Part I: Intro to Autonomics and Adrenergic Signaling Flashcards
What two systems is the Nervous system made up of?
Central and Peripheral Nervous System
What is the central nervous system made up of?
Brain Spinal Cord
What pathways is the peripheral nervous system made up of?
Sensory Pathways (Afferent) Motor Pathways (Efferent)
What two systems make up the Motor Pathway (Efferent)
Somatic Nervous System (Voluntary) Autonomic Nervous System (Involuntary)
What are the divisions of the autonomic nervous system?
Sympathetic Division Parasympathetic Division
Describe the Autonomic Nervous System Anatomy
Neurons and Ganglia of the Autonomic Nervous System
- Ganglia are collections of synapses protected by a barrier
- Parasympathetic NS has long preganglionic and short post-ganglionic neurons
- Sympathetic NS has short preganglionic and long post-ganglionic neurons
- Somatic NS has no ganglia between the spinal cord and the target organ—just one long neuron
Chemical neurotransmitters utilized by ANS
Acetylcholine (Ach)
Norepinephrine (NE)
Epinephrine (EPI)
Dopamine (not a direct neurotransmitter in SNS, but important precursor to NE and EPI)
Other: ATP, Adenosine, Serotonin, peptides such as Atrial Naturetic Factor
Acetylcholine (Ach)
Released by preganglionic fibers (short), somatic neurons and post-ganglionic neurons in the parasympathetic NS
Norepinephrine (NE)
Released by postganglionic fibers in the sympathetic NS
Epinephrine (EPI)
Released into general circulation by the adrenal medulla, a de facto sympathetic post-ganglionic tissue
Organs in which the SNS and PNS have opposing effects
Heart - Rate, Contractility, force
Lungs - Bronchoconstriction
GI and Bladder - Motility of longitudinal muscle and tone of detrusor muscle, Sphincters, PNS indirectly controls SNS
· Salivary, Lacrimal, nasopharyngeal, and most sweat glands
Eye - Pupillary constriction, accommodation for near and far vision
Anatomy of the eye based on picture from slides
Examples of PNS and SNS cooperation
·Sweating
Generalized hydration of the skin controlled by the PNS.
Localized sympathetic cholinergic sweating in the palms, underarms
·Pulmonary secretions
PNS controls mucus secretions in the lungs
SNS controls watery secretions in the lungs
·Male Sexual response
Point and Shoot
Special Situations for PNS and SNS
Pregnant uterine myometrium - Inhibited with SNS stimulation
Female sexual response - Complicated
Organs/tissues exclusively controlled by the SNS
·Blood vessels
Exclusively sympathetic innervation of major blood vessels leads to vasoconstriction as the basal tone (maintaining blood pressure even at rest)
Exclusively sympathetic innervation of blood vessels to gut, kidney and skin
Sympathetic innervation of blood vessels in striated (skeletal) muscle and liver is vasodilating
Blood flow to the heart and brain is mostly controlled by local factors and pressure differentials, not by the autonomic nervous system
·Kidney vasoconstriction and renin secretion
·Liver glycogenolysis, fat cell lipolysis, pancreatic insulin secretion
·Skeletal muscle metabolism (NOT contraction)
Adrenergic Receptor Subtypes
Gaq activates phospholipase C-b enzymes
- Increased Ca++ levels in smooth muscle lead to contraction
Gas activates adenylyl cyclase (and L-type Ca++ channels in the heart)
- Increased cyclic AMP and cytosolic Ca++ increases heart rate and contractility
- Increased cyclic AMP in smooth muscle promotes relaxation
Gai inhibits adenylyl cyclase
- Decreased cyclic AMP in smooth muscle promotes contraction
- Decreased cyclic AMP in heart decreases rate and contractility
- Activates K+ channels to cause inhibition of presynaptic neurotransmitter release
Cardiac Signal Transduction
Smooth muscle signal transduction
Receptor regulation
Supersensitization
- Occurs following long term blockade of receptors with antagonists
- Up-regulation (increased levels) of receptors leads to supersensitivity to activation
- Problematic if taking b-blockers (antagonists) longterm.
- Abrupt withdrawal of b-blockers increases likelihood of a myocardial infarction for up to 2 weeks following cessation of therapy
Baroreflex - Cardiac Effects
Changes in blood pressure normally activate baroreceptors sensors on the aorta, sending a signal through an afferent nerve to the brainstem. Connections in the brain stem monitor blood pressure and send messages through the efferent vagus nerve to change heart rate in compensation by increasing or decreasing ACh release from vagus nerve.
If blood pressure ⬆ then heart rate ⬇
If blood pressure ⬇ then heart rate ⬆
Baroreflex - Vascular Effects
Change the tone of the major blood vessels in compensation for changes in blood pressure.
Function of Adrenergic Signaling
(Preparing for vigorous activity or potential trauma)
- Shunt blood away from digestive and house keeping organs (skin, GI, kidney, bladder)
- Shunt blood to skeletal muscle for vigorous activity
- Shunt blood to lungs, heart, brain for alertness and vigorous activity
- Increase energy availability, increase blood glucose levels
- Increase O2 supply in anticipation of increased demands
- Increased cardiac output in anticipation of increased demand
- Preparation for trauma and blood loss
- Decrease in activity of housekeeping, reproductive, and digestive organs (GI, bladder, uterus)
- Open pupils for more light input and better vision
- Increase alertness, wakefulness, preparation for activity, focus, vigilance
Shunt blood away from digestive and house keeping organs (skin, GI, kidney, bladder)
- Alpha-1 mediated vasoconstriction
Shunt blood to skeletal muscle for vigorous activity
- Beta-2 mediated vasodilation
- Greater effect of EPI than NE
Shunt blood to lungs, heart, brain for alertness and vigorous activity
- NE and EPI have very slight direct vasodilatory effects in these organs
- Alpha-1 mediated vasoconstriction of major blood vessels creates a pressure differential that diverts blood to heart, brain, and lungs
- Local vasodilatory factors in heart, lung, and brain also contribute to increased blood flow
Increase energy availability, increase blood glucose levels
- Alpha-2 mediated inhibition of insulin release from pancreatic islets
- Beta-2 mediated glucagon secretion from pancreas
- Beta-2 mediated increases in glycogenolysis and gluconeogenesis in liver
- Beta-2 mediated glycogenolysis in skeletal muscle
- Beta-2 mediated K+ uptake into skeletal muscle, slight depolarization to prepare for activity
- Beta-3 mediated lipolysis and mobilization of fat reserves
Increase O2 supply in anticipation of increased demands
- Beta-2 mediated bronchodilation
- Beta-2 mediated inhibition of mast cell degranulation
Increased cardiac output in anticipation of increased demand
- Beta-1 mediated increases in heart rate, force, and contractility
Preparation for trauma and blood loss
- Alpha-2 mediated potentiation of platelet aggregation
- Beta-1 mediated increases in renin secretion leading to vasoconstriction
Decrease in activity of housekeeping, reproductive, and digestive organs (GI, bladder, uterus)
- Beta-2 mediated relaxation of myometrial (uterine) smooth muscle
- Beta-2 mediated relaxation of GI smooth muscle
- Alpha-2 mediated inhibition of ACh release onto GI smooth muscle
- Alpha-1 mediated constriction of uritogenital muscles and sphincters
Open pupils for more light input and better vision
- Alpha-1 mediated constriction of iris radial muscles leading to mydriasis
Increase alertness, wakefulness, preparation for activity, focus, vigilance
Beta and Alpha-mediated effects on the Central Nervous System
Alph-1 (G-alpha-q)
*Pulmonary, cardiac, and cerebral vasculatures are initially constricted by SNS stimulation through a1 receptors; however, local vasodilatory peptides and other factors increase blood flow to the lungs, heart, and brain with full SNS stimulation.
Alpha-2 (G-alpha-i)
#Multiple adrenergic subtypes are present in the CNS that suppress appetite, and increase alertness, general excitability, & focus
Beta-1 (G-alpha-s)
Beta-2 (G-alpha-s)
Beta-3 (G-alpha-s)
The Adrenergic Nerve Terminal
Catecholamines
EPI, NE, and Dopamine
Catechol ring (dihydroxy aromatic ring) and amine group
Tyrosine
Amino acid precursor to all catecholamines
Transported into the nerve
Tyrosine Hydroxylase (TH)
- Cytosolic Enzyme
- Rate limiting enzyme and highly regulated
- Negative feedback inhibition by increased catecholamine levels
- Positive feedback stimulation by impulse regulation
- When the neuron is stimulated, Ca++ levels increase to stimulate TH
- Inhibited by a-methyl-r-tyrosine (Metyrosine)
- Non-selective inhibition of all catecholamine biosynthetic pathways
- Useful only for treatment of pheochromocytoma-adrenal tumor which produces excess EPI
Aromatic L-amino acid decarboxylase (L-AAD)
- Cytosolic enzyme
- Non-specific enzyme, decarboxylates other aromatic amino acids as well
- Inhibitors are adjunct Tx in Parkinson’s disease, e.g. Carbidopa
Phenylethanolamine-N-methyl transferase (PNMT)
- Catalyzes NE to EPI
- Only present in the adrenal medulla and the CNS, not present in SNS nerve terminals
- Cytosolic Enzyme
Dopamine-beta-hydroxylase (D-beta-H)
- Vesicular Enzyme
- Dopamine must first be transported into vesicle to be converted to NE
- Non-specific enzyme, hydroxylates other aromatic amino acids as well
Positive and Negative Regulation of Catecholamines
- Stress-induced release of glucocorticoids stimulates synthesis of TH and PNMT in adrenal medulla chromaffin cells– positive regulation
- Epinephrine negatively regulates PNMT activity by feedback inhibition
· Vesicular Uptake
- Vesicles actively take up dopamine, NE, and EPI through the vesicular monoamine transporter (VMAT)
- Catecholamines are labile and need to be protected and stored in in vesicles
- Dopamine vesicular uptake is required for NE synthesis
- Reserpine (Serpasil®) blocks vesicular uptake of catecholamines
· Termination of NE and EPI action by recycling
- Neuronal transporter, norepinephrine transporter (NET, also known as Re-uptake I)
- Specific re-uptake of NE into pre-synaptic nerve terminals
- Large transporter molecule which has a bidirectional function
- High selectivity for specific biogenic amines, stereoselective, and of moderate capacity
- Distribution restricted to SNS nerve terminals and the CNS
- OCT Organic cation transporter
- Also known as extraneuronal transporter (ENT) or Re-uptake II
- Non-neuronal biogenic amine transporter
- Low selectivity, high capacity system
- Mops up EPI distributed into circulation (no Uptake I system for EPI, only Uptake II)
Indirect agonists
- Uptake inhibitors
- Releasing agents
Indirect Agonists
Increase the duration of action of NE in the synaptic cleft
e.g. Cocaine and tricyclic antidepressants (TCAs)
Releasing Agents
- Drugs which cause unregulated release of the endogenous transmitter
- Compete with NE at the NET for uptake into the nerve terminal and vesicles
- Displace NE from vesicles and from the nerve terminal causing build up in the synapse (panel B below)
- Tachyphylaxis
- Initial increase in NE release followed by decreasing NE release as indirect agonist depletes supply of NE
e. g. tyramine and amphetamine
- Initial increase in NE release followed by decreasing NE release as indirect agonist depletes supply of NE
Mixed function agonists
Drugs with indirect + direct effects
e.g. ephedrine
Indirect or mixed function agonists are used as…
General Sympathomimetics
General Sympathomimetics are used for…
- #### Stimulants, appetite suppressants, exercise enhancers, “neuroenhancers” and decongestants
- ##### CNS effects promote alertness, wakefulness and an ability to concentrate and focus, along with irritability and vigilance
- ##### CNS (hypothalamus) and GI effects reduce appetite
- ##### Bronchodilation and skeletal muscle vasodilation increase exercise capacity
- ##### Decongestant effects decrease nasal mucus membrane swelling & thin secretions
Side effects of sympathomimetics
- hypertension
- tachycardia
- insomnia
- appetite suppression
- dry mouth
- restlessness
- anxiety
- urinary retention
- risk of stroke
sympathomimetic contrandications
- coronary artery disease
- pregnancy
- diabetes
- hyperthyroidism
- benign prostatic hyperplasia
