The Autonomic Nervous System

Overview of the Autonomic Nervous System (ANS)

• Central nervous system (CNS) includes the brain and spinal cord.
• Peripheral nervous system (PNS) consists of nerves connecting the body to the brain.
• Autonomic functions are involuntary, while somatic functions are voluntary.
• The sympathetic nervous system is associated with fight/flight, and the parasympathetic with rest/digest.
• Autonomic function is integrated and regulated at many levels, from the CNS to the effector cells; and mostly uses negative feedback
• Autonomic reflexes are especially important in understanding cardiovascular responses to autonomic drugs

Functions of the Autonomic Nervous System

• The autonomic nervous system (ANS) controls involuntary body functions and responds to environmental and bodily changes without conscious thought.
• The ANS maintains blood pressure, continence, and vision adjustments.
• The autonomic nervous system (ANS) is involved in pupil constriction and dilation
• This occurs from the amount of light detected by the retina within the CNS
• Conserving energy involves decreasing heart rate and constricting pupils via the parasympathetic pathway.
• Expending energy involves increasing heart rate and dilating pupils via the sympathetic pathway.

Anatomical and Functional Differences in ANS

• Most organs get innervation from sympathetic and parasympathetic nerves, which use different neurotransmitters at different receptors
• ANS pharmacology may seem intimidating due to the involvement from nearly all organ systems
• It is enough to focus on the properties of each system impacted by ANS drugs
• ANS drugs are crucial in dramatic medical situations, such as beta agonists opening airways for asthma and epinephrine for anaphylaxis/shock
• In the autonomic nervous system (ANS), two neurons are required to reach their target organ.
• A preganglionic neuron from the CNS will synapse on the Ganglia containing the postganglionic neuron, subsequently synapsing on the target organ
• Central ganglia are located near target organs
• Spinal cord ganglia are located near the spinal chord
• Physiologic antagonism takes place in the opposing effects are mediated by different chemicals and receptors, such as ACh constricting pupils and NE dilating pupils.
• Two systems work together in opposite ways, to balance each other
• The SNS is catabolic and thoracolumbar
• The PSNS is anabolic and craniosacral
• The preganglionic in the PSNS are long and synapse 1:1 for localized action
• The preganglionic in the SNS are short and synapse onto many cells for diffuse action
• PSNS is the predominant tone and has the greater tissue influence when the body is at rest, compared to the SNS
• There are exceptions where the SNS is the predominant tone, including blood vessels and sweat glands.
• The Midbrain and Medulla integrate the functions of the SNS/PSNS to respond to sensory input of the sensory PSNS, and it controls the SNS outflow

Neurotransmitters in the ANS

• Acetylcholine and Norepinephrine are responsible for neurotransmission.
• Two main types of neurotransmitters mediate ANS effects: acetylcholine at cholinergic receptors, and norepinephrine at adrenergic receptors.
• All preganglionic neurons and PSNS postganglionic neurons release Acetylcholine (ACh)
• Acetylcholine (ACh) is produced from acetyl coenzyme A and choline.
• Enzymatic degradation by acetylcholinesterase enzymes terminates ACh rapidly in the synapse.
• Nicotinic and muscarinic are the two main types of cholinergic receptors.
• Ligand-gated ion channels characterize nicotinic ACh receptors, found at the motor endplate, in all ANS ganglia, and in the adrenal medulla.
• GPCR receptors characterize muscarinic ACh receptors, found on target organs of the postganglionic fibers, primarily in the PSNS.
• Norepinephrine (NE) is released by most postganglionic neurons in the SNS.
• Dopamine produces NE, and NE can be further metabolized to Epinephrine
• Reuptake transporters primarily terminate NE in the synapse
• Monoamine oxidase and COMT can also inactivate NE.
• Adrenergic receptors respond to norepinephrine and catecholamines.
• There are two main types of adrenergic receptors with subtypes: Alpha and Beta
• 1 receptors are GPCR and stimulatory, found mainly on blood vessels.
• 2 receptors are GPCR and inhibitory, where presynaptic activation of a2 decreases NE release.
• Beta 1 and Beta 2 receptors are all GPCRs and stimulatory, but their location varies

GPCR Signaling

• Gs, Gi, Gq signaling pathways contribute to the effects on Autonomic drugs
• Adrenergic receptors are often concentrated at sites where postganglionic neurons release neurotransmitter.
• Adrenergic neurotransmitters like Epinephrine and Norepinephrine get transferred through out the body from adrenal glands into the blood
• Circulating Norepinephrine and Epinephrine circulating can bond anywhere in the body, including immune and blood cells
• Presynaptic receptors are located there the neurotransmitter gets released from the axon
• They give feedback in the synapse about the neurotransmitter, allowing modulation of release
• NE activates alpha 2 receptors to turn down NE release

Control of Specific Organs

• The iris radial contracts radial dilator muscle, while the PSNS M activation contracts the circular
• The bladder SNS B activation stimulates production, while the alpha 2 reduces it
• The PSNS M contracts ciliary muscle, changing the shape for near vision
• Most other organs use opposition to provide autonomic effects via different transmitter and receptors
• The PNS controls heart/airway function while the SNS opposes
• The M3 activation contracts airways decreasing bronchodilation and mucus
• Stimulation is greater when sympathetic responses are required
• The M3 promotes secretion of mucus saliva etc
• 2 inhibits secretion
• The smooth muscle walls of the GI tract are controlled as follows: PNS stimulates contraction, SNS reduced tone
• Sphincters: PNS relaxes, SNS contracts
• Secretion PNS activate, SNS inhibits
• the urinary bladder: M3 activates to dispel urine and B3 relaxes the detrusor
• M3 urehtra sphincter will let urine go but S1 will constrict to hold urine
• Alpa 1 a constric smooth muscles for urine flow
• The brain input is from the PNS/SNS
• Heat rates use pacemakers that generate cardiac action potentials
• Force of cardiomyocyte contraction intensity
• The heart gets input from PSNS and SNS to regulate HR and function
• The kidney stimulates rennin with beta 1 action on the kidney cells.
• Resistance involves resistance of blood vessels
• Beta 2 activation causes VSMC relaxation while Alpha 1 (and 2) causes VSMC construction

ANS Pharmacology: Adrenergic Agonists

• ANS drugs mimic sympathetic responses.
• ANS drugs either activate (direct-acting) or boost (indirect-acting) adrenergic receptors.
• The opposite are sympatholytics, which refer to that block or oppose SNS effects
• Remember the principles of fight / flight and rest / digest to explain the many receptor effects
• Pay attention to the type and location of receptors, focusing on the most important locations for each receptor.
• Understand the differences between receptor binding for agonists vs. antagonists

Adrenergic Agonists

• Sympathomimetic drugs mimic how the sympathetic nervous system works, either by directly activating or indirectly boosting adrenergic receptors
• Alpha receptor agonists can be alpha 1 (vasoconstriction, pupil dilation) and alpha 2 (Decrease SN activity and blood flow regulation)
• The nonselective receptor Isoproterenol has B1 and 2 receptors
• Direct-acting sympathomimetics increase activation by using a more selective design for a recpetor
• Target: Direct vs indirect acting. the chemical class is catecholamines
• Catecholamines have short half lives for poor bio avi

ANS Regulation of Blood Volume

• B1 activation on kidney cells stimulates rennin, which increase the blood via retaining more water
• Vasoconstriction is related to regulation of blood volume
• Thirst is also related to blood volume regulation

Selective Alpha 1 Agonist: Phenylephrine

• Causes constriction of the vascular smooth muscle to treat congestion, treat hypotension in shock, and for pupil dilation in ophthalmology
• Systemic vasoconstriction using vasoconstriction, but this time it's orally used PO to treat orthostatic hypotension
• Alpha 1 constriction of the bladder results in urinating as an adverse effect
• This leads to bradycardia from high blood pressure

Selective Alpha 2 Agonists

• Clonidine can treat opioid withdrawal symptoms
• It decreases sympathetic outflow from the CNS by treating hypertension
• Can also vasodilate the heart as well
• Methyldopa lowers SN activity

Selective Beta 1 Agonists

• Dobutamine increases heart rate and force which causes cardiac output
• Can be used as a stress test for echocardigrams in patients that cannot exercise
• Short half life
• Terbutaline Beta 2 is a smooth muscle relaxant that bronchodilates in asthma and relaxes the uterus
• Can have negative effects such as increased glucose and tremors due to muscle spindles

Selective Beta 3 Agonists

• Mirabegron relaxes detrusor, reducing bladder and easing tension

Mixed Adrenergic Agonists

• Catecholamines act on adrenergic receptors, with limited CV effects
• Epinephrine and norepinephrine act like this due to the catechol groups. There are also Synthetic ones
• The heart increases and the vascular function is vasodilated with effects on the respiratory pathway
• Broncodilation with the Alpha 2. used when those effects are needed.
• It does NOT affect the CV due to the hydroxyl groups.

Indirect-Acting Adrenergic Agonists

• These have sympathetic activity by increasing catecholamine levels, with the following main mechanisms:
  • Blocking reuptake from synapse back into neaural
  • Preventing degradation by enzymes, such as MAOi's
  • Interfering with neurotransmitter storage for release from vesicles
• Cocaine blocks DA, the NE and SN, resulting in euphoria. It also blocks actions from the action potentials
• Reuptake Inhibitors: increase the transmitters and reuptake and treat the anxiety and depression
• Releasing Agents: can reduce filling, increase build up, reverse direction with the up take, and action independent of the vesicles.

ANS Pharmacology: Adrenergic Antagonists & Integrating Concepts

• Adrenergic antagonists are drugs that generally decrease sympathetic activity
• Sympatholytics refer to drugs that decrease sympathetic activity.
• Drugs in this are category are direct acting—ie they block receptors.
• Thinking or remembering how the receptors function is important

• A summary of how the adrenergic agonists are shown below
• Alpha 1: Contraction, constriction
• Alpha 2: reduces sympatethic tones
• Beta 1: increased heart rate/force
• Beta 2: relaxed smooth muscles in the vessel, lungs, etc
• Beta 3: Relaxes the detrusor for the bladder and less pushing during urination

Nonselective Alpha Antagonists

• Phenoxybenzamine: Reduces/prevents hypertensive crisis from PCC (Pheochromocytoma (PCC) tumors secrete catecholamine) – It is helpful from PCC surgery,

• This is helpful for PPC from its non-competitive agonist

• Phentolamine: rapidly reverses constriction from the extravasation of NE

• Rapid to work. Opens vesicles

• Treats bladder reduction