Transcript 3-CHANNA general anesthetics 441 lecture2011.ppt

GERERAL ANESTHESIA
AND PHARMACOLOGY OF
GENERAL ANESTHETICS
Amir B. Channa FFARCS,DA(ENG)
Department of Anesthesia & Intensive Care
King Khalid University Hospital
Riyadh
Anesthesia Types
• Local Anesthesia: loss of sensory perception over a
small area of the body
• Regional Anesthesia: loss of sensation over a
specific region of the body (e.g. lower trunk)
• General Anesthesia: loss of sensory perception of
the entire body
Anesthesia
The administration of drugs
that alleviate pain or other
sensation and movement
General
Local
Effects a specific region of the PNS
Effects CNS
General anesthesia is a state of reversible
loss of consciousness for
the purpose of carrying out surgery.
Desirable components of
anesthesia
1.
2.
3.
3.
4.
5.
6.
Immobility in response to noxious stimulus
Anxiolysis
Amnesia
Analgesia
Unconsiousness
Muscle relaxation
Loss of autonomic reflexes
Historical Perspectives
History
First attempts
Egyptian - compression
Grecian - wine and
mandragora
Scythian - hemp
Indian - hemp
Chinese - hemp
Effects of general anesthesia
•Low Dose Effects
•High Dose Effects
•Amnesia
•Deep sedation
•Euphoria
•Muscle relaxation
•Analgesia
•Diminished motor responses
•Hypnosis
•Diminished autonomic responses
•Excitation
•Myocardial protection from ischemia
•Hyperreflexia
•Cardiovascular/respiratory depression
•Hypothermia
•Nausea, vomiting
•Death (1 per 250,000)
Before Anesthesia
•Surgery uncommon
•Aseptic technique unknown
•Surgical pain relief
• alcohol,
• hashih,
• opium
• physical methods (ice, ischemia)
• unconsiousness (blow to head, strangulation)
• simple restraint most common
General Anesthetics
Parenteral
Inhalational
Gas
nitrous oxide
Volatile liquids*
halothane
isoflurane,
desflurane,
sevoflurane
Induction Agents
Barbiturates eg
thiopentone
Propofol
etomidate etc
Benzodiazepines
midozolam
Opioids
(fentanyl)
Sufentanil
remifentanil
NMRELAXANTs
*In
the beginning there was ether & chloroform
1.
Suxa
2. Atracurium
Phases of Anesthesia
Induction:
putting the patient to sleep
Maintenance: keeping the patient asleep (without awareness)
Emergence:
waking the patient up
(recovery)
Dose Response Relationships
Coma
Barbiturates
Medullary depression
Benzodiazepines
CNS Effects
Anesthesia
Hypnosis
Sedation, disinhibition, anxiolysis
Increasing dose
Possible selective anticonvulsant
& muscle-relaxing activity
CLASSIFICATION OF GENERAL
ANESTHETICS
1. Intravenous agents
•primarily used for induction
•Barbiturates: thiopentone and methohexitone
•Benzodiazepines: midololam* lorezepam
•Etomidate
•Ketamine
•Propofol
•TIVA PROPOFOL (total IV anesthesia)
INTRAVENOUS ANAESTHETICS
• Rapid onset (seconds)
• Rapid awakening (minutes)
• Danger of overdose due to irrevocability of i.v. injection
• Redistribution determines duration of action
GENERAL ANAESTHETICS
CLASSIFICATION
2. Inhalational agents
•primarily used for maintenance
•2a: Volatile agents
•Isoflurane
•Sevoflurane
•Desflurane
•Halothane, Enflurane
•Diethyl ether, chloroform, cyclopropane
•2b: Anesthetic gases
•Nitrous Oxide- currently used
•Xenon- in the near future?
Mechanisms of Action
1. Enhanced GABA effect on GABAA Receptors
– Inhaled anesthetics
– Barbiturates
– Benzodiazepines
- Etomidate
- Propofol
2. Block nicotinic receptor subtypes (analgesia)
– Moderate to high conc’s of inhaled anesthetics
3. Activate K channels (hyperpolarize Vm)
– Nitrous oxide, ketamine, xenon
4. Inhibit NMDA (glutamate) receptors
– Nitrous oxide, ketamine, xenon, high dose barbiturates
5. Inhibit synaptic proteins (NT release)(amnesia)
6. Enhance glycine effect on glycine R’s (immobility)
Inhalational Agents
Nitrous oxide (Gas)
N
O
N
Anesthesia machine work station
Halogenated hydrocarbons (Volatile)
Preanesthetic Medications
•Benzodiazepines
•Opioids
•Reduce anxiety
•Provide analgesia
•Midazolam, diazepam
•Fentanyl
•Barbiturates
•Anticholinergics
•Sedation
•Amnesia, prevent bradycardia,
•Pentobarbital
and fluid secretion
•Antihistamines
•Scopolamine
•Prevention of allergic reactions
•Muscle relaxants
•Diphenhydramine
•Facilitation of intubation
•Antiemetics
•Prevent aspiration of stomach contents
•Reduce postsurgical nausea and vomiting
•Ondansetrone
CHARACTERSITICS OF AN
IDEAL ANAESTHETIC
1. Rapid and pleasant induction
2. Rapid changes in the depth of anesthesia
3. Adequate muscle relaxation
4. Wide margin of safety
5. Absence of toxic/adverse effects
6. No emergence problems
No single agent yet identified is an ideal anesthetic
Anesthetic Uptake and Distribution
•Vessel Rich Group (VRG)
•CNS and visceral organs
•High blood flow (75%) and low capacity
•Muscle Group (MG)
•Skin and muscle
•Moderate flow and high capacity
•Fat Group (FG)
•Low flow and high capacity
•Vessel Poor Group
•Bone, cartilage, ligaments
•Low flow and low capacity
Search for the molecular mechanism(s) of general anesthesia
Xe
Isoflurane
Halothane
......
Molecular
(lipids & receptors)
Cellular (synapses)
Mechanism of action: Intravenous
Anesthetics
•Cause anesthesia via GABAa receptors
•Specific selective targets
•Specific sites for specific effects
•Different anesthetics have different mechanisms
Anesthetic of the Future: Xenon
•Rare gas extracted from air
•Very expensive to produce
•Close to ideal anesthetic
•Low blood and tissue solubility
•(rapid induction/recovery)
•Potent
•Not metabolized (totatally inert)
•Nonflammable
•Minimal side effects
THERAPEUTIC GASES: Oxygen
•Administered to prevent hypoxic injury
•Hypoxia can result from:
•Hypoxemia (problem with lungs)
•Inadequate delivery to tissues
•Impaired utilization
•Can have toxic effects
•Due to free radical generation
THERAPEUTIC GASES:
Nitric Oxide
•Important cell signalling molecule
•Can selectively dilate pulmonary vasculature
•Administered to newborns with persistent pulmonary
hypertension
•Under investigation for many disease states
•Can have toxic effects
Regional Effects
• Immobilization in response to surgical incision
(spinal cord)
• Sedation, loss of consciousness (thalamic firing)
• Amnesia (hippocampal neurotransmission)
Parenteral Anesthetics
(Intravenous)
• Most commonly used drugs to induce
anesthesia
– Barbiturates (Thiopental* &
Methohexital)
– Benzodiazepines (Midazolam)
– Opioids (Morphine & Fentanyl)
• Propofol*
– Etomidate
* Most commonly used for
induction
Barbiturates & Benzodiazepines MOA:
1) Both bind to GABAA receptors, at different sites
• Both cause increase Cl- influx in presence of GABA
• BNZ binding can be blocked by flumazenil
2)
Barbs at high doses - are also GABA mimetic,
block Na channels & NMDA/glutamate Rs
GABA
Barbiturates
Benzodiazepines
(w/ &)
O-
Flumazenil
Classic Stages of Anesthesia*
• Stage 1: Analgesia
– decreased awareness of pain, amnesia
• Stage 2: Disinhibition
– delirium & excitation, enhanced reflexes, retching,
incontinence, irregular respiration
• Stage 3: Surgical Anesthesia
– unconscious, no pain reflexes, regular respiration,
BP is maintained
• Stage 4: Medullary Depression
– respiratory & CV depression requiring ventilation &
pharmacologic support.
* Seen mainly with Ether. Not all stages are observed with modern GAs.
Barbiturates
• Thiopental & methohexital are highly lipid soluble & can produce
unconsciousness & surgical anesthesia in <1 min.
• Rx: induction of anesthesia & short procedures
• Actions are terminated by redistribution
• With single bolus - emergence from GA occurs in ~ 10 mins
• Hepatic metabolism is required for elimination
Thiopental (Pentothal ®):
• Barbs are respiratory & circulatory depressants
(Contraindicated: hypovolemia, cardiomyopathy, betablockade,etc.)
• Psychomotor impairment may last for days after use of a single
high dose
• Taste of garlic prior to anesthesia
• Potentially fatal attacks of porphyria in pts with a history of acute
or intermittent porphyria.
• Delay giving other drugs (e.g. NMJ blockers) until barb has
cleared the i.v. line to avoid precipitation.
Propofol (Diprivan ®)
• Produces anesthesia as rapidly as i.v. barb’s & but
recovery is more rapid than w/ barb’s.
• Recovery is not delayed after prolonged infusion
(due to more rapid clearance).**
• Patients are able to ambulate sooner & patients
“feel better” in the post-op period compared to other
i.v. anesthetics.
• Antiemetic effects (pts w/ risk of nausea)
• Can cause marked hypotension (>barbs)
• Commonly used as component of “balanced
anesthesia” for maintenance of anesthesia following
induction of anesthesia.
** More rapid discharge from the recovery room
Etomidate (Amidate ®)
• Rapid induction (~1 min)
• Used as a supplement with nitrous oxide for short
surgical procedures
• Short duration of action (3-5 mins)
• Hypnotic, but not analgesic
• Little effect on CV & Respiration
• Can cause post-op nausea & decrease cortisol
production w/ long term infusion*.
• Primarily used in pts w/ limited cardiac or
respiratory reserve (safer than barbs or propofol in
pts w/ coronary artery dx., cardiomyopathy, etc.)
* increased mortality
Benzodiazepines
• Midazolam (> Diazepam & Lorazepam)
– Used to produce anxiolysis, amnesia & sedation
prior to induction of GA w/ another agent.
– Sedative doses achieved w/in 2 min, w/ 30 min
duration of action (short duration).
– Effects are reversed with flumazenil.
Opioids (Morphine, Fentanyl &
Remifentanil*)
• GAs do not produce effective analgesia (except for
ketamine).
• Given before surgery to minimize hemodynamic
changes produced by painful stimuli. This reduces GA
requirements.
• High doses can cause chest wall rigidity & post-op
respiratory depression
• Therapeutic doses will inhibit respiration (CO2)
• Used for post-op analgesia
• Remifentanil is an ester opioid metabolized by plasma
esterases. It is very potent but w/ a short t1/2 (3-10
mins).
Ketamine
• A “dissociative anesthetic” that produces a cataleptic state
that includes intense analgesia, amnesia, eyes open,
involuntary limb movement, unresponsive to commands or
pain.
• Increases heart rate & blood pressure (opposite of other
GAs)
• Can be used in shock states (hypotensive) or patients at
risk for bronchospasm.
• Used in children & young adults for short procedures
• Side Effects: nystagmus, pupillary dilation, salivation,
• Hallucinations & vivid dreams emergence delirium
Inhaled Anesthetics
• Easily vaporized liquid halogenated hydrocarbons
• Administered as gases
(gas)
Inhaled Anesthetics
• Partial pressure or “tension” in inspired air is a measure of
their concentration
• The speed of induction of anesthesia depends on:
– Inspired gas partial pressure (GA concentration)
– Ventilation rate
– GA solubility (less soluble GAs equilibrate more quickly
with blood & into tissues such as the brain)
Minimum Alveolar Concentration
• The minimum alveolar anesthetic concentration
required to eliminate the response to a painful
stimulus in 50% of patients
• A measure of GA potency.
• It’s “a population average”.
• 1.3 MAC - 100% will not respond to stimuli.
• When several GAs are mixed, their MAC values are
additive (e.g. nitrous oxide is commonly mixed w/
other anesthetics).
MAC %
Nitrous Oxide
Halothane
Methoxyflurane
>100
0.75
0.16
MAC & Patient Conditions
•
•
•
•
Pregnancy -  MAC (elevated progesterone)
Elderly -  MAC (less brain activity)
Chronic Alcoholics - MAC (cross-tolerance)
Acute alcohol poisoning -  MAC (additive)
Bispectral Index Monitor (EEG) is used to measure a patient’s “anesthetic depth”.
BIS LEVEL
100
80
60
40
0
CLINICAL STATE
Awake
Sedated
Moderate hypnotic level (no recall)
Deep hynotic level
Isoelectric EEG
Elimination
• Anesthesia
is most commonly terminated by redistribution
of drug from brain to the blood & out through the lungs.
• The rate of recovery from anesthesia for GAs with low
blood:gas PCs is faster than for highly soluble Gas.
- Time is $$ in the O.R. & recovery room
Blood:Gas PCoeff
Haltothane
2.30
Desflurane
0.42
Sevoflurane
0.69
• Halothane & methoxyflurane undergo hepatic metabolism
& can cause liver & kidney toxicity.respectively
Properties of Inhaled anesthetics
Nitrous Oxide
–
–
–
–
–
MAC > 100% : Incomplete anesthetic
Good analgesia
No metabolism
Rapid onset & recovery
Used along w/ other anesthetic; fast induction & recovery
Halothane
–
–
–
–
–
–
The first halogenated inhalational anesthetic
Not pungent (use for induction w/ children)*
Medium rate of onset & recovery
Although inexpensive, its use has declined
Sensitizes the heart to epi-induced arrhythmias
Rare halothane induced hepatitis
* fewer side effects also seen in children
Properties of Inhaled anesthetics
Desflurane
– Most rapid onset of action & recovery of
the halogenated GAs (low PC)
– Widely used for outpatient surgery
– Irritating to the airway in awake patients & causes
coughing, salivation & bronchospasm (poor induction
agent)
– Used for maintenance of anesthesia
Sevoflurane
– Very low blood:gas partition coefficient w/ relatively rapid
onset of action & recovery *
– Widely used for outpatient surgery*
– Not irritating to the airway
– Useful induction agent, particularly in children
* Similar to Desflurane
Properties of Inhaled anesthetics
Isoflurane
– Medium rate of onset & recovery
– Used for induction & maintenance of anesthesia
– Isoflurane “was” the most commonly used inhalational GA in the
US. Has been largely replaced by Desflurane.
Methoxyflurane
– Now widely considered obsolete
– Slow onset & recovery
– Extensive hepatic/renal metabolism, w/ release of F- ion causing
renal dysfunction
Toxicity
• Malignant Hyperthermia
– Esp. when halogenated GA used with succinylcholine
– Rx: dantrolene (immediately)
• Halothane:
– Halothane undergoes >40% hepatic metabolism
– Rare cases of postoperative hepatitis occur
– Halothane can sensitize the heart to Epi (arrhythmias)
• Methoxyflurane
– F release during metabolism (>70%) may cause renal
insufficiency after prolonged exposure.
• Nitrous oxide
– Megoblastic anemia may occur after prolonged exposure due
to decreases in methionine synthase activity
(Vit B12
deficiency).
MUSCLE PHYSIOLOGY
Neuromuscular Junction
Skeletal muscles stimulated by motor neurons
Components of somatic nervous system –
Nerves “reside” in brain or spinal cord –
Threadlike extensions travel to muscle cells –
“Axon”
Divides profusely as it
enters the muscle
Each axonal ending forms
branching neuromuscular
junction with a single
muscle fiber
Only one neuromuscular –
junction per muscle fiber
MUSCLE PHYSIOLOGY
Neuromuscular Junction
Axonal ending and muscle fiber very close
Not touching –
1 – 2 nanometers (nm) apart –
Separating space termed “synaptic cleft” –
Gel-like extracellular
substance rich in
glycoproteins
NMJ Blockers(TWO TYPES)
Depolarising & Nondepolarising
•
•
•
•
Depolarising Agent Succinylcholine,
Non Depolarising Agent Curare Type ie
Atracurium
Cisatracurium & Rocuronium
– relax skeletal muscle
– facilitate intubation**
– insure immobility
• Reversed by neostigmine* & glycopyrrolate*
during post-op period
* quaternary drugs; ** intubation is usually needed for airway maintenance & to prevent aspiration.
DEPOLARIZER
NON-DEPOLARIZERS
d-Tubocurarine(dTC)
Pancuronium
Vecuronium
Rocuronium
Nimbex
Atracurium
Mivacurium
Doxacurium
Metocurine
Gallamine
Pipecuronium
NON-DEPOLARIZERS
Reversal •
NEOSTIGMINE AND ARTROOINE •
OR NEOSTIGMINE AND •
GLYCOPYROLATE
Dantrolene
• Interfers with the release of calcium from the sarcoplasmic
reticulum through the SR calcium channel complex.
• Used to prevent or reverse malignant hyperthermia (which is
otherwise fatal in ~50% of cases w/o dantrolene).
• Given by i.v. push at the onset of symptoms (e.g. an
unexpected rise in CO2 levels)
• Supportive measures & 100% O2 are also used to treat
malignant hyperthermia
Nausea & Vomiting
• General anesthetics effect the chemoreceptor
trigger zone & brainstem vomiting center (cause
nausea & vomiting)
• Rx:
- Ondansetron (5-HT3 antagonist) to prevent
- Avoidance of N2O
- Propofol for induction
- Keterolac vs. opioid for analgesia
- Droperidol, metaclopromide & dexamethasone
The End