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 needs- digestion, elimination, urination, relaxation “Fight or Flight” Sympathetic Activities that deal with facing threats (historically)- breathe, move, see far

Autonomic Nervous System

Autonomic NS

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   cAMP  Protein Kinase A – Examples, α 2, β 1, and β 2 (V 2 nd H 2 ) Gi-  Adenylcyclase   cAMP   PKA – i.e. α 2, M 2 G q -  Phospholipase C   IP3   Ca – i.e. α 1, M 1, M 3 (V 1, H 1 ) DAG   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

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 cAMP= tunes down NE release (presynapic terminal) β 1 - Gs, increased cAMP= increased rate and contractility (heart) β 2- Gs, increased cAMP= 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 can 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- D1= D2>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 cAMP 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 anti- cholinergics- 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