Autonomics Flashcards
1
Q
A more appropriate name for anticholinergic drugs is
A
antimuscarinic drugs
2
Q
The Autonomic Nervous System:
◼Located in both the ___ & ___
◼Coordinates and maintains a steady state among the _____________ organs
◼Neurons
- _____________ (myelinated)
- _____________ (unmyelinated)
◼Two divisions classified anatomically (often physiologic antagonists) = _____________ & _____________
A
CNS & PNS visceral (internal) Preganglionic Postganglionic Sympathetic & Parasympathetic
3
Q
SNS “Fight or Flight” - Sympathetic innervation:
◼ Preganglionic neurons cell bodies located in ?, within the ?
A
T1 - L2-3 of spinal cord
Intermediolateral horn of grey matter
4
Q
SNS “Fight or Flight” - Sympathetic innervation:
Post ganglionic neuron cell bodies are located in ?
◼ _____________ chains (either side spinal column)
◼ _____________ ganglia (i.e. celiac, superior, inferior mesenteric ganglia in abdomen)
A
ganglia
Paravertebral
Prevertebral
5
Q
SNS “Fight or Flight” - Sympathetic innervation:
◼______ preganglionic neurons, ______ post
A
Short, long
6
Q
PSNS “Rest and Energy Restoration” - Parasympathetic innervation:
Pre-ganglionic neurons arise in
◼ Cranial (medullary)…….
◼ Sacral (spinal) regions……
A
CN 3,7, 9, 10
S2-4
7
Q
PSNS “Rest and Energy Restoration” - Parasympathetic innervation:
Post-ganglionic neurons cell bodies located in:
◼ Target ______
◼ Discrete ganglia in the _____ and _____ (i.e. ciliary ganglia)
A
organs
head and neck
8
Q
PSNS “Rest and Energy Restoration” - Parasympathetic innervation:
◼ _____ preganglionic neurons, _____ post
A
Long, short
9
Q
SLIDE 7, review/know
A
review/know
10
Q
Summary of ANS Functions:
◼Often SNS & PSNS actions are ___________ of one another
◼SNS = self __________: most important function is maintenance of ___________
◼PSNS = ____ for the organism but “________” visceral functions such as digestion
A
antagonistic
preservation, vasomotor tone
rest, excitatory
11
Q
Summary of ANS Functions (cont): ◼ Many organs have innervation by both SNS and PSNS - Examples = ◼ Exceptions to this rule however: - Only innervated by SNS = ◼ Only innervated by PSNS =
A
bladder, cardiac muscle, GI
Sweat glands & Blood vessels (Muscarinic receptors present though)
Ciliary muscle of the eye & Bronchial smooth muscle (B2 receptors present though ~ Epi from Adrenal Medulla)
◼ Important! Receptors can be present in a tissue and NOT be innervated. If this is the case….. that receptor will only respond when something is circulating in the blood (drug or hormone)
12
Q
SNS:
◼ __________ response with diffuse innervation
◼ ________ changes
◼ ________
◼ ___________ massive response- fight or flight
A
Amplification
Postural
Exercise
Emergency
13
Q
PSNS:
◼ discrete and narrowly _______ responses
A
targeted
14
Q
SNS and PSNS:
Both systems exhibit “baseline tone”at rest
◼ __ = vagal predominance
◼ _________ = SNS tone
A
HR
Blood vessels
15
Q
SLIDE 11, review!
A
Fig 9-2 Range and Dale: Note receptor types & where Ach and NE (NA) released
16
Q
Receptors in the Peripheral Nervous System:
◼ Cholinergic Receptors =
◼ Adrenergic receptors =
A
- Nicotinic Ach receptors (Nm and Nn)
- Muscarinic Ach receptors (M1-5)
- alpha (1,2)
- beta (1, 2, 3)
◼ Disclaimer: When we discuss receptor types and affinities this is an oversimplification… For example, there are at least 3 subclasses of alpha 1 & 3 subclasses of alpha 2 receptors! Also many co-transmitters are released with NE and Ach
17
Q
Receptors in the Peripheral Nervous System: 3 major anomalies (exceptions to the rule) are
◼ ____________ (acts like a ganglia but releases NE and Epi as HORMONES)
- Norepi __%
- Epi __%
◼ ____________
- Innervated anatomically by ____
- Post ganglionic nerve releases Ach onto a _________ Ach receptor
- Thus … “sympathetic cholinergic fibers”
**EXAM QUESTION
◼ Blood vessels
- No innervation by ____
- However, there are __________ Ach receptors present on the blood vessels (activate NO with eventual vasodilation if you had a situation with circulating Ach)
**EXAM QUESTION
A
Adrenal medulla, Norepi 20%, Epi 80%
Sweat glands, SNS, muscarinic
PSNS, muscarinic
18
Q
SLIDE 14, review, memorize, KNOW!!!
A
PRINT!!!
19
Q
SLIDES 16-19, review Table 11.1 Range and Dale
A
Per Dr. B!!!!
20
Q
alpha 1: Most vascular smooth muscle; (i.e blood vessels, sphincters & bronchi) = (action) Iris (radial muscle) = Pilomotor smooth muscle = Prostate and Uterus = Heart =
A
contraction Contraction (dilates pupils= mydriasis) Erects Hair Contraction Increases force of contraction (B-1 more important though)
21
Q
alpha 2: Platelets = (action) Adrenergic & cholinergic nerve terminals *presynaptic = Vascular smooth muscle = GI tract = CNS =
A
Aggregation
Inhibits transmitter release (decrease BP and HR)
Contraction (postsynaptic) OR Dilation (pre-synaptic, CNS)
Relaxation (presynaptic)
Sedation and analgesia via ↓SNS outflow from brain stem
22
Q
beta 1:
Heart Kidneys = (action)
A
↑ force & rate of contraction Stimulation of renin release
23
Q
beta 2: Respiratory, uterine, vascular, GI, GU (visceral smooth muscle) = (action) Mast Cells = Skeletal muscle = Liver = Pancreas = Adrenergic Nerve Terminals =
A
Promotes smooth muscle relaxation ↓ Histamine release Potassium uptake, dilation vascular beds, tremor, ↑speed contraction Glycogenolysis ↑ Insulin secretion ↑release of NE
24
Q
beta 3:
Fat cells = (action)
A
Activates lipolysis; thermogenesis
25
D1:
| Smooth muscle = (action)
Post-synaptic location; Dilates renal, mesenteric, coronary, cerebral blood vessels
26
D2:
| Nerve endings = (action)
Pre-synaptic - Modulates transmitter release; nausea and vomiting (anti N/V or causes?)
27
SNS Pharmacology: Overview of Drug Classes
| Endogenous catecholamines =
Epi, Norepi, Dopa
28
SNS Pharmacology: Overview of Drug Classes
| Synthetic catecholamines =
Isoproterenol, Dobutamine
29
SNS Pharmacology: Overview of Drug Classes
Synthetic non-catecholamines
- Indirect acting =
- Direct acting =
Ephedrine, mephentermine, amphetamines
- sledge hammer; acting on release of NT, not receptor stimulation
Phenylephrine, Methoxamine
30
SNS Pharmacology: Overview of Drug Classes
| Selective Alpha-2 agonists =
Clonidine, dexmedetomidine
31
SNS Pharmacology: Overview of Drug Classes
| Selective Beta-2 adrenergic agonists =
Albuterol, terbutaline, ritodrine
32
SNS Pharmacology: Overview of Drug Classes used in Anesthesia
◼ Direct Agonists – varied affinities for.........
◼ Indirect Agonists =
Alpha 1, Alpha 2, Beta 1, Beta 2
↑ release of neurotransmitters
Overall activity of these drugs is governed by their affinity, efficacy and selectivity with respect to different types of adrenoreceptors.
33
All ___________________ are Beta-phenylethylamine derivatives.
◼ An _________ group side chain
◼ _________ group on the 3,4 carbons of benzene ring→catechol (Maximal _____ and _____ receptor activity)
◼ Thus the name _________________
```
sympathomimetics
amine (NH2)
Hydroxyl
alpha and beta
catechol-amine
```
34
Sympathomimetics: Mechanism of Action
Activation of G-protein coupled receptor (D,beta,alpha)
◼ _______ = the drug increases endogenous norepinephrine release from post-ganglionic SNS nerves which then activates the receptor
◼ _______ = the drug binds to the receptor and activates the Gprotein itself
Indirect
| Direct
35
Sympathomimetics: Mechanism of Action
◼ _________ will activate or inhibit an intracellular enzyme (adenylate cyclase→cAMP, phospholipase C) or will open or close an ion channel
◼ Usually the __________ “cascade” has an eventual positive or negative effect on the amount of intracellular Calcium = physiological effect we see clinically
G-protein
| G-protein
36
Sympathomimetics: Mechanism of Action
◼Different parts of the body have different types and densities of _________ (skeletal muscle VS venous smooth muscle VS myocardium VS bronchial smooth muscle etc.)
◼***The specific effect depends on the ____ of receptor stimulated, receptor ________ in a given tissue, and what the __________________ activate at a molecular level in the cell.***
◼Receptors will ____ or ____ regulate based upon plasma concentrations of sympathomimetic
receptors
type, density, second messengers
up or down
37
Termination of effect/Metabolism of Sympathomimetics:
Catecholamines
◼REUPTAKE I
- Uptake I = __________ reuptake
- Uptake II = __________ uptake
◼MAO & COMT are responsible for catecholamine ___________ in the _____ removing them from reuse
◼_____
*metabolism of Catecholamines < or > that of Non-catecholamines because of __ group
```
neuronal
extraneuronal
catabolism, brain
Lungs
>, OH?
```
38
Termination of effect/Metabolism of Sympathomimetics:
Non-catecholamines
◼___
◼______________________
```
MAO
Urinary excretion (unchanged) ~ polar
```
39
How would MAO inhibitors cause a problem in terms of NE and beta 1?
Inhibition of MAO metabolism of NE, leaving an elevated reuptake storage of NE (presynaptic) available for release upon next stimulation. When this excessive storage of NE is released, along with NE from post - ganglionic nerves, Injected Drugs and Epinephrine/ Norepinephrine excreted from the adrenal medulla circulating in the blood stream can result in excessive concentrations of NT.
*Remember the exception is B2 which NE cannot activate (but epi can).
40
How would MAO inhibitors cause a problem in terms of serotonin?
MAO inhibitors elevated the levels of NE, SEROTONIN, and dopamine. When given a drug, like Demerol, that blocks presynaptic serotonin reuptake, this can result in serotonin hyperstimulation.
*MAOIs used in treatment of depression and parkinson's
41
Selectivity of Adrenoreceptor Agonists:
◼ alpha-agonists
Phenylephrine - alpha _ > alpha _ >>>>> beta (0 clinical effect)
Clonidine - alpha _ > alpha _ >>>>> beta
◼ Mixed alpha- and beta-agonists
NE* - alpha _ = alpha _; beta _ >>>>>>> *beta _
Epinephrine - alpha _ = alpha _; beta _ = beta _
*(remember this is what is released by post-ganglionic nerves in the SNS – now does it make sense why B2 receptors are present in many tissues but NOT innervated…)?????????????????????????????????
alpha 1 > alpha 2
alpha 2 > alpha 1
alpha 1 = alpha 2; beta 1 >>>>>>> *beta 2
alpha 1 = alpha 2; beta 1 = beta 2
42
```
Selectivity of adrenoreceptor agonists:
◼ beta-agonists
Dobutamine - beta _ > beta _ >>>> alpha
Isoproterenol - beta _ = beta _ >>>> alpha
Terbutaline/albuterol - beta _ >> beta _ >>>> alpha
◼ Dopamine agonists
Dopamine D_=D_ >> ____ >> ____
Fenoldopam D_>>D_
```
beta 1 > beta 2 >>>> alpha
beta 1 = beta 2 >>>> alpha *Chem pacemaker
beta 2 >> beta 1 >>>> alpha *EX: beta 1 comes in to play upon extended use of nebulizer
D1=D2 >> beta >> alpha
D1>>D2
43
Endogenous Catecholamines:
Epinephrine = _____________****
◼ Many physiological functions (acts on all 4 Adrenergic receptors)
◼ Most potent activator = ______ receptors
◼ Routes: __ or __
◼ Very ______ lipid soluble = _____ CNS effect
◼ Onset: (SQ) ____ min (IV) ____ min
◼ Duration: ____ min
◼ Indications:
```
The prototype
alpha
SQ or IV
poorly, little
(SQ) 5-10 min (IV) 1-2 min
5-10 min
```
Bronchial asthma
*if servere and give after beta 2 agonist
Acute allergic reaction
Cardiac arrest, asystole
Electromechanical dissociation
V.fib. unresponsive to initial defibrillation
Infusion to increase myocardial contractility
* beta 2 = peripheral vasodilation
* beta 1 = contraction
44
Epinephrine dosing:****
◼ Standard bolus dose for resuscitation is _______ IV
◼ Can start with _-_mcg/kg
◼ Need infusion – with single bolus dose CV effects dissipate after _-_min? So if no dissipation, cont. infusion?
- 1-2mcg/minute IV = _____
- 4-5mcg/min IV = _____
- 10-20mcg/min IV = ___________
```
10mcg/kg IV
2-8mcg/kg
1-5min?
Beta-2 *asthma
Beta-1
Alpha & Beta
```
45
Cardiovascular Effects of Epinephrine:****
*Epinephrine stimulates all adrenoreceptors
Major role - BP regulation:
◼ alpha 1 =
◼ alpha 2 =
◼ beta 1 =
◼ beta 2 =
◼ ***With moderate epinephrine doses: ___ tends to increase ~ beta _, alpha _; ___ tends to decrease ~ beta _, & ___ stays the same***
◼ alpha 1 = vasoconstriction = ↑ BP, ↑ CVP, ↑ Cardiac work
* skin, mucosa, hepatic, renal
◼ alpha 2 = negative feedback = ↓ BP
◼ beta 1 = increased contractility, HR, CO – ↑ BP
**increase in phase 4 depolarization = arrhythmias in older pts
◼ beta 2 = peripheral vasodilation = ↓ BP
*skeletal muscle
◼ ***With moderate epinephrine doses: SBP tends to increase ~ beta 1, alpha 1; DBP tends to decrease~ beta 2, & MAP stays the same***
46
Cerebral Effects of Epinephrine:****
At clinically relevant doses minimal vasoconstriction of arterioles in:
◼ _________ vasculature (__________ cerebral blood flow in general, even with normal __ secondary to redistribution of blood flow)
◼ _________ vasculature
◼ _________ vasculature
◼ Makes sense doesn’t it? ~ Fight or Flight!
Cerebral, increase, BP
Coronary
Pulmonary
47
Ocular Effects of Epinephrine:****
Accommodation for far vision
◼ alpha 1 = mydriasis (pupil dilation)
Regulation of intraocular pressure
◼ alpha 1, alpha 2 = increase _______ outflow
◼ beta 1 - increase production of _____________
```
alpha 1 = mydriasis (Contraction of radial muscles of the eye = pupil dilation)
humoral (body fluid)
aqueous humor (clear fluid filling space in front of eyeball between lens and cornea) *EX: BB for glaucoma!
```
48
Respiratory Effects of Epinephrine:****
◼Dilate smooth muscles of bronchial tree = ◼Decreased release of vasoactive mediators (histamine) in bronchial vasculature =
◼Reduce mucosal secretion - decongestant =
◼What are the anesthetic considerations here?
◼Dilate smooth muscles of bronchial tree = beta 2 ◼Decreased release of vasoactive mediators (histamine) in bronchial vasculature = beta 2
◼Reduce mucosal secretion - decongestant = alpha 1
◼***With a beta blocker you see the opposite effect that is why asthmatics do not get beta-blockers – even the selective B-1 types like esmolol can adversely impact bronchial tone. B-2 stim also decreases the release of vasoactive mediators associated with symptoms of bronchial asthma.
49
GI Effects of Epinephrine:****
◼ Decreased digestive secretions =
◼ Decreased peristalsis =
◼ Decreased splanchnic blood flow =
◼ Decreased digestive secretions = alpha 2
◼ Decreased peristalsis = alpha, beta 2- direct smooth muscle relaxation
◼ Decreased splanchnic blood flow = alpha 1 –blood flow drastically reduced even if BP relatively normal
50
GU Effects of Epinephrine:****
◼ Renal Vasculature (***hint: Important!!!!!)
- alpha 1 = renal blood flow drastically ________ even if __ relatively normal
- beta 1 = kidney ________ renin release
*** Hint: think about why beta blockers might decrease BP…
◼ Bladder
- alpha 1 = ___________ of urethral sphincter - urinary continence?
- beta 2 = _________ - decreases urinary output?
◼ Erectile tissue
- alpha 1 - facilitates __________
◼ Uterus
- beta 2 - relaxation - _______ labor
```
reduced, BP
increase
contraction
relaxation
ejaculation
inhibits
```
***Epi is estimated to be 2-10X more potent than norepi for decreasing renal vascular resistance. Key point here – kidneys are going to take a big hit with epinephrine consider a vasodilator to accompany epi gtt.
51
Metabolic Effects of Epinephrine:****
◼Increased liver glycogenolysis and promotion of insulin release =
◼Increased adipose tissue lipolysis =
◼Inhibition of insulin release (more minor effect because opposed by beta 2 ) =
◼Again makes sense doesn’t it?
◼In the peri-op period do you think IDDM patients need more or less insulin?
*Low dose epi can also cause a mild ___________ secondary to activation of the Na-K pump transfer of K into cells.
◼Increased liver glycogenolysis and promotion of insulin release = beta 2
◼Increased adipose tissue lipolysis = beta 3
◼Inhibition of insulin release (more minor effect because opposed by beta 2 ) = alpha 2
◼Yes/More
*Low dose epi can also cause a mild hypokalemia secondary to activation of the Na-K pump transfer of K into cells.
52
Norepinephrine (Levophed) Highlights:****
◼ Dose for hypotension __________
◼ Peripheral IV administration dangerous if IV _______
◼ Potent _____ and _____ effects
◼ Minimal _____ effects
- Intense ______________ of skeletal muscles, liver, kidneys, cutaneous tissue (at risk for metabolic acidosis, and gigit loss)
- _________ SBP, DBP, MAP
- ***Baroreceptors activated = __________ HR & __________ respiration***(increase acetylcholine = increased vagal response....to compat, give anticholinergic)***
- ***__________ venous return, CO, HR (despite __ effect)***
```
4-16 mcg/min
infiltrates
alpha and beta-1
beta-2
vasoconstriction
Increased
Decreased, Decreased
Decreased, B1
```
***Endogenous neurotransmitter released from post-ganglionic sympathetic nerve endings. Mix in 5% glucose solution to prevent oxidation. Because of the lack of beta 2 effect you will get intense arterial and venous vasoconstriction and no bronchodilating effects. THIS DRUG WILL BUY YOU TIME BUT WILL DO A LOT OF DAMAGE IF YOU DO NOT FIX THE UNDERLYING PROBLEM (I.E HYPOVOLEMIA)***
53
Dopamine - Highlights:****
◼ Endogenous precursor of ______________
◼ Stimulates all __________ receptors including dopamine receptors
*least harmful and first choice for ______ pts
*1st line for ________ support
norepinephrine
adrenergic
renal
inotropic
54
Dopamine - Highlights:****
Dosing guidelines*
◼ _-_ mcg/kg/min = ___________ receptor stimulation dominate (“renal dose dopamine” – misleading term )
◼ _-_ mcg/kg/min = ______ receptor stimulation dominate
◼ >__ mcg/kg/min = ______ receptor stimulation dominate
* Just because one receptor is dominate at a dosage range does not mean other effects will not occur; dosage ranges are not reliable predictors of expected plasma concentration
1-3 mcg/kg/min, Dopamine 1
3-10 mcg/kg/min, Beta 1
>10 mcg/kg/min, Alpha
55
Dopamine - Highlights:****
◼ Peripheral IV administration dangerous if IV _______
◼ _________ myocardial contractility, renal blood flow, urine output, GFR
◼ Also _________ endogenous norepinephrine release = why dopamine not as useful with depleted _______________ stores
◼ *__________ with dobutamine to reduce afterload & improve cardiac output*
◼ __________ at carotid bodies – patient may have altered response to hypoxia?
◼ Increased __________ pressure
```
infiltrates
increases
increases, catecholamine
Synergistic
Inhibitory
intraocular
```
56
Isoproterenol - Highlights:****
◼Selective ___ and ___ agonists
◼_________ HR, contractility, and _______ release with __________ SVR
◼The “________________”
◼ _-_ mcg/min for heart block & bradydysrhythmias ◼Rapid metabolism by _____ (need infusion)
◼What kind of patient is at risk with use of this drug?????
B-1 and B-2
Increases, renin (↑SBP), decreased (↑SBP, ↓DBP, ↓MAP)
chemical pacemaker
1-5 mcg/min *(unless profound bradycardia?)
COMT
CAD
57
Dobutamine - Highlights:****
◼Dose =
*>__ = profound dysrhythmia = do NOT do that!
◼_____ selective at < _mcg/kg/min (weak activity at the SA node)
◼Weak _____ stimulation at >_mcg/kg/min (2 stereo-isomers are antagonistic at alpha receptors?)
◼Improves __ without increasing __ or __ substantially (good in ___)
◼Is a coronary artery vaso______
```
2-10 mcg/kg/min
10 mcg/kg/min
B-1, 5
Alpha-1,5
CO, HR, BP, CHF
dilator
```
58
Ephedrine - Highlights:****
◼ Indirect and direct agonist at ____ and ____ receptors
◼ “Weak __________” (term a little misleading) lasts __X longer
◼ Given __, __, __
◼ Used frequently during __________ to correct ___________ (________ HR)
◼ Dose ? IV; ? IM
◼ ______________ with repeated dosing
- Norepi ________
- Receptor occupation ____ ½ life – CV compensation?
◼ Excreted unchanged in urine (about __%) & slowly metabolized by ___ and conjugated in _____; E1/2 life _ hours
alpha and beta *(indirect = non-beta2, direct = beta2)
Epinephrine, 10
PO, IM, IV
anesthesia, hypotension, increases *(use only when both BP and HR are down)
10-25mg, 10-50mg *(give 5-10 at a time...can always give more, but.....)
Tachyphylaxis
depletion
long
40, MAO, liver, 3 *(polar/H2O soluble)
59
Phenylephrine (Neo-Synephrine) Highlights:****
◼ Primarily _______-adrenergic receptor stimulant
◼ Mostly direct acting
◼ Venoconstriction arterial constriction
◼ Less potent & longer lasting than ______________
◼ Dose: ? IV or ? infusion
◼ Used frequently during __________ to correct __________ (__________ HR)
◼ _________ MAP, SBP, DBP, SVR; _________ HR, CO
◼ Use in __ anesthesia being reconsidered for use
◼ Drug Error Alert (sounds like neostigmine – don’t call it “neo”)!!!!
```
alpha 1
>
norepinephrine
50-200mcg, 20-50 mcg/min
anesthesia, hypotension, decreases *(use when BP is down and HR is up)
increased, decreased
OB
```
60
If your patient gets an overdose of phenylephrine or epinephrine what should you give???
BB would be fatal because alpha 1 is main issue!
| Give alpha 1 antagonist or vasodilator (i.e. nitroprusside or nitroglycerin), and then can give BB?
61
```
Selective Beta-2 Agonists Overview:
◼Relax ? & ? smooth muscles
◼__________ duration of action due to different placements of their ________ groups on the benzene ring
◼Routes of administration =
◼Useful in.......
◼Side Effects =
```
Relax bronchiole & uterine smooth muscles
Sustained, hydroxyl
PO, inhalation, SQ or IV
Premature labor, asthma, COPD
Tremor (B2 in skeletal muscle), reflex tachycardia (vasodilation and B2 in heart)
62
Table 12-2 Stoelting useful for comparison among agents
Table 12-2 Stoelting useful for comparison among agents
63
Albuterol - Highlights:****
◼ _________ for selective Beta-2 agonists
◼ Preferred choice for _____________ due to asthma
◼ MDI: ______ per puff x 2 puffs q ____hrs, max ____ puffs.
◼ Nebulization for life threatening asthma: _______ for _ hrs.
◼ Can cause __________ and __________ with large doses
```
Prototype
bronchospasm
100ug, 4-6, 16-20
15mg/hr, 2
tachycardia and hypokalemia
```
64
Other Common Beta-2 Agonists:
◼Terbutaline
◼Salmeterol
◼Ritordine
Terbutaline - Oral, SC (0.25 mg), or puffs. For asthma or premature labor.
Salmeterol - MDI, Duration of action > 12 hours; otherwise similar clinical effect as albuterol.
*continue usual regime perioperatively bc of duration?
Ritordine
◼ For treatment of premature labor
◼ Has some beta 1 activity, thus inc. HR and CO.
◼ Can cause pulmonary edema due to decreased excretion of sodium, potassium and H2O.
*Less commonly used, Rural use, older
65
Drugs Your Patients might be taking:
Direct-acting Sympathomimetics: Non-Catecholamines
Alpha 1-agonists
◼Midodrine (ProAmatine) =
◼Oxymetazoline tetrahydrozoline, xylometazoline =
postural hypotension
| nasal and ocular decongestants, *nasal intubation?
66
```
Additional Alpha-selective adrenoreceptor agonists your patient might be taking
◼Alpha 2-selective agonists:
◼ __________ SNS output from CNS
◼ __________ BP
◼ Sedation and __________
```
Clonidine (partial agonist)
Dexmedetomidine (full agonist)
methyldopa
Decreased
Decreases
analgesia
67
Drugs your patient might be taking:
Indirect-acting Sympathomimetics
```
Amphetamine
◼ increases release of __, ___ and ________
◼ ________ reuptake
◼ ________ vesicular transport
◼ Inhibits ____
```
Methamphetamine
◼ similar to amphetamine but _____ CNS effects
Methylphenidate (Ritalin), pemoline (Cylert) =
```
Amphetamine
◼ increases release of NE, 5HT (serotonin) and dopamine
◼ Blocks reuptake
◼ Blocks vesicular transport
◼ Inhibits MAO
```
Methamphetamine
◼ similar to amphetamine but higher CNS effects
Methylphenidate (Ritalin), pemoline (Cylert) - amphetamine variants - ADHD
*titrate cautiously, not indirects?
68
Drugs Your Patient Might Be Taking:
Inhibitors of Catecholamine Storage and Reuptake
Reserpine
◼ Vesicles lose ability to store __, ___ and ________
◼ ___ breaks down excess except in high doses
◼ ____________ and __________ depression common
Cocaine
◼ Prevents reuptake of.........
◼ Interferes with _______________ transport
NE, 5HT (serotonin) and dopamine
MAO
Hypotension and psychiatric
NE, 5HT (serotonin) and dopamine
catecholamine
*increased NE = cardiac concerns!
69
Selectivity of Adrenoreceptor Antagonists:
KNOW THIS SLIDE per DR B!
Alpha-antagonists
Prazosin, terazosin, doxazosin -
Phentolamine -
Yohimbine, tolazoline -
Mixed alpha- and beta-antagonists
Labetalol, carvedilol -
Beta-antagonists
Metoprolol, atenolol, esmolol -
Propanolol, nadolol, timolol -
Butoxamine -
Alpha-antagonists
Prazosin, terazosin, doxazosin - alpha 1 >>>> alpha 2 Phentolamine - alpha 2 = alpha 1
Yohimbine, tolazoline - alpha 2 >> alpha 1
Mixed alpha- and beta-antagonists
Labetalol, carvedilol beta 1 = beta 2 >/= alpha 1 > alpha 2
Beta-antagonists
Metoprolol, atenolol, esmolol beta 1 >>> beta 2
Propanolol, nadolol, timolol beta 1 = beta 2
Butoxamine beta2 >>> beta 1
70
Alpha-Antagonists Cardiovascular effects:
◼ Alpha 1 antagonism
- Decreases ___ and lowers __
- Postural ____________ due to failure of venous vasoconstriction upon standing
◼ Alpha 2 antagonism
- __________ norepinephrine release from nerve terminals
- Blocking the __________ feedback mechanism
*Non-selective effects?
PVR, BP
hypotension
Increases
negative
71
Alpha-Antagonists GU effects:
◼ Blockade in ________ and ________ cause muscle relaxation and ease micturation (urination)
◼ _____
◼ _________ nasal congestion
prostate and bladder
Miosis
Increased
72
```
Alpha Antagonists: Phentolamine
◼____________ alpha blocker
◼Causes: vaso______, ________ BP, ________ HR and CO.
◼Used in:
- IV dosing:
- Onset _ minutes; DOA ____ min
◼ Also used in:
- __-__ mg in __ml
```
Nonselective
vasodilation, decrease, increase
Hypertensive emergencies, usually in pheocromocytoma or autonomic dysreflexia
30-70 mcg/kg IV
2, 10-15
Local infiltration for accidental extravascular administration of sympathomimetics
2.5-5.0 mg in 10ml
73
Alpha Antagonists: Phenoxybenzamine
◼ Binds ________
◼ Alpha _ activity > alpha _.
◼ ________ SVR, vaso_______
◼ Pro-drug w/ _ hr onset time; ____ acting (E1/2t of __hrs) ...... *no good intraop!
◼ Preop for pts with __________________, can be used for pts with __________________
```
covalently (stuck together for long time?)
1,2
Decreased, dilation
1, Long, 24
pheochromocytoma, Raynaud’s disease
```
74
Alpha Antagonists Your Patients May be Taking:
Prazosin ****
◼Control __ in pheochromocytoma
◼Selective alpha _ blocker (minimal alpha _)
◼Less reflexive __________ (remember alpha 2 is inhibitory to NE release)
Yohimibine
◼Alpha _ selective blocker
◼Increases the release of Norepi from ___synaptic neuron
◼Used w/ ?
BP
1,2
tachycardia
2
post
orthostatic hypotension, impotence
75
Alpha Antagonists Your Patients May be Taking for BPH:
◼ Terazosin and Tamulosin
- ____ acting selective alpha __, particularly effective in prostatic smooth muscle relaxation
Long, 1a
76
```
Beta-adrenergic receptor antagonists:
Prevent sympathomimetics (via competitive antagonism) from provoking a beta response on the:
◼ Heart
◼ Airway
◼ Blood vessels
◼ Juxtaglomerular cells
◼ Pancreas
```
◼ Heart - Improve O2 supply and demand balance
◼ Airway - Can provoke bronchospasm
◼ Blood vessels - Vasoconstriction in skeletal muscles; PVD symptoms ↑
◼ Juxtaglomerular cells - ↓ renin release – indirect way of ↓BP
◼ Pancreas - Decreased stimulation of insulin release by epi/norepi at B2 and then masked symptoms of hypoglycemia B1?
77
Beta-adrenergic receptor antagonists:
Mechanism of action:
◼ _________ binding to beta receptors (influence inotropy, chronotropy)
◼ _________ and __________ inhibition - large doses of agonists will completely _________ antagonism
◼ Chronic use is associated with increase in the # of __________ (upregulation)
◼ So what happens if we stop them suddenly peri-operatively????
Selective
Competitive and reversible, overcome
receptors
The response is worse than it would have been to have never started then to begin with!
78
Beta-adrenergic receptor antagonists:
◼ Derivatives of the beta agonist,______________, thus possessing some sympathomimetic effects
◼ Substitution on the _____________
isoproterenol
| benzene ring
79
```
Beta-adrenergic receptor antagonists:
Classification:
◼Non selective (beta 1 & 2) -
◼Cardioselective (beta 1 only) -
◼Large doses ____ selectivity
```
◼Non selective (beta 1 & 2, less desirable) - propranolol, nadalol, timolol, pindolol
◼Cardioselective (beta 1 only, preferred) - metoprolol, atenolol, acebutolol, betaxolol, esmolol = long acting & good for OR
◼Large doses lose selectivity
80
Propranolol –The prototype****
◼Non __________
◼Lacks _____________ activity, thus a ____ antagonist
◼_____ at B1 and 2
◼Administered in a stepwise manner until goal of _____ bpm is achieved
selective
sympathomimetic, pure
Equal
55-60
81
Propranolol –The prototype****
Cardiac effects:
◼__________ HR, contractility, and CO
◼Blockade of __ receptors-increased PVR, increased coronary vascular resistance
◼However due to decreased HR and CO, oxygen demand is ________, opposing the above effects ◼Sodium ________ due to renal system response to drop in __
Decreased *especially prominent during exercise and sympathetic outflow
B2
lowered
retention, CO
82
Propranolol –The prototype****
Pharmacokinetics:
◼Goes thru _________ first-pass effect (_____%)
- Oral dose much _____ than IV dose
- ________ IV or _______ (give slowly 1mg q 5 min) ◼Protein bound (______%)
◼Metabolized in _____, E1/2t of ____hrs (will be ↑in low hepatic blood flow states)
◼__________ clearance of amide LAs due to a drop in hepatic blood flow ~ metabolism inhibition
◼↓the pulmonary fist pass effect of _______
```
significant, 90-95%
larger
0.05mg/kg IV or 1-10mg (give slowly 1mg q 5 min)
90-95%
liver, 2-3hrs
Decreases
fentanyl
```
83
Beta-adrenergic receptor antagonists your patients might be taking:
Timolol
◼ Non _________ beta blocker
◼ Used to tx _________-decreases intraocular pressure by ↓ production of aqueous humor
◼ Eye drops can cause.............
Nadolol
◼ Non _________ beta blocker
◼ No significant __________ (renal/biliary elimination)
◼ E1/2t of __-__hrs take _X daily
selective
glaucoma
↓BP, ↓HR and ↑ airway resistance
selective
metabolism
20-40hrs take 1X daily
84
```
Metoprolol****
◼ ________ beta 1 blocker
◼ Decreases ________ and ________
◼ Selectivity is ____ related
◼ About __% goes thru first pass effect
- PO __-___mg
- IV _-__ mg
◼ E1/2t of ____hrs
*increased lipid solubility = increased CNS/depression??
```
```
Selective
inotropy and chronotropy
dose
60
PO 50-400mg
IV 1-15 mg
3-4hrs
```
85
Atenolol****
◼ ____ selective beta 1 antagonist and thought to have the ____ CNS effects
◼ E1/2t is ____hrs
◼ ___ metabolized in liver, excreted via _____ system, therefore E1/2t is increased markedly in pts with _____ disease
◼ Very useful in _______ patients with ___
Most, least
6-7hrs
NOT, renal, renal
cardiac patients with CAD
*Peri-operative administration of atenolol to patients at high risk for CAD significantly decreases incidence of myocardial ischemia. Because of selectivity atenolol can be considered for use in carefully monitored DM patients?
86
Betaxolol- Patient might be on this drug…
◼ Cardioselective beta _ blocker
◼ E1/2t is __-__hrs
◼ Single dose _____ for HTN
◼ Topical useful for _______, with less risk of brochospasm as seen with timolol, so good alternative choice in asthmatics with glaucoma
*less effect if stop taking.....more worried if someone were to stop/forget to taking propranolol!?
1
11-22hrs
daily
glaucoma
87
Esmolol
◼Selective beta _ antagonist
◼_____ onset, _____ acting
◼Dose = _______ IV (_______ IV), infusion = _____________
◼DOA=
◼Effects __ without decreasing __ significantly in small doses
◼In doses used, it does not occupy sufficient beta receptors to cause __________ inotropy
◼E1/2t is _ minutes
◼_______ hydrolyzed by ________ esterases
- Not the same esterases as cholinesterases responsible for metabolism of ___, therefore no effect on ___ metabolism
```
1, however, CI'd w/ asthmatics
Rapid, short
0.5mg/kg IV (10-180mg IV), infusion = 50-300 mcg/kg/min
*start small and step wise increase to effect!
15min
HR, BP, negative
9 minutes
Rapidly, plasma esterases, sux squared
```
***Only IV. Great for blunting short lived noxious stimuli in OR or for controlled hypotension. Need to be careful of use if patient has profound sympathetic mediated vasoconstriction because can precipitate CV collapse?
88
Side effects of beta-blockers:
◼CV System-________ HR, Contractility, BP ◼Exacerbation of ___ (block of beta -2 = __________) ◼_________ airway resistance-____________
◼Metabolism-alter carbohydrate and fat metabolism, mask hypoglycemic _________ in HR
◼Distribution of extracellular potassium = ______ uptake of potassium into skeletal muscles
◼Interaction with anesthetics = may have _________ BP with ___
◼Nervous system = _______ & _______
◼GI = ______, ______ and ______
```
decrease
PVD, vasodilation
Increased airway resistance-bronchospasm
elevation
inhibit
decreased, AIs
fatigue, lethargy
Nausea, vomiting and diarrhea
```
89
Relative Contraindications beta-blockers =
◼ Pre-existing AV heart block or cardiac failure
*monitor ECG for ST changes, not just HR!
◼ Reactive Airway Disease
◼ Diabetes Mellitus (without BS monitoring)?
◼ Hypovolemia
90
Clinical uses of beta-blockers:
◼Treatment of ___
◼Management of _______
◼Decrease mortality in treatment of post __ pts
◼Used periop and preop for pts at risk for __ ◼Suppression of _____arrythmias
◼Prevention of excessive ___________ nervous system activity *like Dr B's friend before exams ;-)
```
HTN
Angina
MI
MI
tachy
sympathetic
```
91
Combined alpha & beta blockers:
Labetalol
◼Selective at alpha _ and beta _ and _ receptors
◼IV Beta to Alpha Blockade ratio = ___
◼Metabolism conjugation of glucuronic acid in _____;
```
alpha 1 and beta 1 and 2 receptors
7:1
liver, 5, urine
5-8hrs, liver
↓ BP, SVR, HR. CO is unaffected
drop in BP
0.1-0.5 mg/kg
5mg, hypertension
orthostatic hypotension, bronchospasm, heart block, CHF, bradycardia
```
* Onset = how quickly to titrate
* Quick = Esmolol, Longer = Labetalol
92
Botulinum toxin:
- Prevents _________ of ___synaptic vesicles
- Prevents release of ___ at __ receptors
exocytosis, pre
| ACh at Nm receptors
93
Cholinergic Receptor Subtypes:
```
Nicotinic receptors (Ach)
◼ ______________ structures
◼ Function as _____________ ion channels =
```
Muscarinic receptors (Ach)
◼ ________ coupled
◼ M_, M_, M_ = inositol phosphate pathway =
◼ M_, M_ inhibit adenylyl cyclase reduce cAMP =
Pentameric (5 subunit)
ligand-gated, increased Na and K perm. = depolarization
G-protein
M1, M3, M5, increased free Ca2+ and decreased K cond.
M2, M4, increase K cond. = repol/hyperpol
94
Cholinergic Receptor Subtypes:
| ◼M1:
◼M1: CNS, stomach
95
Cholinergic Receptor Subtypes:
| ◼M2:
◼M2: cardiac muscle, CNS, airway smooth muscle
96
Cholinergic Receptor Subtypes:
| ◼M3:
◼M3: airway smooth muscle, glandular tissues
97
Cholinergic Receptor Subtypes:
| ◼M4:
◼M4: CNS
98
Cholinergic Receptor Subtypes:
| ◼M5: :
◼M5: CNS
99
Cholinergic Receptor Subtypes:
| ◼Nm:
◼Nm: skeletal muscle at NMJ
100
Cholinergic Receptor Subtypes:
| ◼Nn:
◼Nn: autonomic ganglia, adrenal medulla, CNS
101
Antimuscarinic Drugs - MOA and structure:
◼ ____________ antagonize acetylcholine (Ach) at muscarinic receptors (only)
◼ Cation portion of the drug fits into _____ place on the anticholinergic receptor and reversibly inhibits _____ binding
◼ Allow __________ responses to predominate
◼ This competitive inhibition can be reversed if _____ concentration is ↑
◼ Natural (_________ & _________) are tertiary amines – alkaloids of belladonna plants
◼ Semi-synthetic (___________/________) - quaternary ammonium derivative
```
Competitively
Ach’s, Ach
sympathetic
Ach
atropine & scopolamine
glycopyrrolate/Robinal
```
102
Semi-synthetic (glycopyrrolate/Robinal) - quaternary ammonium derivative - are _______ and will NOT cross the ______________?
charged
| BBB/membranes
103
Antisialagogues =
substances that decrease the production of saliva and their effect is opposite to that of sialagogues. Their origin may be both natural and synthetic.
*caution with BPH!!??
104
Mydriasis =
Dilated pupils
105
```
Atropine:
Sedation, mydriasis & motion induced nausea =
↑ HR =
Relax Smooth Muscle =
Anti-sialagogue =
```
```
Atropine:
Sedation, mydriasis & motion induced nausea = +
↑ HR = +++
Relax Smooth Muscle = ++
Anti-sialagogue = +
```
106
```
Scopolamine:
Sedation, mydriasis & motion induced nausea =
↑ HR =
Relax Smooth Muscle =
Anti-sialagogue =
```
```
Scopolamine:
Sedation, mydriasis & motion induced nausea = +++
↑ HR = +
Relax Smooth Muscle = +
Anti-sialagogue = +++
```
107
```
Glycopyrrolate:
Sedation, mydriasis & motion induced nausea =
↑ HR =
Relax Smooth Muscle =
Anti-sialagogue =
```
```
Glycopyrrolate:
Sedation, mydriasis & motion induced nausea = 0
↑ HR = ++
Relax Smooth Muscle = ++
Anti-sialagogue = ++
```
108
Antimuscarinics - Pharmacokinetic Highlights:
◼IV Atropine onset is _ minute; duration of action of __-__ minutes; E1/2t is ___ hrs; __% unchanged via urine the rest is undergoes hydrolysis
◼IV Glycopyrrolate ______ onset of _-_ minutes; duration of action of __-__ minutes; E1/2t is ___ hrs; __% unchanged via urine
◼Scopolamine extensively metabolized with only _% excreted unchanged in the urine
1, 30-60, 2.3, 18
slower, 2-3, 30-60, 1.25, 80
extensively, 1
109
Antimuscarinics - Pharmacokinetic Highlights:
| Onsets =
Atropine < Glycopyrrolate
110
Antimuscarinics - Pharmacokinetic Highlights:
| DOA =
Atropine = Glycopyrrolate
111
Antimuscarinics - Pharmacokinetic Highlights:
| E1/2t =
Atropine > Glycopyrrolate
112
```
When might a CRNA use these drugs?
◼Pre-operative –
◼Treatment of _____cardia
◼With _________________ drugs (always given when antagonizing NMB)
◼Promoting ________ in unstable patients
```
When might a CRNA use these drugs?
◼Pre-operative – antisialagogue or sedation, nausea prevention
◼Treatment of bradycardia (especially vagal stimulation related)
- Magnitude of effect depends on baseline vagal tone
- Young patients high tone = more tachycardia
- Elderly patients less tone = less pronounced tachycardia
◼With anticholinesterase drugs (always given when antagonizing NMB)
◼Promoting amnesia in unstable patients
113
Anticholinesterase drugs:
Anticholinesterases are a class of drugs that decrease breakdown of acetylcholine (a chemical messenger in the brain) and can be used in conditions whereby there is an apparent lack of this messenger transmission such as in Alzheimer's disease.
114
When might a CRNA use these drugs? (cont.)
◼Bronchodilation (___________)
- MDI dose = _______ x _ puffs
- Nebulizer dose = ________
- Onset __-__ minutes
- Consider in:
◼Mydriasis and cycloplegia (ophtho cases)
- Note: anticholinergics may be dangerous in patients with narrow angle _________ (increases ___)
◼To reduce _____ and ______ spasm r/t opioids
```
Ipratropium****
40-80mcg, 2
0.25-0.5 mg
30-90
asthmatics, COPD, and smokers prior to airway instrumentation
```
glaucoma, IOP
biliary and ureteral
115
Scopolamine dosing****
• IM (pre-op)
• Transdermal
- Nausea
0.3-0.5 mg or 5mcg/kg
1.5mg
5mcg/hr X 72 hrs
116
Atropine dosing****
• IV (pre-op)
• IV (bradycardia)
• Nebulizer (bronchodilate)
0.2-0.4 mg
0.4-1.0 mg
2mg in 5ml NS
117
Glycopyrrolate dosing****
| • IV (pre-op and bradycardia)
0.1-0.2 mg
118
Central Anticholinergic Syndrome:
___________ and _______ (unlikely with __________)
◼ Restlessness, hallucination
◼ Somnolence and unconsciousness
◼ Delayed emergence/recovery in PACU
◼ Physostigmine 15-60 mcg/kg IV repeated as needed q1-2 hours
Scopolamine and atropine (unlikely with glycopyrrolate)
119
Central Anticholinergic Syndrome:
◼ Physostigmine __________ IV repeated as needed q___ hours
◼ Anticholinesterase
***Physostigmine is the only commonly used anticholinesterase drug that crosses the BBB.
15-60 mcg/kg, 1-2
120
Other Muscarinic Antagonists your patient may take:
◼Ipratropium (Atrovent), tiotropium (Spiriva)
-for
-MOA
◼Oxybutynin (Ditropan), tolterodine (Detrol)
-for
-MOA
◼Darifenacin (Enablex), solifenacin (Vesicare)
-for
-MOA
COPD, Bronchodilator
overactive bladder, Nonspecific M-rec
overactive bladder, M3 specific
121
AChE Inhibitors:
◼ Elevates concentration of endogenously released ___ in synapse by decreasing its _________
◼ Increases transmission at __ junction (reverses competitive ___)
◼ __________ parasympathetic tone
◼ __________ central cholinergic activity
ACh, metabolism
Nm, NMB
Increases
Increases
122
AChE Inhibitors: Uses
◼Useful in diseases of the __ junction
- ______________ - pyridostigmine, neostigmine
◼ __________
- Increases outflow of aqueous humor - physostigmine (Isopto)
◼ __________ distension
- Increases smooth muscle motility - neostigmine
◼AD and other forms of ________ dysfunction
- Tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne)
Nm, Myasthenia gravis (***autoimmune destruction of Nm receptors)
Glaucoma
Abdominal
cognitive
123
AChE Inhibitors: Adverse effects
◼Peripheral ACh effects of GI tract such as......
◼Dose-dependent
N/v/d, anorexia, flatulence, abdominal cramping
124
AChE Inhibitors: Contraindications =
◼Unstable or severe cardiac disease
◼Uncontrolled epilepsy
◼Active PUD
125
Drugs Your Patient Might be Taking: Muscarinic Agonists
◼Diagnosis of asthma =
◼Miosis and decreased intraocular pressure =
◼GI and urinary tract motility - post-op and post-partum urinary retention, neurogenic bladder =
Drugs Your Patient Might be Taking: Muscarinic Agonists
◼Diagnosis of asthma = Methacholine
◼Miosis and decreased intraocular pressure = Carbachol
◼GI and urinary tract motility - post-op and post-partum urinary retention, neurogenic bladder = Bethanechol
126
Nicotinic Agonists: Depolarizing Muscle Relaxant
| ◼ _______________ - Continuous activation of nicotinic receptor channels results in depolarization blockade
Succinylcholine
127
Nicotinic Antagonists: Non-Depolarizing Muscle Relaxants
◼ _________ endogenous ACh binding to nicotinic receptors and subsequent muscle cell depolarization
◼ Paralysis
◼ Drugs =
Prevent
| Pancuronium, vecuronium , rocuronium
