Pharmacology 2 Flashcards
The ability of LA’s to block the conduction of nerve fibers depends on what three factors?
the nerves being blocked, chemical structure, and physiochemical properties of the LA
What is the functional unit of peripheral nerves?
axon
What is the function of Schwann cells?
support and insulate axons
What are nodes of Ranvier?
segments of axon that do not contain myelin, where conduction is propagated.
What is the primary site of action of LA’s and where are they located?
Na channels, in the nodes of ranvier.
What is saltatory conduction?
action potentials jumping between nodes of Ranvier
Describe the difference myelin makes in nerve conduction.
Myelinated nerves are larger, conduct impulses faster, and are more difficult to block.
What are the three layers of connective tissue of nerves?
Epineurium - outer
perineurium
endometrium - inner
Which connective tissue layer holds fascicles together to form a peripheral nerve?
epineurium
What is the resting membrane potential of peripheral nerves?
-70 to -90mV
What is the primary mechanism that creates the ionic gradient for electrical potential?
Na-K/ATPase
What equation expresses the charge created by the K concentration gradient?
Nernst
Besides K, what ions have a minor role in establishing intracellular resting membrane potential?
Na and Cl
What happens to membrane potential when an electrical impulse is generated?
Na channels open, and membrane potential reaches +20 mV then the concentration reverses. Na channels close, K channels open. Na is removed by the NaK/ATPase (3 Na out, 2 K in)
What state of Na channels do LA’s bind?
Open and inactive.
Not the closed state.
What is the guarded receptor or modulated receptor hypothesis of LA’s?
LA’s preferentially bind to Na channels when they are in the resting or open states.
What is a use-dependent or phasic block?
LA’s work faster as the Na channels is repetitively depolarized.
The more frequently the channel is stimulated the more time it is in the open or resting state.
Where are the Na channel binding sites for LA’s located?
internal opening
Is the ionized or nonionized portion of a LA more likely to bind to Na channels?
ionized
The nonionized portion crosses the cell membrane, but the ionized portion actually binds the Na channels
Which LA can penetrate the lipid bilayer and can directly inhibit the Na channel without entering the axoplasm first?
Benzocaine (secondary amine)
What is the order of differential block?
autonomic function - first superficial pain perception temperature motor function proprioception
What are characteristics and function of A-alpha fibers?
largest diameter (12-20)
heavily myelinated
fast conduction
motor function and proprioception
What are characteristics and function of A-beta fibers?
diameter 5-12
myelinated
motor function, touch and pressure
What are characteristics and function of A-gamma fibers?
diameter 3-6
myelinated
muscle spindles and reflexes
What are characteristics and function of A-delta fibers?
diameter 1-5
myelinated
slowest conduction of the A fibers
pain and temperature sensation
What are characteristics and function of B fibers?
smaller diameter and less myelin than A fibers.
preganglionic autonomic nerves
What are characteristics and function of C fibers?
smallest diameter 0.3-1.3
slowest conduction
pain and temperature
What is the ratio between the magnitude of the action potential and the magnitude of the critical membrane potential?
safety factor or conduction safety
What are the two type of LA’s used in clinical practice?
aminoesters
aminoamides
What are the three characteristic segments of LAs?
intermediate ester or amide carbon group
unsaturated aromatic ring
amine end
What parts of LA structure are hydrophilic and lipophilic?
lipophilic benzene ring
hydrophilic amine
Name the LA.
How are ester LAs metabolized?
plasma and tissue cholinesterase via hydrolysis
How are amide LAs metabolized?
liver by CYP1A2 and CYP3A4
Which class of LA is more likely to cause an allergic reaction?
ester
Which class of LAs tend to be shorter acting?
esters due to metabolism. Tetracaine is the exception
What is the mechanism for amide LAs being longer acting?
more lipophilic and protein bound and require transport to the liver for metabolism
What determines offset and termination of LAs effect?
systemic absorption
What factors have a significant impact on LA duration of action?
vascularity and blood flow of injection area, lipid and protein binding, and vasoconstrictors
What determines local anesthetic potency?
lipid solubility
What does increased lipid solubility correlate to?
increased protein binding, increased potency, longer DOA, higher tendency for cardiac toxicity
The addition of a butyl group to the amide end of mepivicaine yields what LA?
bupivicaine
The addition of a butyl group to the aromatic end of procaine yields what LA?
tetracaine
What determines a LAs duration of action?
protein binding and lipid solubility
What proteins do LAs mainly bind?
alpha1-acid glycoprotein. They are weak bases
What is the most important determinant of LAs onset of action?
ionization.
Do LAs with a pKa closer to physiologic pH have a slower or faster onset?
Faster, the nonionized fraction will be a higher.
Despite its high pKA which LA has a rapid onset of action? Why is this?
Chloroprocaine, due to high concentrations injected
Which two LAs have low potency and short DOA?
procaine and chloroprocaine
Which two LAs have intermediate potency and DOA?
mepivicaine and lidocaine
Which 3 LAs have high potency and long DOA?
tetracaine, bupivicaine, and ropivicaine
Which LAs do not produce relaxation of vascular smooth muscle? 3
cocaine, ropivicaine, and lidocaine
What are the consequences of LAs causing vasodilation?
increased absorption, limits DOA, increase potential for toxicity
What is the mechanism of cocaine causing vasoconstriction?
it blocks reuptake of NE
What is the order of tissue absorption from greatest to least?
interpleural > intercostal > caudal > epidural > brachial plexus > sciatic femoral > subcutaneous
What determines the peak plasma concentration of a LA?
total dose
The addition of epinephrine to what two LAs for epidural does not decrease peak plasma levels?
prilocaine and bupivicaine
What is the concentration of epi added to LAs?
1:200,000 or 5mcg/mL
How does the addition of sodium bicarbonate affect LA?
speeds onset of sensory and motor block
How does the addition of hyaluronidase affect LAs?
facilitates diffusion of LA in the tissues
What are the undesirable effects of adding hyaluronidase to LAs?
allergic reactions, shortened DOA, increased risk of toxicity
What tissue group receives the greatest amount of LA from redistribution?
muscle
How are ester LAs metabolized?
plasma cholinesterase
How are amide LAs metabolized?
in the liver by P450 enzymes mainly 1A2 and 3A4
What is the primary factor that determines the elimination of amide LAs?
hepatic blood flow
What are the most common causes of LAST?
IV injection or absorption from large volumes injected into vascular tissues
Are inhibitory or excitatory neurons blocked first in LAST?
inhibitory - mechanism of seizure (lack of inhibition of excitatory neurons)
What is the first observed arrhythmia of LAST and the most serious?
Bradycardia
V-fib
Most reported deaths from LAST are involve which LA?
Bupivicaine
What is the progression of symptoms in last?
agitation, tinnitus, circumoral numbness, blurred vision, metallic taste, muscle twitching, coma and seizures, cardiac and respiratory arrest
What are the preferred medications for seizure suppression in LAST?
benzos
What is the treatment of LAST?
20% lipid emulsion 1.5mL/kg over 1 minute
infusion 0.25mL/kg
What medications are avoided in treating LAST?
vasopressin, CCBs, B-blockers
What are essential first steps in managing LAST?
avoid hypoxia and acidosis
Which class of LAs has the higher incidence of allergic reactions? Why?
Esters Metabolite PABA (para-aminobenzoic acids)
What preservatives of LAs can cause allergic reactions?
methylparaben, paraben, metabisulfite
What is methemoglobin?
oxidized form of hemoglobin with reduced O2 carrying capacity. Causes Left shift of oxygen-Hgb response curve
What is the formula for methemoglobin?
HbFe3OH
What are clinical symptoms of methemoglobinemia?
hypoxia unresponsive to increased O2
abnormal colored blood
Normal PaO2, with low SpO2
Cyanosis
Which local anesthetics are most likely to cause MetHgb?
benzocaine and prilocaine
What is the mechanism of Prilocaine causing MetHgb?
metabolite o-toulidine oxidizes Hgb to MetHgb
What is the treatment for MetHgb?
Methylene Blue 1-2mg/kg over 3-10 minutes
What complication of LA’s presents as bowel and bladder dysfunction, bilateral LE weakness and sensory impairment?
Cauda equina syndrome
What is the only naturally occurring LA?
cocaine
What is the maximum dose of cocaine?
5mL of 4% or 200mg
What is the onset and duration of EMLA cream?
1 hour onset
2-3 hour duration
What are the concentrations of Tetracaine, Epinephrine and Cocaine used for traumatic lacerations?
Tetracaine: 1%
Epi: 1:200,000
Cocaine: 4%
What is the maximum dose of exparel?
266mg
What makes up tumescent local anesthesia?
lidocaine, sodium bicarb and epinephrine
What is the maximum dose of lido for tumescent anesthesia?
35-55mg/kg
Where are supraspinal opioid receptors primarily located?
midbrain and medulla
Spinal anesthesia occurs by activation of what receptors?
presynaptic opioid receptors
What are the cellular mechanisms of opioids?
activation of G-proteins, decrease adenylate cyclase, decrease cAMP, decease pre- and postsynaptic Ca conduction, increase K conduction
What are the effects of Mu receptors?
supraspinal analgesia, euphoria, decreased ventilation
What are the effects of kappa receptor stimulation?
spinal anesthesia, sedation and miosis
What are the effects of delta receptor stimulation?
spinal analgesia, response to enkephalins, and modulate mu receptors
How does dose of opioids effect their termination?
small doses- effect is terminated by redistribution
large doses- effect is terminated by metabolism
Which opioid metabolite is neurotoxic and may accumulate in the elderly or those with decreased liver or kidney function?
meperidine - normeperidine
How are opioids excreted?
primarily by the kidney
secondarily by the billiard system and GI tract
What type of pain are opioids most effective for?
visceral continuous dull pain
Where do the analgesic properties of opioids come from? 2
- directly inhibit ascending transmission of pain signals from the dorsal horn
- activate pain control pathways descending from the midbrain to the dorsal horn
How do opioids increase ICP?
from respiratory depression induced hypercarbia
Rank the potency of opioids used in anesthesia?
Sufent > fent = remi > alfent
Which opioid receptor is most likely to cause dysphoria?
kappa receptors
opioid agonists at what receptors are more likely to cause respiratory depression>
Mu and kappa
How do opioids effect the CO2 response curve?
right shift. Require a higher CO2 to stimulate repirations
How do opioids stimulate N/V?
stimulate the chemoreceptor trigger zone, and vestibular system.
What are the cardiac effects of opioids?
bradycardia from vagal stimulation
vasodilation
Which opioids cause histamine release leading to HoTN?
morphine, meperidine, and codeine
What are the GU effects of opioids?
detrusor muscle relaxation, urinary spincter contraction -> urinary retention.
Kappa receptor agonist cause diuresis.
Skeletal muscle rigidity is most often caused by what opioids?
Fentanyl and its derivatives
especially Remi infusions
opioid induced muscle rigidity is mediated by what receptors?
central mu
Stimulation of what opioid receptors cause pruritis?
Mu
What medication is considered first line treatment of opioid induced pruritis?
nalbuphine
What are the endocrine effects of opioids?
release of vasopressin
inhibition of corticotropin, gonadotropin, and thyrotropin
What are the most common side effects of spinal administration of opioids?
pruritis and urinary retention
What is the most common serious complication of intrathecally administered opioids?
respiratory depression
Which intrathecally administered opioid has the longest duration of action?
morphine`
What are the uses of methadone?
chronic pain, opioid abstinence syndromes, heroin addiction
What receptors is meperidine an agonist at?
mu
What is the metabolite of meperidine and its effects?
normeperidine - decreases the seizure threshold
Which opioid can induce serotonin syndrome if combined with MAOIs?
meperidine
Which opioid reduces shivering? What receptor does it act on?
Meperidine. Kappa
How is alfentanil metabolized?
N-dealkylation and O-demethylation by P450
Which medication can prolong the metabolism of alfentanil leading to respiratory depression and sedation?
erythromycin
How is fentanyl cleared and metabolized?
cleared by hepatic blood flow
metabolized by N-dealkylation and hydroxylation
Which phenylpiperidine opioid is the most potent?
sufentanil
Which receptors is sufentanil an agonist at?
Mu
How is sufentanil metabolized?
O-demethylation and N-dealkylation
Sufentanil causes the most respiratory depression in which age group? Why?
elderly. smaller Vd
How does tramadol exert its effects?
mu agonist
inhibits NE and serotonin
stimulates 5-hydroxytryptamine release
What are the three opioid agonist/antagonists (partial agonists)?
Buprenorphine, Nalbuphine, Butorphanol
What do you need to know about buprenorphine?
mu agonist
long DOA = 8 hours
naloxone not effective
significant respiratory depression
What do you need to know about Butorphanol?
Kappa agonist, mu antagonist
more potent than morphine
can be given intranasal
treats shivering
What do you need to know about Nalbuphine?
Kappa agonist, Mu antagonist
reverse respiratory depression but maintain analgesia
Naloxone ineffective
antagonist pruritis
What are the three opioid antagonists?
naltrexone, naloxone, nalmefene
What is the MOA of naloxone?
blocks the opioid receptors and reverses respiratory depression and opioid analgesia
What are the potential side effects of naloxone?
pulmonary edema and increased catecholamine release leading to V-Fib
What do you need to know about nalmefene?
half life 10 hours
DOA 8 hours
dose is 0.1-0.5 mcg/kg
not for opioid dependent patients
What do you need to know about naltrexone?
longest DOA - 24 hours
used in alcohol withdrawal programs
prevents euphoric effects of opioids
active metabolite half life exceeds that of the parent compound
What enzymes do NSAIDs and acetaminophen inhibit?
cyclooxygenase
What are the beneficial effects of NSAIDs and acetaminophen?
NSAIDs: analgesic, antipyretic, anti-inflammatory
Acetaminophen: analgesic, antipyretic
In which patients is toradol avoided?
asthma, elderly, renal or GI dysfunction, bleeding disorders
What is the dose of acetaminophen in children?
15mg/kg
What is the preferred method to determine neuromuscular blockade?
quantitative method with a numerical value
MMG, AMG, KMG, EMG
What is the preferred site for determining the level of neuromuscular blockade?
adductor muscle of the thumb via the ulnar nerve
What brach of the facial nerve is stimulated to assess NMB’s? What are the muscles stimulated?
temporal. Corrugator supercilii (eyebrow) Orbicularis oculi (around the eye)
What is the order of NMB onset and recovery?
Eye muscles, then extremities, neck and chest trunk muscles, abdominal muscles, diaphragm.
Recovery is opposite
Which muscle of the eye is more resistant to NMB?
corrugated supercilii
Describe single twitch monitor.
0.1-1Hz for 0.1-0.2 milliseconds.
muscle movement = not 100% paralyzed
no movement = 100% paralyzed
Describe TOF monitor.
4 stimuli every 0.5 seconds at 2 Hz for 2 seconds
How much paralysis occurs with each amount of twitches?
0/4: 100%
1/4: 90-95%
2/4: 80-85%
3/4: 75-80%
What is the ideal degree of paralysis for surgery?
1 or 2 twitches (85-90% block)
Describe Double burst stimulation
two short bursts of 50 Hz tetanus separated by 0.75 seconds.
Describe tetanus?
continuous stimulation for 5 seconds at 50 or 100Hz
Describe post-titanic count.
50 Hz for 5 seconds, wait 3 seconds, then a series of single 1 Hz twitch stimulations
What is the ED95 of succinylcholine?
0.3 mg/kg
How does NMB potency affect speed of onset?
Lower the potency the faster the speed of onset
How do patients with atypical pseudocholinesterase respond to succinylcholine?
prolonged response
For Succinylcholine what is the:
half life:
DOA:
full recovery:
half life: 2-4 min
DOA: 5-10 min
full recovery: 12-15 min
How is succ metabolized?
By pseudocholinesterase into succinylmonocholine and choline
How does succ affect ICP?
increases by 10-15 for 5-8 minutes.
Prevented with a nondepolarizer
What medications should be given before a second dose of succ?
Atropine or Glyco
A second dose of succ is most likely to cause bradycardia in which patient population?
peds
Which of the following are “nonspecific esterases”?
paraoxonase and albumin esterase
What are all the names for AchE?
"The 1 and True Specific Genie" Type 1 True Specific Genuine
What are all the names for pseudocholinesterase?
“The 2nd But False Plasma Princess”
Type 2, Butylcholinesterase, False, Plasma, Pseudocholinesterase
Serum, benzoyl, nonspecific
What populations is PChe decreased in?
Pregnant, newborns, infections, PE, muscular dystrophy, MI
What type of PChE does dibucaine inhibit?
typical or usual PChE
Not atypical
What drugs may inhibit Cholinesterase?
Donepezil, Rivastigmine, Galantamine
What is the dose of Succ for obese patients?
1mg/kg based on TBW
How does succ affect IOP?
increases by 5-15 mmHg for 10 minutes.
Airway is the priority, seeing is overrated
What situations cause an up regulation of AChR’s?
upper/lower motor neuron denervation, infection, muscle trauma, muscle tumor, muscle inflammation, burns, immobilization, chemical denervation
Succ is safe within what time period after a burn?
48 hours
Where are succ induced myalgias most likely to occur?
subcostal region, trunk, neck, upper abs, shoulders
What does of nondepolarizers reduce the incidence of myalgias and fasciculations?
10-30% of ED95
How can we prevent fasciculations?
Lidocaine, NSAIDS, higher dose of Succ
Who is most prone to fasciculations?
young, physically inactive women
What populations have the lowest incidence of myalgias?
extremes of age, pregnant
What are the doses of vec, roc, and Atracurium to prevent fasciculations?
0.04mg/kg Roc, 1.5mg Atracurium, 0.3mg Vec
What dose of Succ causes a phase 2 block?
6-8mg/kg
What is the preferred nondepolarizer for RSI?
Roc
What is the relationship between NDNMB potency and onset?
inverse.
The lower the potency the faster the onset
Giving 10% of the intubating dose of a NDNMB prior to induction is referred to as what?
priming. It speeds the onset but produces respiratory depression in some patients
What is the dose, onset, DOA, and elimination of Roc?
Dose: 0.6-1.2mg/kg
Onset: 45-90 seconds
DOA: 30-60 minutes
Elimination: biliary excretion unchanged
What is the dose, onset, DOA, and elimination of Vec?
Dose: 0.1mg/kg
Onset: 3 minutes
DOA: 30-45 minutes
Elimination: Liver and kidney
What is the dose, onset, DOA, and elimination of Pancuronium?
Dose: ED95 0.14mg
Onset: 4 minutes
DOA: 60-90 minutes
elimination: kidneys,
What is the dose, onset, DOA, elimination, and metabolite of Atracurium?
Dose: 0.1-0.25mg/kg Onset: 1-3 minutes DOA: 30-60 minutes elimination: Hoffman Metabolite: laudanosine Histamine release
What is the dose, onset, DOA, elimination, and metabolite of Cisacurium?
Dose: 0.1mg/kg Onset: 2-4 minutes DOA: 30-60 minutes elimination: Hoffman Metabolite: laudanosine
What is the dose, onset, DOA, elimination, and metabolite of Mivacurium?
Dose: 0.08mg/kg
Onset: 2-4 minutes
DOA: 15-20 minutes
elimination: plasma cholinesterase
What are the CV effects of Atracurium and mivacurium? What causes this?
increased HR and decreased BP
Histamine release
Which NMB has vagolytic properties?
Pancuronium
What NMB’s are preferred for patients with liver and kidney disease?
Atracurium and Cisatracurium
How should you dose NMB’s for obese?
Ideal body weight
How does core temperature affect DOA of NMB’s?
hypothermia prolongs DOA
What two categories of drugs are most likely to cause allergic reactions/
Antibiotics and NMB’s
What are the main components of the allergic sites on NMB’s?
quaternary and tertiary ammonium ions
Which of the cholinesterase inhibitors is used to treat myasthenia gravis, and rarely used in anesthesia?
Pyridostigmine
What is the gold standard type of monitoring to determine residual paralysis?
Quantitative
What is the most rapid acting cholinesterase inhibitor?
edrophonium. 30-60 seconds, DOA 5-10 minutes. Renal elimination
Neostigmine
Onset 4-8 minutes
DOA 30-120 minutes
Liver and Kidney metabolism
What are the vagal effects seen if you only give a cholinesterase inhibitor?
Diarrhea, Urination, Miosis, Bradycardia, Bronchoconstriction, Emesis, Lacrimation, Laxation, Salivation
Which anticholinergics are tertiary amines?
Atropine and scopolamine
What are adverse reactions to sugammadex?
N/V, allergy, HTN, bradycardia
What increases potency of LAs?
increasing lipid solubility, increased carbon atoms, adding a halide to the aromatic ring, an ester linkage, or the presence of large alkyl groups on the tertiary amide nitrogen.
