IV anesthetic agents Flashcards
Anesthetic options
Local anesthesia with or without sedation
Regional anesthesia with or without sedation
- Spinal
- Epidural
- Nerve blocks
General Anesthesia
- May be combined with any of the above
Plan for anesthesia is based on
- The age and medical condition of the patient
- Type and duration of surgery
Balanced anesthetic technique
- amnesia
- analgeisa
- muscle relaxation
surgery = extremely stressful
- psychological
- physiological
- blood loss –> cardiovascular stress
- fluid shifts –> respiratory stress
- temp changes –> organ insult/removal
anesthesia = goal is to maintain physiological stability and maintain end organ homeostasis
Drugs used for anesthesia
- Intravenous anesthetic agents
- Inhalation anesthetic agents: e.g. isoflurane, desflurane, sevoflurane
- Sedatives: e.g. midazolam, diazepam
- Narcotics/Opioids: e.g. morphine, fentanyl
- Local anesthetics: e.g.lidocaine, bupivacaiane
- Muscle relaxants: e.g. succinylcholine, rocuronium
- Others: antiemetics, anticholinergic, reversal agents
Classification of IV anesthetic agents
ISOPROPYLPHENOL
Propofol
PHENCYCLIDINE
Ketamine
CABOXYLATED IMIDAZOLE
Etomidate
ALPHA2 ADRENERGIC AGONIST
Dexmedetomidine
BARBITURATES
Thiopental, Methohexital
BENZODIAZEPINES
Diazepam, Midazolam, Lorazepam
Propofol
- physicochemical properties
- mechanism of action
Physicochemical properties
- Milky white solution, PH 7, Concentration 10mg/ml
- Contains10% soyabean oil, 2.25% glycerol and 1.2% lecithin = derived from eggs
- Available formulations support bacterial growth despite the addition of retardants
–> Sterile technique is important
–> Must be used within 6 hours of being
opened
–> Caution in patients with egg allergy
Mechanism
- potentiation of cl- current mediated through the GABA type A receptor complex
- GABA A receptors are present on the postsynaptic neurons. They are ligand –gated. Binding of GABA molecules on their binding sites on the receptor triggers opening of a chloride ion selective pore. The increased chloride conductance inhibits the firing of new action potentials. Propfol acts on The GABA A receptor and potentiates the effect of GABA)
Propofol - pharmacokinetics
- Rapidly metabolized in the liver
- Inactive, water soluble metabolites are excreted by the kidneys
- Wake up after an induction bolus
- –> Occurs in 8 t0 10 minutes
- –> Due to the redistribution from highly perfused (brain) to poorly perfused (skeletal muscles) organs
Tissues are grouped into hypothetical compartments based on perfusion.
An important implication of different compartments and perfusion rates is the concept of redistribution. After a given amount of drug is administered, it reaches the highly perfused compartments first where it can equilibrate and rapidly exert its effects. With time, compartments with lower perfusion rates receive the drug and equilibrium is achieved between the blood and these tissues. As the tissues with lower perfusion, absorb the drug, drug transfers from the highly perfused compartment into the blood stream in order to maintain equilibrium throughout the body. This lowering of drug concentration in one compartment by delivery into another compartment is called redistribution
Propofol - effects
Central Nervous system:
- Hypnotic with no analgesic properties
- Decreases the cerebral blood flow and cerebral metabolic rate
- Decreases intracranial pressure
- Anticonvulsant effect
- Neuroprotective during focal brain ischemia
Cardiovascular system:
- Profound vasodilatation, reduction in preload and afterload
- Decrease in systemic blood pressure
- More pronounced with elderly patients, hypovolemic patients and rapid injection
- Inhibits the normal baroreceptor reflex
Respiratory system
- Potent respiratory depressant, produces apnea after an induction dose
- Suppresses upper airway reflexes, well suited for instrumentation of the airway
Pain on injection
Antiemetic effect –> mechanism unclear
Propofol infusion syndrome
- Lactic acidosis after infusions > 75mcg/kg/min for more than 24 hours
- Mechanism unclear, may reflect poisoning of the electron transport system and impaired oxidation of long chain fatty acids (cytopathic hypoxia)
- Reversible in early stages by prompt discontinuation of propofol infusion, may result in cardiogenic shock and death
Propofol - clinical uses
Induction of anesthesia:
- Bolus of 1 to 4 mg/kg IV
Maintenance of Anesthesia:
- As a infusion, in combination with volatile anesthetics and opioids (balanced anesthesia regimen) or with opioids and benzodiazepines (total intravenous anesthesia technique)
Sedation:
- Repeated boluses and/or intravenous infusion for procedure like endoscopy, MRI, dental extractions etc
Propofol - advantages and disadvantages
Advantages
- Amnesia
- Rapid onset of action and recovery
- Antiemetic
- Neuroprotective properties
Disadvantages
- Pain on injection
- Not analgesic
- Cardiovascular and respiratory depression
- Caution in patients with egg allergy
- Propofol infusion syndrome
Ketamine
- physicochemical properties
- mechanism of action
Physicochemical properties:
- Water soluble phencyclidine derivative
- Two stereo isomers exist, only the racemic mixture is available the US
- Available concentrations of 10, 50, 100mg/ml
Mechanism –> antagonism of NMDA receptor
- NMDA receptors are activated by glycine and glutamate which open channels on the receptor allowing the influx of Ca and NA into the cell and K out of the cell. Ketamine by antagonizing these actions produces a state of dissociative anesthesia
Ketamine - pharmacokinetics
- Highly lipid soluble, low protein binding
- Rapid onset, relatively short duration of action
- Peak plasma concentration of ketamine occur within 1 minute after IV and 5 minutes after IM injection
- Effect of a single bolus is terminated by redistribution
- Metabolized in the liver to Nor ketamine (less potent)
- Nor ketamine is conjugated to inactive water soluble metabolites and then excreted in the urine
- Elimination half-time is 2 to 3 hours
Ketamine - effects
Central Nervous system:
- Produces “dissociative anesthesia”: a cataleptic state where the eyes remain open with a slow nystagmic gaze
- Potent analgesic
- Cerebral vasodilation and increase in CBF
- Increase in CMRO2
- Can precipitate myoclonic and seizure like activity in normal patients, does not alter seizure threshold in epileptics, considered to possess anticonvulsant activity
Cardiovascular system:
- Centrally mediated sympathetic stimulation −> Î BP, HR, CO and myocardial O2 consumption
- In critically ill patients, with limited ability to increase their sympathetic nervous system activity, can cause myocardial depression
Respiratory system:
- No significant respiratory depressant effect
- Apnea can occur if administered rapidly IV
- Upper airway skeletal muscle tone as well as airway reflexes are relatively well maintained
- Bronchodilatation
- Salivary and tracheobronchial secretions (decreased when combined with glycopyrrolate)
Emergence Reaction:
- Nightmares, hallucinations, distorted visual, tactile and auditory sensitivity
- Can be decreased by combining with a benzodiazepine (midazolam)
Ketamine - clinical uses
Induction of anesthesia:
- 1 to 2mg/kg IV or 2 to 5 mg/kg IM
Maintenance of anesthesia:
- Infusion 15 to 75 mcg/kg/min in combination with other drugs
Sedation:
- For short, painful procedures, e.g. dressing changes, suturing
Ketamine - advantages and disadvantages
Advantages:
- Analgesia
- Minimal respiratory depression
- Can be given via IV, IM, oral, rectal epidural routes
Disadvantages:
- Emergence delirium
- Increased secretions
Etomidate
- physicochemical properties
- mechanism
Physicochemical properties:
- Carboxylated imidazole derivative
- D-(+) isomer is active, hypnotic properties
- Available as a 2mg/ml solution in 35% propylene glycol, PH 6.9
Mechanism of action:
- Binds directly to specific sites on the GABAA receptors and enhances the affinity of the inhibitory neurotransmitter (GABA) for these receptors
Etomidate - pharmacokinetics
- Weak base, 99% ionized at physiologic PH
- Penetrates the Brain rapidly, peak levels reached within 1 minute of IV injection
- Recovery depends on redistribution
- 76% bound to albumin
- Metabolism is primarily by ester hydrolysis to inactive metabolites that are excreted in the urine and bile
- Elimination half life of 2 to 5 hours
Etomidate - effects
Cardiovascular system:
- Cardiovascular stability after bolus injection
- Minimal change in BP, HR and SVR
- Minimal depression of myocardial contractility
Respiratory System:
- Minimal depressant effect on ventilation
- Apnea may occasionally occur after rapid IV injection
Central Nervous System:
- Potent cerebral vasoconstrictor, decreases cerebral blood flow and metabolic rate
- Myoclonic activity in 50% patients, may be associated with seizure like activity on the EEG
Endocrine System:
- Adrenocortical suppression
- Dose dependent inhibition of enzyme 11-beta-hydroxylase which converts cholesterol to cortisol
- Enzyme inhibition lasts for 4 hours after an induction dose
Etomidate - clinical use
Induction of anesthesia
- especially in patients with an unstable CV system
- induction dose is 0.2-0.4 mg/kg
Etomidate - advantages and disadvantages
Advantages:
- Cardiovascular stability
- Minimal respiratory depression
Disadvantages:
- Pain on injection
- Myoclonic movements
- Adrenocortical suppression
DEXMEDETOMIDINE
- physicochemical properties
- mechanism of action
Physicochemical properties:
- Active derivative of medetomidine, an imidazole derivative
- Water soluble
- Available as a parenteral formulation
Mechanism of action:
- Stimulation of Alpha2 receptors in locus coeruleus region of the brain
- Inhibition of the release of norepinephrine resulting in inhibition of neuronal firing in the spinal cord and brain and termination of propagation of nerve signals
The locus coeruleus (means dark blue spot— azure appearance in unstained brain tissue)) is a nucleus in the pons (part of the brainstem). It is the principal site for brain synthesis of nor epinephrine
DEXMEDETOMIDINE - effects
Central nervous system:
- Sedation
- Analgesia
- No significant effect on cerebral metabolic rate and intracranial pressure
Cardiovascular system:
- Cardiovascular depression
- Bradycardia
- Hypotension
Respiratory system:
- Minimal depressant effect on respiration
- No effect on respiratory rate
- Small to moderate decrease in tidal volume
- Ventilatory response to carbon dioxide is unchanged
DEXMEDETOMIDINE - clinical uses
Sedation:
- Short-term sedation of intubated and ventilated patients in the ICU
- Radiological procedures, MRI and interventional radiology
General Anesthesia:
- 0.5 to 1mcg/kg loading dose followed by an infusion of 0.5 to 0.7 mcg/kg/hr, decreases the dose requirement for inhaled anesthetics and analgesics
DEXMEDETOMIDINE - advantages and disadvantages
Advantages:
- Sedation and analgesia without respiratory depression
Disadvantages:
- Hypotension and bradycardia especially with bolus dose
- Longer onset and offset times than propofol
Barbiturates
- physicochemical properties
- mechanism of action
Physicochemical Properties
- Derived from barbituric acid
- –> Thiobarbiturates: Thiopental
- –> Oxybarbiturate: Methohexita
- Available as sodium salts, reconstituted with water:
- –> 2.5% solution: Thiopental
- –> 1% solution: Methohexital
- Alkaline solutions (PH > 10)
Mechanism of action
- Binds directly to specific sites on the GABAA receptors and enhances the affinity of the inhibitory neurotransmitter (GABA) for these receptors
Barbiturates - pharmacokinetics
Pharmacokinetics
- Metabolized in the liver by
- –> Oxidation
- –> Desulfuration
- –> N-dealkylation
- Inactive metabolites are excreted in the urine
- Drugs that cause enzyme induction enhance barbiturate metabolism
- Methohexital is cleared more rapidly than thiopental (shorter elimination half-time)
Barbiturates - effects
Central nervous system:
- Sedation, anesthesia
- No analgesic properties, may reduce the pain threshold (antianalgesic)
- Cerebral vasoconstriction, ↓CBF, ↓ICP,
- ↓CMRO2; dose dependent up to a maximum dose at which the EEG becomes a flat line
- Methohexital activates epileptic foci (exception)
Cardiovascular system:
- Peripheral vasodilatation with modest ↓ in BP
- Exaggerated in patients with hypovolemia or cardiac disease who are less able to compensate for the effects of peripheral vasodilatation
Respiratory system:
- Respiratory depressant effect: ↓minute ventilation, tidal volume and respiratory rate
- ↓ventilatory responses to hypercapnia and hypoxia
- Inadequate suppression of airway and laryngeal reflexes
Precipitation when mixed with acidic drugs in an IV line
Pain and tissue injury on accidental infiltration into paravenous tissue
Pain, intense vasoconstriction and gangrene on intra-arterial injection
Exacerbation of acute intermittent porphyria;
- Stimulation of enzyme D- aminolevulinic acid synthetase causing an increased production of heme
Acute intermittent porphyria
Autosomal dominant metabolic disorder affecting the production of heme, the oxygen binding group of hemoglobin). Patients lack the enzyme porphobilinogen deaminase essential for synthesis of heme. Thus there are high concentrations of porphobilinogen in the cytoplasm. Symptoms include: severe abdominal pain, dark urine, peripheral numbness, tachycardia, hypertension, agitation, hallucinations, delirium, and seizures.
Barbiturates - clinical uses
Induction of anesthesia:
- Thiopental 3-5mg/kg
- Methohexital 1-1.5mg/kg
Neuroprotection:
- Treatment of raised intracranial pressure
- Treatment of focal cerebral ischemia
Benzodiazepenes
- physicochemical properties
- mechanism of action
Midazolam, Diazepam, Lorazepam
Physicochemical properties
- Midazolam available as a parenteral solution (1mg/ml, 5mg/ml)
- Diazepam available as oral and parenteral solutions (5mg/ml)
- Highly protein bound to albumin
- Highly lipid soluble
Mechanism of Action
- Enhance the affinity of the GABA receptor for GABA → increased Chloride conductance → hyperpolarization of post synaptic cell membrane → postsynaptic neurons more resistant to excitation
Benzodiazepenes - pharmacokinetics
Pharmacokinetics
- Rapid onset of action (lipid solubility and penetration of blood brain barrier)
- Termination of effects by redistribution
- Hepatic metabolism:
- –> Midazolam to1-hydroxymidazolam (inactive)
- –> Diazepam to desmethyldiazepam and oxazepam (both active)
- The elimination half-life of diazepam greatly exceeds that of midazolam, resulting in a longer duration of action
Benzodiazepenes - effects
Central nervous system:
- Sedation, hypnosis, anterograde amnesia
- Anticonvulsant
- Decrease CMRO2 and CBF
- No neuroprotective properties
Respiratory system:
- Minimal respiratory depression
Cardiovascular system:
- Decrease in systemic vascular resistance and blood pressure (midazolam > diazepam)
- Cardiac output not affected
- Pain on injection with diazepam
Benzodiazepenes - clinical uses
Preoperative medication: - Midazolam • IV: 0.1mg/kg, maximum 2mg • PO: 0.5 – 0.7 mg/kg • Rectally: 0.7 – 1mg/kg • Intranasal (not commonly used) - Diazepam • PO 5 to 10 mg
Sedation for short procedures
- Midazolam produces more rapid onset, greater amnesia and less postoperative sedation than diazepam
Suppression of seizure activity
