Flood chapter 25: Resp pharmacology Flashcards
(195 cards)
1
Q
Medications delivered to the lungs can have what effects
A
Direct effects on the airway
Systemic effects
Both direct and systemic
2
Q
Pharm agents administered via the lungs allow for rapid uptake of drugs into ________or immediate ________
A
the blood stream
use by the cells of the airway
3
Q
Action of inhaled anesthetics on the brain
A
Anesthesia
4
Q
Action of inhaled anesthetics on the lungs
A
Bronchodilation
5
Q
Direct effects of inhaled anesthetics
A
Bronchodilation from action on the lungs
6
Q
Systemic effects of inhaled anesthetics
A
Anesthesia from action on the brain
7
Q
Beta-adrenergic agonists delivered via aerosol exert direct effect on bronchial smooth muscle with few systemic effects. This would be an example of?
A
direct effect only
8
Q
Drugs administered via airway are excellent for parenchymal diseases such as asthma and COPD because?
A
They take advantage of the rapid exposure to blood and pulmonary parenchymal cells.
9
Q
Autonomic Nervous System (ANS) is divided into?
A
Divided into Sympathetic Nervous System (SNS) and Parasympathetic Nervous System (PNS)
10
Q
Regulates airway caliber (diameter), airway, glandular activity and airway microvascular.
A
Parasympathetic Nervous System (PNS)
11
Q
__________ provides the preganglionic fibers
A
Vagus Nerve
12
Q
Preganglionic fibers synapse with postganglionic fibers in the_________
A
airway parasympathetic ganglia
13
Q
Acetylcholine activates _____________ to produce bronchoconstriction.
A
the muscarinic (M3) receptor of postganglionic fibers of the PNS
14
Q
Anticholinergics can provide bronchodilation even in the resting state because?
A
the PNS produces a basal level of resting bronchomotor tone.
15
Q
Plays no direct role in control of airway muscle tone.
A
SNS
16
Q
________ adrenergic receptors (a lot of them) are present on airway smooth muscle cells and cause bronchodilation (via stimulatory G mechanisms)
A
Beta-2
17
Q
What is exact role of NANC?
A
Not well defined
It has excitatory and inhibitory neuropeptides that influence inflammation and smooth muscle tone respectively.
18
Q
ANS also influences bronchomotor tone through
A
NANC system
19
Q
the main inhibitory transmitters thought to be responsible for airway smooth muscle relaxation are?
A
Vasoactive Intestinal Peptide (VIP) and Nitric Oxide (NO)
20
Q
The main excitatory transmitters shown to cause neurogenic inflammation, including bronchoconstriction are?
A
Substance P (SP) and Neurokinin A (NKA)
21
Q
The mainstay therapy for bronchospasm, wheezing, and airflow obstruction is
A
Beta-adrenergic agonists.
22
Q
Identify features of beta-adrenergic agonists used in clinical practice
A
Typically delivered via inhalers or nebulizers
Beta-2 selective
Divided into short and long acting therapies
23
Q
Identify systemic adrenergic agonists
A
Terbutaline
Epinephrine
Albuterol
24
Q
Identify short acting inhaled adrenergic agonists
A
Albuterol
Levalbuterol
Metaproterenol
Pirbuterol
25
Identify long acting inhaled adrenergic agonists
Salmeterol
Formoterol
Arformoterol
26
Name short acting Inhaled cholinergic antagonists
Ipratropium
27
Name long acting Inhaled cholinergic antagonists
Tiotropium
28
Name systemic cholinergic antagonists
Atropine
Scopolamine
Glycopyrrolate
29
Short acting Beta-2 Agonist Therapy is effective for
rapid relief of wheezing, bronchospasm and airflow obstruction.
30
____________ are used as maintenance therapy providing improved lung function and reduction in symptoms and exacerbations.
Long acting Beta-2 Agonists Therapy
31
Short acting Beta-2 agonists Bind to the Beta-2 adrenergic receptor located on the plasma membrane of
smooth muscle cells
epithelial
endothelial
and many other types of airway cells.
32
How does cAMP cause smooth muscle relaxation?
Not precisely known
Decreases in calcium release
Alterations in membrane potential
33
What unique properties allow for longer duration of action of LABA
Salmeterol has a longer duration because of a side that chain binds to the Beta-2 receptor and prolongs the activation of the receptor.
Formoterol has a lipophilic side chain allowing for interaction with the lipid bilayer of the plasma membrane. This allows a slow and steady release prolonging its duration of action.
34
Clinical effects of short acting B2 agonists is seen in minutes and lasts?
up to 4-6 hours.
35
Used primarily as rescue therapy
short acting B2 agonists
36
Long Acting B2 agonists are prescribed for?
Symptom control when short acting used > 2 x week
Combination therapy with inhaled corticosteroid where they are effective in reducing symptoms, reducing exacerbation and improving lung function while minimizing the dose of inhaled corticosteroids.
37
Combination therapy of LABA with inhaled corticosteroid are effective in
reducing symptoms
reducing exacerbation
improving lung function while minimizing the dose of inhaled corticosteroids.
38
B2 agonist side effects
Tremors
Tachycardia
Temporary reduction of PO2 of 5 mmHg In severe asthma
Hyperglycemia
Hypokalemia
Hypomagnesemia
39
Tremors and Tachycardia with B2 agonist is secondary to
Direct stimulation of the Beta-2 adrenergic receptor in skeletal muscle or vasculature.
40
Temporary reduction of PO2 of 5 mmHg In severe asthma with B2 agonist use is secondary to?
Beta-2 mediated vasodilation in poorly ventilated lung regions.
41
These side effects of B-2 agonist therapy tend to decrease with regular use.
Hyperglycemia
Hypokalemia
Hypomagnesemia
42
Beta-2 adrenergic Tolerance likely reflects?
Beta-2 adrenergic receptors down regulation
43
Withdrawal of a Beta-2 agonist after regular use can produce
transient bronchial hyperresponsiveness (exaggerated bronchial restriction)
44
_____ is not affected by B2 agonist tolerance
bronchodilation
45
Tolerance to Beta-2 agonists can occur with regular use over _______period
period of weeks
46
Evidence of Beta-2 agonists tolerance
Decrease in duration of bronchodilation
Decrease in magnitude of side effects (such as tremors and tachy etc.).
47
Use of _______ without concomitant use of a steroid inhaler as been shown to be associated with fatal and near-fatal asthma attacks.
long acting Beta-2 agonist therapy
48
Prudent to reserve long acting Beta-2 agonists for those pts who?
Are poorly controlled on inhaled steroids alone.
Have symptoms perilous enough to warrant the potential added risk.
49
B2 agonist Inhalation route should be first line treatment d/t
possibilities of side effects with IV formulations
50
The side effects of systemic adrenergic agonists is similar to inhalational adrenergic agonists with _________ being the most common.
tremors and tachy
51
Inhaled anticholinergics are used for
maintenance therapy and tx of acute exacerbations in obstructive disease
52
Use of _________ in COPD as maintenance and rescue therapy is standard treatment.
inhaled anticholinergics
53
Anticholinergics are used for maintenance therapy in asthma. True/False
False
Anticholinergics are NOT used for maintenance therapy in asthma. Only recommended for use in acute exacerbations.
54
3 subtypes of muscarinic receptors in the airway are
M2: Not targeted by inhaled anticholinergics
M1 and M3: Targets of inhaled anticholinergic therapy.
55
M2 receptors are responsible for?
Responsible for limiting production of Ach and protect against bronchoconstriction.
Is NOT the target of inhaled anticholinergic, but is antagonized by them.
56
Muscarinic 1 (M1) and Muscarinic 3 (M3): These receptors are responsible for
bronchoconstriction and mucus production and are the targets of inhaled anticholinergic therapy.
57
M1 and M3 receptor action
Acetylcholine binds to the M3 and M1 receptors and causes smooth muscle contraction.
This smooth muscle contraction is produced from increases in cyclic guanosine monophosphate (cGMP) or by activation of a G protein (Gq)
Gq activates phospholipase C to produce inositol triphosphate (IP3)
IP3 causes release of calcium from intracellular stores and activation of myosin light chain kinase causing smooth muscle contraction.
Anticholinergics inhibit this cascade and reduce smooth muscle tone by decreasing release of calcium from intracellular stores.
58
Ipratropium (Atrovent)
Classified as a short acting anticholinergic.
Commonly used as maintenance therapy for COPD.
Also used as rescue therapy or both COPD and asthmatic exacerbations (not indicated for routine management of asthma).
Ipratropium treatment increases in exercise tolerance, decrease in dyspnea, and improved gas exchange.
59
Tiotropium (Spiriva):
Only long acting anticholinergic available for COPD maintenance therapy.
Reduces COPD exacerbations, respiratory failure, and all-cause mortality
60
This drugs is associated with CV and CVA complications however, studies do not consistently support this claim
Tiotropium
61
Inhaled Anticholinergics _________ absorbed and serious side effects are uncommon
Poorly
62
Inflammatory cell types present in COPD
Neutrophils
macrophages
CD 8 + T lymphocytes
eosinophils
63
prominent cells in the inflammatory composition of Asthma
Eosinophils (Most)
mast cells (2nd most)
CD 4 + T lymphocytes
macrophages
64
Anti-Inflammatory response in COPD and asthma can be predicted by?
Inflammatory cell types present in sputum; biopsy specimens; and bronchoalveolar lavage fluid.
65
the primary target of ICS is?
Glucocorticoid receptor alpha (GRα) located in the cytoplasm of airway epithelial cells
66
In asthma, treatment with ICS will?
ICS reduces inflammatory changes associated with the disease.
Improves lung function; reducing exacerbations that result in hospitalization and death.
67
ICS treatment in COPD
ICS as a monotherapy is discouraged.
ICS are used in combination therapy with a long-actin B-adrenergic agonists (LABA).
The synergistic effect reduces inflammation
Combination of ICS and LABA are recommended for severe to very severe COPD pts.
68
ICS are added to the asthma regimen when ?
When there is an increase in frequency or severity of exacerbations
69
Evidence does show ICS decrease ___________ in asthma.
hospitalizations and deaths
70
Combination of ICS and LABA are recommended for
severe to very severe COPD pts.
71
ICS/LABA has been shown to improve mortality in COPD pts. T/F?
FALSE : It hasn't been shown to improve mortality.
The combination has been reported to improve lung function and reduce exacerbations
72
Steroid receptor MOA
Steroid enters the cell through passive diffusion leading to binding of the steroid ligand to the glucocorticoid receptor alpha, dissociation of heat shock proteins, and subsequent translocation to the nucleus.
This complex can bind to promoter regions of DNA sequences and either induce or suppress gene expression.
Its can also Interact with transcription factors such as the one responsible for pro-inflammatory mediators (without binding to DNA) and repress expression of those genes
It can also affect chromatin structure; influence the winding of DNA; reduce access of RNA and thus reduce expression of inflammatory gene products
73
Passive diffusion of steroids into the cell allows for
Binding of the steroid ligand to the glucocorticoid receptor alpha.
Dissociation of heat shock proteins.
Subsequent translocation to the nucleus.
74
After translocation to the nucleus, the steroid- glucocorticoid receptor alpha complex can?
Bind to promoter regions of DNA sequences and either induce or suppress gene expression.
Interact with transcription factors such as the one responsible for pro-inflammatory mediators (without binding to DNA) and repress expression of those genes
Affect chromatin structure; influence the winding of DNA; reduce access of RNA and thus reduce expression of inflammatory gene products
75
ICS has reported increase in pneumonia and severe pneumonia in patients with?
COPD
However no reported increase in death
76
What are the side effects of ICS in patients with COPD and Asthma
candidiasis
pharyngitis
easy bruising
osteoporosis
cataracts
elevated intraocular pressure
dysphonia and growth retardation in children.
77
The recommended duration of Systemic corticosteroids in COPD patients should not exceed 2 weeks because
Side effects with No added benefit to longer duration.
78
In Asthma, systemic Corticosteroids are recommended for exacerbations that are?
Severe with a peak expiratory low of <40% of baseline.
Mild to moderate exacerbation with no immediate response to short acting Beta-adrenergic agonists.
79
Recommend duration for systemic corticosteroids in asthma is?
3-10 days without tapering.
80
Some Asthma and COPD pts will receive long term oral corticosteroid therapy b/c?
their disease is difficult to manage
81
SYSTEMIC CORTICOSTEROIDSSIDE EFFECTS
```
Hptn
Hyperglycemia
Adrenal Suppression
Increased Infections
Cataracts
Dermal Thinning
Psychosis
PUD
```
82
Arachidonic acid is converted to leukotrienes via?
the 5-lipoxygenase pathway
83
What are the end products of the 5-lipoxygenase pathway.
Leukotrienes C4, D4 and E4
84
Leukotrienes will cause?
bronchoconstriction
tissue edema
migration of eosinophils
increased airway secretions.
85
2 types of leukotriene modifiers are?
Leukotriene Receptor Antagonists
Leukotriene Inhibitors i.e Zileuton
86
antagonizes the 5-lipoxygenase inhibiting the production of leukotrienes
Leukotriene Inhibitors i.e Zileuton
87
Leukotriene Modifiers therapeutic effects in asthma
Improve lung function
Reduce exacerbations
Used a long-term asthma therapy
88
First line for long term treatment of asthma
ICS
ICS are superior to leukotriene modifiers for long term therapy and should be first line treatment. Both used together improve control of asthma symptoms as opposed to ICS alone.
89
_________ is known to cause a reversible hepatitis in 2% - 4% of patients.
Zileuton
90
An unclear link exists between _____________ and Churg-Strauss Syndrome
Leukotriene Antagonists
91
A form of necrotizing vasculitis in which there is a prominent lung involvement with severe asthma, eosinophilia, and granulomatous reactions. Will have skin lesions that are tender SQ nodules and bruise like spots
Churg-Strauss Syndrome
92
_____ stabilize submucosal and intraluminal mast cells
Mast Cell Stabilizers e.g. Cromolyn Sodium and Nedocromil
93
MOA of mast cell stabilizers
They interfere with the antigen-dependent release of mediators, such as histamine and slow-reacting substances of anaphylaxis that cause bronchoconstriction, mucosal edema, and increased mucus secretions.
94
Most common side effects of mast cell stabilizers are
GI upset
coughing
throat irritation
95
used as preventative tx before exercise or known allergen exposure
Mast Cell Stabilizers e.g. Cromolyn Sodium and Nedocromil
96
Mast Cell Stabilizers are not first line therapy for asthma but provides alternative tx when?
when conventional therapies are not optimal
97
Nonselective inhibitor of phosphodiesterase and increases levels of cAMP and cGMP causing smooth muscle relaxation.
Theophylline
98
Theophylline MOA
Nonselective inhibitor of phosphodiesterase and increases levels of cAMP and cGMP causing smooth muscle relaxation.
Antagonizes A1 and A2 adenosine receptors causing smooth muscle relaxation via inhibition of the release of histamine and leukotrienes from mast cells.
Activates histone deacetylase and reduces the expression of inflammatory genes.
Theophylline and aminophylline are reported to improve diaphragmatic function however data is inconsistent
99
In asthma theophylline reduces ______
Reduces number of eosinophils in bronchial specimens and has anti-inflammatory effect
100
In COPD theophylline reduces ______
reduces the number of neutrophils in sputum, and has an anti-inflammatory effect
101
Theophylline is used as an alternative therapy for COPD and Asthma due to
Requires monitoring of blood levels
Side effects prominent at blood levels > 20 mg/L
102
Most common side effects of Theophylline are?
```
headache
nausea
vomiting
restlessness
abdominal discomfort
GERD
diuresis
```
103
Most significant side effects of Theophylline are?
seizures
cardiac arrhythmias
death
104
Inhaled anesthetic with most bronchodilation
Sevo
Sevo produces greater reduction in respiratory system resistance than Iso or halothane
105
All inhaled anesthetic produce bronchodilation except
Desflurane
106
Volatile Agents likely induce bronchodilation by
↓intracellular calcium, partly mediated by an ↑ in intracellular cAMP
↓ sensitivity of calcium mediated by protein kinase C.
107
Volatile induced bronchodilation Effect is seen in distal airway smooth muscle secondary to?
T-type voltage-dependent calcium channel which is sensitive to volatile anesthetics.
108
Limitations of using volatile anesthetics as sole agents for status asthmaticus are?
Potential although rare for MH
Hypotension
Issues using outside an OR
109
Airway smooth muscles are relaxed when using which IV anesthetics
Propofol
Ketamine
Midazolam
110
Etomidate or thiobarbiturates do not affect bronchomotor tone. T/F
True
111
What is the mechanism of reduction of bronchomotor tone for IV Anesthetics?
Not known
Ketamine is thought to have a direct relaxant effect on smooth muscle.
Propofol is thought to reduce vagal tone and have a direct effect on muscarinic receptors by interfering with cellular signaling and inhibiting calcium mobilization
112
_________ found in propofol prevents the inhibition of vagal-mediated bronchoconstriction.
The preservative metabisulfite
113
Systemic Local anesthetics are Primarily used to?
suppress cough and blunt hemodynamic response to tracheal intubation.
Some studies suggest LA may cause bronchial smooth muscle relaxation, it is limited by toxicity and other more potent bronchodilators
114
Reynolds number indicating mixture of laminar and turbulent flows
2,000 and 4,000
115
Reynolds number indicating laminar flows
< 2,000
Air during quiet breathing are < 2,000 throughout most of the upper and lower airway
116
Reynolds number associated with turbulent flow
> 4,000
117
When a gas or liquid flows through a straight unbranched tube, flow will usually be laminar and resistance is directly proportional to _________ of the gas or liquid and inversely proportional to ______________
the viscosity
the radius (actually the 4th power of the radius).
(Poiseuille’s law)
118
At very high flow rates or when gas flows through an irregular tube or orifice, flow tends to be more turbulent and resistance becomes proportional to _______________ of the gas and inversely proportional to _____________
the density
the radius (actually to the 5th power of the radius)
119
A dimensionless number that allows estimation of whether a flow is turbulent or laminar
Reynolds Number (velocity x diameter x density / viscosity)
120
Heliox
A combination of Helium and O2, (80%/20%) has a density approx. 0.33 that of air and 0.30 that of O2 .
Conditions of high turbulent flow in large airways due to a mass or edema, breathing a mixture of helium and oxygen (having a low Reynold’s Number) will decrease dyspnea for some patients.
Does not help in COPD or Asthma:
121
__________ release from mast cells and basophils is responsible for airway inflammation and bronchoconstriction in asthma
Histamine
122
ANTIHISTAMINES
Histamine release from mast cells and basophils is responsible for airway inflammation and bronchoconstriction in asthma
Not standard therapy for asthma. However using antihistamines and leukotrienes modifiers for allergen-induced bronchoconstriction has shown promise for diminishing early and late allergen responses
Allergen induced asthma or patients having an allergic reaction in the OR may benefit from antihistamines to attenuate the role that histamine plays in bronchconstriction.
123
Magnesium Sulfate
Not standard therapy for asthma exacerbations
Can be used as in nebulized form for bronchodilation.
Not a first line drug
Potential benefit when nebulized with a Beta-adrenergic agonists
124
The main principles of PHTN management are?
Reduce RV afterload
Preserve coronary perfusion
Avoid reduction in BP
125
Patients with PHTN have High risk for ________ and ______________surgeries.
High risk for cardiac and non-cardiac surgeries.
126
Patients with PHTN Have poor cardiorespiratory reserve and are at risk of pulmonary hypertension crisis resulting in
heart failure
respiratory failure
dysrhythmias
127
Primary goal of Pulmonary Vasodilators is?
reducing the consequences of an elevated pulmonary vascular resistance and the resulting RV dysfunction.
(Attempting to improve contractility of the RV are generally not effective)
128
An increase in PAP may be the result of
increased Peripheral Vascular Resistance (PVR)
increased CO
an increase in Left Arterial Pressure (LAP)
129
[PVR X CO] + LAP
PAP
130
N-methyl-D-aspartic acid (NMDA) receptor antagonist that also binds to opioid receptors and muscarinic receptors
Ketamine
131
Ketamine should be used with caution in patients with PHTN because?
It is thought to cause pulmonary vasoconstriction
132
Ketamine MOA
Not fully understood.
It is an N-methyl-D-aspartic acid (NMDA) receptor antagonist and also binds to opioid receptors and muscarinic receptors
Appears to stimulate release as well as inhibit neuronal uptake of catecholamines which may account for its cardiostimulatory and bronchodilatory effects.
133
The hemodynamic effects of a bolus of Ketamine can be attenuated or abolished with premedicants such as
droperidol, dexmedetomidine, or benzodiazepines.
134
The concern of using propofol in PHTN is?
The decrease in SVR which can effect intracardiac shunting (if present) and can lead to decreased in coronary artery perfusion of the RV resulting in RV dysfunction.
135
In animal studies have shown that during increased tone conditions in the pulmonary vasculature propofol may act as _______________?
a pulmonary vasoconstrictor.
136
Etomidate
Is an imidazole (2 of 5 atoms is Nitrogen) mediates clinical actions primarily at GGABA-A receptors
Appears to have vasorelaxant properties in isolated pulmonary arteries
Stable hemodynamic profile
Pts with cardiac disease: induction dose increases MAP, decreased SVR and decreased PAP
In Peds without PHTN no significant change in hemodynamics was shown with induction dose of etomidate.
137
In pts with cardiac disease etomidate induction dose will?
increases MAP
decreased SVR
decreased PAP
138
Nitrous oxide typically avoided in PHTN because?
It is believed to cause pulmonary vasoconstriction. This constriction may be release of catecholamines from sympathetic nerves supplying the pulmonary vasculature.
139
Rocuronium, Cisatracruium and Vecuronium have little to no effect on most cardiac indices in pts undergoing CABG. T/F
True
140
Magnesium use in PHTN
Vasodilator in both systemic and pulmonary circulations
MOA of mag ability to cause vasodilation is likely though its effects on membrane channels involved in calcium flux and through its action in the synthesis of cAMP.
Mag has been used with controversy to treat persistent PHTN of newborns
141
Thoracic Epidural Anesthesia (TEA) may decrease PAP through?
decreases in CO or attenuation of pulmonary sympathetic outflow.
142
TEA depresses ______ in acute PHTN
RV function
143
Unilateral thoracic paravertebral block with lidocaine has been shown to decrease _____________ up to _________% and significantly decrease systemic pressure. This may be attenuated by using epinephrine
myocardial contractility
30%
144
Decreases myocardial contractility up to 30% and significantly decrease systemic pressure.
Unilateral thoracic paravertebral block
145
Can patients with PHTN receive regional and TEA?
YES
Potential benefits outweighs risks of hypotension and RV dysfunction
Pts with PHTN, careful titration and monitoring must be done.
146
Neurotransmitter receptors of the pulmonary vasculature includes:
```
Adrenergic
Cholinergic
Dopaminergic
Histamine
Serotonin
Adenosine
Purines
peptides
```
147
Pulmonary vasculature
Sympathetic activation will generally result in an increase in PVR.
Administration of acetylcholine induces pulmonary relaxation.
Pts with chronic secondary PHTN undergoing anesthesia for cardiac surgery show norepinephrine and phenylephrine increase PAP and PVRI with minimal change in CI.
Norepinepherine decreases mPAP to MAP ratio but phenylephrine did not. This suggest phenylephrine may be a better choice of vasopressor
148
Vasodilator in PHTN
rapid onset
short half-life
produce regional pulmonary vasodilation
This would:
Avoid systemic hypotension
Avoid potential adverse effect on ventilation perfusion matching that limit use of systemic agents in critically ill pts
Therefore inhaled vasodilators are attractive as they preferentially dilate ventilated alveoli and have less systemic effects.
149
Ideal Pulmonary Vasodilator Should have
rapid onset
short half-life
produce regional pulmonary vasodilation
150
Dose of iNO is controversial but typical doses are?
10-40 ppm
151
Studies demonstrate NO reduces
need for extracorporeal membrane oxygenation (ECMO)
requirement for O2 therapy following ICU discharge
152
Methemoglobin levels need to be monitored when NO is administered for ?
more than 24 hours.
153
In theory, heart and lung transplant pts should benefit from NO due to
pulmonary vasodilation and related improvement of acute RV failure.
154
Prostaglandins actions are
relaxation of vascular smooth muscle
inhibition of growth of smooth muscle cells
powerful inhibition of platelet aggregation.
155
Epoprostenol
Prostaglandin delivered by nebulizer through a ventilator circuit.
It has a short T1/2 causing inefficiencies with nebulization.
156
Synthetic drugs such as prostanoids, treprostinil, and iloprost are
Prostaglandins being researched as vasodilators and may only required intermittent administration.
157
Prostacyclin can be delivered by nebulizer into a ventilator circuit at a starting dose of _________ with clinical effects evident within ________
50 ng/kg/min
10 minutes
158
Inhaled prostacyclin decreases ________with maintenance of favorable systemic pressures but does not change PaO2 during one lung ventilation (OLV)
PVRI and PAP
159
Prostaglandins and iNO have what in common
Both affect platelet function
Although clinical relevance of platelet inhibition with these inhaled agents is unknown, they could theoretically contribute to periop bleeding in large surgeries; also a concern with neuraxial analgesia
160
MOA of phosphodiesterase inhibitors
Phosphodiesterase inhibitors prevent the degradation of cGMP and cAMP which are activated by NO and are intermediaries in a pathway that leads to vasodilation.
This vasodilation is via the activation of protein kinases, and reduction in cytosolic calcium.
161
An adenosine-3’, 5’- cAMP-selective phosphodiesterase enzyme (PDE) inhibitor
Milrinone
162
Milrinone
Is an adenosine-3’, 5’- cAMP-selective phosphodiesterase enzyme (PDE) inhibitor
Milrinone nebulized has shown to lead to a relative reduction in PVR compared to SVR
Milrinone selectively dilates the pulmonary vasculature without systemic effects.
Milrinone (+) inhaled prostacyclin demonstrates a potentiation and prolongation of the pulmonary vasodilation effect.
163
Phosphodiesterase __________ have a higher expression in pulmonary circulation versus the systemic circulation and thus their inhibitors have a relative selective effect on PVR as opposed to SVR.
Phosphodiesterase 5 (PDE5)
164
________ have been demonstrated to enhance effects of NO and may blunt rebound pulmonary pressure that occur during weaning off of inhaled NO.
Sildenafil
165
All volatile anesthetics inhibit HPV in dose dependent fashion. Rank from the most to least inhibition.
halothane>enflurane>isoflurane/desflurane/sevoflurane
166
What is the effect of IV anesthetics on hypoxic pulmonary vasoconstriction
IV anesthetic agents have no effect on Hypoxic Pulmonary Vasoconstriction (HPV)
167
HPV
At 1 MAC ISO, SEVO, DES are weak and equipotent HPV inhibitors
Nitrous inhibits HPV and is usually avoided during thoracic anesthesia
HPV decreased by vasodilators such as NTG and Nitroprusside.
Thoracic epidural sympathetic blockade probably has little or no direct effect on HPV
Thoracic epidural anesthesia can have an indirect effect on O2 if hypotension is allowed and a fall in CO
168
Lungs
Receive essentially entire CO and has enormous vasculature bed surface area (70 – 100 m2 ).
Contain nearly half body’s endothelium
High perfusion of 14 ml/min/g tissue (next highest is renal at 4 ml/min/g tissue
169
Lung perfusion in ml/min/g
14 ml/min/g tissue
170
Pulmonary Uptake (or extraction)
is used to describe transfer from blood to lung: Does not indicate if the substance is metabolized for returned back to the blood with or without alteration.
171
First Pass Uptake
describes the amount of substance removed from the blood on the first cycle through the lungs
172
Clearance
describes a substance undergoing actual elimination
173
Lung Effects
Lungs has a pronounced impact on the blood concentration of substances even when does not secrete or break down these substances
Happens because of simple uptake and retention of substances, often followed by release back into the blood
Capacitor Effect: a rapid rise or fall in concentration is attenuated
174
Lungs found to have substantial concentration of Cytochrome P 450.
These are particularly located within?
Type II pneumocytes
Clara cells
Endothelial cells
175
The activity of Cytochrome P 450 in the lungs are very small to ______ % of that of the liver
33%
176
Compare first pass of opioids
Fentanyl has a first pass uptake of up to 90%.
Sufentanil demonstrates an first pass uptake a little more than half of Fentanyl
Morphine is about 10% first pass uptake
177
Lidocaine first pass
Lidocaine: first pass uptake is ~ 50% with significant retention at 10 minutes.
Lidocaine demonstrates increased uptake with higher blood pH.
178
Compare first pass of thiopental, ketamine and propofol
Thiopental ~ 15% first pass with little or no metabolism
Ketamine little less than 10% without metabolism
Propofol is thought to be 30% first pass and negligible metabolism by the lungs
179
The lungs play a critical role in renin-angiotensin system because?
High concentrations of angiotensin-converting enzyme (ACE) reside in the pulmonary endothelium.
180
Angiotensin formation
Kidney responds to changes in physiologic changes such as vascular volume, BP and adrenergic stimulation by the cleaving of prorenin, the resultant “renin” catalyzes the formation of angiotensin I from angiotensinogen.
ACE then converts angiotensin I to the vasoconstrictor angiotensin II
Angiotensin II is not taken up or further metabolized by the endothelial cell but immediately retuned to the blood.
Thus ACE inhibitors have been useful for systemic hypertension
181
Bradykinin is produced from_________ through the action of _______.
kininogen
plasma kallikrein
182
Bradykinins effects include:
Antithrombotic
Profibrinolytic activity in the coagulation s system
Modulation of NO and prostacyclin release
183
Bradykinins metabolism
Its metabolized by several petidases
184
Bradykinin eliminated
It is eliminated on first pass through the lungs
185
Bradykinin in Lung
Bradykinin has a vasodilating effect on normal pulmonary vessels
Bradykinin is vasoconstriction in destroyed pulmonary endothelium
Bradykinin is a bronchoconstrictor
Side Effects of ACE inhibitors such as angioedema, cough, and some of the benefits such as decreased MI and improved renal function all involve modification of bradykinin metabolism.
186
Norepinephrine demonstrates a ______to _____-% first-pass uptake. However, dopamine, isoproterenol, and epinephrine have essentially no uptake.
35% to 50%
187
Biogenic amines are composed of?
Histamine
Serotonin (5-hydroxytryptamine or 5-HT);
Three naturally occurring catecholamines dopamine, norepinephrine, and epinephrine
188
5-HT is produced predominately by.
the gastrointestinal tract’s chromaffin cells
189
Ingested tryptophan undergoes a two-step conversion which is?
first by tryptophan-5-hydroxylase and then by L-amino acid decarboxylase to serotonin.
190
Mast cells and neuroendocrine cells in the lung are also capable of producing serotonin by
uptake of tryptophan along the same enzymatic pathway.
191
Once released from the gastrointestinal tract, there is avid uptake of 5-HT, particularly by
nerve endings and platelets.
192
MAO inhibitors block the cytosolic metabolism of 5-HT but not its uptake, whereas several drugs, including volatile anesthetic agents, block __________
uptake but not intracellular metabolisms.
193
________ is a useful marker of carcinoid syndrome with increased histamine turnover.
5-HIAA
194
The pulmonary uptake of 5-HT by the lung is typically reported to be ___________ meaning that little 5-HT reaches the systemic vasculature under normal circumstances.
90% or greater
195
In carcinoid the reason that the right heart shows the greatest myocardial and valvular injury in this syndrome is?
the right heart receives a high concentration of 5-HT before being extracted and metabolized by the pulmonary circulation.
