Unit 4 Flashcards
Loading dose
(Vd x desired Cp)/ bioavailability
Bioavailability=1 when directly injected into blood stream
Vd
Amount of drug/desired plasma concentration
Assumes- drug is instantly available, no elimination before fully circulating
Distribution of H2O in 70 kg patient
TBW= 40L ECF= 14 L Plasma= 4 L Instestitial fluid= 10L ICF= 28L
Low Vd
Less than 0.6 L/kg or 42L Hydrophilic Not into fat Lower dose for higher plasma concentration Ex: NMB’s
High Vd
>0.6 L/kg or 42 L Lipophilic Distributes into fat Higher dose for plasma concentration Ex: prop
Clearance
Volume of plasma cleared per unit time
Directly proportional- clearing organ, extraction ratio, drug dose
Inversely proportional- half life, drug conc in central compartment
Steady state
Rate of administration=rate of elimination
Achieved after 5 half times
2 part compartment model
A- redistribution with steep slope, steeper slope=larger Vd=lipophilic, t 1/2 alpha
B- elimination, t 1/2 beta
Ionization and pharmacology
Water- hydrophilic, lipophilic Not active Less likely hepatic bio transformation More likely renal elimination Can’t diffuse across lipid bilayer (Opposite for unionized)
Acid and bases in solution
Acid wants to donate protons
Base wants to accept protons
Like dissolves like (are more unionized in like solution)
Weak acid in preparation
Paired with a positive ion
Ex: Na, Ca, Mg
Sodium thiopental
Weak base in perpetration
Paired with negative ion
Ex: chloride, sulfate
Lidocaine hydrochloride, morphine
Fetal ion trapping
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
Percent change
((New value-old value)/ old value) x 100
Albumin
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
A1 acid glycoprotein
Binds basic drugs
Increase- surgical stress, MI, chronic pain, RA, age
Decreased- neonates, pregnancy
Beta globulin
Binds basic drugs
Zero order kinetics
Constant amount of drug per time
More drug than enzyme
Linear graph
Ex: aspirin, phenytoin, alcohol, warfarin, heparin, theophylline
1st order kinetics
Constant fraction of drug per time
Less drug than enzyme
Logarithmic = curved graph
Majority of drugs are 1st order
Phase 1
Modification (oxidation, reduction, hydrolysis)
Increases polarity of molecule
Most carried out by P450 system
Phase 2
Conjugation
Adds on endogenous, highly polar, water soluble substrate to molecule
Enterohepatic circulation into bile happens after conjugation, ex: diazepam
Phase 3
Excretion/elimination
ATP dependent Carrie protons transport drugs across cell membranes
In kidney, liver, and GI tract
Goal of metabolism
Change a lipid soluble, pharmacologically active compound into a water soluble, pharmacologically inactive byproduct
Perfusion dependent hepatic elimination
ER > 0.7
Dependent on liver blood flow
Fentanyl, lidocaine, propofol
Capacity dependent hepatic elimination
ER < 0.3
Changes in hepatic enzyme activity or protein binding have profound impact on clearance
Diazepam, rocuronium
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
Cyp 3A4 drugs
Opioids- fent, alfent, student, methadone
Benzodiazepines- midazolam, diazepam
LAs- lido, bupi, topi
Cyp 3A inducers and inhibitors
Inducers- alcohol, rifampin, barbs, tamoxifen, carbamazepine, St. John’s wart
Inhibitors- grapefruit, cimetidine, erythromycin, anole antifungals, SSRI’s
CYP 2D6 drugs
Codeine to morphine
Oxycodone
Hydrocodone
CYP 2D6 inducers and inhibitors
Inducer- disulfiram
Inhibitors- isoniazid, SSRI’s, quinidine
Organic anion and cation transporters
In proximal renal tubules
OAT- lasix, thiazides, penicillin
OCT- morphine, meperidine, dopamine
Urine pH
AAA= acidic drugs are better absorbed in an acidic medium BBB= basic drugs are better absorbed in a basic medium
Altering urine pH
Acidifying urine- ammonium chloride and cranberry juic
Helps eliminate basic drugs
Alkalizing urine- sodium bicarb and acetazolamide
Helps eliminate acidic drugs
Pseudocholinesterase
Succ
Mivacurium
Ester LA’s
Nonspecific esterases
Remi
Esmolol (RBC esterase)
Etomidate
Atracurium
Alkaline phosphatase
Fospropofol
Hoffman elimination
Ph and temp dependent
Cisatracurium
Atracurium
Pharmacodynamics
Relationship between effect site concentration and clinical effect
What the drug does to the body
Pharmacokinetics
Relationship between drug dose and plasma concentration
What the body does to the drug
Pharmacobiophasics
PK and PD together
Relationship between plasma concentration and effect site concentration
Potency
Dose require to achieve a clinical effect
On X axis
Affected by absorption, distribution, metabolism, elimination, and receptor affinity
ED50 and ED90
Efficacy
Intrinsic ability of drug to elicit a clinical effect
On Y axis- heigh of plateau
Therapeutic index
LD 50/ED 50
Chirality
Typically tetrahedral bonding of carbon binding to 4 different atoms
Enantiomers
Chiral molecules that are non superimposable mirror images of each other
Meds prepared as single enantiomers
Levobupivacaine
Ropivacaine
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
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
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
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
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
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
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
Etomidate
GAGA a agonist
Dose: 0.2-0.4 mg/kg
P450 and plasma esterases- awakening due to redistribution
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
Etomidate and cortisol
Etomidate inhibits 11 beta hydroxylase (adrenal medulla) and 17 alpha hydroxylase
Suppresses adrenocortical function for 5-8 hours (up to 24)
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
Thiopental effects
Hotn, decreased preload, myocardial expression
Histamine release
Reflex tachycardia from baroreceptor
Respiratory depression an bronchoconstriction
Deceased CMRO2, CBF, ICP, EEG
No analgesia
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
Dexmedetomidine
Alpha 2 agonist
Loading dose : 1mcg/kg over 10 min
Maintenance: 0.4-0.7 mcg/kg/hr
P450
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
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
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
Diazepam
Enterohepatic recirculation
T 1/2 43 hours
Pain on injection due to propylene glycol
Lorazepam
6 hours
Slow onset so not useful as anticonvulsant
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
Alkylphenol
Prop, fosprop
Arlcyclohexlamine
Ketamine
Imidazole
Etomidate, dex
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
Vapor pressure
Pressure exerted by a vapor in equilibrium with its liquid or solid phase in closed container
Directly proportional to temp
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
Sevo physiochemical properties
Vapor pressure- 157 Boiling point- 59 Molecular weight (g)- 200 Unstable in CO2 absorber Forms compound A
Des physiochemical properties
Vapor pressure- 669 Boiling point- 22 Molecular weight (g)- 168 Stable in hydrated absorber Unstable in dehydrated absorber Carbon monoxide
Iso physiochemical properties
Vapor pressure- 238 mmHg Boiling point- 49 Molecular weight- 184 Stable in hydrated absorber Unstable in dehydrated absorber Carbon monoxide
N2O physiochemical properties
Vapor pressure- 38,770
Boiling point- -88
Molecular weight- 44
Stable in absorber
Solubility
Ability of gas to dissolve into blood and tissues
Polar solute= hydrophilic
Nonpolar solute= hydrophobic
Sevo solubility coefficients
Blood gas- 0.65
Oil gas- 47
Des solubility coefficients
Blood gas- 0.42
Oil gas- 19
Iso solubility coefficients
Blood gas- 1.46
Oil gas- 91
N2O solubility coefficients
Blood gas- 0.46
Oil gas- 1.4
FA/FI
FA= partial pressure of anesthetic inside the alveoli FI= concentration of anesthetic exiting vaporizer
Solubility and FA/FI
Low solubility —> less uptake in blood —> increased rate of rise —> faster equilibration of FA/FI —> faster onset
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
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
Uptake is dependent on:
Tissue blood flow
Solubility of anesthetic in the tissue
Arterial blood: tissue partial pressure gradient
Vessel rich group
CO= 75%, body mass=10%
Heart, brain, kidney, liver, endocrine glands
First to equilibrate with FA
Muscle and skin
CO= 20%, Body mass= 50%
Fat
CO= 5%, Body mass= 20%
High capacity to store large amounts due to lipid solubility of agents
Vessel poor group
CO < 1%, body mass=20%
Tendons, ligaments, cartilage, and bone
Doesn’t really contribute to uptake
How inhaled agents exit body
Elimination from lungs- exhalation
Hepatic biotransformation
Percutaneous loss- minimal, not clinically significant
Hepatic biotransformation numbers
DIS (alphabetical order), rule of 2’s
Des- 0.02%
Iso- 0.2%
Sevo: 2-5%
Nitrous- 0.004%
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
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
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
Concentration effect
Concentrating effect
Augmented gas flow
Concentrating effect
Higher concentration of agent to alveolus = faster onset
Only relevant with N2O
Concentrating effect and augmented gas inflow
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
Ventilation effect
Greater alveolar ventilation leads to greater Fa/Fi rise
Spontaneous ventilation- alveolar ventilation decreased with deepening anesthetic depth, protective mechanism
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
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
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
R to L shunt examples
Tetralogy of Fallot Foramen ovale Eisenmengers syndrome Tricuspid atresia Epstein’s anomaly
Left to right shunt
Volatiles- no meaningful effect
IV agents- slow IV induction, agent recirculates to lungs
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
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
N2O and vitamin B12
Irreversibly inhibits B12 which inhibits methionine synthase (required for folate metabolism and myelin)
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
Increasing MAC
Chronic alcohol use Increased CNS neurotransmitters- acute meth, acute cocaine, MAOIs, ephedrine, levodopa Hypernatremia Infants 1-6 months Hyperthermia Red hair
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
No effect on MAC
K changes Mag changes Thyroid changes Gender PaCO2 15-95 Htn
Meyer Overton rule
Lipid solubility directly proportional to potency of inhaled anesthetic
Greater solubility = lower MAC
Unitary hypothesis
All anesthetics share similar MOA but may work at different site
Inhalation agent stimulation and inhibition
Stimulates inhibitory pathways- GABA A, glycine, K
Inhibits stimulatory pathways- NMDA, nicotinic, Na, dendritic spine function and motility
Volatiles in brain
GABA A
Stimulates it
Increas Cl influx and hyperpolarizes neurons
Volatiles in SC
Immobility in ventral horn
Glycine, NMDA, and Na
N2O and xenon receptors
NMDA antagonism
K 2P channel stimulation
Blood pressure
Decreased dose dependently
Decreased intraceullar Ca in vascular smooth muscle
Sevo causes least SVR decrease
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
Contractility
Small decrease but preload responsive
Coronary vascular resistance
Increases blood flow in excess of O2 demand
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
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
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
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
PaO2 changes
Impaired chemoreceptor response for several hours
Greatest biotransformation impacts hypoxic drive the most (halothane>sevo>iso>des)
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
SSEP
Integrity of dorsal column (medial leminiscus)
Perfused by posterior spiral arteries
MEPs
Monitor corticospinal tract
Perfused by anterior spinal artery
Components of monitored potentials
Amplitude- strength of response
Latency- speed of conduction
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
Brain auditory and visual evoke
Brain auditory- most resistant to anesthetics
Visual- most sensitive
