alpha 1 Postsynpatic effector cell, Formation of IP3 and DAG, especially smooth muscles increased intracellular calcium Alpha 2 Presynaptic adrenergic Inhibition of adenylyl cyclase nerve terminals, platelets, Decreased cAMP lipocytes, smooth muscle ALPHA ADRENOCEPTORS  Alpha 1 adrenergic receptor ALPHA ADRENOCEPTORS α2 activation Platelet aggregation Inhibition of transmitter release in adrenergic and cholinergic nerve terminals Some vasocontriction Inhibition of lipolysis Inhibition of renin secretion Inhibition of insulin secretion  BETA ADRENOCEPTOR RECEPTOR RECEPTOR SITE POSTRECEPTOR MECHANISM Beta 1 Postsynaptic effector cell, Stimulation of adenylyl cyclase especially heart, lipocyte, brain Increased cAMP Presynaptic adrenergic and cholinergic nerve terminals in JG apparatus of renal tubules, ciliary body epithelium Beta 2 Postsynaptic effector cell of Stimulation of adenylyl cyclase smooth muscle and cardiac Increased cAMP muscle Activation of cardiac Gi under some conditions Beta 3 Postsynaptic effector cell of Stimulation of adenylyl cyclase lipocytes and heart, GI tract Increased cAMP BETA ADRENOCEPTOR  Beta-1 adrenoceptor BETA ADRENOCEPTOR β1 activation Increase force and rate of contraction of the heart Stimulates renin secretion β2 activation vasodilatation  ↓ BP Promotes skeletal muscle potassium uptake Activates hepatic glycogenolysis  ↑ glucose β3 activation Activates lipolysis  ↑ fatty acids  ↑ glucose Relaxes bladder detrusor muscle BETA ADRENOCEPTOR  BETA ADRENOCEPTOR RECEPTOR RECEPTOR SITE POSTRECEPTOR MECHANISM Beta 1 Postsynaptic effector cell, Stimulation of adenylyl cyclase especially heart, lipocyte, brain Increased cAMP Presynaptic adrenergic and cholinergic nerve terminals in JG apparatus of renal tubules, ciliary body epithelium Beta 2 Postsynaptic effector cell of Stimulation of adenylyl cyclase smooth muscle and cardiac Increased cAMP muscle Activation of cardiac Gi under some conditions Beta 3 Postsynaptic effector cell of Stimulation of adenylyl cyclase lipocytes and heart, GI tract Increased cAMP BETA ADRENOCEPTOR Beta-2 adrenoceptor BETA ADRENOCEPTOR β1 activation Increase force and rate of contraction of the heart Stimulates renin secretion β2 activation vasodilatation  ↓ BP bronchodilation Promotes potassium uptake Promotes gluconeogenesis Activates glycogenolysis  ↑ glucose β3 activation Activates lipolysis  ↑ fatty acids  ↑ glucose Relaxes bladder detrusor muscle  BETA ADRENOCEPTOR RECEPTOR RECEPTOR SITE POSTRECEPTOR MECHANISM Beta 1 Postsynaptic effector cell, Stimulation of adenylyl cyclase especially heart, lipocyte, brain Increased cAMP Presynaptic adrenergic and cholinergic nerve terminals in JG apparatus of renal tubules, ciliary body epithelium Beta 2 Postsynaptic effector cell of Stimulation of adenylyl cyclase smooth muscle and cardiac Increased cAMP muscle Activation of cardiac Gi under some conditions Beta 3 Postsynaptic effector cell of Stimulation of adenylyl cyclase lipocytes and heart, GI tract Increased cAMP BETA ADRENOCEPTOR β1 activation Increase force and rate of contraction of the heart Stimulates renin secretion β2 activation vasodilatation  ↓ BP bronchodilation Promotes potassium uptake Activates glycogenolysis  ↑ glucose β3 activation Activates lipolysis  ↑ fatty acids  ↑ glucose Relaxes bladder detrusor muscle DOPMAINE RECEPTORS RECEPTOR RECEPTOR SITE POSTRECEPTOR MECHANISM D1 (DA1), D5 Brain Stimulation of adenylyl cyclase Effector tissues especially Increased cAMP smooth muscle of the renal vascular bed D2 (DA2) Brain Inhibition of adenylyl cyclase Effector tissues especially Increased potassium smooth muscle conductance D3 Presynaptic nerve terminal D3 Brain Inhibition of adenylyl cyclase D4 D4 Brain Inhibition of adenylyl cyclase Cardiovascular system DOPAMINE RECEPTORS D1 activation Dilates renal blood vessels  ↑ renal blood flow Natriuresis Dilates coronary, splanchnic, and other resistance vessels D2 activation Modulates neurotransmitter release Suppresses norepinephrine release DIRECT-ACTING ADRENOCEPTOR AGONISTS Norepinephrine α1 = α2 ; β1 > β2 Epinephrine α1 = α2 ; β1 = β2 PHARMACOLOGIC MODIFICATION FUNCTION CLASSIFICATION RECEPTOR AFFINITY RECEPTOR REGULATION STRUCTURE MODIFICATION OF AUTONOMIC FUNCTION PROCESS AFFECTED Action potential propagation Transmitter synthesis Transmitter storage Transmitter release Transmitter reuptake after release Receptor activation or blockade Enzymatic activation of transmitter PROCESS AFFECTED BY DRUGS IN THE SYMPATHETIC NERVOUS SYSTEM PROCESS SNS drug Action Transmitter synthesis Alpha- (-) tyrosine hydroxylase blocks methyltyrosine synthesis Transmitter storage Reserpine Prevents / depletes storage Transmitter release Tyramine, Promotes transmitter release Amphetamine Transmitter reuptake Cocaine, TCA (-) uptake; increase transmitter effect after release on postsynaptic receptors Receptor activation Norepinephrine Binds to α receptor; (+) contraction or blockade Phentolamine Binds to α receptor; (-) activation Isoproterenol Binds β receptors; (+) adenylyl cyclase Propanolol Binds β receptors; (-) activation Enzymatic activation tranylcypromine (-) MAO; increases stored transmitter of transmitter pool DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM Sympathomimetics / Adrenoceptor agonists Adrenoceptor antagonists CLASSIFICATION of AGONISTS Direct Indirect ▫ Displacement transmitters from nerve endings ▫ Inhibition of reuptake Mixed RECEPTOR REGULATION - Desensitization ▫ Tolerance, refractoriness, tachyphylaxis ▫ Mechanisms: ‘ Transcriptional or translational changes in the receptor protein level or its migration to the cell surface ‘ Covalent modification of the receptor RECEPTOR REGULATION - Desensitization Homologous ▫ Exclusive to the receptors that have been repeatedly or continuously activated by an agonist ▫ E.g. G-protein couples receptor kinase (GRK) RECEPTOR REGULATION - Desensitization Heterologous ▫ Diminution in the response of one receptor by its agonist also occurs to another receptor that has not been directly activated by the agonist ▫ E.g. Second messenger feedback mechanism Chemistry of Sympathomimetic drugs - Substitution on the benzene ring Chemistry of Sympathomimetic drugs -substitution on the benzene ring Chemistry of Sympathomimetic drugs -substitution on the benzene ring Chemistry of Sympathomimetic drugs - substitution in the amino group Chemistry of Sympathomimetic drugs - substitution in the amino group Chemistry of Sympathomimetic drugs - substitution in the amino group Chemistry of Sympathomimetic drugs -substitution on the alpha carbon Chemistry of Sympathomimetic drugs -substitution on the beta carbon ADRENOCEPTOR AGONISTS DIRECT-ACTING ADRENOCEPTOR AGONISTS Alpha Phenylephrine, α1 > α2 >>>>> β agonists Methoxamine, Midodrine (desglymidodrine) Xylometazoline Oxymetazoline Clonidine, α2 > α1 >>>>> β Methylnorepinephrine (methyldopa) Guanfacine, guanabenz Dexmedetomidine DIRECT-ACTING ADRENOCEPTOR AGONISTS Mixed alpha and Norepinephrine α1 = α2 ; β1 > β2 beta agonists or Non- selective Epinephrine α1 = α2 ; β1 = β2 agonists DIRECT-ACTING ADRENOCEPTOR AGONISTS Beta Dobutamine β1 > β2 > > > > α agonists Isoproterenol β1 = β2 > > > > α Terbutaline, β2 > > β1 > > > > α metaproterenol, albuterol, ritodrine Mirabegron β3 Dopamine Dopamine , Levodopa D1 = D2 > > β > > α agonists Fenoldopam D1 > > D2 Cardiovascular responses to sympathomimetic amines MIXED-ACTING ADRENOCEPTOR AGONIST Ephedrine Pseudoephedrine Phenylpropanolamine INDIRECT-ACTING ADRENOCEPTOR AGONISTS Promote Amphetamine norepinephrine Metamphetamine release Phenmetrazine Methylphenidate Modafinil Tyramine Foods reputed to have a high content of tyramine or other sympathomimetic agents INDIRECT-ACTING ADRENOCEPTOR AGONISTS Inhibit Atomoxetine catecholamine Reboxetine re-uptake Sibutramine Duloxetine Milnacipran Cocaine Therapeutic uses of sympathomimetics CARDIOVASCULAR APPLICATIONS Acute hypotension ▫ E.g. Shock, Cardiogenic shock and acute heart failure ▫ epinephrine, dobutamine, dopamine Chronic orthostatic hypotension ▫ E.g midodrine, ephedrine, phenylephrine Cardiac applications ▫ E.g. Heart block and cardiac arrest ▫ epinephrine Therapeutic uses of sympathomimetics CARDIOVASCULAR APPLICATIONS Local vasoconstrictor ▫ Hemostatic ‘ Facial, oral, and nasopharyngeal surgery ‘ Gingivectomy ‘ E.g. epinephrine ▫ Decongestant ‘ E.g. psuedoephedrine, ephedrine, xylometazoline, oxymetazoline Therapeutic uses of sympathetic agonists CARDIOVASCULAR APPLICATIONS Hypertension ▫ Central –acting sympathoplegic drugs ‘ methyldopa (Aldomet), Clonidine (Catapres) ‘ Moxonidine, Rilmenidine ‘ Apraclonidine, Brimonidine, Tizanidine, Dexmedetomidine ‘ Guanbenz (Wytensin), Guanfacine (Tenex) Therapeutic uses of sympathomimetics PULMONARY APPLICATIONS – Asthma 2-selective agonists Short-acting Long-acting ▫ Bambuterol ▫ Albuterol / Salbutamol ▫ Clenbuterol ▫ Metaproterenol ▫ Formoterol ▫ Terbutaline ▫ Salmeterol ▫ Bitolterol ▫ Tolubuterol ▫ Fenoterol ▫ Levalbuterol Ultra Long-acting ▫ Pirbuterol o Indacaterol o Olodaterol o Vilanterol Therapeutic uses of sympathomimetics ANAPHYLAXIS Syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension Epinephrine 0.3 to 0.5 mg (0.3 to 0.5 ml of a 1:1000 solution) Therapeutic uses of sympathomimetics OPHTHALMIC APPLICATIONS Mydriasis (Localize lesions of Horner’s syndrome) ▫ Phenylephrine Glaucoma ▫ Apraclonidine, brimonidine (alpha 2 selective) ▫ Beta-blocking agents* (e.g. Timolol) ▫ Epinephrine, dipivefrin Therapeutic uses of sympathomimetics GENITOURINARY APPLICATIONS Preterm labor ▫ Isoxuprine ▫ Ritodrine ▫ Terbutaline Overactive bladder ▫ Mirabegron Stress incontinence ▫ Ephedrine ▫ Pseudoephedrine Therapeutic uses of sympathomimetics CNS APPLICATIONS Mood-elevation Nacrolepsy – Modafinil, armodafinil Appetite suppressant – Amphetamine-like agents Attention-deficit hyperactive disorder (ADHD) ▫ Methylphenidate, Atomoxetine, Riboxetine, clonidine and guanfacine Diarrhea secondary to autonomic neuropathy in DM ▫ Clonidine Therapeutic uses of sympathomimetics OTHER APPLICATIONS Narcotic and alcohol withdrawal - clonidine Menopausal hot flushes - clonidine Sedation - Dexmedetomidine Muscle relaxant - Tizanidine ADRENERGIC AGONIST ADVERSE EFFECTS Palpitations Dizziness Nervousness or tremor Tachycardia Cardiac arrhythmias Anginal pain Hypertension ADRENERGIC AGONIST ADVERSE EFFECTS Tissue necrosis (when applied to laceration of periphery, for example, nose, fingers, and toes) Hyperglycemia Headache and insomnia ADRENERGIC AGONIST CONTRAINDICATIONS AND PRECAUTIONS Angina Coronary insufficiency Hypertension Cardiac arrhythmias Angle-closure glaucoma Organic brain damage Hyperthyroidism ADRENERGIC AGONIST DRUG INTERACTIONS CNS drugs (e.g., alcohol, monoamine oxidase inhibitors (MAOIs), and antidepressants) Propranolol (Inderal) or other beta-adrenergic blockers Terazosin (Hytrin) or other alpha-adrenergic blockers ADRENOCEPTOR ANTAGONIST Alpha receptor antagonist Mechanism of action ▫ Reversible (e.g. Phentolamine, prazosin) ▫ Irreversible (e.g. Phenoxybenzamine) Alpha receptor antagonist Mechanism of action ▫ Reversible (e.g. Phentolamine, prazosin) ‘ Duration of action is dependent on the following: ‘ half-life ‘ Rate of dissociation from the receptor ▫ Irreversible (e.g. Phenoxybenzamine) Alpha receptor antagonist Mechanism of action ▫ Reversible (e.g. Phentolamine, prazosin) ▫ Irreversible (e.g. Phenoxybenzamine) ‘ Effects persist after plasma clearance ‘ Restoration of tissue responsiveness depend on the synthesis of new receptors Alpha antagonist Pharmacologic effects Cardiovascular ▫ Lowers PVR  lowers BP ▫ Epinephrine reversal ▫ Orthostatic hypotension ▫ Tachycardia Alpha antagonist Pharmacologic effects Other effects ▫ Miosis ▫ Nasal stuffiness ▫ Decreased resistance to urine flow Alpha receptor antagonist selectivity Prazosin, terazosin, α1 > > > > α2 doxazosin Phenoxybenzamine α1 > α2 Phentolamine α1 = α2 Rauwolscine, α2 > > α1 yohimbine, tolazoline  Alpha receptor antagonist Non-selective Alpha-1 Alpha-2 selective selective Phenoxybenzamine Prazosin Yohimbine Terazosin Phentolamine Doxazosin Alfuzosin Tamsulosin Indoramin Urapidil Bunazosin Alpha antagonist Clinical uses Pheochromocytoma ▫ (e.g. phenoxybenzamine, metyrosine, reversible alpha-1 blockers, calcium channel blocker) Hypertensive emergencies (limited application) Chronic hypertension ▫ (e.g. Prazosin) Alpha antagonist Clinical uses Peripheral vascular disease ▫ (Reynaud’s phenomenon) ▫ (e.g. Prazosin, phenoxybenzamine, calcium channel blockers) Urinary obstruction (BPH) ▫ (e.g. Prazosin, terazosin, doxazosin, tamsulosin) Erectile dysfunction ▫ (e.g. Phentolamine) Alpha antagonist Clinical uses DM II ▫ (e.g. Alpha-2 receptor blockers) Depression ▫ (e.g. Alpha-2 receptor blockers) Alpha receptor antagonist SIDE EFFECTS Postural hypotension Tachycardia Nasal stuffiness Decreases resistance to flow of urine Dizziness, headache Ejaculation dysfunction, decreased libido, impotence Beta receptor antagonist selectivity Metoprolol, acebutolol, β1 >>> β2 alprenolol, atenolol, betaxolol, celiprolol, esmolol Propanolol, carteolol, β1 = β2 penbutolol, pindolol, timolol Butoxamine β2 >>> β1 Beta receptor antagonist selectivity Beta receptor antagonist Non- Beta-1 Non- Beta-1 selective selective selective selective (1st gen) (2nd gen) (3rd gen) (3rd gen) Nadolol Acebutolol Carteolol Betaxolol Penbutolol Atenolol Carvedilol Celiprolol Pindolol Bisoprolol Bucindolol* Nevibilol Propanolol Esmolol Labetolol Timolol Metoprolol Medroxalol* Beta receptor antagonist Mixed antagonist Labetalol β1 = β 2 > α1 > α2 carvediol, medroxalol, bucindolol Beta receptor antagonist Pure antagonist Partial agonist Inverse agonist (betaxolol, metoprolol) PHARMACOLOGICAL/PHARMACOKINETIC PROPERTIES OF β ADRENERGIC RECEPTOR BLOCKING PHARMACOLOGICAL/PHARMACOKINETIC PROPERTIES OF β ADRENERGIC RECEPTOR BLOCKING PHARMACOLOGICAL/PHARMACOKINETIC PROPERTIES OF β ADRENERGIC RECEPTOR BLOCKING Beta receptor antagonist Pharmacologic actions CARDIOVASCULAR SYSTEM ▫ Lower blood pressure ▫ Inhibit renin release ▫ Heart ‘ negative chronotropic and inotropic effect ‘ Slowed AV conduction (increase PR interval) ▫ Increased peripheral vascular resistance Beta antagonist THIRD-GENERATION β RECEPTOR ANTAGONISTS WITH PUTATIVE ADDITIONAL MECHANISMS OF VASODILATATIONODILATION Mechanisms underlying actions of vasodilating ß blockers in blood vessels Beta receptor antagonist Pharmacologic actions RESPIRATORY TRACT ▫ Increased airway resistance Beta receptor antagonist Pharmacologic actions EYE ▫ Decreased aqueous secretion from ciliary epithelium  reduce IOP Beta receptor antagonist Pharmacologic actions METABOLIC AND ENDOCRINE EFFECTS ▫ Inhibit lipolysis ▫ Inhibit glycogenolysis ▫ Increased VLDL concentration, decreased HDL, no effect on LDL Beta receptor antagonist Pharmacologic actions NOT RELATED TO BETA-BLOCKADE ▫ Intrinsic sympathomimetic activity ▫ Local anesthetic action (membrane-stabilizing action)Exception: Timolol ▫ Attenuate oxygen free radical-initiated lipid metabolism ▫ Inhibit vascular smooth muscle mitogenesis Beta receptor antagonist Clinical Uses Hypertension Ischemic heart disease, myocardial infarction ▫ Timolol, propanolol, metoprolol Cardiac arrhythmias ( SVT and ventricular, atrial flutter and fibrillation, ventricular ectopic beats) Heart failure ▫ Metoprolol, bisoprolol, carvedilol Other cardiovascular disorders (cardiomyopathy, dissecting aortic aneurysm) Beta receptor antagonist Clinical Uses Glaucoma ▫ Timolol (1 mg/day), betaxolol, carteolol, levobunolol, metipranolol Hyperthyroidism ▫ Propranolol Neurologic disease ▫ Migraine - Metoprolol, atenolol, timolol, nadolol ▫ Tremors ▫ Anxiety – low dose propranolol ▫ Symptomatic alcohol withdrawal – propranolol Beta receptor antagonist Clinical Uses Miscellaneous ▫ Liver cirrhosis ▫ Esophageal varices ‘ propranolol, nadolol ‘ Sclerotherapy – nadolol + isosorbide mononitrate Beta receptor antagonist SIDE EFFECTS Hypotension Bradycardia Bronchoconstriction / airway obstruction Fatigue or lethargy Nausea and vomiting Hypoglycemia CNS: Confusion, mild sedation, vivid dreams, depression Beta receptor antagonist CONTRAINDICATION AND PRECAUTION Congestive heart failure Atrioventricular block Ischemic heart disease Hypotension, shock Asthma / COPD Diabetes Beta receptor antagonist DRUG INTERACTIONS Digitalis Insulin or oral antidiabetic agents Theophylline MAOIs and tricyclic antidepressants Epinephrine Calcium channel blockers (verapamil) Alcohol Quinidine fluoxetine Therapeutic uses of indirect acting sympathoplegics CARDIOVASCULAR APPLICATIONS Hypertension ▫ Ganglion – blocking agent ‘ Trimethapan (Arfonad), Mecamylamine (Inversine) ▫ Adrenergic neuron-blocking agents ‘ Guanethidine (Ismelin), Reserpine