Sterile Drug Products Used in the Anesthesia Practice...

Sterile Drug Products Used in the Anesthesia Practice Setting: Part 1PharMEDium Lunch and Learn Series

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Sterile Drug Products Used in theAnesthesia Practice Setting: Part 1

December 9, 2016

Featured Speaker: Julie A. Golembiewski, PharmD

Clinical Associate Professor, Department of Pharmacy PracticeClinical Associate Professor of AnesthesiologyUniversity of Illinois at ChicagoColleges of Pharmacy and Medicine

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Sterile Drug Products Used in the Anesthesia Setting – Part 1

Julie Golembiewski PharmDDecember 9, 2016

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Spinal

TYPES OF ANESTHESIA

Local Infiltration

Drug-induced, reversible state of

unconsciousness to facilitate the

performance of surgery

Drugs Used:

General Anesthetics

Loss of sensations in a region of the body

Drugs Used:

Local Anesthetics

Loss of sensations in one part of the

body

Drugs Used:

Local Anesthetics

General Spinal & Epidural Local

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TYPES OF ANESTHESIA

Local anesthesia together with sedation and

analgesia

Drugs Used:

Local Anesthetics, Sedatives, Analgesics

Loss of sensations in a region of the body

Drugs Used:

Local Anesthetics

Monitored Anesthesia Care Peripheral Nerve Block

Peripheral Nerve Block

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GENERAL ANESTHESIA

JAMA 2011;305(10):1050 9

WHERE IS GENERAL ANESTHESIA PERFORMED?

• Hospital – Operating room and nonoperating room locations– Patient may or may not go home after procedure

• Ambulatory Surgery Center (ASC)– Same-day surgical care– Patient is expected to go home after procedure

• Doctor’s office– Some procedures performed in offices (e.g.

cosmetic, dental) require general anesthesia or monitored anesthesia care

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• Hospital and ASC– Licensed facility

• Equipped and operated in accordance with local, state and federal laws and regulations

• Qualified personnel and proper equipment

– Adherence to American Society of Anesthesiologist (ASA) and American Association of Nurse Anesthetists (AANA) Standards, Guidelines and Policies

• Doctor’s office– Licensed facility (?)– ASA and AANA guidelines outline what should

be in place to provide safe patient care

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THE OPERATING ROOM

Anesthesia Care Provider

Surgeon 12



MEDICATION ON THE STERILE FIELD (ADMINISTERED BY SURGEON)

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MEDICATIONS USED BY ANESTHESIA

Gemensky J. US Pharm. 2015;40(3):HS8-HS12

http://www.carefusion.com/our-products/browse-brands/pyxis

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INFECTION CONTROL FOR ANESTHESIA CARE PROVIDERS

• Basic infection control & standard precautions

• Safe injection practices• Aseptic technique

• CDC’s One & Only Campaign

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GENERAL ANESTHESIA

• Benzodiazepines

• Propofol, etomidate

• Inhaled anesthetic agents

• Neuromuscular blocking agents and reversal agents

JAMA 2011;305(10):1050

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Preoxygenation, +/- premedication with midazolam, monitors placed then proceed with general anesthesia . . .

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Ind

uct

ion

/ In

tub

atio

nPropofol (to produce unconsious-ness)

NMBA (to facilitate intubation

+/- opioid

Mai

nte

nan

ce Inhaled Anesthetic Agent (e.g. sevoflurane)

Non-depolarizing NMBA to maintain paralysis

+/- other drugs as needed

Em

erg

ence

/ R

eco

very Turn off

inhaled anesthetic agent

Reversal of NMBA (with neostigmine & glycopyrrolate) 17

BENZODIAZEPINES –Midazolam, Lorazepam

• Indication: sedation, amnesia, anxiolysis

• With higher dose, sedation progresses to hypnosis but never really reaches a true general anesthetic state

• Reduces anesthetic requirements

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• Lorazepam contains propylene glycol

– Pain on injection, venous sequelae

– Possible accumulation during continuous infusion (ICU)• Metabolized to lactic acid lactic acidosis

• Midazolam

– Water soluble no propylene glycol in injection

– Bioavailability• Oral: ̴ 30%• Intranasal: ̴ 50%

– Adverse effects• Respiratory depression

(additive with opioids)• Hypotension

COMPARISON OF AGENTS

Lipid-soluble Water -soluble

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COMPARISON OF AGENTS

Property Midazolam Lorazepam

Onset < 3 min 20 - 40 min

Amnesia ++++ ++++

Duration (single dose)

1 - 2 hours 6 - 8 hours

Ability to ↓ BP +++ ++

Active metabolite Yes No

Routes of Admin IV, IM, oral, Intranasal

IV, IM, oral

Dose

(adult, IV, sedation, premedication)

0.5 – 2 mg 1 – 2 mg

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Thiopental Methohexital

Elimination t ½ 11.6 min 3.9 min

Clearance 3.4 ml/kg/min 10.9 ml/kg/min

Adult dose 3 – 5 mg/kg 1 – 1.5 mg/kg

Thiopental

BARBITURATESTHIOPENTAL, METHOHEXITAL

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ADVERSE EFFECTS

• Transient hypotension with compensatory tachycardia

• Apnea, laryngospasm, bronchospasm

• Seizures

• Spastic movement

• Hiccups

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ETOMIDATE• Rapid onset and awakening, reflecting redistribution of drug

• Cardiovascularly stable

• Adverse effects• Spontaneous/involuntary movements

• Inhibition of enzymes involved in cortisol and aldosterone synthesis adrenocortical suppression • Increased risk of adrenal insufficiency and mortality in critically ill patients who received etomidate for induction1

• Higher rate of adrenal insufficiency and mortality in patients with sepsis who received etomidate for intubation2

1 Intensive Care Med 2011;37(6):901-9102 Crit Care Med 2012;40(11):2945-2953 23

PROPOFOL

• Rapid onset and awakening following induction dose, likely with less “hangover” than methohexital, thiopental or etomidate

• Sedation general anesthesia– Monitored Anesthesia Care (sedation, adults): 25 – 75

mcg/kg/min – Induction of anesthesia (adults): 1 – 2.5 mg/kg IV– Maintenance of anesthesia: 50 – 200 mcg/kg/minute

• Antiemetic effects

• Although clearance of propofol exceeds hepatic blood flow, duration of action increases with longer infusion

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CONTEXT-SENSITIVE HALF-TIME

• Computer modeling that takes into account:– Drug behavior in compartments– Effect of drug distribution and metabolism– Effect of duration of administration

• Definition: time required for plasma concentration to decrease by 50% after infusion is stopped

• Cannot be predicted by the drug’s elimination half-life

• Not a constant number as method for plasma level decline shifts from redistribution to elimination

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Hughes, Glass and Jacobs Anesthesiology 1992;76:336

Context-Sensitive Half-Time of Select Anesthesia Drugs

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• Pain on injection• Hypotension• Lactic acidosis (“propofol infusion syndrome”)

– Described in children and adults receiving > 75 mcg/kg/hr for > 24 hours

• Metabolic acidosis has occurred following intra-op propofol infusion

• Lipid solution strongly supports bacterial growth, despite addition of EDTA or sodium metabisulfite– Use aseptic technique– Discard solution after 12 hours

PROPOFOL –ADVERSE EFFECTS

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PROPOFOL: DANCING WITH A “WHITE RABBIT” C.F. WARD MD CSA BULLETIN SPRING 2008

“As someone who initially was trained with thiopental (Pentothal) as the induction agent of choice, propofol represented a significant change in my practice. I even remember my first experience using propofol: a young woman who was emerging from a MAC anesthesia looked at me as though I were a masked Brad Pitt and told me that she felt simply wonderful. This bore no resemblance to my experience with other sedation agents, and I felt then that this might become an issue of concern for propofol. A feeling of euphoria with no residual “hangover” might suggest propofol is a near perfect mood-altering drug, but it is one that possesses a very thin window separating the dreamy state from the nonresponsive.”

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http://www.usdtl.com/media/infographics/propofol-abuse-and-dangers

One addiction center’s experience (1990 to 2010)

• 22 health care professionals, all provided anesthesia

• 13 physicians, 8 nurses, 1 dentist

• Generally started using propofol to get sleep, then quickly developed addiction characteristics

"Propofol addiction is a virulent and debilitating form of substance dependence with a rapid downhill course“

Source: Earley & Finvert J Addiction Medicine 2012;7(3):169

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KETAMINE• Phencyclidine derivative with dose-dependent

effects– High (1 - 5 mg/kg) doses “dissociative anesthesia”

• Eyes are open with slow nystagmus gaze• Patient may appear to be awake but is noncommunicative• Varying degrees of skeletal muscle movements• Intense amnesia and analgesia

– Moderate doses (0.5 – 1 mg/kg) sedation and analgesia– Low doses (< 0.5 mg/kg) analgesia and reversal of

opioid tolerance/hyperalgesia• NMDA receptor antagonism

• Metabolized to norketamine (active, renally excreted)

• Adverse effects– Psychomimetic – hallucinations, dysphoria, restlessness,

disorientation, vivid dreams, emergence delirium– CNS/ocular – ↑ICP, diplopia, nystagmus – Cardiovascular – arrhythmia, ↑ BP, ↑HR

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“REBIRTH” OF KETAMINE • Acute postoperative pain

– Some studies have shown ketamine to be beneficial in controlling postoperative pain and reducing opioid requirements

– Pre- or perioperative bolus and postoperative infusion for up to 48 hours

• Chronic pain– Used to treat chronic pain syndromes, particularly those

with a neuropathic component– Some studies demonstrated long-term analgesia (up to 3

months) following prolonged infusion (4-14 days)– Some studies have found oral ketamine improved

measure of pain in opioid tolerant, chronic pain patients• Depression and chronic pain

– Low dose infusion over several hours has been shown to provide nearly immediate relief for some patients

Br J Clin Pharmacol 2014;77(2):357 BioMed Research International 2015, Article ID 749837Medscape Medical News www.medscape.com May 17, 2016 31

INHALED ANESTHETIC AGENTS

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UPTAKE AND DISTRIBUTION OF INHALED ANESTHETICS

• Goal of inhalation anesthesia is to develop and maintain an anesthetizing partial pressure of the anesthetic at the brain

• A series of partial pressure gradients beginning at the anesthesia machine serve to drive the inhaled anesthetic across barriers to the brain

Anesthesia machine > delivered > inspired > alveolar > arterial > brain33

• The faster an agent reaches equilibrium, the faster the onset of action

• Agents with low solubility will equilibrate quickly and have:– A fast onset– Quicker response to intraoperative concentration

changes– Faster wake-up time after a long duration of

administration

EQUILIBRIUM

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Agent Blood/

Gas

Brain/

Blood

Muscle/

Blood

Fat/

Blood

Isoflurane 1.4 1.6 4.0 45

Desflurane 0.42 1.3 2.0 27

Sevoflurane 0.65 1.7 3.1 47

PARTITION COEFFICIENT

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• Desflurane– Most irritating to airway

• Can cause breath-holding, coughing, and laryngospasm at higher concentrations not used for induction of general anesthesia

• Transient increase in HR and BP with abrupt increase in concentration

• Sevoflurane– Least irritating to airway and can be used to

induce general anesthesia– Compound A

• Degradation product of sevoflurane when it comes into contact with soda lime

• Causes renal injury in rodents, but no reports of nephrotoxicity in humans

AGENTS

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NEUROMUSCULAR BLOCKING DRUGS -

INDICATIONS

1. Facilitate intubation2. Maintain paralysis during surgery3. Paralysis in the ICU for mechanically ventilated

patients (severe Acute Respiratory Distress Syndrome)

Remember –NMBAs do not produce sedation or

analgesia!37

NORMAL NEUROMUSCULAR FUNCTION

1. Nerve impulse triggers . . . 2. Release of acetylcholine

(Ach) from vesicles3. Ach diffuses across

synaptic cleft to nicotinic receptors located on motor end plate

4. Motor end plate depolarizes muscle contraction

5. Ach quickly diffuses away from motor end plate and is broken down by acetylcholinesterase (AChE) enzyme repolarization muscle relaxation

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DEPOLARIZING – Succinylcholine

Binds to the nicotinic receptor membrane depolarization transient fasciculations. Succinylcholine is resistant to acetylcholinesterase prolongeddepolarization muscle paralysis

NONDEPOLARIZING – Rocuronium, vecuronium, cisatracurium, atracurium, pancuronium

Competitive antagonist at neuromuscular junction (blocks effects of acetylcholine muscle paralysis)

MECHANISM OF ACTION

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INTUBATION

• Most common type of intubation is endotracheal intubation

• Breathing tube is passed through the mouth, through the larynx, and into the trachea

• Breathing tube is attached to a ventilator

• Patients may need to be intubated in the operating room, emergency room or intensive care unit

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RAPID SEQUENCE INTUBATION(WHEN ONSET TIME REALLY DOES MATTER)

• Goal: Minimize time airway is unprotected– Intubation within 60 seconds NMBA with an onset

of action of ≤ 60 seconds

• Indication: Patients at risk for aspiration of gastric contents if regurgitation occurs– Pregnant patient– Diabetic patient– Patient with a history of gastrointestinal reflux– Morbidly obese patient

Succinylcholine, Rocuronium

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SUCCINYLCHOLINE

• The only depolarizing neuromuscular blocking agent

• Indication: to facilitate endotracheal intubation– A nondepolarizing NMBA is administered for

paralysis during surgery

– Adult dose: 1 – 1.5 mg/kg

• Onset: 30 – 60 seconds

• Duration: 5 - 8 minutes– Metabolized by plasma cholinesterase

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SUCCINYLCHOLINE

• Advantages– Produces an intense paralysis rapidly

• Most reliable and predictable NMBA

– Effect wears off before an adequately preoxygenated patient becomes hypoxic

• Disadvantages– Adverse effects– Malignant hyperthermia trigger

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NONDEPOLARIZING AGENTS

Drug Onset DurationPrimary Route of Elimination

CV Effects

Rocuronium 60 - 90 sec

30 - 40 min

Hepatic,

30% renal

None

Atracurium 2 – 3 min 30 – 40 min

Hofmann elim., ester hydrolysis

↓ BP

Cisatracurium 2 – 3 min 30 – 40 min

Hofmann elimination,

ester hydrolysis

None

Vecuronium 2 – 3 min 30 – 40 min

Hepatic None

Pancuronium > 3 min > 60 min Renal HR

Indication: Facilitate intubation, maintain paralysis

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MONITORING - TRAIN OF FOUR NERVE STIMULATION

• Train of four– Four electrical stimulations at 2 Hz

delivered every 0.5 second

• Stimulation of the peripheral nerve and visually observing the resulting muscle contraction

• Stimulation of the ulnar nerve at the wrist causes contraction of the adductor pollicus the thumb twitches

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NEUROMUSCULAR BLOCKADE AND RECOVERY: ANTICHOLINESTERASE ENZYME

NMBD competitively inhibits Ach

During recovery,concentration of NMBD decreases

Neostigmine inhibitsAch breakdown

Increased Ach displaces remainingNMBD from receptor

Muscle functionincreases

Ach = acetylcholine

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• Agents– Neostigmine, edrophonium, pyridostigmine

• Mechanism of action– Inhibit action of AChE enzyme increased

concentration of Ach at nicotinic and muscarinic receptors

• Increased Ach at nicotinic receptors therapeutic effect (muscle contraction)

• Increased Ach at muscarinic receptors adverse effects (bradycardia, hypotension, nausea/vomiting, salivation)

REVERSAL OF NM BLOCKADE: ANTICHOLINESTERASES

(AKA CHOLINESTERASE INHIBITORS)

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• Effectiveness depends on degree of neuromuscular recovery present – Best given when four twitches are visible

• Anticholinergic agent (e.g. glycopyrrolate, atropine) is always given with the anticholinesterase to minimize adverse effects

• Adult dose– Neostigmine 25 - 70 mcg/kg + 0.2 mg glycopyrrolate

for every 1 mg neostigmine

– Typical dose: 3 mg neostigmine + 0.6 mg glycopyrrolate

REVERSAL OF NM BLOCKADE: ANTICHOLINESTERASES

(AKA CHOLINESTERASE INHIBITORS) (CONT)

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• Approved in United States in December 2015– FDA delayed ruling to

review data from hypersensitivity study

• Selective binding agent designed to encapsulate circulating rocuroniumand to a lesser extent, vecuronium

SUGAMMADEX

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SUGAMMADEX VS. NEOSTIGMINE

Sugammadex Neostigmine

Fast onset (about 2 min) Slower onset (about 17 min)

Predictable, although some variation in individual response has been reported

Less predictable

• Any depth of block can be reversed by increasing dose

• Risk of recurrence of residual block if insufficient dose was given

• Spontaneous recovery must have started (at least 2 twitches are present) for reversal to be effective

• Maximum dose is 5 mg for an adult

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SUMMARY• Drugs used by anesthesia include:

– Midazolam • Provides amnesia, anxiolysis, sedation

– Induction agents (loss of consciousness)• Propofol, etomidate, methohexital

– Maintain general anesthesia• Inhaled anesthetic agent or propofol infusion

– Ketamine • Postoperative pain, reduce opioid requirement

– Neuromuscular blocking drugs• Facilitate intubation, maintain paralysis during surgery• Reversal with neostigmine + glycopyrrolate

• Part II of this webinar (February 10th 2017) will cover:– Vasopressors, beta blockers, antihypertensives, local

anesthetics, epidural analgesics– Medication safety

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