Sedative-Hypnotics Flashcards
What is chemical formula for propofol?
2,6-di-isopropophenol
What is composition of propofol?
- 1.2% egg
- 10% soybean oil
- glycerol base
- 2.25% solution
- Supports bacterial growth
- Can increase plasma glycerides with prolonged infusion
- Egg yolk allergy
- Anaphylactoid rections reported
What is problem with egg yolk allergies with propofol?
Usually people are allergic to egg white, so they are able to tolerate the egg yolk in propofol
What are some alternate brands/formulations of propofol
- Diprivan-EDTA (disodium edetate)
- Propofol (generic)
- Ampofol- low lipid formulation
- Aquavan
What can generic propofol cause?
Bronchospasms (sodium metabisulfite)
What is diprivan?
EDTA preservative- Disodium edetate
What is ampofol?
- Low lipid forumulation
- `5% soy, 0.6% egg lecithin
- Does not need preservative
- Higher incidence of pain with injection
- Very expensive, not a lot of facilities
What is aquavan?
Prodrug- adding groups to parent drug (ie : phosphate monoesters)
- hydrolysis in plasma, can be unpredictable
- hasn’t taken off in market
- slower onset
- higher vd
- higher potency
What is main mechanism of action of propofol?
GABA (major)
(glycine minor only)
- Decreases rate of dissociation of GABA from GABAa
- No spinal cord depression
Pharmackokinetics of propofol?
Vd?
Clearance vs perfusion dependent?
T1/2 elimination?
What effects pharmacokinetics?
- Vd 3.5-4.5 L/kg
- Huge
- clearance exceeds hepatic blood flow.
- Capacitance dependent (enzyme dependent)
- 2-3 comparatment mode of distribution
- Weight, co-existing disease, age, co-admin of other drugs affect pharmacokinetics
- t 1/2 elim 0.5-1.5 hours
T 1/2 elim of propofol? Vd?
T1/2= 0.5-1.5 hours
Vd 3.5-4.5 L/kg
What do you need to consider about patient when dosing propofol?
- Weight
- i.e.-obese, propofol is stored in fat, takes longer to leave body
- co-existing disease
- age
- i.e. younger, muscular person would need more
- co-admin of other drugs
- move through similar enzymatic breakdown
CNS effects of propofol?
- Chloride channel activation of B1 subunit of GABA receptor and NMDA inhibition
- Rapid onset, one arm-brain circulation
- Decreases CBF, ICP, CMRO2, CPP = cerebral protective
- EEG burst suppression
- Age affects ED95
- ED 95- Highest in toddlers, decreases with age
- elderly need to reduce dose
- ED 95- Highest in toddlers, decreases with age
- Hiccoughing, muscle twitching can occue
- hallucinations opisthotonis (spasm of muscles on back of neck, causing head to arch back)
- decreases IOP
- Antioxidant effect resembles Vit E–> cerebral protection
Respiratory effects of propofol?
- Apnea following induction dose
- Decreases TV, RR
- Decreases vnetilatory response to CO2 and hypoxia
- PaCO2 rises, pH decreases
- bronchodilation in COPD patients
- Hypoxia vasoconstriction remains intact
CV effects of propofol?
- 25-40% decrease in BP
- Greater than STP (sodium thiopental)
- Dose dependent myocardial depression and vasodilation
- Similar decreases in SV, CO, SVR
- Heart rate unchanged (Baroreceptor inhibition?)
Other effects of propofol?
- Does not potentiate muscle relaxants!
- Myoclonus
- higher than with TPL but less than with etomidate and brevital
- Pain on injection
- Antiemetic and antipruritic at sub-hypnotic doses, 10 mg
- mechanism of anti emetic/pruritic effect unknown
- Amnestic at doses >30 mcg/kg/min
- Crosses placenta, rapidly removed from fetal circulation
Propofol induction dose? Maintenance? Sedation?
- Induction 1-2.5 mg/kg
- as high as 3 mg/kg in toddlers d/t pharmacokinetics
- GA maintenance 100-300 mcg/kg/min
- Sedation infusion 25-100 mcg/kg/min
Metabolism of propofol?
- Conjugated in liver to water soluble compounds
- CP-450 system
- Liver function does not affect rate of metabolism
- still reduce doses if patient has liver dx
- Metabolites mostly inactive
- 4-hydroxypropofol is 1/3 potent
- Renal excretion
- CRF doesn’t affect clearance
- Highly metabolized, less than 3% excreted unchanged
Etomidate composition?
- Carboxylated imidazole derivative
- Imidazole refers to parent compound C3H4N2
- Propylene glycol solvent<— painful
- pH 6.90- water soluble in solution
- at physiologic pH becomes highly lipid soluble
Etomidate MOA?
- Selective GABA
- binds to specific site on receptor
- Increases affinity of GABA to GABAa
Pharmacokinetics etomidate?
- Onset of action rapid, one arm to brain
- Highly lipid soluble, weak base pH8.2
- Vd- 2.5-4.5 L/kg
- Redistribution terminates hypnotic effect
- 3 compartment model
- elimination half life 3-5 hours
- High hepatic extraction ratio and clearnace
- changes in liver blood flow or function will prolong effect
- 75% protein bound
Vd and elim 1/2 life of etomidate?
Vd 2.5-4.5 L/kg
T1/2 elim= 3-5 hours
Protein bound etomidate?
75%
CNS effects of etomidate?
- Rapid loss of consciousness after single dose
- No analgesia
- Direct cerebral vasoconstriction results in decreaesd CBF, ICP, CMRO
- Reduces IOP
- Increases EEG activity in epileptogenic focci
- Rare association with grand mal sz
- higher risk in pt with sz hx
- Produces myoclonic movmenet
- also possess anticonvulsant properties
Respiratory effect?
- Ventilatory response to CO2 depressed minimally
- Decrease in TV, increase in RR
- Hiccups or coughing
CV effects of etomidate?
- MINIMAL effects on cardiovascular function due to lack of effect on SNS baroreceptors
- HR, ABP, PAP, CO, SVR, PVR unchanged!
- this is what sets this drug apart
Endocrine effects of etomidate?
- Dose dependent reversible inhibition of 2 enzymes in biosynthesis of cortisol/aldosterone
- major: 11-beta-hydroxylase
- minor: 17-alpha-hydoxylase
- Results in adrenocortical suppression for 4-8 hours reduces mineralcorticoid and corticosteroid production
- Not too much clinical significant for us
- we don’t know full implications long term dosing but one shot deal not a big deal
Etomidate induction dose? Maintenance? Sedation? Rectal?
- Induction
- 0.2-0.6 mg/kg **0.3 mg/kg<< this is the most cardiac stable dose.
- Maintenance
- infusion 10 mcg/kg/min with n2o and opioid
- Sedation
- 5-8 mcg/kg/min for short procedure
- Rectal
- 6.5 mg/kg used in peds
Other effects etomidate?
- High incidence of N/V (30-40%)
- Myoclonic movement (30-60%)
- due to disinhibiting extrapyramidal system
- Enhances NDMR activity
Metabolism of etomidate?
- Liver, ester hydrolysis or N-dealkylation to carboxylic acid
- Biotransformation 5x faster than TPL
- 85% Renal, 13% biliary excretion
- 2% excreted unchanged
- NO ACTIVE METABOLITE
Composition of ketamine?
- Phencyclidine derivative
- PCP derivative
- Lipid soluble
- prepared in acidic solution
- Racemic mixture of equal parts R and S enantiomer
- S enantiomer more potent analgesic, undergoes faster metabolism and has lower incidence of emergence delirium
- nasal spray is example s enantiomer
- S enantiomer more potent analgesic, undergoes faster metabolism and has lower incidence of emergence delirium
Mechanism of action for ketamine?
- NMDA (n-methyl d-aspartate) ionotropic receptor for glutamate most potent activity
-
Why people become unconscious
- glutamate= excitatory. If you inhibit it, then you’ll lose consciousness
-
Why people become unconscious
- Opioid Mu, Delta, Kappa, Sigma(dont’ think of sigma as opioid receptor anymore)
- Monoaminergic- involves descending inhibitory pathways- for antinociception
- Muscarinic- antagonist
- calcium channels
How do NMDA receptors work?
- Activation of NMDA receptors results in opening of an ion channel which is nonselective to cations
- allows flow of Na and small amounts of Ca into cell and K out of cell
- Calcium flux through NMDAr is thought to play critical role in synaptic plasticity, cellular mechanism for learning and memory
- NMDA receptor is intersting becaues it is both ligand and voltage dependent
Metabolism of Ketamine?
- First pass effect
- hepatic microsomal enzymes
- N-demethylation followed by hydroxylation
- norketamine (metabolite 1- only 20-25 % activity of parent cmpd
- hydroxylated to hydroxynorketamine
- Conjugation water soluble
- urinary excretion
- total body clearance is roughly equal to liver blood flow
- Changes in liver blood flow affect clearance
- perfusion dependent (blood flow dependent)
Pharmacokinetics of ketamine?
Lipid solubility? VD, Elim 1/2 time?
- 2 compartment model
- High lipid solubility–> large Vd
- Rapid onset, short duration
- VD 3L/kg (large)
- Elimination 1/2 time 2-3 hours
Pharmacologic CNS effects ketamine?
- Crosses BBB
- Depresses neuronal function in association area of cerebral cortex and thalamus
- stimulates the hippocampus (limbic) causing “dissociative state”
- Amnesia not as prominent as benzos
- Onset 30 seconds max effect 1 min
- Termination of effect if rapid after single bolus (15 min) due to redistribution
*
CNS effects ketamine?
- Nystagmus, pupil dilation
- Salivation, lacrimation
- Increased skeletal muscle tone, non purposeful movement
- Myoclonic activity
- increases ICP, CBF, Metabolic rate, ICP
- Increases IOP
- Emergence reactions
- dreming, out of body sense of floating, excitement, illusion
- relatively common (10-30%) of pt who received ketamine as part of anesthetic
Spinal anesthesia with ketamine?
- Dose 0.2-0.5 mg/kg IV
- Mu receptor activity
- s enantiomer has some mu activity
- NMDA antagonism
- S isomer has high affinity for excitatory NMDA receptor in dorsal horn
Respiratory effects of ketamine?
- Minimal effects
- no alteration CO2 response
- bronchial smooth muscle relaxation
- sns activity
- Increases PVR
- Increases in salivation
CV effects of ketamine?
- Sympathomimetic-NMDA effect
- not a peripheral effect
- probably occurs because of NMDA receptor activity in nucleus tractus solitarus
- Increases BP, HR, CO
- Inhibits reuptake of NE
- Increases myocardial work and o2 consumption
- however, ketamine is direct myocardial depressant, especially in critically ill pt with minimal NE stores
- only reason it is not a depressant is because of the SNS response!
- however, ketamine is direct myocardial depressant, especially in critically ill pt with minimal NE stores
Doses ketamine? Premed, induction, mainenance, po/iv/im?
- Premedication:
- sedative/analgesic 0.2-0.5 mg/kg
- Induction: 1-2 mg/kg IV, 4-8 mg/kg IM
- Maintenance 1-2 mg/kg/hr
- Can be administered PO, IV, IM, nasally
- PO and internasal dose: 6 mg/kg
Contraindications for ketamine?
- Increased ICP (with normocapnia?)
- Open eye injury
- CAD (as sole anesthetic) (Increases work in heart)
- Vascular aneurysms (increase in BP)
- Uncontrolled systemic or pulmonary HTN
- Certain psych diseases
- schizophrenia
- personaility d/o
Composition and MOA of dexmedetomidine?
- Water soluble
- Selective alpha-2 adrenergic agonist
- 1620:1 alpha 2: alpha 1
- Of all anesthetics it produces sedation that most closely mimics physiological sleep
- locus ceruleus (hypnosis)<– main impact. produces
- spinal cord (analgesia)
CNS effects dexmedetomidine
- Decrease CBF
- NO CHANGE IN ICP or CMRO2
- Decrease MAC of volatile agents and opioid requirement
- Depresses thermoregulation (hypotehermia, depresses shivering)
CV effects of precedex?
- CV effects
- Decreased HR, SVR, BP
- Bolus can cause transient increase BP and decrease HR
- Potential for severe bradycardia
- heart block, asystole
- attenuates CV response to noxious stimuli- decreases catecholamine levels during GA
Respiratory effects of dexmedetomidine?
- Minimal change in RR, moderate decrease in TV
- No change CO2 responsiveness
- Upper airway obstruction possible
Metabolism of dexmedetomidine?
- Rapid metabolism
- conjugation
- n-methylation
- hydroxylation
- Metabolites cleared urine and bile
- 90% protein bound
- E 1/2t= 2-3 hours
- inhibit CYP 450- interfere with clearance of other drugs? i.e. opioids?
Dose precedex?
- adjunct to GA
- 1mcg/kg bolus over 10-15 minutes; followed by 0.2-1 mcg/kg/hr infusion
Dexmedetomidine antagonist?
- Atipamezole- specific and selctive antagonist that rapidly and effectively reverses sedative and CV effects of dex
- Researched in humans as a potential anti-parkinson’s drug
Which drugs (benzos and sedatives) cause pain on injection?
Propofol, Etomidate, Diazepam, Lorazepam
Which drugs cause myoclonus ( all classes we’ve learned)
Propofol
Etomidate (30-60%)
Ketamine
Methohexital (Brevital)
Drugs that have active metabolites?
Ropivicaine
lidocaine
midazolam
diazepam
ketamine
propofol
Drugs that decrease IOP
Barbiturates, propofol, etomidate
Which drugs induce hepatic enzymes?
Barbituates
Which drugs are impacted by hepatic blood flow?
Etomidate
Ketamine
means they have high hepatic extraction ratio!
Which drugs release histamine?
Barbituates
Which drugs are water soluble?
Midazolam
Precedex
Etomidate
How is precedex’s CNS activity different from other sedation meds?
Decreases CBF with NO change in ICP/CMRO2
