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Sympathomimetics

Dive into the world of autonomic nervous system drugs with this comprehensive review covering common methods of manipulating the ANS, parasympathetic and sympathetic agents, drug targets, receptors, and specific drug classes. Explore the effects of sympathetic activities and parasympathetic functions, as well as detailed information on cholinergic agonists, antagonists, and sympathetic drugs. Uncover the complexities of drug interactions with the autonomic nervous system and their varied therapeutic uses.

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Sympathomimetics

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  1. Sympathomimetics

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

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

  4. Autonomic Nervous System

  5. Autonomic NS

  6. 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

  7. 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

  8. Second Messengers • Gs- Adenylcyclase cAMPProteinKinase A • Examples, α2, β1, and β2 (V2 nd H 2 ) • Gi- Adenylcyclase  cAMP  PKA • i.e. α2, M2 • Gq- Phospholipase C  IP3  Ca • i.e. α1, M1, M3 (V1, H1) DAG  PKC

  9. 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

  10. 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

  11. Indirect Cholinergic Agonists • All are reversibleacetylcholinesterase 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

  12. 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!!!

  13. 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)

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

  15. Cholinergic Poison= too much parasympathetic

  16. 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

  17. Anticholinergic Toxicity

  18. 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

  19. Sympathetic drugs

  20. 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

  21. 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

  22. Alpha antagonists • Mixed α1 and α2 (Almost never used) • Phenoxybenzamine,Phentolamine • α1 specific • Prazosin, Doxasosin, (Cardura), Terasozin (Hytrin), Tamsulosin (Floxax) • α2 specific • Mirtazapine (Remeron)

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

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

  25. 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

  26. 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

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

  28. 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

  29. 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

  30. “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)

  31. 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

  32. 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

  33. 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

  34. 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…

  35. 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..

  36. 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

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