Time to Sleep Anesthesia Pharmacology ReviewJASON F HEUER, MSN, CRNA

Pharmacokinetics

▪ The effect of the body on a drug from administration to elimination

▪ Allows for determining properties of drug molecules such as half-life, onset, duration of effects, drug dosing, among others.

1. Routes2. Solubility3. Absorption4. Distribution5. Metabolism6. Elimination7. Half-life8. Volume of Distribution

Pharmacodynamics

The effect of a drug on the body

Major goal to determine the proper drug dose to elicit desired effect while avoiding toxicity.

1. Receptor Theory- “Lock and Key” model2. Agonists/Antagonists3. Receptor Regulation4. Receptor Types – (i.e. Ligand-gated ion channels, G-protein coupled

receptors)

Cultural, Environmental, and Genetic Influences

▪ Factors include age, gender, body weight, allergies, smoking, dietary habits, and concurrent medications.

1. Influence on biochemical enzyme systems – (i.e. cytochrome P-450 system)

2. Dietary Influences – vitamin K, Herbal supplements, phytochemicals3. Alcohol consumption – acute vs. chronic 4. Smoking – Increased dosages of NMB, opioids, sedatives needed5. Genetic Influences – Malignant Hyperthermia

Benzodiazepines

• MIDAZOLAM (VERSED)

• LORAZEPAM (ATIVAN)

• DIAZEPAM (VALIUM)

• ALPRAZOLAM (XANAX)

BENZODIAZEPINE ANTAGONIST• FLUMAZENIL (ROMAZICON)

Benzodiazepines

▪ Represent class of drugs that possess varying degrees of anxiolysis, sedation, and anticonvulsant actions; spinal cord-mediated skeletal muscle relaxation; and amnestic properties.

A) Clinical Uses: 1) anxiety 2) insomnia 3) seizure 4) muscle spasm

B) Routes: oral, IM, IV, intranasally, and rectally

C) Onset/Peak: IV- circulated to brain within seconds; Oral- peak plasma levels achieved in 1-2 hours; IM- well absorbed and peak plasma levels achieved in 30-90 minutes.

D) MOA: promote binding of the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to GABAA subtype receptors in cerebral cortex, cerebellar cortex, and thalamus. Binding results in extended opening of chloride channels, causing hyperpolarization of postsynaptic cell membrane and making cells LESS EXCITABLE.

Benzodiazepines

E) Metabolism: undergo hepatic metabolism by the cytochrome P-450 induction system. Some, such as Diazapam, have active metabolites that can still produce sedative effects, resulting in elimination half-life up to 20 hours. Midazolam has active metabolites that are quickly conjugated and exhibit no secondary effects after metabolism.

Midazolam half-life = 1.7 – 2.6 hours

F) Physiologic Effects: Reduction in cerebral oxygen metabolism and cerebral blood flow. Provide some cerebral protection against hypoxia and useful anticonvulsants for seizures. Little effect on cardiovascular system. Cardiac output not altered and changes in blood pressure due to changes in SVR. Respiratory depression observed in patients with existing respiratory disease. Increasing PaCO2 levels can cause respiratory depression. Synergistic effect with narcotics. Benzodiazepines depress swallowing reflex and upper airway activity, increasing risk of pulmonary aspiration.

G) Elimination: Eliminated through renal system. VOD, half-life, and clearance unaffected with renal insufficiency. Renal failure may enhance metabolite accumulation.

Benzodiazepines

H) Adverse Effects and Contraindications: Most significant concern is respiratory depression. Less common are venous irritation, weakness, headache, blurred vision, N & V, and epigastric distress. FDA categorizes BZ’s as either Category D or X, which means potential for harm in unborn has been demonstrated (floppy infant syndrome, neurodevelopmental delays, motor impairment). Adverse effects increased in elderly population, resulting in potential cognitive symptoms postoperatively.

Flumazenil (Romazicon): only known antagonist approved by FDA that inhibits the effects of BZ’s. Competitively inhibits activity at GABA/benzodiazepine receptor complex. Can be administered IM or IV. Caution must be used as half-life of benzodiazepines is longer than half-life of Flumazenil (0.7 – 1.3 hours), thus resedation can occur. Patients should be monitored closely following administration.

Anesthetic Induction Agents

• PROPOFOL (DIPRIVAN)

• ETOMIDATE (AMIDATE)

• KETAMINE (KETALAR)

Anesthetic Induction Agents-PROPOFOL

Represent drugs that induce loss of consciousness and facilitate intubation and subsequent airway management. Paradigm shifting from one of primarily agents to achieve anesthetic induction to that of total IV anesthesia (TIVA).

PROPOFOL

A) Clinical Uses: Induction and maintenance of general anesthesia, sedation, hypnosis.

B) Routes/Dosages: IV; Induction of general anesthesia achieved with IV dose of 1.5-2.5 mg/kg. Pediatric patients require a larger induction dose due to a larger VOD and elevated clearance rate, whereas elderly patients generally require induction dose reduced by 25-50%. Maintenance of general anesthesia with Propofol accomplished at rates between 100-300 mcg/kg/min. Maintenance of sedation for MAC or ICU typically accomplished at 25-100 mcg/kg/min.

C) Onset: produces unconsciousness in 30 seconds

PROPOFOL

D) MOA: exerts its sedative-hypnotic characteristics predominantly on GABAA receptors within CNS, permitting increase of chloride transmembrane conduction, allowing for hyperpolarization and inhibition of neurons.

E) Metabolism: Hepatic metabolism is extensive and rapid. Cytochrome P-450 hydroxylation of Propofol into active metabolite one-third as potent occurs. Although controversial, pulmonary uptake and elimination may be responsible for extrahepatic metabolism. Unique characterstic is there is rapid redistribution of Propofol away from effect site (brain) to less well-perfused tissues (muscle), which accounts for rapid decline in plasma levels. Allows for rapid reawakening when compared to other IV induction agents.

PROPOFOL

F) Physiologic Effects: decreases cerebral blood flow, ICP, and CPP. Significant cardiovascular effects produce decrease in BP, CO, and SVR due to relaxation of vascular smooth muscle and inhibition of sympathetic nervous system. Negative inotropic effect and depression of baroreceptor reflex, causing bradycardia and possible asystole. Causes dose-dependent depression of ventilation, leading to apnea in 25-35% of patients who receive induction dose. Sedative infusions depress tidal volumes and respiratory rate, resulting in hypoxia and hypercarbia. **Antiemetic and anticonvulsant properties

G) Elimination: Primarily renal with evidence of pulmonary elimination. Rapid redistribution and metabolism responsible for characteristic rapid reawakening, with no evidence that hepatic or renal dysfunction impacts this.

H) Adverse Effects and Contraindications: Pain on injection; strongly supports bacterial growth (12 hour expiration with EDTA); Relative contraindication (reduced dose) in patients with hypotension, decreased CO, or hemorrhagic shock. Propofol infusion syndrome (>24 hrs) described as unexplained tachycardia, metabolic acidosis, myocardial dysfunction, and possible rhabdomyolysis in patients receiving infusion.

ETOMIDATE

ETOMIDATE

A) Clinical Uses: Used as an alternative to Propofol when hemodynamic stability is critical. Not to be used for prolonged sedation. Does not provide analgesia.

B) Routes/Dosages: IV; Induction of general anesthesia achieved with IV dose of 0.2-0.4 mg/kg.

C) Onset: reaches brain concentrations within 1 minute

D) MOA: exerts its sedative-hypnotic characteristics predominantly on GABAA receptors within CNS, permitting increase of chloride transmembrane conduction, allowing for hyperpolarization and inhibition of neurons.

ETOMIDATE

E) Metabolism: Rapid awakening primarily due to redistribution of the active drug to neurologically inactive sites. Full recovery result of rapid hepatic metabolism that occurs by hydrolysis and plasma esterases.

F) Physiologic Effects: Etomidate is a vasoconstrictor and decreases cerebral blood flow by 35%, thus reducing ICP. CPP is maintained. May produce convulsion like EEG patterns thus exercise caution in focal epileptic patients. Relatively cardiovascular stable even in presence of existing CV disease. Considered induction agent of choice for patients with CV disease because Etomidate possesses minimal alpha-adrenergic agonist properties. Although apnea is a possibility, respiratory suppression less dramatic when compared with other induction agents.

ETOMIDATE

G) Elimination: Primarily renal; Less than 3% of drug recovered unchanged in urine, whereas 85% of inactive metabolite in urine and 13% in bile. Distribution half-life of approximately 2.6 minutes, and elimination half-life of approximately 5 hours.

H) Adverse Effects and Contraindications: The primary restricting factor for Etomidate as an induction agent is its ability to suppress adrenocortical function (adrenal glands) after a single dose. May last between 5-24 hours and results in diminished cortisol and aldosterone levels. Morbidity and mortality increased in septic patients who receive one-time dose of Etomidate.

KETAMINE

KETAMINE

A) Clinical Uses: Induction of anesthesia with hemodynamic instability; chronic pain; useful with the difficult to manage patient and short painful procedures such as dressing changes for the burn patient.

B) Routes/Dosages: IV, IM; Induction of general anesthesia achieved with IV dose of 1-2 mg/kg, or IM 4-8 mg/kg

C) Onset: peak plasma concentrations within 1 minute IV and 5 min following IM administration

D) MOA: interacts with multiple binding sites throughout the body including: N-methyl-D-aspartate (NMDA), nicotinic and muscarinic cholinergic, monoaminergic, and opioid receptors. Also interacts with voltage gated Na and Ca receptors.

KETAMINE

E) Metabolism: Biotransformation of Ketamine occurs in the liver and produces several active metabolites. Intial pathway is Cytochrome P-450 into Norketamine which is 1/5 – 1/3 as potent as Ketamine. Initial awakening is due to redistribution to nonactive compartments.

F) Physiologic Effects: increases cerebral blood flow as much as 60%, potentially putting patients with elevated ICP at risk. May play a neuroprotective role due to effect at NMDA receptors implicated as source of cerebral ischemic damage. Direct negative inotropic effects, but overshadowed by stimulation of SNS, resulting in elevation of hemodynamic parameters. Systemic and pulmonary pressures, heart rate, CO, and myocardial oxygen demand all elevated within 3-5 min. Effect on ventilation minimal. Increased salivary production and secretion. Upper airway reflexes remain intact and a potent bronchial dilator. Emergence phenomena have an occurrence rate between 5-30% described as floating, vivid dreams, and hallucinations. May inhibit platelet aggregation.

KETAMINE

G) Elimination: Primarily renal; Less than 4% recovered unchanged in urine, whereas less than 5% found unchanged in fecal excretion.

H) Adverse Effects and Contraindications: Potential for increasing ICP. Increased salivary production may lead to coughing, laryngospasm, and aspiration. Production of “dissociative” state a limiting factor for use. Administration of benzodiazepine been shown to significantly decrease occurrence of emergence delirium.

Opioid Agonists, Antagonists, and Agonist-Antagonists FENTANYL

MORPHINE

HYDROMORPHONE (DILAUDID)

REMIFENTANIL

MEPERIDINE

NALBUPHINE

NALOXONE (NARCAN)

MECHANISMS OF PAIN

Nociception is the process in which painful stimuli are detected, transduced, and transmitted peripherally and in the CNS.

Tissue injury activates inflammatory process which results in influx of mediators into injured tissue. Signals initiated in peripheral nociceptors are carried to dorsal horn of spinal cord. Output neurons from dorsal horn ascend spinal cord via A-delta and C-fibers in the spinothalamic tract to the thalamus and finally somatosensory cortex.

Opioid receptors affect transmission of painful stimuli by opening Na, K, and Ca channels, thus decreasing the firing of action potentials in neurons.

CONSEQUENCES OF PAIN

Acute pain found to stimulate neuroendocrine stress response, increasing adrenergic neural activity, sympatethic tone, and catecholamine concentration.

CV-related effects include hypertension, tachycardia,and increase myocardial O2 demand and irritability, which can precipitate myocardial ischemia and infarction.

From respiratory standpoint, pain increases minute ventilation in response to increase in body O2 consumption

When surgery involves abdominal or thoracic cavities, respiratory effects include hypoventilation, decreased tidal volume, ability to cough, and the development of atelectasis.

Additional adverse responses include anxiety, sleep disturbances, and depression.

OPIOID RECEPTORS

Three different opioid receptors discovered in the 1970’s in different parts of brain.

µ1 (mu) and µ2 most related to analgesia. Other effects include respiratory depression, bradycardia, GI dysmotility, sedation, and euphoria. µ receptors located in cerebral cortex, thalamus, hypothalamus, midbrain, pons, medulla, dorsal horn of spinal cord, and peripheral tissues among others.

Activation of κ (kappa) opioid receptors also associated with analgesia, although not as strongly as µ or delta receptors. Also associated with dysphoria.

Multiple more opioid receptors have been identified.

FENTANYL

A) Clinical Uses: Rapid onset and short duration make it an ideal opioid for acute pain and balanced anesthetic. Blunt sympathetic stimulation during direct laryngoscopy, suppress stress response, sedation, premedication in elderly.

B) Routes/Dosages: IV, SQ, intrathecal, or epidural. Fentanyl is 100 times more potent than Morphine and is more specific for µ receptors than other receptors. 100 mcg – 1 mg for induction of GA

100 mcg of Fentanyl equivalent to 10 mg Morphine

C) Onset: Onset almost immediate with duration of effects 30 minutes to 1 hour.

D) MOA: interacts with opioid receptors(primarily µ) in CNS, opens K-channels to inhibit firing of AP’s in pain pathways.

FENTANYL

E) Metabolism: Most IV Fentanyl metabolized on first pass in the liver by cytochrome P-450 system (CYP3A4). Fentanyl least affected by genetic variability in CYP system, making it good choice for perioperative analgesia.

F) Physiologic Effects: Bradycardia, minimal if any negative inotropic effects, primarily provides hemodynamic stability with induction of GA. Exogenous opioids reduce production of cortisol.

G) Elimination: Primarily renal; 75% cleared in urine, mostly of metabolites. 10% unchanged in urine.

H) Adverse Effects: Opioid-induced sedation, respiratory depression (attributed to µ2 receptors on brainstem), biliary spasm, decrease GI motility, nausea, increase chest rigidity

MORPHINE

A) Clinical Uses: Intermediate acting opioid that can be used intraoperatively or postoperatively. Is the gold standard all other opioids in comparison.

B) Routes/Dosages: IV, PO, intrathecal, or epidural (Preservative-free Duramorph, Astromorph) Fentanyl is 100 times more potent than Morphine and is more specific for µ receptors than other receptors. 100 mcg – 1 mg for induction of GA

100 mcg of Fentanyl equivalent to 10 mg Morphine

C) Onset: 5-10 minutes, duration 2-4 hours.

D) MOA: interacts with opioid receptors(primarily µ) in CNS, opens K-channels to inhibit firing of AP’s in pain pathways.

MORPHINE

E) Metabolism: Primarily phase 2 metabolism via glucuronic acid, leading to development of morphine-3-glucuronide M3G and M6G (active metabolites that make of 70%). M6G provides analgesia and can accumulate with renal disease.

F) Physiologic Effects: Bradycardia, minimal if any negative inotropic effects, primarily provides hemodynamic stability with induction of GA. Exogenous opioids reduce production of cortisol.

G) Elimination: Primarily renal

H) Adverse Effects: Renal buildup of active metabolite M6G. Hydromorphone should be considered as intermediate opioid in patients with decreased renal function.

HYDROMORPHONE – DILAUDID

A) Clinical Uses: Intermediate acting opioid that can be used intraoperatively or postoperatively. Particularly useful for treating moderate to severe pain.

B) Routes/Dosages: IV, PO;

1.5 mg Dilaudid equivalent to 10 mg Morphine.

100 mcg of Fentanyl equivalent to 10 mg Morphine

C) Onset: 5 minutes, duration 4-5 hours.

D) MOA: interacts with opioid receptors(primarily µ) in CNS, opens K-channels to inhibit firing of AP’s in pain pathways.

HYDROMORPHONE – DILAUDID

E) Metabolism: Primarily phase 2 metabolism via glucuronic acid. Lacks active metabolites that accumulate with renal disease.

F) Physiologic Effects: Bradycardia, minimal if any negative inotropic effects, primarily provides hemodynamic stability with induction of GA. Exogenous opioids reduce production of cortisol.

G) Elimination: Primarily renal

H) Adverse Effects: Opioid-induced sedation, respiratory depression (attributed to µ2 receptors on brainstem), biliary spasm, decrease GI motility, nausea, increase chest rigidity

REMIFENTANIL

A) Clinical Uses: As an infusion intraoperatively

B) Routes/Dosages: IV, 0.1 – 0.5 mcg/kg/min as part of balanced anesthetic

C) Onset: almost immediate, duration 5-10 minutes; half-life 10-20 minutes

D) MOA: interacts with opioid receptors(primarily µ) in CNS, opens K-channels to inhibit firing of AP’s in pain pathways.

REMIFENTANIL

E) Metabolism: Breakdown occurs by hydrolysis by esterases present in tissue and blood. Renal and hepatic disease states do not affect metabolism.

F) Physiologic Effects: Boluses can lead to significant respiratory muscle rigidity and apnea.

G) Elimination: Primarily renal

H) Adverse Effects: Significant bradycardia, increased chest rigidity

MEPERIDINE

Use had decreased significantly due to increased awareness of the risk of toxicity related to metabolite normeperidine.

Increased levels of normeperidine associated with seizures.

The American Pain Society recommends not using meperidine in patients with Sickle Cell, CNS disorders, renal disease, or in children.

When combined with MAO inhibitors, multiple adverse effects include severe respiratory depression, hypotension, and coma.

Meperidine administration is more effective treatment for shivering than equianalgesic doses of other opioids. Reduces shivering threshold.

AGONIST-ANTAGONISTS- NALBUPHINE (NUBAIN)

A synthetic opioid agonist-antagonist that has strong κ agonist binding and is a µ receptor antagonist.

Provides analgesia with less risk of respiratory depression. Can also immeliorate adverse effects such as itching, respiratory depression.

Recommended IV dose is 10 mg for 70-kg adult.

Onset is 2-3 minutes with duration of analgesic activity 3-6 hours.

OPIOID ANTAGONIST – NALOXONE (NARCAN)

Naloxone is first-line opioid antagonist used for patients with respiratory depression or significant sedation resulting from opioids

Strong competitive antagonist for µ receptors, but also has antagonist effects at other opioid receptors.

The average serum half-life is 64 minutes, thus redosing may we warranted if longer duration opioids were administered.

Naloxone typically provided as 0.4 mg/ml and should be diluted in 10 mL saline (0.04mg/ml) and administered 0.5 mL at a time to prevent development of severe pain and withdrawal manifestations (seizures, arrhythmias).

NONOPIOID ANALGESICS ASA, ACETAMINOPHEN, IBUPROFEN

KETOROLAC (TORADOL)

KETAMINE

CENTRALLY ACTING ALPHA-2 AGONISTS1) Clonidine 2) Dexmetotomidine

(Precedex)

KETOROLAC (TORADOL)

A) Clinical Uses: Indicated for short-term management of moderate-severe acute pain as sole drug, or in combination with opioids.

B) Routes/Dosages: IV, IM, PO, Intraarticular.

Ketorolac 30 mg IM produces analgesia equivalent to Morphine 10 mg

Patients age 16-64 years and weigh ≥ 50 kg with normal renal function can receive 120 mg per day IV, not to exceed 5 days. No more than 60 mg/day with impaired renal function, elderly, and weight.

C) Onset: Onset dose dependent and ranges from 30 min – 1 hour. Peak effect for IV or IM Ketorolac is 1-2 hours.

D) MOA: inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor

KETOROLAC (TORADOL)

E) Metabolism: Metabolized primarily by phase 2 glucoronic acid conjugation; Clearance less than opioids, but further reduced in the elderly. Elimination half-life about 5 hours.

F) Physiologic Effects: Antipyretic, anti-inflammatory, and analgesic. Inhibits platelet thromboxane production and platelet aggregation. Decreased prostaglandin synthesis produces negative effect on the gastric mucosa (GI ulcers, bleeds). May cause renal toxicity by inhibiting renal prostaglandins directly involved in maintenance of renal hemodynamics. Has little to no effect on biliary tract dynamics.

G) Elimination: Primarily renal

H) Adverse Effects: Bleeding, renal toxicity, bronchospasm in patients with asthma, ASA sensitivity, GI ulcers

Inhalation Anesthetics

NITROUS OXIDE

HALOTHANE

SEVOFLURANE

DESFLURANE

ISOFLURANE

Inhalation Anesthesia

Introduction of inhaled anesthetics dates back to 1500’s and synthesis of ether. Nitrous oxide synthesized in 1774.

Ether inhalation was successfully used for surgical procedures as early as 1842 by Crawford Long.

Until the 1920-30’s, chloroform and ether were principal anesthetizing agents.

1940’s-50’s saw the development of early modern inhaled anesthetics.

Halothane introduced in 1953 and rapidly displaced all other agents as the primary inhaled anesthetic (later found to induce significant hepatic toxicity)

The inhaled anesthetics used in modern anesthesia care include nitrous oxide, isoflurane, desflurane, and sevoflurane.

Inhalation Anesthesia

A single mechanism of action still not discovered explaining the effects of inhaled anesthetics.

Many theories point to multiple anesthetic molecule – receptor interactions that include inhibition of neurotransmitter release, neurotransmitter inactivation, voltage gated ion channels, GABA and NMDA receptors, etc. Ultimate action seems to occur on neuronal membrane proteins in CNS.

The primary clinical measure of inhaled anesthetic’s potency is MAC (minimum alveolar concentration)

MAC represents the percentage of agent required to abolish movement in response to stimuli (skin incision) in 50% of patients.

MAC values: N2O-105%, Isoflurane-1.17%, Sevoflurane 1.8%, Desflurane-6.6%

Effects of Inhalation Anesthesia

Neurologic: decrease cerebral metabolic rate, can produce isoelectric EEG, ↑ ICP, ↓ CPP, potential neuroprotective effects

Cardiovascular: Predictable reduction in arterial BP by decreasing afterload (SVR). Desflurane, Isoflurane may increase HR, possible cardiprotection, ↑ arrhythmia generation, prolong QT

Respiratory: relax airway smooth muscle but ↑ airway resistance by decreasing net lung volume. Pungency complications include resliratory irritation with ↑ secretions, coughing, and laryngospasm.

Renal and Hepatic Systems: only Sevoflurane undergoes significant metabolism, with up to 5% metabolized. Still associated with postop liver dysfunction through metabolites such as Trifluoroacetate.

Malignant Hyperthermia

An inherited, potentially fatal syndrome that susceptible patients develop when they receive inhaled anesthetics (Isoflurane, Sevoflurane, Desflurane), the skeletal muscle relaxant Succinylcholine, and possibly N2O.

MH linked with mutations in the gene for the skeletal muscle, ryanodine (Ryr1) receptor. Offending agents cause cascade of events that include uncontrolled calcium release within skeletal muscle cell, leading to muscle rigidity and life-threatening hypermetabolism.

The Midwest appears to have the highest incidence of MH in the US.

The caffeine-halothane contracture test is “gold standard” diagnostic test for MH

Symptoms due to hypercatabolic state causing very high temperatures, ↑ HR and CO2 production, acidosis, rigid muscles, and rhabdomyolysis.

Malignant Hyperthermia

Treatment includes the following:

1) Discontinue agent and hyperventilate with 100% O2 at high flows.

2) Administer sodium bicarbonate, 1-2 mEq/kg IV

3) Administer muscle relaxant Dantrolene 2.5 mg/kg as soon as possible. If not improving, administer up to 10 mg/kg.

4) Institute cooling measures (lavage, cooling blanket, cold IV solutions)

5) Administer inotropes and antiarrhytmics prn

6) Monitor and treat urine output, hyperkalemia, blood gases, clotting abnormalities, etc.

7) 24-hour hotline available for consultation of suspected MH cases (1-800-MH-HYPER)

Neuromuscular Blocking Drugs

DEPOLARIZING Succinylcholine

NON-DEPOLARIZING Rocuronium Vecuronium Pancuronium Atricurium Cisatricurium

Mechanisms of Action

Skeletal muscle receives innervation from motor nerves that arise from cell bodies in ventral horn of spinal gray matter.

Interaction between nerve and muscle occurs at neuromuscular junction (NMJ), where nerve terminates near area on muscle fiber called motor end plate.

Acetylcholine (ACh) produced by nerve interacts with nicotinic receptors on motor end plate causing depolarization of motor nerve axon and muscle fibers it innervates.

Enzyme acetylcholinesterase hydrolyzes ACh and choline/acetate recycled into presynaptic nerve terminal.

DEPOLARIZING RELAXANTS- Succinylcholine

Unique mechanism of acting as an agonist at the nicotinic receptor on NMJ

Succinylcholine comprised of 2 ACh molecules that mimics endogenous ACh.

A) Clinical Uses: Short term muscle relaxation in anesthesia or critical care, primarily for facilitation of endotracheal intubation, treat laryngospasm, ECT.

B) Routes/Dosages: IV, IM, IO 0.5-2 mg/kg

C) Onset: Almost immediate; duration of action 2-5 min

D) MOA: interacts with nicotinic receptors on NMJ causing muscle depolarization; the NMJ remains depolarized for minutes until metabolized.

DEPOLARIZING RELAXANTS- Succinylcholine

E) Metabolism: Metabolized by breakdown of ester linkage by plasma cholinesterase formed in liver. Unlike ACh and ACh-esterase.

F) Physiologic/Adverse Effects: Bradycardia developing into cardiac arrest, hyperkalemia, muscle pains, ocular HTN, malignant hyperthermia, prolonged paralysis.

Serum K+ rises by approximately 0.5 mEq/L. However, strong hyperkalemic response seen in certain populations such as burn patients, muscular dystrophies, immobility, and sepsis. Histamine release possible cause of anaphylactoid reaction.

Malignant hyperthermia- Succinylcholine more potent trigger than volatile agents.

No reversal for Succinylcholine-induced prolonged paralysis

Non-DEPOLARIZING RELAXANTS- Rocuronium, Vecuronium, Cisatricurium

Non-depolarizing muscle relaxants (NDMR) consist of 2 classes:

1) Aminosteroids- Rocuronium, Vecuronium, Pancuronium

2) Benzylisoquinolones- Atricurium, Cisatricurium

MOA: Antagonists at the nicotinic receptor, blocking the binding of ACh and potential for muscle depolarization.

Clinical Uses: Short to long term muscle relaxation

NON-DEPOLARIZING RELAXANTS

Rocuronium prototype for Aminosteroid class. Intermediate duration with faster onset (1-3 min) makes it a useful alternative to Succinylcholine for rapid sequence intubation (RSI).

0.6 – 1.2 mg/kg intubating dose, maintenance dose 10-20%

Dosing based on ideal body weight (IBW) rather than actual.

25% of neuromuscular recovery occurs in 20-45 minutes. (versus 40 min for Vecuronium and 60-90 min for Pancuronium.

Metabolism by many means. 10-30% of aminosteroid relaxants undergo metabolism by hepatic enzymes with remaining unchanged in bile or urine.

Low incidence of side effects. Minimal crossing of placenta and blood-brain barrier, so no effect of fetus or cerebral function.

NON-DEPOLARIZING RELAXANTS

Atricurium and Cisatricurium prototypes for Benzylisoquinolines.

Because of organ-independent metabolism, these drugs are most desirable in elderly or those with renal insufficiency.

Undergo ester hydrolysis and Hoffman elimination in the plasma, thus providing no risk to patients with underlying liver or renal disease.

Histamine release from Atricurium make it less favorable choice in presence of asthma, carcinoid tumor, and other histamine sensitive condition.

Cisatricurium twice as potent and no histamine release.

Atricurium 0.5 mg/kg intubation dose. Onset 2-3 min. 25% recovery 40 min

Cisatricurium 0.2 mg/kg intubation dose. Onset 2-3 min. 25% recovery 45-60 min

Precautions & Monitoring

Despite pharmacological reversal, the incidence of residual relaxation is high.

Residual relaxation postoperatively contributes to reduced hypoxemic drive, pharyngeal dysfunction (airway protection), and great risk of respiratory compromise.

Advanced age, abdominal/chest surgery, administration of opioids, OSA, obesity all factors that may compound otherwise inconspicuous effect.

Ulnar nerve peripheral nerve monitoring most commonly used

Train-of-four count and ratio(T4 /T1) help determine subjective amount of residual blockade

Can have 4/4 twitches with approximately 50% of receptors stilled blocked.

Reversal of Muscle RelaxationANTICHOLINESTERASES NEOSTIGMINE

EDROPHONIUM

PYRIDOSTIGMINE

ALZHEIMERS DEMENTIA DRUGS Donepezil Rivastigmine Galantamine

Anticholinesterases-ACh-E inhibitors

A) Clinical Uses: Myasthenia gravis, Alzheimers, reversal of muscle paralysis, glaucoma, tx of urinary retention or bowel evacuation, anticholinergic toxicity, and organophosphate poisoning.

B) Routes/Dosages: Neostigmine 0.05 mg/kg or 5mg/100kg

C) Onset: 7-10 minutes

D) MOA: All anticholinesterases exert effects by inhibiting endogenous enzyme acetylcholinesterase (Ach-E), thus allowing ACh to build up within NMJ and compete with NDMRs for nicotinic and muscarinic receptors.Work both pre- and post-synaptically to increase bioavailability of ACh. Physostigmine only one to cross blood-brain barrier for treatment of central anticholinergic crisis.

Anticholinesterases-ACh-E inhibitors

E) Metabolism/Elimination: Neostigmine undergoes hydrolysis by cholinesterase as well as hepatic enzyme metabolism. Renal clearance accounts for 80% of elimination within first 24 hours.

F) Physiologic/Adverse Effects: Actions on the parasympathetic nervous system cause bradycardia, increased salivation, bronchoconstriction, GI tract hypermotility. Conflicting evidence regarding Neostigmine and increased PONV. Reports of complete heart block, asystole and prolonged QT (especially in heart transplant patients).

Always administered concurrently with anticholinergic drug (Glycopyrrolate or Atropine) to offset muscarinic effects.

Cholinergic crisis

A toxic syndrome occurring as a result of overdose of anticholinesterases (as in MG oral tx) or organophosphates (insecticides, lubricating oils, and chemical nerve agents).

Effects manifest from excessive ACh at muscarinic and nicotinic receptors.

SLUDGEM - (Salivation, Lacrimation, Urination, Diaphoresis, GI, Emesis, Miosis)

Edrophonium is anticholinesterase used to differentiate inadequate anticholinesterase therapy vs cholinergic crisis in myasthenic patient. If symptoms improve, r/t inadequate therapy. (1 mg IV every 1-2 min)

Treatment of cholinergic crisis is to use anticholinergics that cross the blood-brain barrier (AFLOP-Atropine, Fluids, Oxygen, Pralidoxime)

Anticholinergics

ATROPINE

GLYCOPYRROLATE (ROBINUL)

SCOPOLAMINE

INHALATION AGENTS Ipratropium Tiotropium

Anticholinergics – Muscarinic Receptor Antagonists

A) Clinical Uses: Tx of bradycardia, concurrent use with anticholinesterase for reversal of muscle paralysis, bronchodilation, prevention of motion-induced nausea, preoperative to dry secretions

B) Routes/Dosages:

IV, IM Atropine 0.4 – 1 mg adults, 10-20 mcg/kg children

IV, IM Glycopyrrolate 0.1-0.4 as premedicant, 0.1 – 1.0 mg with reversal

IV, IM, ophthalmic, TD, PO- Scopolamine 0.3-0.6 mg adults IV or IM; transdermal patch 1.5 mg

C) Onset: Atropine onset approximately 1 minute with DOA 30-60 min

Glycopyrrolate onset 2-3 min with DOA 30-60 min

.

Anticholinergics – Muscarinic Receptor Antagonists

D) MOA/Physiologic Effects: competitively and reversibly bind to muscarinic cholinergic receptors at PNS sites on smooth muscle, cardiac muscle, and gland cells; as well muscarinic receptors in CNS.

Antimuscarinic agents block M2 receptors at the SA and AV nodes, thus producing an increased HR.

They produce bronchodilation (COPD) and decreased airway resistance

Antimuscarinics decrease intestinal motility as well as greatly diminish secretions from lacrimal, gastric, pancreatic, salivary, and bronchial glands.

Varying degrees of excitement,depression sedation in the CNS; Have been associated with increased incidence of postop delirium in elderly.

ATROPINE

Considered the prototypical antimuscarinic agent.

Of all the anticholinergic drugs, Atropine is the most effective for treating bradycardia associated with vagal-mediated reflex responses such as peritoneal stimulation, the baroreceptor reflex, and eyeball pressure.

Because of its rapid onset of action, Atropine is best paired with Edrophonium for skeletal muscle relaxant reversal.

GLYCOPYRROLATE (ROBINUL)

Does not cross blood-brain barrier thus minimal CNS effects.

Is a potent antisialagogue and used for specific procedures where inhibition of salivary and tracheobronchial secretions is desired without sedative effects.

Vagolytic effect on the heart is similar to the effects of equipotent doses of Atropine but with delayed onset.

D/t slower onset and longer duration, Glycopyrrolate best used with Neostigmine for reversal of muscle relaxation.

General rule: 0.2 mg Glycopyrrolate for every 1 mg Neostigmine.

SCOPOLAMINE

Crosses blood-brain barrier and CNS effects include drowsiness and amnesia.

Transdermal preparation of Scopolamine proven effective for protecting against motion-induced nausea and vomiting.

Antiemetic effects are prophylactic. Much less effective after PONV has developed.

Is the most potent antisialagogue used in anesthesia. Scopolamine depresses the RAS and has additive effects with opioids, benzodiazepines, and anesthetics.

Caution warranted in patients with glaucoma d/t increase in IOP of muscarinic receptor blockers, especially Scopolamine

Antiemetics

ONDANSETRON

DEXAMETHASONE

BUTYROPHENONES Droperidol Haloperidol

PhenothiazinesProchlorperazine (Compazine)Promethazine (Phenergan)

POSTOPERATIVE NAUSEA AND VOMITING (PONV)

The general incidence of vomiting is believed to be 30%, nausea 50%, and in a subset of high-risk patients as high as 80%.

Positive risk factors for PONV include:

female sex, history of motion sickness, nonsmoking, younger age, postoperative opioids, duration of anesthesia, type of surgery (laparoscopic, chole, gynecological), use of volatile anesthetics and nitrous oxide, general vs regional anesthesia.

Society for Ambulatory Anesthesiology released new guidelines in 2014

GUIDELINE: Reduce baseline risks factors that increase incidence of PONV:

1) Use regional over GA if possible 2) Preferential use of Propofol infusion 3) Avoidance of N2O 4) Avoid volatile anesthetics 5) Minimize perioperative opioids 6) Adequate hydration

POSTOPERATIVE NAUSEA AND VOMITING (PONV)

GUIDELINE: Administer PONV prophylaxis using 1-2 interventions in adults at moderate risk for PONV.

Recommended pharmacologic anitemetics for PONV prophylaxis include:

5-hydroxytryptamine (5-HT3 ) receptor antagonists (Ondansetron, Dolasetron)

Neurokinin-1 (NK-1) receptor antagonists (Aprepitant)

Corticosteroids (Dexamethasone, Methylprednisolone)

Butyrophenones (Droperidol, and Haloperidol)

Antihistamines (Meclizine)

Anticholinergics (Scopolamine)

5-HT3 Serotonin Receptor Antagonists (Ondansetron)

The emetic center consists of various scattered neurons throughout the body that control the components of the vomiting act.

Sensory input from many areas of the body such as pharynx, GI tract, direct stimulation of cerebral cortex, signals from sensory organ (sights, smells), input from chemoreceptor trigger zone (CTZ) in the fourth ventricle, or inner ear signal can all stimulate the emetic center to initiate vomiting.

Serotonin receptors located throughout GI tract and CTZ, thus blocking these receptors greatly reduces the effects anesthetic drugs can have in inducing PONV.

Although other drugs are more effective at treating nausea, 5-HT3 receptor antagonists are of the most effective in treating vomiting.

5-HT3 Serotonin Receptor Antagonists (Ondansetron)

Currently there are 6 different 5-HT3 receptor antagonists identified as having efficacy in managing PONV.

Ondansetron was the prototype and is the “gold standard” by which other antiemetics are compared.

Designated as a first-line treatment regimen for PONV.

The usual adult dosage is 4-8 mg over 2 to 5 minutes. Onset of action is 30 min with an elimination half-life of 4 hours.

Ondansetron is as effective as Dexamethasone and Haloperidol IV, with no difference in effect on the QT interval (lengthening of QT has been reported).

Best administered within 30 min of end of surgery

2 most commonly reported side effects are slight headache and dizziness.

Corticosteroids – Dexamethasone (Decadron)

Has been shown to effectively prevent PONV

A prophylactic dose of 4 to 5 mg IV for patients at increased risk for PONV is recommended after induction of anesthesia rather than at end of surgery.

For PONV prophylaxis, the efficacy of Dexamethasone 4 mg IV is similar to Ondansetron 4 mg IV and Droperidol 1.25 mg IV.

More recent studies using the higher dose of 8 mg IV. Preoperative Dexamethasone 8 mg may enhance the quality of recovery from anesthesia by reducing nausea, pain, and fatigue.

Data on safety is inconclusive. In most studies, a single dose of perioperative Dexamethasone does not appear to increase the risk of wound infection.

Studies do show significant increases in blood glucose 6-12 hours postoperatively. Labile diabetic patients should be relative contraindication.

Butyrophenones- Droperidol, Haloperidol

Older, standard, neuroleptic-type antipsychotics that possess significant sedative and antiemetic properties.

Protect against PONV-inducing effects of a variety of endogenous and exogenous agonists that stimulate CTZ in the medulla.

Droperidol has been a useful first-line antiemetic since the 1970’s.

In 2001, FDA changed “black box” labeling requirement d/t reports of QT interval prolongation and torsades de pointes.

Before administration of Droperidol, it is now recommended that a 12-lead ECG is performed. If QT > 440 ms, than Droperidol should not be given.

ECG should be monitored for 2-3 hours following administration.

Because of potential for proarrythmic effects and death, Droperidol should be reserved for patients who fail to respond to first-line agents.

Adult dose for PONV is 0.625 mg IV.

The use of Haloperidol as an IV antiemetic is not an FDA-approved indication.

PhenothiazinesProchlorperazine (Compazine), Promethazine (Phenergan)

Similar to butyrophenones, the phenothiazines believed to exert their antiemetic effects primarily by antagonism of central dopaminergic receptors in the CTZ. They also antagonize histamine 1 and cholinergic receptors.

All phenothiazines are capable of producing extrapyramidal symptoms and sedation.

Second or third-line antiemetics

Compazine has a more rapid onset and less sedating effect than Phenergan.

Compazine can produce CNS depression, hypotension, and EPS. Usual dose is 5-10 mg IV.

Phenergan long been used to treat PONV, breakthrough N&V in CINV, allergic blood reactions and anaphylaxis. Usual dose is 10-25 mg IV.

Treatment of PONV

When N&V occur postoperatively, tx sould be administered with a different class antiemetic than was given prophylactically. Multimodal combination therapy recommended for all patients with moderate risk for PONV.

If none given, the recommended tx is a low-dose 5-HT3 receptor antagonist

Alternative tx for established PONV include Dexamethasone 2-4 mg IV, Droperidol 0.625 mg IV, or Phenergan 6.25-12-5 mg IV.

Propofol 20 mg bolus as needed can be considered for rescue therapy for patients still in PACU. Antiemetic effect of single dose Propofol brief.

Repeating the medication given for PONV prophylaxis within the first 6 hours confers no additional benefit.

Although isopropyl alcohol inhalation has not been shown to be effective for the prophylaxis of PONV, it was effective in achieving a quicker reduction in nausea severity compared with Phenergan or Ondansetron.

Drugs for BP Control ADRENERGIC AGONISTS

Phenylephrine (Neosynephrine) Ephedrine

ADRENERGIC ANTAGONISTS AND MIXED ANTAGONISTS Beta-blockers Labetelol Ca2+ - channel blockers (Nicardipine)

OTHER Hydralazine

ADRENERGIC AGONISTS

The term adrenergic refers to the effects of epinephrine (adrenaline) on SNS, as opposed to the cholinergic effects of acetylcholine on PNS.

Adrenergic receptors divided in 2 general categories: 1)alpha α 2)beta β

α1-receptors are adrenoreceptors located throughout smooth muscle, blood vessels, gut, uterus, lung, and GI system. Activation increases intracellular Ca2+ which leads to muscle contraction. Associated with bronchoconstriction, vasoconstriction, uterine contraction, and contraction of sphincters in GI and GU tracts. Most important CV effect is vasoconstriction.

α2-receptors are located in brain, platelets, pancreatic cells, and blood vessels. Responsible for some smooth muscle vasoconstriction. Stimulation of α2-receptors in CNS causes sedation and reduced sympathetic outflow (Precedex).

ADRENERGIC AGONISTS

β1-receptors are located on heart and kidneys. Agonists at these receptors cause ↑ HR, contractility, excitability, and conduction. ↑ RAAS and BP.

β2-receptors are located on bronchi, blood vessels, uterus, eyes, urinary tract. Agonists relax vascular, bronchial, GI, and GU smooth muscles.

ADRENERGIC AGONISTS-Phenylephrine

Phenylephrine- a noncatecholamine with predominantly direct α1-agonist activity.

Used to treat hypotension, as a nasal decongestant, mydriatic agent, and relieve drug-induced priapism.

Primary effects is peripheral vasoconstriction with rise in SVR and arterial BP. Reflex bradycardia can reduce CO.

Phenylephrine use in obstretric anesthesia controversial. Studies have shown that it can be used to manage hypotension during OB anesthesia d/t less fetal acidosis compared with Ephedrine. Does potentially cause ↓ uterine blood flow.

IV boluses of Phenylephrine (50-100 mcg) rapidly reverse reductions in BP caused by peripheral vasodilation. Onset almost immediate.

A continuous infusion of 5-100 mcg/min or 0.25-1 mcg/kg/min to maintain arterial BP at expense of renal blood flow.

ADRENERGIC AGONISTS- Ephedrine

Ephedrine – a mixed (direct and indirect) acting sympathomimetic that acts as direct agonist at α and β receptors, as well releasing catecholamines from vesicles (indirect).

Causes ↑ BP, HR, contractility, and CO. It crosses blood-brain barrier and can act as CNS stimulant. Dilates bronchioles.

Used in tx of asthma d/t bronchodilator effects, manage hypotension, nasal decongestant,

Considered as preferable for OB ansesthesia by some because it does not decrease uterine blood flow.

In adults, IV bolus of 2.5-10 mg to maintain BP. Onset 2-3 minutes