IV Anaesthetics Flashcards
Propofol
Physicochemical
- 2,6-diisoproppylphenol
- 1% propofol, 10% soybean oil (solubilising agent), 2.25% glycerol (isotonic), 1.2% purified egg phospholipid (emulsifying agent), NaOH (buffer to adjust to pH 7), water (adjust volume), antimicrobial agent (EDTA), prevent oxidative decomposition (sodium metabisulfate)
- Other formulations - medium chain TGAs (decr pain on injection
- Weak acid with pKA 11 - almost entirely unionised
- Dose 2mg/kg , 3-5mg/kg children, 1-1.5mg/kg elderly, 0.2-0.25mg/kg severely shocked
- MOA - enhancement of GABA-induced Cl- currents. Effects on glycine receptors, nACHR, D2 receptors, Na channels
PK
- A - rapid onset and offset, time to peak effect 90s
- D - after bolus, rapid re-distribution and elimination -> offset of effect. Initial distribution T1/2 = 2-8mins, then rapid elimination phase T1/2 = 30-60mins, slower elimination phase (redistribution from poorly perfused tissue) - CSHT
- Target plasma conc for unconsciousness 2-2.5ug/ml and for maintenance 2-6ug/ml
- CSHT approx 10mins for <3hr infusion, and ~40mins for infusions up to 8hrs
=> Central compartment smaller in elderly due to reduced CO.
=> Largely unionised
=> 98% protein bound in plasma
- M - high hepatic ER. Oxidised (phase II) in liver by CYP2B6 and CYP3A4 to inactive glucuronides and sulphates
- E - renal, not impaired by hepatic or renal disease. Extremely high clearance 30-60ml/kg/min - greater than HBF, suggests extra-hepatic (pulm) metabolism
CNS
- Hypnosis
- ↓CBF
- ↓ICP
- ↓CMRO2
- Excitatory effects - subcortical origin, dystonic movements, euphoria, hallucinations
- ↓IOP
- Antipruritic
- Anticonvulsant
- EEG - slowing to burst suppression
CVS
- Arterial vasodilation -> ↓SVR -> ↓MAP
- Venous vasodilation -> ↓VR
- Myocardial depressant (↓SNS activity)
- May cause bradycardia (depressed baroreceptor reflex)
- ↓Myocardial blood flow and O2 consumption
RS
- Resp depression
- ↓Resp response to hypoxia and hypercapnia
- Suppressed upper airway reflexes
- Bronchodilation
- Potentiates HPV
GIT
- ↓HBF
- Anti-emetic
Other
- Pain on injection
- Fat overload sydrome
- Propofol infusion syndrome - develops after prolonged sedation (>4mg/kg/h >48hrs), metabolic acidosis, rhabdo, incr lipids, cardiac failure
- Green urine and hair after prolonged infusion (accumulation of quinols)
- Safe in MH
Thiopental
- Thiobarbiturate, weak acid
- Administered as sodium salts diluted in a water base at an alkaline pH (500mg yellow powder - stable in solution for 24-48hrs)
- pH 10.8, pKa 7.6 (61% unionised at pH 7.4)
- Contains 6% sodium bicarb and N2 - N2 prevents reaction with CO2 which would ↓pH and ↓solubility. Na2Co3 - pH (enol) and bacteriostatic
- Precipitates if combined with NaCl (need to dilute with 20mL water)
- Keto-enol tautomerisation - allow for the formation of water soluble enol in alkaline solution. Injection changes tautomer to keto form at pH 7.4 - lipid soluble
- Racemic mixture - S(-) isomer 2x potency of R(+)
- Dose 3-7mg/kg for induction, acts in one arm-brain circulation time (40s) and lasts for 5-15mins
- MoA - potentiation of GABAA receptor enhancing Cl- conduction and at higher doses direct activation, antagonist at glycine, AMPA, and 5-HT
PK
- A - rapid onset and offset as single dose. High blood flow to brain, highly lipophilic, low degree of ionisation. Accumulates with repeated or prolonged administration (lipophilicity, large Vd, and low rate of hepatic cl)
- D - rapid redistribution to fat and muscle -> rapid offset. VD = 2L/kg, 60-80% plasma protein bound mainly to albumin, 40% sequestered in RBC
- M - Hepatic via oxidation, metabolites mostly inactive, water soluble and excreted in urine. Pentobarbital (active metabolite),
- E - readily excreted in urine or a glucuronic acid conjugates in the bile. Elimination T1/2 11hrs
Other
- Plasma metal levels almost equal to mother - protein binding half, foetus more sensitive due ton increased unbound fraction, increased further with foetal acidosis as a result of ion trapping
CNS
- Hypnosis
- ↓CBF
- ↓ICP
- ↓CMRO2
- ↓IOP
- Anticonvulsant
- Antanalgesic in small doses (Decr pain threshold)
- EEG (alpha -> theta -> delta -> burst suppression -> isoelectric)
CVS
- Venous vasodilation > arterial vasodilation
- Direct negative inotropic effect
- Compensatory tachycardia (preserved baroreceptor reflex)
RS
- Resp depression
- Intact upper airway reflexes
- Bronchospasm
- ↓vent response to hypoxia and hypercapnia
GIT
- ↓HBF
- Hepatic enzymes induction
Misc
- ↓UO
=> ↓CO -> ↓RBF
=> ↑ADH
- Anaphylactic reactions (1:20,000)
- Tissue necrosis after extravasation
- Accidental arterial injection -> microembolisation -> ischaemia
- Contraindicated in porphyria
- Aspirin is highly bound to plasma proteins and will displace thio, incr unbound fraction
Benzodiazepines
MoA
- Positive allosteric modulators of GABAA receptors
=> bind to a/gamma interface -> ↑ affinity of GABA for GABAA receptors -> ↑frequency of opening of Cl- ion channel -> ↑Cl- transmission -> hyperpolarisation of membrane -> potentiation of inhibitory effect of GABA
- Binds to receptors with high affinity - binding stereoselective and saturable
- GABA A a1 subunit mediates sedative, amnesic, and anticonvulsant actions of benzo
- Midaz has KOP activity in vitro
Two BDZ receptor subtypes
- BDZ1 - in spinal cord and cerebellum -> anxiolysis
- BDZ2 - in spinal cord, hippocampus and cerebral cortex -> sedation and anti-convulsant
Order of receptor affinity (potency)
=> Loraz > midaz > diaz
CNS
- ↓CBF
- ↓CMRO2
- Little or no change ICP
- Anxiolysis
- Sedation
- Anterograde amnesia
- Anticonvulsant effect
- ↓MAC
CVS
- ↓SVR -> ↓MAP
- CO unaltered or small ↓
- Variable effect on HR
RS
- Resp depression - primarily due to ↓Vt
- ↓Hypercarbic drive
- Depression of upper airway reflexes
Miscellaneous
- Skeletal muscle relaxation
Midazolam
Physicochemical
- Water soluble imidazobenzodiazepine (water soluble when formulated in a buffered acidic medium pH 3.5)
=> Imidazole ring is a tautomer at different pH and accounts for changes in solubility
=> Ampoule pH <4 - open ring, water soluble, no carrier needed
=> Blood pH >4 - closed ring, lipid soluble, crosses BBB
- pKa 6.5 (90% unionised pH 7.4)
- Dose IV induction 0.3mg/kg (onset 2mins), IV pre-induction adjuvant 0.025mg/kg, IM 0.08mg/kg, PO premed 0.5mg/kg
- Routes - IV, IM, SC, PO, IN, PR
- Onset IV 2min, peak IV 10mins, duration IV 1-6hrs
- MOA - GABAA receptors, positive allosteric modulate at alpha-gamma interface
PK
- A - rapid onset and offset compared to other BDZ, onset slower than propofol and thio
- Short duration of action due to lipophilicity, high metabolic clearance, rapid rate of elimination. PO bioavailability 50%
- D - 95% plasma protein bound, VD 1L/kg, rapidly distributed (distribution T1/2 10mins)
- M - completely metabolised in liver by CYP3A4 and CYP3A5. Metabolised via hydroxylation to 1-a-hydroxy-midazolam (50% activity of midaz), oxazepam (active) -> glucuronidation
- E - renally excreted predominantly as metabolites. Short CSHT and great Cl compared to diaz and loraz. T1/2B = 2-4hrs
CNS
- Hypnosis
- Sedation
- Anxiolysos
- Anterograde amnesia
- Dose dependent ↓CMRO2 and CBF
- Anti-nociceptive (intrathecal)
- Anti-convulsive
- EEG - unable to produce burst suppression
- Paradoxical excitement
CVS
- ↓BP
- ↓SVR
- ↑HR
- Preserve contractility
- Preserve homeostatic reflex mechanisms (ventricular filling pressure and CO maintained post induction)
- Obtunds pressor response to intubation in combination with fent
RS
- Resp depression
=> ↓VT offset by ↑RR (MV mild decrease/ stable)
- Impairs ventilatory response to hypercapnia
- ↓Muscular tone (incr risk upper airway obst)
- BDZ + opioids - synergistic resp depression
GIT/ renal
- ↓HBF
- ↓RBF
- ↓PONV
Other
- ↓adrenergic response to stress
- Significant inhibition of phagocytosis and leukocyte bactericidal activity
- Abuse potential
Special points
- Flumazenil is specific antagonist
- ↓MAC of volatiles by ~15%
- Reversed by physostigmine, flumazenil, glyco
- Possibly has anti-tumour properties at supra clinical doses
Diazepam
- Two benzene rings + one diazepine ring
- Preparation
=> 40% propylene glycol (makes soluble in water), 10% alcohol, buffers, preservative
PK
- A - Good PO absorption and bioavailability 94%. Time to peak plasma conc 60mins
- D - 95% protein binding, VD 1.5L/kg
- M - Hepatic, oxidation (de-methylation). Des-methyl-diazepam (similar PK to diazepam but much longer T1/2B up to 100hrs) - further metabolised to oxazepam; temazepam is also metabolite
- E - renal excretion, T1/2B 20-45hrs
Flumazenil
- Imidazole-benzodiazepine derivative
- Reversal of BDZ effects
- Dose 0.1mg increments up to 2mg every 1-2mins, onset within 2mins
- pKA 1.7, weak acid
- MoA - competitive BDZ antagonist
PK
- Mod lipid solubility
- Protein binding 50%
- Short T1/2B <1hr (may require infusion)
- Significant hepatic metabolism
- Inactive metabolites excreted in urine
PD
- May lower seizure threshold -> seizures
=> Mixed drug overdose (e.g BDZ + TCA)
=> Epileptic patients
- N+V
- Withdrawal sx in presence of physical dependence to BDZs
- No CVS effects (HTN/ dysrhythmias)
- Reduces post-op shivering
Ketamine
- Phencyclidine derivative
- One chiral centre -> two optical isomers
=> S(+) - better analgesia, more rapid metabolism less intense emergence phenomena
=> R(-)
=> Either racemic or single S(+) enantiomer - Weak base, partially water soluble, 5-10x more lipophillic than thio
- pKa 7.4
Dose - Induction GA = IM 4-10mg/kg (onset 2-8mins), IV 0.5-2mg/kg (onset 30-60s), SL, PO, IN, PR - MOA - non-competitive antagonist at NMDA and glutamate receptors. Muscarinic ACh receptor antagonist. Effects on opioids receptors (MOP + KOP). Decr monoamime reuptake. Decr VDNaC
PK
- Rapid onset and offset, described by 2 compartment model
- A - PO bioavailability 20-25%, IM 93%
- D - 20% plasma protein bound (low protein binding and highly lipophilic so rapidly accumulates in CNS), VD 3L/kg. Distribution T1/2 10mins
- M - N-demethylation to norketamine by CYP3A4 in liver, norketamine is active metabolite (30% potency) - metabolised to inactive glucuronide
- E - excreted in urine, active metabolites can accumulate in renal failure. Cl high = 17ml/kg/min (equal to HBF). T1/2B 2.5hrs
CNS
- Dissociated anaesthesia
- Amnesia
- Analgesia (decr excitability, windup, synaptic reinforcement and long term potentiation)
- ↑ CBF
- ↑IOP
- ↑ICP (no clinically significant effect in TBI)
- ↑CMRO2
- Involuntary movements
- Emergence phenomena - vivid dreaming
- Pupils dilate, nystagmus
- Excitatory CNS effects, EEG - theta wave activity, atypical EEG (does not correlate with level of anaesthetic)
CVS
- ↓reuptake of adrenaline and norad => ↑circulating catecholamine => ↑SNS => ↑HR, ↑CO, ↑BP
- Direct myocardial depressant effect (mild)
RS
- ↑RR
- Preserved laryngeal reflexes
- ↑Tracheobronchial secretions
- ↑PVR - may worsen pulm HTN
- Bronchodilation
- Maintains resp response to hypercapnia
GIT
- Hypersalivation
- PONV
Misc
- ↑Muscle tone
- ↑Uterine tone - useful for PPH
- Porphyria
- Abuse potential
- Tolerance with repeat exposure
- Incompatible with thio
- Safe in MH
Dexmeditomidine
- Imidazole derivative
- Enantiopure
- No additive, safe for neuraxial use
- pKa 7.1
- 1mcg/kg bolus over 10mins, followed by 0.1-1mcg/kg/hr (up to 24hrs)
- Given IV, IN
- MoA - highly selective a2 agonist (a2:a1 1600:1). Sedating effects by activating a2 receptors in the spinal cord and locus ceruleus to ↑K+ conductance => hyper polarisation => decr neuronal firing and decr Na release. Gi => Inhibits adenyl cyclase => decr cAMP => decr SNS
=> Presynaptic a2-adrenoceptors inhibit the release of NA, attenuating vasoconstriction
PK
- 3 compartment model (LBM in obese patients)
- A - PO unpredictable
- D - 94% protein bound, VD 1.5L/kg - highly lipophilic, crosses BBB. Distribution T1/2 6mins
- M - extensive near complete hepatic metabolism via N-methylation to inactive metabolites
- E - Really excreted, T1/2B 2hrs (much shorter than clonidine), Cl 39L/hr (reduced in hepatic impairment)
CNS
- Sedative (a2 at locus coeruleus)
- Anxiolytic
- Amnesia
- Analgesia - augments effects of opioids by both spinal and supra spinal mechanisms
- Maintains CBF to CMRO2 relationship
- MAC sparing for volatiles (up to 80%)
- Possible neuroprotective
- After cessation - rebound HTN, agitation - a2-receptor upregulation
CVS
- ↓HR, ↓MAP + ↓CO
- ↓Myocardial O2 demand
- Initially peripheral vasoconstriction due to peripheral a1 stimulation -> transient HTN -> followed by more sustained ↓BP
RS
- Minimal effect - relatively preserved resp drive
- Slight reduction in response to CO2
GIT
- ↓saliva production
- Nausea
Other
- ↓adr and NA
- ↓shivering
Etomidate
- Imidazole derivative
- Enantiopure R-isomer (R(+) isomer 10x more potent)
- In aqueous solution with 35% propylene glycol and water (pH 8.1)
- Weak base, pKA 4.2
- Dose 0.3mg/kg (reduce in elderly)
- MoA - Potentiates GABAA receptors
PK
- Rapid onset and offset even with infusion, acts within 10-60s (one arm-brain), duration 6-10mins
- 3 compartment model
- D - 75% protein bound (albumin), uncharged drug highly lipophilic and readily cross BBB, VD 4.5L/kg
- M - via hepatic and plasma esterases to produce inactive metabolites, metabolised via ester hydrolysis
- E - 85% excreted in urine, Cl 1500ml/min. Elimination T1/2 - 2-4hrs (slow distribution from peripheral compartments)
CNS
- ↓CBF
- ↓ICP
- ↓CMRO2
- ↓IOP
- Incr muscle tone
- Involuntary movements and tremor on induction
- PONV
- EEG slowing to burst suppression
- Anticonvulsant
CVS
- Cardiostable
- Less hypotension than others
- Slight ↓CO and SVR
- Tachycardia with high doses
RS
- Resp depression
- ↓Resp response to hypercapnia
Other
- Pain on injection
- Thrombophlebitis
- Anti-platelet effect
- Sedation by infusion associated with incr mortality in ICU - inhibits cortisol and aldosterone synthesis
- Porphyria
- inhibits 11B-hydroxylase
