Anesthesia and Opiate Analgesia

What are the 5 primary effects of anesthesia?

• Unconsciousness

• Amnesia

• Analgesia

• Inhibition of autonomic reflexes

• Skeletal muscle relaxation

Anesthesia overall MOA

Suppression of normal activity of the CNS

• Focus is on the synapse: can be pre- or post synaptic

• Cumulative effect can produce strengthened inhibition of CNS

Choosing anesthesia

• IV has replaced inhaled in most cases of rapid induction (other than pediatrics)

  • These drugs should be part of a balanced anesthesia approach

  • Often used for sedation during procedures: relaxing them to be more compliant (do not meet all 5 of the criteria)

  • May see mixture of IV and inhaled in the OR

• Most agents are lipophilic → preferentially partition into lipophilic tissue (brain and spinal cord), which accounts for rapid onset

Propofol MOA

• GABA-A potentiation

  • Propofol increases the effects of GABA (inhibitory neurotransmitter) and increases chloride influx into neurons, causing hyper-polarization and a decreased chance of firing

  • At higher levels it can also directly activate GABA-A receptors

• Hypnotic (not analgesic)

• Must use within 12 hours of opening

Propofol Routes

• IV bolus (induction)

• IV infusion (TCI or manual maintenance)

• MAC/ICU sedation

Propofol Indications (4)

• Most common IV induction agent

• Maintenance anesthesia

• ICU sedation

• Conscious sedation

Propofol Adverse Effects

• Most profound hypotension: causes significant peripheral vasodilation which can cause more hypotension

  • Does not allow for compensatory tachycardia to overcome the hypotension

• Potent respiratory depression and apnea common

• Propofol infusion syndrome

  • Metabolic acidosis, rhabdomyolysis, hyperkalemia, cardiac and renal failure, hepatic issues

  • Often fatal with prolonged high dose infusions

Propofol Contraindications (4)

• Egg/soybean allergy

• Severe reactive airway disease

• Hypovolemia

• Critical hemodynamic instability

Benzodiazepines MOA

• GABA-A mediated chloride potentiation

• Most useful for anxiolysis and anterograde amnesia

  • Very helpful for pre-medication before procedures to help them forget what you are going to do

Benzodiazepines Reversal

• Flumazenil: short duration (20 minutes) and re-sedation is possible

Benzodiazepines Indications (4)

• Pre-operative period (less so diazepam)

• IV sedation

• Seizure suppression

• Regional anesthesia sedation: may be used in OR if full anesthesia is not reached

Benzodiazepines Routes and Distinction

• Midazolam

  • IV, IM, or oral

  • Shortest context sensitive half-time

• Lorazepam

  • IV, IM, and oral (very painful to give IM because of how thick it is)

  • Slow onset and prolonged duration

• Diazepam

  • Poor water solubility

  • Has longer onset (not quite as long as lorazepam)

  • Usually given orally

Benzodiazepines BLACK BOX

• Respiratory depression

  • Alone: minimal

  • With opioids: severe respiratory depression

Etomidate MOA

• GABA-A potentiation: hypnotic (not analgesic)

• Derivative of imidazole

Etomidate Route

• IV bolus for induction (do not do continuous infusion due to endocrine concerns)

• Mixed with polyethylene glycol for stability

Etomidate Key Advantages

• Minimal BP changes: agent of choice for hemodynamically compromised, cardiac surgery patients

Etomidate Adverse Effects

Endocrine

• 11 beta hydroxylase inhibition: adernocorticoid suppression (4-8 hours)

• Limit continuous infusion

CNS

• Myoclonic activity (will appear right with infusion)

Post-op

• More post-op N/V than other agents

Etomidate Contraindications

• Adrenocorticol insufficiency

• Critical illness with adrenal reserve concern

• Planned continuous infusion

Ketamine MOA

• NMDA receptor (binds glutamate) antagonism

• Only IV anesthetic with significant analgesia

  • Partially water soluble and highly lipid soluble

• Sympathomimetic

• Dissociative state

  • Observed after induction

  • Patients eyes often open with slow nystagmic gaze but completely dissociated

Ketamine Routes

• IV (bolus/infusion)

• IM: especially pediatric (conscious sedation)

• Oral/rectal/epidural for pre-medication

Ketamine Indications (4)

• General anesthesia induction/maintenance

• Pain control for people who are opiate tolerant

• Hemodynamically preserved (trauma/critically ill)

• Reactive airways (bronchodilation)

Ketamine: Emergent reaction

Emergence reaction

• Vivid dreams and hallucinations or out of body experiences: may come out of anesthesia confused/agitatrd

• Can be mitigated by giving benzodiazepines

Does increase salivation

• Need to make sure that they are not aspirating on their saliva if the lose the ability to swallow

Ketamine Profile

CV

• Sympathomimetic: increase BP, HR, CO

• Only for hemodynamically competent

CNS

• Cerebral vasodilation

• Not recommended for patients with elevated ICP

Used for someone who you want to give anesthesia with significant analgesia

Dexmedetomidine MOA

• Highly selective alpha 2 adrenergic agonist

  • CNS alpha 2 activation → produces sedation which resembles physiologic sleep

• Can be counteracted by alpha 2 adrenergic antagonist

Dexmedetomidine Indications (4)

• Short term sedation of intubated ICU patients

• Adjunct to general anesthesia

• Continuous sedation

• Awake fiber optic intubation sedation

  • Good medication to be used for awake trials (they do not care)

Dexmedetomidine Route

• IV loading dose and infusion (not a rapid bolus → can cause hypertension and bradycardia)

Dexmedetomidine Adverse Effects

• Hypnosis

• Cardiovascular

  • Bradycardia and decreased SVR

  • Hypotension

  • Bolus: transient BP then pronounced bradycardia

• Respiratory

  • Small tidal volume decrease

• CNS

  • Minimal ICP/CMRO2 change: advantage for neurosurgery

What are opiates used for?

• Routinely used post-op for pain control/analgesia

  • Opiates treat both sensory and emotional components of pain (contrast to NSAIDs/Tylenol, which has no significant effect on emotional aspect)

Opiates MOA

• Binds to GPCR located in the brain and spinal (areas involved in transmission and modulation of pain) → produces analgesia

  • Frequently repeated doses of opiates can cause loss of effectiveness

Morphine MOA

• Mu opioid agonist (u1 > u2)

• Hydrophilic: slower CNS penetration

• Gold standard for cancer pain

Morphine Routes

• Oral

• IV

• IM/SC

• Epidural/intrathecal (highly effective)

• Rectal

• Sublingual

Morphine Indications (4)

• Moderate to severe acute and chronic pain

• Post operative pain

• Cardiac/Pulmonary emergencies

• Cancer pain

Morphine Adverse Effects

Respiratory depression

• Dose dependent

• Decreases rate, tidal volume, ventilatory response to CO2

• Apnea possible

• Incomplete tolerance persists

GI

• Constipation: no tolerance and most persistent

• N/V

Renal

• M3G/M6G metabolite accumulation

Codeine MOA

• Prodrug requiring CYP2D6 conversion to morphine

• Weak mu opioid agonist

Codeine Pharmacogenomics

Poor metabolism

• Minimal morphine → analgesia

Ultra-rapid metabolism

• Excessive morphine → respiratory depression risk

Codeine Routes

• Oral

• IM/SC

Codeine Indications (3)

• Mild to moderate pain

• Cough suppression

• Often combined with acetaminophen (have to be aware of dosage changes and the safety profile of the combined medication

Codeine Adverse Effects

• Similar to morphine but less severe

• FDA cautions with pediatric use

• Taking it with CYP2D6 inhibitors reduce analgesia

Oxycodone MOA

• Semisynthetic mu opioid agonist

• Much more potent than morphine

Oxycodone Routes

• Oral immediate release

• Oral extended release (OxyContin)

• IV (hospital only)

• Intranasal

Oxycodone Indications (5)

• Moderate to severe pain

• Post operative pain

• Cancer pain

• Acute pain (immediate release)

• Chronic pain (extended release)

Oxycodone Metabolism

• Multiple pathways (CYP3A4, CYP2D6)

• Active metabolites

  • Oxymorphone: no significant accumulation with normal renal function

Oxycodone BLACK BOX

• Major opioid of abuse

  • Extended release particularly targeted

  • 2010: tried tamper resistant reformulation

Hydrocodone MOA

• Semisynthetic opioid from codeine

• Less potent than morphine

• Most potent effect from hydromorphone metabolite

Hydrocodone Routes and Combinations

• Oral

• Almost always combined with acetaminophen/ibuprofen

Hydrocodone Indications (4)

• Mild to moderate pain

• Post operative pain

• Chronic pain (very common in outpatient)

• Cough suppression

Hydrocodone: Critical

Acetaminophen toxicity

• Monitor total daily maximum acetaminophen (maximum is 4 g/day)

• Check all medications

• Check risk of liver failure

2014: moved from schedule III to schedule II

• Higher risk of abuse

• Cannot give standing refills and have increased monitoring

Hydromorphone MOA

• Semisynthetic opioid from morphine

  • 7.5 times more potent than oral morphine

Hydromorphone Routes

• Oral (IR/solutions)

• IC

• SC

• IM

• Epidural

• Rectal

• Intranasal (ER)

Hydromorphone Indications

• Moderate to severe pain

• Post operative pain

• Cancer pain

• When other opioids are inadequate (more of a step up)

Hydromorphone Advantages

• No major CYP interactions

• Intermediate lipophilicity (faster CNS penetration)

• Less metabolite accumulation then morphine

Hydromorphone BLACK BOX with benzodiazepines

• Higher abuse potential

• Causes severe respiratory depression with benzodiazepines

Methadone MOA

• Synthetic mu opioid agonist

• Secondary NMDA receptor antagonist

• Very long acting

  • See steady state in 1-2 weeks

• Very lipophilic

  • Large volume of distribution

  • High protein binding and tissue accumulation: feel effects for longer

Methadone Indications (3)

• Chronic pain (not acute)

• Cancer pain

• Opioid use disorder maintenance therapy: for people with dependency on opioids

Methadone Adverse Effects

• QT prolongation

  • Dose dependent

  • Risk of TdP

  • Monitor at higher doses (100-120 mg/day)

• CYP inhibitors increase levels (overdose)

• Inducers decrease levels (withdrawal)

Has BLACK BOX for both QT prolongation and CYP interactions

Tramadol MOA

• Weak mu opioid

• Has monoamine reuptake: serotonin and NE

• Active metabolite O-desmethyltramadol

Tramadol Indications

• Moderate pain (when NSAIDs contraindicated)

• Outpatient pain: lower abuse potential

Tramadol Routes

• Oral: immediate and extended

• IV

• IM

Tramadol Adverse Effects

• MAOI use

• Seizure risk: lowers threshold for seizures (dose dependent)

• Insomnia

• Tremor

• Sweating

• Increased anxiety

• Serotonin syndrome risk of using concurrent SSRIs/SNRIs

Tramadol Drug Interactions

• CYP2D6 inhibitors reduce analgesia

• Inducers increase risk with seizures

• BLACK BOX: benzodiazepines