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General anesthetics cont. (PRE- AND POSTANESTHETIC MEDICATION (Objective:…
General anesthetics cont.
Intravenous anesthetics
GENERAL PROPERTIES OF I.V. ANESTHETICS
Chemical properties
I.v. anesthetics are relatively hydrophobic and lipophilic compounds
Chemical classes
Barbiturates: thiopental, methohexital
propofol, etomidate, ketamine
MOA
All (except ketamine) activate the GABA-A receptor
Barbiturates also inhibit the neuronal N-type acetylcholine receptor
Ketamine inhibits the NMDA-type glutamate receptor
Pharmacokinetics
Tissue distribution and redistribution of i.v. anesthetics
IMMEDIATELY AFTER I.V. INJECTION, they distribute rapidly to the well-perfused tissues,
including the brain → general anesthesia occurs rapidly (within ~ 1 min)
LATER, they redistribute to the less well-perfused tissues, such as the muscle, skin and adipose tissue.
These have large mass → remove the anesthetic from the brain → the patient wakes up in a few minutes
The anesthetic action of i.v. anesthetics is terminated by redistribution, not by elimination.
The rate of redistribution is quite similar for all i.v. anesthetics;
therefore, after a single anesthetic dose, their duration of action is also similar (i.e., 5-10 min).
The rate of redistribution of i.v. anesthetics may decrease in patients with
decreased tissue perfusion (e.g., in cardiac failure and septic shock)
decreased muscle and adipose tissue mass (e.g., in elderly or malnourished patient)
In such conditions, the dose of i.v. anesthetic should be lowered lest the anesthesia should be too long
Elimination of i.v. anesthetics
All i.v. anesthetics are eliminated by biotransformation, e.g., by CYP-catalyzed oxidation (barbiturates,
ketamine), glucuronidation (propofol), and hydrolysis (etomidate)
There are significant differences in the rate of elimination of i.v. anesthetics;
this is reflected in their elimination half-lives
Thiopental is eliminated very slowly: T1/2β = 12 hrs
The others are eliminated relatively rapidly: T1/2 = 1-4 hrs
Propofol is eliminated most rapidly (by glucuronidation); T1/2β = 1-2 hrs.
Clinical use
All may be given as a single dose for
induction of anesthesia before inhalation anesthesia, if the inhal. anesthetic slowly induces anesthesia
(e.g., halothane), or has unpleasant odor or airway irritating property (e.g., isoflurane, desflurane)
short anesthesia for short surgery or painful intervention (e.g., reposition of a dislocated joint)
Some
continuous infusion to produce long-lasting anesthesia.
After discontinuation of the infusion, the patient wakes up in 10 minutes even if propofol was infused
for 3 hours. Propofol is the preferred i.v. anesthetic for TIVA (total intravenous anesthesia). At a lower
dose rate, propofol is also used for continuous sedation of patients in ICUs
Specific properties of I.V. anesthetics
Barbiturates
Thiopental
Methohexital
Dose
Thiopental
3-5 mg/kg i.v
Methohexital
1-1.5 mg/kg) i.v.
Onset of action
~20 sec; induction is rapid and smooth
Duration of action: ~5-10 min, for both
Elimination
CYP
Thipental
Oxidative desulfuration
methohexial
N-demethylation
Both
Hydroxylation on the aliphatic chains linked to C5 of the barb. ring
Half life
Thiopental
12 h
Methohexital
4 h
Advantages
Decrease cerebral metabolic rate and O2 utilization by the brain
Decrease the cerebral blood flow which decreases the incracranial pressure -> decrease of ocular pressure
exert anticonvulsive effect → thiopental is valuable in the treatment of status epilepticus
Disadvantages
Incompatibility
injectible solution is basic, can precipitate as free acid in a acidic solution
Exert vascular irritative effect
If the i.v. injected thiopental conc. is >2.5%, it may induce pain and thrombophlebitis
If injected intra-arterially, it induces endarteritis and gangrene
Barbiturates induce respiratory depression
In asthmatics, they may induce histamine release and wheezing
Barbiturates induce hypotension by causing both
vasodilatation
negative inotropic effect
barbiturates should not be injected:
too rapidly → excessive decrease in cardiac contractility
to a patient who can not compensate for ↓ blood pressure
Barbiturates induce ALA synthetase
First enzyme in heme synthesis
Cause accumulation of porphyrins in patients deficient in some
downstream enzymes of the heme synthetic pathway.
Propofol
Dose
1.5-2.5 mg/kg
Onset and duration of anesthesia
after a bolus dose, anesthesia develops in ~20 sec
recovery
within 10 min after a 3-hr infusion
within 40 min after an 8-hr infusion
Elimination
By glucuronidation (mainly) and sulfation at the hydroxyl group
T1/2β = 2 hrs
Usage
TIVA in infusion
used by orthopedic surgeons in SCOLIOSIS CORRECTION SURGERY
Also used for continuous sedation in intensive care units
Advantages
Propofol ↓ cerebral metabolic rate, O2 consumption
→ ↓ cerebral blood flow, intracranial and intraocular pressure
Propofol has antiemetic effect
Disadvantages
Has venoirritative effect → pain; prevented by lidocaine i.v
Has respiratory depressive effect
Decreases blood pressure because of vasodilatation and negative inotropic effect
Special disadvantages
Propofol is a water immiscible oily substance
emulsion is used as an i.v. anesthetic
Propofol Infusion Syndrome
Occurs with high dose
Mech
Toxic effect on mitrochondria, mainly in skeletal and cardiac muscle
acts as a weak protonophoric uncoupler
Diffuses into Mit., dissociates its phenolic proton, thus dissipating the inwardly directed H+ gradiant that drives ATP synthase.
Consequences
Cardiac failure: acute refractory bradycardia (may lead to asystole), hypotension, and ST elevation
Rhabdomyolysis → ↑serum K+, ↑serum CK, myoglobinuria → renal failure
Hepatomegaly with fatty liver (probably caused by inhibition of fatty acid oxidation)
High serum triglyceride levels
Lactic acidosis
Etomidate
Dose
0.2-0.4 mg/kg
Rapidly and ultra short acting (4-8 min) anesthetic
Elimination
Ester hydrolysis in the liver
T1/2β = 3 hrs
Other disadvantages
often induces nausea and vomiting
appears to have proconvulsive effect (contraindicated in seizures)
causes pain on injection
Advantages
↓ cerebral metabolic rate, O2 consumption → ↓ cerebral blood flow, intracranial and intraocular pressure
little respiratory depression
little or no decrease in blood pressure and may slightly increase the heart rate
→ the CARDIOVASCULAR FUNCTION IS STABLE during etomidate anesthesia → etomidate is usually reserved for patients at risk for hypotension and/or myocardial ischemia
Ketamine
Dose
0.5-1.5 mg/kg
Onset of action
1-2 min
Duration of anesthesia: 10-15 min
Elimination
CYP-catalyzed N-demethylation
T1/2β = 3 hrs
Effects
Analgesic effect
outlasts the anesthetic effect
used by ambulance services for sedation and pain suppression in patients
Induce disagreeable dreams and hallucinations
This occurs seldom in children → ketamine is a preferred anesthetic in pediatric surgery
Indirect sympathomimetic effect
Because it ↓ neuronal reuptake of catecholamines
both peripherally and centrally
↑ blood pressure
↑ heart rate, cardiac output, myocardial O2 consumption
↑ cerebral blood flow, ↑ intracranial pressure
Pupillary dilation, nystagmus, lacrimation
Bronchodilation
Indication
at risk for hypotension
asthmatic
Contraindicated
Risk for myocardial ischemia
↑ intracranial pressure
GENERAL ANESTHETIC PROCEDURES USING OPIOIDS IN COMBINATION WITH BENZODIAZEPINES OR BUTYROPHENONES
Opioids
Preferred opioids
Fentanyl
Relatively long acting opioid
T1/2 = 4 hrs
100-150 µg/kg
Sufentanyl
Super potent opioid
0.25-0.5 µg/kg
T1/2 = 2 hrs
Remifentanyl
ultrashort-acting opioid
T1/2 = 4 min
0.1-0.5 µg/kg/min
may be used for
TIVA with propofol
Unwanted effects
Respiratory depression
Chest wall and laryngeal rigidity
Decreased gastrointestinal and bladder motility
Combination of opioids with benzodiazepines
Effect
Combination of a high dose opioid analgesic with a high dose i.v. benzodiazepine produces a general anesthetic state.
Advantage
The opioid-benzodiazepine combination does not affect cardiac function adversely
This combination is used in patients undergoing cardiac surgery or other major surgery when the patient’s circulatory reserve is limited
Properties
They lack general anesthetic properties
cause amnesia.
competitively antagonized by flumazenil
The benzodiazepines used in anesthetic procedures fall into two categories
Not water-soluble
diazepam, lorazepam
prolonged elimination
non-aqueous vehicle causes pain and irritation upon i.v. administration
Water-soluble
Midazolam
rapidly eliminated
half-life 2-4 hrs
slow-onset CNS depressant (sedative) effect
inadequate alone for surgical anesthesia
Combination of opioids with butyrophenones
Effect
combination of a neuroleptic
with a narcotic analgesic drug produces neurolept
analgesia, a state of quiescence with indifference to pain, but with maintained consciousness
fentanyl + droperidol + nitrous oxide → loss of consciousness = Neurolept anesthesia
Advantage
Consciousness is maintained, permitting communication with the patient
The circulation is not affected adversely
Used when the patient
needs to be communicated with, e.g. during inner ear surgery
impaired cardiac function
Preferred combination
fentanyl plus droperidol
Fixed combination: THALAMONAL
Disadvantage
Neurolept analgesia causes dysphoria, therefore it is rarely used nowadays
PRE- AND POSTANESTHETIC MEDICATION
Objective: To relieve anxiety, induce amnesia, and
to prevent unpleasant dreams caused by
ketamine
Benzodiazepines (midazolam, diazepam, lorazepam)
To extremely concerned patients (cancer, open-heart surg.):
Benzodiazepine + Narcotic analgesic (opioid) + Scopolamine
Objective: To potentiate the action of anesthetics
Benzodiazepines (e.g., midazolam i.v. or i.m.)
Narcotic analgesics (e.g., fentanyl, sufentanyl)
Barbiturates
α2-Receptor agonists
Non-narcotic analgesic (e.g., ketorolac)
Objective: To decrease bronchial/salivary secretions
Atropine
Objective: To prevent aspiration of the gastric juice
H2 rec antagonist + metoclopramide (a prokinetic drug)
Objective: To prevent adverse effects of anesthetics
β-receptor antagonist: against halothane-arrhythmia
Atropine: against halothane-bradycard
Disulfiram: (inhibits CYP2E1): against halothane-hepatitis
To prevent postoperative emesis
D2-receptor antagonists: droperidol, metoclopramide
5-HT3 receptor antagonists: ondansetron
Propofol induction (propofol has antiemetic effect)
To suppress postanesthesia shivering
Opioids lower the shivering trigger-temperature
Post-operative pain control
Opioids (e.g., fentanyl)
NSAIDs (e.g., ketorolac, 30-60 mg i.v.)