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Anesthesia Pharmacology Chapter 14: General Anesthesia
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Intravenous drugs: Rationale for use with inhalational anesthetics
Provide hypnosis
Enhance or provide analgesia
Provide muscle relaxation
Reduce visceral reflex responses
Enable lower doses of inhalational agent to be used
Intravenous Barbiturates: Anesthesia
Thiopental (Pentothal)
Methohexital
sodium
(Brevital Sodium)
Thiamylal Sodium (Surital)
Thiopental
Overview:
Unconsciousness after 10 - 20 sec following i.v. injection (2.5% isotonic solution)
Rapid recovery (20-30 min) due to redistribution from brain to peripheral tissues
Thiopental (and other barbiturates) are poor analgesics and may actually increase (at inadequate dosage) sensitivity to pain.
This effect on pain may result in increased sympathetic activity: tachycardia, sweating, tachypnea, increased blood pressure and dilated pupils.
Initially, thiopental often causes coughing, laryngospasm and bronchospasm.
Dose-related respiratory depression, profound at higher doses.
Limited cardiovascular effects, except in the presence of hypovolemia, sepsis, or other circulatory instability. In that case a standard thiopental dose can result in a hypotensive response.
Skeletal muscle relaxation is transient.
Thiopental crosses the placental barrier and depresses the fetus.
Thiopental Advantages:
Rapid induction and fast recovery (faster recovery with methohexital)
Little postoperative excitement or vomiting
Useful in combination with other anesthetics
Thiopental Disadvantages
Cough, laryngospasm, bronchospasm
Histamine release
Overdosage difficult to reverse in the absence of specific barbiturate antagonists.
Thiopental Contraindications:
Variegate porphyria or acute intermittant porphyria: absolute contraindication.
In these cases, thiopental or other barbiturates can cause nerve demyelination and CNS lesions which may result in pain, weakness and life-threatening paralysis
[Kennedy, S.K. and Longnecker, D.E., History and Principles of Anesthesiology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E,Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p 321 - 328.]
Intravenous Benzodiazepines and Anesthesia
Diazepam(Valium)
prototype drug
Midazolam (Versed)
Lorazepam (Ativan)
Diazepam
Drowsiness occurs several minutes after I.V. administration. Lorazepam slightly slower and Midazolam slightly faster onset compared to diazepam.
Benzodiazepines are effective in promoting sedation and reducing anxiety. They are amnestic in most patients.
Amensia is anterograde and lasts about 6 hours.
Used alone benzodiazepines have limited depressant effects on the cardiovascular/respiratory system.
CNS depression can be reversed by the specific anatagonist flumazenil (Romazicon).
When benzodiazepines are administered in combination with opioids, significant cardiovascular and respiratory depression may occur.
Benzodiazepines are not analgesic.
Benzodiazpines in Anesthesia
Benzodiazepines may be used alone for procedures not requiring analgesia, such as Endoscopy, DC cardioversion, Cardiac catherization, Certain radiological procedures
Benzodiazepines reduce the likelihood of seizures when local anesthetics are used for regional procedures
Benzodiazepines are often used in combination with other drugs for "balanced anesthesia"-which may include Opioids, Muscle relaxants, Thiopental for induction and an inhalational agent
Clinically: Lorazepam (Ativan) is a very effective anterograde amnestic; Midazolam (Versed) has a more rapid onset of action and a shorter duration
Kennedy, S.K. and Longnecker, D.E., History and Principles of Anesthesiology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E,Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p 324.
Intravenous Opioids: Anesthesia: Morphine, Meperidine (Demerol), Fentanyl (Sublimaze),Sufentanil (Sufenta), Alfentanil (Alfenta), Remifentanil
Opioids are used typically to suppliment inhalational or i.v. anesthetics.
Respiratory depression, hypotension, post-operative nausea or vomiting are associated with opioid use.
In certain procedures, large dose morphine can be used to obtain anesthesia;
Morphine-nitrous oxide combination has been used in cardiovascular surgery.
Fentanyl (Sublimaze) and related agents
I.V. fentanyl causes analgesia and unconsciousness.
Compared to morphine, fentanyl is:
more amnestic
less likely to provoke hypotensive or hypertensive responses
shortened duration of respiratory depression.
These factors have led to fentanyl and related agents to become preferable to morphine.
Fentanyl is often combined with a muscle relaxant and nitrous oxide or low doses inhalational agent for anesthesia.
Alfentanil and sufentanil are more potent than fentanyl and produce analgesia and, at higher concentrations, anesthesia.
Remifentanil is a new potent agent which produces analgesia very rapidly.
It is readily metabolized resulting in a rapid recovery time.
Respiratory depression caused by opioids are reversible using specific narcotic antagonists, such as naloxone (Narcan).
The duration of action of naloxone is only 60 to 90 minutes so repeated dosing may be required to prevent recurrence of respiratory depression. (other narcotic antagonists: naltrexone (ReVia), nalmefene (Revex))
Kennedy, S.K. and Longnecker, D.E., History and Principles of Anesthesiology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E,Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p 325 - 326.
Intravenous Combinations: Neuroleptic-Opioids: Innovar
Neurolept analgesia is useful for minor surgical procedures, some radiological procedures, burn dressing, and endoscopy.
Neuroleptic agents such as droperidol (Inapsine) cause a reduction in anxiety and a state of indifference.
Droperidol is an antiemetic and has adrenergic blocking (alpha block) activity.
When combined with an opioid such as fentanyl (Sublimaze), a state of neurolept analgesia results.
Addition of nitrous oxide can transition neurolept analagesia to neurolept anesthesia.
Neurolept analgesia/anesthesia may be especially useful in the elderly, debililitated or seriously ill patient.
The combination of droperidol and fentanyl is Innovar.
Innovar produces slight circulatory effects, but can cause significant respiratory depression.
Droperidol can cause neuroleptic malignant syndrome (rarely).
The low incidence of extrapyramidal side effects associated with droperidol use may be effectively treated with the anti-cholinergic (anti-muscarinic) drug, benztropine (Cogentin).
Kennedy, S.K. and Longnecker, D.E., History and Principles of Anesthesiology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E,Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p 326.
Ketamine (Ketalar) produces a state that is characterized by sedation, amnesia, analgesia and immobility.
This type of anesthesia has been termed "dissociative anesthesia" because of patient's subjective impression of being dissociated from the environment.
Significant amnesia and analgesia rapidly follow injection.
Muscle tone tends to increase.
Arterial blood pressure, heart rate and cardiac output increase, probably due to increased sympathetic outflow.
Recovery is slower than with barbiturates, perhaps reflecting difference site of action (cortex/limbic for ketamine; brainstem for barbiturates).
Awakening may be associated with bad dreams and
hallucinations which may recur.
These adverse experience are less common in children and can be diminished by concurrent administration of benzodiazepines.
In conjunction with diazepam, ketamine may be useful in managing emergency surgery, trauma, dressing changes and certain pediatric radiological procedures.
Kennedy, S.K. and Longnecker, D.E., History and Principles of Anesthesiology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E,Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p 326- 327
I.V. propofol rapidly induces anesthesia, similar to thiopental.
Duration of propofol anesthesia can be increased by repeated administration or by combination with inhalational agents, nitrous oxide, or opioids.
Propofol causes peripheral vasodilation which leads to a decrease in blood pressure, but the agent is not arrhythmogenic.
Propofol does not adversely affect hepatic or renal function.
Emergence from propofol anesthesia is rapid with minimal postoperative confusion.
Postoperative GI upset occur at a similar frequency to that of thiopental.
Propofol is now commonly used in ambulatory surgery settings.
Kennedy, S.K. and Longnecker, D.E., History and Principles of Anesthesiology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E,Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p 326- 327
Preanesthetic Medication: Rationale: Preanesthetic Medication Properties:
Primary Goals:
Anxiety relief without excessive sedation
Amnesia during perioperative period while retaining cooperation
Relief of preoperative pain
Secondary Goals:
Reduction in the requirement for inhalational agents
Reduction in side effects associated with some inhalational agents.
Side effects include salivation, bradycardia, postanesthetic vomiting.
Reduction in acidity and volume of gastric contents.
Reduction of stress in perioperative period.
Preanesthetic Medication: Rationale
Primary Goals:
Anxiety relief without excessive sedation
Amnesia during perioperative period while retaining cooperation
Relief of preoperative pain
Secondary Goals:
Reduction in the requirement for inhalational agents
Reduction in side effects associated with some inhalational agents.
Side effects include salivation, bradycardia, postanesthetic vomiting.
Reduction in acidity and volume of gastric contents.
Reduction of stress in perioperative period.
Preanesthetic Medication: Sedative-Hypnotics
Benzodiazepines are frequently used as preanesthetics because of the following properties:
Anxiolytic
Sedation
Relatively little respiratory and cardiac depression
Raise threshold for CNS toxicity of local anesthetics
Amnesia
Barbiturates (pentobarbital and secobarbital) also produce sedation and reduce presurgical apprehension.
However, barbiturates when administrated to patients in pain can result in disorientation.
Diazepam (Valium): widely used, active orally, absorption unreliable by the parenteral route of administration; little effect on respiration and does not increase respiration depression caused by opioids.
Lorazepam (Ativan): oral or parenteral administration; good amnestic.
Midazolam (Versed): good amnestic, rapid onset, short duration; popular in same-day surgery setting due to rapid return of normal mental status; when administrated in combination with opioids, there is a decrease in catecholamine release in surgery;
Flumazenil (Mazicon), a benzodiazepine antagonist is effective in even more rapidly reversing sedative effects of midazolam (Versed)
Preanesthetic Medication: Opioids
Opioids are frequently used as preanesthetics because of the following properties:
Presurgical pain relief
Anxiolytic (questionable)
Sedation
Reduction in the amount of general anesthesia required (about 10% - 20% reduction\
Respiratory depression
Prolongation of awakening from general anesthesia
Biliary/uterine spasm due to effects on smooth muscle,
Wheezing in asthmatics,
Constipation/urinary retention
Nausea and vomiting,
Hypotension,
Respiratory depression resulting in increased ICP (due to CO2 retention which produces cerebral vasodilation)
Pruritis
Morphine
Morphine: Clinical Uses
Relieves severe and chronic pain
Reduces pulmonary edema and pain of myocardial infarction
Reduces preoperative pain
Anxiolytic (controversial)
Relieves dyspnea in acute congestive heart failure
Reduces amount of inhalational agent required in General Anesthesia
Morphine: Contraindications (partial listing)
Hypersensitivity to opioids
Increased ICP (intracranial pressure)
Convulsive disorders
Acute alcoholism
Acute asthma
Severe respiratory depression
Prostatic hypertrophy
Severe hepatic or renal insufficiency
Acute ulcerative colitis
Addison's disease
Safe use in pregnancy not established (Category B; D in long-term use or high dose use)
Morphine: Cautious Use (partial listing):
Toxic psychosis
Cardiac arrhythmias
Emphysema
Elderly
Very young
Labor
Morphine: Side Effects (Partial listing)
CNS: respiratory depression, euphoria, dysphoria, CNS stimulation
CV: bradycardia, palpitations, syncope, orthostatic hypotension
GI: constipation, nausea, biliary colic
GU: Urinary retention/urgency
Allergic: pruritis
Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp 794-795; Kennedy, S.K. and Longnecker, D.E., History and Principles of Anesthesiology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p 304.]; Barash, P.G., Cullen, B.F, Stoelting, R.K. In, Handbook of Clinical Anesthesia (Third Edition), Lippincott-Raven, 1997, p.267, 639
Meperidine [Demerol]
Meperidine [Demerol]: Clinical Uses
Relieves severe and chronic pain
Reduces preoperative pain
Anxiolytic (controversial)
Relieves dyspnea in acute congestive heart failure
Reduces amount of inhalational agent required in General Anesthesia
Meperidine [Demerol]: Contraindications (partial listing)
Hypersensitivity to meperidine
Acute abdomen (prior to diagnosis)
Convulsive disorders
Severe respiratory depression
Severe hepatic or renal insufficiency
Acute ulcerative colitis
Safe use in pregnancy (prior to labor) not established (Category B; D in long-term use or high dose use)
Meperidine [Demerol]: Cautious Use (partial listing):
Increased ICP
Head injury
Supraventricular arrhythmia
Emphysema
Hepatic or renal impairment
Elderly
Addison's disease
Prostatic hypertrophy
Hypothyroidism
Glaucoma
Meperidine [Demerol]:Side Effects (Partial listing)
CNS: respiratory depression, dizziness, sedation, euphoria, dysphoria, CNS stimulation, convulsions
CV: bradycardia, tachycardia, palpitations, syncope, orthostatic hypotension, cardiovascular collapse/arrest (toxic doses)
GI: constipation, nausea, biliary colic, dry mouth
Allergic: pruritis
Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp 726-727
Fentanyl [Duragesic, Sublimaze]
Fentanyl: Clinical Uses
Short acting analgesic used during perioperative periods.
Combined with droperidol or with diazepam producing neuroleptanalgesia
Suppliment in general/regional anesthesia
In high-risk cardiac surgery it may be used with a muscle relaxant and oxygen for anesthesia when the use of additional anesthetics cannot be tolerated
Fentanyl: Contraindications (partial listing)
Patients who have received MAO inhibitors within the previous 2 weeks
Myasthenia gravis
Severe respiratory depression
Safe use in children under 2 years not established
Safe use in pregnancy not established (Category C)
Fentanyl: Cautious Use (partial listing)
Head injuries
Increased ICP
Renal/hepatic dysfunction
Bradyarrhythmia
Elderly
Very young
COPD/other respiratory conditions
Fentanyl: Side Effects (Partial listing)
CNS: respiratory depression, sedation, convulsion (high dose)
CV: bradycardia, cardiac arrest, syncope, orthostatic hypotension
GI: constipation, nausea, vomiting
Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp 515-516
Hydroxyzine (Vistaril) and droperidol have useful antiemetic actions.
Postoperative nausea/vomiting may be reduced by substituting an NSAID (such as ketorolac) for opioids that would otherwise be used.
Ondansetron (Zofran)
5-HT3 receptor blocker
minimal effects on dopamine, histamine, adrenergic or cholinergic receptor activity
Very effective for prevention of nausea and vomiting caused by chemotherapy or surgery. -- major role in management of severe nausea and vomiting due to anticancer drugs
Clinical Use:
Dosage: 4-8 mg IV (administered over 2-5 minutes just before anesthesia induction)
Highly effective in reducing postoperative nausea/vomiting incidence -- particularly in susceptible patient groups:
Ambulatory gynecologic surgery
Middle ear surgery
Oral or IV reduces incidence of postoperative vomiting in preadolescent children undergoing:
ambulatory surgery, e.g. tonsillectomy, strabismus surgery
Ondansetron: effective both for prophylaxis and treatment of postoperative nausea/vomiting
decreases incidents & intensity of postoperative nausea & vomiting -- but does not totally eliminate this problem
Major advance: reduced side effects compared to previously used antiemetic drugs such as:
phenothiazines, antihistamines, butyrophenones
Propofol for induction and maintenance of anesthesia may be as effective as ondansetron in reducing/preventing postoperative nausea & vomiting
Side Effects:
Surgical patients:
3% increased liver transaminase enzyme levels
3% headache
No sedation, hypotension, dysphoria, extrapyramidal reactions which are side effects associated with other antiemetic drugs
Tropisetron (Navoban):
5-HT3 receptor blocker
Effective in managing symptoms induced by carcinoid syndrome-- also some gastrokinetic characteristics
Effective in preventing chemotherapy/radio therapy-induced emesis
Effective in preventing postoperative nausea/vomiting when administered before general anesthetic induction
Granisetron (Kytril)
More selective 5-HT3 receptor blocker compared to ondansetron
Clinical Use:
Effective in the chemotherapy-induced emesis prevention
Effective in preventing postoperative nausea/vomiting
Elimination half-life: nine hours, compared to about three hours for ondansetron: suggesting less frequent dosing with granisetron.
Significantly higher cost-- could limit clinical use
Dolasetron (Anzemet):
Highly potent/selective 5-HT3 receptor blocker
Clinical Use:
Effective in preventing chemotherapy-induced nausea/vomiting
Effective in reducing likelihood of postoperative nausea & vomiting
Antiemetic effect due to long-acting, active metabolite (hydrodolasetron; elimination half-life = approximately 8 hours)
Kennedy, S.K. and Longnecker, D.E., History and Principles of Anesthesiology In, Goodmanand Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p 304; Stoelting, R.K., "Renin, Plasma Kinins, and Serotonin", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 398-407
Phenothiazines (e.g. promethazine, i.m.):
Properties that favor use as preanesthetics
sedation
antiarrhythmic
antiemetic
antihistaminic
These agents may be combined with an opioid or barbiturate.
Phenothiazines can prolong postanesthetic sleep, cause hypotension and respiratory depression.
Butyrophenones (droperidol)--warning issued recently by the FDA citing risk due to an unacceptable incidence of QT prolongation.
Sedation is a common side effect of antihistamines.
Hydroxyzine (Vistaril) is used (now less commonly) as a preanesthetic, although --benzodiazepines are used more frequently
Hydroxyzine Vistaril
produces CNS depression
anticholinergic properties
antiemetic properties
antihistaminic properties
bronchodilator properties
Clinical Uses
reduces anxiety
controls nausea and emesis
reduces opioid requirement before/after surgery
management of chronic urticaria, atopic/contact dermatoses
treatment of alcohol withdrawal symptom
Anticholinergics:Anticholinergics are used as preanesthetics primarily to decrease vagal effects that occur during surgery
Atropine
dry mouth,
blurred vision;
this dosage will not block parasympathetic effects induced by visceral traction, massage/manipulation of the carotid sinus or by succinylcholine.
I.V. atropine can reverse these effects.
Glycopyrrolate (Robinul) (quaternary amine):
less sedation than scopolamine;
very effective against secretions;
much less tachycardia than atropine; but more effective in blocking bradycardia.
Clinical Uses:
Parenteral use a preanesthetic medication;
Interoperative medication
Reversal of neuromuscular blockade
Management of peptic ulcer
GI conditions associated with hyperacidity, spasm, hyper motility
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Gastrokinetic agents: useful in reducing gastric fluid volume.
Rationale: Reduction of gastric fluid volume: important to decrease risk of aspiration pneumonitis
High-risk patients:
Acute pain; "full stomach" -- emergency surgery
Patient with hiatus hernia
Patient with esophageal reflux
Aspiration gastric contents may lead to chemical pneumonitis
Pulmonary aspiration of gastric content: rare in elective surgery
Drinking clear fluid -- up to three hours before surgery: no measurable gastric volume or pH effect in healthy children (age group: 2-12 years){note: healthy patients; clear liquids only}
in adults: possibly, relatively high-risk of pulmonary complications if aspiration volume:
> 25 ml and
pH < 2.5
Metoclopramide (Reglan)
Classification: dopamine antagonist
Gastrokinetic activity:
stimulates upper gastrointestinal motility
increases gastroesophageal sphincter tone
relaxes the pylorus
relaxes the duodenum
Increases of the rate of gastric emptying
Oral: 10 mg -- onset within 30-60 minutes
Parenteral: 5-20 milligrams -- 15-30 minutes before induction
IV administration over 3-5 minutes-- prevents abdominal cramping (occurs with more rapid infusion)
No guarantee of gastric emptying with metoclopramide
significant gastric fluid could still remain
prior administration of other drugs (e.g. opioids) or concurrent atropine administration may offset metoclopramide's effect on the upper gastrointestinal tract.
Gastric volume will not be reduced further (elective surgery) in the presence of already small gastric volumes
May not be effective: following sodium citrate administration
Particularly effective in reducing aspiration pneumonia risk when metoclopramide is combined with a H2 receptor antagonist (e.g. Ranitidine) before elective surgery
Generally favorable risk: benefit ratio in the use of these drugs to reduce the risk of pulmonary complications from aspiration
Use of gastrokinetic drugs does not diminish the need for correct, diligent anesthetic techniques to protect the airway during anesthesia:
induction
maintenance
emergence
Moyers, J.R., Preoperative Medication, Chapter 21, In: Clinical Anesthesia 3rd edition, (Barash, P.G., Cullen, B.F. and Stoelting, R.K., eds) Lippincott-Ravin, Philadelphia, New York, 1997, pp. 519-529
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