Pharmacology: Autonomic Nervous System / Sympathetic PDF

Module 4 Pharmacology: Autonomic Nervous System / Sympathetic OUTLINE ▪ Extrinsic innervation of GIT I. Introduction II. Sympathetic Nervous System − Sympathetic A. Anatomy and...

Module 4 Pharmacology: Autonomic Nervous System / Sympathetic OUTLINE ▪ Extrinsic innervation of GIT I. Introduction II. Sympathetic Nervous System − Sympathetic A. Anatomy and A. Biosynthesis − Parasympathetic (more dominant effect in GIT) Physiology B. Receptors, Location, → Substances that may affect the GIT: B. Sympathetic vs. Response ▪ Substance P Parasympathetic C. Sympathetic Agonists ▪ Vasoactive intestinal peptide (VIP) D. Sympathetic ▪ Neuropeptide Y Antagonists B. Sympathetic vs. Parasympathetic I. INTRODUCTION Sympathetic aka “Adrenergic Nervous System” A. Anatomy and Physiology Parasympathetic aka “Cholinergic Nervous System” Figure 1. Somatic nervous system vs. autonomic nervous system Central Nervous System: brain and spinal cord → 2 Effector: ▪ Somatic nervous system Figure 2. Diagram of anatomic and neurotransmitter features of autonomic and somatic − skeletal muscles → voluntary motor nerves. ▪ Autonomic nervous system − smooth muscles → involuntary Parasympathetic Parts of or Sympathetic Receptors Neurotransmitter the Spine Synaptic Neurotransmission (Origin) Transmission of neural impulses → presynapse → synaptic cleft Cranial Nicotinic, Acetylcholine Parasympathetic → postsynapse (Cervical) Muscarinic (ACh) Presynapse contains vesicles that serves as storage area for the Thoracic Sympathetic α, β, D Catecholamines neurotransmitters. Lumbar Sympathetic α, β, D Catecholamines ↑ Ca+2 will move the presynaptic vesicles closer to the synaptic Nicotinic, Sacral Parasympathetic Acetylcholine cleft and neurotransmitters will be released. These Muscarinic neurotransmitters will then bind to the receptors in the postsynapse Sympathetic Parasympathetic Preganglionic Shorter Longer Autonomic Nervous System fiber Postganglionic Longer Shorter 3 Important Components: fiber Sympathetic Ganglion Closer to spinal Closer to the target organ Parasympathetic cord Enteric nervous system *All preganglionic receptors are parasympathetic to where ACh → Affects the gastrointestinal tract (GIT) binds. ▪ Intrinsic innervation of GIT − Auerbach plexus: involved more in motility o Myenteric plexus − Meissner plexus: involved more in secretion o Submucosal plexus Module 4 Pharmacology-Pharmacokinetics and Biopharmaceutics  Recall: Cranial nerves (Oh Oh Oh, To Touch And Feel a Virgin Girl’s II. SYMPATHETIC NERVOUS SYSTEM Vagina Ah Heavenly) A. Biosynthesis of Catecholamines I Olfactory VII Facial Location: Brain, spinal cord, post-ganglionic sympathetic fibers, II Optic VIII Vestibulocochlear and adrenal medulla III Oculomotor IX Glossopharyngeal IV Trochlear X Vagus Steps of Biosynthesis V Trigeminal XI Accessory Nerve (Pare True Love Does Not Exist) VI Abducens XII Hypoglossal → Parasympathetic cranial nerves (1973): Cranial Nerve X, IX, VII, and III → Vitamin K dependent clotting factor (1972): Clotting Factor X, IX, VII, II Effects of sympathetic vs. parasympathetic: Sympathetic Parasympathetic (Adrenergic) (Cholinergic) Principal Catecholamines Acetylcholine Neurotransmitter “Fight, Flight, “Rest and Digest” Fright” Effect on eyes Mydriasis Miosis (pupillary dilation) Effect on heart Tachycardia Bradycardia (↑ HR) (↓ HR) Effect on lungs Bronchodilation Bronchoconstriction / bronchospasm Effect Smooth Relax Contract in GIT muscle Sphincter Contract Relax Effect Detrusor Relax (Urination) on Contract urinary Figure 3. Pathway of catecholamine synthesis. Urethral Contract Relax bladder Sphincter Effect on male sex Ejaculation Erection Epinephrine produces sympathetic effects. organs (Shoot) (Point) Rate limiting step: Conversion of Tyrosine to L-DOPA; tyrosine “Point and Shoot” decarboxylase is inhibited by Metyrosine. Effect on sweat Sweating Sweating Dopamine must immediately undergo vesicular uptake so that glands (Apocrine: palms (Eccrine) monoamine oxidase (MAO) cannot destroy it. and soles) → Reserpine inhibits vesicular uptake; ↓ dopamine which will risk patient for depression Conversion of dopamine → norepinephrine happens in the adrenal medulla. Causes release of NE (AETA): → Amphetamine → Ephedrine → Tyramine → Angiotensin II Inhibits release: Guanethidine , Guanadrel Fate of Norepinephrine Bind to the receptor → Reuptake ▪ Inhibited by: − Selective Norepinephrine Reuptake Inhibitor (SNRI): Venlafaxine and Duloxetine (Antidepressants) − Cocaine − Tricyclic antidepressants (TCA): Imipramine and Amitriptyline Module 4 Pharmacology: Autonomic Nervous System / Sympathetic  → Metabolized (MAO, COMT) Causes tremors ▪ MAO is inhibited by (MPITS): Intracellular shift of K+ toward the cell, hence hypokalemia. − Moclobemide (vs. MAO-A), Phenelzine, Isocarboxazid, Tranylcypromine, Selegiline (vs. MAO-B) Recall: Other factors causing hypokalemia (IBA ka Pumasok): − PIT: Nonselective Insulin, β2 receptor, Alkalosis ▪ COMT inhibitors: - capone Dopamine Receptor (D1, D2, D3, D4) B. Receptors, Location, Response D1 → afferent arteriolar dilation → promotes urination by α1 Receptor (GQ) increasing GFR Blood vessels: vasoconstriction D2 – D4 Eyes: mydriasis (radial muscles) → (+) nausea, vomiting due to loss of peristalsis Piloerector muscle: piloerection (goosebumps) → Stomach distention → Dopamine Urinary bladder: urinary retention Dopamine antagonist: Metoclopramide (Placil ®) → Detrusor: relax Inhibits GABAergic neurons → Urethral sphincter: contract Recall: α2 Receptor (G1) Excitatory: Glutamate, Aspartate Presynapse Post synapse Inhibitory: GABA, glycine ↓ sympathetic tone → vasoconstriction Dopamine inhibits GABAergic vasodilation start sedation, depression → Parkinson’s Disease ▪ Degeneration of the substantia nigra β1 Receptor (Gs) ▪ ↓↓ Dopamine ▪ Akinesia, rigidity Heart (+) inotropic effect → ↑ contractility ▪ Treatment (Tx): Administer levodopa + carbidopa (+) chronotropic → ↑ HR → Psychosis: ↑↑ Dopamine (+) dromotropic → ↑ conduction velocity ▪ Schizophrenia Kidneys – ↑ renin secretion − Tx: Dopamine antagonist which are typical antipsychotics. o Phenothiazine (Chlorpromazine, Thioridazine) o Butyrophenone (Haloperidol, Droperidol) o Thiothixene (vs. Atypical antipsychotic like clozapine which can cause agranulocytosis) → Prolactin inhibition ▪ Adverse effect of dopamine antagonists. ▪ Example: Hyperprolactinemia (milk production) ▪ Tx: Bromocriptine C. Sympathetic Agonist Direct-acting MOA: Directly stimulate the sympathetic receptors a. Non-selective (α, β, D) → Natural catecholamines → Epinephrine – α1, β1, β2 → Norepinephrine - α1, β1 → Dopamine ▪ Dopamine receptors ▪ β1 receptor ▪ α1 receptor Pharmacokinetics → Very poor oral bioavailability ▪ Limits own absorption Recall: α1 – vasoconstriction ▪ Extensive first pass effect Figure 4. Renin-angiotensin-aldosterone system. → Metabolism: MAO, COMT ▪ Metabolite: VMA = vanillylmandelic acid β2 Receptor (Gs) Lungs: bronchodilation Recall: pheochromocytoma – tumor in the adrenal medulla Uterine smooth muscle: relaxation (tocolytic effect) − ↑↑↑ Epinephrine Blood vessel: vasodilation − ↑↑↑ MA → urine, serum Module 4 Pharmacology: Autonomic Nervous System / Sympathetic  Pharmacodynamics c. Β1 selective → Epinephrine → Example: Dobutamine ▪ 1st line cardiac stimulant in Advanced Cardiac Life Support ▪ Can be used for pharmacologic stress testing (ACLS) Recall: Stress Test – measures how much the heart can handle ▪ 1 mg every 2 mins. (3-5 mins) Exercise: Treadmill Recall: cardiac arrest → cardiopulmonary resuscitation Drug: Dobutamine, Dipyridamole (+) chest compression d. Β2 selective ▪ 1st line agent against anaphylactic shock Short-acting Long-acting − Anaphylaxis: IgE-mediated release of histamine; two or (SABA) (LABA) more organ systems are involved Salbutamol Salmeterol − Gell and Coomb’s Albuterol Formoterol o I. Immediate hypersensitivity Terbutaline Bambuterol → Uses: Recall: Hypersensitivity vs. Anaphylaxis ▪ Bronchodilator (bronchial asthma, COPD) Hypersensitivity Anaphylaxis − Reliever (PRN) for acute exacerbation or flare Receptor H1 α1, β1, β2 o Salbutamol: 1 inhalation every 20 mins for 3 doses Treatment Antihistamine Epinephrine − Controller for maintenance (same receptor → (different receptor o LABA + Steroids pharmacologic → physiologic o Budesonide + Formoterol (Symbicort®) antagonist) antagonist) o Salmeterol + Fluticasone (Seretide®) Recall: Anaphylactoid shock is non-IgE mediated and seen in ▪ Tocolytic agent (uterine smooth muscle relaxation) patients using opioids and curare derivatives − Terbutaline o Indication: For pre-term labor (off label use) ▪ Vasoconstrictor o Avoid if patient has hyperthyroidism or Type 2 − Example: Epinephrine + Lidocaine (local anesthetic) diabetes mellitus − All local anesthetic agents will cause vasodilation except Recall: Hyperthyroidism increases thyroid hormones which cocaine. Ephedrine is administered to constrict the blood upregulates the β1 receptors in the heart → (+) ionotropic, vessels hence, keeps the concentration of the chronotropic, dromotropic anesthetic in the target site of action. o Note: Terbutaline has significant β1 activity ▪ Dipivefrin → prodrug o vs. symptomatic bradycardia − Drug for glaucoma Recall: Management of preterm labor (STAT): → Norepinephrine (Levophed®) - Steroids for lung maturity ▪ 1st line inotropic agent in septic shock - Tocolysis (Nifedipine) ▪ Infection activates cytokines inflammatory mediators which - And transfer to causes vasodilation and decreases BP - Tertiary hospital ▪ Norepinephrine has no significant activity on β2 receptors, Type 2 DM which is a vasodilator. - Terbutaline → gluconeogenesis (new sources → → Dopamine glucose) ▪ Administered as an IV infusion ▪ Management of hyperkalemia ▪ Effect depends on the dose − AE: Hypokalemia Low dose D1 receptor in the kidneys: ↑ GFR − Hypokalemia is more common because kidney can 15 μg/kg/min propylhexedrine, methoxamine ▪ vs. cardiogenic shock ▪ Phenylephrine and Oxymetazoline (Drixine®) nasal spray ▪ vs. septic shock → Uses: ▪ SE: tachyarrhythmia due to excessive β1 stimulation ▪ Vasoconstrictor effect → nasal decongestant − Constrict → shrinkage of tissues → facilitate better b. Beta non-selective (β1 and β2) drainage → Example: Isoproterenol ▪ Management of conjunctivitis or “sore eyes” ▪ 1st drug → metered dose inhaler (MDI) vs. bronchial asthma − Usually viral (Adenovirus) and is self-limiting ▪ Causes vasodilation − Tetrahydrozoline (Visine®) → vasoconstriction ▪ Adverse Effects (AE): Tachyphylaxis or rapid development decreases redness of tolerance o Only for symptomatic relief − Tendency to ↑ dose o AE: Exacerbation of hypertension, urinary retention, − ↑ β2 → Bronchodilation (good effect) peripheral vasoconstriction (can lead to digital − ↑ β1→ Tachyarrhythmia (bad effect) necrosis), rhinitis medicamentosa (rebound ▪ Isoproterenol is seldom used these days because it can congestion), mydriasis (blurring of vision) cause overstimulation of β receptors Module 4 Pharmacology: Autonomic Nervous System / Sympathetic 4 of 6  f. α2 agonist Cocaine Recall: Presynapse (vasodilation) vs postsynapse → Local anesthetic (vasoconstriction) → Ester ▪ Clonidine → Causes vasocontraction − vs. hypertension (hypertensive emergency) − JNC 7 severe hypertension Centrally-acting Urgency Emergency Example: Phenylpropanolamine, Methylfenidate, Amphetamine, (+) headache (+) end organ damage Phentermine, Phenmetrazine (+) anxiety stroke Uses: (+) shortness of breath myocardial infarction → ADHD eclampsia ▪ Methylfenidate, Amphetamine intracerebral hemorrhage → Anorexians (↓ appetite) ER ICU ▪ Phentermine, Phenmetrazine Captopril Goals: → Narcolepsy Labetalol ↓ BP by NMT 25% within 1 AE: Addiction (especially Amphetamine), primary pulmonary Clonidine hour hypertension increase risk for stroke BP ≤ 160/100 mmHg within 6 hours D. Sympathetic Antagonist − Antihypertensive for dialysis patients Alpha Blockers o For dialysis: ↓ blood volume; ↓BP – hypotension a. Non-selective (α1 , α2) − Derivatives: Apraclonidine, Brimonidine o Nasal decongestant → Irreversible: Phenoxybenzamine − Adjunct in Attention Deficit – Hyperactivity Disorder → Reversible: Phentolamine (ADHD) b. Selective (α1 , α2) − AE: Rebound hypertension with missed doses (Management: vasodilator like sodium nitroprusside IV), → α1: -zocin, i.e. Prazocin, Tamsulocin sedation, depression) → α2: -zocin, i.e. Yohimbine, Rauwolfscine ▪ Methyldopa (Aldomet®) Uses: − MOA: “false neurotransmitter” → Pheochromocytoma – tumor in the adrenal medulla − MethyDOPA → Methyldopamine → ▪ ↑↑ Epinephrine → Vanillylmandelic acid (VMA) Methynorepinephrine ▪ (+) Hypertension − Use: hypertension in pregnancy ▪ Diagnosis:2 Recall: Methyldopa, Hydralazine, Labetalol, Nifedipine − Imaging (CT scan, MRI) - Gestational hypertension: BP ≥ 140/90 mmHg after 20 − VMA assay (urine, serum) weeks age of gestation ▪ Management: - Preeclampsia: (+) proteinuria; (+) severe features − Surgery (preoperative: Phenobarbital, Hexobarbital, - Eclampsia: (+) generalized tonic-clonic seizures Secobarbital) - Cure: Delivery of child − Pharmacologic: α-blocker; β-blocker − AE: Hepatotoxicity (NMT 2g/day), (+) Direct Coomb’s → Raynaud’s phenomenon Test for hemolytic anemia, sedation, depression ▪ Digital vasoconstriction in response to cold environment ▪ Management: g. Dopamine agonist − Ca2+ channel blockers → vasodilation → Fenoldopam − α-blockers ▪ Vasodilator vs. severe hypertension → Urinary retention → Bromocriptine ▪ Seen in patients with Benign Prostatic Enlargement (BPE) ▪ Indication: hyperprolactinemia Recall: Hypertrophy vs. hyperplasia − Hypertrophy: ↑ size of cells Indirect-acting − Hyperplasia: no. of cells MOA: There are 2 mechanisms ▪ Management: Tamsulosin → Release of norepinephrine → Carcinoid syndrome ▪ e.g. Amphetamine, Ephedrine, Tyramine, Angiotensin II ▪ Tumor affecting the enterochromaffin-like cells → Reuptake of norepinephrine ▪ ↑↑ Serotonin ▪ e.g. SNRI, TCA, Cocaine ▪ (+) Flushing, watery diarrhea, headache ▪ Management: Ephedrine (Ma Huang) − Phenoxybenzamine (serotonin antagonist) → MOA: release of norepinephrine (indirect) and direct stimulation of α and β receptors → Erectile disfunction ▪ Example: Phentolamine → vasodilation → Uses: ▪ Currently: Sildenafil ▪ Nasal decongestant (vasoconstriction) ▪ ↑ nitric oxide, ↑ cGMP, vasodilation ▪ Intraoperative hypotension AE: Orthostatic hypotension (BP decrease > 20/10mmHg) → AE: Excess may lead to hypertension Module 4 Pharmacology: Autonomic Nervous System / Sympathetic  Recall: Baroreceptor reflex mechanism For stable congestive heart failure or ejection fraction of less than − (On standing) blood pulled down to the lower 40% extremities → ↓ circulating blood volume → ↓ BP → [Mnemonic: Baba CHF Mortality] Bisoprolol, Carvedilol, (detected by baroreceptors and send signals to the Metoprolol brain to active sympathetic nervous system) Serve as Class II anti-arrhythmic agents − Brain activates the blood vessels through α1 receptors → [Mnemonic: PEA] Propranolol, Esmolol, Acebutolol causing vasoconstriction and the heart through β1 Other uses receptors causing (+) inotropic, chronotropic, and → Prophylaxis for migraine headache dromotropic effects; both causing increase in BP → Management of performance anxiety − α1 blockers (“-zocin”) inhibits occurrence of → For tremors vasoconstriction → For patients with hyperthyroidism − Exhibit First Dose Phenomenon with symptomatic ▪ High levels of thyroid hormones → upregulate β1 receptors orthostatic hypotension and possible syncope in the heart Beta Blockers Watch Out For: Classification Rebound tachycardia / hypertension (except for CLAP) Based on selectivity Mask symptoms of hypoglycemia Selective / Cardio-selective Recall: Hypoglycemia Non-Selective − Hypoglycemia → stimulate signals to the counter (β1 Blockers) [Mnemonic: NBEAM] regulatory hormones that increase glucose (epinephrine, Pindolol Nebivolol glucagon, GH, cortisol) Nadolol Bisoprolol, Betaxolol − Epinephrine attaches to sympathetic receptors → (+) Propranolol Esmolol palpitations, lightheadedness, diaphoresis Timolol Acebutolol, Atenolol − β blockers act on the same receptors masking symptoms Metoprolol elicited by epinephrine during hypoglycemic state Not for patients with COPD Recent guidelines allow − Conclusion: Patients with Type 2 DM taking OHA and β and asthma (since blocking β2 cardio-selective β blockers blockers may have hypoglycemia with no palpitations, → bronchoconstriction) with asthma and COPD lightheadedness, diaphoresis since β blockers mask symptoms of hypoglycemia Based on intrinsic sympathomimetic activity [Mnemonic: CLAP] → Associated with less rebound tachycardia Contraindications: → Carteolol, Labetalol, Acebutolol, Pindolol According to Canadian guidelines, > 65 years old. Based on membrane stabilizing activity [Mnemonic: PALM] Bradycardia (β blockers have negative dromotropic effect) → Propranolol, Pindolol, Acebutolol, Labetalol, Metoprolol Heart block (β blockers have negative chronotropic effect) → Likened to class I anti-arrhythmic Na+ channel blockers Unstable CHF ▪ Lead to hyperpolarization → cell-stabilizing Low exercise tolerance → Local anesthetic effects Concurrent use of calcium channel blockers ▪ Not to be given to the eye → may not be able to detect → Non-dihydropyridine (Verapamil, Diltiazem) → bradycardia, (-) foreign objects inotropic effect, ↓ heart rate Mixed activity (α and β) → Carvedilol, Labetalol Uses For hypertension with post myocardial infarction → Goal of β blockers: decreased workload in the heart Recall: β1 Actions − Heart: (+) inotropic, chronotropic, dromotropic − Kidneys: affect RAAS through aldosterone → increasing sodium, water reabsorption → increase in resistance in blood vessels → increased workload in the heart − β1 blockers target pathway in kidneys Recall: First line for hypertension − Calcium channel blockers − ACEIs, ARBs − Thiazide diuretics “Cornerstone” for the management of chronic stable angina pectoris or ischemic heart disease Module 4 Pharmacology: Autonomic Nervous System / Sympathetic