They inhibit the action potential excitable cells (neurons and cardiac myocytes)
specifically, they work at the membrane bound voltage gated Na channels
.... forms of LAs block .... at the (alpha/beta) subunit on the (extracellular/intracellular) side*
(notice the difference in pH)
Local anesthetics bind the alpha subunit on the intracellular membrane, thus inhibiting the .... influx associated with membrane depolarization*
LAs have greatest affinity for Na channels in the (resting/open,active/inactivated) states*
open and inactivated
Binding of LAs is facilitated by ...
depolarization and frequency of depolarization
LAs bind more to neurons that fire (more/less) rapidly
membrane depolarization causes a conformational change in the Na channel, converting it to an open state. Na rush into the open pore. Then the channel goes into inactive state.
That LAs inhibition is both voltage and frequency dependent with greater binding occurring in nerve fibers that are firing more rapidly is known as*
Use Dependent Block
Resting membrane potential to depolarization in neuron
-70mV to +35mV
Does the Action Potential take place with a LA? Does binding alter the resting membrane potential?
No, AP is not met so there is no depolarization
No, LAs do not alter the resting membrane potential
What is sensitivity to local anesthetics determined by?
Comparing nerve fibers of the same type, does small or large diameter increase sensitivity to LAs?
with or without myelin?
axonal diameter and myelination
Rank these for LAs inhibition:
autonomic, motor, sensory
A > S > M
Potency correlates with a LAs ability to do what?*
permeate lipid membranes (lipid solubility)
What factors affect potency?
fiber size, type, myelination, pH, frequency of nerve stimulation, electrolyte concentration
How does acidic pH affect potency?
How does hypokalemia and hypercalcemia affect potency?
What is the most potent (most lipid soluble) LA?
What does duration correlate with?
Potency and Lipid Solubility
Highly lipid soluble LAs have a (longer/sorter) DOA secondary to slow diffusion from lipid rich environments to the bloodstream
lipid solubility correlates with what?
plasma protein binding
Greater protein binding means that the LA will work (longer/shorter)
What Plasma protein do LAs mainly bind?
alpha-1 acid glycoprotein
Degree of protein binding determines
Duration of action
Local anesthetics onset correlates with
lipid solubility and pKa
pH at which the fraction of ionized and non-ionized drug is equal
Clinically, what does bicarbonating LAs do? When is this important?
It speeds up onset.
Diffuse epidurals for vaginal births (have sensory/pain relief, but can still push) that have to go to C-section. For emergency C section, time is critical, if you add bicarbonate to the LA, you can have the perfect block and have a C section without having to put the patient to sleep and without having to worry about intubating
What does adding epinephrine to an LA do?
It can double the DOA (more so with lidocaine and not with bupivacaine due to different MOAs)
Epinephrine added to LA block given on finger or penis can cause what complication?
ischemia or other injury due to epi causing vasoconstriction
Do moist mucus membranes or intact skin cause more rapid absorption of LA when placed directly on the skin?
mucus membranes (intact skin will require a higher concentration)
EMLA cream contains what?
1:1 5% Lidocaine 5% prilocaine in an oil in water emulsion
How long does EMLA take to achieve anesthesia for peripheral line placement?
What are the contraindications of EMLA?
mucus membranes, broken skin, infants younger than 1 month, patients with predisposition for methemoglobinemia
What is absorption of injected LAs dependent on?
What factors will affect the absorption of injects LAs?
site of injection, presence of vasoconstrictors, and local anesthetic agent
Site of injection: Which has the highest to lowest levels of blood flow?*
For rapid intubation, which drug is often used because it can activate so quickly?*
works in 45 seconds and breaks down in 7.
NOTE: The new drugs we have can inactivate steriodal NMBD in less than 1.5 mins
What is a new non-depolarizer? What are its benefits?
Reduces histamine release, more cardiac stability, organ independent metabolism
What is a side effect of antimuscarinics?
What is a new reversal agent that binds to rocuronium or vecuronium and inactivates it in 1.5 minutes?
Sugammadex (a new cyclodextrin)
Does sugammadex work on non-steroidal neuromuscular blockers?
no, only on steroidal
Onset of Blockade begins with (small/large) muscles?*
small: eyes and digits, then muscles of the trunk, then intercostals, and finally diaphragm
Reversal of neuromuscular blockade begins with (small/large) muscles?*
Opposite of onset: diaphragm, then intercostals, then muscles of the trunk and abdoment, then eyes and digits
NOTE: Consciousness and sensorium remain undisturbed
What is involved in the reversal of the neuromuscular blockade?
AchEI prevents breakdown of Ach, competitive inhibition of neuromuscular blockade, but this can cause unwanted side effects at muscarinic and nicotinic receptors so you have to use an antimuscarinic like atropine and glycopyrolate
How does an anesthesiologist measure clinically how paralyzed the patient is?
Electrical twitch monitors
How do anesthesiologists determine how much drug to give?*
Use dose in which 95% of receptors are blocked (ED95)
If you are not completely paralyzed, a typical twitch monitor, which uses 4 electrical pulses, will cause what to happen?
Thumb will move
What is the problem with the twitch monitor?
You can have 4/4 twitches and still have 2/3 receptors blocked
How do you determine if someone is completely recovered?
Sustained motor activity for 5-10 seconds (lift head, squeeze finger) - this is more sensitive than twitch
What are three methods for monitoring neuromuscular blockade?*
single twitch (determines degree), tetanus (adequacy), and train of four
What is the technical assessment of adequacy of neuromuscular blockade?*
Assessment of FADE with 50Hz stimulation over 5-10 seconds
What is the clinical assessment of adequacy of reversal of neuromuscular blockade?*
Ability to SUSTAIN motor activity for 5-10 seconds
What inhaled anesthetics do we use most often today?Why? Which is least pungent?*
Desflurane and Sevoflurane
Quick onset and recovery
What is stage 1 of anesthesia?*
What is stage 2 of anesthesia?*
What is stage 3 of anesthesia?*
What is stage 4 of anesthesia?*
Medullary paralysis - failure of ventilation and circulation
What inhaled anesthetic is used on children who don't have IVs due to being less pungent?
What IV induction of anesthesia agent is most often used for adults?
What are mitigating factors that change the dose of anesthetic?
Someone who is a chronic alcoholic is going to require more anesthesia.
Elderly or pregnant woman will require less.
Higher MAC dose needed for
young, chronic alcoholic, hypernatremia, cocaine
Lower MAC dose needed for
pregnancy, elderly, hyponatremia, anemia, lithium
What is Nitrous Oxide not used much anymore?
Not potent and associated with nausea and vomiting
(only gas currently being used to aid general anesthesia)
Why don't we give halothane anymore?
Slow recovery and under certain conditions it can give PT hepatitis
All inhalation agents cause what?
If you want to know how much anesthetic to give scientifically, what do you use?
Brain wave monitor
What does the Bispectral Index Monitor (brain wave monitor) show you? What is the scale?*
Depth of anesthesia with a scale from 0-100
What is the target dose on a brain wave monitor? What happens if it is below this number?*
40, no recall.
Above 40, say someone who came in and didn't tell you they were a chronic alcoholic would be above 40 and would have recall so you would have to increase the dose
What is the primary receptor that inhalation anesthetics work on?
What are the general anesthesia characteristics of inhalation anesthetics?*
controllability and non-specific
Factors governing uptake of a volatile anesthetic?*
cardiac output, solubility, and uptake
Low blood solubility for a given volatile anesthetic would provide for a (quicker/slower) uptake and effect
and faster recovery
Which inhalation anesthetic has the quickest recovery?*
A high cardiac output would provide more toward muscle and result in a (quicker/slower) onset
What is MAC?*
Minimum Alveolar concentration. A measure of the potency.
MAC is a guide to dosing each agent
What does a MAC of 1 mean?
Dose that prevents movement of a patient 50% of the time to painful stimulus
What does a MAC of 1.3 mean?
Dose that prevents movement of a patient 100% of the time to painful stimulus or incision
As a person gets older what happens to the MAC dose?
It becomes less
What is the unitary hypothesis?
Proposes that all inhalation agents share a common MOA
What is our most common IV anesthetic?*
etomidate and Midazolam are also used
Total IV Anesthesia
mostly lipophilic in nature - rapid onset, rapid termination
What is Etomidate used for?*
Good for elderly people with limited cardiopulmonary reserve (minimal CV and respiratory depressant effects)
doesnt have the depressant effects of propofol
What properties does etomidate have?
Hypnotic but not analgesic
MINIMAL HEMODYNAMIC EFFECTS
fast onset, fast recover, adrenocortical supression, pain at injection site
What do we use Midazolam, which is a Benzodiazepine, for?
before surgery for amnesia because people get scared.
Ketamine has (analgesia/amnesia)?
Potent analgesic, used for shock patients (increase HR, CO, BP)**** and chronic pain patients
What type of agonist is dexedetomidine?* What is it used for?
alpha 2 receptors, used for sedation
sedative medication used in the OR - relatively unique in its ability to provide sedation without causing respiratory depression
What drug is selective in its reversal of benzos?
What is the MOA of benzodiazepines?
Activate GABAs receptor complexes and enhance CL- current to hyperpolarize neurons and reduce their excitability
What is the specific binding site for benzos?
BZP binding site on GABAa
midazolam 2x greater affinity for receptors than diazepam
analgesics such as .... are given as a supplement to volatile anesthetic gases and contribute to the overall MAC*
Narcotics: morphine and fentanyl (sublimaze)
all have a degree of respiratory depression, which is increased when combined with anesthetics
Has poor CNS penetration and an onset of 15-30 mins
What opiate do we give today in the OR?
Fentanyl - 100x more potent. Contributes to analgesia
more lipid soluble than morphine 75% first pass pulmonary uptake 83% protein binding
What opiate has 1000x potency of morphine?
What is the treatment for post operative nausea and vomiting?