anesthetic agents jehn mihill. objectives to review some commonly used anesthestic agents to...
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ANESTHETIC AGENTS
Jehn Mihill
Objectives
To review some commonly used anesthestic agents
To discuss briefly some definitions related to the pharmacology of these medications
To discuss some common applications of these drugs in the context of your everyday work
Some definitions
Half life (T1/2)
The time taken for the plasma concentration of a drug to fall by 50% when first order kinetics are observed
Volume of distribution (Vd)
The volume into which a drug appears to be uniformly distributed at the concentration in plasma
- Influenced by lipid solubility, binding to plasma proteins and molecular size.
- - A low Vd indicates drug mainly restricted to intravascular space. High Vd indicates significant tissue uptake
Redistribution-the process by which a drug is moved from the
vessel rich group to the vessel poor group- This is the primary method responsible for the
termination of effect of the majority of anesthestic drugs
- Pharmacokinetics- Commonly explained as what the body does to
the drug- Pharmacodynamics- - what the drug does to the body
Pharmacokinetics (simplified) Absorption : the process of a substance
entering the blood circulation
Metabolism (biotransformation) Role of metabolism is to convert active lipid
soluble drug into water soluble and often inactive drug
Phase 1 reaction: Redox reaction (addition of a polar group), that
prepares the drug for phase 2 reaction, and sometimes inactivates the drug
Phase 2 reaction:- Glucoronidation (addition of an ionized group to
the drug) that prepares the drug for excretion, and often inactivates the drug
Excretion: The elimination of substances from the body. (often done by the kidneys- but can be lungs etc)
Plasma concentration curves Drugs injected intravenously are removed
from the plasma through two primary mechanisms: (1) Distribution to body tissues and (2) metabolism + excretion of the drugs. The resulting decrease of the drug's plasma concentration follows a biphasic pattern
Types of induction agents
Propofol Barbiturates: Thiopental, Methohexital Benzodiazepines: Midazolam, Diazepam Phenylcyclidines: Ketamine Etomidate Dexmedetomidine
The ideal IV anesthestic
Physicochemical water soluble long shelf life stable on exposure to light Pharmacokinetics small volumes required short duration of effect; rapidly
inactivated
The “ideal” IV anesthetic
Physicochemical- water soluble
- long shelf life; stable on exposure to light
Pharmacokinetics - small volumes required
- short duration of effect; rapidly inactivated
Year of introduction of different IV anesthetics 1935 – Thiopental 1957 – Methohexital 1960 – Droperidol 1965 – Ketamine 1965 – Diazepam 1972 – Etomidate 1977 – Propofol 1978 – Midazolam 2000 – Dexmedetomidine
Propofol
HistoryPhysicochemical propertiesPharmacokineticsEffects on organ-systemsClinical uses
History
1st clinical trial reported by Kay and Rolly in 1977
Initial formulation with Cremophor resulted in anaphylactoid reactions
Reformulated as a lipid emulsion Today is the most frequently
used IV anesthetic
Physiochemical properties
Alkylphenol Oil at room temperature, insoluble in
aqueous solution, highly lipid soluble Present formulation: 1% propofol + 10%
soybean oil + 2.25% glycerol + 1.2% egg phosphatide + 0.005% disodium edetate
Stable at room temperature Not light sensitive
Pharmacokinetics
Two-compartment model Redistribution half-life 2-8 minutes Elimination half-life around 4 hours
- rapid liver metabolism extrahepatic metabolism (lungs) excreted by the kidneys Context-sensitive half-time < 40
minutes (for infusions up to 8 hours)
Pharmacology
Primarily a hypnotic agent Mechanism NOT fully understood –
evidence points to binding to the beta subunit of the GABAA receptors in the hippocampus and prefrontal cortex
Produces a sense of well-being by increasing dopamine levels in the nucleus accumbens
Antiemetic effect by decreasing serotonin levels in the area postrema
Pharmacology
Anticonvulsant at induction doses
Decreases ICP and reduces CMRO2 while maintaining autoregulation
Dose-dependent duration of apnea after induction
During infusions TV is preferentially decreased, while RR is maintained
Pharmacology
Most prominent CVS effect – decrease in SBP by 25-40%, mostly by reducing SVR
Atenuates the tachycardic response to hypotension (resets the baroreflex)
Preserves the global myocardial oxygen supply-demand ratio
Effective in treating pruritus induced by spinal opiates
Clinical Uses
Induction and Maintenance of anesthesia
Sedation for countless procedures OK for Neuro (ECTs) and Cardiac cases ED95 unpremedicated patients 2.5mg/kg Earlier return of psychomotor function
than thiopental or methohexital Lower incidence of PONV than any other
hypnotic agent
Side Effects
Pain on injection Myoclonus < than etomidate, but > than
thiopental Propofol Infusion Syndrome
-lethal, first described in children subsequently in critically ill adults with infusions 5mg/kg/hr for > 48 hours;
includes cardiomyopathy, skeletal myopathy, hyperkalemia, lipemia, metabolic acidosis
Barbiturates
History Thiopental, Methohexital Physicochemical properties Pharmacokinetics Effects on organ-systems Clinical uses
History
Barbital – 1st barbiturate with sedative properties described in 1903
Hexobarbital – 1st short acting barbiturate introduced clinically in 1932 in Europe
Thiopental – introduced clinically in North America by R. Waters and J. Lundy in 1935 was characterized after Pearl Harbor as “the ideal form of euthanasia in war surgery”
Physicochemical
Water soluble salts in alkaline solutions; if alkalinity is reduced barbiturates precipitate as free acids
Thiopental is stable for 1 week if refrigerated after reconstitution
Methohexital remains stable for 6 weeks The groups (aryl or alkyl) attached to
the C atom in position 5 are responsible for the hypnotic activity
Pharmacology
Mechanisms of action remain largely unknown
evidence shows that binding of a barbiturate to the GABAA receptor both enhances (at low barbiturate concentrations) and mimics (at high concentrations) the action of GABA on the GABAA receptor, thus enhancing the actions of this inhibitory neurotransmitter
Pharmacology
Dose-related decrease in CMRO2 until isoelectric point is reached; after that, cerebral metabolic rate remains at 50% of baseline
Parallel reductions in CBF (the ratio of CBF to CMRO2 is unchanged) and ICP
CPP is preserved because ICP decreases to a greater extent than MAP
Protection from incomplete cerebral ischemia
Pharmacology
Cardiovascular depression from both cardiac and vascular effects.
Peripheral vasodilation is accompanied by a decrease in contractility secondary to reduced availability of Ca to myofibrils. In addition HR is increased.
Patients without adequate compensatory mechanisms may therefore display serious hemodynamic depression
Clinical Uses
Excellent hypnotic – onset 15 seconds No analgesia Thiopetal – analgesic at low doses Methohexital is cleared more rapidly
than thiopental – recovery profile similar to propofol
Contraindications
Porphyria may be precipitated by the administration of thiopental
Garlic and onion taste in 40% of patients Allergic reactions such as facial edema,
bronchospasm and anaphylaxis have been reported
Local tissue irritation at the site of injection leading in rare cases to tissue necrosis
Benzodiazepines
History Midazolam, Diazepam, Lorazepam Physicochemical properties Pharmacokinetics Effects on organ-systems Clinical uses
History
Chlordiazepoxide(Librium) was discovered accidentally to have sedative, hypnotic and amnestic effects in the early 1960’s when a patient who was taking it fell, fractured her sacrum, yet did not remember the trauma, nor did she complain of pain
Diazepam(Valium) was first used in 1965 Lorazepam(Ativan) was synthesized in
1971 Midazolam(Versed) was introduced in
1978 1977 specific benzodiazepine receptors
were described
Physicochemical
Highly lipid soluble at physiologic pH, water soluble when formulated in a buffered acidic medium (pH 3.5)
Midazolam solution contains 0.8% NaCl, 0.01% disodium edetate and 1% benzyl alcohol
pH is adjusted to 3 with HCl
Pharmacokinetics
Biotransformation occurs in the liver, the metabolites have activity and over time can accumulate
Termination of action is the result of redistribution from the CNS to other tissues
Midazolam has greater hepatic clearance than diazepam and lorazepam
All 3 are affected by obesity
Pharmacology
Hypnotic, sedative, anxiolytic, amnesic, anticonvulsant, and centrally produced muscle relaxant activities
Mechanism of action is well understood: occupation of the BDZ receptor modulates GABA
BDZ receptors are found in the olfactory bulb, cortex, cerebellum, hippocampus, substantia nigra and inferior colliculus
Pharmacology
Log-term exposure to benzodiazepines produces tolerance
Reduce CMRO2 and CBF in a dose-related manner, while maintaining their normal ratio
Increase the seizure threshold Produce dose-related ventilatory
depression and act synergistically with opioids even though they act at different receptors
Pharmacology
Only slight reduction in MAP HR and CO are maintained – safe for use
in aortic stenosis Act synergistically with opioids in
decreasing systemic BP – probably due to reduced sympathetic tone when the drugs are given together
Clinical Uses
Preoperatively for sedation and anxiolysis
Intraoperatively during local or RA Induction of GA: 0.2mg/kg No analgesia Recent reports focused on the potential
role of IT midazolam as an adjunct to IT opioids
Phencyclidines (Ketamine) History Physicochemical properties Pharmacokinetics Effects on organ-systems Clinical uses
History
Phencyclidine was introduced in clinical use in 1958, but produced an unacceptably high rate of postanesthetic hallucinations and delirium. Still used illicitly today for recreational purposes.
Ketamine, one of 200 derivatives of phencyclidine was released for clinical use in 1970
Physicochemical
Partially water soluble Prepared as an acidic solution – pH 3.5 to
5.5 containing the preservative benzethonium chloride
Racemic mixture of 2 enantiomers in equal amounts
The isomer S(+) is also available commercially
Pharmacokinetics
Metabolized by the liver to a compound (norketamine) with significantly less activity (20%)
Two-compartment model Distribution half-life: 11-16 minutes Elimination half-life: 2-3 hours
Pharmacology
Produces dissociative anesthesia – patients appear to be in a cataleptic state – eyes are open, cough and swallow reflexes are present, yet there is no recall of surgery or anesthesia
Selectively depresses neuronal function in neocortex and thalamus, while stimulating parts of the limbic system
NMDA receptor interaction may mediate the hypnotic and analgesic effects
Some opioid mu receptor activity has been described for the S(+) enantiomer
Pharmacology
Increases CMRO2, CBF and ICP 10-30% of adult patients who receive
ketamine as a major part of the technique experience emergence reactions such as illusions, vivid dreaming and extracorporeal experiences – usually they abate within 1 hour from emergence
Benzodiazepines – most effective treatment for emergence reactions
Pharmacology
Minimal effect on the central respiratory drive
Bronchial smooth muscle relaxant Increases HR, BP, myocardial work and
oxygen consumption. This hemodynamic changes are not related to the dose used or to the baseline cardiac function of the patient
Clinical Uses
Preventive analgesia 10-20 mg IV Ideal choice for cardiac tamponade and
restrictive pericarditis Excellent choice for severe reactive
airway disease Excellent choice for anterior mediastinal
mass when spontaneous ventilation must be preserved
Good choice for sedation of uncooperative patients (pediatric, MR, etc)
Excellent additive to postop pain control
Etomidate
History Physicochemical properties Pharmacokinetics Effects on organ-systems Clinical uses
History
Synthesized in 1964 Introduced in clinical practice in 1972,
gained quickly widespread popularity due to its hemodynamic stability
Early enthusiasm was tempered by reports of inhibition of steroid synthesis as well as a relatively high incidence of PONV
Physicochemical
Imidazole derivative Exists as 2 stereoisomers, but only the
(+) isomer is active as a hypnotic Water insoluble Unstable in a neutral solution Formulated as a propylene glycol
solution (35%) with a pH of 6.9
Pharmacokinetics
Metabolized in the liver to inactive form Excreted by the kidney (85%) and bile
(13%) Initial distribution half-life of 2.7 minutes Elimination half-life around 4 hours Clearance by the liver is high
Pharmacology
Hypnosis is achieved in one arm-brain circulation after an induction dose
Mechanism of action not elucidated; appears to be similar to that of propofol, involving the GABAA receptor
0.3mg/kg reduces CBF by 34% and CMRO2 by 45% without change in MAP
Reduces ICP by up to 50% and the intraocular pressure by 30-60%
Pharmacology
Associated with grand mal seizures; has been shown to produce increased EEG activity in epileptogenic foci
High incidence of myoclonic movement thought to be associated with centers in the brainstem
Hiccups or coughing may accompany induction
40% incidence of PONV
Pharmacology
1983 report on ICU patients sedated with etomidate >5 days showed higher mortality when compared to a similar group that received high-dose steroids as part of the trauma protocol.
Dose-dependent, reversible, inhibition of ascorbic acid synthesis, which is required for steroid production in humans. Indeed vit C supplementation restores cortisol levels to normal after etomidate use
Pharmacology
Several studies throughout the 1990’s showed that after etomidate induction the nadir of cortisol levels remains in the low-normal range, that the adrenocortical suppresion lasts <20 hours, and that high-stress surgery can overcome this temporary suppresion
Clinical Uses
Ideal choice for the cardiovascularly compromised patient undergoing high-stress surgery (aortic, valve, CABG)
Ideal for rapid sequence induction in cardiac and lung transplantation
Sedation for cardioversion in CAD, MI Sedation for ECTs – can produce longer
seizures than possible with other agents Often used in trauma
Dexmedetomidine
History Pharmacokinetics Effects on organ-systems Clinical uses
History
Initial observation of the reduction of the MAC of halothane by clonidine sparked the interest in alpha2 agonists
Early 2000’s - dexmedetomidine - has 1600 fold greater selectivity for the alpha2 than the alpha1 receptor
Parmacokinetics
Rapid distribution Extensively metabolized by the liver Excreted in both urine and feces Elimination half-time: 2 hours Context sensitive half-time: 4 minutes
after a 10-minute infusion to 4 hours after an 8-hour infusion
Pharmacology
Acts on alpha2 receptors in the locus ceruleus (sedative effect) and spinal cord (analgesic effect)
The sedative effect is exerted through the endogenous sleep-promoting pathways
Amnestic in a dose-dependent manner Decreases HR, SVR and indirectly
myocardial contractility Biphasic hemodynamic response after a
bolus injection (BP up by 22% within 5 minutes then down by 15% from baseline within 1 hour)
Clinical uses
Premedicant: 0.33-0.67mcg/kg 15 minutes before surgery attenuates response to ET intubation
Sedation in mechanically ventilated ICU patients - advantages over propofol: requires significantly less opioid and HR were slower (!CAD patients) – disadvantage: more recall
Loading dose 2.5mcg/kg/hr for 10 minutes , then maintenance infusion of 0.1-1mcg/kg/hr
Droperidol
History Effects on organ-systems Clinical uses
History
Introduced in the 1960’s as a derivative of haloperidol – used in combination with fentanyl (Innovar) first by DeCastro and Mundeleer during their research into neuroleptanesthesia, the “artificial hibernation
Use today severely restricted by the black box warning regarding potential for fatal arrhythmias
Pharmacology
Acts centrally and results in a submaximal inhibition of GABA receptors and full inhibition of alpha2-acetylcholine receptors – this explains the anxiety, restlessness and dysphoria that occur despite apparent tranquility and cataleptic immobility
Action on GABA receptors in the chemoreceptor trigger zone is responsible for the antiemetic effect
Pharmacology
Extrapyramidal signs – worsens symptoms of Parkinson’s disease
Causes balance disturbances May precipitate malignant neuroleptic
syndrome May prolong the QT interval (delay
myocardial repolarization) and precipitate torsades de pointes – dose dependent
Clinical Uses
Effective antiemetic: 0.6-1.25 mg IV for a 70kg adult reduces the incisence of PONV by 60%
Equally effective to ondansetron Efficacy enhanced by combination
with ondansetron and dexamethasone
Effective in the treatment of pruritus secondary to opioid administration
Summary
Propofol – most commonly used IV anesthetic; formulated in a lipid emulsion; rapid onset & offset; antiemetic effect
Thiopental & Methohexital – formulated as Na salts in a water base at alkaline pH; rapid onset & offset; provide cerebral protection; contraindicated in porphyria
Summary
Midazolam – primarily premedicant for anxiolysis and amnesia; rapid onset & offset; lack of active metabolites
Ketamine – provides both a dissociative state of hypnosis and analgesia; sympathomimetic action preserves cardiac function; preserves autonomic reflexes; minimal effect on respiration
Summary
Etomidate – used primarily for induction in cardiovascularly compromised patients; inhibits adrenocortical synthesis
Dexmedetomidine – sedation, hypnosis and analgesia; dose-related biphasic effect on BP; minimal effect on respiration
Droperidol – produces a state of neuroleptanesthesia in large doses; effective antiemetic; prolongs QT interval
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