Unit 4 Flashcards
(132 cards)
1
Q
Loading dose
A
(Vd x desired Cp)/ bioavailability
Bioavailability=1 when directly injected into blood stream
2
Q
Vd
A
Amount of drug/desired plasma concentration
Assumes- drug is instantly available, no elimination before fully circulating
3
Q
Distribution of H2O in 70 kg patient
A
TBW= 40L ECF= 14 L Plasma= 4 L Instestitial fluid= 10L ICF= 28L
4
Q
Low Vd
A
Less than 0.6 L/kg or 42L Hydrophilic Not into fat Lower dose for higher plasma concentration Ex: NMB’s
5
Q
High Vd
A
>0.6 L/kg or 42 L Lipophilic Distributes into fat Higher dose for plasma concentration Ex: prop
6
Q
Clearance
A
Volume of plasma cleared per unit time
Directly proportional- clearing organ, extraction ratio, drug dose
Inversely proportional- half life, drug conc in central compartment
7
Q
Steady state
A
Rate of administration=rate of elimination
Achieved after 5 half times
8
Q
2 part compartment model
A
A- redistribution with steep slope, steeper slope=larger Vd=lipophilic, t 1/2 alpha
B- elimination, t 1/2 beta
9
Q
Ionization and pharmacology
A
Water- hydrophilic, lipophilic Not active Less likely hepatic bio transformation More likely renal elimination Can’t diffuse across lipid bilayer (Opposite for unionized)
10
Q
Acid and bases in solution
A
Acid wants to donate protons
Base wants to accept protons
Like dissolves like (are more unionized in like solution)
11
Q
Weak acid in preparation
A
Paired with a positive ion
Ex: Na, Ca, Mg
Sodium thiopental
12
Q
Weak base in perpetration
A
Paired with negative ion
Ex: chloride, sulfate
Lidocaine hydrochloride, morphine
13
Q
Fetal ion trapping
A
Fetal pH= slightly acidotic Weak base (LA) is mostly unionized in mom Travels into baby and becomes ionized in acidic fetus Cause my maternal ALKALOSIS and fetal ACIDOSIS
14
Q
Percent change
A
((New value-old value)/ old value) x 100
15
Q
Albumin
A
Most plasma protein Determines plasma oncotic pressure T 1/2 = 3 weeks - charge Binds acidic drugs mostly Decreased- liver and renal disease, old age, malnutrition, pregnancy
16
Q
A1 acid glycoprotein
A
Binds basic drugs
Increase- surgical stress, MI, chronic pain, RA, age
Decreased- neonates, pregnancy
17
Q
Beta globulin
A
Binds basic drugs
18
Q
Zero order kinetics
A
Constant amount of drug per time
More drug than enzyme
Linear graph
Ex: aspirin, phenytoin, alcohol, warfarin, heparin, theophylline
19
Q
1st order kinetics
A
Constant fraction of drug per time
Less drug than enzyme
Logarithmic = curved graph
Majority of drugs are 1st order
20
Q
Phase 1
A
Modification (oxidation, reduction, hydrolysis)
Increases polarity of molecule
Most carried out by P450 system
21
Q
Phase 2
A
Conjugation
Adds on endogenous, highly polar, water soluble substrate to molecule
Enterohepatic circulation into bile happens after conjugation, ex: diazepam
22
Q
Phase 3
A
Excretion/elimination
ATP dependent Carrie protons transport drugs across cell membranes
In kidney, liver, and GI tract
23
Q
Goal of metabolism
A
Change a lipid soluble, pharmacologically active compound into a water soluble, pharmacologically inactive byproduct
24
Q
Perfusion dependent hepatic elimination
A
ER > 0.7
Dependent on liver blood flow
Fentanyl, lidocaine, propofol
25
Capacity dependent hepatic elimination
ER < 0.3
Changes in hepatic enzyme activity or protein binding have profound impact on clearance
Diazepam, rocuronium
26
extraction ratio
How much drug is delivered and how much is removed by that organ
(Arterial concentration- venous concentration)/arterial concentration
1 means 100% of what is delivered is being cleared
0.5 means 50% of what is being delivered is being cleared
27
Cyp 3A4 drugs
Opioids- fent, alfent, student, methadone
Benzodiazepines- midazolam, diazepam
LAs- lido, bupi, topi
28
Cyp 3A inducers and inhibitors
Inducers- alcohol, rifampin, barbs, tamoxifen, carbamazepine, St. John’s wart
Inhibitors- grapefruit, cimetidine, erythromycin, anole antifungals, SSRI’s
29
CYP 2D6 drugs
Codeine to morphine
Oxycodone
Hydrocodone
30
CYP 2D6 inducers and inhibitors
Inducer- disulfiram
| Inhibitors- isoniazid, SSRI’s, quinidine
31
Organic anion and cation transporters
In proximal renal tubules
OAT- lasix, thiazides, penicillin
OCT- morphine, meperidine, dopamine
32
Urine pH
```
AAA= acidic drugs are better absorbed in an acidic medium
BBB= basic drugs are better absorbed in a basic medium
```
33
Altering urine pH
Acidifying urine- ammonium chloride and cranberry juic
Helps eliminate basic drugs
Alkalizing urine- sodium bicarb and acetazolamide
Helps eliminate acidic drugs
34
Pseudocholinesterase
Succ
Mivacurium
Ester LA’s
35
Nonspecific esterases
Remi
Esmolol (RBC esterase)
Etomidate
Atracurium
36
Alkaline phosphatase
Fospropofol
37
Hoffman elimination
Ph and temp dependent
Cisatracurium
Atracurium
38
Pharmacodynamics
Relationship between effect site concentration and clinical effect
What the drug does to the body
39
Pharmacokinetics
Relationship between drug dose and plasma concentration
| What the body does to the drug
40
Pharmacobiophasics
PK and PD together
| Relationship between plasma concentration and effect site concentration
41
Potency
Dose require to achieve a clinical effect
On X axis
Affected by absorption, distribution, metabolism, elimination, and receptor affinity
ED50 and ED90
42
Efficacy
Intrinsic ability of drug to elicit a clinical effect
| On Y axis- heigh of plateau
43
Therapeutic index
LD 50/ED 50
44
Chirality
Typically tetrahedral bonding of carbon binding to 4 different atoms
45
Enantiomers
Chiral molecules that are non superimposable mirror images of each other
46
Meds prepared as single enantiomers
Levobupivacaine
| Ropivacaine
47
Examples of enantiomers being different
S-bupivacaine (levobupivacaine) less cardiotoxic than R or racemic mixture
S ketamine is less likely to cause emergence delirium than R- also more potent
48
Propofol
GABA A agonist
Induction: 1.5-2.5 mg/kg IV
Infusion: 25-200 mcg/kg/min
Liver P450 and extra hepatic clearance in lungs
Antipruiritic and anti emetic (10-20 mg with 10mcg/kg/min inf)
Generic preparation can cause bronchospasm
49
Prop effects
```
Decreased BP, SVR, contractility
Less sensitive to CO2
Decreased CMRO2, CBF, ICP, IOP
No analgesia
Green urine= phenol excretion
Cloudy urine= uric acid excretion
```
50
Propofol infusion syndrome
Increased long chain triglycerides impairs oxidative phosphorylation and fatty acid metabolism
Acute refractory bradycardia to asystole and one of these: met acidsosis, rhabdo, enlarged/fatty liver, renal failure, hyperlipidemia, lipemia
Prop dose > 4 mg/kg/hr for >48 hours
More in kids
51
Fospropofol
Aqueous solution- no burning or lipid bacteria growth
Prodrug- converted to prop by alkaline phosphatase
Slower and longer DOA
Bolus: 6.5 mg/kg
repeat bolus: 1.6 mg/kg not more than q4m
Causes genital/anal burning
52
Ketamine
NMDA antagonist
Racemic mixture
IV: induction 1-2 mg/kg, maintenance 1-3mg/min
IM: 4-8 mg/kg
P.O.: 10mg/kg
Liver P450 metabolism- induces its own metabolism
Norketamine- Active metabolite, less active, renal excretion
53
Ketamine effects
Increased SNS tone, CO, HR, SR, PVR- all effects from an intact SNS, depleted catecholamines= myocardial depressant
Bronchodilation, maintains resp drive, increased secretions
Increased CMrO2, CGF, ICP, IOP, EEG, nystagmus, emergence delirium
Relieves somatic pain
Off label depression use
Very little protein binding
54
Etomidate
GAGA a agonist
Dose: 0.2-0.4 mg/kg
P450 and plasma esterases- awakening due to redistribution
55
Etomidate effects
```
Hemodynamics stability
Mild resp dep
Decreased CMRO2, CBF, ICP
CPP same
No analgesia
Myoclonus- increased risk of seizures in patients with seizure history
PONV
```
56
Etomidate and cortisol
Etomidate inhibits 11 beta hydroxylase (adrenal medulla) and 17 alpha hydroxylase
Suppresses adrenocortical function for 5-8 hours (up to 24)
57
Thiopental
```
Barbiturate
Water soluble, highly alkaline
GABA A agonist
Dose: adult 2.5-5 mg/kg, kid 5-6 mg/kg
P450- awakening due to redistribution
```
58
Thiopental effects
Hotn, decreased preload, myocardial expression
Histamine release
Reflex tachycardia from baroreceptor
Respiratory depression an bronchoconstriction
Deceased CMRO2, CBF, ICP, EEG
No analgesia
59
Acute intermittent porphyria
Defect in heme synthesis that promotes accumulation of heme precursors- due to induction of ALA synthase in heme precursor production
S/S: abdominal pain, psych symptoms, delirium, seizures, neuropathy, coma
Drugs to avoid (induce ALA synthase)- barbs, etomidate, glucocorticoids, hydralazine
Glucose and heme arginine reduce ALA synthase activity
60
Dexmedetomidine
Alpha 2 agonist
Loading dose : 1mcg/kg over 10 min
Maintenance: 0.4-0.7 mcg/kg/hr
P450
61
Dexmedatomidine effects
Bradycardia, hotn
Rapid administration—> htn from alpha 2 stim, short lived
No respiratory depression
Decreased CBF, no CMRO2 or ICP changes
Resembles natural sleep
Antishivering effect
Analgesia- alpha 2 stim in dorsal horn of SC
62
Midazolam
Imidazole IMG- opens and increases water solubility in acidic pH
GABA a agonist- increases frequency of channel opening
1st pass metabolism=50% bioavailability
P450
1 hydroxymidazolam= active metabolism, 1/2 potency, prolonged in renal failure
63
midazolam effects
Minimal with sedation, decreased BP and SVR with induction dose
Minimal resp with sedation, resp dep with induction dose (potentiated with opioids)
Anterograde amnesia
Anticonvulsant
No analgesia
64
Diazepam
Enterohepatic recirculation
T 1/2 43 hours
Pain on injection due to propylene glycol
65
Lorazepam
6 hours
| Slow onset so not useful as anticonvulsant
66
Flumazenil
```
Competitive GABA a receptor antagonist
Reverses benzo overdose
Initial dose:0.2 mg IV
Titration in 0.1 dose increments
Short DOA (30-60 min)
Reverses sedative more than amnestic effects
```
67
Alkylphenol
Prop, fosprop
68
Arlcyclohexlamine
Ketamine
69
Imidazole
Etomidate, dex
70
Identifying volatiles
Iso- 5 fluorine and 1 chlorine (increases potency), chiral carbon, methyl ethyl ether
Des- 6 fluorines, chiral carbon, fully fluorinated, methyl ethyl ether
Sevo- 7 fluorines, no chiral carbon, methyl isopropyl ether
71
Vapor pressure
Pressure exerted by a vapor in equilibrium with its liquid or solid phase in closed container
Directly proportional to temp
72
Partial pressure
Vol% x total gas pressure= partial pressure of gas
Determines depth of anesthesia, NOT vol percent
Leads to under dosing of des above sea level
73
Sevo physiochemical properties
```
Vapor pressure- 157
Boiling point- 59
Molecular weight (g)- 200
Unstable in CO2 absorber
Forms compound A
```
74
Des physiochemical properties
```
Vapor pressure- 669
Boiling point- 22
Molecular weight (g)- 168
Stable in hydrated absorber
Unstable in dehydrated absorber
Carbon monoxide
```
75
Iso physiochemical properties
```
Vapor pressure- 238 mmHg
Boiling point- 49
Molecular weight- 184
Stable in hydrated absorber
Unstable in dehydrated absorber
Carbon monoxide
```
76
N2O physiochemical properties
Vapor pressure- 38,770
Boiling point- -88
Molecular weight- 44
Stable in absorber
77
Solubility
Ability of gas to dissolve into blood and tissues
Polar solute= hydrophilic
Nonpolar solute= hydrophobic
78
Sevo solubility coefficients
Blood gas- 0.65
| Oil gas- 47
79
Des solubility coefficients
Blood gas- 0.42
| Oil gas- 19
80
Iso solubility coefficients
Blood gas- 1.46
| Oil gas- 91
81
N2O solubility coefficients
Blood gas- 0.46
| Oil gas- 1.4
82
FA/FI
```
FA= partial pressure of anesthetic inside the alveoli
FI= concentration of anesthetic exiting vaporizer
```
83
Solubility and FA/FI
Low solubility —> less uptake in blood —> increased rate of rise —> faster equilibration of FA/FI —> faster onset
84
Increased FA/FI
Faster onset and curved pushed up
High FGF and alveolar ventilation
Low FRC, time constant, and anatomic dead space
Low solubility, CO, and Pa-Pv difference
85
Decreased FA/FI
Slower onset and curve pushed down
Low FGF and alveolar ventilation
High FRC, time constant, anatomic dead space
High solubility, CO, and Pa-Pv difference
86
Uptake is dependent on:
Tissue blood flow
Solubility of anesthetic in the tissue
Arterial blood: tissue partial pressure gradient
87
Vessel rich group
CO= 75%, body mass=10%
Heart, brain, kidney, liver, endocrine glands
First to equilibrate with FA
88
Muscle and skin
CO= 20%, Body mass= 50%
89
Fat
CO= 5%, Body mass= 20%
| High capacity to store large amounts due to lipid solubility of agents
90
Vessel poor group
CO < 1%, body mass=20%
Tendons, ligaments, cartilage, and bone
Doesn’t really contribute to uptake
91
How inhaled agents exit body
Elimination from lungs- exhalation
Hepatic biotransformation
Percutaneous loss- minimal, not clinically significant
92
Hepatic biotransformation numbers
DIS (alphabetical order), rule of 2’s
Des- 0.02%
Iso- 0.2%
Sevo: 2-5%
Nitrous- 0.004%
93
Liver metabolism halogenated agents
P450 system- CYP2E1
Des and iso- metabolized to inorganic fluoride ions and trifluoroacetic acid (TFA)
Halothane- up to 40% liver metabolism —> halothane hepatitis (immune mediated)
Sevo- metabolized to inorganic fluoride ions (no TFA), concerns of high output renal failure
94
High output renal failure
Comes from sevo metabolism
Unresponsive to vaso
S/S- polyuria, hypernatremia, hyperosmolarity, increased plasma creatinine, inability to concentrate urine
Doesn’t actually happen
95
Sodalime and breakdown of halogenated anesthetics
Sevo- compound A in soda lime, desiccated soda lime increases production
Des and iso- carbon monoxide in desiccated soda lime
96
Concentration effect
Concentrating effect
| Augmented gas flow
97
Concentrating effect
Higher concentration of agent to alveolus = faster onset
Only relevant with N2O
Concentrating effect and augmented gas inflow
98
Augmented gas flow
Breath after concentrating effect has increased anesthetic in tracheal gas to replace lost alveolar volume
Causes increased alveolar ventilation and augments FA
Temporary
99
Ventilation effect
Greater alveolar ventilation leads to greater Fa/Fi rise
| Spontaneous ventilation- alveolar ventilation decreased with deepening anesthetic depth, protective mechanism
100
2nd gas effect
Rapid uptake of N2O
Alveolus shrinks and alveolar volume decreases
Relative increase in concentration of 2nd gas
Other gas concentration is higher than if it was given alone
Transient
101
Diffusion hypoxia
Large volume of N2O from body into alveoli quickly
Dilutes O2 and CO2- causes temporary diffusion hypoxia and hypocarbia
100% O2 for 3-5 min when N2O turned off
102
Right to left shunt
Blood leaving R heart bypasses lungs - doesn’t pick up O2 or inhalation agent
Volatiles- lower solubility agents more affected, desflurane impacted most
IV agents- faster IV induction, blood bypasses lungs and travels to brain faster
103
R to L shunt examples
```
Tetralogy of Fallot
Foramen ovale
Eisenmengers syndrome
Tricuspid atresia
Epstein’s anomaly
```
104
Left to right shunt
Volatiles- no meaningful effect
| IV agents- slow IV induction, agent recirculates to lungs
105
Nitrous in closed air spaces
N20 34x more soluble than N2
Compliant airspace- N2O increases volume, will convert to a fixed airspace
Fixed airspace- increases pressure of space
106
Ocular bubbles
SF6- discontinue N2O 15 min before, avoid for 7-10 days after
Air- avoid for 5 days
Perfluoropropane- 30 days
Silicone- can use N2O
107
N2O and vitamin B12
Irreversibly inhibits B12 which inhibits methionine synthase (required for folate metabolism and myelin)
108
MAC
Measure of potency
MAC awake- 0.4-0.5, where patient can open their eyes, typically where awareness is prevented
Mac bar- 1.5 MAC, block autonomic response
109
Increasing MAC
```
Chronic alcohol use
Increased CNS neurotransmitters- acute meth, acute cocaine, MAOIs, ephedrine, levodopa
Hypernatremia
Infants 1-6 months
Hyperthermia
Red hair
```
110
Decreasing MAC
```
Acute alcohol intoxication
IV anesthetics
N2O
Opioids
Alpha. Agonists
Lithium
Lido
Hydroxyzine
Hyponatremia
Old age (6% per decade after 40)
Prematurity
Hypothermia
Hotn
Hypoxia/anemia
Bypass
Met acidosis
Pregnancy
PaCO2 > 95 mmHg
```
111
No effect on MAC
```
K changes
Mag changes
Thyroid changes
Gender
PaCO2 15-95
Htn
```
112
Meyer Overton rule
Lipid solubility directly proportional to potency of inhaled anesthetic
Greater solubility = lower MAC
113
Unitary hypothesis
All anesthetics share similar MOA but may work at different site
114
Inhalation agent stimulation and inhibition
Stimulates inhibitory pathways- GABA A, glycine, K
| Inhibits stimulatory pathways- NMDA, nicotinic, Na, dendritic spine function and motility
115
Volatiles in brain
GABA A
Stimulates it
Increas Cl influx and hyperpolarizes neurons
116
Volatiles in SC
Immobility in ventral horn
| Glycine, NMDA, and Na
117
N2O and xenon receptors
NMDA antagonism
| K 2P channel stimulation
118
Blood pressure
Decreased dose dependently
Decreased intraceullar Ca in vascular smooth muscle
Sevo causes least SVR decrease
119
Heart rate
Direct decrease dose dependently- decreased SA node automaticity and conduction velocity, increased repolarization time cause prolonged QT
Des (and iso) can increase heart rate- pulmonary irritation causing SNS activation
N2O activates SNS and increases HR
120
Contractility
Small decrease but preload responsive
121
Coronary vascular resistance
Increases blood flow in excess of O2 demand
122
Coronary seal
With increased O2 demand, vessels dilate
O2 extraction ratio= 75% so increase blood flow to increase O2
Stenotic vessels maximally dilated beyond stenosis- cant dilate further
Directs blood flow towards healthy tissue at expense of diseased tissue
Example of revere Robin Hood effect
123
Pulmonary effects of volatiles
```
Decreased TV
Increased RR
Decreased response to CO2 and increased apneic threshold (usually 3-5 mmHg below patients normal PaCO2)
Upper airway obstruction
Decreased FRC
Bronchodilators
```
124
CO2 response curve
Right shift- MV les than predicted for given PaCO2 (respiratory acidosis), ex: GA, opioids, metabolic alkalosis
L shift- MV greater than predicted for given PaCO2 (respiratory alkalosis), ex: anxiety, stimulation metabolic alkalosis, increased ICP
125
PaO2 sensing
Peripheral chemoreceptors in carotid bodies- monitor for hypoxemia
Carotid bodies- glossopharygeal nerve, sensitive to change in arterial gas tensions
Aortic bodies- vagus nerve, sensitive to BP changes
126
PaO2 changes
Impaired chemoreceptor response for several hours
| Greatest biotransformation impacts hypoxic drive the most (halothane>sevo>iso>des)
127
Neurological effects
Reduce CMRO2 (N2O increases it)
Sevo can produce seizure activity- more with hypocapnia and peds inhalation inductions
increased CBF, blood volume, and ICP
cerebral autoregulation normally 50-150mmHG, decreased in dose dependent fashion so CBF dependent on BP
128
SSEP
Integrity of dorsal column (medial leminiscus)
| Perfused by posterior spiral arteries
129
MEPs
Monitor corticospinal tract
| Perfused by anterior spinal artery
130
Components of monitored potentials
Amplitude- strength of response
| Latency- speed of conduction
131
Monitored potential changes with agents
Decreased amplitude- by 50%
Increase latency- by 10%
TIVA
Less than 0.5 MAC agent with no N2O
No muscle relaxants with MEPs
132
Brain auditory and visual evoke
Brain auditory- most resistant to anesthetics
| Visual- most sensitive
