Autonomics Flashcards
Autonomic preganglionic neurons are
myelinated
Autonomic postganglionic neurons are
unmyelinated
Sympathetic preganglionic cell bodies are located where?
Intermediolateral horn of T1-L2/3
Sympathetic postganglionic cell bodies are located where?
Paravertebral chains and prevertebral ganglia (i.e. celiac, superior, inferior mesenteric ganglia)
Parasympathetic preganglionic innervation can be described as…
Cranio-sacral (CN 3,7,9,10 and spinal segments S2-4)
Parasympathetic postganglionic neuron cell bodies are located where?
In target organs and discrete ganglia in the head and neck (i.e. ciliary ganglia)
Most organs have both SNS and PSNS innervation, name four exceptions
Only SNS innervation-
Sweat glands
Blood vessels (muscarinic receptors present, but NO direct innervation)
Only PSNS innervation-
Ciliary eye muscles
Bronchial smooth muscle (B2 receptors present, but NO direct innervation)
Blood vessels and bronchial smooth muscle have receptors for PSNS and SNS, respectively, but no direct innervation from these systems. How are the receptors activated?
By circulating drug/hormones.
Does the heart exhibit baseline SNS or PSNS baseline tone?
PSNS
Do blood vessels exhibit baseline SNS or PSNS baseline tone?
SNS
With respect to the autonomic nervous system, all preganglionic neurons have what type of receptor? Are these ligand gated ion channels or GCPRs?
Nicotinic receptors (Nn). Ligand gated ion channels.
The somatic efferent system uses what type of receptor for impulse transmission? Is this a ligand gated ion channel or a GCPR?
Nicotinic receptors (Nm). These are ligand gated ion channels.
Within the sympathetic sub-division, what is the primary neurotransmitter?
NE
What are the two exceptions to NE being the primary neurotransmitter of the SNS?
Sweat glands- postganglionic receptor is muscarinic and responds to ACh.
Adrenal medulla- Tissue itself is “postganglionic” and release Epi and NE (80/20) directly into the blood stream.
SNS postganglionic neurons are typically what type of receptors? Are the GCPRs or ligand gated ion channels?
Most are adrenergic receptors that respond to NE. These are GCPRs. The exceptions are sweat glands and the adrenal medulla.
PSNS postganglionic neurons display what type of receptor? What is the bodies neurotransmitter for these receptors? Are the GCPRs or ligand gated ion channels?
Muscarinic receptors that respond to ACh. These are GCPRs.
Cholinergic receptor subtypes in the body-
Nicotinic- Nm and Nn
Muscarinic- M1-5
Adrenergic receptor subtypes in the body-
Alpha 1, 2
Beta 1,2,3
Grossly simplified, of course!
Sympathetic cholinergic fibers can only be associated with….?
Sweat glands.
Remember, anticholinergics don’t touch your SNS, except they will prevent sweating.
Explain the signaling, messengers, and physiologic response of M1 activation.
Signal- excitatory, CNS
Messengers- IP3 and DAG –> increased free Ca and decreased K conductance
Response- Increased CNS activity, modulation at ganglia
Explain the signaling, messengers, and physiologic response of the M2 activation.
Signal- inhibitory, cardiac
Messengers- inhibit adenylate cyclase –> decrease in cAMP –> increase in K conductance
Physiologic response- decreased HR and decreased contractility
Explain the signaling, messengers, and physiologic response of the M3 activation.
Signal- excitatory, smooth muscle and glands
Messengers- IP3 and DAG –> increased free Ca
Response- Smooth muscle contraction, gland activation
Explain the signaling, messengers, and physiologic response of the A1 activation.
Signal- excitatory, blood vessels
Messengers- IP3 and DAG –> increased free Ca
Response- Vasoconstriction by smooth muscle contraction
Explain the signaling, messengers, and physiologic response of the A2 activation.
Signal- inhibitory, blood vessels, pre-/post- synaptic CNS
Messengers- inhibit adenylate cyclase –> decrease in cAMP –> increase K conductance
Response- Vasodilation by increased K conductance. Inhibits neurotransmitter release from neurons.
Explain the signaling, messengers, and physiologic response of Beta activation.
Signal- Excitatory or inhibitory depending on cAMP action (cAMP is INCREASED though).
Messengers- Increase in cAMP
Response- Relaxation of smooth muscle, stimulates cardiac muscle (increase in rate and contractility)
Alpha 1 agonist effects at-
Vascular smooth muscle Iris Pilomotor smooth muscle Prostate/Uterus Heart
Contraction, vasoconstriction Contraction, dilation or mydriasis Erects hair Contraction Increase contractility (B1 more important)
Alpha 2 agonist effects at-
Platelets Presynaptic adrenergic & cholinergic terminals Vascular smooth muscle GI tract CNS
Aggregation
Inhibits transmitter release (decrease BP and HR)
Contraction (post-synaptic) OR dilation (pre-synaptic, CNS)
Relaxation (presynaptic)
Sedation/analgesia via decrease SNS outflow
Beta 1 agonist effects at-
Heart
Kidneys
Increase force and rate of contraction
Stimulate renin release
Beta 2 agonist effects at-
Visceral smooth muscle
Mast cells
Skeletal muscle
Liver
Pancreas
Adrenergic Nerve Terminals
Smooth muscle relaxation
Decrease histamine release
Dilate vascular beds, tremor, increase speed of contraction, K uptake (decreased serum levels of K)
Glycogenolysis, gluconeogenesis
Increase insulin secretion
Increase NE release
Beta 3 agonist effects on fat cells
Activate lipolysis, thermogenesis
D1 agonist effects on smooth muscle
Post-synaptic location, dilates renal, mesenteric, coronary, and cerebral vascular beds
D2 agonist effects on nerve endings
Pre-synaptic location, modulates transmitter release, nausea/vomiting
Name the endogenous catecholamines
Epi, Norepi, Dopa
Name some synthetic catecholamines
Isoproterenol, Dobutamine
Name some synthetic non-catecholamines
Indirect- ephedrine, mephentermine, amphetamine
Direct- phenylephrine, methoxamine
Name two selective A2 agonists
Clonidine, dexmedetomidine
Name some selective B2 agonists
Albuterol, terbutaline, ritodrine
All sympathomimetics are derivatives of what?
Beta-phenylethylamine
Where are the hydroxyl groups located on a catecholamine?
Positions 3,4 on the benzene ring
What is the rate limiting enzyme in catecholamine synthesis in the body?
Tyrosine hydroxylase (Tyrosine –> Dopa)
End physiological effects from sympathomimetics usually involve a change in what?
Intracellular calcium, either increased or decreased
What terminates the effects of catecholamines?
Reuptake (I- neuronal, II-extraneuronal)
MAO A/B
COMT
Lungs
What terminates the effects of non-catecholamines?
MAO
Urinary excretion
Is phenylephrine more selective for A1 or A2?
A1
Is clonidine more selective for A1 or A2?
A2
Describe norepinephrines receptor selectivity
A1=A2, B1 much more than B2 (almost NO activity at B2, no effect at clinical doses)
Describe epinephrines receptor selectivity
A1=A2, B1=B2
Is dobutamine more selective for B1 or B2?
B1
Is isoproterenol more selective for B1 or B2?
Equal activity at both
Describe dopamines receptor selectivity
D1=D2»B»A
Describe fenoldopam in terms of receptor selectivity
D1»D2
Most potent Alpha activator
Epi
Routes for Epi
SQ or IV
Does Epi have CNS effects?
No, poor lipid solubility
Epi onset
SQ- 5-10min
IV-1-2 min
Duration of Epi
5-10 min
Indications for Epi
Bolus- Bronchial asthma, acute allergic reaction, arrest/asystole, PEA, V.fib
Infusion- Increase contractility
Epi dosing
Bolus for resus- 10mcg/kg IV, can start at 2-8mcg/kg
1-2mcg/min- Beta2
4-5mcg/min- Beta1
10-20mcg/min- Alpha and Beta (more of a pure pressor)
CV effects of Epi
A1- vasoconstriction- increased BP, CVP, cardiac work
A2- negative feedback- decrease BP
B1- increased HR, CO, contractility, BP
B2- peripheral vasodilation- decrease BP
Effect of epi at moderate doses on SBP, DBP, and MAP
SBP increases (B1, A1) DBP decrease (B2) MAP tends to be the same, can increase or decrease
What effect does epi have on skeletal muscle vascular beds?
Vasodilation
Epi effects on cerebral vasculature
Minimal vasoconstriction–> increased cerebral blood flow even with normal BP
Epi effects on the eye
A1- mydriasis (big wide eyes to see that bear)
A1, A2- increase humoral outflow
B1- increased aqueous humor production
Epi effects on Resp
B2- Dilate smooth muscle, decrease histamine release
A1- Reduced mucous secretion
Epi effects on GI
A2- Decreased secretions
A1, A2, B2- Smooth muscle relaxation
A1- Drastically reduced splanchnic blood flow even with normal BP
Epi effects on Renal/GU
A1- Drastic reduction in renal blood flow even with normal BP
B1- Increased renin release
A1- Increased urethral sphincter tone
B2- Bladder relaxation–> reduced urine output
A1- Facilitates ejaculation
B2- Relaxes uterus
Epi metabolic effects
B2- Liver glycogenolysis
B3- lipolysis
A2- Inhibition of insulin release
Do IDDM patients need more or less insule peri-op?
More!
NE dosing
4-16 mcg/min for hypotension
Describe NE effects on B2
Minimal, would require “stupid” doses.
Why does NE drop HR in an otherwise healthy person?
Vasoconstriction –> increased BP –> baroreceptors activate –> HR decreases
What type of drug do you want to use for an infiltrate of NE or Epi?
Alpha blocker given SubQ around the infiltrate (something like phentolamine)
Dopamine is a precursor to what in the body?
NE
What receptors does dopamine stimulate?
All adrenergic including the dopamine receptors
Dopamine dosing
1-3mcg/kg/min- D1 receptors
3-10mcg/kg/min- B1 effects
>10mcg/kg/min- Alpha effects (pressor)
Dopamine increases/decreases contractility, renal blood flow, urine output, and GFR.
Increases
Does dopamine have any indirect effects?
Yes, releases endogenous NE. May be less effective if body stores are depleted
Dopamine effects on IO pressure
Increased
What nice synergistic effect do dopamine and dobutamine have?
Reduced after load and increased CO
Dopamine inhibits what that may alter pt response to hypoxia?
Carotid bodies
Isoproterenol is selective for which adrenergic receptors?
B1 and B2
Cardio effects of iso
Increased HR and contractility Decreased SVR (SPB up, DBP down, MAP down)
Iso dosing for heart blocks and bradicardia
1-5mcg/min
Iso is rapidly metabolised by what enzyme?
COMT
You might want to think twice about giving iso to a pt with what disease? Why?
Parkinsons
entacapone, tolcapone, and nitecapone are COMT inhibitors used in Parkinsons
Dobutamine dosing
2-10mcg/kg/min
Dobutamine is selective for which receptors at <5mcg/kg/min
B1
Dobutamine is selective for which receptors at >5mcg/kg/min
A1, though somewhat weakly due to stereo antagonism
Dobutamine improves CO without doing what?
Without increasing HR or BP, nice for CHF
What effect does dobutamine have on the coronary arteries?
Dilation
Ephedrine dosing
10-25mg IV, 10-50mg IM
Ephedrine acts through what type of mechanism at alpha and beta receptors?
Mostly indirect, also minor direct effects
Compared to epi, how long does ephedrine last?
10 times longer
Ephedrine. Tachyphylaxis.
Of course.
How do we get rid of ephedrine?
40% unchanged in urine. MAO and liver get the rest. E1/2 life of 3 hours.
Neo hits what receptors?
Mostly A1, direct acting
Does neo work more on the venous or arterial side?
Venous
Is neo longer or shorter lasting than NE?
Longer
Neo dosing
50-200 mcg IV or infusion of 20-50 mcg/min
Will Neo tend to increase or decrease HR?
Decrease. Venous constriction –> increase return –> yada yada –> baroreceptors
Should we call neo, neo?
No, sounds like neostigmine
Albuterol is selective for
B2
Albuterol dosing
MDI- 100mcg per puff, 2 puffs q4-6hrs, max 16-20 puffs
Neb for severe asthma 15mg/hr for 2 hours
Large doses of albuterol can give you
Tachycardia and hypokalemia
Terbualine, Salmeterol, and Ritordine are B2 agonists used for what?
Terbutaline- Asthma or premature labor SC dose 0.25mg
Salmeterol- Asthma, MDI lasts >12 hours, otherwise similar to albuterol
Ritordine- premature labor. Some B1, so HR and CO increase. Can cause pulm. edema r/t decreased Na, K, and H2O excretion
Some direct-acting, non-catecholamine, sympathomimetics working at A1
Midodrine- postural hypotension
Oxymetazoline, xylometazoline- nasal/ocular decongestants
A2 selective agonists your pt might be taking
Clonidine- partial agonist
Methyldopa
Drugs your patient might be taking: Indirect-acting Sympathomimetics
Amphetamine (Adderall, Dexedrine)- increases NE, 5HT, and dopamine release. Blocks reuptake. Blocks vesicular transport. MOA inhibitor.
Methamphetamine- similar to amphetamine, but stronger CNS effects
Methylphenidate (Ritalin), Pemoline (Cylert)- amphetamine like variants for ADHD
Drugs Your Patient Might Be Taking: Inhibitors of Catecholamine Storage and Reuptake
Reserpine- Vesicles lose ability to store NE, 5HT, and dopamine. MAO breaks down excess except in high doses. Hypotension, depression common.
Cocaine- Blocks NE, DA, 5HT reuptake. Interferes with their transport as well.
A-antagonists, A1 selective
Prazosin, terazosin, doxazosin- super A1 selective
A-antagonists, non-selective
Phentolamine
A-antagonists, A2 selective
Yohimbine, tolazoline - modestly A2 selective
Mixed A,B antagonists
Labetalol, carvedilol B1=B2>A1>A2
B-antagonists, B1 selective
Metoprolol, atenolol, esmolol
B-antagonists, non-selective
Propranolol, nadolol, timolol
B-antagonists- B2 selective
Butoxamine
A1-antagonist effects on BP
Decreased PVR–> lower BP
Postural hypotension common side effect. Venoconstriction responsible for compensation when standing.
A2-antagonist effects
Increased NE release from nerve terminals, removes normal negative feedback mechanism
A-antagonist effects at GU, eyes, nose
GU muscle relaxation, eases micturition
Causes miosis
Increased nasal congestion
Most A-antagonists bind competitively. Name one that binds covalently. In what case might we want to use such a drug?
Phenoxybenzamine binds covalently to A receptors. Useful where risk of overwhelming catecholamine release is high, such as in pheochromocytoma resection or highly resistant hypertension
Phentolamine dosing
Hypertensive emergency- 30-70mcg/kg IV, onset 2 minutes.
Extravascular sympathomimetic administration- 2.5-5.0 mg in 10ml given SubQ around the site.
Phentolamine CV effects
Decrease BP, increase HR and CO.
Phenoxybenzamine effects, onset, E1/2 time
A1>A2
Decrease SVR, vasodilation
1 hour onset time, pro-drug needs to be metabolized. E1/2 time of 24 hours.
Uses for Prazosin
Control BP in pheochromocytoma
Mostly A1, minimal reflex tachycardia
Uses for Terazosin and Tamulosin
Long acting A1a used for prostatic smooth muscle relaxation (BPH)
Beta-antagonist effects at- Heart Airway Blood vessels Juxtaglomerular cells Pancreas
Improved O2 supply/demand Can provoke bronchospasm Vasoconstriction in skeletal muscles, increase PVD Decrease renin release--> decrease BP Decrease insulin release
Chronic B-antagonist administration can cause what? What do we need to be careful about regarding this?
Up-regulation of B-receptors, need to be careful about suddenly stopping B-antagonists (like, don’t)
Can beta blockade be overcome with agonist?
Yes, large doses will compete with antagonists for binding sites
B-antagonists are derivatives of what drug class?
Sympathomimetics (specifically isoproterenol). They can maintain some of these effects.
Substitution occurs on the benzene ring.
B-antagonists, non-selective
Propranolol, nadalol, timolol, pindolol
Cardioselective (B1) antagonists
Metoprolol, atenolol, acebutolol, betaxolol, esmolol
Large doses lead to selectivity loss
Propranolol basics
Pure antagonist
B1=B2
Dose increased until HR of 55-60 is achieved
Propranolol CV effects
Decreased HR, contractility, CO particularly during exercise/SNS outflow
B2 blockade increases PVR, increased coronary vascular resistance
Overall, CV work/O2 requirement is lowered
Na retention related to drop in CO effects at the kidneys
Propranolol pharmacokinetics Dose Protein binding Metabolism E1/2 time Interactions
Large first-pass effect (90-95%), oral dose much larger than IV. 0.05mg/kg IV or 1-10mg. Max 1mg/min.
Highly protein bound (90-95%)
Metabolized in the liver, E1/2 time 2-3hrs
Reduces clearance of amide LAs due to drop in hepatic blood flow
Decreases the pulmonary first pass effect on fentanyl
Timolol uses, effects
Nonselective, used in glaucoma.
Reduces production of aqueous humor–> decrease IOP
Decrease in BP, HR, increase in airway resistance
Nadolol highlights
Nonselective
No significant metabolism (renal/bile excretion)
E1\2 time of 20-40hrs, taken 1x daily
Metoprolol dosing
60% first pass
PO 50-400mg
IV 1-15 mg
Metoprolol basics
B1 selective
Decrease inotropy and chronotropy
Nonselective at higher doses
E1/2 time of metoprolol
3-4hrs
Which beta blocker is MOST selective at B1?
Atenolol. Also has the lowest CNS effects.
E1/2 time of atenolol
6-7hrs
How is atenolol eliminated?
Renally
Atenolol is great for
Cardiac pts with CAD
When is betaxolol usful?
Medication regimen complexity reduction (taken once a day) E1/2 time of 11-2hrs
Also used in glaucoma when pt is susceptible to bronchospasm (more selective than timolol)
Esmolol dosing
0.5mg/kg IV (10-180mg IV) DOA= less than 15 minutes
Infusion can be started at 50-300mcg/kg/min
Esmolol CV effects
Decrease in HR without significant BP effects at small doses
Does not cause negative inotropy at clinical doses
E1/2 time of esmolol. How is it metabolized?
9 minutes. Broken down by plasma esterases.
In pts known to have difficulty breaking down sux, what type of precautions are needed when giving esmolol?
None, different set of plasma esterases for each drug. Esmolol away.
B-blocker side effects
Decreased HR, contractility, BP
PVD exacerbation
Increased airway resistance
Altered fat/carb metabolism. Masks HR increase in hypoglycemia
Increased serum K
Decreased BP with inhaled anesthetics
Fatigue, lethargy, n/v, diarrhea
Relative B-blocker contraindications
AV block, heart failure (short term)
Reactive airway
DM (needs vigilant BS monitoring)
Hypovolemia
Indications for B-blockers
HTN
Angina
Post-MI mortality reduction
Peri-op for pts at high MI risk
Tachyarrythmias
Excessive SNS disorders, NAP student
Labetalol basics
Combined A/B blocker- selective at A1, B1, B2
7:1 Beta to Alpha blockade
Labetalol dosing, effects, E1/2 time
0.1-0.5mg/kg IV (5mg at a time IV for mild hypertension)
Decreased BP, SVR, HR. CO about the same.
E1/2 time 5-8hrs, longer in liver disease
Labetalol side effcts
Orthostatic hypotension, bronchospasm, heart block, CHF, bradycardia
