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246 Cards in this Set
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normal therapeutic range PHT
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10-20 mg/L
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what's the correlation b/x PHT dose and concentration?
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very poor to determine b/c it is highly variable
~1/3 pts. fall in therapeutic range |
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What are 4 characteristics for when drug monitoring is appropriate?
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Serum concentrations are a reasonable reflection of drug concentrations at site of action, probable therapeutic response
Relatively well defined therapeutic range Therapeutic range is narrow, i.e. therapeutic and toxic concentrations are relatively close to each other High degree of interpatient or intrapatient variability in response to a given dose |
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Describe concerns regarding PHT efficacy/toxicity
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High degree of interpatient variability in drug response at given concentrations
Many patients will have symptoms of toxicity at concentrations <20 mg/L or be symptom-free at >20 mg/L (Variability!!) Therapeutic efficacy of phenytoin may be difficult to determine if seizure activity is infrequent or well controlled, or if drug use is only prophylactic (e.g., trauma or surgery) |
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list the PHT concentrated related toxiciies
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Nystagmus
Decreased mental acuity Ataxia |
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describe Nystagmus
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typically horizontal fast movement of eyes
Far lateral @ >20 mg/L At 45 degrees @ >30 mg/L Straight ahead @ >40 mg/L |
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describe decreased mental acuity
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Usually most obvious at concentrations >40 mg/L, but may be seen at <20 mg/L
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describe ataxia
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Usually most obvious at >40 mg/L, but may be observed at >20 mg/L
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At which PHT concentrations does nystagmus, ataxia, and mental status changes occur?
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Nystagmus: 13-40 mg/l
ataxia: 26-43 mg/l mental change: 39-58 mg/l |
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List the concentration Independent PHT toxicities
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Hypertrichosis, acne, coarsening of facial features
Gingival hyperplasia Hypocalcemia, osteomalacia Folate deficiency |
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what order drug is PHT?
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zero order
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desc. zero order model
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kinetics are capacity limited and concentration dependent metabolism
Clearance is determined by the relationship between Vmax and Km |
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In 1st order elimination, what stays constant?
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CL stays constant (ex: 50%)
amt. of drug eliminated (per hour) changes |
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in zero order elimination what stays constant?
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amt. of drug eliminated(per hour) is fixed amt (ex: 50 mg/hr).
CL is variable |
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what weight do you use when dosing/ using eqns for PHT on a mg/kg basis? Why?
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IBW
want to err on the lesser side of toxicity(more conservative dosing) |
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what Vmax for PHT do we use in estimation?
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mean = 7mg/kg/day
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what Km for PHT do we use in estimation?
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mean = 4 mg/L
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what happens to Vmax as we age?
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decreases...
b/c liver is much larger in proportion to body size in children vs. adults |
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what happens to Km as we age?
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increases
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what is F for PHT?
what is Cmax for PHT? |
F = 1.0
Cmax = 3-12 hrs |
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what happens to the F of PHT when dose is increased?
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bioavailability decreases with increased dose
*if need >400 mg/day, increase dosing frequency from QD to BID/TID |
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What is the Vd and protein binding of PHT?
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Vd = 0.7 L/.kg
PB = 90%, primarily ablumin |
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what increases free fraction PHT w/ decreased albumin?
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burn, cirrhosis, pregnancy, nephrotic syndrome
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what increases freee fraction PHT w/ decreased binding affinity?
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renal failure, jaundice, displacement by other drugs (valproate)
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what are unbound PHT conc. correlated with?
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efficacy, toxicity
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what is the free fraction of PHT?
what is therapeutic range free PHT? |
FF = 10%
range = 1-2 mg/L |
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Describe PHT metabolism
(where, extraction ratio, CL) |
70-80% hepatic metabolism to inactive compounds (principally p-HPPH); metabolites conjugated and excreted in urine
Low-intermediate extraction ratio drug CLH = fu x CLint Clearance = concentration-dependent and capacity-limited |
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what are low extraction ratio drugs dependent on?
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intrinsic CL
protein binding (NOT blood flow) |
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Desc. T1/2 concept of PHT
Is it appropriate? |
Concept of “half-life” not appropriately applied to phenytoin because of zero-order behavior
t1/2 varies because CL changes with changing plasma concentrations “Average half-time” = 22 hours but highly variable |
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what is the PHT time to steady state?
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7-10 days but highly variable
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which drugs decrease PHT metabolism? what happens to PHT conc?
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PHT conc. increase
Isoniazid, chloramphenicol, cimetidine, fluconazole, propoxyphene, acute ethanol ingestion |
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which drugs increase PHT metabolism? what happens to PHT conc?
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PHT conc. decrease
Phenobarbital, carbamazepine, chronic ethanol ingestion |
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Desc. protein binding interaction b/w PHT and VPA?
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VPA protein binding = approximately 90-95%, primarily to albumin
VPA displays saturable protein binding within therapeutic range (~50-100 mg/L) VPA free fraction: 5-10% @ 40-50 mg/L 15% @ 100 mg/L 25% @ 150 mg/L Also potential for significant pharmacokinetic drug interaction with phenytoin Begins to displace phenytoin from albumin at VPA levels > 40 mg/L |
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when to monitor PHT levels
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Trough samples most useful
When to check blood concentrations: 2-4 hours after IV loading doses for acute seizure control; may repeat 2-3 days after starting maintenance dosing when less rapid control required, check levels 6-7 days after initiation of maintenance regimen; may repeat in 2-4 weeks every 3-6 months in patients with stable phenytoin concentrations and satisfactory clinical response 6-7 days after addition or removal of other drugs known to interact with phenytoin evidence of drug-related toxicities unusual or uncontrolled seizure activity Both total and unbound plasma concentrations should be checked in patients with altered serum albumin or significant renal dysfunction if unbound levels not available, calculate corrected concentrations and adjust dosing appropriately |
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Current anesthetic gasses
KNOW!! |
Halothane (not commonly used)
Enflurane Desflurane Isoflurane Sevoflurane Nitrous Oxide |
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what are anesthetic gasses used in combination with?
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Muscle paralysis (anticholinergics)
--Keeps the patient from moving and reduces the amount of anesthesia necessary. Antiemetic/antacid therapies --Vomit or stomach acid can be deadly during surgery |
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what are the molecular mechs. of general anesthesia?
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Potentiation of GABA receptors (inhibitory)
--Many inhibitory neurons are GABAergic Inhibition of excitatory neurotransmitter receptors --Not well defined yet |
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what is the key component of all anesthetic gasses?
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all have HALIDE ion substiutions associated (Br, F, Cl)
***Except for NO |
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General process of uptake and distn of anesthetic gasses
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Anesthetic gasses have to get from the lungs to the brain
We can break this down into: 1. Transfer from lung to blood 2. Absorption of gas by various tissues (including the brain) |
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what are we interested in
Uptake and Distn anesthetic gasses: partial pressure |
We aren’t interested in the amount of gas dissolved in the blood.
Instead, we want to know the partial pressure of the gas trying to leave the blood |
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Desc. uptake and Distn anesthetic gasses:
transfer from lung to blood |
Different gasses transfer to blood with different speeds.
NO fastest halothane middle methyloxyflurane Different people transfer gas with different efficiencies. Diseases which can adversely effect gas transfer includes: Chronic Obstructive Pulmonary Disease Emphysema (often, but not always, caused by smoking) |
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Desc. uptake and Distn anesthetic gasses:
transfer from blood to lung |
What goes in…. must come out.
Decreased induction of anesthesia indicates that there will be a decreased recovery from anesthesia |
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Desc. uptake and Distn anesthetic gasses:
solubility |
The more soluble the gas the LONGER it takes to get to the CNS (b/c gas wants to stay in the blood)
A gas must fill its blood compartment before it can begin moving out into other tissues --Poorly soluble gasses fill the compartment immediately --Highly soluble gasses take time to fill the compartment Nitrous Oxide: Poorly soluble Rapid anesthesia Halothane: Better solubility Slower anesthesia |
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compare NO and halothane solubility and speed of anesthesia
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Nitrous Oxide:
Poorly soluble Rapid anesthesia Halothane: Better solubility Slower anesthesia |
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what are the 2 major factors of absorption of anesthetic gas from blood to tissue
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Solubility of gas in the tissue
Degree of blood flow through the tissue |
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Desc. uptake and distn anesthetic gasses:
solubility in the tissues |
The solubility of gasses in lean (non fatty) tissue is roughly equal to that of blood.
CNS gray matter is considered lean tissue Solubility of gasses in fatty tissue is higher than in blood Fat becomes a depot for anesthetic gasses |
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Desc. uptake and distn of anesthetic gasses in regards to blood flow
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Tissues with poor blood flow will take up anesthetic gas slowly.
Adipose tissue is poorly supplied with blood vessels Tissues with lots of blood vessels will take up anesthetic gas quickly The CNS is heavily supplied with blood vessels |
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what happens to anesthetic gasses when admin. stops?
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The gas reverses its direction of diffusion.
Exactly the same factors govern uptake and elimination. Liver metabolism results in halide ions and free radicals which can cause liver toxicity |
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therapeutic index of anesthetic gasses
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range from 2-4
general anesthetics have very small margins of safety |
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list the stages of anesthesia
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Analgesia
Delirium Surgical Anesthesia Medullary Depression |
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what does anesthesia OD result in?
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Overdose results in medullary depression and cardiac depression
Symptoms include:respiratory depression, apnea, hypotension, and asystole |
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features of halothane
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Causes liver toxicity in 1:30,000 patients.
Newer gasses have replaced halothane |
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features of desflurane, sevoflurane, isoflurane
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Low blood solubility makes these great for outpatient procedures
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features of NO
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Requires almost 100% of the lung volume to achieve anesthesia (explains Wells’ failure in 1845).
Used alone for analgesia (20% nitrous oxide is equivalent in strength to morphine) Used in combination with barbiturates as anesthesia for certain surgeries. |
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what are the injectible barbiturate anesthetics?
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Thiopental, Methohexitol Sodium, Thiamylal sodium
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what do injectable barbiturates do?
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Potentiates GABA and inhibits glutamate receptors
Injectable Single bolus produces unconsciousness for 30 min. Longer infusion produces unconsciousness which lasts for hours – due to partitioning into fatty tissues. |
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what are local anesthetic structures based on?
what 3 features do they all have? |
structure of cocaine
All have a hydrophobic group and an amine substituted hydrophilic group linked by a spacer |
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what does the hydrophobic group on local anesthetic do?
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The hydrophobic group increases the potency and duration of the drug.
Hydrophobicity also correlates with toxicity |
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what does the hydrophilic group on local anesthetic do?
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The hydrophilic group contributes both to potency and to diffusion to its site of action
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which local anesthetics are esters?
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cocaine
procaine |
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which local anesthetics are amides?
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lidocaine
mepivacaine |
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what is the MOA of local anesthetics?
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All local anesthetics bind to a specific site within the pore of the voltage sensitive sodium channel and stabilize it in the inactivated state
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Desc. process of how local anesthetics bind to sodium channel?
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1. uncharged drug diffuses through the membrane
2. the drug enters the channel from the cytoploasm side, picks up a charge, and binds inside the pore 3. The drug stabilizes the sodium channel in the inactivation state (an example of allosteric modulation) |
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why is the hydrophobic group important in local anesthetics?
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If the local anesthetic is charged it will not enter the cell.
If the local anesthetic is VERY hydrophobic, it will not easily leave its site of application. Topical anesthetics (for use on cuts) are often very hydrophobic. |
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when do local anesthetics bind to Na channel?
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Local anesthetics only bind when the channel is open.
The more often the channel opens the more chances the drug has to enter The more active the nerve, the more sensitive it will be to local anesthetic action. |
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Which nerves fire more frequently?
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Small sensory nerves are most sensitive to local anesthetic action, in part, because they fire most frequently.
C fibers: unmyelinated, carry pain information Ad fibers: myelinated, carry pain and temperature information Larger fibers include: Aa, Ab, and Ag which carry postural, touch, pressure, and motor information. |
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what does passive conduction do? which nerves are better at passive conduction?
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Large nerves are better at passive conduction than small nerves.
Passive conduction allows an action potential to “jump” over inactivated sodium channels. |
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desc. general progression of anesthetic action
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Pain fibers are blocked first
Temperature, touch, and deep pressure are blocked next Motor function is blocked last (inter pt. variability) |
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how does pH effect local anesthetics?
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In acidic environments, local anesthetics are protonated (and thus charged).
When carrying a charge, they cannot pass through the cell membrane. As inflamed tissues are acidic environments, it follows that local anesthetics will not work well in inflamed tissues. |
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what is the role of vasoconstrictors in the use of local anesthetics?
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Local anesthetics are usually administered by injection.
--Diffusion into the blood stream allows the drug to leave the tissue and mediates its toxic effects. Vasoconstrictors decrease blood flow thus increasing anesthetic duration and decreasing toxicity. --Clinical preparations often include epinephrine --Injection of the vasoconstrictor with the local anesthetic ensures that vasoconstriction is limited to that tissue. |
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what are the side effects of local anesthetics?
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Systemic administration can occur through injection if the needle accidentally enters a blood vessel.
Preferential blocking of CNS inhibitory neurons can cause seizures At high concentrations, local anesthetics also bind to nicotinic acetylcholine receptors – blocking motor nerves Cardiovascular collapse can occur through inhibition of action potential propagation in the myocardium Hypersensitivity reactions can occur – manifests as allergic dermatitis or asthma. --Patients sensitive to ester linked drugs should receive amide linked drugs Increased GI tone (actually a benefit for bowel surgery |
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what are the side effects of EPI?
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Although generally a vasoconstrictor, epinephrine can also dilate skeletal muscle vasculature via b2 adrenergic receptors – leading to toxicity.
Delayed wound healing, tissue edema, or necrosis Vasoconstriction leads to hypoxia. Epinephrine stimulates oxygen consumption in the tissue – also leading to hypoxia. |
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how are ester linked local anesthetics metabolized?
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Ester linked local anesthetics are rapidly inactivated by plasma esterases.
--Little systemic toxicity possible. --Spinal fluid has no esterase activity making ester linked local anesthetics perfect for spinal anesthesia |
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how are amide linked local anesthetics metabolized?
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Amide linked local anesthetics are inactivated in the liver.
Don’t use amide linked local anesthetics on patients with liver disease |
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how does binding to serum proteins impact local anesthetics?
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Binding to serum proteins reduces inappropriate binding to sodium channels and thus reduces toxicity.
--Plasma proteins increase in a number of disease states including: cancer, trauma (including surgery itself), myocardial infarction, smoking, and uremia. --Plasma proteins are decreased by oral contraceptive usage --Neonates have little plasma proteins and so are more susceptible to local anesthetic toxicity |
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what are the uses of topical anesthesia?
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Administered to the surface of skin, or mucus membranes (nose, mouth, throat, etc).
Used for outpatient procedures Rapidly absorbed into the circulation making systemic toxicity reactions possible |
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what are the clinical uses of infiltration anesthesia?
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Injection directly into the tissue
Commonly used in dentistry Epinephrine is often included in the formulation to increase duration and decrease absorption into the circulation Common local anesthetics include lidocaine, procaine, and bupivacaine |
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what are the clinical uses of nerve block anesthesia?
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Injection near a nerve produces anesthesia to all tissues enervated by that nerve.
The drug is NEVER injected directly into the nerve as it would likely cause nerve damage. Epinephrine increases the duration of effect. Nerves contain many fibers. As the drug diffuses into the nerve, the outermost fibers are affected first. Outer fibers leave the nerve before inner fibers thus outer fibers enervate nearby tissues. Central fibers enervate distant tissues. In the center of the nerve is the blood vessel giving the local anesthetic access to the circulation. Nerve block anesthesia allows a relatively small amount of drug to anesthetize a relatively large area. |
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where should nerve block anesthesia be admin?
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NEAR the nerve, not into the nerve b/c can cause damage
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what are clinical uses of spinal anesthesia?
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Near the bottom of the spinal cord there is a large volume of CSF compared to nerves making injection of drug relatively safe.
The entire lower body is anesthetized with minimal plasma levels of drug. Often used in surgery of the lower abdomen, legs, and peritoneum. Low spinal anesthesia is safer than general anesthesia. --Surgery of the upper abdomen requires a higher injection of drug which has much greater risk; primarily blockade of nerves enervating higher structures. |
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what are the clinical uses of epidural anesthesia?
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The epidural space is just outside the dura mater surrounding the spinal chord and CNS.
Special Catheters have been designed to deliver the local anesthetic to the right place Primary site of action is the nerve root – the point of exit from the spinal chord. |
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Features of procaine
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The 1st synthetic local anesthetic.
Ester linked Low potency, slow onset, and short duration as compared to other local anesthetics |
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side effects of procaine
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Very low toxicity
Metabolites (paraaminobenzoic acid) can inhibit sulfonamide antibiotics. |
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Features of lidocaine and mepivacaine
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Amide linked local anesthetics. Useful for patients sensitive to ester linked local anesthetics.
More potent than procaine; longer lasting with deeper anesthesia. Lidocaine (but not mepivacaine!) is also used as an antiarrythmic agent. Binds to cardiac sodium channels during systole. |
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Desc. process of how lidocaine works as an antiarrythmic
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Restoration of the negative membrane potential supplies the driving force pushing the sodium channel out of the inactivated state.
Lidocaine, when bound to the channel, supplies an opposing force, trying to keep the channel in the inactivation state. Lidocaine does not block the removal of inactivation during diastole, rather, it merely slows it down. |
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features of bupivacaine and etidocaine
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Amide linked local anesthetics with prolonged duration.
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what are the side effects of bupivacaine and etidocaine
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Severe risk of cardiotoxicity if drug gets systemic.
Binds to cardiac sodium channels during systole -->STOP heart (as does lidocaine-->SLOW heart) Due to the high affinity of bupivacaine, it remains bound during diastole. The effects accumulate with each heart beat leading to severe ventricular arrhythmias and myocardial depression. Virtually impossible to treat. |
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features of tetracaine
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Ester linked drug with long duration.
Not highly sensitive to esterases, making it even more dangerous that bupivacaine |
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Compare duration of injectible local anesthetics
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procaine short
lidocaine int. mepivacaine int. bupivacaine long etidocaine long tetracaine long |
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what do topical local anesthetic formulations often include?
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Formulations often include anti-inflammatory agents such as a glucocorticoid or antihistamine
--Used to treat dermatitis --As the skin is not broken, these drugs act locally. Phenylephrine is often included to promote vasoconstriction. --Epinephrine is too poorly absorbed to be used. |
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features of cocaine topical local anesthetic
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acts as local anesthetic and vasoconstrictor
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side effects of cocaine
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CNS effects, highly addictive
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features fo dibucaine
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Quinoline derivative available as cream or ointment
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features of dyclonine hydrochloride
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Rapid onset when absorbed through skin or mucus membranes
Used for endoscopic procedures and to relieve pain after radiation or chemotherapy |
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features of pramoxine hydrochloride
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Unique chemical structure makes pramoxine tolerated by patients sensitive to most other local anesthetics
Too irritating for nose |
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features of benzocaine
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So poorly soluble in water that it can be administered to an open wound without fear of a systemic reaction.
Often formulated with topical antibiotics |
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what does inadequate sedation lead to?
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Inadequate sedation/analgesia increases catecholamine release, increases metabolic rate, adds cardiovascular stress, diminishes immune function, and impairs wound healing.
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what are benefits of sedation?
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Anxiolysis and amnesia.
Reduced O2 consumption and energy expenditure. Improved ventilation. Reduced intracranial pressure. Prevent drug withdrawal. Patient safety. Liability prevention. |
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what are the opiate sedatives?
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morphine
hydromorphone fentanyl |
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what are benzo sedatives?
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diazepam
lorazepam midazolam |
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what are the other sedatives that aren't opiate/benzos
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propofol
haloperidol, neuroleptics dexmedetomidine |
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Defn analgesia
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blunting or absence of sensation of pain or noxious stimuli
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indications for analgesia
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Presence or expectation of pain.
Synergistic therapy with sedation. Prevent withdrawal |
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subjective analgesia pain control monitoring
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facial expressions, guarding, restlessness, anxiety, irritable, sleep disturbance
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objective analgesia pain control monitoring
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diaphoresis, verbal response, tachycardia, hypertension, muscle tension, dilated pupils, tachypnea, spasm. Pain scores
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SCCM analgesia practice parameters
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Provide analgesia before sedation.
Morphine is the preferred agent unless hemodynamic instability is present. Hydromorphone may be substituted for morphine (but limited histamine release). Fentanyl is the preferred agent if hemodynamic instability is present or morphine allergy. Use scheduled or infusion, not PRN. Monitor for effectiveness and withdrawal |
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subjective opiate abstinence/w/drawal syndrome
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agitation, restlessness, irritability, anxiety, insomnia, tremor, dysphoria
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objective opiate abstinence w/drawal syndrome
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tremor, seizure, tachycardia, hypertension, fever, diaphoresis, dilated pupils, vomiting. Validated tools in NICU and PICU
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prevention of opiate w/drawal
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dose weaning, transdermal fentanyl, enteral methadone
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when should you uses the Pain Assessmnt Behavioral Scale (PABS)?
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when can't talk to pt. about their pain
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what do PABS scores mean?
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0 no pain
1-3 mild pain 4-6 mod. pain 7-10 severe pain |
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Defn. sedation
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provision of anxiolysis, hypnosis, or amnesia
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indications for sedation
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Surgical procedures.
Radiologic procedures. Acute event. Mechanical ventilation. Prevent withdrawal |
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SCCM sedation practive parameters
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Provide analgesia first.
Use sedation score to maintain minimum level of sedation. Daily awakening when possible. Midazolam is the preferred agent for rapid sedation of acute agitation but infusions should be < 72 hours. Lorazepam is the preferred agent for sedation. Propofol is the preferred agent when rapid awakening is required. Haloperidol is the preferred agent for delirium. Sedation and analgesia protocols should be used |
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Clinical study: midazolam w/ propofol
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Forty-one studies of 2052 patients comparing midazolam with propofol.
Results: After discontinuation of sedative agent, propofol associated with shorter times to awakening and extubation but no difference for time to ICU discharge. If daily awakening utilized, then no difference. Drug acquisition cost substantially higher with propofol but total cost of sedation cheaper with propofol when sedation duration < 24 hours. Hypertriglyceridemia and hypotension more common with propofol. More opiate use with midazolam |
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Clinical study: midazolam w/ lorazepam
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Seven studies of 367 patients comparing midazolam with lorazepam.
Results: After discontinuation of sedative agent, lorazepam associated with shorter time to awakening. Drug acquisition cost higher with midazolam. Rare adverse events but occasional lorazepam-induced anion gap (due to propylene glycol) and precipitation of infused lorazepam. Equivalent opiate use |
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Clinical study: lorazepam w/ propofol
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Two studies of 64 patients comparing lorazepam with propofol.
Results: No study has evaluated times to awakening, extubation, or ICU discharge. Drug acquisition cost substantially higher with propofol. Hypertriglyceridemia and hypotension more common with propofol and occasional precipitation of infused lorazepam. Equivalent opiate use |
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Daily awakening study
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Awakening is GOOD!
less: ventilation duration ICU days hosp. days complications PTSD |
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what factors contribute to prolonged ventilation?
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intermittent lorazepam
sedation > 5 days concomitant opiates APACHE II >18 (sicker) |
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which is better, paired awakening and weaning or awaking alone?
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PAIRED
if wean and awaken, pt. comes off the ventilator faster |
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Study: barriers to daily awakening
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Receiving neuromuscular blockade.
FIO2 ≥ 70% or PEEP ≥ 14 cm H2O. Hemodynamically unstable. Already “cooperative”. Reduce sedation / analgesia by half every hour until “awake” starting at 03:00-06:00. SBT criteria vary across institutions. ≤ 40% of ICUs practice daily awakening |
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desc. synergistic sedation
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Benzodiazepine or propofol + opiate.
SCCM recommendations. Benzodiazepine + haloperidol. Best for delirium. Benzodiazepine + propofol. Use benzo for maintenance sedation and propofol for acute control. Reduces respective doses by 25-50%. MAY shorten ventilation time compared to benzo alone, reduces cost, and has been shown to reduce adverse drug effects of propofol (hypertriglyceridemia, hypotension). |
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What are some other sedation approaches?
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Analgesia-based (i.e. use high doses of opioids for sedation) shortens ventilator time.
Target-controlled sedation adjusts dose based upon PK/PD and desired level of sedation. Enteral administration. Inhaled anesthetics (need scavenging device). Ketamine provides analgesia but many adverse reactions. Regional anesthesia and analgesia. Sequential therapy of benzo, then prop or dex prior to extubation, provides faster extubation |
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what are the most common sedation assessment tools?
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Ramsay Sedation Scale.
Riker Sedation-Agitation Scale. Richmond Agitation-Sedation Scale (most common) |
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what is BIS?
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Before-after (vital signs vs. BIS) analysis of 57 SICU patients requiring NMB:
Reduced sedative costs by 18% (p>0.05). Reduced recall of pain or fright from 18% to 4% (p<0.05). 50 SICU patients receiving mid/morphine randomized to standard vs. BIS: Similar sedation requirements, ventilator duration, and ICU LOS. |
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level of sedation
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all agents equally efficacious with appropriate monitoring but ≤ 62% of ICUs use sedation scoring
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unique side effects for sedation
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Prolonged awakening (benzos).
Propylene glycol toxicity (anion gap met acidosis) and ppt with lorazepam. Hypertriglyceridemia, pancreatitis, hypercaloric intake, hypotension, preservatives, and possible immunomodulation with prop. |
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what are sedation w/drawal syndrome features?
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Agitation, restlessness, anxiety, insomnia, tremor, tachycardia, hypertension, fever
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unique side effects of propofol?
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In studies and cohort analyses, Tg > 400 mg/dL occurs ≤ 21% with pancreatitis ≤ 1.9%.
Check every 72 hrs but rate dependent. Propofol infusion syndrome (met acidosis, cardiac and renal failure, rhabdo) related to propofol-mediated impaired fatty acid oxidation in myocardium and skeletal muscle. --Risk factors: catecholamines, corticosteroids, severe illness, young age, carbohydrate restriction, high-dose. Immune modulation due to omega-6 fatty acids: After 48 hrs of infusion of propofol, IL-1β, IL-6, and TNF-alpha increased (all decreased with midazolam) but IL-2 decreased (no change with midazolam). Preservative concerns: EDTA chelation of heavy metals, bisulfate-associated lipid peroxidation to cause bronchoconstriction. Vitamin K |
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sedative w/drawal occurance and risk factors
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32% with ≥ 7 days of therapy.
Risk factors: higher mean daily doses, peak doses, and length of administration of opiates and benzodiazepines; propofol therapy; NMB therapy; rates of discontinuation of opiates and benzodiazepines. |
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|
use of propofol for extubation study?
|
26 SICU patients receiving midazolam ≥ 72 hrs randomized to continue mid or propofol:
Extubation occurred faster after stopping sedation with propofol (1.3 ± 0.4 vs. 4 ± 2.4 hrs, p<0.01). Less agitation for 24 hrs before extubation with propofol (8 vs. 54%, p=0.015). |
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Sedation/Analgesia protocols benefits:
KNOW |
Reduce prescribing variability.
Enhance appropriate drug selection. Reduce drug costs. Improve patient comfort and analgesia. Shorten time to awaken. Reduce duration of mechanical ventilation. Reduce length of ICU and hospital stay. Reduce nosocomial infections. Reduce need for tracheostomy. 23-64% of ICUs use a protocol. |
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Defn delirium
|
Disturbances of consciousness with reduced ability to focus or sustain attention,
Change in cognition (e.g. disorientation, memory impairment) or perceptual disturbances. Acute onset (hrs to days) and tends to fluctuate, Exclusion of other causes |
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delirium incidence
|
Variability due to assessment and training methods, frequency of assessment, ICU population (exclusion criteria), etc.
Types: hyperactive (<1.6%), hypoactive (43.5-64%), mixed (6-54.1%). |
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subjective assessment tools for delirium commonly used
|
Confusion Assessment Method (CAM)-ICU.
I ntensive Care Delirium Screening Checklist (ICDSC). |
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risk factors for delirium
|
Pre-existing: dementia, chronic illness, age, depression, smoking, alcoholism, severity of illness.
Precipitating: hypoxia, metabolic / electrolyte, sleep deficits, sepsis, cardiac disturbances, restraint use or immobility, withdrawal syndromes, acute infections, seizures, head trauma or space occupying lesions, dehydration, vascular disturbances, toxicology, medications (benzos, opiates, propofol). |
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|
CAM ICU assessment
What MUST you have? |
1. Acute onset or fluctuating mental status:
Different from baseline or Sedation score fluctuation over 24 hrs (RASS) – can only do if not deeply sedated. 2. Inattention (present if score of ≤ 7/10): SAVEAHAART or ASE pictures. |
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CAM ICU assessment what must you have in addition to Acute onset/change mental status and Inattention?
|
Disorganized thinking:
Four yes/no questions (score each correct answer one point). Command – hold up fingers (score one point if able to do with both hands). Present if cumulative score ≤ 3 OR Altered level of consciousness: Use sedation score. |
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ICDSC assessment components
|
Obvious manifestation scores 1 point with delirium present if cumulative score ≥ 4:
1. Drowsiness or response to mild to moderate stimulation or hypervigilence. 2. Inattention or easily distracted. 3. Disorientation (person, place, time). 4. Hallucination, delusion, or impairment of reality. 5. Agitation or retardation. 6. Sleep/wake cycle disturbances. 7. Symptom fluctuation over previous 24 hrs. Complete the scale over previous 8 or 24 hrs. Good level of agreement with CAM-ICU over 7 days (kappa = 0.8, 95% CI 0.78-0.84). |
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Non-pharm delirium tx
|
Frequent re-orientation, sleep protocols, early mobilization, removal of devices, exercises (ROM), return assisted living devices, disimpaction, hydration, pain protocol, minimize noise.
Reverse risk factors: Minimize sedation, electrolytes, etc. |
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Pharm. options for delirium
|
Intravenous haloperidol used most frequently.
Retrospective cohort showed reduced mortality with haloperidol use (20.5% vs. 36.1%, p=0.004). Usual dosing regimen is 2.5 - 5 mg every 15 minutes for two doses, then double prior dose every 15 minutes to maximum dose of 60 - 120 mg. Once controlled, maintenance therapy is 25-50% of the cumulative dose and should be divided as every 6 - 8 hour dosing. Dose dependent QT-prolongation. Lorazepam is synergistic for control of psychosis. Dexmedetomidine has been shown to reduce delirium postop vs. propofol (8% vs. 50%, p<0.05). May reduce incidence by starting daily enteral neuroleptic (olanzapine 10-20 mg or quetiapine 50-400 mg or risperidone 0.5-3mg PO BID). Benztropine or diphenhydramine can be used for dystonia/EPS prophylaxis. Bromocriptine, amantadine, dantrolene have been tried for neuroleptic malignant syndrome |
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|
what is dexmedetomidine used for in sedation?
|
Selective alpha-2-adrenoceptor agonist with some analgesia.
Half-life of 2 hrs. Metabolized by cytochrome P450 and direct glucuronidation to inactive metabolites. Dose: (load of 1 g/kg) then 0.2 - 0.7 g/kg/hr but usually avoid load and higher doses in ICU. Advantage: patients sedated BUT arousable and minimal respiratory depression. Concerns: cost, hypotension (30%), bradycardia (8%), withdrawal hypertension? About 25-33% of patients receive dex above the max dose and for > 24 hrs. Use: short-term (≤ 24 hrs), soon to be extubated, ? etoh withdrawal. |
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what are benefits of Dex?
|
NO respiratory depression and DONT have to stop the drug to wake pts.
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|
Case:
53 yo male admitted to the MICU with CAP / COPD exacerbation (PMH of COPD, CAD, and NIDDM). Intubated for hypoxia and eventually placed on Assist Control, 15/15-18 bpm, 8 mL/kg, 70%, and 7 cm H2O PEEP to maintain PaO2 ≥ 90 mmHg and O2sat ≥ 80%. Patient is “agitated and restless” (not autoPEEP). What is the appropriate method to “comfort” this patient? |
Midazolam and fentanyl provided at minimal doses (infusion and PRN) according to sedation / analgesia scores of “calm and cooperative” and “pain free.”
Sedation and analgesia assessed hourly. Daily awakening implemented with SBT. Risk factors for withdrawal and delirium assessed. Delirium assessed every shift. Nonpharmacologic therapies implemented. Consider haloperidol, especially if sedation / analgesia doses are escalating |
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PTSD consideration w/ sedation
|
3.2-14.8%
Risks: age, female, restraint use, prolonged sedation, sedation dose. Greater recall of delusional memories |
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|
delusional recall w/ sedation
|
34%
Risks: severity of illness, longer ICU stay, sedation scores indicating awake, sedation dose |
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Indications for NMB
|
Mechanical ventilation.
Control elevated intracranial pressure. Control shivering, tetanus. Combativeness. Intubation. Procedures or diagnostic studies |
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benefits of NMB
|
Reduce O2 consumption and energy expenditure.
Improve ventilation (reduce intrinsic PEEP, inhibit respiratory drive, ventilator synchrony). Reduce ICP. Patient safety |
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|
SCCM practice parameters
|
NMB does NOT provide sedation or analgesia, JUST paralysis.
Pancuronium is the preferred agent unless hemodynamic instability is present. Vecuronium is the preferred agent if hemodynamic instability is present. Cisatracurium or atracurium should be used if significant hepatic and renal dysfunction |
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NMB drugs and type of elimination
|
Recuronium hepatic
Cisatracurium blood metab Pancuronium hepatic/renal Vecuronium hepatic/renal Doxacurium renal |
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adverse effects NMBs
|
Histamine release = decreased Bp (At > Mi > Ve = others).
Vagolytic = increased Bp (Pa > Ve > Ro = others). Reduced corneal reflex (tape eyes, lacrilube tid). Polyneuropathies, prolonged weakness, myopathies (Ve or Pa) - reduced with TOF monitoring. Tolerance (Atra). Reduced lymphatic blood flow |
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factors that enhance NM blockade
|
Hypothermia.
K , Ca, Phos, Mg. Neuromuscular disorders (MG, MD, MS). Drugs (CCB, B-blockers, CYA, antiarrhythmics, diuretics, Li, Mg, clinda, aminoglycs, corticosteroids). |
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factors that reduce NM blockade
|
Sepsis.
Burns. Trauma. Hepatic failure. Malnutrition. K, Ca, Phos, Mg. Drugs (antiepileptics, theophylline, sympathomimetics). |
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Train of Four NMB monitoring
|
Using peripheral nerve stimulation, monitor number of twitches of ulnar nerve or facial nerve in response to preset amount of current (40 mAmp).
Response of 4/4 is < 75% paralyzed, 3/4 is 75-80% paralyzed, 2/4 is 80-90% paralyzed, 1/4 is 90-100% paralyzed, and 0/4 is 90-100% paralyzed. Use of TOF reduces drug cost and occurrence of neuropathies |
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NMB monitoring
|
Train of Four
Ventilator synchrony and/or decrease ICP |
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Spinal Cord injury:
when should you give methylprednisolone? |
if treated within 8 hrs of injury, give 24 hr treatment
if treated within 3-8 hrs after injury, give 48 hr treatment |
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MOA methylprednisolone
|
anti-inflammatory, inhibits lipid breakdown at site of injury, enhanced blood flow at site of injury
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3 levels of CNS complexity
|
Convergence of neuronal signals
Molecular complexity - interactions between signaling mechanisms Coordination of CNS to produce specific behaviors |
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Fxn of Receptors, membrane transporters and ion channel proteins
|
Fundamental molecular and cellular processes needed for neuron function
Drug Targets |
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which ions have higher extracellular concentration?
|
Na
Ca Cl |
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which ions have higher intracellular concentration?
|
K
|
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what are the types of ion gradients?
|
concentration(chemical)
electrical electrochemical Nernst potential conductance |
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what do membrane transporters transport?
|
Small lipid soluble substances
Water-soluble substances, including small charged particles such as ions |
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What are the types of transporters critical to neuronal fxn?
|
Active transport systems, esp. Na+,K+ ATPase
Transmitter uptake processes Ion channels |
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Desc. primary active transport
|
Primary active transporters - directly require energy input usually via ATP and ATPase activity
Several types but most critical one for neuronal function = Na+,K+ ATPase |
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Desc. how the NaKATPase works
|
Na+-driven pump, i.e., the concentration of Na+ inside the cell determines pump activity (along with available ATP)
When [Na+]i rises, the pump is activated Basic process: 3 Na+ bind to transport protein inside the cell - conformational change + ATPase activity (phosphorylate protein) - releases Na+ to outside of cell; binds 2 K+ ions - conformational change - release K+ inside cell Bottom line - move Na+ out of cell and K+ into cell - both ions are moved AGAINST their electrochemical gradients, therefore requires considerable amount of energy expenditure - estimated that in some cells as much as 50% of a cell's energy is used to operate this pump Purpose: maintain the ionic conditions necessary for normal cellular functioning. |
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what is the purpose of the NaKATPase pump?
|
maintain the ionic conditions necessary for normal cellular functioning.
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Desc. secondary active transport
|
Secondary active transporters - indirectly require energy input (ATP and ATPase activity) via maintenance of ionic gradients which drive these secondary transport
Types: Symport, antiport |
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Desc. Symport
What is an example of this? |
Movement of two substances in the same (sym-) direction (either into or out of the cell)
One down its gradient = driving force The other against its gradient = reason why you need an active transport process Often driven by Na+ gradient into cell, a powerful driving force; a large electrochemical gradient Binding of Na+ ion(s) to transport protein along with the second substance - conformational change in protein - release of substances into cell Indirectly requires energy input - uses gradients established by primary active pumps, e.g., Na+,K+ ATPase pump, to drive these transport systems - hence the name "secondary active" transport process Ex: Na-glucose symport |
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Desc. antiport
What is an example of this? |
Movement of two substance in opposite (anti-) directions (i.e., one into and other out of the cell)
One down its gradient = driving force The other against its gradient = reason why you need an active transport process EXAMPLES 3Na+/Ca2+ antiport (exchange) - especially important in heart and smooth muscle cells Na+/H+ antiport (exchange) - in kidney, GI and other epithelial cells |
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Desc. NT uptake
|
Specific secondary active transporter proteins - closely related (molecular basis) to glucose transporters
Most require the presence of Na+; some require the presence of Na+ and Cl- Specific transporters exist for the uptake of: Biogenic amines - NE, DA, 5-HT Amino acid transmitters - GABA, glycine, glutamate, choline (not ACh) Specificity - amine transporters do not transport amino acids and vice-versa; separate and specific transporters for each neurotransmitter |
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why are neurons drug targets?
|
Drug targets - numerous drugs are used to block these transport mechanisms to enhance the concentration of NTs in the synapse and increase and prolong the action of these
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which NT's/ions are involved in Co-transport NT uptake?
|
Na, Cl with gradient (out to in)
NT: NE, DA, 5-HT, GABA, Glycine vs. gradient (out to in) |
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which NT's/ions are involved in Co-transport and countertransport?
|
Na with gradient (out to in)
K, OH- with gradient (in to out) NT: glutamate vs. gradient (out to in) |
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|
which ions have specific channels?
|
Na, K, Ca, Cl
some overlap |
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|
diff. subtypes of ion channels
|
K 5 diff subtypes
Ca 3 diff subtypes: L, N, T |
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|
Important property of ion channels: hydrophobic/philic
|
Protein within the membrane consists of hydrophobic amino acids (water-hating; lipid-loving) - allows protein to exist in the lipid environment of the membrane
However, amino acids that face the inside of the pore or channel are somewhat hydrophilic = water-loving; this allows the channel to let ions through without repelling them |
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interaction b/w ions and ion channels
|
Cross talk between ions and ion channels - a specific ion channel can be regulated by other ions, e.g., Mg2+ can regulate Ca2+ channel activity (see glutamate receptors below); Ca2+ can regulate one subtype of K+ ion channel activity; etc.
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|
what are the various potential mechs for gating an ion channel?
|
Conformational change in portion of the structure
Conformation change in all subunits Ball and chain concept |
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|
what are the categories of ion channels?
|
passive: remain open
gated: ligand(direct/indirect), voltage, mechanoreceptor gated |
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Desc. Ligand gated ion channels
|
controlled by the action of a ligand (chemical substance = NT, mediator, drug, etc.)
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desc. direct ligand gated ion channels
|
when the receptor is the ion channel; i.e. ligand binds directly to a subunit of the ion channels and causes a conformation change to open or close the channel
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|
desc. indirect ligand gated ion channels
|
ligand binds to a receptor, activates an intracellular signal transduction cascade; a second messenger acts on channel to open or close it (e.g., phosphorylation/dephosphorylation)
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desc. voltage gated ion channels
|
controlled by a change in the membrane potential
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|
desc. mechanoreceptor gated ion channels
|
controlled by a change in the membrane conformation due to mechanical event
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|
what is resting membrane potential?
|
Starting point = cell in the resting (unactivated) state = resting membrane potential (RMP)
RMP = the potential difference (or the voltage difference) across the neuronal cell membrane; always related to the extracellular space RMP in neurons = ~ -65 to -70 mV, i.e., the intracellular space is negative relative to the extracellular space |
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|
what causes RMP?
|
Separation of positively and negatively charged substances by the cell membrane - these include ions or other charged substances such as proteins
Channels and transporters |
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|
what is the main mech of establishing RMP?
|
passive ion channels
K+ efflux through passive K ion channels is the principal determinant of RMP |
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|
Desc. passive ion channels action in establishing RMP
|
Passive channels exist in neuronal membranes that allow the flux of ions into or out of the cell, most importantly Na+, K+ and Cl- ions
Equilibrium determined by Electrochemical gradients across the cell membrane Membrane conductance determined by number and state of ion channels Equilibrium is described by the Nernst equation, giving rise to the Nernst potential K+ efflux through passive K+ ion channels is the principal determinant of the RMP in neurons All three ion fluxes contribute to the RMP but K+ conductance is greater than Na+ or Cl- conductance End result is a membrane potential close to the equilibrium potential for K+ alone, approx. -65 to -70 mV |
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|
recognize neuron structure components:
multipolar neuron dendrite soma axon hillock axon terminal synapse post-synapse |
Multipolar neuron
Motor neurons Interneurons Dendrites = receiving end Soma = cell body - synthesis of all neuronal components; also receives signals Axon hillock = initial segment Axon - conducts APs from soma to terminal region; myelin sheaths Terminal (presynaptic) - release of neurotransmitter; reuptake of transmitter Synapse Post-synaptic sites/neuron/membrane |
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RMP in neurons
|
Basal state - no neuronal activity
Limits of the potential across neuronal cell membranes is determined by the equilibrium potentials for Na+ (+60mV) and Cl- (-90-100 mV) Membrane potential can be perturbed to be anywhere in between these limits |
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Desc. EPSP
|
Activation of a ligand-gated Na+ ion channel = depolarization = excitation = an EPSP - destabilizes neuron
Unitary EPSP = depolarization caused by all NTs from one vesicle; sum these to get total EPSP for one burst of NT release Graded potential - directly proportional to the extent of activation of ion channels, therefore the number of NT molecules activating the ion channels |
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|
desc. IPSP
|
Activation of a ligand-gated Cl- ion channel or of a K+ ion channel - opens channels, allows Cl- ions to enter neuronal cell or allows K+ ions to leave cell
Interior of cell becomes less positive/more negative = hyperpolarization = inhibition = an IPSP - stabilizes neuron Graded potential just as with EPSP except in opposite direction |
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Desc. propagation and degredation of EPSPs or IPSPs
|
Signal (depolarization or hyperpolarization) travels along dendrite and soma
Signal degrades over time and distance from site of stimulus Need very large EPSP or IPSP to reach axon hillock or initial segment before it degrades back to RMP |
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|
what is temporal summation?
|
High frequency bursts
|
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|
what is spatial summation?
|
More than one neuron activates post-synaptic neuron at the same time
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|
Desc. final signal resulting from summation of IPSP and EPSP
|
Final signal to reach the axon hillock/initial segment is the summation of all EPSPs and all IPSPs generated in the dendrites/soma
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|
what is threshold MP?
|
To generate an action potential the EPSP must be strong enough to reach threshold depolarization voltage of approx. -45 mV
Threshold voltage = voltage required to trigger conformational change in voltage-dependent fast Na+ channels; below threshold, these channels remain closed |
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|
Desc. mech. of AP generation
|
Event #1 - RMP
Event #2 - reach threshold; fast (<1 msec) voltage-dependent Na+ channels detect change in membrane voltage, change conformation and open; millions of Na+ ions rush in; increased intracellular Na+ - causes further depolarization toward equilibrium potential for Na+ (+ voltage) - goes to approx. +20mV membrane potential Event #3 - peak; slower (1-2 msec) voltage-dependent K+ channels open in response to depolarization; K+ ions leave cell, thereby removing some of the positive charge build-up inside the cell; results in repolarization Event #4 - repolarization; time-dependent inactivation gates on Na+ channels begin to close; stop influx of Na+ ions; contributes to repolarization Event #5 - hyperpolarization; voltage-dependent K+ ion channels begin to close; in meantime, repolarization overshoots and hyperpolarizes membrane Event #1 - voltage-dependent K+ ion channels closed; voltage-dependent Na+ channels gates close and Na+ channel time-dependent inactivation gates re-open = RMP |
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|
how long does AP generation process take?
|
entire process complete in ~5 msec; therefore can generate up to 200 APS/sec (frequency of 200Hz
|
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|
what is refractory period?
absolute vs. relative |
Absolute refractory period: during the AP
Relative refractory period: during hyperpolarized state |
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|
desc. propatation of APs
|
Influx of Na+ ions causes depolarization that spreads to adjacent segment of neuron
Adjacent segment reaches threshold - activate voltage-gated Na+ channels - generates new AP - all or none Keeps going to terminal |
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|
why doesn't AP travel backwards
|
Does not travel in retrograde fashion because:
Absence of voltage-gated Na+ channels in soma and dendrites Previous segment of axon in refractory state |
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|
what is the purpose of myelinated axons?
|
Myelin sheaths/Schwann cells - wrap around axon - spaces = Nodes of Ranvier which contain high concentration of voltage-gated Na+ channels
AP jumps from one node to the next = saltatory conduction - very fast up to 120 m/sec |
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|
what neuron features increase conduction velocity?
|
increased diameter
presence of myelin (motor=fast, pain/sensory=slow) |
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|
How are NT released from neurons
|
AP reaches neuron terminal
Opens voltage-gated Ca2+ channels (N-type Ca2+ channels - different from L-type in smooth muscle, heart) Ca2+ ions enter terminal region, activate intracellular processes to allow NT vesicles to fuse to terminal membrane and release contents to synapse (exocytosis |
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|
what does omega-conotoxin do?
|
•Source - marine snails
•Blocks N- type Ca2+ channels in neuronal terminals •Prevents activation of neuron terminal •Prevents release of neurotransmitter |
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|
what does botulinum toxin do?
|
•Source - Clostridium botulinum bacteria (anaerobic); toxin produced in bacteria contaminated food; or toxin produced in intestines after ingestion of spores
•Toxin inactivated by 100°C for 10 min; spores require 120°C heat for inactivation •Toxin enters all peripheral (but not CNS) cholinergic nerve terminals (i.e., neurons that produce the neurotransmitter, acetylcholine) in skeletal muscle, glands, heart, smooth muscle •Toxin prevents release of acetylcholine •Severe case - descending paralysis - eyes, head, neck, dry mouth, swallowing, speech, arms, thorax, legs, GI symptoms; respiratory muscle paralysis leads to death (7.5% of cases) (note- sensory nerves not affected) •Treatment - antitoxin or supportive therapy |
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|
what does black widow spider venom do?
|
•Enters cholinergic nerve terminals
•Causes burst release of acetylcholine •Depletes acetylcholine stores •Symptoms - initial cholinergic overactivity followed by loss of cholinergic |
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|
what do uptake inhibitors do?
|
•Prevents re-uptake of neurotransmitter or metabolites
•Examples - cocaine in adrenergic neurons; causes exaggerated adrenergic effects; SSRIs inhibit 5-HT reuptake - anti-depressant |
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|
what do drugs that inhibit release do?
|
•Autoinhibition - NT acts on pre-synaptic receptors to inhibit own release
•Cross inhibition by other NTs and |
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|
what do enzyme inhibitors do?
|
•Inhibit synthesis enzymes - decrease NT stores; decrease neuronal function
•Inhibit degradation enzymes; potentiate neuronal responses •Example - acetylcholinesterase inhibitors (insecticides; nerve gases) - inhibit metabolism of acetylcholine; potentiate cholinergic responses - heart, BP, glands, skeletal muscle, CNS |
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|
what are the 2 general categories of receptors in the CNS
|
ionotropic
metabotropic |
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|
desc. ionotropic receptors
|
Ionotropic (direct) = ligand-gated ion channels where the NT binds directly to the channel
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|
desc. metabotropic receptors
|
Metabotropic (indirect) = receptor linked to signal transduction mechanism, usually G protein coupled receptor (GPCR), leading to increase in second messengers
Second messengers can link to alteration in ion channels or alter cell metabolism or even contribute to transcriptional regulation |
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|
what are the primary inhibitory NTs?
|
GABA
glycine |
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|
what are the primary excitatory NTs?
|
glutamate
ACh |
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|
mech of GABA
|
GABA-a : Cl conductance
GABA-b: K conductance |
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|
mech of glycine
|
Cl conductance
|
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|
mech glutamate
|
glutamate: IP3/DAG increase
non-NMDA: Na, K conduct NMDA: Ca, Na, K conduct |
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|
mech ACh
|
nicotinic: Na, K, Ca conduct
muscarinic: IP3/DAG increase, decrease K OR... decrease cAMP, increase K |
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|
Mech. 5-HT
|
5HT1A: decrease cAMP, increase K
5HT3: increase Na and K |
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|
Desc. glutamate metabotropic receptor action
|
GPCR - linked to PLC and production of IP3 and DAG; IP3 increases intracellular Ca2+ via release from SER
|
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|
desc. glutamate non-NMDA receptor action
|
open Na+, K+ channel - Na+ influx >>> K+ efflux - leads to fast depolarization/EPSPs - activation/excitation of target neurons
NOTE - these can be subdivided further by specific agonists than activate these receptors, e.g., AMPA, kainate |
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|
desc. glutamate NMDA receptor action
|
1.Primarily a Ca2+ ion channel (different from voltage-gated L-type/ dihydropyridine sensitive or N-type/CTX sensitive Ca2+ channels); also allows Na+ and K+ flow
2.Ca2+ that enters cell activates many metabolic processes in neuron leading to relatively long-lasting effects 3.Channel only functions when glycine is bound to it 4.Unique channel because it is regulated by both glutamate and by voltage At RMP, channel is blocked by Mg2+ ions Only during depolarization of the neuron in the presence of glutamate is Mg2+ expelled from channel thereby opening the channel 5.Channel opens and closes slowly therefore relatively slow EPSP, slow response 6.PCP binds to and inhibits channel (only when in open state) 7.This channel does not contribute to fast EPSPs - only non-NMDA receptors do; this channel receptor acts only after depolarization by non-NMDA or other receptors and then contributes to depolarization and other effects |
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|
How is glutamate important to learning/memory?
|
Long-term potentiation - one of the processes required for memory
Release of glutamate from presynaptic neuron activates Metabotropic receptor to increase IP3 and intracellular Ca2+ Ionotropic non-NMDA receptor channel - EPSPs and depolarization/excitation of neuron In turn - this activates (w/glutamate) the NMDA receptor/channel - influx of Ca2+ Increased intracellular Ca2+ activates numerous biochemical pathways - one of which results in release of a transmitter that acts back on the presynaptic neurons to continuously activate release of NT (glutamate) = LTP; continuous postsynaptic neuron activation leads to formation of memory ***Bottom line - glutamate important excitatory NT in CNS for activation of many CNS processes from motor functions to memory |
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|
desc. GABAergic feedback circuit
|
GABAergic feedback interneuron which suppresses activity of initial excitatory neuron; feedback neuron synapses close to axon hillock to increase Cl- influx and prevent depolarization
|
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|
how do anti-psychotics work?
|
Anti-psychotics drugs essentially act by blocking dopamine (D2) receptors and reduce dopamine neurotransmission in specific brain regions (e.g., forebrain).
|
|
|
How do anti-depressants work?
|
Many anti-depressants drugs act by blocking reuptake (transporters) of biogenic amines in CNS neurons.
Initially, drugs were developed that blocked reuptake of norepinephrine, e.g., TCAs More recently, selective inhibitors of serotonin reuptake were developed and are widely used, e.g., SSRIs (Prozac, Paxil, Zoloft, Effexor) |
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|
How are Na channels targeted to treat epilepsy?
|
Na+ channels (voltage-gated) - required for generating APs in neurons
Epilepsy - rapid depolarizations/APs in neurons - fast recovery and repetitive firing (remember AP is only a few ms in duration) Inactivation gate = time-dependent gate to inactivate Na+ channels = refractory period; if you prolong inactivation state/prolong refractory period = reduced firing rate = reduced activation of neurons = reduced activity = reduced epileptic seizure Ex: CBZ, PHT, VPA, lamotrigine |
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|
How are Ttype Ca channels targeted to treat epilepsy?
|
T-type Ca++ channels = low threshold Ca2+ channels
Appear to be related to absence seizures - spike and wave EEG pattern Localized to thalamus (part of circuitry and reciprocal firing of thalamus-cerebral cortex in absence seizures) Opening these channels allows Ca2+ entry into neurons - leading to depolarization/activation Drugs that inhibit T-type Ca++ channels are effective in treating absence seizures = ethosuximide, dimethadione, valproate |
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|
How is GABA involved in seizure treatment?
|
GABA - principal inhibitory NT in CNS; potentiation of GABA should inhibit seizure activity
Drugs that act on GABA neurons/GABA-a receptors ***enhance inactivation |
|
|
which drugs act on GABA to treat seizures?
|
benzos, barbiturates, VPA, vigabatrin, gabapentin, pregabalin, felbamate
|
|
|
what do benzos do?
|
bind to GABA-a receptors/Cl- ion channels to produce an allosteric effect, i.e., potentiates actions of GABA on GABA-a receptors to increase Cl- influx = hyperpolarization/inhibition
|
|
|
what do barbiturates do?
|
same as benzodiazepines at lower doses but at higher doses appear to activate directly (directly gate) the GABA-a receptor/Cl- channel to open it and increase Cl- influx = hyperpolarization = inactive neuron - reduce seizure activity. Direct gating can lead to profound CNS depression that is not seen w/benzodiazepines
(benzo's bind to GABA-a receptors/Cl- ion channels to produce an allosteric effect, i.e., potentiates actions of GABA on GABA-a receptors to increase Cl- influx = hyperpolarization/inhibition) |
|
|
what does VPA do?
|
may increase GABA release via inhibition of its metabolism
|
|
|
what does vigabatrin do?
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(gamma-vinyl-GABA) - believed to act by inhibiting GABA transaminase metabolism of GABA - increasing GABA concentrations - increasing GABA output - potentiating GABA inhibitory effects
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what does gabapentin do?
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originally designed as GABA agonist - but does not appear work this way; alternative mechanisms include - increase stimulated GABA release via increased GABA reuptake; inhibits voltage-gated L-type Ca++ channels in neuron terminals (binds to alspha-2-delta subunit of channel protein) thereby reducing neurotransmitter release (e.g., excitatory NTs such as glutamate, NE, Substance P)
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what does pregabalin do?
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Pregabalin - also inhibits voltage-gated Ca++ channels producing same effects as gabapentin
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what does felbamate do?
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Potentiates GABA-a Cl- channels - potentiates inhibition
Inhibits NMDA-evoked responses - inhibits glutamate-induced Ca++ influx - inhibits excitatory input Result - inhibition of neurons; control of seizure activity (wide spectrum of activity) |
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what sedatives/hypnotics/anti-anxiety drugs target GABA?
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Ethanol - potentiates GABA-a receptor function, i.e., inhibition via increased Cl- conductance
Benzodiazepines; Barbiturates |
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desc. glutamate excitotoxicity
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Excessive glutamate in the CNS has been known for many years to cause neuronal cell damage and death; in several disease states (stroke, ALS, severe epilepsies, others), glutamate levels are increased which led to the hypothesis that excessive glutamate is one possible cause of neuronal damage associated with these diseases
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what is ischemic stroke?
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Ischemic stroke - interrupt blood supply; neurons in the center of the affected area die from severe ischemia and energy deprivation. In surrounding areas, neurons appear to die from excessive glutamate receptor stimulation.
Normal function - glutamate depolarizes neurons via non-NMDA ionotropic receptors Glutamate levels are tightly controlled by the uptake of glutamate into neurons or astrocytes (glial cells). Symport: Na+-dependent secondary active transport, i.e., Na+ gradient drives the uptake process. In glia, glutamate is metabolized to glutamine; released and taken up by neurons to resynthesize glutamate. |
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what happens during ischemia?
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Reduce supply of oxygen and glucose needed for normal cellular metabolism; reduce ATPase activity
Result - decreased Na+,K+ ATPase pump activity which reduces normal gradients; and reduced metabolism of glutamate to glutamine Result - reduced Na+ gradient and reduced glutamate gradient (less metabolism to glutamine) causes less uptake of glutamate thereby increasing its concentration in the synapse = potentiates glutamate actions. Glutamate actions = depolarization of neuron via non-NMDA receptors which causes Mg2+ to leave NMDA receptor/ion channel when glutamate is present allowing Ca2+ influx into neuron; at same time, glutamate is activating its metabotropic receptor linked to IP3 and Ca2+ Prolonged, intense stimulation - increased intracellular Ca2+ activates numerous processes including activation of enzymes which cause cell damage and cell death Secondary effect - ischemia also disrupts K+ homeostasis by inhibiting two energy-dependent transporters: the Na+,K+ ATPase pump and the Na+, K+, Cl- co-transporter - result is increased extracellular K+ and depolarization of membrane toward threshold - increases excitability of neurons adding to release and overload of glutamate in synapse leading to further neuronal activation and cell death. |
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How do nerve gasses work?
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soman = AChEI - elevates ACh levels - increases neuronal excitation - causes seizure activity; non-cholinergic nerves are recruited/activated including glutamate neurons causing excessive release of glutamate which in turn leads to events listed above - depolarization, increased NMDA receptor activation - increased Ca2+ influx - cell death; glutamate activates ACh neurons leading to continuous release of ACh and further excitation and prolongation of seizure activity.
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what can be done to treat nerve gasses?
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muscarinic antagonists are useful if given prophylactically or within short period of time after soman exposure; once seizures begin, anti-muscarinics are ineffective by themselves; however, specific NMDA receptor antagonists in combination with muscarinic receptor antagonist can alleviate seizure activity
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