Introduction to the Autonomic Nervous System and Drugs

Introduction to the Autonomic Nervous System and Drugs affecting the Parasympathetic Nervous System Brody’s Human Pharmacology Chapters 8 & 9 Peripheral Nervous System Somatic Autonomic Sympathetic Parasympathetic adrenergic cholinergic NE, EPI, Ach Ach Anatomy of Autonomic Nervous System (ANS) • Preganglionic neurons - cell bodies are within the CNS • Postganglionic neurons - Originate at the ganglion and terminate in the innervated tissue • Sympathetic neurons - Originate from thoracic and lumbar spinal nerves • Parasympathetic neurons - Originate from the cranial and sacral nerves Autonomic Nervous System Two Opposing divisions – Sympathetic • Fight or flight – Parasympathetic • Rest and Digest • Fig 8-1, p 90 Sympathetic Nervous System • Actions due to both direct stimulation and by stimulation of adrenal medulla – Increase heart rate and BP – Mobilize energy stores – Increase blood flow from skin and internal organs to skeletal muscles and heart – Dilation of pupils and bronchioles • Adjusts body to stressful situations but does not play a major role in maintaining normal body function Parasympathetic System • Rest and Digest - Maintains essential body functions • Preganglionic neurons - cranial & sacral areas and are longer than the preganglionic fibers of the sympathetic system • Necessary for life Chemical Signaling Between Cells • Neurotransmitters – Method used by neurons (nerve cells) – Each neuron is individual unit – Neurotransmitters are released at nerve terminals – Rapid system • How does the nervous systems use of neurons compare to the endocrine systems use of hormones? – Hormones are released by endocrine cells into the blood stream – Broad effects on target cells – Slower system than neurotransmitters Schematic Diagram of ANS Neurotransmitters Acetylcholine (Ach) Norepinephrine (NE) Epinephrine (Epi) Dopamine (D) Receptors Nicotinic (N) Adrenergic (a and B) Muscarinic (M) Note - Preganglionic nerve length Note - Neurotransmitter locations Cholinergic Neurotransmitter • Acetylcholine • Cholinergic receptors at preganglionic synapses of the parasympathetic and sympathetic systems, parasympathetic synapses, adrenal medulla and somatic junction • Nicotinic receptors - preganglionic synapses - Not important pharmacologically • Muscarinic receptors - postganglionic synapses of the parasympathetic system and in the sweat glands of the sympathetic system – Multiple subtypes however medications that bind to specific muscarinic receptors have not been developed. Adrenergic Neurotransmitters • Norepinephrine – Adrenergic receptors - Postganglionic sympathetic synapse • Epinephrine – Adrenergic receptors • Dopamine – D1 Dopaminergic receptors - Activation will increase blood flow to the kidneys due to vasodilation of the renal vascular beds Neurochemical Transmission Autonomic Receptors • Multiple receptors types are involved with the autonomic nervous system. The major ones we will discuss in this class are: – Cholinoceptors (Cholinergic) • Muscarinic • Nicotinic – Adrenoceptors (Adrenergic) • Alpha – Alpha 1 – Alpha 2 (Presynaptic receptor) • Beta – Beta 1 – Beta 2 Autonomic Reflexes • Not all autonomic drugs will cause the exact effect expected because of autonomic reflexes (feedback loops) • Homeostatic Response – compensatory response produced by the body to try and counteract a drug induced response • Example – Norepinephrine when used as a drug is an adrenergic agonist with more alpha effects than beta – The direct beta effects should still cause an increase heart rate however, the heart rate goes down with a slow infusion. Why? – The alpha induced vasoconstriction raises the blood pressure. To compensate the body stimulates the parasympathetic system to reduce the heart rate. Organs Controlled by Multiple ANS pathways • Eye - example of an organ system controlled by multiple pathways ANS • Autonomic drugs are used in the eye in the treatment of glaucoma and for diagnostic purposes Muscles of the eye pupil – Iris • Radial muscle Major receptor Effect Effect on alpha 1 Contraction Mydriasis Mydriasis Miosis • Circular muscle Drug effects: Cholinergic Anticholinergic muscarinic Contraction Miosis Mydriasis muscarinic Contraction – Ciliary Accommodation beta 2 Relaxation Drugs Affecting the ANS • Sympathetic (NE) – Sympathomimetics – Adrenergic antagonists (beta/alpha blockers) • Parasympathetic (Ach) – Cholinergic – Anticholinergic Autonomic Drugs used to treat Glaucoma • Cholinergic agents – contract circular muscle which puts pressure on trabecular meshwork to increase aqueous humor outflow – Ocular Side effects: – Miosis – Accommodation • Sympathomimetics – contract radial muscle which increase the outflow of aqueous humor – Ocular Side effects • Mydriasis • Beta blockers – decreases the production of aqueous humor – Ocular Side effects - None Cholinergic Agonists (Ch 9) • Act on receptors that are activated by acetylcholine • Mechanism of Action – Direct Acting - resemble acetylcholine – Indirect Acting – Inhibit acetylcholinesterase • Reversible (competitive) • Irreversible (non-competitive) • Receptor types – Muscarinic – Nicotinic • Cholinergic receptors are located in multiple locations but these drugs are mainly used to stimulate the parasympathetic system Receptor Types • Muscarinic receptors – found mainly on the effector cells of the parasympathetic system • Nicotinic receptors – stimulate nerve cells of the sympathetic, parasympathetic ganglia, and skeletal muscle neuromuscular junctions – No clinical value to artificial stimulation Other Cholinergic Receptors • Central Nervous System • Neuromuscular junction of the somatic nervous system • Ach is a major neurotransmitter Effects of Cholinergic Drugs on Organ Systems • Eye - Pupil contracts (miosis), contraction of ciliary muscle for near vision • Cardiovascular - decrease cardiac rate, force, usually reduces peripheral vascular resistance • Respiratory - Contract bronchial smooth muscle and increase secretory activity • GI - Increase peristalsis and relax sphincters, Increase secretory activity (salivary and gastric secretion glands) Effects of Cholinergic Drugs (cont) • Genitourinary- Contracts detrusor and relax sphincter • Secretory glands – Stimulates sweat, lacrimal and nasopharyngeal glands • SLUDE – salivation/sweating, lacrimation, urination, defecation, excretion Major Therapeutic Uses of Cholinergic Agonists • Glaucoma • GI and Urinary tract stimulation • Neuromuscular Junction  myasthenia gravis (Current Medical Diagnosis & Treatment 2007 – p. 1058)  curare-induced neuromuscular paralysis (reverse) • Anticholinergic Overdose • Alzheimer’s Disease Direct Cholinergic Agonists (Cholinomimetic) Bethanechol (Urecholine®) • Resistant to acetylcholinesterase • MOA – stimulate cholinergic receptors causing contraction of bladder detrusor and sphincter relaxation • Indication – Urinary retention after surgery or postpartum • Adverse affects – sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea and bronchospasm • Contraindications – Physical obstruction and asthma • Oral tablets and injection for subcutaneous use Glaucoma (Current page 161-163) • A condition of increased intraocular pressure (IOP) • 2% of individuals over 40 have glaucoma • Open Angle Glaucoma – Aqueous humor outflow is constantly subnormal, Gradual and asymptomatic onset • Angle-Closure Glaucoma – Results from closure of the anterior chamber angle causing severe pain and vision loss. No abnormal resistance to aqueous humor outflow , Medical emergency with acute onset Pilocarpine (Isopto Carpine®, Ocusert®) {BCF} • MOA - Contraction of ciliary muscle attached to the trabecular meshwork to enhance aqueous humor outflow • IOP decreases in 1 hour • Adverse reactions – Miosis (reduced night vision), decreased far vision and brow aches • Products – Ophthalmic: 0.25 – 10% drops, 4% ointment and Ocuserts – Oral pilocarpine (Salagen®) is used to treat xerostomia (dry mouth) • Place in therapy – Historically an initial treatment of choice for glaucoma but has been replaced by newer agents • Indicated for both angle-closure and open-angle glaucoma Cholinesterase Inhibitors • Indirect Cholinergic agents • Acetylcholinesterase cleaves acetylcholine to acetate and choline both in the pre and post synaptic cleft. • Inhibiting enzyme prolongs the duration of endogenous acetylcholine • Agents divided into two categories – Reversible – Inhibitors that compete with cholinomimetic substrates for acetylcholinesterase binding sites • Most of the agents that have therapeutic applications – Irreversible – Inhibitors that permanently bind with acetylcholinesterase • Most of these agents are used as Insecticides or nerve agents Physostigmine ®) (Antilirium • Mechanism of action - binds with acetylcholinesterase and prevents it from destroying acetylcholine – prolongs action of Ach • Indications – Treatment for anticholinergic overdose (atropine, tricyclics and phenothiazines) • Adverse reactions – Can enter CNS and cause convulsions in high doses – Vomiting, salivation, and bradycardia from systemic use – Miosis and allergic irritation from ophthalmic use • Injection Neostigmine (Prostigmin®) • Mechanism of action – Anticholinesterase agent that does not enter CNS • Clinical Indication – antidote for neuromuscular blockers, myasthenia gravis and GI and urinary tract retention • Adverse reactions – salivation, flushing, decreased BP, diarrhea • Available systemic injection Pyridostigmine (Mestinon®, NAPP) • MOA: Reversible anticholinesterase • Used for myasthenia gravis treatment more often than neostigmine due to its longer duration of action • Fewer side effects than neostigmine in myasthenia gravis • Available as oral tablets & syrup; injection Nerve Agent Pre-treatment Pyridostigmine (NAPP) • Mechanism of action - Protects acetylcholinesterase enzymes from irreversible anticholinesterases (nerve gas {soman}) by using a reversible anticholinesterase • Approved by the FDA for this indication 2003 • Stocked by US forces starting in 1996 and used during the Gulf war Excerpt from DoD, Rand Study on Gulf War Health Issues, Oct 99 • After lengthy deliberation, permission to use the drug was granted by the FDA in 1990. … the Defense Department agreed to some special requirements, including special labeling, record keeping, and the provision of information "to medical and paramedical personnel, and to individual service members for ... products intended for self-administration." Actual implementation was inconsistent, record keeping inadequate, and information - prepared for distribution to the troops - not delivered. • Learning point – Even though this drug is now approved (Feb 03) for nerve agent prophylaxis, if you are involved with investigational drugs – Document as required and inform your troops as required Edrophonium (Tensilon®) • Clinical indication – diagnosis of myasthenia gravis • More rapidly absorbed and shorter duration of action than neostigmine Irreversible Anticholinesterases (Cholinesterase Inhibitors) • Toxins, Poisons, Nerve agents, Insecticides • Permanently inactivates acetylcholinesterase enzymes requiring the synthesis of new enzyme molecules • Antidote = Pralidoxime / 2 PAM Chloride (Protopam) will reactivate cholinesterase if used before aging (the loss of an isopropyl group from the enzyme) – most reactivation occurs at neuromuscular junction (prolonged use results in paralysis) – Atropine (an anticholinergic agent) in conjunction with Pralidoxime for muscarinic effects (bronchoconstriction,vomiting, bradycardia, miosis, incontinence) Echothiophate (Phospholine®) • Irreversible anticholinesterase used to treat glaucoma • Echothiophate is only irreversible anticholinesterase agent used medically on a regular basis • Side effects are similar to pilocarpine Other Agents • Use in Alzheimer’s – not ANS drugs; cholinesterase inhibitors that work on the CNS to treat mild to moderate Alzheimer’s • Mechanism of action – Increase cerebral concentrations of acetylcholine by inhibiting acetylcholinesterase • • • • Tacrine (Cognex®)- First agent approved Donepezil (Aricept®) Galantamine (Reminyl®) Rivastigmine (Exelon®) General Toxic Effects • Direct acting cholinergic agonists – Muscarinic symptoms - Vasodilation (flushing), sweating, bradycardia, bronchoconstriction, GI distress, belching, nausea and vomiting, diarrhea, salivation – Nicotinic symptoms – All the above and convulsions, coma, respiratory arrest, hypertension and cardiac arrhythmias • Anticholinesterase Agents (Organophosphates) – Signs of acute intoxication • Same as the symptoms above but miosis (reduction in pupil size) also occurs as well Cholinergic Antagonists (Ch 9) • May be referred to as cholinergic blockers, cholinoceptor-blocking drugs, anticholinergic drugs, antimuscarinic • Interrupts parasympathetic signals • Antinicotinic – Ganglionic Blockers, little therapeutic use – Neuromuscular Blockers, used as muscle relaxants Antimuscarinic Agents • Block muscarinic receptors on the effector organs parasympathetic nervous system and on sweat glands (exception from sympathetic system) • Specificity for muscarinic receptors is key reason behind their usefulness because they have little effect at skeletal neuromuscular junction or autonomic ganglia Atropine Sulfate • General Pharmacological Effects - A belladonna alkaloid competitively blocks muscarinic receptors from acetylcholine - ability to cross the CNS • Indications – Eye - Diagnostic use only - Causes mydriasis (pupil dilation) and cycloplegia (inability to focus). Increases intraocular pressure in patients with glaucoma – GI - Antispasmodic agent for GI tract and bladder - Reduces motility and slightly reduces hydrochloric acid secretion. – Antidote for cholinergic agonists - organophosphate overdoses – Cardiovascular applications • Adverse Reactions - (autonomic)- dry mouth, blurred vision, dry eyes, tachycardia, and constipation; (CNS) - restlessness, confusion, and hallucinations Belladonna Alkaloid Belladonna alkaloid means the drug is derived form the deadly nightshade plant (Atropa belladonna) Atropine Cardiovascular Effects • Atropine is used in ACLS protocols – In Pulseless Electrical Activity and Asystole it is used after Epinephrine – Bradycardia – First drug used for symptomatic sinus bradycardia • Improves sinus node and atrioventricular node conduction by inhibiting vagal activity • Cardiovascular effects vary depending on dose – both tachycardia and bradycardia (low dose) are possible. – At normal doses it blocks vagal slowing resulting in tachycardia. Anticholinergic Contraindications • Contraindications - Narrow angle glaucoma, Tachycardia, GI or GU Obstructive disease, Myasthenia gravis, Asthma (Atropine only) • Myasthenia gravis - Anticholinergics contraindicated however (Atropine and propantheline) may be used in conjunction with Anticholinesterase medications to reduce GI side effects • Atropine in asthma - Systemic absorption and CNS penetration results in side effects and toxicity Anticholinergic warnings • Heat prostration - due to decreased thermoregulatory sweating • Chronic diarrhea - Do not use chronic diarrhea - temporarily control diarrhea but may contribute to an intestinal obstruction • Gastric ulcer - These will delay gastric emptying time Scopolamine • Belladonna alkaloid with similar peripheral effects and greater CNS effects compared to atropine • Indications – Motion Sickness - topical patch used to treat motion sickness (vertigo). One patch lasts for 3 days. – Surgery; block short-term memory, reduce the flow of saliva (antisialagogue). Atropine also used for this purpose but does not cause the amnesia effect • Adverse Reactions - Similar to atropine: drowsiness (17%), dry mouth (67%), blurred vision, pupil dilation. Wash hands after handling patch. Belladonna Alkaloids (Donnatal®) • Indication – GI Antispasmodic – Only treats the symptoms not underlying problem • Composed of atropine, scopolamine and hyoscyamine (another anticholinergic belladonna alkaloid) – In addition each preparation contains phenobarbital • 16.2mg per tablet and 5ml of elixir • Causes drowsiness and anticholinergic side effects (dry mouth, urinary retention, constipation, and increased sensitivity to light) • Preparations – Donnatal tablets and Donnatal Extentabs – Donnatal elixir – The elixir also contains 23% alcohol Dicyclomine (Bentyl®) {BCF} • Another anticholinergic/ GI antispasmodic • Indication - Treatment of dysfunctional bowel/irritable bowel syndrome. • Dosage forms - Oral and injection. Oral dosing requires qid dosing and adverse effects may prevent effective dosing • Contraindicated in infants less than six months old deaths have occurred due to aspiration Oxybutynin (Ditropan®) {BCF} • Anticholinergic that exerts direct antispasmodic effect on smooth muscle. – 1/5 the anticholinergic activity of atropine but 4-10 times the antispasmodic activity. • Indication - Bladder instability and overactive bladder (OAB) • Agent most commonly used to produce anticholinergic effect in lower urinary tract, improves bladder capacity and voiding dysfunction • Now available in a patch Tolterodine (Detrol®) {BCF} • Anticholinergic indicated for overactive bladder • Tolterodine and oxybutynin are equivalent in efficacy but tolterodine is reported to be better tolerated • Currently, due to cost factors, reserve medication for patients who have failed or are intolerant to oxybutynin • Trospium (Sanctura®) approved May 04 • Solifenacin (Vesicare®) approved Nov 04 • Darifenacin (Enablex®) approved Dec 04 Ipratropium (Atrovent®) {BCF} • Indication – Bronchospasm associated with COPD; rhinorrhea • Available as an inhaler, solution for nebulization, and nasal spray (for rhinorrhea) • Bronchodilation - Effects localized predominantly in the lungs (minimal systemic absorption) - bronchodilation caused by inhibiting cyclic guanosine monophosphate in the lungs • Has anti-secretory properties – Not an important clinical feature in COPD – Important in the nasal spray version used for perennial rhinitis Tiotropium (Spiriva®) • Indication – Bronchospasm associated with COPD • Available as a dry powdered inhaler • Same MOA as ipratropium but dosed one puff daily • Slowly (over 24 hours) dissociates from M1 and M3 receptors (almost like non-competitive inhibition) Anticholinergics in Parkinson’s Disease • Several anticholinergics used to treat Parkinsonism – purpose is to lower the amount of acetylcholine in the CNS in an attempt to keep it in balance with dopamine – Benztropine, Trihexyphenidyl • What pharmacokinetic trait would be important for an anticholinergic drug to be effective for this indication? Ganglionic Blockers • No selectivity - block receptors on both the parasympathetic and sympathetic ganglia • Rarely used therapeutically • Nicotine can act as a ganglionic blocker at high doses – Low doses – ganglionic stimulation causing euphoria and arousal. It also causes relaxation, and improves attention – High doses – ganglionic blockade (depolarization blockade) causing respiratory paralysis and hypotension Neuromuscular Blocking Drugs • Nicotinic receptors on the neuromuscular skeletal muscle junctions – Antagonists (nondepolarizing) – Agonists (depolarizing) • Indication – Surgery to produce complete muscle relaxation Nondepolarizing blockers • Tubocurarine - Developed from Curare - used to by Amazon hunters to paralyze game. • Competitive blocker - action reversed by increasing concentration of acetylcholine with cholinesterase inhibitors (neostigmine, edrophonium and pyridostigmine) • MOA – Low dose - Combine with receptor and prevent ACh binding. Overcome by increasing concentration of acetylcholine (ie. Physostigmine) – High doses- the ability of acetylcholine reversal is reduced due to the blockage of the end plates • Nondepolarizing agents - pancuronium and vecuronium Depolarizing Agents • Attaches to nicotinic receptor and depolarizes the junction but remains on the receptor for a “long” time • Succinylcholine – duration of action is short • Indication - Rapid Intubation • Adverse Effects – Malignant hyperthermia Review Cholinergic agents – Direct (act like ACh) • Bethanechol (urinary retention) • Pilocarpine (glaucoma) – Indirect (take out AChe) • Reversible – Physostigmine, Neostigmine, Pyridostigmine, Edrophonium – Diagnosis/tx of MG; reversal of NMBs; anticholinergic OD • Irreversible – Nerve agents, Echothiophate (glaucoma) Review Anti-cholinergic agents – Competitive antagonists (with ACh) – • • • • • • Atropine (many uses) Scopolamine (Pre-op, motion sickness) Homatropine (diagnostic dilation) Donnatal, Dicyclomine (GI) Oxybutynin, Tolterodine, (GU) Ipratropium, Tiotropium (COPD) Review • Somatic agents – Depolarizing agent (agonizes receptor) – Succinylcholine – Non-depolarizing agents (blocks receptor) • - oniums • Vecuronium, pancuronium