Sweatman - Anesthesia Flashcards
1
Q
What are the currently approved inhalational anesthetics?
A
- GASES: nitrous oxide (N2O)
- LIQUIDS (volatile): Halothane, Enflurane, Isoflurane, Desflurane, and Sevoflurane
- NOTE: these agents + the IV agents are capable of rendering the pt unconscious, and are sometimes referred to as general anesthetics
2
Q
What is analgesia?
A
- Relief of pain without intentional production of altered mental state (may be secondary)
3
Q
What is anxiolysis?
A
- DEC apprehension with no change in level of consciousness
4
Q
What is conscious sedation?
A
- Dose-dependent
- Protective reflexes maintained
- Independent maintenance of airway/O2 sats/ventilation
- Response to physical/verbal stimulation
5
Q
What is deep/unconscious sedation?
A
- Profound effects, with loss of 1 or more of the following:
1. Protective reflexes
2. Independent maintenance of airway/O2 sats/ventilation
3. Response to physical/verbal stimulation - NOTE: this state does NOT mean the pt is unconscious, but can be transitioned to unconsciousness with add’l drug application
6
Q
What is general anesthesia?
A
- Sensory, mental, reflex, and motor blockade
- Concurrent loss of all protective reflexes
7
Q
What are general anesthetics? Name 2 critical features of these agents.
A
- Agents capable of producing reversible depression of neuronal function, producing loss of ability to perceive pain and/or other sensations (and often loss of protective reflexes)
1. Maintaining patent airway often required, and + pressure ventilation may be needed to counteract depressed spontaneous ventilation or drug-induced neuromuscular blockade
2. Inhalational and IV dosing preferred bc they offer more immediate control over dose and duration of action -> minute-to-minute control
8
Q
What is the Myer-Overton hypothesis? Caviat?
A
- States that anesthetic activity is directly linked to lipid solubility
- Caviat: this is not the entire story -> modifying anesthetic agents to make them more lipid soluble can completely remove any anesthetic qualities, so this relationship is more complex than stated by the hypothesis
9
Q
How does lipid solubility affect anesthetic potency? How is this measured?
A
- Higher lipid solubility = higher potency of the drug in producing unconsciousness
- Lipid solubility is described by the physical chemical property known as the oil gas partition coefficient
1. Larger oil-gas partition coefficient = more lipid soluble drug
10
Q
What is MAC?
A
-
Minimum alveolar concentration: the concentration in inspired gas required to render half of a gp of pts unconscious/unresponsive to painful stimulus
1. Used clinically to compare/determine potency of different anesthetic agents
2. Lower required MAC = more potent anesthetic - In clinical practice, it is customary to titrate dose of anesthetic upwards to successfully anesthetize patients
11
Q
What are the common mechanistic attributes of the inhalational anesthetics (chart)?
A
- COMMON: potentiation of INH and INH of stimulatory pathways in the CNS
1. Reinforcement of GABA and glycine INH signalling
2. Reinforcement of two pore potassium channel activity
3. Inhibition of glutamatergic signaling - NOTE: subtle differences in activity on other receptor systems gives rise to differences in effects experienced by patients receiving anesthesia
1. All 4 also INH NMDA and Ach
2. Isoflurane potentiates serotonin; others INH it
3. Only NO does NOT INH voltage-gated K channels
12
Q
How does anesthesia affect cortical interactions? Compare this to wakefulness.
A
- ANESTHESIA: feedback transfer entropy (red) reduced, implying DEC in front-to-back interactions
- WAKING: transfer entropy, a measure of directional interactions among brain areas, is balanced in feed forward (green) and feedback directions
- NOTE: in the bottom image, an awake rat shows a response in the visual occipital cortex, then the parietal association cortex when exposed to a flashing light
1. Under anesthesia, the occipital response is preserved (shorter), and the parietal response is attenuated, indicating anesthesia reduces cortical interactions, reducing integration
13
Q
Where in the body do anesthetics have an effect?
A
- The agent distributes throughout the body, incl. to peripheral neurons
- Overall effect of the drug includes:
1. Direct effect in the CNS, AND
2. Modulation of ascending neural pathways to the CNS, AND
3. Modulation of descending pathways to peripheral tissues
14
Q
What are the Guedel stages of anesthesia? What changes precede and follow them?
A
- INITIAL admin of anesthetic yields a period of delirium: exaggerated mechanics of respiration (incl. breath holding), INC in BP and skeletal mm tone, dilation of pupil
1. Probably from removal of INH neural pathways prior to anesthetic concentrations being achieved - NEXT, pt slips into unconsciousness w/dose-dependent loss of respiratory function, CV function (decline in BP), and loss of protective reflexes and mm tone
- LASTLY, pt who is very deeply anesthetized is at greater risk of expiring during procedure + will take much longer time to recover consciousness -> anesthesiologists must maintain sufficient depth of unconsciousness for clinical procedure, while not producing too deep a level of unconsciousness
15
Q
What 2 “functions” are lost first when administering anesthetic to a pt?
A
- Explicit memory and perceptive awareness
1. These losses can precede production of analgesia, so it is customary in anesthesia to rely on analgesics to ensure pt is pain-free - NOTE: action on the various neuronal pathways requires different drug concentrations
16
Q
What is unique about the structure of the volatile agents?
A
- Simple, diverse, and contain a halogen, like FLUORINE
1. Propensity for fluorine to produce renal damage and dysfunction, BUT
2. Fluorine also removes the explosive nature of the volatile liquids (which have the capacity to explode given the vital spark) - NOTE: claims that one isomer of these asymmetric carbon atom racemic mixtures possess greater anesthetic potency, but no definitive evidence of this
17
Q
What are volatile anesthetics most often administered with? How do you calculate the partial/tension pressure of the gases in the mixture?
A
- Volatile anesthetics are most commonly administered in conjunction with nitrous oxide and oxygen
- Multiply their percentage in the mixture by the total pressure (760 mm Hg at sea level) -> partial pressure is thus proportional to the gas’ concentration in the overall mixture
18
Q
What is the significance of the blood/gas partitioning #’s for the volatile liquid anesthetics?
A
- Equilibration of the anesthetic gas between alveoli and bloodstream is a gradual process -> when completed, the partial pressure of anesthetic component in admixture is equal to that in the systemic circulation
- The absolute mass of anesthetic is different, however, and dictated by the blood/gas partitioning characteristics of the individual agent
- For halothane, the # is 2.3, which means at equilibrium, where Halothane occupies 2% volume in gaseous phase, it occupies 2.3x that, or 4.6% volume, in the blood -> the partitioning # is:
1. Different for each inhaled gas, and
2. Is the major reason for differences in anesthesia onset time when the mask is applied
19
Q
What are some of the differences b/t MAC’s, partition coefficients, and metabolism of the inhalational agents?
A
-
MAC’s: note how little of the anesthetic is required in the mixture to produce unconsciousness (Halothane lowest and nitrous oxide highest)
1. 105% MAC for N2O: incomplete anesthetic that is useful when mixed w/a volatile agent (additive effect in producing unconciousness, so dose required for individual effect approximately halved) -> no good for major surgery if used alone (hyperbaric chamber) - BLOOD/GAS FIGURES: newer drugs like Sevoflurane and Desflurane (lowest) require far less accumulation than Halothane (highest), so equilibration is achieved more rapidly
- As with the blood, the newer anesthetics equilibrate more rapidly into the BRAIN than does Halothane -> this accounts for some of the differences seen in time taken to produce unconsciousness
- METABOLISM: 20% of Halothane (highest) metabolized (mostly hepatically), but the newer agents (Desflurane lowest) and N2O undergo very little conversion
- NOTE: Xenon has a very rapid equilibration, but cost is prohibitive for use as an anesthetic
20
Q
How does lipophilicity affect time to equilibration?
A
- The lipophilic anesthetic agents dissolve in the lipid component in the blood (analogous to o/drugs binding to plasma proteins) -> this dissolved fraction is incapable of equilibration into o/tissues
1. More lipophilic = more time to equilibration - While all of the inhaled agents are lipophilic, they vary in the degree of lipophilicity
1. IMAGE: comparison of equilibration of relatively insoluble N2O and very soluble halothane -> N2O reaches saturation in blood rapidly in comparison to vast appetite blood lipid has for halothane, which must be assuaged before substantial quantities can reach the brain (this process takes time)
21
Q
How do the partitioning differences b/t the anesthetic agents impact their entry into AND escape from tissues?
A
- Newer agents (Desflurane and Sevoflurane) equilibrate more rapidly into the brain and produce a faster onset of unconsciousness than does Halothane
- At the same time, once the procedure is finished and the anesthetic turned off, the newer agents rapidly re- equilibrate from the brain to blood and then to alveoli, flooding back into the lungs and permitting a more rapid recovery of consciousness than with halothane
22
Q
How are anesthetics distributed in the body? Why is this important?
A
- As with any drug, they are freely distributed in the body based on partitioning characteristics and blood supply to the tissue
- This is how the ascending and descending neuronal signals to the brain can be modified
- NOTE: red arrows indicate induction pathways, and blue arrows indicate emergence pathways (large arrows indicate net movement of the anesthetic agent)
23
Q
In what sequence do anesthetics distribute into and are they eliminated from the body?
A
- Accumulation is dependent on rate of delivery to the tissue, and occurs most rapidly with high-flow organs, incl. the brain, and less rapid distribution into skeletal mm and adipose tissue
- Once anesthetic is turned off, elimination of drug is most rapid in high flow organs
1. Overall duration of elimination is governed by rate of release from adipose tissue - NOTE: while highly lipophilic drugs tend to accumulate in fat, this only occurs to a significant extent w/protracted anesthetic administration
24
Q
What are 6 factors that influence the rate of anesthetic equilibration into the brain?
A
- Concentration of inspired gas: this is the only factor the anesthesiologist has calibrated control over
1. Onset of unconsciousness after mask application can be hastened by temporarily INC % of anesthesia delivered w/e/breath (i.e., may be at 1.3% during sx procedure, but 5% during anesthesia induction) - Respiration rate
- Solubility: partition coefficient
- Rate of blood flow to the lungs
- Cardiac output
- Tissue distribution
25
Q
How can ventilation rate affect the delivery of anesthetic to the blood?
A
- While this parameter is not adjusted clinically, delivery of anesthetic to the blood can also be hastened by INC the ventilation rate
1. Higher ventilation rate = higher rate of distribution to the blood - This has a more profound effect on rapidly equilibrating N2O than it does on halothane, which must saturate a much larger component of the blood in order to reach equilibrium
26
Q
What are the respiratory effects of the inhaled agents?
A
- INC respiration rate and DEC tidal volume, leading to regular, rhythmic, shallow breathing
- Reflex response to PaCO2 blocked by all except N2O (this is an important benefit of this agent)
- In sum, with INC delivery of anesthetic and depth of unconsciousness, there is both a loss of responsiveness to rising carbon dioxide levels and a reduction in tidal volume
27
Q
How is the CV system affected by the inhalational agents?
A
- INC drug delivery & depth of unconsciousness = DEC blood pressure and cardiac output (varies by agent)
- Potential places in neuronal control of CV system where this may occur (may be a combo of these):
1. Direct depression via DEC SYM outflow
2. Peripheral ganglion blockade, leading to DEC adrenal catecholamine release
3. Baroreceptor attenuation via DEC Ca2+ flux and vagal stimulation - N2O has no significant CV effects unless it is given with opioid, which blocks reflexive sympathomimetic effects
- NOTE: this is dependent on concurrent pathology and medical hx, cardioactive drugs, & mechanical ventilation
28
Q
What are some of the key differences b/t the various inhalational anesthetics (AE’s, pain relief, mm relaxation)?
A
- Pungent odor may irritate some pts, and produce tracheobronchial irritation
- NO reliable production of analgesia, except for N2O
- NO effect on mm relaxation, except for Isoflurane and Enflurane
- All volatile agents lead to loss of protective reflexes (except N2O when used alone)
- HALOTHANE sensitizes the myocardium to circulating catecholamines, and can be pro-arrhythmogenic
1. Can also cause halothane hepatitis: metabolism in liver can give rise to highly-reactive intermediate that binds to hepatic protein and causes damage; observed most frequently in women who had experienced prev exposure to this agent (damage involved some immune component)
2. Halothane now RARELY (if ever) used clinically in the US (replaced by newer agents) - ENFLUORANE pro-epileptic in susceptible individuals, an effect not recorded with the other anesthetic agents
- NOTE: regardless of mm relaxation or pain relieving qualities, it is customary to admin NM blocking drug and an analgesic (N2O or opioid)
29
Q
What are some of the potential AE’s of N2O?
A
-
Teratogenic in animal models: scavenging equipment to minimize ambient levels of anesthetic gases
1. Reports of INC spontaneous abortion rates in F exposed to drug in workplace
2. Sporadic reports of neuro deficits in infants due to myelin sheath degeneration on chronic exposure - INH of Vit B12 synthetase, and def may lead to myelin sheath degeneration, but there has been no evidence of this in the literature (even after millions of exposures)
30
Q
What are 3 special problems with N2O?
A
- SECOND GAS EFFECT: high volume of N2O in the admixture + relative insolubility = rapid uptake of gas from alveoli, including any accompanying anesthetic or O2 (via mass action-effect)
- DIFFUSIONAL HYPOXIA: admin O2 to maintain oxygenation in immediate post-anesthetic phase bc lg quantities of anesthetic gas exiting body via exhalation
- N2O SOLUBILITY: 34x that of nitrogen, so potential problem with air spaces (bowel sx, pneumothorax, middle ear) -> possibility of INC pressure in gas-containing areas of the body (may lead to perforation of ear drum)
31
Q
Why do we use N2O?
A
-
Distinct pharmacologic properties: analgesic action, lack of effect on protective reflexes, minimal adverse effect on heart and respiration
1. Reduces potential CV and respiratory AE’s - Differs significantly in unit cost compared with volatile agent -> bc anesthetic effects are additive, reduced requirement for expensive volatile component of the mixture, saving cost
32
Q
How much of the typical admixture is nitrous oxide? What are the potential benefits of DEC this amount?
A
- Nitrous oxids is the major component of the inhaled admixture -> 70 to 80% of total volume
- Need to accommodate such a high volume of N2O compromises ability to provide high levels of O2
- A # of clinical papers have outlined potential benefits of INC O2 tension during sx procedures, which appears to:
1. DEC infection rate
2. Lower post-op complications
3. Lower the incidence of N/V, and
4. DEC other unfortunate attribute of nitrous oxide - We may see change in N2O usage in the future
33
Q
What are the current IV anesthetic agents (induction and additional)?
A
- INDUCTION AGENTS: Thiopental (was most common, but largely supplanted by P and E), Propofol, Etomidate (barbiturate)
- ADDITIONAL AGENTS (onset of action longer than that for the induction agents, but commonly part of anesthetic regimen):
1. Ketamine, Diazepam, Lorazepam, Midazolam
2. Morphine, Meperidine, Fentanyl, Remifentanil
34
Q
What are the 4 pillars of balanced anesthesia?
A
- Relieve anxiety
- Relax muscles
- Induce unconsciousness
- Prevent secretions
- NOTE: by combining several drugs, e/with a specific purpose, minimum concentration of e/drug can be employed while ensuring pt’s comfort and well-being are not compromised
35
Q
What is the “formulation problem” for the IV anesthetics? Solutions? Side effects?
A
- PROBLEM: lipophilic drugs dissolved in aqueous solutions
- SOLUTIONS: pH adjustments (Thiopental in Na2CO3)
1. Propylene glycol surfactant (Etomidate)
2. Egg phosphatide, soybean oil, glycerol, EDTA, sodium metabisulfate (Propofol) - SIDE EFFECTS: drugs formulated w/surfactants can sometimes give rise to a direct toxicity to the lining of the vein into which it is being administered, aka thrombophlebitis
1. This can sometimes be avoided by diluting the drug and giving it more slowly bc a concentration and speed sensitive event - NOTE: Fospropofol was a 2nd-gen pro-drug devo’d to INC solubility, but was withdrawn from the market
36
Q
How do the structures of the IV anesthetics differ from those of the inhalational drugs?
A
- In comparison with the inhalational drugs, the IV anesthetics are chemically much more complex
- Note the different structural classes (attached) and resultant different receptor specificities
37
Q
Do all IV anesthetics affect the CNS in the same manner?
A
- NO: just because 2 drugs can both anesthetize the patient, it does not mean the unconscious state is produced in precisely the same manner in each
- IMAGE: rat brains with radiolabeled glu to measure metabolic activity -> highest in red areas, lowest blue
1. Note that Thiopental reduces neuronal activity throughout the brain, while Ketamine is much more selective in the areas of the brain it has impacted
38
Q
What are the chief targets of the IV anesthetics in the CNS (chart)?
A
- Act primarily by reinforcing the INH action of GABA and glycine
- Propofol and Ketamine also INH the NMDA receptor system for glutamate
- All of these also exhibit at least minor INH of nicotinic and muscarinic Ach receptors
- Barbiturates show minor INH of serotonin, while Ketamine shows minor potentiation of serotonin
- NOTE: inhalational drugs differ in that they all INH NMDA receptors and also potentiate two pore K+ channels
39
Q
How are the MOA’s of the barbiturates, benzos, Etomidate, and Propofol similar? Which of these is most unique?
A
- All act to reinforce the INH effects produced by endogenous GABA binding its receptor
- PROPOFOL: unusual in that at high concentrations it is capable of functioning like GABA itself
40
Q
Which 2 IV anesthetics have action in INH glutamate signaling? How do their MOA’s differ in this respect?
A
- Ketamine and Propofol
- But, they work at different locations to interrupt the function of the ion channel
1. Propofol blocks binding of glutamate to its receptor (NMDA)
2. Ketamine works to physically occlude channel
41
Q
Describe the 2 ascending arousal systems. Why are these important to understanding the effects of the drugs presented in this series of lectures?
A
- CHOLINERGIC: cell groups in upper pons, pedunculopontine (PPT), and laterodorsal tegmental nuclei (LDT) activate the thalamus
- MONOAMINE: activates cerebral cortex to facilitate processing of inputs from thalamus –> arises from neurons in monoaminergic cell gps, incl. tuberomamillary nucleus (TMN) containing histamine, A10 cell gp (DA), dorsal and median raphe nuclei (serotonin, 5-HT), and locus ceruleus (noradrenaline)
1. Also receives contributions from peptiderfic neurons in lateral hypothalamus containing orexin or melanin P concentrating hormone and from basal forebrain neurons that contain γP aminobutyric acid (GABA) or ACh - GABA functions as a negative reulator of these ascending pathways, and is an INH of neuronal activity in the cortex itself
- Integral nature of these multiple neuronal pathways in maintenance of consciousness shows how drugs as diverse as antihistamines, anticholinergic, and GABA reinforcers can all produce sedation as an intended or adverse effect
42
Q
How do the barbiturates and the benzos affect the GABA A receptor? Differences? Similarities?
A
- BARBITURATES: prolong binding of GABA to its receptor, INC strength of INH effects of endogenous GABA -> INC efficacy
1. At high concentrations, they are capable of opening Cl- channel in the ABSENCE of GABA - BENZOS: cause allosteric change in receptor activity, shifting the dose-response curve for GABA binding to the left -> INC potency, but NOT efficacy
- This difference translates to a significant difference in safety of the 2 drug classes
- BOTH require endogenous GABA to reinforce the INH actions of GABA in the CNS
43
Q
How do the safety profiles of benzos and barbiturates differ?
A
- With INC dose, barbiturates produce greater CNS depression, ultimately leading to coma and death
- Benzos, on the other hand, exhibit a “ceiling effect,” in the extent to which they produce CNS depression
1. Greater safety for benzos compared to the barbiturates
2. Except when combined with other CNS-depressants, like drugs or alcohol, it is very difficult for a patient to OD on benzos
44
Q
Describe the time course of IV anesthetic distribution in the body. Compare this to the inhalational anesthetics.
A
- When compared with the onset of anesthesia with an inhaled anesthetic, the effects of an IV induction agent are almost instantaneous
- Drug rapidly distributes out of plasma into high flow organs, and then over time, re- distributes to other organs and ultimately to adipose tissue
- Accumulation in adipose tissue is governed by the relatively poor blood supply -> ultimate release of drug from adipose tissue is the rate limiting step in final elimination of drug following surgery
45
Q
Describe the pharmacokinetic profiles of the IV anesthetics.
A
- LONG elim half-lives, but SHORT duration of action
- Rapidly distribute into CNS, but easy passage back out of brain when concentration gradient inverts
- Short duration of action in the CNS if applied as a single dose w/o supplementation
- Awakening of pt is due only to drug re-distribution; timescale is far too short for metabolism or excretion to have had a meaningful impact upon drug load in the body
46
Q
What 3 factors affect the half-lives of IV anesthetics? How do these influence the behavior of anesthesiologists?
A
- After prolonged infusions, drug half-lives & durations of action dependent on complex interactionn b/t drug redistribution, accumulation in fat, drug metabolic rate
1. Half lives of several agents INC dramatically w/duration of drug administration - Anesthesiologists use this info to reduce rate of drug admin as sx proceeds to ensure accumulation does not get out of hand
1. It is possible for admin of some drugs to be terminated before sx is complete in the certain knowledge that levels of drug in the body are sufficient for the remainder of the procedure
47
Q
What are some things that can affect the CV response to the IV anesthetics?
A
- May vary from patient-to-patient, as dictated by individual factors shown in the attached image, like:
1. Environmental factors,
2. Concurrent drug therapy, and
3. CV pathology
48
Q
What are some of the pharmacological effects of a single induction dose of the IV anesthetics on the brain, CV, and respiratory systems (table)?
A
- CEREBRAL VASCULATURE: w/exception of Ketamine, remaining drugs have depressant effect on cerebral BF, O2 requirements, and intracranial pressure
1. These are consistent w/general CNS-depressive effects produced
2. Ketamine INC cerebral BF and ICP - CV SYSTEM: divergence in drug effects
1. Thiopental and Propofol: slight stimulatory effect on HR and INH effect on CO and MAP
2. Etomidate: no discernible effect on heart or vasculature (good for cardiac patient)
3. Ketamine: cardio-stimulatory - RESPIRATORY FUNCTION: with the exception of ketamine, remaining agents have an INH effect
49
Q
What is a unique AE of Thiopental?
A
- Porphyria, enzyme induction
- Barbiturates are quintessential CYP enzyme inducers: potential drug-drug interactions + exacerbation of porphyria
50
Q
What is unique about Propofol?
A
- Anti-emetic: useful when sx involves drugs that produce N/V as an AE
- Propofol infusion syndrome: protracted Propofol admin can lead to life-threatening and ultimately fatal CV and organ-systems failure of unkown etiology in some pts (little understood phenomenon that is currently under investigation)
51
Q
What is unique about Etomidate?
A
-
INH of steroidogenesis: potentially fatal adverse consequences (fatalities documented in elderly care facilities following protracted admin)
1. Reductions in cortisol levels can be observed following just a single dose; in this instance, however, no long-term consequences ensue - Not used in the ICU for the above reason
52
Q
What is unique about Ketamine?
A
- Analgesic; IM route when venous access impractical
- Intact pharyngeal/laryngeal reflexes
- Bronchodilator for refractive asthma
-
Hallucinations w/emergence from unconsciousness: may require tx with benzo
1. Structurally, ketamine related to phencyclidine (Angel-dust)
53
Q
What is a dissociative anesthetic? Which drug does this name apply to?
A
- KETAMINE is a dissociative anesthetic: patients unconscious from this drug may actually present with their eyes open, although they are unconscious and pain free
- “Lights on, but nobody is home”
54
Q
What is propofol infusion syndrome? Risk factors? Tx?
A
- IATROGENIC disease: metabolic acidosis, rhabdo of skeletal and cardiac mm, arrhythmias, myocardial and renal failure, hepatomegaly
- RISK FACTORS: poor oxygen delivery, sepsis, serious cerebral injury, high propofol dosage
- TX: stop drug, cardiocirculatory stabilization, correction of metabolic acidosis -> hemodialysis
1. Pts usually minimally responsive to inotropes or cardiac pacing, i.e., diminished response to cardio-active drug support
55
Q
What are the benzodiazepines and their attributes? Metabolism/half-lives?
A
- Useful when no analgesia is required
- Anticonvulsant, amnesia; while they could be used to produce unconsciousness, onset of effect would be longer than that for Propofol, Etomidate, or Thiopental
- Wide therapeutic safety margin (unlike barbiturates)
- Specific antagonist: Flumazenil -> acute AE’s can be rapidly reversed
- Minimal CV and respiratory depression if used alone: use with opioids suggests sympathomimetic effect (like N2O)
- Drugs in attached table are those most commonly assoc w/anesthetic regimens -> selected based on required duration of effect (shown in table)
56
Q
When might you observe a cardiodepressant effect with the benzos?
A
- Where a cardio-active drug prevents INC in HR or contractility OR hemorrhage prevents blood mobilization from periphery
- NOTE: under normal circumstances, benzos produce little discernible action on CV system -> venodilation or reduced CO are typically compensated for in manner shown in the attached image
57
Q
What are the pluses and minuses of opioid use during surgery?
A
- PRO: absence of direct effects on heart, maintenance of regional BF auto-regulation, DEC airway reflexes (facilitating intubation), pain relieved but pt arousable, and non-organotoxic (no malignant hyperthermia)
- CON: incomplete amnesia, histamine-related rxns, INC blood requirements, prolonged respiratory depression in ICU, CV instability (bradycardia, hypo- or HTN, addition of N2O results in CV depression)
58
Q
How can opioids affect the CV system?
A
- Depends on speed of injection, presence of other cardioactive agents
- BRADYCARDIA: via vagus or directly on SA/AV nodes
- HYPOTENSION: secondary to histamine release
- HTN: reflex (light anesthesia), renin-angiotensin effect, intense pressor effect w/Naloxone (catecholamine release?)
- NOTE: Morphine and synthetic (potent) Fentanyl congeners; act at opiate receptors (OP1-3) in spinal cord and CNS
59
Q
What are some of the AE’s associated with the opioids?
A
- Dose-dependent resp depression: DEC PaCO2 responsiveness in carotid bodies, reversal with antags (Naloxone, Nalmefene), but run risk of INH analgesia
1. Entero-hepatic recirculation of opioid - Muscle rigidity: “wooden chest” syndrome
- INC intracranial BF and pressure (INC PaCO2)
- N/V, constipation, miosis
- OD triad: pinpoint pupils, DEC respiration, coma
60
Q
How do anesthetics affect the normal ventilation response to PaCO2?
A
- When an opiate is admixed w/an anesthetic, both components produce depressant effects on reflexive PaCO2 stimulation of respiratory function
- Anesthesiologist carefully monitors this parameter during surgery
77
Q
What is the MOA of the local anesthetics?
A
- Thought to work on voltage-gated Na+ channels involved in process of neuronal conduction
- Drug must be capable of passing through neuronal membrane (lipophilic) to reach binding site on inner surface of Na+ channel
- Portion of drug action also thought to arise from local anesthetic dissolved in neuronal membrane, leading to swelling, or loss of flexibility, modulating normal Na+ channel function
- In presence of local anesthetic, critical threshold for spontaneous opening of Na+ channels in immediate vicinity is never reached, so AP not propagated
- NOTE: image on bottom left a theoretical MOA that has never been clinically proven
80
Q
Where in the neural path do local anesthetics work? How is this different than the opioids?
A
- Local anesthetics block voltage-gated Na+ channels located in the NERVE AXON
1. They have NO EFFECT in dorsal horn of spinal cord (synaptic connection w/2o neurons) or at afferent nociceptors (where opiates act)
81
Q
Describe the concept of frequency-dependent blockade by the local anesthetics. Implications?
A
- Bulky drug prefers activated or inactivated states, where access to channel binding site is possible due to arrangement of its 4 subunits (spatial distance)
1. Given that activated state is so transient, majority of drug binding takes place with inactivated Na+ channels - Frequency of NN depolarization is important in allowing drugs to access binding site in Na+ channel
1. These drugs are more effective when NN is more spontaneously active
82
Q
What is the pKa of most of the local anesthetics? Why does this matter?
A
- Majority of local anesthetics are WEAK BASES with a pKa of around 8 -> basic drugs most likely to be in their non-ionized form when pH > or = pKa
- Local anesthetics must pass through lipid envo of neuronal mem to reach binding site on inner surface of Na+ channel -> passage of any drug across bio mem contingent on drug being in neutral of uncharged state
- These drugs are most likely to have access to binding site when pH outside the neuron > 8
83
Q
What is the pH within nerves? How much of the drug will reach its binding site if the extraneural pH = 9?
A
- Invariant at approximately 7
- At extraneural pH of 9, 10x more drug exists in neutral state and passes easily across NN membrane
- Once inside NN, based on local pH of 7, 10x more drug exists in ionized/charged form, which is necessary for binding to Na+ channel binding site
84
Q
How much local anesthetic will reach its binding site if the extraneural pH = 6? Implications?
A
- Only extremely low proportion of applied drug can access the NN -> 1/100 exists in non-ionized form outside NN, then only multiplied by 10x upon entry
- This will lead to a weaker and less durable NN block (or a failed one); for this reason, app of local anesthetic in areas of inflammation is discouraged (more acidic)
1. Invariably leads to doc reapplying drug and potentially surpassing recommended dose; this can lead to acute toxicity and untimely demise
85
Q
What are the 3 anatomical aspects of NN block?
A
- 1) Anesthetic diffuses down concentration gradient: block runs proximal to distal
a. Fibers in center of bundle serve distant body locations and those in outer layers serve local anatomic locations -> blocking effect most rapid in outer fibers/local areas and progresses to distal tissues - 2) Diffusion, dispersion, dilution, absorption
- 3) Concentration gradient now reversed: recovery runs proximal to distal
a. Outer fibers lose blocking concentration most rapidly, while those in center of bundle retain blocking conc longest -> NN function regained in proximal tissues most rapidly - THIS PHENOMENON IS NOT DUE TO LOCAL ANESTHETIC, BUT ANATOMIC CONSIDERATIONS
86
Q
Briefly describe the importance of the structures of the local anesthetics.
A
- In order to bind Na+ channel receptors, these drugs require an amine and type of aromatic appendage to provide lipophilicity
- Linker region of some significance with regard to site and extent of metabolic degradation (amides HEPATIC; esters NON-HEPATIC)
- NOTE: actual structure more complex, with each component impacting pKa, lipophilicity, and kinetics of drug binding its receptor
87
Q
Which drug is the exception to the “i” = amide rule? How so?
A
- ARTICAINE: classified as amide, but loss of biological activity after ester cleavage
1. Rapidly metabolized to articainic acid, inactive product (non-hepatic) - NOTE: also has thiophene ring (to give it lipophilicity) rather than benzene ring in other agents
90
Q
What happens to the local anesthetics following drug infiltration? Implications?
A
-
Systematization: only a small portion of applied drug produces neuronal blockade (see figure for other pathways)
1. Rate and extent of systematization has important consequences for pt safety
91
Q
When should you be prepared for systemic toxicity with the local anesthetics? How can you avoid this?
A
- Be prepared for toxicity:
1. When approaching maximal dosing limits
2. Whenever there is potential for a direct IV injection - First part of treatment is AVOIDANCE: stay below max recommended dose, and use every effort to avoid inadvertent IV injection
- Ask pt to report symptoms of minor toxicity (these are typical early symptoms for non-dental drug app):
1. Ringing in ears, metallic taste, numbness of lips and tongue
2. If reported, STOP injection IMMEDIATELY
92
Q
What are the systemic toxicities experienced with rising serum levels of local anesthetic?
A
- See attached image for those of Lidocaine
1. Initial anticonvulsant/anti-arrhythmic axns for which Lidocaine is sometimes used clinically give rise to CNS excitation, then depression, coma, respiratory and CV arrest - Although serum concentrations at which such effects are experienced varies from drug to drug, these are common events
94
Q
How are vasoconstrictors used with the local anesthetics?
A
- Vasoconstrictors PROLONG DURATION (several-fold) and IMPROVE INTENSITY of blockade
1. W/o vascoconstrictor, removed anesthetic cannot aid in NN blockade - Local anesthetics move down concentration gradient, but co-admin of vasoconstrictor temporarily removes gradient b/t infiltrated drug and vasculature, permitting larger portion of drug to pass down gradient into adjacent NN bundle
96
Q
What are the most common vasoconstrictors used in the US? What are some complications and interactions you should be concerned about?
A
- Epinephrine or Levonordefrin
- Most complications due to injection anxiety: pallor, unrest, sweating, fatigue, palpitations, N/V (possibility that epi producing cardio tonic effect)
- Toxic rxns may be evident: in small children with large doses, or exaggerated responses with sedatives
- Interaction possible with: beta-blockers (attached image), TCA’s, halothane, HTN, heart block, cerebral vascular insufficiency, drugs that affect SYM NS
- NOTE: aspiration test will not always show i.a. placement
97
Q
In which pre-existing conditions should you be worried about the admin of epinephrine?
A
99
Q
Compare the physical and chemical properties of the local anesthetics. Which are the fastest-acting? Most potent (table)?
A
- Most potent: Procaine, Mepivacaine, Prilocaine (rapid onset)
- Least potent: long-acting drugs
100
Q
What components of the local anesthetics determine their potency, time of onset, metabolism, and duration?
A
- POTENCY: lipid solubility -> enhanced diffusion
- TIME OF ONSET: dissociation constant -> determines amt of drug in lipid-soluble state (lower pKa)
- METABOLISM: chemical linkage (hepatic vs. non)
- DURATION: protein binding -> determines affinity for binding site on Na+ channel
106
Q
What are some things that affect drug distribution when administered epidurally?
A
- Baricity (density compared to CSF) and patient orientation
- Larger dose = higher block; higher concentration = higher block; higher volume = greater spread
- INC solution temp = INC spread: solution becomes viscous (thick, sticky) at low temp, limiting CSF spread
- Diffuses across dura to act on NN roots (rather than spinal cord itself): subarachnoid injection blocks same NN -> also diffuses into paravertebral area via inter-vertebral foramina, producing multiple paravertebral blocks
107
Q
How can baricity be adjusted? How does gravity influence mvmt in spinal cord based on baricity?
How could this be useful?
A
- ISOBARIC (mix local anesthetic w/CSF) = remains essentially at level injection was made
- HYPERBARIC (mix LA w/dextrose solution) = migration of solution downwards, relative to gravity (actual direction depends on positioning of pt)
- HYPOBARIC (mix LA w/sterile water) = drug will move upwards, relative to gravity
- EXAMPLE: prior to hip replacement sx, density of drug solution and pt orientation may be combined to produce neuronal blockade only on side where sx will take place
122
Q
What are benzos used for perioperatively? Provide some examples.
A
- Sedation, amnesia, anxiolysis
- NO ANALGESIA
- Choice would be dictated by intended duration of drug action (see attached image)
1. SHORT: Midazolam
2. LONG: Diazepam
124
Q
What effects do H1 antags provide that H2’s do not?
A
- H1 antags (1st-gen) produce sedation +:
1. Anti-cholinergic effect, drying secretions
2. Prophylaxis of emesis - These are in direct contrast to H2 antags (i.e., Ranitidine) that provide none of these
125
Q
How are the opioids used peri-op? Problems?
A
- Analgesia -> ONLY IF PT IS IN PAIN
- Act on opioid receptors in CNS + spinal cord (note that Morphine is the only one listed here that can’t be given PO)
- PROBLEMS: orthostatic hypoTN, epigastric distress, antidiarrheal, INC sphincter tone
1. N/V via chemoreceptor trigger (dopa antag) + delay of GI transit (must be restored b4 pt can be discharged) + INC GI secretions
2. Resp depressant + coma-inducing + miosis-inducing (characteristic triad of OD)
131
Q
Why are peri-op antiemetics critical? Potential targets?
A
- N/V esp. troublesome in day surgery
- May arise from med condition or drugs used as part of anesthetic regimen (i.e., nitrous oxide)
- Routine prophylaxis:
1. Wide choice of agents
2. Costs vary - TARGETS: dopamine, serotonin, muscarinic, histamine, opiate receptors to prevent emesis arising from CTZ or emetic signals from GI tract
- EXAMPLES: Ondansetron, Scopolamine
134
Q
How are anti-chol used peri-op? Provide some examples.
A
- Used pre-op; lack of specifity -> use “as needed”
- Tx of reflex bradycardia
- Block musc effect of anticholinesterases, which INC activity at both nicotinic and muscarinic receptors
- Drying of secretions
- ATROPINE: most appropriate to block vagal activity
- GLYCOPYRROLATE: most potent in reducing tracheo-bronchial secretions
135
Q
What is done for rapid sequence intubation (RSI) prophylaxis?
A
- In the few minutes immediately preceding intubation:
1. Oxygenation: gives anesthesiologist several mins to accomplish successful intubation before O2 tension declines substantially (see attached image)
2. Pre-tx in high-risk pts (3 min wait) with prophylactic drugs
136
Q
What 4 drugs may be used prophylactically in RSI? How? What for?
A
- Used for situations in which pts may experience raised ICP
- Also used in younger pts with bradycardia from sustained vagal stimulation
- Admin PRIOR TO intubation: having waited 2-3 mins for drugs to take effect, pt then receives sedative and short-acting NM blocker (usually succinylcholine)
- NOTE: vecuronium is a non-depolarizing NM blocker
142
Q
What are some drug types that can cause delirium and cognitive decline (table)?
A
- This includes not only drugs commonly admin’d in peri-op period, but also to chronic drug tx, for example, in tx of Parkinson’s disease, which therapy would be maintained during hospitalization
143
Q
What variables are associated with delirium and cognitive decline (table; 5)?
A
- Cognitive decline may have occurred prior to sx
- There appears to be little correlation bt cognitive decline and:
1. Type of anesthesia and
2. CV stability in post-op
144
Q
Why is there such a high likelihood of drug-related complications in the peri-op period?
A
- More drugs than at any other time: 8-10 pre-op and 8-10 during anesthesia (see attached image: incidence of adversity INC dramatically once you reach 10 drugs)
- Possibility of other concurrent meds
- COMPLICATIONS:
1. Admin
2. Allergic/immune rxns
3. Drug-drug interactions: other anesthetics, ancillary meds in “cocktail,” longstanding meds unrelated to sx - Genetic predisposition to unusual rxn
146
Q
What are some drugs that are maintained during hospitalization (table)? Why?
Provide 2 examples of things that will most likely be managed differently peri-op.
A
- Better for pt to maintain good drug control of long-standing conditions that to have to deal with add’l health variable as these drug levels decline, and the condition worsens during hospitalization
- Diabetes: slide we don’t have to memorize about approach to managing glycemic control
- Coagulation: same as above
