Unit 4: Pharmacology 1 Flashcards
What is volume of distribution? How is it calculated?
Volume of distribution (Vd): relationship between a drug’s plasma concentration following a specific dose
-theoretical measure of how a drug distributes throughout the body
Vd = amount of drug / desired plasma concentration
It assumes two things:
- drug distributes instantaneously (full equilibration occurs at t = 0)
- drug is not subjected to biotransformation or elimination before it fully distributes
What are the implications when a drug’s Vd exceeds TBW? What if Vd is less than TBW?
If Vd > TBW (>0.6 L/kg or >42 L) – drug is assumed to be lipophilic
- distributes into TBW + fat
- requires higher dose to achieve a given plasma concentration
- ex: propofol, fentanyl
If Vd < TBW (<0.6 L/kg or <42 L) – drug is assumed to be hydrophilic
- distributes into some or all of the body water, but doesn’t distribute into fat
- requires a lower dose to achieve a given plasma concentration
- ex: NMBs (ECF), albumin (plasma)
How do you calculate the loading dose for an IV medication? How about a PO medication?
Loading Dose = Vd x Desired Plasma Concentration / Bioavailability
For IV Drug: bioavailability is always 1 (all of the drug enters the bloodstream)
For PO Drug: bioavailability will be less than 1
*any other route than IV may not be absorbed completely and/or may be subject to first-pass metabolism in the liver – reduce bioavailability
What is clearance? What factors increase/decrease it?
Clearance = volume of plasma that is cleared of a drug per unit of time
Directly proportional to:
- blood flow to cleaning organ
- extraction ratio
- drug dose
Inversely proportional to:
- half life
- drug concentration in the central compartment
What is steady state? How many 1/2-times does it take to occur?
Occurs when the amount of drug entering the body is equivalent to the amount of drug eliminated from the body – Stable Plasma Concentration
-each of the compartments has equilibrated
**Achieved after 5 half-times
Describe the alpha- and beta distribution phases on the plasma concentration curve
Alpha Distribution Phase:
- describes drug distribution from the plasma to the tissues
Beta Distribution Phase:
- begins as plasma concentration falls below tissue concentration
- concentration gradient reverses, which causes the drug to re-enter the plasma
- describes drug elimination from the central compartment
**plasma concentration curve graphically depicts the biphasic decrease of a drug’s plasma concentration following a rapid IV bolus
What percentage of initial drug dose REMAINS in the blood after each half-life?
0 half-time = 100% 1 half-time = 50% (50% eliminated) 2 half-time = 25% (75% eliminated) 3 half-time = 12.5% (87.5% eliminated) 4 half-time = 6.25% (93.75% eliminated) 5 half-time = 3.125% (96.875% eliminated)
What is context sensitive half-time?
It is the time required for the plasma concentration to decline by 50% after discontinuing the drug
Discuss the context sensitive half-time of fentanyl, alfentanil, sufentanil, and remifentanil. Which has the longest? Which has the shortest, why?
Longest = Fentanyl (context sensitive half-time for an infusion increases as a function of how long it was infused)
-also true for alfentanil and sufentanil
Shortest = Remifentanil (it is quickly metabolized by plasma esterases so it has a similar context sensitive half-time regardless of time infused)
What is the difference between a strong and weak acid or base?
Difference is the degree of ionization
- if you put a strong acid or strong base in water it will ionize completely
- if you put a weak acid or weak base in water a fraction will be ionized and the remaining fraction will be non-ionized
*acid donates a proton – base accepts a proton
What i s ionization? What 2 factors determine how much a molecule will ionize?
Ionization describes the process where a molecule gains a positive or negative charge
Amount of ionization is dependent on:
- pH of the solution
- pKa of the drug
What occurs when pKa and Ph are the same?
50% of the drug is ionized and 50% is non-ionized
How does ionization affect solubility?
Ionized = Water Soluble
- hydrophilic
- lipophobic
Non-Ionized = Lipid Soluble
- lipophilic
- hydrophobic
How does ionization affect a drugs pharmacologic effect?
Ionized = Not Active
Non-Ionized = Active
How does ionization affect hepatic biotransformation?
Ionized – hepatic biotransformation is LESS likely
Non-Ionized – hepatic biotransformation is MORE likely
How does ionization affect diffusion across lipid bilayer?
Ionized: does not cross blood brain barrier, GI tract, or Placenta
Non-Ionized: does cross blood brain barrier, GI tract, and Placenta
What is the basic rule about acids and bases being put in acidic and basic solutions?
- In ACIDIC solution, weak BASES are more IONIZED and water-soluble
- In BASIC solution, weak BASES are more NON-IONIZED and lipid soluble
- In ACIDIC solution, weak ACIDS are more NON-IONIZED and lipid soluble
- In a BASIC solution, weak ACIDS are more IONIZED and water-soluble
How can you tell if a drug is an acid or a base by looking at its name?
Most drugs are weak acids or bases and usually prepared as a salt that dissociates in solution
- Weak acid is paired with a positive ion such as sodium, calcium, or magnesium
- Weak base is paired with a negative ion such as chloride or sulfate
What are the three key plasma proteins? Does each bind acidic drugs, basic drugs, or both?
- Albumin: primarily binds to acidic drugs (also binds to some neutral and basic drugs)
- Alpha1-acid Glycoprotein: binds to basic drugs
- Beta-globulin: binds to basic drugs
What conditions reduce the serum albumin concentration? (5)
- Liver disease
- Renal disease
- Old age
- Malnutrition
- Pregnancy
What conditions increase alpha1-acid glycoprotein concentration? (5)
- Surgical stress
- Myocardial infarction
- Chronic pain
- Rheumatoid arthritis
- Advanced age
What conditions decrease alpha1-acid glycoprotein concentration? (2)
- Neonates
- Pregnancy
How do changes in plasma protein binding affect plasma drug concentration?
Decreased PP Binding –> Increased Cp
Increased PP Binding –> Decreased Cp
How do you calculate changes in plasma protein binding?
[Free Drug] + [Unbound Protein Binding Sites] [Bound Drug]
- if a drug is 98% bound and the bound fraction reduces to 96%, the unbound or free fraction has increased by 100% (free fraction went from 2% to 4%)
*Calculate the percent change to complete the calculation
% change = [(New Value - Old Value) / Old Value] x 100
What is first-order kinetics?
A constant FRACTION of drug is eliminated per unit of time
- drug is cleared from the body at a rate proportional to its plasma concentration
- Most drugs follow this model
What is zero order kinetics? What drugs follow this?
A constant AMOUNT of drug is eliminated per unit time
- describes the situation where there is more drug than enzyme
- rate of elimination is independent of plasma drug concentration
ex) Aspirin, Phenytoin, Warfarin, Heparin, and Theophylline
What is the function of a phase 1 reaction?
Phase 1 reactions result in small molecular changes that increase polarity (water solubility) of a molecule to prepare it for a phase 2 reaction
-most phase 1 biotransformation are carried out by the P450 system
What are the three phase 1 reactions?
Oxidation: removes electrons from a compound
Reduction: adds electrons to a compound
Hydrolysis: adds water to a compound to split it apart (usually an ester)
What is the function of a phase 2 reaction? List 5 common substrates
Phase 2 reaction conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule – results in a water soluble, biologically inactive molecule ready for excretion
Typical Substrates:
- Glucuronic acid
- Glycine
- Acetic acid
- Sulfuric acid
- Methyl group
What is enterohepatic circulation?
Some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation
Ex: Diazepam and Warfarin
What is the extraction ratio?
A measure of how much drug is delivered to a clearing organ vs how much drug is removed by that organ
- ER of 1 means that the clearing organ removes 100% of the delivered drug
- ER of 0.5 means that the clearing organ removes 50% of the delivered drug
How do you calculate the extraction ratio?
ER = (Arterial Concentration - Venous Concentration) / Arterial Concentration
Regarding hepatic clearance, what is PERFUSION-dependent elimination?
For a drug with a high hepatic extraction ratio (>0.7), clearance is dependent on liver blood flow
- hepatic blood flow greatly exceeds enzymatic activity, so alterations in hepatic enzyme activity has little effect
- increased liver blood flow = increased clearance
- decreased liver blood flow = decreased clearance
Regarding hepatic clearance, what is CAPACITY-dependent elimination?
For a drug with a low hepatic extraction ratio (<0.3), clearance is dependent on the ability of the liver to extract the drug from the blood
- changes in hepatic enzyme activity or protein binding have a profound impact on the clearance of these drugs
- since only a small amount of drug is removed per unit time, alterations in liver blood flow minimally affect clearance
- Enzyme induction = Increased clearance
- Enzyme inhibition = Decreased clearance
Which drugs have a low hepatic extraction ratio? (7)
- Rocuronium
- Diazepam
- Lorazepam
- Methadone
- Thiopental
- Theophylline
- Phenytoin
*affected by CYP activity
Which drugs have a intermediate hepatic extraction ratio? (4)
- Midazolam
- Vecuronium
- Alfentanil
- Methohexital
Which drugs have a high hepatic extraction ratio? (15)
- Fentanyl
- Sufentanil
- Morphine
- Meperidine
- Naloxone
- Ketamine
- Propofol
- Lidocaine
- Bupivacaine
- Metoprolol
- Propranolol
- Alprenolol
- Nifedipine
- Diltiazem
- Verapamil
What is the difference between a hepatic enzyme inducer and enzyme inhibitor? List examples of each.
Enzyme Inducer: increase clearance, decrease drug plasma level, and dose increase may be requires
- ex: tobacco smoke, barbituates, ethanol, phenytoin, rifampin, carbamazepine
Enzyme Inhibitor: decrease clearance, increase drug plasma level, and dose decrease may be required
- ex: grapefruit juice, cimetidine, omeprazole, isoniazid, SSRIs, erythromycin, ketoconazole
What two drug classes and seven drugs are metabolized by pseudocholinesterase?
Some Neuromuscular Blockers:
- SUX
- Mivacurium
Ester-Type Local Anesthetics:
- Chloroprocaine
- Tetracaine
- Procaine
- Benzocaine
- Cocaine (also metabolized by the liver)
What six drugs are metabolized by non-specific plasma esterases?
- Esmolol
- Remifentanil
- Remimazolam
- Clevidipine
- Atracurium (and Hofmann elimination)
- Etomidate (and hepatic)
What drug is biotransformed by alkaline phosphatase hydrolysis?
Fospropofol
-propofol prodrug under the trade name Lusedra
What is the definition of pharmacokinetics?
“What the body does to the drug”
- explains the relationship between the dose you administer and the drug’s plasma concentration over time
- affected by absorption, distribution, metabolism, and elimination
What is the definition of pharmacobiophysics?
Considers the drug’s concentration in the plasma and the effect site (biophase)
What is the definition of pharmacodynaamics?
“What the drug does to the body”
-explains the relationship between the effect site concentration and the clinical effect
What is potency and how is it measured?
Potency = the dose required to achieve a given clinical effect (x-axis of dose-response curve
ED50 and ED90 are measures of potency
-represent the dose required to achieve a given effect in 50% and 90% of the population
How is potency measured on the dose-response curve?
Drug A is more potent than Drug B
- Drug A: curve shifts left with –> increased affinity for receptor –> higher potency –> lower dose required
- Drug B: curve shifts right with –> decreased affinity for receptor –> lower potency -> higher dose required
What is efficacy, and how is it measured on the dose-response curve?
Efficacy = measure of the intrinsic ability of a drug to produce a clinical effect
Height on the plateau on the y-axis represents efficacy
- higher plateau = greater efficacy
- lower plateau = lower efficacy
What does the slope of the dose-response curve tell you?
How many of the receptors must be occupied to elicit a clinical effect
- steeper slope = small increase in dose can have profound clinical effect
- flatter slope = higher doses are required to increase clinical effect
What is the differences between a full agonist, partial agonist, antagonist, and inverse agonist?
- Full Agonist: binds to a receptor and turns on a specific cellular response
- Partial Agonist: binds to a receptor, but it is only capable of partially turning on a cellular response (less effective than full agonist)
- Antagonist: occupies the receptor and prevents an agonist from binding to it (has no efficacy)
- Inverse Agonist: binds to the receptor and causes an opposite effect to that of a full agonist (negative efficacy)
What is competitive antagonism? give an example
Competitive antagonism is REVERSIBLE
-increasing the concentration of the agonist can overcome the competitive antagonism
Ex: Atropine, Vecuronium, Rocuronium
What is noncompetitive antagonism? give an example
Noncompetitive antagonism is NOT reversible
- drug binds to a receptor and its effect cannot be overcome by increasing the concentration of an agonist
- only by creating new receptors can the effect of a noncompetitive agonist be reversed – why DOA is so long
Ex: ASA and Phenoxybenzamine
What is ED50?
the dose that produces the expected clinical response in 50% of the population
it is a measure of potency
What is TD50?
the dose that will produce toxicity in 50% of the population
What is the therapeutic index?
Helps determine the safety margin for a desired clinical effect
TI = TD50 / ED50
- drug with a narrow TI has narrow margin of safety
- drug with a wide TI has a wide margin of safety
What is chirality?
A division of stereochemistry – deals with molecules that have a center of 3D asymmetry
- in biologic systems, this type of asymmetry generally stems from the tetrahedral bonding of carbon (carbon binds to 4 different atoms)
- A molecule with 1 chiral carbon will exist as 2 enantiomers (the more chiral carbons in a molecule, the more enantiomers created)
What is an enantiomer? What is the clinical relevance?
Enantiomers are chiral molecules that are non-superimposable mirror images of one another
Different enantiomers can produce other clinical effects – for example the side effect profile of one enantiomer of a drug can be different from another enantiomer of the same drug
What is a racemic mixture? List some commonly used examples
Racemic mixture contains 2 enantiomers in equal amounts
1/3 of the drugs we admin are enantiomers (about all of these are racemic mixtures)
-Ex: Bupivacaine, Ketamine, Isoflurane, and Desflurane
What is the mechanism of action of Propofol?
Direct GABA-A agonist –> increases Cl- conductance –> Neuronal hyperpolarization –> Prevent action potential
What is the dose, onset, duration, and clearance mechanism for propofol?
Dose: induction 1.5 - 2.5 mg/kg IV – infusion 25-100 mcg/kg/min
Onset: 30-60 sec
Duration: 5-10 min
Clearance: Liver (P450) + Extrahepatic metabolism (lungs)
What are the CV and respiratory effects of propofol?
CV Effects:
- decreased BP (due to decreased SNS tone and vasodilation)
- decreased SVR
- decreased venous tone –> decreased preload
- decreased myocardial contractility
Respiratory Effects:
- shifts CO2 response curve down and to the right (less sensitive to CO2) –> respiratory depression and/or apnea
- inhibits hypoxic ventilatory drive
What are the CNS effects of propofol?
- Decreased CMRO2
- Decreased cerebral blood flow
- Decreased ICP
- Decreased IOP
- No analgesia
- Anticonvulsant properties
What is the formulation of propofol? Is there a pt population where this is a problem?
It is prepared as a 1% solution in an emulsion of egg lecithin, soybean oil, and glycerol
-despite concerns that propofol might precipitate anaphylaxis in pts with egg, soy, and/or peanut allergy, there is no evidence to support this
What is propofol infusion syndrome?
Propofol contains long chain triglycerides, and is increased LCT load impairs oxidative phosphorylation and fatty acid metabolism
This starves cells of O2, particularly in cardiac and skeletal muscle
*associated with high mortality rate
What are the risk factors for propofol infusion syndrome?
- Propofol dose >4 mg/kg/hr (67 mcg/kg/min)
- Propofol infusion duration >48 hr
- Adults > Children
- Inadequate O2 delivery
- Sepsis
- Significant cerebral injury
What is the clinical presentation of propofol infusion syndrome?
Clinical presentation includes acute refractory bradycardia –> asystole + at least one of the following:
- metabolic acidosis (base deficit > 10 mmol/L)
- rhabdomyolysis
- enlarged or fatty liver
- renal failure
- HLD
- lipemia (cloudy plasma or blood) may be an early sign
When must a propofol syringe be discarded? How about an infusion?
Syringe = within 6 hours
Infusion = within 12 hours
What preservatives are used in brand and generic propofol? what pt population are at risk?
Diprivan (brand) contains EDTA as a preservative – not a problem for any pt population
Generic propofol formulation contain different preservatives:
- metabisulfite can precipitate bronchospasm in asthmatic pts
- avoid benzyl alcohol in infants
How can propofol injection pain be minimized?
- Injecting into a larger more proximal vein
- Lidocaine (before or mixed)
- Giving an opioid before
What dose of propofol can be used to treat PONV?
10 - 20 mg IV or Infusion of 10 mcg/kg/min
How is fospropofol converted to its active form?
It is a prodrug –> propofol is the active metabolite
Alkaline Phosphatase converts fospropofol to propofol
*explains the slower onset (5-13 min) and longer duration (15-45 min)
What is the primary mechanism of action for anesthesia produced by ketamine?
NMDA receptor antagonist (antagonizes glutamate)
- secondary receptor targets include opioid, MAO, serotonin, NE, muscarinic, and Na+ channels
- ketamine dissociates the thalamus (sensory) from the limbic system (awareness)
What are the potential routes of admin for ketamine? Include the doses for each
IV: induction 1-2 mg/kg – analgesia 0.1-0.5 mg/kg
IM: 4-8 mg/kg
PO: 10 mg/kg
What is the onset, duration, and clearance mechanism for ketamine?
Onset: IV 30-60 sec – IM 2-4 min – PO variable
Duration: 10-20 min (may require 60-90 min to return to full orientation)
Clearance: Liver (P450) – produces active metabolite (norketamine: 1/3 -1/5 potency)
What are the CV effects of ketamine?
- Increased SNS tone
- Increased CO
- Increased HR
- Increased SVR
- Increased PVR (caution use in severe RV failure)
- Sub-hypnotic doses (<0.5 mg/kg) usually don’t activate the SNS
*it is a myocardial depressant – myocardial depressant effects are unmasked in pts with depleted catecholamine stores (sepsis) or sympathectomy
What are the respiratory effects of ketamine?
- Bronchodilation
- Upper airway muscle tone and airway reflexes remain intact
- Maintains respiratory drive (brief period of apnea may occur following induction)
- Doesn’t significantly shift CO2 response curve
- Increased oral and pulmonary secretions –> increased risk of laryngospasm
What are the CNS effects of ketamine?
- Increased CMRO2
- Increased cerebral blood flow
- Increased ICP
- Increased IOP
- Increased EEG activity (caution if hx of seizures)
- Nystagmus
- Emergence delirium
What is the presentation, treatment, and risk factors for emergence delirium with ketamine use?
Presentation: nightmares and hallucinations (risk persists for up to 24 hrs)
Treatment: benzodiazepines are most effective way to prevent (midazolam > diazepam)
Risk Factors: age >15, female, ketamine dose >2 mg/kg, hx of personality disorder
Discuss the analgesic properties of ketamine
- Provides good analgesia and opioid sparing effect (only induction agent)
- Relieves somatic pain > visceral pain
- Blocks central sensitization and wind-up in the dorsal horn of spinal cord
- Prevents opioid induced hyperalgesia (after remifentanil infusion)
- Excellent for burn pts (frequent dressing changes) and those with pre-existing chronic pain syndromes
What is the dose, onset, duration, and clearance mechanism for etomidate?
Dose: 0.2-0.4 mg/kg IV
Onset: 30-60 sec
Duration: 5-15 min
Clearance: Hepatic P450 + plasma esterases
What are the CV and respiratory effects of etomidate?
CV Effects:
- minimal changes in HR, SV, or CO (key benefit is hemodynamic stability)
- SVR is decreased (accounts for small decrease in BP)
- doesn’t block SNS response to laryngoscopy
Respiratory Effects:
- mild respiratory depression
What are the CNS effects of etomidate?
- Decreased CMRO2
- Decreased cerebral blood flow (cerebral vasoconstriction)
- Decreased ICP
- CPP remains stable
- No analgesia
What is the relationship between etomidate and myoclonus?
Myoclonus is involuntary skeletal muscle contractions, dystonia, or tremor
It is likely due to an imbalance between excitatory and inhibitory pathways in the thalamocortical tract – it is not a seizure
What is the relationship between etomidate and seizure activity?
If the pt does not have a hx of seizures, etomidate doesn’t increase the risk
If the pt has a hx of seizures, etomidate can increase epileptiform (seizure like) activity and possibly increase risk of seizures
What is the relationship between etomidate and adrenocortical suppression?
Cortisol and aldosterone synthesis are dependent on enzyme 11-beta-hydroxylase and 17-alpha-hydroxylase
- etomidate is known inhibitor of these
- single dose of etomidate suppresses adrenocortical function for 5-8hrs – reason why you should avoid it in pts reliant on the intrinsic stress response (sepsis or acute adrenal failure)
- mortality may be increased by etomidate (particularly in pts with sepsis)
Which induction agent is most likely to cause PONV?
Etomidate
What are the two sub-classes of barbiturates? List examples
Thiobarbiturates: there is a sulfur molecule in the second position (increases lipid solubility and potency)
ex: thiopental, thiamylal
Oxybarbiturates: there is an oxygen molecule in the second position
ex: methohexital, pentobarbital
What is the mechanism of action of thiopental?
GABA-A agonist –> depresses the reticular activating system in the brainstem
- Low/Normal Dose: increases affinity of GABA for its binding site
- High Dose: directly stimulates the GABA-A receptor
What is the dose, onset, duration, and clearance mechanism for thiopental?
Dose: adult 2.5-5 mg/kg – children 5-6 mg/kg
Onset: 30-60 sec
Duration 5-10 min
Clearance: Liver (P450) – redistribution (not metabolism) determines awakening
*repeated doses –> tissue accumulation –> prolonged wake up time + hangover effect
What are the CV and respiratory effects of thiopental?
CV Effects:
- HoTN is primarily the result of venodilation and decreased preload – myocardial depression is a secondary cause
- causes non-immunogenic histamine release (can contribute to HoTN - short lived)
- baroreceptor reflex is preserved –> reflex tachycardia helps restore CO
- less HoTN compared to propofol
Respiratory:
- respiratory depression (shifts CO2 curve to the right)
- histamine release can cause bronchoconstriction (caution w/ asthma
What are the CNS effects of thiopental?
- Decreased CMRO2
- Decreased cerebral blood flow (cerebral vasoconstriction)
- Decreased ICP (used in treatment in intracranial HTN)
- Decreased EEG activity (can cause burst suppression and/or isoelectric EEG –> neuroprotection)
- No analgesia
In what circumstances can thiopental be used for neuroprotection?
Focal ischemia
-ex: carotid endarterectomy, temporary occlusion of cerebral arteries
*Not for global ischemia
What is the pathophysiology of acute intermittent porphyria?
- Heme is a key component of Hgb, myoglobin, and cytochrome P450 enzymes
- Porphyria is caused by a defect in heme synthesis that promotes the accumulation of heme precursors (ALA induction)
- The porphyrias can be classified as acute or cutaneous – Acute intermittent porphyria is most common and most dangerous type
What drugs should be avoided in the pt with acute intermittent porphyria? Why?
Any drug or condition that induces ALA synthase will accelerate the production of heme precursors and must be avoided
Drugs to Avoid: barbs, etomidate, ketamine, ketorolac, amiodarone, calcium channel blockers, birth control pills
Conditions to Avoid: emotional stress, prolonged NPO status
What is the treatment for acute intermittent porphyria?
- Liberal hydration
- Glucose supplementation (reduces ALA synthase activity)
- Heme arginate (reduces ALA activity)
- Prevention of hypothermia
What is the risk of intra-arterial injection of thiopental? What is the treatment?
Intra-arterial injection –> intense vasoconstriction + crystal formation (occludes blood flow) + inflammation –> tissue necrosis
Treatment:
- injection of vasodilator (phentolamine or phenoxybenzamine)
- sympathectomy (stellate ganglion block or brachial plexus block)
What induction agent is the gold standard for ECT therapy? Why?
Methohexital
-decreases seizure threshold and produces a better quality seizure
What is the mechanism of action for dexmedetomidine?
Alpha-2 agonist –> Decreases cAMP –> Inhibits the locus coeruleus in the pons (sedation)
- analgesia is produced by alpha-2 stimulation in the dorsal horn of the spinal cord (decrease substance P and decrease glutamate release
What is the dose, onset, duration, and clearance mechanism for dexmedetomidine?
Dose: loading 1 mcg/kg over 10min – maintenance 0.4-0.7 mcg/kg/hr
Onset: 10-20 min
Duration: 10-30 min (after infusion stopped)
Clearance: Liver (P450)
What are the CV effects of dexmedetomidine?
Most Common = Bradycardia and Hypotension
*rapid admin can cause HTN (alpha-2 stimulation in vasculature -> temporary vasoconstriction –> HTN) – short lived
Why is dexmedetomidine attractive for procedural sedation?
It doesn’t cause respiratory depression
- no change in oxygenation
- no change in blood pH
- no change in slope of CO2 response curve
What are the CNS effects of dexmedetomidine?
Produces sedation that resembles natural sleep
- sedation is result of reduced SNS tone and decreased level of arousal
- patients arouse easily
- doesn’t provide reliable amnesia
- Decreases CBF
- No change in CMRO2
- No change in ICP
How does dexmedetomidine produce analgesia?
By alpha-2 stimulation in the dorsal horn of spinal cord
-decreased substance P and decreased glutamate release
Aside from IV, what other routes can dexmedetomidine be administered? What is the dose?
Nasal and Buccal Routes
- 3-4 mcg/kg 1 hr prior to surgery
- high degree of bioavailability
- useful for preop sedation in children
How does the imidazole ring in Midazolam affect its solubility?
Imidazole ring can assume an open or close position depending on the environmental pH
- Acidic pH –> ring opens –> Increases water solubility
- Physiologic pH –> ring closes –> Increases lipid solubility
*Midazolam is water soluble inside the vial, it doesn’t require a solvent such as propylene glycol
What is the mechanism of action for midazolam?
GABA-a agonist: increases frequency of channel opening –> neuronal hyperpolarization
*most GABA-a agonists increase open TIME but benzos increased open FREQUENCY
What are the IV and PO doses for midazolam? Why are they different?
IV sedation: 0.01-0.1 mg/kg
IV induction: 0.1-0.4 mg/kg
PO sedation in kids: 0.5-1 mg/kg
*PO bioavailability is 50% due to significant 1st pass metabolism
Which induction agents produce an active metabolite?
- Midazolam: 1-hydroxymidazolam (1/2 potency)
- Ketamine: norketamine (1/3 - 1/2 potency)
- Fospropofol: propofol
*Propofol, Etomidate, and Dexmedetomidine do not produce active metabolites
What are the CV and respiratory effects of midazolam?
CV Effects:
- sedation dose = minimal effects
- induction dose = decrease BP and SVR
Respiratory Effects:
- sedation dose = minimal effects
- induction dose = respiratory depression
- opioids potentiate respiratory depressant effects, even at doses for sedation
- pts w/ COPD are more sensitive to respiratory depressant effects
What are the CNS effects of midazolam?
Sedation Dose: minimal effects on CMRO2 and CBF
Induction Dose: decreased CMRO2 and CBF
- can’t produce isoelectric EEG
- anterograde amnesia (not retrograde)
- anticonvulsant
- anxiolysis
- spinally mediated skeletal muscle relaxation (antispasmodic)
- no analgesia
What are the unique features of remimazolam?
- It’s ultra-short acting benzo
- Vial must be protected from light
- Single use vial must be discarded 8hrs after reconstitution
- Metabolized by plasma esterases
- Contraindicated in pts with a history of severe hypersensitivity reaction to Dextran 40
What is the reversal agent for benzodiazepines? How does it work?
Flumazenil is a competitive antagonist of GABA-a receptor
Initial dose = 0.2 mg IV – titrate in 0.1 mg increments Q1 min
- very high affinity but has short duration of action (30-60 min)
- repeat doses may be necessary to prevent re-sedation
What are potential side effects of flumazenil?
Does NOT increases SNS tone, anxiety, or neuroendocrine evidence of stress like naloxone
Can precipitate signs of withdrawal in benzo-dependent patients (including seizures)
How can you tell the difference between the chemical structures of the halogenated agents?
Count the halognes:
- Halothane = 3 fluorine + 1 bromine atom
- Iso = 5 fluorine + 1 chlorine
- Des = 6 fluorine
- Sevo = 7 fluorine
How does fluorination affect the physiochemical characteristics of halogenated anesthetics?
Adding fluoride ions tends to:
- decrease potency,
- increase vapor pressure
- increase resistance to biotransformation
*even though sevo is heavily fluorinated, its ~3x as potent as des (most likely due to bulky propyl side chain)
What is vapor pressure, and how is it affected by the ambient temperature?
Vapor Pressure: pressure exerted by a vapor in equilibrium with its liquid or solid phase inside of a closed container
-it is directly proportional to temperature (Increased temp = Increased vapor pressure)
How is anesthetic delivery affected by altitude? When does this matter?
- Anesthetic depth is determined by partial pressure of anesthetic agent in the brain (Partial Pressure of a Gas = Vol% x Total Gas Pressure)
- As atmospheric pressure decreases at higher elevations –> Vol% remains the same but partial pressure of gas decreases (Risk of under dosing anesthetic agent)
- For Sevo and Iso at elevation under dosing is not a problem – conventional variable bypass vaporizer automatically compensates for elevation change
- For Des at elevation under dosing IS a problem –the injector design on the Tec 6 vaporizer doesn’t compensate for elevation (18.4% reduction at 1 mile above sea level compared to sea level)
What are the vapor pressures of Sevo, Des, Iso, and N2O?
Sevo = 157
Des = 669
Iso = 238
N2O = 38,770
Which inhalation anesthetics are stable in soda lime? What byproducts can each agent produce in soda lime?
Sevo: not stable – compound A (occurs in functional soda lime and worse if soda lime is desiccated)
Des: not stable – carbon monoxide (only if desiccated)
Iso: not stable – carbon monoxide (only is desiccated)
N2O: stable – none
What is solubility and how is it measured?
Solubility = tendency of a solute to dissolve into a solvent
-in the case of inhalation anesthetics, its the anesthetic agent’s ability to dissolve into the blood/tissues
Blood:Gas partition coefficient = relative solubility of an inhalation anesthetic in the blood vs in the alveolar gas when the partial pressure between the 2 compartments are equal
What is the Blood:Gas solubility for Sevo, Des, Iso, and N2O?
Des = 0.42
N2O = 0.46
Sevo = 0.65
Iso = 1.45
How do we establish an anesthetic concentration inside the alveolus?
- Turn on vaporizer (creates concentration gradient that pushes anesthetic agent from vaporizer towards the alveoli) – FI
- Ventilation washes the anesthetic agent into the alveoli – FA
- Buildup of anesthetic partial pressure inside the alveoli is opposed by continuous uptake of agent into the blood – Uptake
- CO distributes the anesthetic agent throughout the body – Distribution
What does the FA/FI curve tell us? How does anesthetic solubility affect the FA/FI curve for each agent?
(Order the volatile anesthetics from top to bottom on FA/FI curve)
FA/FI Curve allows us to predict the speed of induction
- Low solubility –> Less uptake into the blood –> Increase rate of rise –> Faster equilibration of Fa/Fi –> FASTER onset
- High solubility –> More uptake into the blood –> Decrease rate of rise –> Slower equilibration of Fa/Fi –> SLOWER onset
What factors affect agent delivery to and removal from the alveoli?
Determinants of Delivery: setting on vaporizer, time constant of delivery system, anatomic dead space, alveolar ventilation, functional residual capacity
Determinants of Uptake: solubility of anesthetic in the blood (blood:gas coefficient), CO, partial pressure gradient between alveolar gas and mixed venous blood
What conditions increase Fa/Fi? Which condition decrease it?
For Fa/Fi to INCREASE (faster onset) – must be greater wash in and/or reduce uptake
- increase wash in: high FGF, high alveolar ventilation, low FRC, low time constant, low anatomic dead space
- decrease uptake: low solubility, low CO, low Pa-Pv difference
For Fa/Fi to DECREASE (slower onset) – must be a reduced wash in and/or increased uptake
- decreased wash in: low FGF, low alveolar ventilation, high FRC, high time constant, high anatomic dead space
- increase uptake: high solubility, high CO, high Pa-Pv difference
In which pt will the onset of sevo be the fastest? Why?
Patient A: HR 55 bpm w/ SV 100mL/beat
Patient B: HR 60 bpm w. SV 85 mL/beat
Patient B
- anesthetic uptake is directly proportional to CO – high CO removes more anesthetic agent from the alveoli, so it slows rate of rise of Fa/Fi – slowing rate of induction
- Pt A has CO of 5.5 L/min and Pt B has CO of 5.1 L/min
What are the four tissue groups? How much CO does each receive?
Vessel-Rich = 75% CO – brain, heart, kidney, liver
Muscle = 20% CO – skeletal muscle, skin
Fat = 5% CO
Vessel-Poor = <1% CO – bone, tendon, cartilage
What 3 ways are inhalation anesthetics removed from the body? For each agent, what percent is attributed to hepatic metabolism?
- Elimination from alveoli (most important)
- Hepatic biotransformation
- Percutaneous loss (minimal)
Hepatic Biotransformation:
- N2O = 0.004%
- Des = 0.02%
- Iso = 0.2 %
- Sevo = 2-5%
- Halotane = 20%
- rule of 2’s
- agents spell DISH
Discuss the FDA recommendations for the minimal fresh gas flow requirements for Sevo
1 L/min for up to 2 MAC hours
2 L/min after 2 MAC hours
*no supporting evidence renal necrosis occurs in humans
What is a MAC hour?
1% Sevo x 2 hrs
2% Sevo x 1 hr
4% Sevo x 30 min
Which volatile agents are metabolized to trifluoroacetic acid? What is a potential consequence of this?
Up to 20% of halothane undergoes hepatic biotransformation – high liver concentration may lead to halothane hepatitis
Des and Iso undergo a much smaller degree of hepatic biotransformation
Remote possibility that TFA could precipitate an immune-mediated hepatic dysfunction (especially w/ previous TFA exposure)
What are the theoretical consequences of sevo metabolism?
its biotransformation results in the liberation of inorganic fluoride ions
- theoretical concerns of fluoride-induced high output renal failure (no solid evidence of it)
- signs of high-output renal failure: polyuria, hypernatremia, hyperosmolarity, increased plasma creatinine, and inability to concentrate urine
*compound A occurs inside the circuit – F-ions production occurs from hepatic metabolism
What is the concentration effect?
Describes an increased rate of alveolar uptake as the concentration of a gas is increased
Function of 2 mechanisms:
- Concentrating effect - N2O is introduced into the lung, volume of N2O going from alveolus to pulm blood is much higher than amount of N2O moving the opposite direction – causes alveolus to shrink and the reduction in alveolar volume causes relative increase in Fa
- Augmented gas inflow - on the subsequent breath, the concentrating effect causes increased inflow of tracheal gas containing the anesthetic agent to replace the lost alveolar volume – increases alveolar ventilation and augments Fa – alveolar volume restores quickly, so it is only temporary
When compared to N2O, Des has a lower blood-gas partition coefficient. Why does the Fa/Fi ratio for N2O rise faster than Des?
Due to the concentration effect
- despite a slightly higher blood:gas partition coefficient, the alveolar partial pressure of N2O rises faster than Des
- this is because we can safely deliver a much higher inspiratory concentration, which negates the small difference imposed by the slightly higher blood:gas partition coefficient
Anesthetic overpressure results in a more profound effect for agents with a higher OR lower blood solubility?
HIGHER blood solubility
- concentration effect says that the higher the concentration of inhalation anesthetic delivered to the alveolus (Fa), the faster its onset of action – this is also called overpressuring
- effect is only clinically relevant for N2O, however it may occur with other gases
- can offset the effects of a higher blood solubility by increasing the inspired concentration on the vaporizer – helps reach Fa/Fi equilibration faster
How does N2O affect the uptake of a halogenated anesthetic during induction? What is this called?
Use of N2O during anesthetic induction will speed up the onset of a second gas
Called the second gas effect
What is diffusion hypoxia? How can it be prevented?
N2O moves from the body towards the lungs –> Dilutes alveolar O2 and CO2 –> Decreased respiratory drive and hypoxia
- it is a risk during emergence
- administering 100% O2 for 3-5 min after discontinuing N2O prevents it
Which inhalation anesthetics are most greatly affected by a right-to-left shunt?
The Fa/Fi of an agent with lower solubility (Des) will be more affected than an agent with higher solubility (Iso)
Which inhalation anesthetics are most greatly affected by a left-to-right shunt?
Left-to-right shunt will not have a meaningful effect on anesthetic uptake or induction time
Why does N2O accumulate in closed air spaces?
It is 34x more soluble than nitrogen – meaning it will enter a space 34x faster than nitrogen can exit that space
What type of spaces does N2O increase volume vs increase pressure?
Increases Volume in Compliant Airspaces:
- fast equilibration between space and blood = pulmonary blebs, air bubbles in the blood, gas bubble in the eye
- slow equilibration between space and blood = bowel, pneumoperitoneum
Increases Pressure in Fixed Airspaces:
- fast equilibration between space and blood = middle ear, brain during intracranial procedures
How does N2O affect a pt with an ocular gas bubble? When can N2O be used in these patients?
N2O can expand the SF6 bubble compromising retinal perfusion – can cause permanent blindness
- discontinue N2O 15min prior to placing SF6 bubble
- avoid N2O for 7-10 days post bubble placement
- if an air bubble is used, avoid N2O for 5 days
- if perfluoropropane is used, avoid N2O for 30 days
- if silicone oil is used, there is no contraindication to N2O
What is the relationship between N2O and anesthesia equipment?
N2O can increase the volume and pressure in:
- ETT
- LMA cuff
- Balloon-tipped pulmonary artery catheter
*attach a manometer to the pilot balloon to check internal pressure
How do we quantify anesthetic potency? What is this value for each inhalation agent?
Minimum Alveolar Concentration (MAC) = Measure of potency
Iso = 1.2%
Sevo = 2.0%
Des = 6.6%
N2O = 104%
What are MAC-bar and MAC-awake?
MAC-bar: alveolar concentration required to block the autonomic response following a supramaximal painful stimulus (~1.5 MAC)
MAC-awake: alveolar concentration at which a pt opens his or her eyes - shows hysteresis in that MAC-awake is ~0.4-0.5 during induction but during recovery MAC-awake is as low as 0.15 MAC
What factors increase MAC?
- Chronic alcohol consumption
- Acute amphetamine intoxication
- Acute cocaine intoxication
- MAOIs
- Ephedrine
- Levodopa
- Hypernatremia
- Increased in infants 1-6 months (sevo is same for neonates and infants)
- Hyperthermia
- Red hair
What factors decrease MAC?
- Acute alcohol intoxication
- IV anesthetics
- N2O
- Opioids (IV & neuraxial)
- Alpha-2 agonists
- Lithium
- Lidocaine
- Hydroxyzine
- Hyponatremia
- Older age (decrease 6% per decade after 40)
- Prematurity
- Hypothermia
- HoTN (MAP < 50)
- Hypoxia
- Anemia
- Cardiopulmonary bypass
- Metabolic acidosis
- Hypo-osmolarity
- Pregnancy –> Postpartum (24-72hr)
- PaCO2 > 95 mmHg
What factors do not affect MAC?
- Hyper or Hypokalemia
- Hyper or Hypomagnesemia
- Hyper or Hypothyroidism
- Gender
- PaCO2 15-95 mmHg
- HTN
How do hyper- and hypothyroidism affect MAC? Why?
they don’t directly affect MAC - but changes in CO associate with these conditions may affect anesthetic uptake and subsequent onset of action
ex: profoundly hypothyroid pts have a reduced CO leading to decreased uptake into the blood and a faster rate of rise of Fa/Fi – making them more susceptible to anesthetic overdose
What is the Meyer-Overton rule?
States that lipid solubility is directly proportional to the potency of an inhaled anesthetic
-implies the number of anesthetic molecules that are dissolved in the brain determines the depth of anesthesia
What is the unitary hypothesis?
states that all anesthetics share a similar mechanism of action, although each may work at a different site
What is the most important site of halogenated anesthetic action in the brain?
Most essential site of volatile anesthetic action is the GABA-A receptor
- GABA-A receptor = ligand-gated chloride channel
- Stimulation increases chloride influx and hyperpolarizes neurons (impairs neurotransmission)
- Volatile anesthetics most likely increase the duration the chloride channel remains open
How do halogenated anesthetics produce immobility?
Produce immobility in the ventral horn of the spinal cord
Which cerebral receptors are stimulated by N2O?
NMDA antagonism
Potassium 2P-channel stimulation
*N2O does NOT stimulate the GABA-A receptor
In which regions of the brain do halogenated anesthetics produce unconsciousness?
- Cerebral cortex
- Thalamus
- Reticular activating system
In which regions of the brain do halogenated anesthetics produce amnesia?
Amygdala
Hippocampus
In which regions of the brain do halogenated anesthetics produce autonomic modulation?
Pons
Medulla
How do halogenated agents reduce blood pressure?
Decrease MAP in a dose dependent fashion – at equivalent doses, there is little difference between agents
- Primary cause = decrease intracellular Ca2+ in vascular smooth muscle –> systemic vasodilation –> decrease SVR and venous return
- Secondary cause = decrease intracellular Ca2+ in the myocyte –> myocardial depression –> decrease inotropy
How do halogenated anesthetics affect HR?
Directly affect cardiac conduction in a dose dependent fashion
- decrease SA node automaticity
- decrease conduction velocity through the AV node, His-Purkinje system, and ventricular conduction pathways
- increase duration of myocardial repolarization by impairing the outward K+ current (prolongs AP duration and QT interval)
- altered baroreceptor function
Why do Des and Iso sometimes have increased HR?
they increase HR from baseline by 5-10% – most likely due to SNS activation from respiratory irritation
-pulm irritation –> SNS activation –> increase norepi release –> beta-1 stimulation
rapid increases in Des (Iso to a lesser degree) cause tachycardia
-opioids or beta-1 antagonists can minimize it
What is the relationship between Iso and coronary steal?
Iso is the most potent coronary artery dilator
- atherosclerotic vessels can’t dilate, while normal vessels can –> this would preferentially divert blood away from areas of higher resistance, starving those regions of O2
** more of textbook thing than a real-world problem
How does N20 (by itself) affect hemodynamics?
It activates the SNS – increases MAP as a function of increased SVR (CVP and right atrial pressure may increase)
It is a myocardial depressant, but the increased SNS stimulation outweighs the physiologic consequences of this
How do halogenated anesthetics contribute to hypercarbia?
Volatile anesthetics cause a dose dependent depression of the central chemoreceptor and the respiratory muscles – contributes to hypercarbia
- alters respiratory pattern (decreased Vt and compensatory increase in RR –> decrease in Ve and increase in Vd)
- impairs response to CO2 (slope CO2 response curvee shifts down and right)
- impairs motor neuron output and muscle tone to the upper airway and thoracic muscles
How do halogenated anesthetics affect cerebral metabolic rate?
CMRO2 is a function of:
- electrical activity (60%)
- cellular homeostasis (40%)
Volatile anesthetics reduce CMRO2 but only to the extent that they reduce electrical activity – once the brain is isoelectric, they can’t reduce CMRO2 any further
*isoelectricity on EEG occurs at 1.5-2 MAC
Compare and contrast the effects of halogenated anesthetics and N2O on cerebral blood flow.
Brain matches its blood flow with its metabolic requirement –> When metabolic demand increases, blood vessels dilate (cerebrovascular resistance decreases) – When metabolic demand decreases, blood vessels constrict (cerebrovascular resistance increases)
- Volatile anesthetics uncouple this relationship (CMRO2 decreases and CBF increases – can increase ICP as well)
- N20 increases CMRO2 and cerebral blood flow appropriately
How do halogenated anesthetics affect evoked potentials? How about N2O?
Des, Iso, and Sevo produce a dose dependent effect of evoked potentials
- decrease amplitude (signal not as strong)
- increase latency (slower signal)
Addition of N2O to halogenated anesthetic agent can lead to a more profound amplitude reduction – do not use during evoked potential monitoring
Which type of evoked potential is most sensitive to the effects of volatile anesthetics? Which is the most resistant?
- Visual evoke potentials are the most sensitive to volatile agents
- Brainstem evoked potentials are the most resistant
- SSEPs and MEPs are somewhere in between
How can N2O cause bone marrow depression?
N2O inhibits methionine synthase and folate metabolism – can cause megaloblastic anemia
