General anesthetics Flashcards
what are the desirable components of general anesthesia?
reversible immobility in response to noxious stimulus
Examples of inhalational, volatile agents?
isoflurane, sevoflutran, desflurane, halothane, enflurane, diethyl ether, chloroform, cyclopropane,
Examples of inhalational, gas agents?
nitric oxide
Examples of Intravenous agents?
barbiturates, benzodiazepines, etomidate, ketamine, propofol,
Midazolam, diazepam
benzos that reduce anxiety
Pentobarbital
barbiturates, sedation
Diphenhydramine
Antihistamines, prevent of allergic reactions
Ondansetron
antiemetic, prevents aspiration of stomach contents, reduces postsurgical nausea and vomiting
Fentanyl
opioid, provides analgesia
Scopolamine
anticholinergic, amniesia, prevents bradycardia and fluid secretion
Muscle relaxant
Facilitation of intubation
Examples of preanesthetics
Midazolam, diazepamPentobarbital, diphenhydramine, ondansetronFentanyl, Scopolamine, muscle relaxants
Ideal Physicochemical anesthetic
water soluble, stable on shelf, lipophilic, small injection volume
Ideal Pharmacokinetic anesthetic
rapid onset, short duration, nontoxic metabolites
Ideal Pharmacodynamic anesthetic
wide margin of safety, no interpatient variability in effects, nonallergenic, nontoxic to tissues
Parenteral anesthetics
barbiturates - thippental opioids - fentanyl benzos - midazolam others - etomidate, propofol
Mechanisms of Action
Enhanced GABA effect on GABAa receptors Block nicotinic receptor subtypes (analgesia) Activate Tandem pore-domain K channels (hyperpolarize Vm) Inhibit NMDA (glutamate) receptors Inhibit synaptic proteins (decrease NT release) (amnesia) enhance glycine effect on glycine R’s (immobility) alpha2A adrenergic receptor agonist - dexmedetomidineVoltage gated ion channels - Ca and Na - impaired function
Enhanced GABA effect on GABAa receptors
inhaled anesthetics BarbituratesBenzos Etomidate Propofol
block nicotinic receptor subtypes (analgesia)
moderate to high conc’s of inhaled anesthetics
Activate tandem pore-domain K channels (hyperpolarize Vm)
inhaled anesthetics, NO, ketamine, xenon
Inhibit NMDA (glutamate) receptors
NO, ketamine, xenon, high dose barbiturates
how do you measure amount of inhaled anesthetics?
partial pressure or “tension” in inspired air
Speed of induction of anesthesia depends on?
inspired gas partial pressure (GA concentration) Ventilation GA solubility (less soluble GAs equilibrate more quickly with blood and into tissues such as the brain)
Name some major nuclei involved in arousal and respiration
Lateral hypothalamus - orexin Locus ceruleus - NorEpi Basal forebrain - Ach Tuberomammillary nucleus - Histamine Pedunculopontine tegmental area - Ach Laterodorsal tegmental area - Ach PAG - dopamine Preoptic area - Galanin, GABADR- serotonin
solubility effects arterial anesthetic levels
most = desflurane, NO, sevoflurane, isoflurane, halothane
Modern agents are
Ethers
Measures of Anesthetic potency
MAC: Minimum alveolar concentration equilibrium concnetration required to prevent the response to a painful stumulus in 50% of patients OR conc at 1 atm that produces immobility in 50% of pts or animals exposed to a noxious stimulus like an EC50 useful for comparison of drugs b/c are consistent and reproducible
MAC awake
MAC at which response to commands are lost
MAC bar
blunt autonomic response
MAC intubation
response to intubation
1.3 MAC
conc. more than 99% will not respond to stimuli
when several GAs are mixed, the MAC values
are additive
MAC is increased by
Hyperthermia, elevated CNS catecholamine NT release, chronic alcohol use, acute cocaine use, hypernatremia
MAC is decreased by
Hypothermia, pregnancy, shock, increasing age, acute alcohol ingestion, CNS-depressant drugs, decreased CNS NT release
Inhaled anesthetics from less to most potent
NO, Desflurane, Sevoflurane, Ether, Enflurane, Isoflurane, Halothane
all agents result in predictable and dose dependent
Hypnosis, amnesia, analgesia, inhibition of autonomic reflexes, muscle relaxation (except N2O)
Induction speed is affected by
Solubility Ventilation rate cardiac output
Vessel Rich group Uptake and distribution
CNS and visceral organs high blood flow (75%) and low capacity
Muscle Group Uptake and distribution
skin and muscle moderate flow and high capacity
Fat group uptake and distribution
low flow and high capacity
Vessel poor group uptake and distribution
bone, cartilage, ligamentslow flow and low capacity
What terminates anesthetic activity
commonly by redistribution of drug from brain to the blood and out through the lungs
What GAs can lead to liver toxicity
halothane and methoxyflurane
properties of NO
MAC > 100%: incomplete anesthetic good analgesia No metabolism rapid onset and recovery used along with other anesthetic fast induction and recovery
properties of Halothane
first halogenated inhalational anesthetic not pungent (used for induction w/ children, few side effects in childern) Medium rate of onset and recovery although inexpensive, its use has declined sensitizes the heart to epi-induced arrhythmias rare halothane induced hepatitis
properties of Desflurane
most rapid onset of action and recovery of halogenated GAs (low PC) widely used for outpatient surgery irritating to the airway in awake patients and causes coughing, salivation, and bronchospasm (poor induction agent) used for maintenance of anesthesia
properties of Sevoflurane
very low blood: gas partition coefficient w/ relatively rapid onset of action and recovery widely used for outpatient surgery not irritating to the airway useful induction agent, particularly in childern
properties of Isoflurane
medium rate of onset and recovery used for induction and maintenance of anesthesia isoflurane “was” the most commonly used inhalational GA in the US. Largely replaced by Desflurane damages mitochondria
properties of Methoxyflurane
widely considered obsolete slow onset and recovery extensive hepatic/renal metabolism, w/ release of F- ion causing renal dysfunction
Malignant Hyperthermia
esp. when halogenated GA used with succinlycholineRx: dantrolene (immediately)
Halothane toxicity
halothane undergoes >40% hepatic metabolism rare cases of postoperative hepatitis occur Halothane can sensitize the heart to Epi (arrhythmias)
Methoxyflurane toxicity
Fluoride release during metabolism (>70%) may cause renal insufficiency after prolonged exposure
NO toxicity
megaloblastic anemia may occur after prolonged exposure due to decreases in methionine synthase activity (vit B12 def)
N&V toxicity
GA effect the chemoreceptor trigger zone and brainstem vomiting center RX: ondansetron (5HT antagonist) to prevent, avoidance of N2O, ketorolac vs. opioid for analgesia, droperidol, metaclopromide and dexamethasone asso with intravenous anesthetics N2O greatest culprit
Drug disposition affect on toxicity
Absorption, distribution, metabolism and elimination Distribution - results in termination of effects of most anesthetics, alteration in physiology (hemodynamics, disease states) Metabolism & elimination - plays a small role in termination of effects
Metabolism as % of administered dose
Halothane - 20% Sevoflurane - 2-5% Isoflurane - 0.2% Desflurane - 0.02%
Intravenous anaesthetic properties
rapid onset (sec), rapid awakening (mins), danger of overdose due to irrevocability of iv injection redistribution determines duration of action
Biotransformation and elimination of most anesthetics is
slow long elimination half lives, but short effects duration of effects is dose-dependent - anesthetic doses result in brief effects, redosing used to prolong effects
Thiopental
“Truth serum”, most frequently used barbiturate, ultra short acting drug, BUT has a long elimination half life duration of action is dose-related anesthetic induction dose lasts 5 minutes
Properties of Thiopental
rapid unconsciousnessgood amnesia, poor analgesia, poor muscle relaxation pleasant induction for the patient
Thiopental Mechanism of action
Binds to GABAa receptor - increases chloride ion flux into cell and stimulates inhibitory neuronal systems
Thiopental CNS effects
reduces cerebral metabolism and oxygen utilization reduces cerebral blood flow, oxygen consumption, blood volume, intracranial pressure, not cerebral perfusion pressure protects brain against hypoxic/ischemic injury
Thiopental Cardiovascular Direct effects
peripheral vasculature: BP, vascualr resistance and cardiac output may decrease it transiently, venodilation may result due to increased venous capacitance and in hypotension in pts in shock,
Thiopental Cardiovascular Indirect effects
Heart rate increased via barostatic reflex
Additional Thiopental organ effects
pts with high sympathetic tone will experience large drop in blood pressure
ex. hypovolemia and heart failure
due to redistribution of cardiac output
Thiopental Respiratory effects
depresses respiration in dose dep fashion - depresses response to hypoxemia and hypercapnia
muscle relaxants required due to retention of tracheal/laryngeal reflexes - hiccups
Thiopental depresses mucociliary clearance
midalozam and lorazepam
benzos
Best amnestic agents
excellent anxiolytics, anti-convulsants, muscle relaxants
bind to distinct sites on GABAa receptor
Midazolam in vial: pH = 3.5
allows the imidazole ring to remain open
maintains water solubility
Midazolam in plasma: pKa = 6.2
on injection, the ring closes and the basic drug becomes 94% unionized
increases lipid solubility, which decreases time to onset on action
Midalozam CNS effects
dose related effects on cerebral metabolism and blood flow
raises seizure threshold - good anticonvulsant
EEG: beta activity
antegrade, not retrograde amnesia
Midazolam CV effects
hypotensive effect similar to thiopental
hypotension exaggerated in hypovolemia
synergistic sedative effect exists with opioids
Midazolam Respiratory effects
hypnotic dose causes apnea
amnestic dose gives minimal depression
Opioid actions
analgesic action via mu receptors
-ones with some hypnotic action, not reliable for amnesia
used for premedication, induction and maintenance of anesthesia and postoperative pain control
Opioid side effects
nose and whole body - Pruritis
chest wall rigidity
Patients forget to breathe
Ketamine mechanism of action
arylcyclohexylamine - like PCP
Non competitive NMDA antagonist
-only IV agent that works mostly via inhibition of stimulatory neuronal systems
-acts on Cortex, limbic system, hippocampus, spinal cord
‘Dissociative’ anesthetic
individuals cognitive function is separated from his physical being
Ketamine CNS effects
Fast acting antidepressant
unpleasant dreams, hallucinations and delirium
incidence higher in adults, females, habitual dreamers, psychological problems
Benzos, barbs, N2O reduce incidence of these effects
increases intracranial pressure 1-60 mmHg
Nystagmus
Ketamine organ side effects
salivary and tracheobronchial secretions are markedly increased
reduced with atropine
Ketamine CV side effects
central sympathetic stimulation results in increased HR, BP, epi and nor epi levels
- offers advantage over thiobarbs when sympathetic stimulation is helpful
- direct myocardial depressant
Ketamine Ventilation side effects
small doses given slowly result in minimal ventilatory depression - profound analgesia reduces airway reflexes
rapid infusion, or combination with benzos potentiates depressant effects
sympathetic stimulation results in bronchdilation via direct smooth muscle effects
Etomidate is a _______ derivative
imidazole
Etomidate CNS side effects
lowers cerebral blood flow and thus intracranial pressure
lowers cerebral metabolic rate for oxygen
Etomidate respiration side effects
minimal ventilatory depressant
lower incidence of apnea - good for short procedures
Etomidate CV side effects
minimal changes in all parameters
Etomidate Musculoskeletal side effects
myoclonus
Propofol mechanism of action
diisopropyl phenol
some action at GABAa complex - binds to a distinct site
may enhance Cl- conductance at glycine receptors
Propofol CNS side effects
reduces cerebral blood flow and meatbolism
autoregulation is maintained in animal studies, along with response to changes in cardiac output
Propofol CV side effects
decreased mean BP, vascular resistance, HR and cardiac output
central venous pressure unchanged
What burns on injection?
Propofol
phenol component
Propofol pharma properties
extremely fast acting - conversation resumed in recovery, clearance exceeds hepatic blood flow
Euphoric - pts feel better the next day
“milk of amnesia”: Fospropofol - prodrug faster onset
Dexmedetomidine site of action
brain (locus ceruleus), spinal cord and autonomic nerves
CNS effects - sedation/hyponsis, anxiolysis and analgesia
Autonomic nerves - decrease in sympathetic activity, BP and HR
selectivity of alpha2/1
Dexmedetomidine > medetomidine > clonidine > I-medetomidine
Prolonged recovery with
Midazolam
opiates
Respiratory depression
midazolam
propofol
opiates
Significant hypotension
midazolam
propofol
dexmedetomidine
Cumulative effects seen with
midazolam
opiates
Constipation
opiates
Lack of orientation and cooperation seen with
midazolam
propofol
opiates
Desflurane
must be delivered using a special vaporizer
NO, nitrous oxide
good analgesia rapid onset/recovery safe, nonirritating incomplete anesthesia no muscle relaxation must be used with other anesthetics for surgical anesthesia
Halothane
reduces hepatic and renal blood flow lowers BP sensitizes myocardium to actions of catecholamine hepatic toxicity arrhythmias
Isoflurane
good muscle relaxant rapid recovery stability of cardiac output does not raise intracranial pressure no sensitization of heart to Epi
Sevoflurane
potential renal toxicity at low flows
bronchial smooth muscle relaxation good for patients with asthma
rapid onset/recovery
not irritating; useful in childern
Thiopental advantages and disadvantages
poor analgesia causes significant nausea little muscle relaxation laryngospasm rapid onset of action potent anesthesia
Propofol
poor analgesia
not likely to cause nausea
rapid onset
lowers intracranial pressure
Dexmedetomidine
no respiratory depression
blunts undesirable CV reflexes
where are opioid receptors and peptides located ?
CNS, PNS, and GI tract
Opioid receptors are inhibitory, they
inhibit release of some NT (5HT, GABA, glutamate, Ach)
and enable the release of dopamine (contributes to dependence potential of opiates)
