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CNS NTs Flashcards

1
Q

Anatomy for Glutamate:

A

Relay neurons all levels and some inter neurons

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2
Q

What are the receptors for Glutamate?

A

NMDA
AMPA
Kainate
Metabotropic

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3
Q

What is the mechanism for NMDA (glutamate)?

A

Excitatory: increase cation conductance (Ca)

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4
Q

What is the mechanism for AMPA (glutamate)?

A

Excitatory: increase cation conductance

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5
Q

What is the mechanism for Kainate (glutamate)?

A

Excitatory: increase cation conductance

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6
Q

What is the mechanism for metabotropic (glutamate)?

A

Inhibitory of presynaptic: decrease Ca and cAMP

Excitatory: decrease K and increase IP3 and DAG

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7
Q

What is the anatomy for glycine?

A

Spinal interneurons and some brainstem interneurons

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8
Q

What is the receptor for glycine?

A

Glycine

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9
Q

What is the mechanism for glycine?

A

Inhibitory: increase Cl

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10
Q

What is the anatomy for GABA?

A

Supraspinal and spinal interneurons pre and post synaptic

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11
Q

What are the receptors for GABA?

A

GABAa

GABAb

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12
Q

What is the mechanism for GABAa?

A

Inhibitory: increase Cl

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13
Q

What is the mechanism for GABAb?

A

Inhibitory in presynaptic: decrease Ca

Inhibitory in postsynaptic: increase K

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14
Q

What anesthetics use the receptor GABAa?

A 
Barbiturates (enhance)
Propofol (enhance)
Etomidate (enhance)
Benzodiazepine (enhance)
Inhaled agents (enhance)
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15
Q

What anesthetics use the receptor glycine?

A

Barbiturates (enhance)
Propofol (enhance)
Etomidate (enhance)
Benzodiazepine (enhance)

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16
Q

What anesthetics use the receptor NMDA?

A 
Ketamine (inhibit)
Inhaled agents (N20) (inhibit)
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17
Q

What anesthetics use the receptor nACh?

A

Barbiturates (inhibit)

Ketamine (inhibit)

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18
Q

What anesthetics use the receptor K+ channels?

A

Inhaled agents (enhance)

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19
Q

Calming and drowsiness, decreases activity, moderates excitement, calms patient

A

Sedation

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20
Q

Produces drowsiness and facilitates the onset and maintenance of a state of sleep

A

Hypnosis

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21
Q

Global but reversible CNS depression resulting in loss of response to and perception of external stimuli “deafferentation”
Not all agents produce identical state
Collection of changes in behavior and perception – anesthetic state is:
•Amnesia
•Immobility to noxious stimuli
•Attenuation of autonomic response to noxious stimuli
•Analgesia
•Unconsciousness

A

Anesthesia

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22
Q

Potential other effects of drugs?

A 
Amnesia 
Analgesia 
Anticonvulsant 
Muscle Relaxation 
Respiratory 
Depression
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23
Q

What are the different drug classes (6)?

A 
Benzodiazepines 
Non-bz sedative hypnotic drugs (z drugs)
Barbiturates 
Melatonin Congeners 
IV Anesthetics 
Inhaled Anesthetics
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24
Q

What is the triad of GA?

A

Unconsciousness
Analgesia
Muscle Relaxation

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25
What can IV agents be used for (5)?
Sedation-based anesthesia Monitored anesthesia care (regional or local + sedation) Conscious sedation (small doses used to alleviate anxiety) Deep sedation Light state of GA
26
What comes with light state of GA?
Loss of protective reflexes Inability to maintain patent airway Lack responsiveness to surgical stimuli
27
IV Anesthetics characteristics of each agent (7)
``` Induction Analgesia Sedation/antianxiety Hypnosis Amnesia Muscle Relaxation Anesthesia ```
28
Non-anesthesia drugs side effects of induction (5)
``` Apnea CV Hiccups Movement Pain - site of injection ```
29
Non-anesthesia drugs side effects of recovery (3)
Nausea Vomiting Restlessness
30
What is GABA?
Inhibitory CNS NTs
31
What kind of structure is GABAa receptor?
Pentameric with subunits alpha, beta, and gamma
32
What subunits of GABA is major isoform?
2 alpha1 2 beta2 1 gamma2
33
Where is the binding site for GABA?
Between alpha1 and beta2
34
Where is the binding site for BZ?
Between alpha1 and gamma2
35
What else is barbiturates known as?
Methohexital (brevital) | Thiopental (pentothal) and Thiamylal are no longer in US
36
Mechanism of action for barbiturates?
``` Enhance GABA (Cl) Increase duration of GABA -High doses activate Cl and depress glutamate binding to AMPa receptor ```
37
What do barbiturates substitutions affect?
Hypnotic potency and anticonvulsant activity
38
What activity does phenobarbital affect?
Anti-convulsive
39
What is thiopental, thiamylal activity?
Greater potency More rapid onset Shorter duration fo action compared to pentobarbital
40
How are barbiturates absorbed?
IV | Rectally in peds
41
What kind of distribution are barbiturates?
High lipid solubility
42
How fast does plasma:brain equilibrium occur in barbiturates?
Rapidly, onset within 30 sec
43
How is barbiturates diffusion to other tissues limits duration of induction?
Waken in about 20min
44
How do you dose elders with barbiturates?
Reduce induction does due to slower redistribution and longer duration of action
45
How is repeated doses (or continuous infusion) affected with barbiturate?
Saturate peripheral compartments and minimize the redistribution effect (increasing duration of action)
46
Does continuous infusion prolong the half life?
Yes
47
How should barbiturates be mixed with other solutions?
Alkaline solution to make soluble
48
What happens with barbiturates when mixed with drugs that are weak bases (rocuronium, lidocaine, labetalol, morphine)?
Precipitation
49
Barbiturate Pharmacodynamics to CNS (5)?
Onset 10-20sec; bolus lasts about 8-20min (half life 3-12hr) Constrict cerebral vasculature (decrease CBF and ICP) Decrease cerebral oxygen Potent antibonvulsant (phenobarbital) Lower pain threshold (hyperalgesic effect) Involuntary muscle movements (excitatory with induction (methohexital))
50
Barbiturate Pharmacodynamics to CV (5)?
Peripheral vasodilation (small decrease in BP) Negative inotropic effects Venous vasodilation (peripheral pooling, decrease preload (CO&BP)) Vagolytic compensatory responses (HR&contractility) Caution in patients without adequate baroreceptor responses (decrease BP&CO) (hypovolemia, beta blocker, CHF)
51
Barbiturate Pharmacodynamics to respiratory (3)?
Depression (medullary center, decrease response to CO2&O2) Don’t completely suppress airway reflexes (muscarinic nerve stimulation-atropine and thiopental to avoid bronchospasm Apnea, bronchospasm (asthma), hiccup, laryngospasm
52
Barbiturate Pharmacodynamics to histamine release?
May cause hypotension, tachycardia Caution in asthma patient Rare allergic reactions
53
Does barbiturates have muscle relaxation?
No
54
Additional info about Barbiturate Pharmacodynamics?
Pain on injection No analgesia Renal/hepatic - no short term toxicities Contraindicated in acute intermittent porphyria
55
What is porphyria?
Neurological disease cause by inadequate porphyria metabolism -rate limiting step in haem synthesis (ALA synthetase)
56
What is porphyrins?
Highly reactive oxidants | Cause toxic neurological sequelae
57
What drug is barbiturates being replaced by?
Propofol
58
Thiopental (4)
Primary use was in induction Used alone for short procedure with no pain Promote sleep for local anesthesia Critical care uses: ICU sedation, increased ICP, epileptic
59
When is methohexital used?
For ECT or epilepsy-related surgical procedures
60
What interactions should be considered for dose reduction in barbiturate?
Combo with opioid alpha2 adrenergic agonist Benzodiazepine Acute ethanol
61
What patients should be considered for dose reductions with barbiturate?
``` Anemia Low protein Decreased CO Shock Elderly ```
62
What drugs are under benzodiazepines (BZ)?
Diazepam Lorazepam Midazolam
63
BZ mechanism of action (5):
Interaction with GABA (inhibitory, Cl) GABA inhibition at all levels (spinal cord to cerebral cortex) Increase efficiency of GABA by increasing frequency of Cl challenge openings Do NOT substitute for GABA, must be present Do NOT directly activate GABA receptor (bind to BZ receptor)
64
What is BZ’s receptor competitive antagonist?
Flumazenil
65
What structure is BZ?
Heterocyclic ring with varied substituents that impact potency and metabolism (diazepine ring)
66
What does BZ water solubility affect?
Parent earl preparations
67
What does BZ lipid solubility impact?
CNS onset
68
What are the kinds of formulations for BZ?
P.O., IM, IV administration
69
How long is diazepam and lorazepam P0 onset?
1-2 hr
70
What is midazolam for PO administration?
Syrup
71
What kind of absorption do you get from IM diazepam?
Painful and erratic
72
What kind of absorption do you get with IM lorazepam and midazolam?
Well absorbed and peak in 90min (lorazepam) and 30min (midazolam)
73
What is the only IV BZ for induction and how is its onset?
Midazolam and among BZ shortest onset (but still longer compared to other classes of agents) -diazepam and others can be given IV but not used for induction due to delayed onset
74
BZ lipid solubility distribution from highest to lowest:
M > D > L
75
Distribution of BZ to brain - time to onset highest to lowest:
L > D > M - L slowest CNS uptake and onset - BZ have slower onset for induction vs propofol
76
What is the redistribution time and what kind of bound is BZ?
``` Rapid redistribution (3-10min), but short duration of effect Highly protein bound (>90%) ```
77
Hepatic metabolism for BZ in mostly phase I or II?
Most phase I oxidation | Phase II conjugation of metabolites for renal elimination
78
Which of BZ are active metabolites?
D and M
79
Which of BZ has the highest to lowest half life?
D > L > M
80
Which of BZ deals with enterohepatic recirc?
D
81
What happens if you high does midazolam?
Accumulation of active metabolite in patients with kidney failure
82
CNS effects of BZ (8)
``` Sedation Hypnosis Anesthesia Amnesia Anticonvulsant Muscle relaxation (not paralysis) Tolerance - physiologic and psychologic (patient history and/or cross tolerance) Dependence ```
83
What kind of CNS effects do BZ have compared to barbiturates?
Decrease CBF, O2 consumption, ICP but at a lesser degree than barbiurates
84
What kind of amnesia does BZ have at CNS level?
Anterograde amnesia
85
Does BZ have analgesic effects?
NO
86
BZ affects on CV?
Minimal effects and may be used to balance effects of other agents Large doses through IV or combo with opioids maybe reduce BP (vasodilation) Possible increase in HR with midazolam
87
BZ affect with respiratory?
Minimal depression alone but additive with other agents Decrease ventilatory response to CO2 Induction apnea
88
Which BZ has the most to least common thrombophlebitis?
D > M >> L
89
Drug interaction will induce or inhibit what enzyme?
CYP P450
90
What does opioids + BZ get?
``` Decrease SVR (hypotension) Caution with patients with ischemic heart disease, valvular heart disease ```
91
Does BZ increase or decrease potency of inhaled agents?
Increase potency (decrease MAC)
92
What are the 5 status that BZ’s are used?
``` Perioperative Sedation-hypnosis with local anesthesia Alone for procedures not requiring analgesia or full anesthesia Control seizures ICU sedation ```
93
What does Flumazenil do?
Reverse symptoms of OD or therapeutic effects of BZ | Does not affect BZ elimination or concentration
94
What is the half life for flumazenil?
54min (duration of action about 20min) Shorter compared to BZ May cause withdrawal in dependent patients, seizures in those at risk
95
Ketamine’s mechanism of action
Inhibit NMDA receptor complex (glutamate receptor)
96
What kind of anesthesia is ketamine?
Dissociative anesthesia - dissociated thalamus (relays sensory) to limbic (awareness)
97
How do you appear with Ketamine?
Awake, eyes open, swallow, muscle contracture, but unable to respond to sensory input -NOT global CNS depression, in fact some stimulation
98
What are some special properties to ketamine?
May limit use or make desirable in certain patient situations
99
What drug is ketamine most similar to?
Phencyclidine (vet anesthetic)
100
What kind of potency is ketamine?
0.1 potency, but has some psychotomimetic effects | May cause some hallucinations at sub-anesthetic doses (midazolam or other sedative will minimize)
101
What is a potent anesthetic without psychotomimetic effects?
S+ isomer | -greater affinity for NMDA receptor (greater potency)
102
Normal absorption for ketamine?
IV or IM
103
Distribution for ketamine?
Lipophilic with rapid brain uptake | -fast onset with short duration (10-15min duration of action)
104
Metabolism for ketamine?
Induction of hepatic enzymes (repeated doses and they develop tolerance) Active metabolite Norketamine (less potent) Extensive hepatic extraction
105
Excretion for ketamine?
Renal elimination of metabolites
106
Dosing for ketamine?
Excellent analgesic at sub anesthetic doses | Can be ‘complete’ anesthetic (analgesic, amnesia, unconsciousness)
107
CNS with ketamine (5)?
Cerebral vasodilator (increased CBF and ICP) Onset 15-30sec and lasts 10-15min Analgesia/amnesia is instant and last 40min Does NOT lower seizure threshold Emergence reactions (10%-30% of adults)
108
What kind of emergence reactions do you get with ketamine?
Delirium, excitement, confusion, euphoria, fear, vivid dreaming, hallucinations First hour of emergence Lower rate in children Minimize with BZ
109
CV with ketamine?
Central sympathetic stimulation, inhibits NorE reuptake | Increases HR, BP, CO
110
When should you use caution or avoid with ketamine?
Patients with CAD, uncontrolled HTN, CHF, or arterial aneurysms
111
What is the exception with ketamine in some patients?
Depleted catecholamines or spinal cord transaction | May see direct myocardial depression (Ca channel blocker) with very large doses (no longer mask sympathetic effects)
112
Respiratory with ketamine?
Minimal effect on ventilatory drive (CO2) Bronchodilator (racemic) which is useful in asthma and peds Increased salivary and trachiobronchial secretions (can premed to reduce)
113
Muscle effect with ketamine?
Myoclonic activity (no change in EEG) No MH Stimulated uterine muscle contraction
114
Which drug interactions block the ketamine sympathetic effects?
Alpha and beta adrenergic receptor antagonists which leads to direct myocardial depressant effects
115
What other drug interactions is ketamine additive with?
Inhaled anesthetics | Propofol, BZ, and other GABA acting agents
116
When is ketamine used?
Used with BZ in emergent and trauma situations, procedures for analgesia and amnesia Now used for severe depression to treat resistant and suicidal
117
Is ketamine an excellent analgesic at sub anesthetic doses?
YES
118
When is ketamine used in anesthesia?
Induction and maintenance
119
Mechanism of action for propofol?
Interacts with GABAa receptor complex (binds to beta subunit) Allosterically increases binding affinity for GABA (hyperpolarization of nerve membrane) Binds to multi ion channels (glutamate related)
120
What is propofol formulation?
NOT water soluble 1% (10mg/ml) solution available as oil in water (O/W) emulsion Lipophilic in 10% fat emulsion
121
What is in propofol?
Soybean oil Glycerol Egg lecithin (egg yolk) Preservatives to prevent bacterial growth (metabisulfite and edetate)
122
What is the problem with lipophilic?
``` Once opened use within 6-8hours Linked to sepsis, mortality, other infectious complications with ICU long term sedation Periodic shortages (problems with particulate matter and microbial contaminations) ```
123
What is the absorption for propofol?
IV only
124
What is the distribution for propofol?
Rapid onset Rapid awakening from single bolus dose (half life 2-8min) Vd reduced in elders (lower dose)
125
Metabolism for propofol?
Hepatic and extra renal clearance - hepatic conjugation to inactive metabolites then really cleared - no dose change for cirrhosis or renal failure
126
Cerebral affect on propofol?
Decrease CBF, blood volume and ICP | Use caution for patients with elevated ICP (can cause critical reduction)
127
Does propofol have analgesic effect?
NO
128
CNS effect from propofol?
Dystonic movements (NOT seizure activity) Has some anticonvulsant properties Tolerance dos not occur in repeated doses Uncommon cause of dependence or addiction
129
CV for propofol?
Reduced BP by 15%-40% (greater than thiopental) - decreased SVR and preload - inhibit baroreceptor response to change in BP (HR unchanged)
130
Who has a greater impact on with propofol?
``` Hypovolemia Elderly LV dysfunction Receiving beta blockers -reduce dose or combo with IV opioid or BZ ```
131
Respiratory with propofol?
``` Profound depression (reduce CO2) Apneic for 30-60sec Inhibits airway reflexes (less cough, layrngospasm) Minimal histamine release Fewer problems with asthmatic patients ```
132
Does propofol have muscle relaxation?
NO
133
Is there pain with injection of propofol and how to fix?
Yes, use lidocaine before or with propofol
134
Other effects of propofol?
Sedative & antianxiety Antiemetic at sub anesthetic doses Antipruritic Safe in OB/GYN (may cause neonatal depressed after prolong infusion)
135
Is there a chance with porphyrinogenic with propofol?
Yes, increases ALA reductive activity
136
When is hypertriglyceridemai possible with propofol?
Critical care and peds | Continuous infusions
137
What is propofol infusion syndrome?
Metabolic acidosis | Lipemic plasma, myocardial failure, hepatomegaly, rhabdomyolysis
138
When is propofol used?
Induction Maintenance ICU
139
What is the rapid onset and awakening for propofol?
10-20sec onset | 2-8min awakening
140
What is TIVA?
Total IV anesthesia | -combo with other short acting agents (remifentanil, alfentanil, sufentanil)
141
What other drug is propofol used with during induction?
Midazolam (additive effects so reduce propofol by 10%)
142
What other drug is propofol used with during TIVA?
Combo with remifentanil and ketamine
143
What do you do to propofol with high concentrations of fentanyl and alfentanil?
May be able to reduce dose
144
Do you change dose of propofol for obesity, cirrhosis, or renal failure?
NO
145
When do you use smaller induction doses of propofol?
Elderly | TIVA
146
What is formulation of fospropofol?
Sterile aqueous clear solution to avoid pain on injection and lipid emulsion Water soluble prodrug Onset and recovery are prolonged compared to propofol Use for moderate IV sedation (MAC) with O2
147
Mechanism of action for etomidate?
``` Enhance GABA (GABAa receptor) -may have dis-inhibitory effect in extrapryramidal area (basal ganglia) that lead to EPS like movement (increased myoclonus compared to other agents) ```
148
What is the absorption for etomidate?
IV
149
What is the distribution for etomidate?
High protein binding, but rapid onset due to high lipid solubility and large non-ionized fraction Recovery depends on redistribution to inactive tissue sites
150
Metabolism for etomidate?
Plasma ester ashes and hepatic CYP enzymes -inactive metabolites
151
How is renal clearance for etomidate?
Of metabolites
152
CNS of etomidate?
Potent short acting hypnotic Onset 20-30sec and lasts 5min Decreases cerebral metabolic rate, CBF, ICP Maintained cerebral perfusion Involuntary muscle movements- dis-inhibitory on EP motor control high rate excitatory phenomena (more than 50% of patients)
153
How can etomidate cause EEG changes?
Enhance some to sensory evoked potentials Useful in intraoperative; epileptic ablation procedures Not evoke seizure undergoing ECT
154
How do you reduce involuntary movement with etomidate?
Pretreat with opioid or BZ
155
CV of etomidate?
Reduce sympathetic NS and baroreceptor responses Mild decline in SVR Not elicit histamine release Low rate of hypersensitivity
156
When is etomidate especially useful?
Impaired LV function Cardiac tamponade Hypovolemia Emergent Rachael intubation
157
Respiratory for etomidate?
Less depression compared to barbiturates and BZ | Does not result in apnea unless with opioids
158
Endocrine of etomidate?
Inhibit adrenal steriodogenesis; interferes with stress response NOT used for ICU sedation Linked to increased mortality after surgery
159
Does etomidate have analgesia?
NO
160
When is etomidate used?
With BZ for induction | In case of CV risk or neurosurgical case
161
What is dexmedetomidine?
Alpha 2 adrenergic receptor agonist used for anxiolytics, sedation, and analgesia
162
When does FDA indication to use dexmedetomidine?
Sedation of intubation and ventilated patient in ICU | Sedation prior to and/or during surgical or other procedures of non-intubate patients
163
What does alpha 2a subtype do?
Mediating sedation Hypnosis Analgesia Sympatholytic
164
What does alpha 2b subtype do?
Vasoconstriction Antishiver Analgesia
165
Mechanism of action for dexmedetomidine?
Selective alpha 2 adrenergic agonist
166
What is the sedation time for dexmedetomidine?
Less than 24 hours; prolong may cause withdrawal, rebound hypertension
167
dexmedetomidine uses (7)?
``` Presedation (nasal or oral in peds) Procedural sedation Supplement to GA (reduce opioid and emergence delirium) ICU sedation (continuous infusion) Treatment/prevention of withdrawal No amnesia Epidural regional analgesia/anesthesia ```
168
CV effects of dexmedetomidine?
Hypotension (25-50%) Bradycardia (5-15%) Withdrawal effects when used >24hrs
169
Respiratory for dexmedetomidine?
Little effect on ventilation vs opiates
170
Does dexmedetomidine cause nausea?
YES
171
Dose for dexmedetomidine?
1mcg/kg IV over 10min with maintenance infusion rate of .2-.7mcg/kg/hr
172
Onset and half life of dexmedetomidine?
Rapid onset | Half life about 2 hours
173
Do you reduce dose in renal and hepatic insufficiency?
YES
174
When do you use caution in dexmedetomidine when in combo with:
Vasodilators Cardiac depressant Drugs that decrease HR
175
What do you do to dexmedetomidine when in combo with other hypnotics and anesthetic agents?
Reduce dose to offset excessive hypotensive effects
176
What other uses are for dexmedetomidine?
Treatment of postoperative shivering (central thermoregulatory inhibition and peripheral effect) Premed to attenuate cardiostimulatory effects of ketamine and intubation
177
When is best to use dexmedetomidine (7)?
``` Drug or alcohol withdrawal Chronic pain Unable/unwilling to take opioids Hypertension Hypotension surgical procedure Ophthalmic surgery Ketamine anesthesia ```
178
How does doxapram affect respiratory and CNS?
Respiratory depression secondary to anesthesia
179
What does doxapram active with low doses?
Carotid chemoreceptors: | Hypoxic drive, COPD, drug induced respiratory depression
180
CNS affect of doxapram?
Seizures, muscle fasciculation, HA, dizzy, agitation, confusion
181
Cardiac affects with doxapram?
Tachycardia, arrhythmia
182
Does doxapram cause nausea?
YES
183
When should you avoid doxapram?
``` Epilepsy Cerebrovascular and CAD Acute head injury HT Asthma ```
184
Dosing for bolus and continuous infusion for doxapram?
IV bolus .5-1mg/kg (increase minute vent) -onset 1min and duration of 5-10min Continuous infusion 1-3mg/min (max dose of 4mg/kg)
185
When does MH normally occur?
Upon anesthesia induction
186
Pathophysiology effect of MH?
Uncontrolled release of intracellular Ca in skeletal muscle (intense muscle contraction and enhanced and sustained ATP activity)
187
How to manage MH (7)?
``` DC inhaled agent and Sux Hyperventilate Administer NaHCO3 Mix dantrolene and give 2.5mg/kg Cooling measures Inotrope, press or, anti arrhythmic Treat hyperkalemia ```
188
How does dantrolene work?
Binds to RyR1 receptor of Ca channel and inhibits Ca release from SR
189
Dosing of dantrolene?
Use sterile water; 20mg/60ml of water 2.5mg/kg every 5min (max 10mg/kg) Half life about 6hrs If symptoms return 1mg/kg every 6hr next 24-48hrs

Pharmacology (14 decks)

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