Pharm General & Local Anesthesia (12/13)
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Example of Historical Anesthesia
- Nitrous oxide: still used today
- chloroform, diethyl ether, trichloroethylene, cyclopropane, halothane, & methoxyflurane
- ether & cyclopropane are highly flammable
- others were fazed out chiefly because of nephrotoxicity & possible hepatotoxicity
What are newer anesthetics more commonly used today?
- there's little structural or chemical relationship between these substances
- reversible loss of consciousness
- the cyclical pattern of electrical activity in the brain that occurs during sleep is absent during anesthesia
- respiratory & hemodynamic parameters should remain stable
- should include hypnosis (sedation), analgesia (pain relief), & muscle relaxation (to reduce unwanted movement during surgery)
- muscle relaxation can come about by using paralyzing agent (NMB eg. non-depol pancuronium) or deep levels of an inhalation agent
The Bispectral Index (BIS)
- used to monitor the activity of the CNS while a patient's under general anesthesia
- a unit-less scale to assist in determining a potential loss of consciousness
- lower numbers correlate with reduced consciousness
- eg. a BIS of 100 means the patient is awake
- 70 = light hypnotic state (low explicit recall)
- 60 = moderate hypnotic state (low consciousness)
- 40 = deep hypnotic state - EEG suppression
What is the mechanisms of action for both inhalationally or intravenously delivered general anesthetics?
- unknown - but thought to involve the modulation of GABA (gamma amino butyric acid) & acetylcholine receptors in the brain
- most agents are GABA agonists, amplifying GABA's inhibitory effects
- they block ascending neuronal arousal pathways
- promote the entry of chloride ions into cells, which in turn results in HYPERpolarization of the cell
- causes decreases in mental alertness, motor activity, seizure activity, & CNS control of autonomic functions
- eg. propofol, benzodiazepines (BDZ) like Ambian
- an α2 agonist that acts in the locus ceruleous to BLOCK the release of norepinephrine
- NOREP would normally serve to upregulate the presence of GABA (increase GABAminergic transmission) but this is inhibited with Dex.
- it's the only agent that may mimic the electrical activity of the brain during "natural" sleep
- this makes it helpful for ICU sedation in reducing delirium
Orexin Receptor Antagonists
- new form of sleeping pill that blocks receptors at which orexin works to promote wakefulness & arousal
- eg. Suvorexant
- block at the spinal chord (medulla, pons)
- work through the arousal pathway
How is general anesthesia administered?
- patients breathe in a mixture of gases containing the correct level of anesthetic gas
- the partial pressure of the anesthestic builds up in the alveoli
- it then enters the blood stream via capillaries (like O2 does) & is transported to all high-flow organs 1st including the brain where it diffuses further
What determines how quickly these gasses/anesthetics start to take effect?
- the partial pressure (gaseous tension) of the gas in the alveolus & then the brain [NOT the concentration/amount in the brain]
- higher the PP, the quicker the anesthetic starts working
- if an agent is insoluble in blood, its partial pressure in the brain will rise quickly
What determines how potent an anesthetic is?
- how LIPID SOLUBLE it is
- potency = amount you need to reach max response
- the more lipophilic a drug is, the less drug you need to reach said drug's maximal response
What components make up the gas being inhaled?
- 1-5% inhaled anesthetic gas
- +30% oxygen
- rest = air or nitrous oxide (NO has a low lipid & blood solubility - is not a very potent anesthetic)
- the anesthetic is given as a small component of the total gases being inhaled
- if an anesthetic is more potent a lower concentration is given for inhalation (1-2%)
- if an anesthetic is less potent, a higher concentration is given (3-5%)
Minimum Alveolar Concentration (MAC)
- the alveolar concentration of an anesthetic gas in a patient population in which 50% of patients will respond to a specific surgical stimulus - that means the other 50% will NOT respond (analogous to ED50)
- a measure of potency NOT concentration
- allows us to compare potencies of the different gasses used
Lower MAC Values
- correlated with higher potencies
- are other variables to consider (patient age, temperature, other medications) that may change MAC
What patient population is usually used to study the MAC for a given anesthetic?
- healthy, college-aged male patients
- women & children are typically not represented in such study groups
How are inhaled anesthetic eliminated from the body?
- ~99% of anesthetic gas in a patient’s body is eliminated unchanged through the respiratory tract by exhalation
- currently used inhaled anesthetic agents undergo almost NO metabolism by the body
What do the MAC values for commonly used agents mean about their potency?
- Isoflurane 1.2% - volatile anesthetic agents
- Sevoflurane 1.8% - volatile anesthetic agents
- Nitrous oxide 105% - true gas
- isoflurane is the MOST potent, NO the least
agents that are liquid at room temperature but can be transformed into gasses through careful use of a vaporizer & administered to patients via a mask or breathing tube in controlled amounts
What are the physiological effects of volatile anesthetic gases on the cardiovascular system?
- direct myocardial depression
- impaired baroreceptor reflexes
- vasodilatation (+ indirect vasodilatation from loss of sympathetic tone from sedation alone)
- increased incidence of dysrhythmias
What are the physiological effects of volatile anesthetic gases on the respiratory system?
- respiratory depression
- decreased respiratory response to hypoxia & CO2 (hypercarbia)
- decreased tidal volume
- increased respiratory rate (may lead to diminished alveolar ventilation)
What are the physiological effects of volatile anesthetic gases on the neuromuscular & neurophysical system?
- decreased then eliminated consciousness/awareness decreased movement in response to painful stimulus
- muscle weakness
- decreased cerebral oxygen consumption
- increased cerebral blood flow (not good for brain surgery)
- the most commonly administered anesthetic gas in the world
- it's noxious to inhale awake, a potent vasodilator, may cause tachycardia at higher concentrations, & it is relatively inexpensive
- used concentrations are between 0.5-2.5% of inspired gas
- is most commonly used for pediatric patients & anesthesia for short procedures because it's NOT noxious to breathe while awake (doesn't irritate the airway) & is rapidly excreted by exhalation
- is LESS potent than isoflurane
- used concentrations are between 1‐6% of inspired gas
- (may cause emergence delirium)
- a true gas that is very impotent (not very powerful)
- used concentrations are between 50‐70%
- it doesn't produce general anesthesia by itself b/c its MAC is so high
- quickly diffuses into closed air-filled spaces, rapidly expanding the size (or pressure) within that space
- can cause harm if a patient already has air trapped in the body where it shouldn't be (eg. pneumothorax)
an abnormal collection of air or gas in the pleural space that separates the lung from the chest wall; may interfere with normal breathing
- when anesthetics are given as an IV bolus they cause RAPID loss of consciousness by an unclear mechanism of action
- just like inhaled gases many IV agents are thought to be GABA agonists
- they may cause myocardial depression or vasodilatation (again from loss of endogenous sympathetic tone from sedation) → leading to hypotension
- they rapidly re-‐distribute away from the brain so that consciousness may begin to return within 5-10 minutes if no other drugs are administered
- an anesthetic given intravenously that has a high lipid solubility & causes rapid loss of consciousness
- is quickly distributed away from the brain so the patient may “wake up” soon afterward if no other drugs are given
- it's rapidly eliminated (has a high clearance rate) from the body & patients return to pre-anesthetic baseline with little hang‐over feeling more quickly than with other drugs
Why does Propofol cause a decrease in blood pressure?
- because it causes a decrease in endogenous sympathetic tone → therefore it should be used CAREFULLY in someone who's been bleeding (can compound already low BP)
- like w/ a ruptured anything, ectopic pregnancy, etc.
- it also has anti-emetic effects (prevents vomiting)
- it's a commonly used anesthetics for non-surgical purposes but should be given in a monitored setting, not at home (MJ)
- a dissociative agent, meaning it'll affects the thalamus & interrupts sensory impulses from the reticular activating system to the cerebral cortex emanating from the limbic system (is involved with awareness)
- on ketamine a patient may appear conscious but can't process or respond to sensory input
What is the mechanism of action of ketamine?
- it's an N‐methyl‐D‐aspartate (NMDA) receptor antagonist
- glutamate (an excitatory NT found throughout the body involved with the perception of pain) usually binds to NMDA receptors
- ketamine also binds to the μ-opioid receptor, which is likely responsible for its analgesic activity
What is a notable side-effect of ketamine?
- it can cause hallucinations (is a “safer” PCP-like agent)
- can also cause hypertension, altered motor function, amnesia, & bronchodilation
- physiologically it may ↑ arterial BP, heart rate, & cardiac output due to central stimulation of the sympathetic nervous system & inhibition of norepinephrine reuptake
- because of this it may be better than propofol in a patient w/ hypotension from hypovolemia
a class of agents that blunt CO2 responsiveness, which if left untreated will eventually lead to CO2 narcosis & death
- bind to 4 specific receptors located throughout the CNS & are most effective at producing pain relief
- 1. μ‐supra spinal: causes analgesia, respiratory depression, physical dependence, muscle rigidity
- 2. Kappa: causes sedation, spinal anesthesia
- 3. Delta: causes analgesia
- 4. Sigma: causes dysphoria, hallucinations, respiratory stimulation
- what inhaled anesthetic gases or intravenous agents are used for
- may or may not require use of an artificial airway
- a patient who remains conscious, but their cognitive functioning/ awareness/ recall has been purposefully diminished with the use of medication
- there's a blurry line between sedation & general anesthesia
- when local anesthetic agents are specifically deposited near large nerves to reversibly cause loss of sensation/motor function to a large area of the body
- eg. an epidural used for labor & delivery
Local Anesthesia (LA)
- substances that produce reversible blockade of neural conduction along peripheral or central neural pathways
- consist of three elements & are either AMIDES or ESTERS
- 1. a lipophilic aromatic benzene ring
- 2. a hydrophilic tertiary amine
- 3. a connecting intermediate chain that provides either an ESTER (CO, safer) or AMIDE (HNC) linkage
- the intermediate chain is what classifies whether an LA is an ester or an amide
How to tell an Amide from an Ester local anesthetic by name
- all amides contain 2 "i" in their generic drug name
- all esters have only 1 "i" in their generic drug name
“morphine of local anesthetics” - it's the reference local anesthetic to which all others are compared to
Ester LA Metabolism
- ester LAs are metabolized by plasmacholinesterase or pseudocholinesterase
- they have a SHORT half life (~1 minute)
- are a good choice if toxicity is a concern (eg. in neonates, infants, or pregnancy)
What is the end product (metabolite) of ester LA metabolism?
- PABA (para-amino-benzoic acid) [also a preservative found in foods & cosmetics]
- this substance can cause LA allergies
Amide LA Metabolism
- amide LAs are generally metabolized in the liver by the CYP 450 enzyme system via N-dealkylation followed by hydrolysis (depending on the LA different subclasses get involved)
- some amide LAs are extracted by first pass metabolism through the lungs
- because the CYP system is involved, factors like hepatic perfusion & chronic liver disease (cirrhosis) or other drugs metabolized by the CYP450 system need to be taken into account when deciding between ester/amides as well as choosing doses
Which has a longer elimination half-life, ester or amide local anesthetics?
AMIDE because they must be transported to the liver & metabolized by CYP450 enzymes → takes ~3 hours
Liver Disease & Local Anesthetics
- disease states or impaired organ systems influence LA break-down
- severe liver disease mostly affects amide LA metabolism
- if the hepatic production of pseudocholinesterase is also impaired (RARE), ester LA will also stay in the system longer
renal disease has limited effects on LA metabolism & excretion
Heart Disease & Local Anesthetics
- decreased cardiac output can REDUCE LA tissue clearance resulting in a prolonged duration of action
- this can lead to toxicity
Pregnancy & Local Anesthetics
- levels of cholinesterases can be reduced resulting in longer-lasting ester LAs
- same thing can happen when an atypical cholinesterase is present
What two other situations will prolong the presence of local anesthetics in the systemic circulation?
- 1. disease states (eg. sepsis & malignancy) that increase plasma proteins & therefore LA protein binding (increasing their duration of action)
- 2. states that specifically increase α1-glycoprotein, a major LA binding protein
LA Mechanism of Action
- LA can exist in a charged or uncharged form
- 1. it must first penetrate the cell membrane via passive diffusion as an uncharged compound
- 2. once inside the neuron the cell milieu ionizes the LA
- 3. the charged LA enters Na+ channels of the cell membrane, where it binds to specific receptors
- *this interrupts Na+ influx & inhibits cell depolarization
- resting & threshold membrane potentials remain the SAME in the presence of a LA, the threshold potential for membrane depolarization is never reached by the action potential when Na+ channels are LA-bound b/c not enough Na+ ever enters fast enough to depolarize the neuron
- action potentials never propagate → area becomes numb
Frequency Dependent Block
- local anesthetic enters INACTIVATED sodium channel more readily than open, intermediate, or resting ones
- if the patient continues to use the area being anesthetized, Na+ channels will be activated then inactivated → LA binding
- aka using the area increases the number of inactivated Na+ channels, which increases the number of channels the LA can readily bind to, which overall increases the speed of onset of a local anesthetic
What are most local anesthetics?
- weak bases
- at equilibrium when the LA exists in equal charged & neutral states, its pH is slightly alkalotic
- the pH at this state is the LAs pKa
- increasing (alkylating) the pH favors uncharged LA
- most most commercial solutions are ACIDIC (pH ~6) to preserve an LA when not in use (decrease bacteria overgrowth)
- adding bicarbonate right before use increases the non-ionized fraction, speeding a LAs onset of action when injected (more uncharged drug would be available for diffusion through the cell membrane)
What is the relationship between physiologic pH (usually 7.4) & pKa of a local anesthetic?
- the closer the local anesthetics natural pKa is to physiologic pH, the FASTER it works
- *LAs pKa = onset of action
What is an example of a local anesthetic that isn't a weak base?
benzocaine, which is acidic
How can a local anesthetic solution be alkylated & what effect does alkylating the a drug solution right before use have on drug action?
- sodium bicarbonate alkylates a solution (pH ~8)
- basic drugs, like most local anesthetics, would exist in their nonionic/lipophilic form → in this state they pass more quickly through neuron cell membranes to affect Na+ channels
- acidic LAs like benzocaine would become ionized in a basic environment; to quicken their onset their drug solution would have to be acidified
What does lipid solubility correspond to for a local anesthetic?
- its Potency (lipid solubility = potency), how quickly it can cross the cell's membrane
- the ability of a drug to easily cross cell membranes depends on its lipid solubility
- the greater the ease of cell membrane crossing, the greater the intensity of drug penetration to sites of action
- the density of the block will be enhanced the more lipid soluble the drug is
How can a local anesthetic be modified to increase its lipid solubility?
- 1. addition of a halide structure to the aromatic lipophilic benzene ring
- 2. extending the tertiary amide nitrogen group (the hydrophilic end) by adding larger alkyl groups in ester LAs
- esters tend to cross faster & adding more carbons helps
What does a local anesthetic's protein binding ability affect?
- the better at binding protein, the longer the local anesthetic lasts (↑ duration of action)
- higher the protein binding ability, the longer the duration of action
- most LAs need to bind & be transported by α1-glycoprotein in the blood (albumin helps as well but more often transports acidic compounds)
- the better attached to α1-glycoprotein, the longer the drug stays in circulation or at the site of injection
- if something is highly protein bound it won't be picked up effectively by the blood - will stay at the site you inject it
- protein binding also facilitates LA attached to its Na+ receptor
Why do local anesthetics work poorly in when injected into inflamed tissue?
- the tissue milieu of inflammation is often acidic, decreasing non-ionized LA fraction
- hyperperfusion (increased metabolism that comes from the body's need to compensate for injury) that results from inflammation contributes to rapid LA absorption away from the target site
- + increased tissue temperature may enhance LA metabolism
Are myelinated or unmyelinated nerve fibers more sensitive to local anesthesia?
- myelinated nerve fibers are more sensitive to LA & are also thicker than unmyelinated fibers
- blocking a few nodes of ranvier blocks an entire nerve
- most motor neurons are myelinated while peripheral nerves consist of a mix of myelinated & unmyelinated fibers in different layers
- *first sympathetic fibers get blocked → sensory fibers → motor neurons last
More detailed sequence & level of neural blockade:
- 1. sympathetic block (vasodilation, skin temp increases)
- 2. loss of pain & temperature sensation
- 3. loss of proprioception
- 4. loss of touch & pressure
- 5. last - loss of motor function
differential nerve blockade
- partially blocking a nerve so that sympathetic & pain fibers are blocked, but sparing most of the motor fibers
- can be achieved clinically by using different amounts and concentrations of LA
- eg. the “walking” epidural for labor pain
Local LA Toxicity
- 1. local anesthetics are directly neurotoxic when administered to nerve cells in high concentration
- 2. cause transient radicular irritation (TRI) or transient neurologic symptoms (TNS) when given intrathecally
- 3. high concentrations of cause muscle necrosis at the site of injection (direct muscle toxicity)
- depicted by the use of very small bore spinal catheters (micro-catheters) for LA administration intrathecally
- LA administered this way would achieve an extremely high concentration at certain spinal nerves, causing cauda equina syndrome (neurologic condition)
What does giving local anesthetics intrathecally cause?
- transient radicular irritation (TRI) or transient neurologic symptoms (TNS)
- symptoms consist of buttock & hamstring pain & are exacerbated by lithotomy positioning during surgery but are usually short lived (3–14 days) & mild, with complete return to normalcy
- incidence is highest with Lidocaine
When does systemic toxicity occurs from giving a local anesthetic?
- when the LA blood level causes generalized symptoms usually caused by accidental intravascular LA injection or unpredictable absorption from a local injection site
- the MORE vascular an area & the closer the injection is to large vessels, the GREATER the possibility of systemic absorption → toxic symptoms
What is the order in which systemic LA toxicity manifests itself?
- 1st CNS symptoms (often excitatory signs)
- 2nd respiratory arrest
- 3rd cardiovascular collapse
CNS Symptoms of LA Systemic Toxicity
metallic taste, tinnitus, light-headedness, numbness of lips & tongue, muscle fasciculations, LOC (loss of consciousness), seizures, or coma
Which sites have the greatest absorption potential for systemic toxicity after injection of a local anesthetic?
- in order from largest toxicity potential
- paracervical (OB/Gyn)
- brachial plexus
- to least
- MORE vascular, closer the injection is to large vessels
CNS Symptoms of LA Systemic Toxicity
- negative inotropy
- refractory cardiac arrhythmias
- loss of vasomotor tone
- CV collapse (difficult to treat)
- all are exacerbated by acidosis, hypercarbia, & hypoxia
- a particularly cardiotoxic LA that in its concentrated form (0.75%) can cause a cluster of cardiac arrests in pregnant women when administered for labor analgesia
- b/c of this it's one of the few LAs with a “Black Box Warning” from the FDA, discouraging use of its high concentration in pregnant patients
- is more used at a lower concentration for its clinically desirable block characteristics
- however its narrow therapeutic window led less toxic bupivacaine derivatives levobupivacaine (a stereoisomer) & ropivacaine to be developed
Treatment of Systemic LA toxicity
- 1. provide additional O2 (hypoxemia enhances toxicity)
- 2. hyperventilate the patient (acidosis & hypercarbia worsen LA toxicity; hyperventilation may treat this)
- 3. Intralipid 20% IV (a fat emulsion used in parenteral nutrition)
How does an intralipid fat emulsion treat systemic LA toxicity?
- “Lipid-sink” Theory: lipids appear to separate LA from the sodium channel & bind it
- it has become the standard emergency treatment during LA toxicity
- works specifically for bupivacaine-induced toxicity & cardiovascular collapse
How much should a local anesthetic dose be reduced for a pregnant patient?
- by 30%
- pregnancy calls for ~30% dose reduction b/c of increased LA sensitivity in this physiologic state
- LAs reach toxic levels sooner in pregnant women when no dose adjustment occurss
- a special kind of local anesthesia toxicity when oxidizing agents OXIDIZE the iron in hemoglobin converting the hemoglobin to methemoglobin
- methemoglobin is unable to accept oxygen → methemoglobinemia
- a variety of LAs can act as an oxidizing agent, especially benzocaine & prilocaine but also lidocaine
- a LA often used in dentistry that's metabolized to o-toluidine derivatives which in large doses will oxidize hemoglobin
- treated using methylene blue
- a local anesthetic used as a topical pain reliever only
- it's acidic, has a secondary hydrophilic amine group (as opposed to tertiary), & doesn't need to traverse the cell membrane to exert its effect
- when too much is absorbed from the mucosa it can cause Methemoglobinemia
Because of its potential to cause Methemoglobinemia, in which populations should Benzocaine not be used as a topical?
- 1. in children
- 2. in anyone w/ open lesions in the area where the topical needs to be applied
How common are true allergies to local anesthetics?
- not very common - are extremely rare for both ester & amide LAs
- many times the “allergy” label is applied to experiences following dental LA w/ epinephrine containing solutions that may cause palpitations from systemic epinephrine absorption
- if someone has a true allergy to a specific amide LA, a different amide LA can still be safely given b/c it'll have different structure & metabolites
- a paraben preservative often added to ester or amide LA multi-dose vials
- it resembles PABA & therefore may be responsible for allergic reactions to LA from such vials
What substance is likely to be included in a commercial LA preparation that contains epinephrine?
- metabisulfite or EDTA as an epinephrine stabilizer & antioxidant
- metabisulfite may cause allergic reactions in individuals with a sulfa allergy
- EDTA containing solutions may bind Ca2+ when the solution diffuses towards muscle tissue which may cause muscle spasm and pain
Mixing LAs with what enhances the safety & quality of a nerve block?
synergistic substances such as epinephrine, opioids, α1 & α2 agonists, or bicarbonate
What effect does epinephrine have on local anesthesia?
- it slows LA absorption from the injection site & increases site concentration by acting as a vasoconstrictor
- overall it decreases the likelihood of systemic LA toxicity & enhances their effects
- also as a NT, it may augment pain INHIBITORY neuraxial pathways in the spinal cord
- however including EPI in a LA mixture may cause unwanted sympathetic stimulation (& should be avoided in patients w/ coronary artery disease)
- applying it to tissues w/ end-arteries may lead to ischemia (eg. injecting it around digits)
What effect do opioids such as fentanyl or morphine have on local anesthesia?
- for intrathecal or epidural LA application they can
- enhance LA effect & allow lower LA concentrations to be equally effective
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