Sympathomimetics

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