Download Sympathomimetics

Sympathomimetics
Overview
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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”
• Sympathetic
• Activities that deal with
facing threats
(historically)- breathe,
move, see far
Autonomic Nervous System
Autonomic NS
Characteristic
Parasympathetic
Sympathetic
Somatic
Loc pregang nerve Cranio-Sacral
Thoraco-lumbar
Length Pregang
Axon
Long
Short
Ganglion NT
ACh
ACh
Receptor type in
ganglion
Nicotinic
Nicotinic
Length Postgang
Short
Long
Effector Organ
Smooth/Cardiac
muscle or glands
Smooth/Cardiac
muscle or glands
Skeletal muscle
NT at effector
ACh
Norepi (usually)
ACh
Type of receptor
Muscarinic
α1, α2, β1, and β2
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 (M1 vs. M2 )
• Adrenergic
– α1, α2, β1, and β2
• Targeting on type allows greater specificity of
action
• Variety of secondary Messengers
Second Messengers
• Gs- Adenylcyclase cAMPProtein Kinase
A
– Examples, α2, β1, and β2 (V2 nd H 2 )
• Gi-  Adenylcyclase  cAMP  PKA
– i.e. α2, M2
• Gq- Phospholipase C  IP3  Ca
DAG  PKC
– i.e. α1, M1, M3 (V1, H1)
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
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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
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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”
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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 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