Adrenergic 

Sympathetic Nervous System (SNS)

·        Adrenergic - any structure or mechanism which is related to the presence or action of norepinephrine (NE) or epinephrine (Epi) as transmitters. Includes drugs and transmitters which act at adrenergic receptor sites 

Adrenergic nerve fibers

 Sympathetic Nervous System (SNS)

Adrenergic receptors

 Sympathetic Nervous System (SNS)

·        Adrenergic receptors - receptors that engage NE or Epi.  They include Alpha 1, Alpha 2, Beta 1, and Beta 2 receptors

Sympathomimetic agents and action

Sympathetic Nervous System (SNS) 

·        Sympathomimetic agents and action - drugs and transmitters that reproduce a SNS effect 

Sympatholytic agents and actions

Sympathetic Nervous System (SNS) 

·        Sympatholytic agents and actions - any agent or mechanism that interferes with the normal activity of the SNS

Cholinergic

Parasympathetic Nervous System (PNS) 

·        Cholinergic - any structure or mechanism that is related to the presence or action of acetylcholine as a transmitter, also drugs which act at cholinergic receptor sites 

Cholinergic nerve fibers

 Parasympathetic Nervous System (PNS)

·        Cholinergic nerve fibers - those fibers that synthesize, store and release acetylcholine

Cholinergic receptors 

Parasympathetic Nervous System (PNS)

·        Cholinergic receptors - receptors that engage acetylcholine.  They include nicotinic and muscarinic receptors. 

Parasympathomimetic (Cholinomimetic) agents and actions

Parasympathetic Nervous System (PNS) 

·        Parasympathomimetic (Cholinomimetic) agents and actions - drugs and transmitters that produce a PNS response 

Parasympatholytic (Cholinolytic) agents and actions

Parasympathetic Nervous System (PNS) 

·        Parasympatholytic (Cholinolytic) agents and actions - any agent or mechanism that interferes with the normal activity of the PNS 

The Efferent division of the peripheral nervous system consists of:

·        Somatic nervous system

·        Autonomic nervous system (ANS)

controls the visceral functions of the body. It is often referred to as the vegetative or involuntary nervous system. It is activated mainly by centers in the spinal cord, brainstem and hypothalamus.

The ANS regulates:

the heart,
smooth muscles: lungs, vasc, GI 

secretions

ANS

/\

/  \

/    \

PNS     SNS

ANS- Regulate heart, smooth muscles (lungs, vasc, GI), & secretions

PNS- rest & digest

SNS - fligh or fight

•Slows heart rate

•Increases gastric secretions

•Empties bladder & bowel

•Focuses eye for near vision

•Constricts pupil

•Constricts bronchi

• increases HR
• increases BP 
• Shunts blood from skin & viscera to skeletal muscles
• Dilated bronchi
• Mobilizes energy stores- from liver,releases glycogen
• eyes dilate (must be able to see far)

SNS -thoracolumbar region

-Preganglionic fibers (short) 

-postganglionic fibers (long)

-Each pre fiber connects with>200 post fibers in the paravertebral chain.

-SNS activation is widespread, important for "flight/fight"

PNS-brain/sacrum

-Preganglionic fibers (long) 

-postganglionic fibers (short)

-Each pre fiber connects connects with only a few post fibers.

-PNS activation are highly localized and specific, it never discharges as a complete system.  mediates "rest and digest" functions.

all preganglionic fibers (both SNS and PNS) release ______  which binds to ______receptors located in the ganglia.  

All PNS postganglionic fibers also release Ach, but the Ach released by these postganglionic fibers binds to muscarinic receptors located in the target cells.  

 (a) postganglionic fibers that supply the sweat glands release Ach, 

(b) the adrenal glands release epinephrine in response to stimulation by SNS preganglionic fibers. 

1. Na transports into cell& choline hitches a ride

2. acetyl co-enzyme A catalyzed RXN-->adds acetyl group, turns it into acetylcholine

3. packaged into vesicles

4. Ca channels opened by depolarizing currents, vesicle moves into synapse by exocytosis mediated by Ca

5vesicle move from cytoplasm close to synaptic terina

6. Ach no binds to nicotini/muscarinic receptor

7. biodegreade. cholinesterase biodegrades ach into choline & acetate.

8. choline is recyled & taken up by neuron

9. Binds to

• a) post-synaptic receptor to cause an action
• b) neuron from which it was just release to stop    the release of more Ach. Causes opening of K channel which facilitates repolarization
• c) biodegrades & is recyled

tyrosine--> dopa--> dopamine--> and converted by an exzyme.

1. dopamine sequestered inot vesicel & becomes NE.

2. influx of ca causes release

4. NE:

a. binds to post synaptic receptor, which is activated.

b. metabolized by COMT excreted in urine

c. reuptake

d. binds to presynaptic receptors to open K channel.

are found in 3 locations: 

(a) ANS ganglia (A group of nerve cells forming a nerve center, especially one located outside the brain or spinal cord)

(b) adrenal medulla secretory cells (makes catecholamines ex:

(c) skeletal muscle. 

 Nicotinic receptors function as ligand-gated ion channels, and their activation regulates the flow of ions into and out of cells. 

Family of neurotransmitters containing dopamine, norepinephrine and epinephrine, produced and secreted by cells of the adrenal medulla in the brain. Catecholamines have excitatory effects on smooth muscle cells of the vessels that supply blood to the skin and mucous membranes and have inhibitory effects on smooth muscle cells located in the wall of the gut, the bronchial tree of the lungs, and the vessels that supply blood to skeletal muscle. There are two different main types of receptors for these neurotransmitters, called alpha and beta adrenergic receptors. The catecholamines are therefore are also known as adrenergic neurotransmitters

a group of substances derived from tyrosine that act as hormones to stimulate cellular activity and carry nerve impulses through the body.

FACTS

Ach activates two types of receptors, nicotinic and muscarinic. 

Ach molecules are stored in vesicles in the cytoplasm and released in response to calcium influx. 

Ach disengages from the receptor and undergoes enzymatic hydrolysis by acetylcholinesterase.  

Muscarinic receptors all belong to the family of G-protein coupled receptors.

Let's clarify some terminology before discussing drugs that act on the PNS.

Drugs that we commonly refer to as "cholinergics" and "anticholinergics" are really muscarinic receptor agonists and antagonists. Theoretically, anticholinergic drugs block both nicotinic and muscarinic receptors. But when the term "anticholinergics" is used, it generally refers to drugs that block receptors at effector organs (muscarinic) not receptors at the ganglia (nicotinic).  

•Binds to M3 receptors

•Indicated for urinary retention in postoperative or postpartum patients

•Causes bladder muscle contraction and sphincter relaxation

•AEs include: salivation, lacrimation, bronchospasm, diarrhea, & bradycardia

reversibly block Ach binding to muscarinic receptors.  Because they block PNS output, they tip the ANS balance in favor of the SNS.  Therefore, a muscarinic antagonist will have effects that are similar to an adrenergic agonist.  These effects include increased heart rate, bronchodilation, decreased GI peristalsis, inhibition of urination, and mydriasis (pupillary dilation).

The clinical uses of anticholinergic agents can be summarized as follows:

1.      Bradycardia - increase heart rate and cardiac output (atropine)

2.      Asthma and bronchitis - induce bronchodilation (ipratropium)

3.      Anesthesia adjunct - reduce secretions (atropine, scopolamine)

4.      Peptic ulcer disease and IBS - decrease GI motility (propantheline, glycopyrolate)

5.      Motion sickness - reduction of vestibular disturbance (scopolamine)

6.      Induction of mydriasis (atropine, cyclopentolate) 

Muscarinic Antagonist Prototype: Atropine

•A nonselective competitive muscarinic agonist

•Indicated for

–Bradycardia

–Pupil dilation for eye exams

–GI hypermotility

•Contraindications

–Glaucoma

–Urinary retention

–Tachycardia

• Hyperthermia - because Ach binds to muscarinic receptors in sweat glands and induces sweating
• Anhidrosis
• Dry mouth
• Blurred vision
• Sedation, amnesia, delirium hallucinations, convulsions
• Constipation
• Urinary retention

a muscarinic receptor antagonist is an agent that reduces the activity of the muscarinic acetylcholine receptor. Acetylcholine (often abbreviated ACh) is a neurotransmitter, whose receptor is a protein found in synapses and other cell membranes. Besides responding to their primary neurochemical, neurotransmitter receptors can be sensitive to a variety of other molecules. Acetylcholine receptors are classified into two groups based on this:

• muscarinic, which respond to muscarine
• nicotinic, which respond to nicotine

s a drug which enhances the action at the nicotinic acetylcholine receptor (nAChR).

Examples include:

• nicotine (by definition—the "nicotinic acetylcholine receptor" is named for its affinity for nicotine)
• acetylcholine, the endogenous agonist of nAChRs
• choline

Depolarizing Neuromuscular Blocking Drugs

The only depolarizing neuromuscular blocker currently in clinical use is succinylcholine

  Succinylcholine binds to Nm receptors on the motor end-plate and induces depolarization.  However, unlike Ach which rapidly dissociates from the Nm receptor, succinylcholine remains bound and prevents the end-plate from repolarizing.  Thus, the end-plate is in a state of constant depolarization, resulting in muscular paralysis.  

Nondepolarizing Neuromuscular Blocking Drugs

These drugs are reversible antagonists of nicotinic receptors.  As such, they can bind to Nm receptors, thus blocking depolarization of skeletal muscle fibers and producing motor paralysis.  However, they can also bind to Nn receptors in ganglia and produce autonomic effects.  The major autonomic effect is hypotension (because blocking Nn receptors in SNS ganglia causes arterial vasodilation).  Nondepolarizing blocking drugs can be reversed by administering cholinesterase inhibitors.  

Cholinesterases have anticholinergic effects

2.Anticholinesterases have cholinergic effects and can be used as toxic agents i.e., sarin, organophosphate insecticides.  Toxic effects reflect muscarinic activation and include:

Eyes: miosis, blurred vision, ciliary spasm

Respiratory:bronchoconstriction

GU: involuntary urination

GI:defecation, cramps, N&V

CV: bradycardia

Secretions: sweating and salivation

Cholinesterase inhibitors are used for the following: 

·    to reverse neuromuscular blockade induced by

nondepolarizing agents

·    to improve muscle strength in myasthenia gravis

·    to manage gastroesophageal reflux (i.e., Reglan)

·    to treat glaucoma 

Epinephrine binds to all four adrenoceptors

Epinephrine has a greater affinity for beta than alpha receptors

NE binds to alpha1, alpha2, and beta1

NE has a greater affinity for alpha than beta receptors

Located in:

–Eyes (produce mydriasis)

–Blood vessels (vasoconstriction)

–GU (ejaculation, prostate contraction)

–Bladder base, urethral sphincter (smooth muscle contraction)

Prototypic agonist is phenylephrine

–Used to induce pupillary dilation

Prototypic antagonist is prazosin

–Used to manage HTN

–Used to manage BPH

Located in:

–Presynaptic nerve terminals (inhibit neurotransmitter release)

–Blood vessels (vasoconstriction)

Prototypic agonist is clonidine

Inhibits NE release (NE can bind to alpha 1 and cause vasoconstriction)

Inhibits sympathetic outflow in CNS

Located in heart

–Increase cardiac rate (chronotropic effects)

–Increase force of contraction (inotropic effects)

Prototypic agonist is isoproterenol

–nonselective beta agonist

–used for bronchodilation (beta 2)

–used as cardiac stimulant

Prototypic antagonist is metoprolol

–Heart: reduces rate and force of contraction; inhibits impulse conduction

–Kidney: suppresses renin secretion

Used to manage HTN: Mechanisms

–Reduced cardiac output

–Reduced renin release

–Reduced sympathetic output in CNS

Prototypic agonist is terbutaline

Lungs: Bronchodilation

Used to manage asthma