05a - Intro to Autonomic Pharmacology

autonomic nervous system (ANS)

controls involuntary functions including heart rate, blood pressure, pupil size, digestion, bronchial tone, gland secretion, sweating, urinary bladder infection, blood vessel tone

• outflow comes from CNS, specifically the spinal cord and brainstem

  • CNS = brain + spinal cord

• sympathetic and parasympathetic systems differ anatomically by where their outflow exits the CNS

  • sympathetic = thoracolumbar outflow

  • parasympathetic = craniosacral outflow

• sympathetic and parasympathetic systems also differ by where their ganglia sit

  • sympathetic = near spinal cord and paravertebral chain

    • short preganglionic fiber; long postganglionic fiber

    • diffuse output pattern → chain allows signals to travel up/down the chain before synapsing

  • parasympathetic = near or inside target organ

    • long preganglionic fiber; short postganglionic fiber

    • targeted output pattern → specific and localized response

• dual innervation → most organs are innervated by both sympathetic and parasympathetic fibers

sympathetic nervous system

“fight or flight” and “restore and repair” response

• “fight or flight” → increased heart rate, increased blood pressure, pupil dilation, bronchodilation, blood flow redistribution, energy mobilization

• “restore and repair” → maintain fluid balance, increase ADH, increase aldosterone, activate renin-angiotensin system, promote coagulation after injury, increase plasminogen activator inhibitor activity

• outflow comes from thoracic and lumbar spinal cord

• short preganglionic fiber; long postganglionic fiber

• diffuse output pattern → chain allows signals to travel up/down chain before synapsing

parasympathetic nervous system

“rest and digest” response

• “rest and digest” → digestion, sleep/rest, GI motility, glandular secretion, slower heart rate, urination, pupillary constriction

• outflow comes from cranial and sacral regions

• long preganglionic fiber; short postganglionic fiber

• targeted output pattern → specific and localized response

afferent vs efferent neurons

afferent arrives at CNS; efferent exits CNS

• efferent neurons → carry signals from CNS to effector organ

• afferent neurons → carry sensory signals from periphery to CNS

autonomic neurotransmitters

• sympathetic innervation of adrenal medulla:

  • preganglionic neuron → acetylcholine → nicotinic receptor on chromaffin cells of adrenal medulla → epinephrine → adrenergic receptor of effector organs

  • epinephrine released in blood and acts as a hormone because it is distributed systemically

• sympathetic innervation:

  • preganglionic neuron → acetylcholine → nicotinic receptor on postganglionic neurons (N_n) → norepinephrine → adrenergic receptor of effector organs (⍺/β)

• parasympathetic innervation:

  • preganglionic neuron → acetylcholine → nicotinic receptor on postganglionic neurons (N_n) → acetylcholine → muscarinic receptor on effector organs

• somatic innervation:

  • somatic motor neuron → acetylcholine → nicotinic receptor on skeletal muscle cells (N_m)

somatic nervous system

controls voluntary skeletal muscle movement

• release acetylcholine and act on nicotinic muscle receptors (N_m)

• innervates skeletal muscle

• do not have ganglia

• myelinated and produce fast responses

generalized cholinergic junction

1. choline uptake in nerve terminal via active transport

2. choline comes with acetyl-CoA, catalyzed by choline acetyltransferase (ChAT), to form acetylcholine

3. ACh is transported into vesicles

4. action potential reaches nerve terminal, and Ca²⁺ enters

5. vesicle fuses with membrane via vesicle attachment membrane proteins (VAMPS)

6. synaptosome-associated proteins (SNAPS) dock vesicle to membrane

7. ACh is released by exocytosis into synaptic cleft

8. ACh binds muscarinic (M₁ - M₅) or nicotinic receptors (N_n, N_m)

   • muscarinic receptors → GPCRs that activate phospholipase C to produce DAG and IP₃, increasing intracellular release of Ca²⁺

   • nicotinic receptors → ligand-gated ion channel that stimulates flow of Na⁺ through channel

9. OR ACh is rapidly broken down by acetylcholinesterase on effector membrane, into choline and acetate

   • anticholinesterases inhibits AChE, causing stimulation of cholinergic receptors from increased ambient levels of ACh, due to decreased ACh breakdown

10. choline is recycled into the nerve terminal

generalized noradrenergic junction

1. tyrosine enters nerve terminal

2. tyrosine hydroxylase converts tyrosine to DOPA

3. aromatic L-amino acid decarboxylase (AAADC) converts DOPA to dopamine

4. dopamine enters vesicle

5. dopamine-β-hydroxylase (DβH) converts dopamine to norepinephrine

   • reserpine → inhibits dopamine uptake into vesicle

6. NE released into nerve terminal with nerve stimulation

7. NE acts on ⍺ and β receptors on effector cell

8. OR NE can act on ⍺₂ and β₂ receptors on the nerve itself presynaptically

   • ⍺₂ → autoreceptor that inhibits further NE release

   • β₂ → heteroreceptor that stimulates NE release

     • NE is a weak β₂ agonist; epinephrine can also stimulate β₂ receptor

9. OR NE can be taken back up by NET

   • 80-90% of NE is reclaimed by adrenergic nerve terminal

   • cocaine → indirect adrenergic agent that inhibits NET to block NE uptake, allowing more NE to be taken up by ⍺ and β receptors

direct-acting adrenergic agonists

directly stimulate adrenergic receptors; responses may be potentiated by cocaine, reserpine, and guanethidine

• selective:

  • ⍺₁ → phenylephrine

  • ⍺₂ → clonidine (presynaptic)

  • β₁ → dobutamine

  • β₂ → terbutaline

• non-selective:

  • ⍺₁, ⍺₂ → oxymetazoline

  • β₁, β₂ → isoproterenol

  • ⍺₁, ⍺₂, β₁ → norepinephrine

  • ⍺₁, ⍺₂, β₁, β₂ → epinephrine

indirect-acting adrenergic agents

increase adrenergic signaling without directly activating receptors

• releasing agents → amphetamine, tyramine

  • response abolished by prior treatment with reserpine or guanethidine

• uptake inhibitor → cocaine (on NET)

• monoamine oxidase (MAO) inhibitors → selegiline

  • responsible for breaking down NE in presynaptic nerve terminal

• catechol-O-methyltransferase (COMT) inhibitors → entacapone

  • present in effector cells postsynaptically

mixed-acting adrenergic agonists

can stimulate adrenergic receptors directly, promote NE release, and affect uptake/metabolism pathways

• ⍺₁, ⍺₂, β₁, β₂ → ephedrine

• response reduced with prior treatment with reserpine or guanethidine

adrenergic antagonists

• ⍺₁ → prazosin, doxazosin

• ⍺₂ → yohimbine

• ⍺₁, ⍺₂ → phenoxybenzamine

• β₁ → atenolol, metoprolol

• β₂ → butoxamine

• β_1, β₂ → propranolol

• ⍺₁, ⍺_2, β_1, β₂ → labetalol

structures of the chambers of the eye

• circular/sphincter muscle → muscarinic receptor

  • contraction causes miosis (pupil constriction)

• radial/dilator muscle → ⍺₁ adrenergic receptor

  • contraction causes mydriasis (pupil dilation)