Quiz 2 Intravenous Induction Agents Flashcards
Where is the synthesis and storage of neurotransmitter molecules?
The synaptic vesicle.
The reuptake of the neurotransmitter is sponged up by what?
Presynaptic neuron.
Where do the neurotransmitter molecules get released?
Synaptic cleft
Where does binding of a neurotransmitter occure?
Postsynaptic membrane.
What are some drug classes that interact with the GABA receptor?
- GABA
- Benzodiazepine
- Propofol
- Neurosteriods
- Volatile Anesthetics
- Ethanol
What receptor does Precedex work on?
Alpha 2
Is Precedex an agonist or antagonist?
Agonist
What are the advantages of anesthesia/induction agents?
- Provide rapid onset of general anesthesia
- Can be used for maintenance phase of general anesthesia
- Can provide sedation for Monitored Anesthesia Care
What is the amount of time CRNAs have between induction agents to maintenance agents?
< 9 minutes
What is needed to have a balanced anesthesia?
- Inhalation agents
- IV induction agents
- Sedative/hypnotic agents
- Opioids
- Neuromuscular blocking drugs
What is in common about all IV INDUCTION agents?
All are lipophilic
What is the one compartment model?
One compartment model describes the bolus of a drug to be rapidly distributed throughout the body evenly.
What is two compartment model?
Considers the body as a compartment with a central compartment with rapid mixing and a peripheral compartment with slower distribution. This means the central compartment has the drug shortly after drug administration and the peripheral compartment gets the drug more slowly.
What is three compartment model?
- Drug is injected and restricted to the central blood volume.
2.Distribution is limited primarily to oxygen rich compartment at first (Brain, liver, kidneys, and gut). - After this a two other phases take place.
-The first is rapid redistribution to vessel poor group (shallow compartment).
Primarily muscle tissues
Phase lasts 2-4 minutes
Patient would awaken from initial
drug administration
-Second is slow distribution phase occurs iwth redistribution into the peripheral compartments (deep compartment.
Fat
What are some IV induction agents?
- Barbiturates
- Benzodiazepines
- Propofol
- Ketamine
- Etomidate
- Dexmedetomidine
Who was the first to introduce barbiturates?
Waters & Lundy introduced thiobarbiturate in 1935.
How many barbiturates have been developed since the 1930?
Over 2000.
What was the barbiturate of choice before it was removed from practice?
Thiopental
What is the description of a barbiturate?
- Any drug derived from barbituric acid
- Barbituric acid lacks CNS activity
- Hypnotic, sedative and anticonvulsant effects occur through substitutions on the N1, C2, and C3 sites.
- To make it lipophilic a substitution has to be placed on the barbituric.
What barbiturate drugs work by substitution at C2?
- -Sulfur-thiobarbiturate-thiopental-pentothal
2. Oxygen- methylated oxybarburate- methohexital-brevital
What is the mechanism of action for barbituates?
- Post synaptic enhancement of GABA mediated inhibitory neurotransmitters
- May also have GABA-mimetic effects
What does barbituates bind to?
Protein binding
-Plasma albumin
-Whent the unbound faction of
barbiturate is increased the observed
clinical effect is greater.
-Situations that increase unbound fraction of barbiturate.
Decrease plasma protein
concentration
Uremia
Hepatic disease
3rd trimester of pregnancy
Competition of other drugs for
protein binding sites
Aspirin
Naproxen
Indomethacin
WarfarinWhat is the pharmacokinetics of barbituates?
- 3 compartment model
- redistribution has a major effecct on the duration of therapeutic action
- Elimination occurs when inactive metabolites are excreted in the urine.
What is the metabolism of barbituates?
-Hepatic metabolism
Primarily by oxidation
Second by N-dealkylation
Desulfuration
Destruction of barbituric acid ring
-Metabolite
Inactive
Excreted in urine
-P450 microsomal system
Enxyme indution occures with chronic
barbiturate use and increases rate of
barbituate metabolismWhat are the CNS effect of barbituates?
-Promply produces a 15-30 loss of LoC
-Produce mild to complete loss of consciousness
-post op drowsiness
-No analgesic properties and is not useful for maintenance of anesthesia
-dose dependent decrease in cerebral metabolic rate of oxygen consuption
-dose dependent decreases in cerebral blood flow
-Decrease in ICP and IOP
-Anesthetic doses have anticonvulsant
properties and can abruptly stop seizures
Do barbiturates cause a dose dependent histamine release?
Yes
What occurs with a barbiturate extravascular injection?
Irritation to surrounding tissue. (Mild vasospasm to sever tissue necrosis.
What occurs with intra arterial injection of a barbituate?
INJECTION
- immediate vasospasm
- severe vasoconstriction
- intense pain
- Blanching of entrire extremity
- High risk for ischemic gangrene
Intervention
- Dilute drug with NS
- Papaverine 40-80 mcg (Vasospasm)
- Stellate ganglion or bbrachial plexus block to increase circulation
- Heparinization if not contraindicated
Benzodiazepines?
- Librium
- Diazepam
- Serax
- Lorazepam
- Midazolam
What are benzodiazepines used for?
- Anxiolytic (amygdala, hippocampus, limbic areas)
- Sedation(brainstem and cortical recptors)
- Anticonvulsant
- Muscle relaxation (spinal cord)
- Amnesia (forebrain and hippocampus)
Benzodiazepines VS. Barbiturates?
- Less tolerance
- Less abuse potential
- Greater margin of safety against overdose
- Fewer and less significant drug interaction
- Do not induce hepatic microsomal enzymes
Chemical structure of midazolam?
- unique
- Imidazole ring
- Does not require a lipid vehicle
What is the mechanism of action for Midazolem?
-Activation of GABAA receptor complex and enhancement of
GABA mediated chloride currents.
-Neurons become hyperpolarized and less excitable.
-Midazolam has greater potency and affinity for
benzodiazepine receptor site on GABAA.
*2-3 times the potency of diazepam
What is the pharmacokinetics of Midazolam?
-Highly lipid soluble thus rapidly enter CNS.
-Highly protein bound
-Despite rapid passage into the brain, midazolam has a slower effect site
equilibrium. IV doses must be spaced to permit observation of peak clinical
effect prior to giving a repeat dose.
0.9 – 5.6 minutes
-CYP substrate
-Urinary excretion
What affects do midazolam have on the CNS?
- Decrease CMRO2 (to a lesser extent than barbiturates)
- Decrease CBF (to a lesser extent than barbiturates)
- Cannot produce an isoelectric EEG
- Little to no change in ICP
- Not neuroprotective
- Potent anticonvulsant properties
- Paradoxical excitement occurs in <1% of patients receiving versed
What affect does midazolam on the cardiovascular?
- Dose dependent decrease in systemic blood pressure.
- Post-induction hypotension is greater after midazolam than diazepam.
- Cardiac output is not changed.
-Blood pressure response is due to decrease in systemic vascular resistance.
Effects of vasodilation are exaggerated in the hypovolemic patient.
Midazolam does not prevent sympathetic response (increased HR & BP) to intubation of trachea.
What effect does midazolam have on the respiratory system?
-Minimal, dose dependent decrease in ventilation.
-Decrease in ventilatory response to CO2.
-May observe a transient period of apnea after a rapid IV dose of drug.
Significant with midazolam
Synergistic and additive with opioids
-Depression of swallowing reflex.
-Decrease in upper airway activity
What side effects do midazolam have?
-Allergic reactions – extremely rare
-Pain on injection
Diazepam – propylene glycol solvent
-Drowsiness, over sedation
-Anterograde amnesia
What are the reversal agents for Benzodiazapines?
-Benzo antagonist- competitive
-200 mcg every 1–2 minutes until the effect is seen, to a
maximum of 3 mg per hour
-Some benzos have longer half lives than flumazemil (ex: midazolam)
What is Propofol?
- The most frequently administered drug for induction of anesthesia.
- Provides excellent IV sedation in both the OR and ICU setting.
- Can successfully be used for IV maintenance of general anesthesia
What are the two reformulation of propofol?
-AstraZeneca
Diprivan
Disodiumedenate (EDTA)
-Propofol
Sodium metabisulfite
May cause sulfite related allergic reaction
Anaphylaxis
Asthmatic episodes in patient with known history of asthma
What are the pharmacokinetics of propofol?
- An IV induction dose of 1.5–2.5 mg/kg/IV causes rapid onset of unconsciousness. (30 seconds)
- Rapid return of consciousness with minimal residual CNS effects is a significant benefit of propofol over other IV induction drugs. (Duration 3-10 min)
-Rapid clearance of propofol from the plasma exceeds hepatic blood flow.
Less “hangover” effect
- Follows the three compartment model in a manner similar to the IV induction drugs.
- CYP substrate and inhibitor (strong 3A4, mod 2C19)
What is the mechanism of action for propofol?
-Propofol is a relatively selective modulator of gamma aminobutyric acid (GABAA) receptors.
What effects do propofol have on the CNS?
-Decrease in CBF
-Decrease in CMRO2
-Decrease in ICP
-Decrease in IOP
-Neuroprotective during focal ischemia
-Possesses anti-epileptic properties
Not a good induction agent for ECT
Decreases seizure activity 35-45%
-May observe twitching or spontaneous movement of patient during induction.
-Not seizure activity
What effects do propofol have on the Cardiovascular?
-Profound decrease in systemic blood pressure.
Significant peripheral vasodilation
Decrease in both afterload and preload
-This blood pressure effect is exaggerated in:
Elderly patients
Patient’s with hypovolemia or decrease intravascular volume
Rapid injection of drug
-Dramatic inhibition of normal baroreceptor reflex.
Small increase in heart rate with decrease in blood pressure
Exaggerated hypotensive response
Profound bradycardia and hypotension in healthy adults.
What effect does propofol have on the respiratory system?
-Potent respiratory depressant.
-Typically produces apnea after induction dose.
-Maintenance infusion will decrease minute ventilation by
decreasing tidal volume and respiratory rate.
-Decrease ventilatory response to hypoxia.
-Decrease ventilatory response to hypercapnia.
-Significant reduction in upper airway reflexes:
Good intubating conditions
Good LMA conditions
Less laryngospasm, bronchospasm and wheezing after
airway instrumentation
What are other effects propofol has?
- Anti-emetic properties
- Does not potentiate muscle relaxants
- Pain on injection
- Bradycardia
- Risk of infection
- Elevated serum triglycerides with prolonged administration
- Potential for pulmonary embolism
- Antipyretic activity
- Antioxidant properties
What is Propofol infusion syndrome?
-Lactic acidosis that occurs in patients who receive prolonged high-dose
infusions for greater than 24 hours.
75mcg/kg/min
-Lactic/metabolic acidosis has been documented after short term,
surgical infusions of propofol.
Kidney failure, rhabdomyolysis, cardiac arrest
-Unexpected tachycardia occuring during propofol anesthesia should
trigger evaluation for possible metabolic/lactic acidosis.
Serum lactate concentration
Arterial blood gas analysis
-Hypertrigyceridemia: hepatomegaly
What is the treatment for propofol infusion syndrome?
- Prompt discontinuation of propofol infusion
- Treatment of lactic acidosis
- Support of multi-system failure
What is Fospropofol (Lusedra)?
- Water soluble pro-drug of propofol
- Same MOA
- Similar side effects
- No lipid vehicle
What is Ketamine?
-Dissociative anesthesia
-EEG dissociation between thalamocortical and limbic system
-Patient is non-communicative
-Resembles a cataleptic state with eyes open and slow nystagmic gaze
-Varying degrees of hypertonicity or purposeful skeletal movement independent of
surgical stimulation
-Amnesia is not complete – !! give a benzodiazepine !!
-Intense analgesia
-Use is significantly limited by possibility of causing emergence delirium
Reduced by benzo use
What is the chemical structure of ketamine?
- Phencyclidine
- 2-(O-chlorophenyl)-2-(methylamino)cyclo-hexanone
- Partially water soluble
What is the pharmacokinetics of ketamine?
- Not significantly bound to plasma proteins
- Leaves blood rapidly to be distributed to tissues
- Extremely lipid soluble and crosses blood brain barrier
- Recovery from a single bolus dose occurs primarily from redistribution
- 3 compartment model of distribution
What is the metabolism of ketamine?
-Extensive metabolism by hepatic microsomal enzymes.
-Demethylation of ketamine to norketamine.
Active metabolite with 1/3rd -1/5th potency of ketamine.
Norketamine may contribute to the prolonged effects of ketamine especially
with repeat doses or continuous infusion.
-Norketamine is hydroxylated and then conjugated into water soluble inactive
glucuronide metabolites which are excreted by the kidney.
What is the mechanism of action of ketamine?
-Binds noncompetitively to the phencyclidine recognition site on N-methyl-D-aspartate
(NMDA) receptors.
NMDA receptor antagonist
-Exerts weak action at GABAA receptor.
-May exert effects at other receptors:
Opioid
Monoaminergic
muscarinic
-Inhibits nitric oxide synthase
analgesic effects
-Inhibits reuptake of catecholamines
Stimulates sympathetic nervous system
-Induces catecholamine release
Beta 2 agonism- respiratory relaxationDoes Ketamine attach to the N-methyl-D-aspartate (NMDA)?
Yes
What effect does ketamine have on the CNS?
-Cerebral vasodilator
Increases cerebral blood flow
Increases CMRO2
-Not recommended for use in patient with intracranial pathology
-Is considered an anticonvulsant
-May be used for status epilepticus when other drugs fail
-May cause myoclonic movement on injection
What effect does ketamine have on the cardiovascular?
-Direct myocardial depressant
Depressant effects are usually masked by stimulation of sympathetic nervous
system
May be significant in critically ill patient with limited reserve to increase
sympathetic activity
-Produces significant, transient increases in systemic BP, HR and CO
Centrally mediated sympathetic stimulation
Associated with increased cardiac work and increased cardiac metabolic
requirement for oxygen
What effect does ketamine have on the respitory?
-No significant respiratory depression
-When used alone, respiratory response to hypercapnia is preserved
-Transient hypoventilation
-May cause short periods of apnea with rapid administration of drug
-Relaxes bronchial smooth muscle and thus may be helpful in patients with
reactive airways or bronchoconstriction
What is etomidate?
- Chemically unrelated to other IV induction agents
- CNS effects result in hypnosis
- No intrinsic analgesic properties
- Minimal cardiovascular effects
What is the chemical structure of etomidate?
- Carboxylated imidazole derivative
- Propylene glycol solvent
- pH of 8.1
- 2 isomers – R+ isomer is hypnotic
- Only IV induction drug that is not a racemic mixture
What is the pharmacokinetics of etomidate?
-Rapid distribution half-life
-Single IV bolus has extremely short duration of action (3-5 min, peak 1 min)
-76% plasma protein binding
-Follows a 3 compartment model
-Hepatic extraction ratio is near 60-70%
-Total body clearance is rapid
-Minimal drug accumulation makes it useful for repeat doses and continuous
infusions
What is the metabolism of etomidate?
-78% metabolized by hepatic microsomal enzymes
Rapid hydrolysis of ethyl-ester side chain to its carboxylic acid ester
This metabolite is a water soluble, pharmacologically inactive compound
-3% of drug is recovered unchanged in the urine
What is the limiting factors affecting use of etomidate?
-Transient depression of adrenocortical function.
Dose – dependent inhibition of adrenocortical enzymes
Reversible inhibition
Lasts 4-8 hours after single bolus induction dose
Greater if continuous IV infusion is used
Theoretically patients with sepsis/hemorrhage may be at a disadvantage
receiving Etomidate if the cortisol response is compromised
-Alternatively, thought to be beneficial suppression of adrenocortical stress
response and an advantage to provide “stress free” anesthetic
What in the mechanism of action of etomidate?
-Potentiation of GABAA mediated chloride shift
What effects does etomidate have on the CNS?
- Decreased cerebral blood flow
- Decreased CMRO2
- Decreased ICP while maintaining CPP
- Maintains cerebral blood vessel responsiveness to changes in CO2 level
- Decrease IOP
What effect does etomidate have on the cardiovascular?
-Provides cardiovascular stability and is drug of choice for patient with unstable
cardiac system.
-Minimal change in HR, BP, CVP.
-Myocardial oxygen supply and demand remains constant by balanced decrease in
both myocardial blood flow and decrease in oxygen consumption.
-Patient’s with aortic or mitral valvular disease may, however, have a significant
-decrease in systemic BP, PAP, PCWP.
What effect does etomidate have on the respiratory?
- Dose dependent decrease in minute volume with a compensatory increase in RR.
- Decrease ventilatory response to CO2.
- Brief periods of apnea followed by hyperventilation.
What other consideration should be thought of for etomidate?
-Increased incidence of PONV
-Does not effect duration of induced seizure activity (good for electro-convulsive therapy)
-No analgesia properties
-Involuntary myoclonic movement is common during induction
Caused by alteration in balance of inhibitory/excitatory influences
on thalamocortical tract
May be decreased by prior opioid administration
-Standard induction dose: 0.2-0.4 mg/kg IV
-No histamine release
-Low incidence of allergic reaction
What is Dexmedetomidine?
(Precedex)
- Highly selective α2-adrenergic agonist
- Active component is the D-isomer of medetomidine
- Water soluble IV formulation
What is the pharmacokinetics of precedex?
- Highly protein bound
- Rapidly metabolized by hepatic microsomal enzymes
- Metabolites excreted in urine and bile
- Clearance is high
- Elimination half-time is short
What is the metabolism for precedex?
- active d-isomer of medetomidine
- metabolized in liver
- eliminated via kidney
What is the mechanism of action for precedex?
- Activates CNS α2 receptors and produces selective α2 agonist effects.
- Hypnosis results from stimulation of α2 receptor at locus ceruleus.
- Analgesia originates at the level of the spinal cord.
- Sedative effect mimic a physiologic sleep state – activates endogenous sleep pathways.
- Potential for tolerance.
What effect does precedex have on the CNS?
- Decrease in CBF
- No change in ICP
- No change in CMRO2
- Decrease in plasma catecholamine concentration
- Decrease in MAC requirement for inhaled anesthetics
- Decrease in anesthetic requirement for opioid
What effects does precedex have on the cardiovascular?
- Moderate decrease in heart rate
- Moderate decrease in systemic vascular resistance
- Bolus of drug may cause brief increase in systemic blood pressure and pronounced bradycardia
What effects does precedex have on the respiratory?
- Small to modest decrease in tidal volume
- No significant change in respiratory rate
- Ventilatory response to CO2 does not change
- May observe mild airway obstruction secondary to sedation
- Synergistic effect with other sedative-hypnotics
What are other consideration for precedex?
-Dose guidelines
0.5 – 1 mcg/kg load over 10-15 minutes
then infusion at 0.2 – 0.7 mcg/kg/hr
MUST decrease all concentrations of other anesthetic agents
-Current uses
Short term sedation in ICU
Sedation for fiber-optic intubation
Decrease post-operative delirium
Decreases arousal and produces a calm patient that can
easily be aroused to full consciousness.
