Week 2: Autonomic Pharmacology

Nervous System

• Nervous system consists of nerve cells that conduct signals/impulses to and from the brain and spinal cord
• Nervous system can be separated into two major systems:
o Central
o Peripheral

• Central (CNS):
o Comprised of brain and spinal cord
• Peripheral (PNS):
o Efferent (carry signals away from the brain/spinal cord)
o Afferent (carry signals towards the brain/spinal cord)

CNS

• Brain and spinal cord are housed within protective cavities

• Brain: Protected via the skull
• Spinal cord: Protected via vertebrae
• Connected to end organs, muscles, blood vessels, and glands via the peripheral nervous system

PNS

• Consists of all non-CNS nerve cells

• Nerves present in limbs and trunk that carry out signals from the brain/spinal cord
• Further broken down into: Autonomic system and Somatic system

Afferent vs. Efferent

• Afferent: Regulates reflexes. Signals CNS to stimulate afferent system

• Efferent: Carries signals from the CNS to end organs

Somatic vs. Autonomic

• Somatic:
o Voluntary motion via skeletal muscle
o Touch, sight, sound
• Autonomic:
o Involuntary maintenance of homeostasis
o Heart rate, respiratory rate, digestion
 • Further broken down into: Afferent and Efferent

ANS

• ANS regulates the activity of the heart, glands, and smooth muscle to maintain physiological normalcy at a
subconscious level (homeostasis)
• Three distinct areas of regulation: Enteric, Parasympathetic, and Sympathetic

Enteric ANS

• Innervates (supplies nerves) to the GI tract, pancreas and gallbladder

• Functions freely from the CNS
• Controls gastric motility via myenteric and submucous plexus
o Range from esophagus to the anus
o Sensory and motor neurons respond to stimuli to digest, absorb, and expel GI contents
• Controls digestive function via hormones:
o Exocrine secretions: gastrin, cholecystokinin, secretin, trypsin, amylase and lipase
o Endocrine secretions: insulin

Parasympathetic ANS

• Maintenance of “essential” functions:

o Digestion and excretion
• Largely counteracts the sympathetic system
o Engages to allow the body to rest/recover
• Deliver stimuli via cranial nerves (I-XII)

Sympathetic ANS

• “Fight or flight” response:

o Triggers a release of epinephrine and norepinephrine causing an increase in blood pressure, heart rate,
respiratory rate

Neurotransmitters

• Function to relay signals between nerve cells and end organs

• Two types of major types, of more than 50, to be reviewed:
o Acetylcholine (ACh): ‘cholinergic’
▪ Acetylcholinesterase (AChE): metabolizes acetylcholine
o Norepinephrine (NE) or epinephrine (EPI): ‘adrenergic’
o Additional include dopamine, serotonin, histamine and GABA

Receptor binding

• Acetylcholine (primary neurotransmitter in the PNS)

o Acts upon both nicotinic and muscarinic receptors, but produces differing responses
o Nicotinic receptors are ionotropic; thus when acetylcholine binds, they allow positively charged ions
(sodium, potassium, calcium) to flow causing depolarization. All are excitatory
▪ N1 receptors: found in neuromuscular junction; muscle movement
▪ N2 receptors: found in the CNS, and ANS/PNS
• Muscarinic receptors, via G (guanine nucleotide-binding)-proteins, change shape when acted upon by
acetylcholine, causing phosphorylation
o M1, M3, and M5 receptors: excitatory
o M2 and M4 receptors: inhibitory
Synthesis of Acetylcholine

Cholinergic Agonists

• ACh is the primary mediator for nerve impulses within the autonomic nervous system
o Both sympathetic and parasympathetic
• Separated by action:
o Direct: stimulate / inhibit release
o Indirect:
▪ Reversible: bind receptors reversibly
▪ Irreversible: bind receptors irreversibly
• Largely utilized for ocular and GI/urinary motility

• Bethanechol (Urecholine): Ach-mimetic

o Acts on the smooth muscle of the bladder causing urination via muscarinic stimulation causing increased
bladder motility and tone
▪ Utilized via the oral route to treat urinary retention
• Pilocarpine (Salagen): Ach-mimetic
o Acts on the cornea to produce contraction (miosis)
▪ Utilized via ocular route to treat glaucoma to reduce intra-ocular pressure
o Also stimulates secretion release e.g. sweat/saliva, and is used in severe dry-mouth via increased
exocrine function

Reversible anticholinesterases

• Also known as acetylcholinesterase (AChE) inhibitors

• Act to increase the activity of acetylcholine via inhibition of enzymatic breakdown

Therapeutic uses

• Physostigmine (Mestinon):
o Inhibits activity of acetylcholinesterases (prolongs ACh activity)
o Utilized via oral route to promote intestinal and bladder motility
 o Utilized via ocular route to produce miosis for eye procedures as well as to treat glaucoma
• Cholinesterase inhibitors used in the treatment of Alzheimer’s disease:
o Donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon)

Irreversible Anticholinesterases

• Most agents are toxic and not routinely utilized in modern medicine
• Isoflurophate:
o Developed by a British scientist, Dr. Saunders
o Originally sought as a combination agent with Mustard Gas for chemical warfare

Anticholinergic agents

• Also referred to as cholinergic antagonists

• Inhibit acetylcholine from binding to target receptors:
o Target muscarinic and/or nicotinic receptors
o One group blocks efferent stimuli of skeletal muscles causing paralysis

Antimuscarinic agents

• Actions oppose cholinergic agents and end signal propagation

• Atropine (Sal-tropin):
o Acts to competitively block ACh from binding
o Utilized via ocular route to produce mydriasis (dilation)
▪ Causes an increase in intra-ocular pressure
o When utilized via IV route can produce:
▪ Bradycardia (low heart rate)
▪ Reduction in GI motility
▪ Xerostomia (severe dry mouth)

Additional Anticholinergic agents

• Scopolamine (Transderm):
o Acts similarly to atropine and prevents ACh binding
o Utilized via topically route for motion sickness
▪ May also block short-term memory
• Ipratropium (Atrovent):
o Structure is similar to atropine, except it is a quaternary amines, rather than tertiary amines
▪ Giving them a ‘positive’ charge and prevents entry into systemic system
o Utilized via inhaled route for treatment of Chronic Obstructive Pulmonary Disease (COPD)
o Utilized via nasal route for seasonal allergies/watery eyes

Nicotinic agonists

• Primarily act to block the ion channels within the ANS, terminating signal transduction
• Utilized topically as a smoking cessation aid (Nicotine patch/gum/lozenge)
o Potentially may increase blood pressure and heart rate
o Thought is to replace toxic nicotine with a cleaner version while still supplying some level of nicotine to
aid patient in quitting

Uses of NMBs

• Act to block ACh transmission at the motor nerve ending

o Agents such as atracurium, cisatracurium, vecuronium and pancuronium produce paralytic effects
 • Typically utilized via IV route for mechanically ventilated patients with severe/dangerous muscle contractions
• Caution with use as they are paralytic agents only!

Adrenergic Agonists

• Stimulated via epinephrine and/or norepinephrine

• Receptors for these agents are found throughout the body but main areas of interest include:
o Heart
o Lungs
o Blood vessels
o Genitourinary

Receptor function

• Adrenergic receptors are separated into two categories:

o α (α1 and α2)
o β (β1 and β2)
• Each receptor produces various responses based on their individual properties

Receptor Effects

• α1 stimulation:
o Incr. intracellular Ca2+ causing vasoconstriction/incr. peripheral resistance which incr. blood pressure
• α2 stimulation:
o Inhibits norepinephrine (NE) and insulin release via feedback mechanisms causing decr. blood pressure
& incr. blood glucose
• β1 stimulation:
o Incr. contractility/chronomaticity via direct stimulation causing tachycardia (incr. heart rate) and incr.
renin release
• β2 stimulation:
o Decr. contractility/chronomaticity via direct stimulation causing vaso- and bronchodilation

Multi-receptor Adrenergic medication

• Epinephrine (Adrenaline):
• Stimulates α and β receptors
• Utilized via IM route for anaphylaxis/hypersensitivity
o Via α1 and β2 stimulation
• Utilized via IV route for critically ill patients requiring blood pressure increases
o Via α1 and β 1 stimulation

α-Adrenergic medication

• Clonidine (Catapres):
o α2 agonist
o Utilized via oral and topical route for patients with hypertension
▪ Secondary, non-approved uses include for tic’s in pediatrics, Tourette’s syndrome, and
adjunctively for nicotine/tobacco withdrawal

β-Adrenergic medications

• Albuterol (Proair), salmeterol (Serevent) and fomoterol (Foradil)

o β2 agonists
o Primarily utilized via inhalation for the treatment of asthma/COPD
 o Newer “ozone-friendly” formulations are available in the U.S.

Indirect and Mixed acting

• Amphetamine (Adderall, Concerta, etc):

o Stimulates α1 and β1 receptors
o Utilized via oral route for treatment of attention deficit/hyperactivity disorder (ADD or ADHD)
• Ephedrine / Pseudoephedrine (Pretz-D / Sudafed):
o Stimulates α and β receptors, and directly act to release NE
o Derived from the Ma-huang plant
o Sold in OTC weight-loss supplements until 2004
▪ Can still be purchased from a variety of online retailers

Adrenergic Antagonists

• Also referred to as adrenergic blockers

• Two major groups:
o α-blockers
▪ α1a-blockers
o β-blockers:
▪ Non-selective (β1 and β2-blockers)
▪ Selective (β1-blockers)

α-blockers

• Includes the following agents:

o Doxazosin (Cardura), prazosin (Minipress), and terazosin (Hytrin)
• Primarily utilized via oral route to control urinary frequency
o Decreases bladder muscle tone
o Also cause vasodilatation via α-blockade
▪ Orthostatic hypotension

α1a-blocker

• Alfuzosin (Uroxotral) and tamsulosin (Flomax):

o Specifically targets α1a receptor, thus minimizing postural hypotension risk while producing prostate
smooth muscle tone reduction

Non-selective β-blockers

• Competitively block the β receptors

• Include the following agents:
o Propranolol (Inderal), timolol (Blocadren) and nadolol (Corgard)
• Block both β1 and β2 receptors
• Not routinely utilized for blood pressure/heart rate reduction
o Propranolol: migraine prophylaxis, anxiety
o Timolol: glaucoma
o Nadolol: GI hemorrhage/bleeding

Selective β-blockers

• Include the following agents:

o Atenolol (Tenormin) and Metoprolol (Lopressor) (regular and long-acting), but there are many others
• Primarily utilized via oral route for heart rate/blood pressure reduction (HR > BP)
 o Must titrate up/down to avoid severe adverse effects due to receptor up/down regulation

Summary

• Of the two major chemical messenger passages, the peripheral nervous system has many pathways
o Innervation is seen throughout the body, unlike the central nervous system
• Autonomic: involuntary bodily functions
• Somatic: voluntary bodily functions