Pharm Induction Drugs Flashcards
Methohexital
(brevital) & Sodium Pentothal
(thiopental/ pentothal)
Structure/Composition
‣ S (-) isomer much more potent than R (+) but are marketed only as a Recemic mixture
Propofol
Structure/composition
Constitution of 1% Propofol (10 mg/ml)
‣10% soy bean oil
‣ 2.25% glycerol
‣ 1.2% purified egg phosphatide (lecithin)
Found in yolks
PROBLEMS: ↑ bacterial growth, ↑ triglycerides in prolonged gtts, pain on injection
Etomidate
Structure/Composition
Only carboxylated imidazole containing compound
35% propylene glycol
Ketamin
Structure/Composition
Phencyclidine Derivative (PCP)
“angel dust”
Preservative: Benzethonium Chloride, inhibits nicotinic ACH receptors which causes SNS stimulation → CV consequences
S (+) Ketamine: More analgesia than R isomer (2x greater than racemic and 4x greater than R (-), ↑ metabolism and recovery, less salivation, Lower incidence of emergence delirium
R (-) Ketamine: Inhibits uptake of catecholamines into the postganglionic nerve endings (cocaine like effect), Less fatigue, Less cog impairment
Structure/Composition
Summary of Induction drugs
BARBS and ketamine are racemic mixtures
Propofol and Etomidate both burn on injection d/t propylene glycol
Ketamine also has preservative but it causes SNS stimulation
Methohexital Category
Oxybarbituate
Sodium Pentothal (thiopental/pentothal)
Category
Thiobarbituate
Barbiturates MOA/Receptor
‣Potentiate GABAachannel activity ; directly mimics GABA
‣Acts on glutamate, adenosine, and neuronal nicotinic acetylcholine receptors.
Propofol MOA/Receptor
GABAa Receptor agonist
↑ Cl- conductance to produce hyperpolorization of postsynaptic membrane
Etomidate MOA/Receptor
Selective modulator of GABAa Receptor
Katamine MOA/Receptor
Non- competitive binding to N-methyl-D- Aspartate (NMDA)
Opioid receptors (mu, kappa, delta, and weak sigma)
GABA a (weak)
and LOTS of others…
Induction Drugs Receptor Summary
All effect GABAa
KETAMINE has lots of active sites
Indication for Barbiturates
PREVIOUS USES:
‣Premedication for hangovers
‣ Grad-mal seizure (use benzo now)
‣ Rectal Admin for young/ uncooperative (but now we use PO versed)
‣Increased ICP, cerebral protection, induction
Indication for propofol
1.induction drug of choice
2. PONV and CINV
2. Continuous gtt: Propofol only or TIVA w/ other anesthetic drugs, ICU 2% solution to ↓ lipids admin.
3. Agent of choice in brief GI endoscopy procedure
4. Mechanical ventilation in ICU/post-op
5. Antipruritic effects
6. Anticonvulsant
Indication for Etomidate
Induction
Indication for Ketamine
- induction
- Withdrawals (potential for abuse tho)
- Good for hypovolemic pt. d/t SNS effects
- Asthmatics and MH d/t bronchodilator effects
- CAD cocktail (see PP slide 30)
- Peds / uncooperative pt : IM
- Burn dressing changes, debridement, skin grafts
- Reversal of opioid tolerance
- Psych disorders
- Restless leg syndrome (PO dose)
Dose Considerations Barbs
Dosed on LEAN body weight: use IBW
Dose Considerations Propofol
PEDS: ↑ dose d/t larger distribution volume and clearance rate.
Elderly: ↓ dose 25-50%
Conscious Sedation:
‣ min. analgesia, amnesia, anticonvulsant, prompt recovery w/o residual sedation, ↓ PONV, use Versed or Opioid as adjunct,
Dose Considerations Etomidate
Rapid IV injection -> apnea
Dose Considerations Katamine
Induction: ↑salivation,
‣give antisialogogue Glycopyrrolate (0.2 mg) > atropine/scoplamine
‣ Give versed IV 5 minutes prior to inhibit SE of emergence delirium
LOC effect: 30 secs – 1 min (IV); 2 to 5 mins (IM)
Return of consciousness (ROC): 10 to 20 minutes
Full consciousness: 60 to 90 minutes.
Amnesia persists after ROC: 60 to 90 minutes
Dose Methohexital
IV 1.5 mg/kg
PR (rectal-kids): 20-30 mg/kg
IV gtt: post-op seizure activity in 1 of 3 patients - lowers the threshold (used in ECT)
Dose Sodium Pentothal
(thiopental/ pentothal)
IV: 4 mg/kg
***re-dose after 30 min d/t rapid redistribution
Dose Propofol
Induction: 1.5 -2.5 mg/kg ( ↑PEDs, ↓old)
Conscious Sedation: 25 -100 mcg/kg/min
Maintenance: 100 - 300 mcg/kg/min
*** rapid injection= LOC in 30 sec
PONV/ Sub-hypnotic dose: 10-15 mg IV followed by 10 mcg/ kg/min
Antipruritic: 10 mg IV
Anticonvulsant: 1 mg/kg IV
Dose Etomidate
IV: 0.3 mg/kg (0.2-0.4)mg
Dose Ketamine
INDUCTION: 0.5 -1.5 mg/ kg IV or 4-8 mg/kg IM
Maintenance and sub anesthetic dose: 0.2-0.5 mg/kg IV
Post op sedation and analgesia:
1-2 mg/kg/hr (also used for ped heart case)
Neuraxial analgesia:
Epidural: 30 mg
intrathecal/spinal/ subarachnoid: 5-50 mg
Barbiturates Onset
Rapid: 30secs
Propofol Onset
*** rapid injection= LOC in 30 sec
Etomidate Onset
within 1 min IV
Ketamine Onset
Onset: 1 min IV, 5 min IM
Duration : 10-20 min
Redistribution Barbs
Rapid redistribution from brain to other tissues
‣after 5 min 1/2 dose available in brain
‣ at 30 minute, 10% of original dose available in brain
‣Initial redistribution to skeletal muscles
‣ Takes 15 minutes to reach equilibrium b/w skeletal
muscles and plasma
‣↓redistribution
‣in shock (↓perfusion)
‣ elderly & women ( ↓ muscle mass)
‣ Drug stored in fat, so redosing and large dosing can have cumulative effects
Barbs context sensitive half-life
Prolonged infusion = lengthy , any drug with large redistribution
Propofol Context sensitive half-life
40 minutes (on 8hr infusions)
Shorter than all barbs, not as lipid soluble
Barbs Half-time
E 1/2 time of Thiopental > Methohexital
Peds: Short half-time d/t ↑ metabolism
propofol half-time
0.5-1.5 hrs
Etomidate half-time
2-5 hrs
Ketamine half-time
2-3 hrs
Return of consciousness (ROC): 10 to 20 minutes
Protein Binding Induction Drugs
Barbs: 70-85%
Etomidate: 76%
Ketamine: none
Induction Drugs Vd
Propofol: 3.5-4.5L/kg
Etomidate: Large
Ketamine: 3L/kg
Barbs Ionization
Methohexital: normal pH 76% non-ionized
Sodium Pentothal
(thiopental/ pentothal): normal pH, 61% non-ionized
Barbs Lipid solubility
Methohexital <Sodium Pentothal
(thiopental/ pentothal)
Etomidate Lipid Solubility
Water soluble at acidic pH, lipid soluble at physiologic pH
Ketamine Lipid Solubility
(5x to 10x than Thiopental)
Brain -> not plasma bound -> distributed to tissues
Largest
Barbs Metabolism
99% hepatocytes
Methohexital: Faster metabolism than thiopental and more rapid recovery from induction
Etomidate Metabolism
Hydrolysis hepatic microsomal enzymes
‣ Plamsa esterases
Propofol Metabolism
Hepatic: CYP 450
Metabolites: Water soluble sulfate and glucoronic acid excreted by kidney
Ketamine Metabolism
Hepatic, CYP 450
ACTIVE METABOLITE: Norketamine (1/3 potency of parent, causes prolonged analgesia)
Barbs Interactions
Enzyme induction when on prolonged gtt
increases metabolism of: anticoagulants, phenytoin, TCA’s, digoxin, corticosteroids, bile salts, vitamin K
Can persist for 30 DAYS!
Ketamine Interactions
Volatile anesthetic → hypotension
NDNMB drugs → enhanced- cholinesterase
Succinylcholine → prolonged
Excretion Induction drugs
All kidney
Etomidate: ‣ 85% in urine
‣ 10-13% in bile (GI)
Clearance Propofol
30-60 mL/kg/min
Plasma (lungs) > Hepatic flow
Tissue uptake > CYP 450
Clearance Etomidate
Clearance 5x faster than thiopenthal
***wake up fast
Clearance Ketamine
High hepatic clearance : 1 L/min
CNS Barbs
‣Cerebral vasoconstrictor (helps with seizures)
‣decreases CBF and decreases CMRO2 by 55%
NO ANALGESIA
CNS Methohexital
‣Lower seizure threshold, induce seizures in temporal lobe resection
‣ Can decrease seizure duration (once pt already has seizure) 35-45% in ECT pts compared to etomidate
CNS Propofol
↓CMRO2, CBF and ICP
‣Auto-regulatory r/t CBF and PaCO2 maintained
‣ EEG changes similar to thiopental
‣ No SSEP suppression unless nitrous or volatiles added
‣ Causes excitatory movements on induction, does produce myoclonus movements.
CNS Etomidate
‣ ↑ incidence of myoclonus (50-80%) Greater than all others
‣ alteration in balance of
inhibitory and excitatory
influences of thalamocortical
tract
‣ give benzo or opiod to inhibit
myclonus (FENT 1-2 mcg/kg
IV)
‣ USE CAUTION WITH SEIZURE
PT!!!
‣ ↓ CBF, CMRO2 35-45%
‣ Direct CEREBRAL VASOCONSTRICTOR
‣↓ ICP
‣Similar EEG changes to Thiopental, but has frequent excitatory spikes.
CNS Ketamine
‣ ↑ ICP
‣ Potent vasodilator, ↑ CBF by 60%
‣ Ceiling effect at 0.5-2 mg/kg IV for ↑ ICP
‣ excitatory activity on EEG
‣ DOES NOT ALTER SEIZURE THRESHOLD
‣ Myoclonus
‣ ↑plitude on SSEP, nitrous reduces this
Induction CNS summary
Analgesia most to least: Ketamine, propofol, then barbs and etomidate has none
Caution in seizure patients with etomidate and methohexital
MYOCLONUS INCIDENCE:
50% to 80% Etomidate > 17% after Thiopental, 13% after Methohexital, 6% after propofol
CV Barbs
‣ Lack of baroreceptor response esp. in hypovolemia, CHF, Beta blockade
‣ Histamine release causes BP drop
CV Sodium Pentothal
(thiopental/ pentothal)
Normovolemia, 5 mg/kg infusion of thiopental:
‣ ↓ 10 - 20 SBP
‣ ↑ 15-20 HR
‣Previous exposure to thiopetnal can induce anaphylactoid response
CV Propofol
‣ ↓ BP (more than thiopental) d/t inhbition of SNS smooth muscle relaxation, ↓ intracellular Ca+
‣ ↓BP exaggerated in hypovolemia, elderly, LV compromise
‣ Laryngoscopy stimulus can ↑ BP
‣↓ HR d/t ↓ SNS , ↓ baroreceptor reflex
‣ Profound brady and asystole even in healthy patients!!!
CV Etomidate
CARDIOPROTECTIVE AGENT
‣ Good for patients with low EF
‣Minimal changes in HR, SV, CO, Contractility
‣ SUDDEN HYPOTENSION w/ HYPOVOLEMIA w/ high 0.45 mg/kg IV induction dose
‣ ❌ histamine or intra-arterial damage
CV Ketamine
‣THINK SNS EFFECTS!
‣ ↑SBP, PAP, CO, MRO2
‣↑ plasma NE and Epi levels
‣ inhibit these effects by admin of
BENZO, volatiles, N20
‣ Can cause sudden ↓BP d/t depletion of catecholamine stores. Direct myocardial suppressant
‣ ephedrine won’t work bcuz indirect action
CV Induction Summary
Etomidate good for heart cases
Propofol and barbs both cause loss of baroreceptor reflex
propofol has most dramatic low BP effect
Etomidate can cause adrenal suppression s/t inability to convert cholesterol into cortisol will reduce ability to use BP meds unless you give stess dose.
Then Ketamine will cause increased circulation of epi and norepi, but eventually will run out of catecholamine stores
Resp Barbs
‣ Dose dependent depression of ventilatory centers (medullary and pontine)
‣ Less sensitive to CO2 (may need CO2 increased to initiate spontaneous respiration)
‣ Return to spontaneous ventilation → slow frequency, decreased Vt.
Resp Propofol
‣ Dose Dependent apnea
‣Synergistic with opioids!! = ↑ resp depression
‣ Maintain hypoxic pulm vasoconstriction response.. V/Q mismatch
‣ Painful surgicial stimulation inhibits ventilatory depression
‣Bronchodilator effects = GOOD
Resp Etomidate
‣ Ventilation depression < barbs
‣ Rapid IV injection = apnea
‣ Vt decreases are offset by compensatory ↑ in Resp rate (transient 3-5 min)
‣ Stimulates CO2 medullary centers
Resp Ketamine
‣ ↑ pulm artery pressure up to 44 mmHG
‣ no depression of ventilation
‣PaCO2 ventilation response maintained
‣ upper airway reflexes and tone maintained = ↑ of laryngospasms
‣ ↑ salivation and tracheobrochial mucous secretions
‣ ↑ bronchodilation (no histamine release)
Barbs Additional Info
KIDNEYS: causes transient ↓ RBF and GFR
INTRA ARTERIAL INJECTION:
‣immediate intense vasoconstriction,
‣causes pain along length of artery,
‣obscure distal pulses,
‣ blanching of extremity then cyanosis
‣ gangrene and permanent nerve damage
TREATMENT: Vasodilators ( lidoaine/ papaverine), adequate perfusion
‣When Somatosensory Evoked Potential (SSEP) monitoring is required, BARBS desired b/c do not effect the neuron transmission when doing SSEP’s
‣Other Oxybarbituates:
Phenobarbital
‣ Pentobarbital
‣ produces excitatory phenomena: Hiccups and myoclonus
‣Other Thiobarbituates:
‣Thiomylal- more potent, replaced an oxygen with a sulfur atom
‣Fat Blood partition coefficient is 11
Propofol Hepatic/renal side effects
‣Liver transaminase and creatinine concentrations remain normal
‣ Prolonged Gtt’s can cause:
‣Hepatocellular injury
‣ PROPOFOL INFUSION SYNDROME
‣ green urine d/t phenols, NO alteration in renal fx.and
‣ Cloudy urine d/t uric acid crystallization
Propofol syndrome
PROPOFOL SYNDROME:
‣ Gtt’s > 75 mcg/mg/min for > 24 hrs
‣ S/sx: Lactic acidoses, Brady-dysrhthmias, Rhabdo.
‣ SEVERE refractory brady in PEDS
‣ DX: ABG and serum lactate
‣ Reversible in early stages
‣ Cardiogenic shock → ECMO
Propofol other info
OTHER: INHIBITS PLATELET AGGREGATION, and ↑IOP
Other Preparations on market (not common)
Ampofol
*Low-lipid emulsion with no preservative.
*Higher incidence of pain on injection.
Aquavan
*Prodrug that obviates pain on injection.
*By-product → unpleasant dysesthia
*Slower onset, larger Vd, and higher potency.
Nonlipid with Cyclodextrins
*In clinical trials
Plasma Levels: unconscious to induction: 2-6 mcg/ml; Awakening 1-1.5 mcg/ml
PONV MOA: Depresses subcortical pathways and has a direct depressant effect on emetic center
Other benefits:
Antipuritic (esp for people that have had neuraxial opioids or cholestasis), anticonvulsant, analgesia at low doses, potent antioxidant (helps liver), BRONCHODILATOR
Etomidate Other Info
no hangover effect or cummulative effects d/t fast clearance
‣ No analgesia, so you will need multimodal anesthesia (need opioid use with laryngoscopy/ traceal intubation)
‣ Adrenocorotical Suppression: Dose depenedent, inhibits the conversion of cholesterol to cortisol,
‣↓ STRESS RESPONSE
‣↓ BP
‣↑Mechanical ventilation
time
‣ USE CAUTION w/ Sepsis
and hemorrhage
