Sympathomimetics Overview Review of Autonomic Nervous System Common

Sympathomimetics

Overview • • • Review of Autonomic Nervous System Common ways of manipulating ANS Parasympathetic agent Sympathetic agents Review by purpose of drugs Non-autonomic uses

Autonomic Nervous System “Rest and Digest” • Parasympathetic • Activities that serve body maintenance needsdigestion, elimination, urination, relaxation “Fight or Flight” vs. • Sympathetic • Activities that deal with facing threats (historically) - breathe, move, see far

Autonomic Nervous System

Autonomic NS Characteristic Parasympathetic Somatic Loc pregang nerve Cranio-Sacral Thoraco-lumbar Length Pregang Axon Long Short Ganglion NT ACh Receptor type in ganglion Nicotinic Length Postgang Short Long Effector Organ Smooth/Cardiac muscle or glands Skeletal muscle NT at effector ACh Norepi (usually) ACh Type of receptor Muscarinic α 1, α 2, β 1, and β 2 Nicotinic

Common Drug targets of autonomic agents • Heart (CV system)-chronotropic, inotropic, dromotrophic effects • Vessels- vasoconstrict/dilate • Lungs- bronchodilate • Gut- increase or decrease motility • Bladder/GU- decrease tone, increase passage • Eye- Mydriatics/Miotics • CNS- Tune up/Tune down • MSK- affect neuromuscular blockade • CNS- sedation, excitation, fear response

Remember discrete effects possible • Whole variety of receptors • Cholinergic – Nicotinic – Muscarinic (M 1 vs. M 2 ) • Adrenergic – α 1, α 2, β 1, and β 2 • Targeting on type allows greater specificity of action • Variety of secondary Messengers

Second Messengers • Gs- Adenylcyclase c. AMP Protein Kinase A – Examples, α 2, β 1, and β 2 (V 2 nd H 2 ) • Gi- Adenylcyclase c. AMP PKA – i. e. α 2, M 2 • Gq- Phospholipase C IP 3 Ca DAG – i. e. α 1, M 3 (V 1, H 1) PKC

Parasympathetic Agents • Cholinergic agonists – Direct- ACh, Bethanecol, Carbachol, Pilocarpine – Indirect (Anticholinesterases)- Neostigmine, Edrophonium, Physostigmine • Cholinergic antagonists – Direct’ish- Atropine, benzatropine, scopalmine, ipratroprium, oxybutin, glycopyrrolate • Others- Hexamethonium, Pralidoxime

Direct Cholinergic Agonists • Systemic rarely used- Bethanecol – Gut- Ileus – Urinary – urinary retention • Topical- more common (Bethanecol, Carbachol) – Glaucoma • Open angle- Contracts ciliary muscle – alters trabecular meshwork &helps drainage • Closed angle- Contracts pupil- pulls away from ciliary body

Indirect Cholinergic Agonists • All are reversible acetylcholinesterase inhibitors • Mainly vary in T 1/2 and pharmokinetics • Uses – Gut- reverse ileus (rarely used) – Glaucoma- Echothiphate, Physostigmine – Reverse neuromuscular blockade (Neostigmine, edrophonium) – Myasthenia gravis- edrophonium for diagnosis, neostig, pyridostig, or neostig for tx

Cholinergic Antagonists • Gut– antispasmodics (IBS)- hyoscyamine and atropine – Reduced secretions- glycopyrrolate and scopolamine • GU- reduce detrussor tone- oxybutin • Eye- atropine will dilate (mydriasis and cycloplegia)- can precipitate angle closure glaucoma- BAD!!!

Cholinergic antagonists • CNS– Sedation- Scopalmine is used for motion sickness – Reverse Parkinsonism- Benzotropine (particularly useful for drug induced parkinsonism or acute dystonia) • Respiratory- Ipratroprium (or more rarely tiatroprium) is a bronchodilator • CV- Atropine will increase heart rate (often used in OR)

Weird Cholinergic Drugs • Hexamethonium- Nicotinic ACh receptor blocker= blocks ganglion – No real clinical indications • Pralidoxime – Dephosphorylates and reactivates acetylcholinesterase (after inactivation by organophosphates)

Cholinergic Poison= too much parasympathetic

Cholinergic Overdoses=too much parasympathetic • Irreversible inhibitors of acetylcholinesterase • Symptoms- Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Excitation skeletal muscle and CNS, Lacrimation, Sweating, and Salivation (DUMBBELSS) • Treatment – Atropine – Pralidoxime

Anticholinergic Toxicity

Anticholinergic Toxicity • Often our fault • Dirty drugs aimed at other receptors- TCA’s, Antihistamines, Antipsychotics • Also plants- nightshade family (Jimson weed) • Mnemonics – Blind as a bat, mad as a hatter, red as a beet, hot as hell, dry as a bone, the bowel and bladder lose their tone, and the heart runs alone – Can't see, can't spit, can't pee, can't shit • Physostigmine or neostigmine common treatments

Sympathetic drugs

Sympathomimetics • Alpha Blockers – α 1, - Prazosin, Doxasosin, Terazosin, Phenoxybenzamine, Phentolamine • Beta blockers – TONS: labetalol, metoprolol, propanolol, nadololol, esmolol, etc… • Sympathetic agonists – α 2 agonists– Clonidine and Guanfacine – Direct β agonists- albuterol, salmeterol, etc. . – Pressors- ephedrine, norepinephrine, dobutamine, dopamine, Ephinephrine • Indirect SNS drugs

Receptor type is important • α 1 – Gq, Ca =contracts smooth muscle (vascular smooth muscle, eye) • α 2 - Gi, decreased c. AMP= tunes down NE release (presynapic terminal) • β 1 - Gs, increased c. AMP= increased rate and contractility (heart) • β 2 - Gs, increased c. AMP= vasodilation, bronchodilation, insulin release

Alpha antagonists • Mixed α 1 and α 2 (Almost never used) – Phenoxybenzamine, Phentolamine • α 1 specific – Prazosin, Doxasosin, (Cardura), Terasozin (Hytrin), Tamsulosin (Floxax) • α 2 specific – Mirtazapine (Remeron)

Indications • 4 th or 5 th line anti-HTN – Except in pheocromocytoma or cocaine- need alpha • BPH- huge market • ? PTSD • Depression- mirtazapine (particularly in old people)

Side effects • • • Orthostatic Hypotension Reflex Tachycardia Dizziness Headache Sedation and increased appetite with mirtazapine

Beta blockers • HUGE NUMBERS • Vary in specificity for β 1 vs β 2 • More β 1 (CV) specific include (begin with a-m) – Metoprolol, carvedilol, atenolol , esmolol • Less specific agents less commonly used – Propanolol, nadolol • Except labetalol- has alpha activity too

Indications • CV – Hypertension (1 st or 2 nd line) – Fast IV agents include esmolol and labetalol – CHF (if symptoms definitely) – Prevention death in CAD, MI – Rate control • Glaucoma- decrease secretion of aqueous humor (open angle)- topical timolol

Side Effects • • • Worsen asthma Bradycardia or AV block Decompensation in CHF exacerbation Hypoglycemia unawareness Problems if anaphylaxis- use Glucagon CNS effects? - depression, impotence

Alpha 2 agonists • Unlike other agonists actually tones down parasymphathetic (α 2 is feedback inhibition) • Clonidine, a- methyldopa and Guanfacine – Rarely used in HTN – Children w/ ADD (particularly if sleep problems due to amphetamine) – Sometimes for impulsive behaviors – Methydopa- HTN in pregnancy

Beta 2 agonists • Short acting- rescue inhalers – Albuterol, terbutaline (rarely used) – Also used for hyperkalemia (increases K uptake into cell) • Long acting– Salmeterol, Formoterol – Always combined with corticosteroids – Increased mortality when used alone? • Toxicities – tachycardia, arrythmia, tremor

“Pressors” • • IV drugs used to support circulation Usually in ICU with close monitoring Almost all act on sympathetic nervous system All tried to use short periods (dangerous)

Direct “Pressors” • Epinephrine- direct agonist of everything – Uses- anaphylaxis, open angle glaucoma, asthma, hypotension • NE- primarily alpha-1 (vasoconstriction) – Septic shock, distributive shock • Isoproterenol= Beta agonist – Cardiac arrest, av block, asthma • Dobutamine- β 1>β 2 – Increases cardiac contractility- cardiogenic shock, heart failure

Pressor Side Effects • Most side effects can be figured out physicologically – i. e. Vasocontriction cause reflex tachycardia • Any beta agonist can cause arrythmias • Concern of decreased renal perfusion w/ pure NE

Indirect Pressors • Ephedrine- Releases stored catecholamines – Hypotension and nasal decongestant • Dopamine- D 1= D 2>B>a – Increasing doses different effects – First increases renal blood flow – Then increases heart rate and contraction – Then finally acts like NE

Indirect Sympathetic drugs • Reserpine- Blocks NE incorporation into presynaptic vesicles – Old anti-HTN, causes depression • Amphetamines- increased release stored catecholamines – Narcolepsy, ADD, ADHD, depression – Can cause HTN, arrythmia • Methylxanthines- i. e. theophylline – Decrease c. AMP degradation and bronchodilate – Dangers w/ lots of interactions, beta agonist effects outside the lungs, etc…

Agents by purpose • CV – Increase rate- Beta agonists and cholinergic blockers= dobutamine, isopreternol, atropine – Slow rate/antiarrythmic= Beta antagonists and cholinergic agents (not used clinically)metoprolol, labetalol, etc. . • Respiratory – Bronchodilators = Beta 2 agonists and anticholinergics- albuterol, ipratroprium, etc. .

Agents by system • GI – Anticholinergics decrease motility- hyocyamine, atropine – Cholinergics- Bethanecol can increase motility (though rarely used) • GU – Alpha antagonists increase urination- Doxasosin, Terasozin – Anti-cholinergics decrease urgency- oxybutinin • Eye- Glaucoma – Cholinergics contract pupil allow drainage – B blockers decrease fluid production