Autonomic Nervous System Drugs: Pharmacology Lecture PDF

DRUGS ACTING ON THE AUTONOMIC NERVOUS SYSTEM I. SYMPATHETIC DRUGS II. PARASYMPATHETIC DRUGS Leeland Anthony L. dela Luna, RPh, PharmD, MS Pharmacology  SYMPATHETIC DRUGS SYMPATHOMIMETICS/ADRENERGICS – Mimetics = MIMICS 1. Direct Sympathomimetics Direct = bind direct t...

DRUGS ACTING ON THE AUTONOMIC NERVOUS SYSTEM I. SYMPATHETIC DRUGS II. PARASYMPATHETIC DRUGS Leeland Anthony L. dela Luna, RPh, PharmD, MS Pharmacology  SYMPATHETIC DRUGS SYMPATHOMIMETICS/ADRENERGICS – Mimetics = MIMICS 1. Direct Sympathomimetics Direct = bind direct to RECEPTOR 2. Indirect Sympathomimetics and Mixed Agents – ↑ sympathetic response = OTHER MEANS  SYMPATHETIC DRUGS SYMPATHOLYTICS/ SYMPATHOPLEGICS – Lytics = LYSE/Break 1. Centrally acting antiadrenergics (targets CNS) Stimulates α2 receptors 2. Peripheral presynaptic antiadrenergics 3. Peripheral postsynaptic antiadrenergics a. α-blockers b. β-blockers  PARASYMPATHETIC DRUGS PARASYMPATHOMIMETICS/ CHOLINOMIMETICS 1. Direct cholinergic agonist Binds DIRECTLY to receptors 2. Indirect cholinergic agents Inhibits Cholinesterase ↓Cholinesterase = ↑ Ach = ↑ Cholinergic effects  PARASYMPATHETIC DRUGS PARASYMPATHOLYTICS/ CHOLINERGIC ANTAGONISTS 1. Muscarinic antagonist/ Antimuscarinic Blocks M receptors 2. Ganglionic blockers Blocks NN 3. Neuromuscular blockers Blocks NM SYMPATHETIC DRUGS  ADRENERGIC DRUGS ADRENALINE is the prototype drug. Its clinical uses are: A - Anaphylactic shock (DOC) B - Bronchial asthma C - Cardiac resuscitation D - During local anaesthesia combined with lidocaine  Direct sympathomimetics NE, Epinephrine and Dopamine are ENDOGENOUS sympathetic agonists Binds to α1, α2, β1, or β2 adrenergic receptors where they “turn on” second messengers  SYMPATHOMIMETICS ACTING AT BETA RECEPTOR SYSTEMS Inotrope Dopamine and Dobutamine – Used in Congestive heart failure and cardiogenic shock Vasopressor – Activate the myocardial beta1 receptor and thus increase the force of contraction of the failing heart This will result in an increase in cardiac output – These drugs are reserved for use in the acute management of heart failure  Direct Sympathomimetics I. Catecholamines (“DENIeD”) II. Non-catecholamines – Dobutamine Longer half-lives Phenylephrine & Methoxamine – Epinephrine – Marketed as nasal and ophthalmic – Norepinephrine decongestants Metaproterenol, Albuterol, – Isoproterenol Bitolterol, Terbutaline, – Dopamine Isoetharine, Salmeterol, Short duration of action Salbutamol Clinically used to treat – Bronchodilators anaphylaxis, cardiac arrest, Ritodrine heart failure and shock – Uterine relaxant Used as IV Used Orally  Major α and β direct-acting agonists Think: Drugs that sound NATURAL in the body. Many uses: –Epinephrine (Adrenalin chloride) Anaphylaxis, Cardiac –Norepinephrine (Levophed) resuscitation, –Dopamine (Intropin) Mydriatic, etc… Specific use: Used for SEPTIC or Life threatening CARDIOGENIC Shock HYPOTENSION; Used to maintain BP  α1-selective direct-acting agonists Starts with “Phenyl – ” Used for Nasal Decongestion –Phenylephrine (Neo-Synephrine) –Phenylpropanolamine Except!!! –Methoxamine (Vasoxyl)  Classification of Sympathomimetics: β- Receptor Specificity/Affinity β-NONselective direct-acting Used for – Isoproterenol (Isuprel) – β1, β2 BRADYCARDIA & Asthma β1-SELECTIVE direct-acting – Dobutamine (Dobutrex) – β1 Used for Acute HEART FAILURE  Beta 2 Agonist CONTROLLERS “FriendS of MR. TAT” RELIEVERS Long Acting Short Acting F-Formoterol M-Metaproterenol R-Ritodrine S-Salmeterol T-Terbutaline A-Albuterol/Salbutamol T-Theophyline (methylxanthine)  Indirect acting agonists Release neurotransmitters from presynaptic nerve terminals to produce a sympathomimetic effect – Amphetamine – Methamphetamine Useful in NARCOLEPSY, hyperkinetic syndrome of children, attention deficit disorder (ADHD)  Mixed sympathomimetics Displace NE from presynaptic terminals and bind to adrenergic receptors – Ephedrine – clinically used to treat narcolepsy – Mephentermine & Metaraminol – Treatment of hypotension caused by ANESTHETICS. – Phenylpropanolamine – Decongestant in oral OTC drugs Can cause HAEMORRHAGIC STROKE  Appetite SUPPRESSANT SYMPATHOLYTIC DRUGS  Presynaptic Adrenergic Blockers Peripheral Presynaptic anti-adrenergics – Guanethidine = ↓ Catecholamine release (reuptake to the vesicles then replace NE) – Guanadrel – Bretylium (no longer used) – Reserpine (deplete catecholamines)  α2-selective direct-acting agonists Can cause SEDATION Centrally Acting ANTIADRENERGICS –Clonidine (Catapres) Used to manage High –Guanfacine Blood Pressure & –Methyldopa (Aldomet) ADHD –Guanabenz Used to manage High Blood Pressure  α1 – adrenergic selective, reversible All drugs that ends in “- ZOSIN” –Prazosin (Minipres) –Doxazosin (Cardura) EFFECTS: –Terazosin (Hytrin) ↓ BP without ↑ HR Cause FIRST DOSE SYNCOPE INDICATION: Hypertension Treat Urinary retention due to BPH  α1,α2 – nonselective blocker Drugs that starts with “Phen-” Irreversible = Longest –Phenoxybenzamine (Dibenzyline) Reversible = Shortest IRREVERSIBLE: Used before operation for –Phentolamine (Regitine) Pheochromocytoma REVERSIBLE: Used to manage paroxysmal HTN due to Pheochromocytoma  α2 – selective blocker, reversible For erectile –Yohimbine dysfunction Migraine & Oxytocic Adjunct Tx for dementia  BETA ADRENERGIC RECEPTOR BLOCKERS These drugs are competitive antagonists of the beta adrenergic receptors Beta blockers are either selective for the beta1 receptor or nonselective beta1 and beta2 antagonists PROTOTYPE DRUG: Propranolol  Beta-blocker main contraindications / cautions “ABCDE” A - Asthma B - Block (heart block)/Bradycardia C - COPD D - Diabetes mellitus E – Electrolyte imbalance (hyperkalemia)  Non Selective Beta Blockers “NSTP” Nadolol Sotalol Timolol Propranolol/Pindolol  Cardioselective Beta Blockers "CaN BEAM" Celiprolol Can cause DYSLIPIDEMIA Nebivolol (most selective) Bisoprolol, Betaxolol Esmolol Atenolol, Acebutolol Metoprolol  Beta blockers with ISA Think: They "COntain Partial Agonistic Activity“ Celiprolol, Oxprenolol Can minimize risk for BRADYCARDIA Pindolol, Penbutolol NON SELECTIVE BLOCKERS Alprenolol No effect on Lipid Levels Acebutolol (B1 selective)  Beta blockers with α1 Blocking Activity LabetAlol = α Does not cause DYSLIPIDEMIA Has added VASODILATING CarvedIlol = 1 effects  Beta 2 Blockers Butaxamine = no clinical use = used in experiments  Adverse effects commonly observed with beta blockers Hypotension Bradycardia Fatigue Drowsiness Bronchoconstriction and sexual dysfunction – commonly observed with propranolol CHOLINERGIC DRUGS  CHOLINERGIC AGENTS I. CHOLINOMIMETICS /CHOLINERGIC AGONISTS II. ANTICHOLINERGICS  CHOLINOMIMETICS A. DIRECT-ACTING CHOLINERGIC AGONISTS B. INDIRECT-ACTING AGENTS (CHOLINESTERASE INHIBITORS) i. Carbamates Physostigmine, Decamecarium, Neostigmine, Edrophonium, Pyridostigmine, Ambenonium ii. Organophosphates Echothiopate, Parathion, Malathion  CHOLINERGIC AGONISTS “ABC MNoP” A - Acetylcholine B - Bethanechol C - Carbachol M - Methacholine N - Nicotine P - Pilocarpine  Cholinergic Agonists Acetylcholine - miosis in cataract surgery Choline derivatives – Carbachol - Used in glaucoma, miosis for surgery – Methacholine – for diagnosis of bronchial airway hyperreactivity – Bethanecol – induce evacuation of non-obstructed bladder Alkaloids – Arecoline – Pilocarpine – For glaucoma, xerostomia – Muscarine – Nicotine – smoking cessation aid  ANTICHOLINESTERASE DRUGS “POP CoRN” Antidote for ATROPINE or scopolamine poisoning P - Physostigmine O - Organophosphates Mainly used for Myesthenia Gravis P - Pyridostigmine C - Carbamates Treats CONFUSION (dementia) related to Alzheimers & R - Rivastigmine Parkinsons N - Neostigmine Reversal agent for NONDEPOLARIZING NMB  Cholinesterase Inhibitors EDROPHONIUM – Competitive antagonist Used in TENSILON Test – Diagnosis of MG CARBAMATES – Compete with Ach for the active site of the enzyme – Physostigmine, Demecarium, Neostigmine, Ambenomium, Pyridostigmine ORGANOPHOSPHATES – Have very high affinity for the active site of the enzyme – Echothiopate – For glaucoma – Parathion, Malathion – Pesticide Diarrhea Urination CHOLINERGIC RESPONSE Miosis Bradycardia, Bronchoconstriction Emesis Lacrimation Salivation Sweating  Cholinesterase inhibitors are used to treat glaucoma and Myasthenia gravis Glaucoma Any of a group of eye diseases characterized by abnormally high intraocular fluid pressure, damaged optic disk, hardening of the eyeball, and partial to complete loss of vision Can lead to irreversible blindness by damaging the optic nerve.  Myasthenia gravis Is a neuromuscular disease leading to fluctuating muscle weakness and fatiguability An autoimmune disorder, in which weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction  Myasthenia gravis Symptom – Ptosis of the left eye (drooping eyelids) Treated medically with: – cholinesterase inhibitors – Immunosuppressants – in selected cases, thymectomy  Classification of Cholinergic AGONISTS Direct-Acting Indirect-Acting Acetylcholine Agonists Antiacetylcholinesterases Choline Esters Pilocarpine Carbamate Organo- Bethanechol Cevimeline Quarternary Physostigmine phosphates Carbachol Alcohols Malathion Neostigmine Tx of DRY MOUTH due Tacrine Echothiophate to SJOGREN’s disease Demecarium Edrophonium Parathion Pyridostigmine Sarin Donepezil Tx of CONFUSION due Isoflurophate to Alzheimer’S Management of GLAUCOMA (vet.med) Soman  CHOLINERGIC ANTAGONISTS MUSCARINIC BLOCKERS GANGLIONIC BLOCKERS NEUROMUSCULAR BLOCKERS – All are competitive antagonists which can be overcome by adequate concentrations of cholinergic agonist  MUSCARINIC ANTAGONIST ATROPINE is the prototype agent Actions are dose dependent – Decreased salivary and bronchial secretions – Decreased sweating – Pupil dilation and tachycardia – Inhibition of voiding – Decreases GI motility – Decreased gastric secretions  Common Antimuscarinic Think: " Inhibits Parasympathetic And Sweat " Ipratropium Pirenzepine Atropine Scopolamine  Muscarinic Antagonist Mydriatic EYE-atropine, homotropine, tropicamide CNS- benztropine, scopolamine Antiparkinson For motion sickness RESPIRATORY- ipratropium For asthma GU- oxybutynin Inhibit voiding GI- pirenzepine, glycopryyolate, propantheline For peptic ulcer Nicotinic - Hexamethonium IBS, Enuresis, Hyperhidrosis HTN Crisis  GANGLIONIC BLOCKERS Occasionally used to treat Ng antagonists Hypertensive crisis Block nicotinic receptors both in the sympathetic and parasympathetic ganglia Seldom used clinically because of the complex and unpredictable actions – Hexamethonium – Mecamylamine – Trimethephan MOA of Ganglionic Blockers blocks Classification of Cholinergic ANTAGONISTS Used as MUSCLE RELAXANT during SURGERY, mechanical ventilation or intubation Muscarinic Neuromuscular Ganglionic Antagonists Blockers Blockers Tertiary Nondepolarizing Depolarizing Amines Nicotine Tubocurarine Atropine Metocurine Scopolamine Nondepolarizing Lethal Injection Atracurium Mecamylamine Pancuronium Quarternary Trimethaphan Gallamine Amine Cause Tx of Malignant Ipratropium TACHYCARDIA HYPERTENSION Depolarizing Propantheline Induce HYPOTENSION Succinylcholine during surgery Cause Malignant Hyperthermia  CLINICAL USES Preanesthetic medication to prevent secretions Prevention of motion sickness For peptic ulcer For irritable bowel syndrome Mydriasis and cycloplegia Adjunct treatment for parkinsonism Antispasmodic Relieve bladder spasm, enuresis, and diarrhea  SIDE EFFECTS Classic anticholinergic/antimuscarinic side effects – Dry mouth, constipation, and tachycardia Severe antimuscarinic effects – Restlessness, headache, rapid and weak pulse, blurred vision, hallucinations, ataxia, “burning” skin and possibly coma Some antipsychotics, antihistamines, antidepressants, and opioids have anticholinergic effects