AUTONOMIC NERVOUS SYSTEM
CLINICAL ANESTHESIA, CHP 15
CARIN HAGBERG, MD

SARA SLABISAK, MS4
Autonomic Nervous System
The wizard of regulation and balance

…involuntary regulation of visceral reflexes
that occur belo...
CENTRAL INTEGRATION
Central Control
Integration of ANS activity occurs at all levels of the
cerebrospinal axis. Can be ini...
PERIPHERAL INTEGRATION
Peripheral Efferent (Motor)
Dual Innervation of all effector organs except
skeletal muscles

!
‣ Pr...
SYMPATHETICS
Thoracolumbar
Originate in the interomediolateral gray column of T1-T12 & L1-L3

!
! ‣ Post-Ganglionic
synaps...
SYMPATHETICS
Cervical Ganglia
T1-T5 spinal segments generate preganglionic fibers 

!
➺ Superior Cervical
➺ Middle Cervica...
PARASYMPATHETICS
Craniosacral
Brainstem, CN 3, 7, 9, 10 

Sacral segments, S2-S4

!
! ‣ Vagus N. (75% PNS activity)
heart,...
Nicotinic: Ionotropic

Open channels for small cations (NA+, K+)
Located in PNS in certain autonomic neurons,
skeletal mus...
CARDIO AUTONOMICS
CHRONOTROPIC

Rate 

! ‣
SNS ↑HR: ↓systolic duration

! ‣
PNS ↓HR: ↓SA node discharge rate
↓AV junctiona...
Heart Rate

Vagal Nodal Innervation [sinoatrial + atrioventricular]

! ‣↓
rate of SA node discharge
‣↓
conduction velocity...
Contractility

Sympathetic Stellate Innervation

Normal SNS tone maintains baseline contractility level

!
Vagal stimulati...
Carotid Sinus Reflex

[carotid sinus + aortic arch]

! cute rise in arterial pressure activates
A
baroreceptors through st...
Valsalva Maneuver
Sustained intrathoracic pressure diminishes venous
return, ↓CO,↓BP 

Reflex vasoconstriction + tachycard...
Venous Baroreceptors

[right atrium + pulmonary v.]

↑HR when stretched by ↑right atrial pressure;
similarly, ↓ venous pre...
HEMODYNAMICS
Sympathetic Control
SNS most important regulator of peripheral circulation with
vasoconstriction > vasodilati...
Primary neural control of CV
function exerted by sympathetic
neurons to:
!

1) SA node to control HR


2) Ventricular myoc...
BRONCHOMOTOR CONTROL
SNS
Bronchi + Pulmonary Vasculature
↳ BronchoDilation + VasoConstriction
✤
✤

Critical to physiologic...
Medulla Central Pattern Generator
Network of neurons that generates
regular, repeating pattern of neural
activity, called ...
Chemoreceptors respond to change in arterial
P02, PCO2, pH. The primary stimulus being pH, a
direct reflection of [PCO2]
!...
Central Medullary Centers
chemosensitive areas of the brainstem
respond primarily to changes in [H+] 

!
!
Acute increase ...
CHEMICAL CODING

Pre Ganglionic
✤

✤

PNS ACh
SNS ACh

Post Ganglionic
✤
✤

PNS ACh
SNS NE
(exception sweat glands)

AUTON...
ACETYLCHOLINE
Most abundant NT in PNS
✦ Synthesized in cytoplasm of axon
terminal from acetylCoA+choline
catalyzed by chol...
Terminal filaments end in presynaptic
enlargements, variscosities, in which NTs are
stored.
!
The rate of synthesis depend...
CATECHOLAMINES
NE is released from localized presynaptic
vesicles of nearly all postganglionic
sympathetic nerves
Addition...
CATECHOLAMINES
Presynaptic Reuptake

!

Major stereospecific; structurally similar compounds may enter
vesicles and displa...
SYMPATHOMIMETICS
Structurally similar to catecholamines, thus
also exhibit effect via adrenergic receptors
All clinically ...
C ORONARY A RTERIES
a1 VasoConstriction

	 Do not rely on Ca2+
↑Preload
↑Afterload
‣

Phenylephrine

a2 VasoConstriction

...
Tubular a1
Predominant in renal vasculature
Renal vasoconstriction
Modulates renal blood flow
Enhance Na+/H2O reabsorption...
Sympathetic influence is most important during stress. When the body is
challenged the sympathetic activity increases leve...
Located in the myocardium, SA node, and ventribular conduction system;
functionally coupled to adenylate cyclase

!

b1 IN...
b1 RENIN RELEASE

Predominant
JuxtaGlomerular Apparatus

B ADRENERGIC

b2 VASODILATION

Improved renal flow

“MEDICINE IS ...
!

Ða1	


HYPOTHALAMUS

Prolactin release

BASAL GANGLIA

Motor function coordination

MEDULLA

ChemoReceptor Zone (N/V)

...
!

Da1	


RENAL TUBULES

Inhibit Na+ reabsorption
Natriuresis, Diuresis

!

JUXTA GLOMERULAR APPARATUS
↑ Renin release

!
...
Agonists
Nicotine prototype
!
Low Dose autonomic ganglia + NMJ
!
!
!
Antagonists
Nicotine prototype
!

High Dose ganglioni...
ACh Derivatives

More selective muscarinic activity than ACh
More resistant to inactivation by cholinesterase and thus
pro...
Cholinesterase Inhibitors

Produce cholinomimetic effecs via inhibition or inactivation of
acetylcholinesterase and/or pse...
disorientation, hallucinations, and delirium (see “Central Anticholinergic Syndrome”).

Atropine readily crosses BBB/place...
Lap G-Tube Placement
9 m/o (4.3 kg) male w/ failure-to-thrive
!
✤
✤
✤

Former 36 wk twin A
SVD w/o complication
At 3 mos o...
Pt came w/ 24 g PIV R hand
Administered
10 mg Propofol
2 mg Rocuronium
5 mcg Fentanyl
✤
✤
✤

3.0 microcuff ETT placed atra...
Administered
‣ 10x neostigmine intended
‣ 10x glycopyrrolate inteneded
! !

Patient is otherwise non-symptomatic
Where to ...
SIDE EFFECTS
‣
‣
‣
‣
‣

Cardiac bradycardia, hypotension

Pulmonary bronchospasm, hypoxia, secretions
GI hypermotility, PO...
PATIENT COURSE
No acute events in IMU

Patient discharged to floor next morning

Standard monitoring on floor for 48 hrs w...
Epigastric Hernia Repair
28 yo (50 kg) ASA I
!
‣

‣

5 mg Vec, TOF kept at 0 throughout case; 90 min surgery time
1 mg atr...
Neuromuscular Blocked by Neostigmine in Anesthetized Man
‣

Studied effects of neostigmine in 26 patients
- Found repeated...
Attendings - Residents - AA/CRNA
~

Clear communication w/ confirmation
Don’t assume preceptee understands
Be careful calc...
Students - Residents - AA/CRNA
~

If you aren’t positive about something...ASK.
If something doesn’t sound right...confirm...
𝒫HENYLEPHRINE
MOA A
DELIVERY Bolus, Peripheral IV
EFFECTS

Venous & Arterial Constriction
↑ Preload
↑ Stroke Volume
Reflex...
NOREPINEPHRINE
!
MOA A > B
DELIVERY IV

!
! FFECTS
E
!
! VasoConstriction
! ‣ Low dose ↑ CO, ↑ BP
! ‣
! High dose arteriol...
EPINEPHRINE
MOA A, B
DELIVERY Central IV
EFFECTS

VasoConstriction
a skin, mucosa, renal
b striated/skeletal m.

INDICATIO...
EPHEDRINE
MOA A, B
DELIVERY IM, IV
EFFECTS
NE Release (predominant indirect)
Restore HR,	 ↑Preload,	 ↑CO,	 ↑BP
VasoConstri...
ISOPROTERENOL

MOA B
DELIVERY IM, SL, Inhalant
EFFECTS
↑ HR
↑ contractility
↓ SVR

INDICATIONS
Potent dysrhythmogenic
Card...
DOBUTAMINE
MOA B1 > B2
DELIVERY IM, SL, Inhalant
EFFECTS
↑ HR
Coronary Artery VasoDilation
↓Diastolic Coronary Filling Pre...
DOPAMINE
MOA D > B
DELIVERY IV

>

A

EFFECTS
d Low “Renal” Dose [0.5-2 mg/kg/min]
→	 	 VasoDilation
→	 	 Tubular

Cell Na...
A-ANTAGONISTS
MOA B1 > B2
EFFECTS
Smooth m. relaxation
Hypotension, Orthostatic hypotension
Tachycardia
Miosis
Diarrhea
Ej...
B-ANTAGONISTS
PROPRANOLOL

MOA Non-selective (B1, B2) 	

EFFECTS
✤ ↓HR, ↓Contractility
✤ ↑SVR
✤ ↓Renin activity	

SIDE EFF...
FENOLDOPAM
MOA D1
DELIVERY Continuous IV
EFFECTS
Potent, Direct Renal Vasodilator
Natriuresis, Diuresis
Increase Creatinin...
CLONIDINE

MOA A2
DELIVERY IV, IM, ED
EFFECTS
Central Anti-HTN
Peripheral Decrease Renin, NE, EPI
Dose-Dependent Analgesia...
DEXMEDETOMIDINE

MOA A2
DELIVERY Continuous IV
EFFECTS
Sedation
Decrease HR, BP
Decrease [Catecholamines]

INDICATIONS
Per...
VASOPRESSIN

MOA V1
DELIVERY SC, IM, IV, INJ
EFFECTS
Passive H2O Reabsorption Increase Extra-Cellular Fluid
Vascular Smoot...
ADENOSINE
DELIVERY IV
EFFECTS

Cardio-Protection

Myocardial O2 Regulation
Atrial Myocyte HyperPolarization
Decreased AP d...
PHOSPHODIESTERASE INHIBITORS
MOA Selective ⊝ PDE III
DELIVERY IV
EFFECTS
Impedes cAMP metabolism
Inotropic + VasoDilation
...
GLUCAGON

MOA GPCR (G protein coupled receptors)
DELIVERY IM, IV
EFFECTS
Inhibit GI Motility
Inorganic Electrolyte Urinary...
DIGITALIS GLYCOSIDES

MOA ⊝ Na+/K+ ATPase ➺ Ca2+
DELIVERY IV
EFFECTS
Inotropic
Enhance Myocardial Automaticity
Slows Condu...
CALCIUM SALTS
DELIVERY IM, IV
EFFECTS
Key Cardiac AP Component
IntraCellular Energy Storage & Utilization
Smooth m: Vascul...
MONOAMINE OXIDASE INHIBITORS

MOA Non-selective inhibition	

EFFECTS
✤ Accumulate: NE, EPI, DA, 5HT
✤ Potentiate sympathom...
THANKS FOR YOUR ATTENTION!
HERZOG’S RULES
1. Be on time.
2. Bust your butt.
3. Play smart.
4. Have some laughs while
you’r...
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Clinical Anesthesia (Barash): Autonomic Nervous System, Chp 15

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Content: Clinical Anesthesia (Paul G. Barash), Chapter 15: Autonomic Nervous System.Event: Senior Seminar / In-Training Exam Review Lecture Series
Venue: The Department of Anesthesiology, UT Houston Medical School

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Clinical Anesthesia (Barash): Autonomic Nervous System, Chp 15

  1. 1. AUTONOMIC NERVOUS SYSTEM CLINICAL ANESTHESIA, CHP 15 CARIN HAGBERG, MD SARA SLABISAK, MS4
  2. 2. Autonomic Nervous System The wizard of regulation and balance …involuntary regulation of visceral reflexes that occur below the level of consciousness ‣ ‣ ‣ ‣ ‣ ‣ ‣ Cardio-Pulmonary Thermoregulation GI motility GU function Metabolic Endocrine Adaptive Stress Response … Essentially, anesthesiology is the practice of autonomic medicine
  3. 3. CENTRAL INTEGRATION Central Control Integration of ANS activity occurs at all levels of the cerebrospinal axis. Can be initiated locally and by centers in the spinal cord, brainstem, and hypothalamus. ! ! Hypothalamus Principle Site various hypothalamic nuclei control both branches of the ANS Long-term BP control, reactions to physical and emotional stress, sleep, and sexual reflexes ! ‣ Medulla Oblongata, Pons Acute Site physiologic responses that must be immediately enacted Integrate momentary hemodynamic adjustments and maintain the sequence/automation of ventilation ! ‣ CENTRAL AUTONOMIC ORGANIZATION “BE KIND, FOR EVERYONE YOU MEET IS FIGHTING A GREAT BATTLE.” IAN MACLAREN
  4. 4. PERIPHERAL INTEGRATION Peripheral Efferent (Motor) Dual Innervation of all effector organs except skeletal muscles ! ‣ Pre-Ganglionic originates within the CNS and relays impulses to ANS ganglia ! ‣ Post-Ganglionic cell bodies originate within the ganglia and axons contact effector organs Sympathetic Thoracolumbar most active during times of excitement and physical activity. ! Parasympathetic Craniosacral most active during rest and stimulates digestive activities. PERIPHERAL ANS ORGANIZATION “IT’S NOT WHAT HAPPENS, IT’S HOW YOU REACT TO IT THAT MATTERS.” EPICTETUS
  5. 5. SYMPATHETICS Thoracolumbar Originate in the interomediolateral gray column of T1-T12 & L1-L3 ! ! ‣ Post-Ganglionic synapse w/ post-ganglionic fibers at exit level course up/down to synapse at paired, lateral ganglia track variable distances and synapse at unpaired, collateral ganglia Adrenal Exception pre-ganglionic fibers pass directly into the adrenal medulla w/out synapsing in a ganglion ! Mass Reflex Diffuse, Physiologic Response SNS post-ganglionic neurons outnumber the pre-ganglionic neurons (20-30:1) PERIPHERAL ANS ORGANIZATION “BE HAPPY - IT’S ONE WAY OF BEING WISE.” COLETTE
  6. 6. SYMPATHETICS Cervical Ganglia T1-T5 spinal segments generate preganglionic fibers ! ➺ Superior Cervical ➺ Middle Cervical ➺ Stellate Stellate Ganglion SNS innervation coronary vasculature, lung, & cerebral circulation. PNS cardiac vagal fibers approach the stellate and join efferent cardiac SNS fibers. ! Left Stellate distribution to posterior and lateral surfaces of both ventricles ! ‣ Right Stellate distribution to anterior epicardial surface and the interventricular septum ‣ Afferent Pain Fibers travel w/ fibers accounting for chest, neck, & upper extremity pain during myocardial infarctions PERIPHERAL AUTONOMIC NERVOUS SYSTEM “DON’T CRY BECAUSE IT’S OVER, SMILE BECAUSE IT HAPPENED.” DR. SEUSS
  7. 7. PARASYMPATHETICS Craniosacral Brainstem, CN 3, 7, 9, 10 Sacral segments, S2-S4 ! ! ‣ Vagus N. (75% PNS activity) heart, lungs, esophagus, stomach, small intestine, proximal colon, liver, gallbladder, pancreas, upper ureters ‣ Sacral nerves distal colon, rectum, uterus, bladder, lower ureters ! Discrete Response Viscera-specific PNS post-ganglionic neurons to preganglionic neurons (1-3:1) PERIPHERAL ANS ORGANIZATION “UPON THE CONDUCT OF EACH, DEPENDS THE FATE OF ALL.” ALEXANDER THE GREAT
  8. 8. Nicotinic: Ionotropic Open channels for small cations (NA+, K+) Located in PNS in certain autonomic neurons, skeletal muscles, and some regions of the CNS. ! SNS & PNS Low-Dose Stimulation ➺  Hypertension, Tachycardia High-Dose Depression ➺  Hypotension ➺  Neuromuscular weakness Muscarinic: Metabotropic Operate via G-proteins; open or close ion channel or activate an enzyme depending upon the postsynaptic neuron. Dominant cholinergic receptor in the CNS. ! Post Ganglionic PNS ➺  Bradycardia ➺  Decreased inotropism ➺  Bronchoconstriction ➺  Miosis, salivation ➺  Increase GI motility & secretions CHOLINERGIC TRANSMISSION “NEVER PRACTICE TWO VICES AT ONCE.” TALLULAH BANKHEAD
  9. 9. CARDIO AUTONOMICS CHRONOTROPIC Rate ! ‣ SNS ↑HR: ↓systolic duration ! ‣ PNS ↓HR: ↓SA node discharge rate ↓AV junctional fiber excitability INOTROPIC Force + Energy ↓Contractile Force ! ‣ Primary Mediator SNS ! ‣ Minor Mediator intrinsic myocardial mechanisms HEMODYNAMICS Coronary Blood Flow ! ‣ Primary Mediator Auto-regulation ! ‣ Minor Mediator ANS CARDIOVASCULAR “HEARTS WILL NEVER BE PRACTICAL UNTIL THEY ARE UNBREAKABLE.” WIZARD OF OZ (1939)
  10. 10. Heart Rate Vagal Nodal Innervation [sinoatrial + atrioventricular] ! ‣↓ rate of SA node discharge ‣↓ conduction velocity Automaticity Spontaneous depolarization magnitude & slope of nodal automaticity are important in the regulation of HR and depend on the activity of the ANS. ! Slowing the rate of depolarization increases time required to reach threshold potential (TP); ↓HR. ! Observed w/ vagal stimulation & ACh agonists CARDIOVASCULAR AUTOMATICITY
  11. 11. Contractility Sympathetic Stellate Innervation Normal SNS tone maintains baseline contractility level ! Vagal stimulation can ↓LV maximum rate of tension development and ↓contractile force by as much as 10-20%. Inotropic Force Myocardial contraction is dependent on the number of contractile element crossbridges and the relative sensitivity to Ca2+ ! Positive inotropic effect is reflected by an increase in pressure-volume work at each end-diastolic volume. ! Observed w/ sympathetic stimulation & beta-adrenergic drugs CARDIOVASCULAR CONTRACTILITY
  12. 12. Carotid Sinus Reflex [carotid sinus + aortic arch] ! cute rise in arterial pressure activates A baroreceptors through stretch-sensitive Na+channels. ↑afferent activity ultimately ↓HR via postsynaptic, medullary control and depresses SNS tone. ‣ ↓ CO + SVR ‣↑ vascular capacitance Volatile & IV anesthetics inhibit regulation of heart rate through this reflex. Concomitant use of calcium-channel blockers, ACE inhibitors, or PDE inhibitors will decrease the cardiovascular response. ! Patients with chronic HTN often exhibit perioperative circulatory instability as a result of a decrease in their baroreceptor reflex response. CARDIOVASCULAR HIGH-PRESSURE ARTERIAL BARORECEPTORS
  13. 13. Valsalva Maneuver Sustained intrathoracic pressure diminishes venous return, ↓CO,↓BP Reflex vasoconstriction + tachycardia ! ! ! Valsalva has been used to identify patients at risk for anesthesia because of ANS instability. ! ! ! ! Dysfunction can be assumed if the HR does not respond appropriately to BP changes. Normal (A) HR moves in a reciprocal direction. Abnormal (B) Valsalva response shown in a patient w/ C5 quadriplegia. CARDIOVASCULAR HIGH-PRESSURE ARTERIAL BARORECEPTORS
  14. 14. Venous Baroreceptors [right atrium + pulmonary v.] ↑HR when stretched by ↑right atrial pressure; similarly, ↓ venous pressure ↓ HR ! ! ! Unlike arterial baroreceptors, venous sensors are not thought to alter vascular tone. Venous baroreceptors sample preload via atrial stretch and arterial baroreceptors survey resistance (afterload) as reflected in MAP . Bainbridge Reflex Characteristic, paradoxical, slowing of HR seen w/ spinal anesthesia. Blockade of SNS levels T1-T4: ablates efferent cardiac accelerator nerves and allows unopposed vagal (afferent) stimulation. CARDIOVASCULAR LOW-PRESSURE VENOUS BARORECEPTORS
  15. 15. HEMODYNAMICS Sympathetic Control SNS most important regulator of peripheral circulation with vasoconstriction > vasodilation Basal Vasomotor Tone Medulla Oblongata continual SNS transmission maintains partial arteriolar & venular constriction. Circulating adrenal Epi has additive effects. ! Venular Tone SNS reduce or increase capacity - by functioning as a reservoir for app 80% total blood volume, small changes in venous capacitance produce large changes in venous return = cardiac preload PERIPHERAL CIRCULATION “A PINT OF SWEAT SAVES A GALLON OF BLOOD.” GENERAL GEORGE PATTON (1944)
  16. 16. Primary neural control of CV function exerted by sympathetic neurons to: ! 1) SA node to control HR 2) Ventricular myocardium to control ventricular contractility 3) Veins to control venomotor tone 4) Arterioles to control vascular resistance HEMODYNAMICS MEAN ARTERIAL PRESSURE
  17. 17. BRONCHOMOTOR CONTROL SNS Bronchi + Pulmonary Vasculature ↳ BronchoDilation + VasoConstriction ✤ ✤ Critical to physiologic stability during stress & exercise Vasculomotor tone adjustment accomodates RV output PNS Ventilation Cycle Reflex Alveolar Duct {Vagal} Receptors ↳ BronchoConstriction + Gland Secretion Hypoxic Pulmonary Constriction ✤ Local phenomenon regulating immediate adjustments Non-Ventilatory Function Metabolizes local mediators {ie, NE} ✤ Converts Angiotensin I ✤ PULMONARY “REMEMBER TO BREATHE. IT IS AFTER ALL, THE SECRET OF LIFE.” GREGORY MAGUIRE
  18. 18. Medulla Central Pattern Generator Network of neurons that generates regular, repeating pattern of neural activity, called the ventilation cycle. Dorsal Respiratory Group Primarily inspiratory neurons Ventral Respiratory Group 2 expiratory and 1 inspiratory regions Pons Inspiratory + Expiratory Facilitate transition between each breath PULMONARY VENTILATION REGULATION
  19. 19. Chemoreceptors respond to change in arterial P02, PCO2, pH. The primary stimulus being pH, a direct reflection of [PCO2] ! Chemoreceptors only responsd to changes in arterial PO2 when it drops below 60 mmHg Chemoreceptors are specialized cells in direct contact with arterial blood that communicate with afferent neurons projecting to respiratory control regions ! Peripheral chemoreceptors are located in the carotid bodies near the carotid sinus PULMONARY PERIPHERAL CHEMORECEPTORS
  20. 20. Central Medullary Centers chemosensitive areas of the brainstem respond primarily to changes in [H+] ! ! Acute increase in PaCO2 is a more potent ventilatory stimulus than an acute increase in arterial [proton] from a metabolic source. ! ! CO2 crosses BBB readily but is not neutralized as quickly - thus, central values are ~10 mm Hg higher than in arterial blood. PULMONARY CENTRAL CHEMORECEPTORS
  21. 21. CHEMICAL CODING Pre Ganglionic ✤ ✤ PNS ACh SNS ACh Post Ganglionic ✤ ✤ PNS ACh SNS NE (exception sweat glands) AUTONOMIC TRANSMISSION “GOD MAY FORGIVE YOUR SINS, BUT YOUR NERVOUS SYSTEM WON’T.” ALFRED KORZYBSKI
  22. 22. ACETYLCHOLINE Most abundant NT in PNS ✦ Synthesized in cytoplasm of axon terminal from acetylCoA+choline catalyzed by choline acetyl transferase. ✦ ! ✦ ✦ ✦ Stored in synaptic vesicles until action potential causes its release via exocytosis. Binds to cholinergic receptors. ! Degraded by AChE at both preand post-synaptic membranes. PARASYMPATHETIC TRANSMISSION “DON’T LONG FOR THE UNRIPE GRAPE.” HORACE
  23. 23. Terminal filaments end in presynaptic enlargements, variscosities, in which NTs are stored. ! The rate of synthesis depends on the level of ANS activity and is regulated by local feedback. ! ! Depolarization releases vesicular contents into synaptic cleft. ! Time for diffusion is directly proportional to the width of the synaptic cleft. AUTONOMIC TRANSMISSION “BE HAPPY, IT’S ONE WAY OF BEING WISE.” COLETTE
  24. 24. CATECHOLAMINES NE is released from localized presynaptic vesicles of nearly all postganglionic sympathetic nerves Additionally, vascular SNS terminals also release ATP as a synergistic cotransmitter ! ! ! ACh stimulates adrenal chromaffin cells to release a surge of EPI and NE, taking the place of postganglionic neurons Sympathetic fibers in the adrenal medulla are preganglionic, thus ACh is the NT SYMPATHETIC TRANSMISSION “PRESSURE IS CALMING TO THE NERVOUS SYSTEM.” TEMPLE GRANDIN
  25. 25. CATECHOLAMINES Presynaptic Reuptake ! Major stereospecific; structurally similar compounds may enter vesicles and displace NE TCAs, cocaine inhibit reuptake = accentuated receptor response Extraneuronal Uptake Minor extraneuronal tissues endocytose & metabolize ! Kidney + Liver Diffusion Minor endogenous catecholamines Major synthetic catecholamines ! ! Vanillylmandelic Acid Major metabolite (80-90%) excreted metabolic products provide a gross estimate of SNS activity and can facilitate the clinical diagnosis of pheochromocytoma and other autonomic disorders SYMPATHETIC TRANSMISSION “DON’T HAVE GOOD IDEAS IF YOU AREN’T WILLING TO BE RESPONSIBLE FOR THEM.” ALAN PERLIS
  26. 26. SYMPATHOMIMETICS Structurally similar to catecholamines, thus also exhibit effect via adrenergic receptors All clinically useful catecholamines are sympathomimetics, but not all sympathomimetics are catecholamines. ! ! Indirect stimulate release of stored NE Efficacy dependent on neuronal storage of endogenous NE. ! ! Direct independent of endogenous NE stores SYMPATHETIC TRANSMISSION “IF YOU JUDGE PEOPLE, YOU HAVE NO TIME TO LOVE THEM” MOTHER THERESA
  27. 27. C ORONARY A RTERIES a1 VasoConstriction Do not rely on Ca2+ ↑Preload ↑Afterload ‣ Phenylephrine a2 VasoConstriction ↑ myocardial ischemia Highly dependent on Ca2+ Inhibit NE release ‣ A ADRENERGIC Clonidine “NOTHING GREAT IN THIS WORLD WAS EVER ACCOMPLISHED WITHOUT PASSION.” HEBBEL
  28. 28. Tubular a1 Predominant in renal vasculature Renal vasoconstriction Modulates renal blood flow Enhance Na+/H2O reabsorption Anti-natriuresis, Anti-diuresis ! Tubular a2 Dominant a receptor Promote Na+/H2O excretion A ADRENERGIC “A MERRY HEART DOETH GOOD LIKE MEDICINE” KING SOLOMON
  29. 29. Sympathetic influence is most important during stress. When the body is challenged the sympathetic activity increases levels of plasma glucose and fatty acids. The extra availability of fuel enables the body to more readily respond to a stressful situation. a2 CENTRAL NEURAXIS A ADRENERGIC “THE BEST WAY IS ALWAYS THROUGH.” ROBERT FROST Inhibit Insulin and ADH release Inhibit bowel activity Increase GH release
  30. 30. Located in the myocardium, SA node, and ventribular conduction system; functionally coupled to adenylate cyclase ! b1 INOTROPIC, CHRONOTROPIC Post-Synaptic Innervated; respond to NE ! ! b2 INOTROPIC, CHRONOTROPIC Pre-Synaptic/Post-Synaptic (EPI) Noninnervated; accelerate NE release 40% atrium, 20-30% ventricle Effects oppose a2 receptors (b2 antagonists = a2 agonists) B ADRENERGIC “MEDICINE IS A SCIENCE OF UNCERTAINTY, AN ART OF PROBABILITY.” WILLIAM OSLER
  31. 31. b1 RENIN RELEASE Predominant JuxtaGlomerular Apparatus B ADRENERGIC b2 VASODILATION Improved renal flow “MEDICINE IS A SCIENCE OF UNCERTAINTY, AN ART OF PROBABILITY.” WILLIAM OSLER
  32. 32. ! Ða1 HYPOTHALAMUS Prolactin release BASAL GANGLIA Motor function coordination MEDULLA ChemoReceptor Zone (N/V) Da1 VASODILATION Postsynaptic; Vascular smooth muscle cells of kidney and mesentery Coronary, cerebral, cutaneous arteries Da2 VASOCONSTRICTION/VASODILATION Postsynaptic (similar to postsynaptic a2); renal vasculature Presynaptic inhibit NE release (presynaptic a2); postganglionic SNS DOPAMINERGIC “HAPPINESS ISN’T GOOD ENOUGH FOR ME - I DEMAND EUPHORIA!” BILL WATTERSON
  33. 33. ! Da1 RENAL TUBULES Inhibit Na+ reabsorption Natriuresis, Diuresis ! JUXTA GLOMERULAR APPARATUS ↑ Renin release ! GASTRO-INTESTINAL ↑ secretions: esophagus, stomach, small intestine Hypomotility DOPAMINERGIC “SPEND THE AFTERNOON. YOU CAN’T TAKE IT WITH YOU.” ANNIE DILLARD
  34. 34. Agonists Nicotine prototype ! Low Dose autonomic ganglia + NMJ ! ! ! Antagonists Nicotine prototype ! High Dose ganglionic/NMJ blockade ! Compete, mimic and interfere with Ach metabolism Hexamethonium, trimethaphan, dtubocure GANGLIONIC DRUGS “A PATH WITH NO OBSTACLES DOES NOT LEAD ANYWHERE.” FRANK CLARK
  35. 35. ACh Derivatives More selective muscarinic activity than ACh More resistant to inactivation by cholinesterase and thus prolonged action. ! Choline Esters Methacholine Slows HR, dilates vessels, increases intestinal tone. Treat over-dose w/ atropine. ‣ PSVT ! Bethanechol GI + Urinary tracts. Post-Op abdominal distension ‣ Gastric atony ‣ Neurogenic bladder ‣ ! Alkaloids Pilocarpine No anesthestic use. Topical miotic in the treatment of glaucoma to reduce IOP . MUSCARINIC AGONISTS DIRECT CHOLINOMIMETICS
  36. 36. Cholinesterase Inhibitors Produce cholinomimetic effecs via inhibition or inactivation of acetylcholinesterase and/or pseudocholinesterase ! Reversible Anion Competition Ammonium compounds; delay hydrolysis from 1 to 8 hrs. Most do not cross the BBB. [Exception: physostigmine] ‣ Neuromuscular blockade reversal ‣ Atropine poisoning, Myasthenia Gravis ! Non-Reversible Esteratic Competition Organophosphates; may last from days to weeks. Highly lipid-soluble, readily pass into CNS. ‣ Glaucoma ‣ Chemical warfare, potent insecticides ! Side Effects ‣ Bradycardia ‣ Hypotension ‣ Bronchospasm ‣ Intestinal spasm ‣ Muscle paralysis (excessive dose) MUSCARINIC AGONISTS INDIRECT CHOLINOMIMETICS
  37. 37. disorientation, hallucinations, and delirium (see “Central Anticholinergic Syndrome”). Atropine readily crosses BBB/placenta ! Reverse muscle relaxant ‣ ↑ CO during sinus bradycardia ‣ Organophosphate antidote ‣ Pre-medication (cardiac patients) ‣ Amnesia induction (trauma patients) ‣ ! Side Effects Central Anticholinergic Syndrome (physostigmine) Scopolamine readily crosses BBB/placenta ‣ ! Amnesia, sedation, euphoria Side Effects Paradoxical bradycardia, mydriasis, cycloplegia Glycopyrrolate does not cross BBB/placenta ‣ ‣ ! ↓salivary,bronchial, pharyngeal secretions ↑ gastric acid pH Figure 15-15. Structural formulas of the clinically useful antimuscarinic drugs. Side Effects heat stroke, fever, delirium, xerostomia, urinary retention, diarrhea CHOLINERGIC ANTAGONISTS “EVERYTHING IN EXCESS IS OPPOSED TO NATURE.” HIPPOCRATES
  38. 38. Lap G-Tube Placement 9 m/o (4.3 kg) male w/ failure-to-thrive ! ✤ ✤ ✤ Former 36 wk twin A SVD w/o complication At 3 mos of age: RSV ➺ cardiac/pulmonary failure ➺ CPR (43 mins) ➺ ECMO (11 days) ➺ shock, liver/kidney failure ✤ Past Medical History ‣ Post fossa SDH w/ non-communicating hydrocephalus ‣ Seizures ! CASE I NEOSTIGMINE
  39. 39. Pt came w/ 24 g PIV R hand Administered 10 mg Propofol 2 mg Rocuronium 5 mcg Fentanyl ✤ ✤ ✤ 3.0 microcuff ETT placed atraumatically (x1 attempt) ‣ Procedure proceeded without complication ‣ Reversal calculated with student and given ‣ Patient breathing well after procedure and extubated without complications ‣ CASE I NEOSTIGMINE
  40. 40. Administered ‣ 10x neostigmine intended ‣ 10x glycopyrrolate inteneded ! ! Patient is otherwise non-symptomatic Where to discharge him to? CASE I NEOSTIGMINE
  41. 41. SIDE EFFECTS ‣ ‣ ‣ ‣ ‣ Cardiac bradycardia, hypotension Pulmonary bronchospasm, hypoxia, secretions GI hypermotility, PONV Opthalmic miosis, decrease intraocular pressure Musculoskeletal potential for recurization ➺ respiratory failure HALF-LIFE ‣ ‣ T1/2 60-90 minutes Intended to give 0.3 mg, patient received 3 mg 1hr 2hr 3hr 3 mg ➺ 1.5 mg ➺ 0.75 mg ➺ 0.375 mg 1.5 hr 3 hr 4.5 hr ! Decision made to admit patient to IMU overnight for closer monitoring and potential for delayed neostigmine toxicity CASE I NEOSTIGMINE
  42. 42. PATIENT COURSE No acute events in IMU Patient discharged to floor next morning Standard monitoring on floor for 48 hrs w/ no complications Patient discharged from hospital on 12/21/12 ‣ ‣ ‣ ‣ WHAT HAPPENED? Calculated dose w/ student (70 mcg/kg) x (4.3 kg) = 300 mcg ‣ ‣ ‣ ‣ Student states “okay” so 3 was administered Student grabs 5 ml syringe of neostigmine Student was asked to put it in a smaller syringe Student begins to switch syringes, but then asks if he can just give it from the current syringe CASE I NEOSTIGMINE
  43. 43. Epigastric Hernia Repair 28 yo (50 kg) ASA I ! ‣ ‣ 5 mg Vec, TOF kept at 0 throughout case; 90 min surgery time 1 mg atropine + 2.5 mg neostigmine given twice due to miscommunication between resident & attending - ‣ ‣ TOF became 0 and patient was once again paralyzed Increased secretions noted but VS remained stable ‣ Ventilated for 35 mins before TOF reappeared ‣ Patient extubated after TOF ratio of 95% ‣ Patient monitored in ICU for 6 hr w/ unremarkable discharge CASE REPORT NEUROMUSCULAR BLOCKADE
  44. 44. Neuromuscular Blocked by Neostigmine in Anesthetized Man ‣ Studied effects of neostigmine in 26 patients - Found repeated doses of 2.5 mg, 2-5 mins apart produced depressed peak tetanic contraction and re-established tetanic fade - - A single dose of 5 mg rapidly produced a slight depression in tetanus and brief reappearance of fade, but not as prominent as repeated doses In patient not given neuromuscular blocking agents, peak tetanic contraction and severe tetanic fade persisted for about 20 minutes CASE REPORT NEUROMUSCULAR BLOCKADE
  45. 45. Attendings - Residents - AA/CRNA ~ Clear communication w/ confirmation Don’t assume preceptee understands Be careful calculating mcg and administering mg Set preceptees for up success, not failure Repitition, repitition, repitition!! LESSONS LEARNED
  46. 46. Students - Residents - AA/CRNA ~ If you aren’t positive about something...ASK. If something doesn’t sound right...confirm. Positive communication feedback, repitition Realize what you know & admit what you don’t know Avoid statements like “that’s what I meant” or “I knew that” LESSONS LEARNED
  47. 47. 𝒫HENYLEPHRINE MOA A DELIVERY Bolus, Peripheral IV EFFECTS Venous & Arterial Constriction ↑ Preload ↑ Stroke Volume Reflex Bradycardia (thus no change in CO)⟷⟷⬄⟷ INDICATIONS Tetralogy of Fallot shunt reversal Increase BP during cardiopulmonary bypass Reverse vasodilatory states Reverse anesthetic hypotension ! SIDE EFFECTS ! Cardiac dysrhythmias → SYMPATHOMIMETICS “CARRY ON AND PRESERVE YOURSELVES FOR BETTER TIMES.” VIRGIL
  48. 48. NOREPINEPHRINE ! MOA A > B DELIVERY IV ! ! FFECTS E ! ! VasoConstriction ! ‣ Low dose ↑ CO, ↑ BP ! ‣ ! High dose arteriolar constriction INDICATIONS Cardiogenic shock Initiate adreneregic response Cardiopulmonary bypass separation Steady hemodynamic maintenance ! SIDE EFFECTS Renal arteriolar constriction → Reflex bradycardia → Oliguria → Tissue necrosis → ! SYMPATHOMIMETICS “IF YOU NEVER ASSUME IMPORTANCE, YOU NEVER LOSE IT.” LAO-TZU
  49. 49. EPINEPHRINE MOA A, B DELIVERY Central IV EFFECTS VasoConstriction a skin, mucosa, renal b striated/skeletal m. INDICATIONS Cardiac arrest Asthma Anaphylaxis Peri-Operative period Produce bloodless field Prolong regional anesthesia ! SIDE EFFECTS ! ! ! Cardiac dysrhythmias → SYMPATHOMIMETICS “DON’T LET YOUR HEARTS GROW NUMB. STAY ALERT.” ALBERT SCHWEITZER
  50. 50. EPHEDRINE MOA A, B DELIVERY IM, IV EFFECTS NE Release (predominant indirect) Restore HR, ↑Preload, ↑CO, ↑BP VasoConstriction: Venous > Arterial Central Redistribution of Blood Restores Uterine Perfusion (hydrated) INDICATIONS Epidural anesthesia hypotension OB/GYN pressor of choice Prolong regional anesthesia ! SIDE EFFECTS ! ! ! Tachyphylaxis → SYMPATHOMIMETICS “NEVER DO ANYTHING AGAINST CONSCIENCE, EVEN IF THE STATE DEMANDS IT.” ALBERT EINSTEIN
  51. 51. ISOPROTERENOL MOA B DELIVERY IM, SL, Inhalant EFFECTS ↑ HR ↑ contractility ↓ SVR INDICATIONS Potent dysrhythmogenic Cardiac failure Chemical pacemaker (3rd degree AV block) Regurgitant aortic valvular disease Pulmonary hypertension ! SIDE EFFECTS Cardiac dysrhythmias → Decrease diastolic perfusion pressure → Increase myocardial O2 demand Redistributes BF nonessential organs, don’t use in shock → SYMPATHOMIMETICS “PRAY FOR THE DEAD AND FIGHT LIKE HELL FOR THE LIVING.” MARY HARRIS JONES
  52. 52. DOBUTAMINE MOA B1 > B2 DELIVERY IM, SL, Inhalant EFFECTS ↑ HR Coronary Artery VasoDilation ↓Diastolic Coronary Filling Pressure Pulmonary Vasculature VasoDilation INDICATIONS Cor Pulmonale Cardiac Units: DBT > DA SIDE EFFECTS → b blockade unmasks a1 agonism ! ! Dramatic ↑ HR → SYMPATHOMIMETICS “READ EVERYTHING.” JIM ROGERS
  53. 53. DOPAMINE MOA D > B DELIVERY IV > A EFFECTS d Low “Renal” Dose [0.5-2 mg/kg/min] → VasoDilation → Tubular Cell Natriuresis →↓ Diastolic BP → ↑ HR b Intermediate Dose [2-10 mg/kg/min] → Chronotropic → VenoConstriction: Preload → Systemic VasoDilation: Afterload a High Dose [ >10 mg/kg/min] → → ↑ BP ↑ SVR INDICATIONS Low-Output Syndrome Congestive Heart Failure Pulmonary Failure Cardiogenic Shock Third-Space Edema ! SYMPATHOMIMETICS “IT’S DIFFICULT TO THINK NOBLY WHEN ONE THINKS ONLY OF INCOME.” JEAN-JAQUES ROUSSEAU
  54. 54. A-ANTAGONISTS MOA B1 > B2 EFFECTS Smooth m. relaxation Hypotension, Orthostatic hypotension Tachycardia Miosis Diarrhea Ejaculatory inhibition Nasal stuffiness ! CLASSIFICATION Phenoxybenzamine Phentolamine Prazosin ! ANESTHETIC MANAGEMENT → Anti-hypertensive, often administered w/ diuretics → Preload IV fluids to ensure adequate central volume SYMPATHOLYTICS “THERE IS A WAY TO DO IT BETTER. FIND IT.” THOMAS EDISON
  55. 55. B-ANTAGONISTS PROPRANOLOL MOA Non-selective (B1, B2) EFFECTS ✤ ↓HR, ↓Contractility ✤ ↑SVR ✤ ↓Renin activity SIDE EFFECTS ✤ Bradycardia, heart block, CHF exacerbation ✤ Bronchospasm ✤ Sedation ✤ Suppression of insulin secretion ✤ Blunting of catecholamine response to hyoglycemia ✤ Rebound ↑HR, NOT orthostatic hypotension A1 LABETALOL MOA Mixed antagonist (A1, B1, B2) ✤ ↓SVR, ↓HR ‣ Very beneficial in coronary artery disease ↓Renin activity SIDE EFFECTS ✤ CHF exacerbation ✤ Bronchospasm ✤ SYMPATHOLYTICS “YOU WERE BORN WITH WINGS. WHY PREFER TO CRAWL THROUGH LIFE?” RUMI
  56. 56. FENOLDOPAM MOA D1 DELIVERY Continuous IV EFFECTS Potent, Direct Renal Vasodilator Natriuresis, Diuresis Increase Creatinine Clearance INDICATIONS Acute Resolution of Severe HTN Vascular Anesthesia Renal Protector ! SIDE EFFECTS → Tachycardia → Vasodilation, ! Hypotension → Flushing, Dizziness, Headache → Hypokalemia DRUG CLASS: OTHER ANTIHYPERTENSIVES “IN WHATEVER YOU DO, FAILURE IS AN OPTION. FEAR IS NOT.” JAMES CAMERON
  57. 57. CLONIDINE MOA A2 DELIVERY IV, IM, ED EFFECTS Central Anti-HTN Peripheral Decrease Renin, NE, EPI Dose-Dependent Analgesia (ED/SAB) INDICATIONS Severe/Renin-Dependent HTN Enhance Post-Op Analgesia Blunt Reflex Tachycardia {Intubation} Reduce Vasomotor Liability Decrease [Catecholamines] SIDE EFFECTS → Sedation → Xerostomia → Hypotension, A AGONIST Bradycardia, Withrawal syndrome “LOVE WHAT YOU DO AND GET GOOD AT IT. COMPETENCE IS A RARE COMMODITY.” JON STEWART
  58. 58. DEXMEDETOMIDINE MOA A2 DELIVERY Continuous IV EFFECTS Sedation Decrease HR, BP Decrease [Catecholamines] INDICATIONS Peri-Operative Hypothermia Anti-Shivering PreMedication: Awake, Fiberoptic Intubation Anxiolytic, Sedative Decrease MAC: Volatile Anesthetics SIDE EFFECTS → Rebound hypertension → HyperExcitability → Arrythmias A AGONIST “ALL IS WELL, PRACTICE KINDNESS, HEAVEN IS NIGH.” JACK KEROUAC
  59. 59. VASOPRESSIN MOA V1 DELIVERY SC, IM, IV, INJ EFFECTS Passive H2O Reabsorption Increase Extra-Cellular Fluid Vascular Smooth m. Intense VasoConstriction Cardiac Myocytes Inotropic INDICATIONS Diabetes Insipidus Abdominal Distension Adjunt Therapy: GI Hemorrhage, Esophageal Varices Septic Shock Pressor Cardiac Arrest 2º Ventricular Arrythmias Pulseless Electrical Activity, Asystole SIDE EFFECTS → Sedation → Xerostomia → Hypotension, Bradycardia NON-ADRENERGIC SYMPATHOMIMETICS “START WHERE YOU ARE, USE WHAT YOU HAVE, DO WHAT YOU CAN.” ARTHUR ASHE
  60. 60. ADENOSINE DELIVERY IV EFFECTS Cardio-Protection Myocardial O2 Regulation Atrial Myocyte HyperPolarization Decreased AP duration Anti-Dysrhythmic Interrupts Re-Entrant AV Nodal Tachycardias Antagonizes Inward Ca2+ Current Vasomotor Tone Regulation INDICATIONS PSVT Conversion ACLS: Narrow-Complex Tachycardia ACLS: Wide-Complex Tachycardia SIDE EFFECTS → Hypotension, Bradycardia → Headache, Dyspnea, Bronchospasm NON-ADRENERGIC SYMPATHOMIMETICS “ALWAYS BE ON THE LOOKOUT FOR THE PRESENCE OF WONDER.” E.B. WHITE
  61. 61. PHOSPHODIESTERASE INHIBITORS MOA Selective ⊝ PDE III DELIVERY IV EFFECTS Impedes cAMP metabolism Inotropic + VasoDilation Diastolic Relaxation Dose-Dependent HemoDynamic Effects INDICATIONS Short-term IV therapy for CHF Decompensated heart failure ! SIDE EFFECTS → Hypotension, ! Bradycardia → Headache, Dyspnea, Bronchospasm NON-ADRENERGIC SYMPATHOMIMETICS “UNLESS YOU HAVE UNANSWERED QUESTIONS, YOU HAVEN’T READ ENOUGH.” DANIEL BERNSTEIN
  62. 62. GLUCAGON MOA GPCR (G protein coupled receptors) DELIVERY IM, IV EFFECTS Inhibit GI Motility Inorganic Electrolyte Urinary Excretion Increased Insulin Secretion Hepatic Glycogenolysis, Gluconeogenesis Inotropic, Chronotropic Anorexia INDICATIONS Insulin-Induced Hypoglycemia Excessive B-blockade SIDE EFFECTS → Nausea, ! Vomiting → Hypoglycemia → HypoKalemia NON-ADRENERGIC SYMPATHOMIMETICS “YOU CAN’T BUILD A REPUTATION ON WHAT YOU INTEND TO DO.” LIZ SMITH
  63. 63. DIGITALIS GLYCOSIDES MOA ⊝ Na+/K+ ATPase ➺ Ca2+ DELIVERY IV EFFECTS Inotropic Enhance Myocardial Automaticity Slows Conductive Tissue Impulse Propagation INDICATIONS Congestive Heart Failure Supra-Ventricular Cardiac Dysrhythmias PSVT Conversion SIDE EFFECTS → Digitalis ! Toxicity → HypoKalemia → Dysrhythmias → GI Disturbance NON-ADRENERGIC SYMPATHOMIMETICS “TAKE IT EASY, BUT TAKE IT.” WOODY GUTHRIE
  64. 64. CALCIUM SALTS DELIVERY IM, IV EFFECTS Key Cardiac AP Component IntraCellular Energy Storage & Utilization Smooth m: Vascular, Uterine INDICATIONS Massive Blood Transfusion HypoCalcemia HyperMagnesemia Ca2+ Channel Blocker Toxicity Osteoporosis SIDE EFFECTS → Dysrhythmias ! → GI Disturbance NON-ADRENERGIC SYMPATHOMIMETICS “NEVER LET YOUR SENSE OF MORALS GET IN THE WAY OF DOING WHAT’S RIGHT.” ISAAC ASIMOV
  65. 65. MONOAMINE OXIDASE INHIBITORS MOA Non-selective inhibition EFFECTS ✤ Accumulate: NE, EPI, DA, 5HT ✤ Potentiate sympathomimetic amines ‣ ‣ ‣ ‣ TRICYCLIC ANTIDEPRESSANTS MOA Inhibit neuronal NE uptake EFFECTS ✤ Atropine ‣ ‣ ✤ Prolonged sedation ‣ ✤ MOA Selectively inhibit neuronal 5HT uptake EFFECTS ✤ Potentiates behavioral changes ✤ Discontinuation not indicated prior to surgery Microsomal enzyme induction ↑metabolism ‣ ✤ SELECTIVE SEROTONIN REUPTAKE INHIBITORS Potentiate TCA; hepatic metabolic competition ‣ ✤ Exaggerated effect 2º anticholinergic property Hypertensive crisis Convulsions Coma Hepatotoxicity Acute HTN, cardiac dysrhythmia Neuroleptics Barbituates Thiopental Ketamine ANTIDEPRESSANTS “THERE’S ALWAYS A REASON TO SMILE. FIND IT.” BOB PARSONS
  66. 66. THANKS FOR YOUR ATTENTION! HERZOG’S RULES 1. Be on time. 2. Bust your butt. 3. Play smart. 4. Have some laughs while you’re at it. “THE FUTURE OF OUR PRACTICE” HAGBERG SARA SLABISAK - MICHAEL EVANS - SETH HAYES - MONICA CHEN

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