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 (M1 vs. M2 )

• Adrenergic– α1, α2, β1, and β2

• Targeting on type allows greater specificity of action

• Variety of secondary Messengers

Second Messengers

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 T1/2 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– α1, - Prazosin, Doxasosin, Terazosin, Phenoxybenzamine,

Phentolamine• Beta blockers– TONS: labetalol, metoprolol, propanolol, nadololol,

esmolol, etc…• Sympathetic agonists– α2 agonists– Clonidine and Guanfacine– Direct β agonists- albuterol, salmeterol, etc..– Pressors- ephedrine, norepinephrine, dobutamine,

dopamine, Ephinephrine• Indirect SNS drugs

Receptor type is important

• α1 – Gq, Ca =contracts smooth muscle (vascular smooth muscle, eye)

• α2- Gi, decreased cAMP= tunes down NE release (presynapic terminal)

• β1- Gs, increased cAMP= increased rate and contractility (heart)

• β2- Gs, increased cAMP= vasodilation, bronchodilation, insulin release

Alpha antagonists

• Mixed α1 and α2 (Almost never used)– Phenoxybenzamine, Phentolamine

• α1 specific– Prazosin, Doxasosin, (Cardura), Terasozin

(Hytrin), Tamsulosin (Floxax)

• α2 specific– Mirtazapine (Remeron)

Indications

• 4th or 5th 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 β1 vs β2

• More β1 (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 (1st or 2nd 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 (α2 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- β1>β2 – 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