CNS I Pharm - Anesthesia Flashcards
Local Anesthetics Overview
A drug that BLOCKS NERVE CONDUCTION when applied LOCALLY TO NERVE TISSUE
All locals share 3 structural features –> AROMATIC RING + TERTIARY NITROGEN and then either an ESTER OR AMIDE
Ester group = Procaine, Cocaine, Tetracaine
Amide = Lidocaine, Bupivacaine, Mepivacaine, Etidocaine
No tertiary nitrogen = BENZOcaine (hydrophobic, so only topical preps)
These preferentially act on PAIN FIBERS (A & C), can block motor neurons at higher doses
Mechanism of action for local anesthetics
Act by blocking SODIUM CHANNELS –> prevent membrane depolarization and AP propagation
Can act outside, middle or inside of receptor (locals work INSIDE except for BENZOCAINE, which works in the middle)
These are all weak bases (unprotonated, lipophilic base form) –> ADD HCL to preparations to ensure they stay in WATER-SOLUBLE SALT FORM (protonated, hydrophilic)
How do local anesthetics get into the cells?
Injected into the perineuronal space…pH = 7.4, pKa = 8.4 (assume) –> 7.4-8.4 = Log (base/salt) —> Salt:Base = 10:1
ONLY BASE FORM gets into the cell membrane and into the neuron
Inside, pH is again 7.4, so equilibrates to 10:1 Salt:base again
Salt form acts on the membrane receptor!
Areas of inflammation/abscesses –> require higher doses because inflammation LOWERS pH (more protons) so ratio of Salt:Base = 100:1 or higher –> even less gets into the neuron to begin with
Mechanism of Action of LA’s (detailed)
Sodium Channels have voltage-sensitive M gate and a time sensitive H gate
At rest, neuronal membrane is resting at about -90 mV (M gate is CLOSED, H gate is OPEN)
When there is a depolarization, the M gate opens (voltage sensitive) and the H gate stays open –> Na+ flies in
After a few milliseconds time-sensitive H gate closes, INACTIVATING the channel –> no APs can activate the sodium channel now as K+ channels repolarize the membrane
LOCAL ANESTHETICS ONLY BIND IN THE ACTIVE STATE (both M and H open)
Use Dependence
LA’s are USE DEPENDENT –> more nerves firing, more effective/more analgesic the drugs are
Decremental Firing
When a local is given, it reaches a limited number of sodium channels on a given neuron
Following injection and the first AP, some LA enters local channels, filling it up
As the second AP propagates, less Na can flow through the occluded/blockd channel – yields a diminished AP in the second channel
Eventually APs will die out! And this is good as it stops pain
BUT, while weaker APs die out, STRONGER APs may still push through the channel and regain strength after they pass the occluded channel!
Miscoding
4 consecutive APs at 2 Hz each are usually registered as “pain”
If those 4 APs a re reduced to 2 APs, the brain may “mis-code” the sensation
This accounts for facial droop seen with agents like lidocaine (think your face is droopy after lidocaine)
All local anesthetics are…
VASODILATORS except for COCAINE (CNS effects and blocks NE reuptake, resulting in vasoconstriction and HEART effects!!!)
These drugs increase blood flow, which shortens their duration of action –> can use EPINEPHRINE to vasoconstrict and slow down the flow, decreasing drug clearance
What is a common side effect of PROCAINE?
Broken down to para-aminobenzoic acid –> CONTACT DERMATITIS is possible
*overall, Locals are very safe drugs
Most common Locals Used?
LIDOCAINE and BUPIVACAINE
Five Types of Anesthesia
Local
Monitored Anesthesia Care –> requires an anesthesia team to monitor the patient’s functions (BP, HR, O2 sat, EKG)
IV delivery, patient sedated but
CONSCIOUS (breast biopsy)
Regional Anesthesia –> Monitored anesthesia care with the addition of a local anestethic at a specific body site to block an entire region of the body (Still conscious - epidural or brachial plexus block are examples)
General anesthesia –> same as regional but patient is UNCONSCIOUS –> mediated via inhalants, opioids, muscle relaxants
General and Regional –> Involves a REGIONAL BLOCK given followed by general anesthesia to render patient unconscious
Ideal Anesthetic Drug Criteria?
Rapid onset Short duration Predictable mechanism of elimination Minimal CV effects Easily identified levels of depth Ease of administration High degree of specificity of action Availability to all age groups No undesirable side effects
Four Criteria for a GENERAL ANESTHETIC
Must make the patient UNCONSCIOUS and AMNESIC with NO RECOLLECTION OF SURGERY
Must PROVIDE ANALGESIA and PAIN CONTROL during the surgery and after the patient wakes up
Drugs must cause IMMOBILITY
Must DECREASE SNS ACTIVITY (measuring SNS via HR, BP is a useful measure of DEPTH – too high HR and BP means not deep enough; too low HR and BP means too deep)
HALOTHANE, ENFLURANE, ISOFLURANE, SEVOFLURANE, DESFLURANE
Nitrous Oxide
Causes AMNESIA, UNCONSCIOUSNESS, ANALGESIA –> Cannot cause immobility or SNS depression
How do anesthetics work?
Liquid form —-vaporizer—> Gaseous anesthetic –> breathing system –> LUNG –> BLOOD –> BRAIN
B/G Solubility Coefficients
Relative affinity that the drug has for the BLOOD PHASE compared to the GAS PHASE when it is in equilibrium
Ex: Diethyl Ether = 12 (HIGH) –> with 13 molecules, 12 enter blood and 1 stays in gas phase
The 12 dissolved molecules DO NOT contribute to the partial pressure because they are bound up by proteins, so equilibrium requires a large amount of ether to be dissolved
Nitrous oxide has a B/G of 0.47 (LOW) –> When 9 molecules enter alveolus, 6 remain in GAS and 3 in BLOOD phase
Since it is low, LESS DRUG IS NEEDED to be dissolved in the blood to reach equilibrium
What do B/G coefficients mean?
LARGE B/G TAKE A LONG TIME TO WORK!
Large = Big blood reservoir to fill before equilibrium can be reached –> takes a longer time to work
Low BG = Small reservoir to fill, FASTER ONSET of ACTION
Specific B/G Values
Diethyl Ether = 12 HALOTHANE = 2.3 ENFURLANE = 1.8 ISOFLURANE = 1.4 SEVOFLURANE = 0.68 DESFLURANE = 0.42 NITROUS OXIDE = 0.47
Low B/G take about 3 minutes to reach equilibrium in vessel rich group (heart, liver, lungs, kidneys, brain) and High B/G take about 10 minutes
Emerging from anesthesia
Turn off the anesthesia 10-15 minutes before end of treatment
This reverses the pressure gradient of the drug so that the venous circulation has a higher anesthetic than the alveolar air, so the drug follows its gradient (out of the blood –> alveolus –> exhaled)
Leaves order it was received (VRG first, then muscle, then fat)
Muscle rich group may not have much anesthesia at all (depends on how long the case is, takes 1-4 hours to reach equilibrium)
Minimum Alveolar Concentration (MAC)
The concentration of anesthetic agent required to render 50% of patients immobile to a surgical stimulus
MAC DEFINES POTENCY
Increasing MAC decreases potency
DECREASING MAC INCREASES POTENCY
Lower MAC = Better Potency
1 MAC = Percent of anesthetic gas in O2 (meaning no other gas besides O2 is in the mixture)
At 1 MAC – 50% are IMMOBILE (all are unconscious at ~0.8 MAC) –> 2 MAC mixtures given to ENSURE immobility (95% are immobile)
0.8 - amnesia, unconscious; takes higher levels to suppress movement than it does to eliminate consciousness
1 MAC = 1 MAC = 1 MAC
MAC Values
HALOTHANE = 0.74 ISOFLURANE = 1.15 ENFLURANE = 1.68 SEVOFLURANE = 2.0 DESFLURANE = 6.0 NITROUS OXIDE = 103
Thus, Halothane is very potent but slow acting, and Des is very fast acting, but less potent
MAC examples
If 1 patient gets 1% Halothane, what does this mean?
0.74% = 1 MAC, so 1% is HIGHER than a MAC –> Patient will be unconscious, amnestic and 50% chance of immobility
1% Isoflurane is LESS than 1 MAC (1.15)
Which WORKS FASTER? Iso because of the LOWER B/G
Which is more anesthetic? HALOTHANE because its MAC is lower and more potent (percentage of gas is the same so just need to look at MAC)
One guy receives 1 MAC HALOTHANE and another receives 1 MAC ISOFLURANE
Faster? Easy – Isoflurane b/c lower B/G
More potent/anesthetic? BOTH ARE THE SAME SINCE 1 MAC = 1 MAC! The mixtures are different (1 MAC Halo means .74% Halo, 99.26% O2, 1 MAC Iso means 98.85% O2)
NITROUS OXIDE
Weak Inhalation Agent – UNCONSCIOUSNESS, AMNESIA, ANALGESIA
NEVER causes immobility or lowers SNS
“Laughing gas” - colorless, odorless, tasteless
B/G = 0.47 (RAPID ONSET/OFFSET)
MAC = 105 = VERY LOW POTENCY!!!! Super High
Use of Nitrous
Sole anesthetic for MINOR SURGICAL PROCEDURES (tooth extractions)
Can be administered with an IV anesthetic or a PIA to create more desirable effect
Good analgesia – ER, Ambulances,e tc
Need about 70% in the mixture to get “light anesthesia” – unconsciousness
MINIMAL CARDIAC/RESPIRATORY DEPRESSION :-)
Side Effects of Nitrous
Diffusion Hypoxia –> such a low B/G; rapidly returns to the alveoli and lungs during emergence; occurs so quickly that Nitrous can actually dilute the normal exchange of O2 and CO2 resulting in diffusion hypoxia –> WEAN PATIENTS off while SIMULTANEOUSLY delivering 100% O2 for 5-10 min
Some toxicity (BM function, Cell mediated immunity, liver function, vitamin B12) but toxicity should NEVER be reached in typical clinical scenarios
What are the FOUR criteria for general anesthetics again?
AMNESIA
ANALGESIA
IMMOBILITY
LOWERED SNS ACTIVITY
Potent Inhalation Agents accomplish this
Ultimate goal of general anesthesia?
To provide anesthesia with as LITTLE CARDIAC AND RESPIRATORY DEPRESSION AS POSSIBLE (these drugs do have dose-related cardiac and resp depression)
Measuring DEPTH of anesthetics
Monitor brain concentration by monitoring the END-TIDAL CONCENTRATION of the agent –> if at equilibrium, there is anesthetic in brain
CV monitors –> HR and BP should be lowered for deep anesthesia (i.e. if HR and BP are too high, it isn’t deep enough and vice versa)
EEG monitor –> placed on forehead to constantly track electrical activity of the brain
Guedel’s Clinical Signs –> combination of ocular, respiratory and somatic muscle tone signs
What are the SIMILARITIES of the PIAs?
Depress the normal ventilatory response to hypercarbia and hypoxia –> these are normally compensatory responses (i.e. body rapidly corrects pH to normal with compensated ventilation) –> These drugs alter the function of peripheral chemoreceptors that detect changes in blood pH
BronchoDILATORS
Inhibit mucociliary function – all PIAs do this, which causes mucous pooling and potential atelectasis; no mucocilia to sweep away pathogens –> can predispose to respiratory infection
Depress CNS –> dose-related CNS depression and thus a decrease in cerebral metabolic O2 consumption that slows metabolism; increase cerebral blood flow thus decreasing cerebral metabolic demand; this is the end goal of all anesthetics!
Depress NMJ –> depress neuromuscular activity, thus they can INCREASE THE DURATION OF MUSCLE RELAXANTS!
Malignant Hyperthermia RISK –> can be lethal!
HALOTHANE
Standard, prototype PIA
Rarely Used today (inexpensive though and used in the rest of the world!)
Addition of FLUORIDE MOIETY made it nonflammable and nonexplosive (direct contrast to ether!)
BUT…the alkane/fluoride structure is also responsible for the DYSRHYTHMIA potential –> sensitizes the heart to CATECHOLAMINES –> can be dangerous!
MAC = 0.74 = VERY POTENT B/G = 2.3 = DELAYED UPTAKE/RECOVERY
Non-pungent so it doesn’t irritate airways –> good for KIDS
Halothane effects on systems
CV –> dose-related cardiac depression (decreased MAP, contractility, CO and myocardial O2 consumption)
NO CHANGE SVR
NO CHANGE HR
Dysrhythmia potential
Pulmonary –> Dose related decrease in RESP FUNCTION –> decreased TV, leads to gradual rise in CO2 –> slight increase in RR
CNS –> Decreases electrical activity; INCREASES cerebral blood flow and blood volume through DILATION of cerebral vessels –> this INCREASES ICP!!!! Not good for neurosurge
Metabolism of HALOTHANE
Takes place in the LIVER! 15-20% recovered as metabolites –> HALOTHANE HEPATOTOXICITY
20% of patients receiving halothane get short-lived HEPATIC INJURY
Tiny percentage get FULMINANT TOXICITY = HALOTHANE HEPATITIS –> massive necrosis with 50-75% mortality rate!!!!!
This risk increases with previous halothane use/exposure
ENFLURANE
Primary PIA of 70s and 80s –> First ETHER anesthetic –> NO RISK FOR DYSRHYTHMIAS!
Moderately pungent, so not for kids!
B/G = 1.8 –> Lower than Halothane, so FASTER onset/offset
MAC = 1.68 –> HIGHER so LESS POTENT
Enflurane effects on systems
CV –> Dose related depression –> lowered MAP, CO, contractility and O2 consumption; ALSO DECREASES SVR and INCREASES HR (unlike halothane which doesnt affect either)
*Pulmonary –> Dose related depression (MORE SEVERE THAN HALO AND OTHERS!)
CNS –> Increases cerebral flow and volume (dilation of the vessels) – so increases ICP (less so than halo, but still concern)
Also has SEIZURE POTENTIAL!!!!! Contraindicated with seizure disorders
Metabolism of Enflurane
Only 2-3% recovered as metabolites
F- is the major one –> high levels cause RENAL IMPAIRMENT –> avoid in renal insufficient patients
ISOFLURANE
Less CV depression, NO CNS Excitatory effects (no seizures!), good muscle relaxation; ether, so no dysrhythmias
Moderately pungent (not for kiddos)
MAC = 1.15 –> Lower than others, HIGH potency
B/G = 1.4 –> Quick Onset/Offset
Isoflurane effects on systems
CV –> Dose related depression, but MAINTAINS CO (decreases SVR and increases HR!!!) –> best so far of Halo/Enflurane
Pulmonary –> Dose related depression, less severe than Enflurane (Halo is a little better)
CNS –> increases flow and volume, so ICP –> less so than Halo or Enflurane! Used with neuro patients but WITH CAUTION
Metabolism of Isoflurane
Good!! No evidence of renal OR hepatic failure!
