autonomic nervous system

Autonomic Nervous System

Trachtegtracht1@d.umn.edu

Autonomic Nervous System

•Autonomic Nervous System defined as nerves outside of the central nervous system (outside bony encasement of nervous system) with two efferent fibers (must have a synapse prior to the final junction with the end organ)

II. Parasympathetic Nervous System

Ach ‡ Ach ‡ Ach ‡ Ach Urinary Bladder

Acetate + Choline

Acetylcholinesterase

NicotinicReceptor

Preganglionic Nerve

Postganglionic Nerve

MuscarinicReceptor

Parasympathetic Nervous System

•Nicotinic Receptor- Comprised of five proteins to form a cation pore; agonists & antagonists not typically used clinically (exception is Nicotine)

• Muscarinic Receptor- protein coupled to GTP-binding proteins to influence adenylyl cyclase, potassium channels or phospholipase C– Bethanecol is agonist; Atropine is antagonist

•Anticholinesterases- potentiate activity of system– Example is neostigmine

Ionotropic ReceptorAch Na

Na

NicotinicReceptor

Nicotinic Receptor

• Because it consists of 5 distinct proteins, there are multiple isoforms

• Ganglionic nicotinic receptors typically are composed of 2 alpha (acetylcholine binding proteins) and 3 ß proteins

Ionotropic ReceptorAch Na

Na

Ach G protein coupled Receptor

Ca

IP3 + DAG

NicotinicReceptor

MuscarinicReceptor

G PLC

Ionotropic ReceptorAch Na

Na

Ach G protein coupled Receptor

PKA (phosphorylation)

cAMP

NicotinicReceptor

MuscarinicReceptor

G AC(-)

Muscarinic Receptors

• Actually five different clones exist

• M1, M3 & M5 couple to Phospholipase C (stimulate it)

• M2 & M4 couple to adenylyl cyclase (inhibit it)

Muscarinic Receptors

• [Muscarinic Receptors on eye (constrict pupil), lacrimal glands (increase secretions), salivary glands (increase secretions), gut (increase secretions & motility), urinary bladder (relax sphincter & contract detrusor to promote urination), lung (contract bronchioles & increase secretions), heart (decrease rate).]

Parasympathetic Nervous System

Can produce the following influences with the agent indicated:– augment peristalsis with bethanecol or neostigmine (promotes defecation)

– contract urinary bladder with bethanecol or neostigmine

– promote erection with a vasodilator (sildenafil (Viagra) preserves cGMP)

– prevent urination caused by overactive bladder (usually detrusor overactivity) with Tolterodine (muscarinic antagonist- others include oxybutynin, Trospium, propantheline, hyoscyamine)

Q1. If you want to induce urination, which of the following strategies is best?1. nicotinic agonist2. nicotinic antagonist3. muscarinic agonist4. muscarinic antagonist5. Anticholinesterase

2. Sympathetic Nervous System

A. Sites of action ß2

Epi Epinephrine

Ach Ach NE NE

α1PostganglionicNerve

PreganglionicNerve

NicotinicReceptors

Adrenal Gland

Sympathetic Nervous System

Nicotinic Receptor- receptor consists of 5 proteins forming a cation pore when activated by acetylcholine agonists & antagonists not used much except in anesthesia or smoking cessation

Beta2 Receptor- protein coupled to GTP-binding protein to activate adenylyl cyclase; chief effects are to relax smooth muscle (bronchiole, uterine, intestinal etc) and to promote glycogenolysis– agonist is Albuterol; no specific ß2 antagonists used

clinically (Propranolol is nonselective ß antagonist)Alpha1 Receptor- protein coupled to GTP-binding protein to

activate phosholipase C; chief effects are to constrict smooth muscle (vascular, pupillary dilator muscle, sphincters)

• agonist is phenylephrine; antagonist is terazosinCan prevent urination with agents potentiating the sympathetic

nervous system (imipramine)

Ionotropic ReceptorAch Na

Na

NE G protein coupled Receptor

Ca

IP3 + DAG

NicotinicReceptor

Alpha 1Receptor

G PLC

Ionotropic ReceptorAch Na

Na

Epi G protein coupled Receptor

PKA (phosphorylation)

cAMP

NicotinicReceptor

Beta 2Receptor

G AC

Other sites of Drug actions in the Sympathetic Nervous System NE ‡ Alpha1 Receptor Nicotinic Receptor NE Axoplasmic uptake pump (cocaine sensitive) NE Postganglionic Nerve NE = Norepinephrine

Sympathetic Nervous System

After Norepinephrine (NE) exocytosis, it can do one of the following:

interact with receptors (α1)

be reaccumulated into the nerve via the axoplasmic pumpbe degraded by monoamine oxidase (actually occurs inside

the nerve)Drugs can affect these processes

Imipramine blocks the axoplasmic pump (as does cocaine)Pargyline blocks monoamine oxidase

Potentiate sympathetic effects by one of the following:add α receptor agonistblock the axoplasmic pump (imipramine)block monoamine oxidase (pargyline)

Inhibit sympathetic effects by antagonizing α receptor

Genitourinary Applications

Contract Urinary Bladder by:• Muscarinic agonists (Bethanecol is example)

• Anticholinesterases (Neostigmine is example)

Genitourinary Applications

• Prevent Urination by:– blocking muscarinic receptors with Tolterodine (Detrol; 1-2 mg bid; $103/month) (others include oxybutynin (Ditropan), Trospium (Sanctura), propantheline, hyoscyamine)- Med. Let. 46: 64, 2004

– stimulating sympathetic nervous system (imipramine) (Tofranil)• used to help children with bedwetting problems• a little dangerous- can cause lethal cardiac arrhythmias, even in children

• bedwetting more commonly treated with antidiuretic hormone currently

– In theory, could combine phenylephrine and albuterol but not done in practice

Genitourinary Applications

• No sympathetic nervous system agents are used to induce urination but α1 receptor blockers are used to ease urination in benign prostatic hyperplasia– Drugs include Terazosin (Hytrin); Doxazosin (cardura); Alfuzosin (uroxatral) and Tamsulosin (Flomax)

Q2: If a patient cannot control urination because of excessive activity of the

parasympathetic nervous system, which of the following is the best strategy for

treatment:1) block sympathetic receptor (Terazosin)

2) activate sympathetics (Imipramine)3) inhibit parasympathetic receptors (Atropine)

4) stimulate parasympathetic receptors (Bethanecol)

5) Use an anticholinesterase (Neostigmine)

Erectile Dysfunction treatment

• Induce erection (in males) by vasodilating– Actual agents used most frequently are Sildenafil (Viagra), Tadalafil (Cialis) and Verdenafil (Levitra)

– they prevent degradation of cGMP by blocking Phosphodiesterase 5

Erectile Dysfunction treatment

• Physiologically, erections are caused by nitric oxide– Nitric Oxide (NO) interacts with soluble guanylyl cyclase to produce cGMP

– cGMP interacts with protein kinase G to phosphorylate proteins

– opens potassium channel to hyperpolarize smooth muscle

– net effect is relaxation of smooth muscle

– phosphodiesterase breaks down cGMP (this step blocked by Sildenafil)

Ionotropic Receptor Ach Na NO Na Guanylyl Cyclase Epi G protein coupled Receptor

PKG (phosph) cGMP GC PKA (phosphorylation) cAMP

Nicotinic Receptor

Beta 2 Receptor

G AC

K

NO

K Guanylyl Cyclase

Sildenafil,Tadalafil

Epi G protein coupled Receptor

PKG (phosph) cGMP GC

GMP (metabolite)

Beta 2Receptor

PDE5

Ionotropic ReceptorAch Na

NO

Na Guanylyl Cyclase

Tyr Kinase

Tyr Kinase NGF

Growth Factor Receptors

Epi G protein coupled Receptor

PKG (phosph) GMP GC

PKA (phosphorylation)

cAMP

NicotinicReceptor

Beta 2Receptor

G AC

Ionotropic ReceptorAch Na

NO

Na Guanylyl Cyclase

Tyr Kinase

Tyr Kinase NGF

Growth Factor Receptors

Epi G protein coupled Receptor

Transcriptional Regulators

Thyroid Hormone

_____________________________(DNA)

PKG (phosph) GMP GC

PKA (phosphorylation)

cAMP

NicotinicReceptor

Beta 2Receptor

G AC