Drugs Flashcards

Question

Hallucinations attributed to opioids

Answer 1

1) Auditory 2) Visual 3) Tactile

Answer 2

1) Hypotheses: opioid-induced dopamine dysregulation 2) Treatment: discontinuing opioid therapy if practical. use of naloxone and κ-selective opioid antagonists

Answer 3

1) Generally producemodest decreasesin CMR and ICP 2) Decrease CBF when they coandministration with nitrous oxide 3) When vasodilation is produced by coadministered anesthetics, opioids are more likely to cause cerebral vasoconstriction. 4) When opioids are administered alone or when the coadministered anesthetics cause cerebral vasoconstriction, opioids usually have no influence or result in a small increase in CBF 5) In summary, opioids, in general, do not significantly effect measures of CBF. 6) opioids do not cause significant increases in ICP undergoing craniotomy for supratentorial space-occupying lesions. Opioid sedation does not alter ICP in patients with head injuries. 7) Opioids may produce increases in ICP in patients undergoing craniotomy for excision of supratentorial space-occupying lesions, especially if intracranial compliance is compromised

Answer 4

1) Mechanisms of opioid-induced muscle rigidity: systemic opioid-induced muscle rigidity is primarily caused by the activation of central μ-receptors, whereas supraspinal δ1 and κ1 receptors may attenuate this effect. 2)incidence increased with age, muscle movements resembling extrapyramidal side effects) 3) Patients with Parkinson disease, particularly if they are inadequately treated, may experience reactions such as dystonia following opioid administration. 4) treatment: -relaxants can decrease the incidence and severity of rigidity - reversed with the μ-receptor antagonist naloxone. - Induction doses of sodium thiopental and subanesthetic doses of diazepam and midazolam can prevent, attenuate, treat rigidity.

Answer 5

1) Heodinamic:↑CVP, ↑ PAP, ↑ PVR 2) Respiratory: ↓ Compliance, ↓ FRC, ↓ ventilation, Hypercarbia, Hypoxemia 3) Mix: ↑ Oxygen consumption, ↑Intracranial pressure,↑ Fentanyl plasma levels

Answer 6

1) Remifentanil induced generalized tonic-clonic seizure-like activity in an otherwise healthy adult. 2") Morphine produces tonic-clonic activity after epidural and intrathecal administration. 3) Focal neuroexcitation on the EEG (e.g., sharp and spike wave activity) occasionally occurs in humans after large doses of fentanyl, sufentanil, and alfentanil 4) Reason : Excitatory opioid actions may be related to coupling to mitogen-activated protein kinase cascades.

Answer 7

Morphine and most μ− and κ−agonists cause constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. Light induces excitation of the Edinger-Westphal nucleus leading to pupillary constriction, which is inhibited by hypercarbia, hypoxia, and nociception. Opioids release the effect of inhibitory neurons on the Edinger-Westphal nucleus, resulting in papillary constriction

Answer 8

1) Odansetron 2) The application of mixed or partial opioid agonists, such as nalbuphine and butorphanol, they may partially antagonize μ receptor function with intact κ actions to maintain analgesia. activation of the κ-opioid receptor inhibits pruritus evoked by subcutaneous and intrathecal morphine in animal models 3) pentazocine (15 mg), an agonist of the κ-opioid receptor and partial agonist of the μ-opioid receptor. 4) intravenous administration of droperidol (1.25 mg), propofol (20 mg), or alizapride (100 mg)

Answer 9

1) OIH was shown to be due to spinal sensitization to glutamate and substance P.216 Activation of glycogen synthase kinase-3β (GSK-3β) contributes to remifentanil-induced hyperalgesia by regulating NMDA receptor plasticity in the spinal dorsal horn; 2) Low-dose buprenorphine (25 μg/h for 24 h), an opioid with NMDA antagonist activity, in patients receiving remifentanil infusion during major lung surgery prevented postoperative secondary hyperalgesia. 3) Butorphanol (0.2 μg/kg) was also effective for prevention of postoperative hyperalgesia after laparoscopic cholecystectomy performed with remifentanil (0.3 μg/kg/min) 4) N2O, an inhalation anesthetic, is an effective NMDA antagonist. Intraoperative 70% N2O administration significantly reduced postoperative opioid-induced hyperalgesia in patients receiving propofol (approximately 120 μg/kg/min) and remifentanil (0.3 μg/kg/min) 5) intraoperative magnesium sulfate (30 mg/kg at induction followed by 10 mg/kg/h) can prevent remifentanil-induced hyperalgesia 6) intraoperative use of naloxone (0.05 μg/kg/h) reduced postoperative hyperalgesia after remifentanil infusion of 4 ng/mL 7) hyperalgesia during the perioperative period is linked to peripheral and central pain sensitization I> This suggests that hyperalgesia due to remifentanil in the early postoperative period may explain the higher incidence of chronic pain

Answer 10

1) Opioids blunt or eliminate somatic and autonomic responses to tracheal intubation 2) Opioids can also help avoid increases in bronchomotor tone in asthma. In addition, fentanyl also has antimuscarinic, antihistaminergic, and antiserotoninergic (morphine not. There is also influence of morphine on respiratory mucus transport, which is one of the most important defenses against respiratory tract infections) 3) remifentanil (effect-site concentration of 2 ng/mL) can suppress coughing induced by extubation after propofol or sevoflurane anesthesia. 4)Fentanyl provoked cough when it was injected rapidly ⇒ increase time of injection., injection of 0,5-1.5 mg/kg lidocaine 1 minute before fentanyl administration decreased cause of cough, preemptive use of fentanyl 25 μg, administered 1 minute before bolus injection of fentanyl (125 or 150 μg), can effectively suppress fentanyl-induced cough.246 Propofol, α2 agonists (clonidine, dexmedetomidine), inhalation of β2 agonists (terbutaline, salbutamol), and NMDA-receptor antagonists (ketamine, dextromethorphan) were also effective for suppression of fentanyl-induced cough 5)nonsmoking women undergoing gynecological surgery who develop fentanyl-induced cough during induction of anesthesia have a higher incidence of postoperative nausea and vomiting (PONV).

Answer 11

1) Opioids activating the μ receptor cause dose-dependent depression of respiration, primarily through a direct action on brainstem respiratory centers. 2). The stimulatory effect of CO2 on ventilation is significantly reduced by opioids. Hypercapnic responses can be separated into central and peripheral components. morphine-induced changes in the central component were equal in men and women, whereas changes in the peripheral component were larger in women 3) the apneic threshold and pressure of end-tidal carbon dioxide (PETCO2) are increased by opioids 4) Opioids decrease hypoxic ventilatory drive.

Answer 12

1,) Plasma fentanyl concentrations of 1.5 to 3.0 ng/mL are associated with significant decreases in CO2 responsiveness. 2) With higher doses of fentanyl (50-100 μg/kg), respiratory depression can persist for many hours. When moderately large doses (20-50 μg/kg or greater) of fentanyl are used, the potential need for postoperative mechanical ventilation should be anticipated. 3)The effects of remifentanil are attenuated rapidly and completely within 5 to 15 minutes following termination of its administration. In healthy humans, the EC50 for depression of minute ventilation with remifentanil and alfentanil was 1.17 ng/mL and 49.4 ng/mL. 4) Naloxone has been accepted as a standard therapy for opioid-induced respiratory depression. 5) However, reports have noted naloxone-resistant respiratory depression after intrathecal morphine administration

Answer 13

1) High dose 2)Sleep 3)Old age 4)Central nervous system depressant 5)Inhaled anesthetics, alcohol, barbiturates, benzodiazepines 6)Renal insufficiency 7)Hyperventilation, hypocapnia 8)Respiratory acidosis 9)Decreased clearance 10)Reduction of hepatic blood flow 11)Secondary peaks in plasma opioid levels 12)Reuptake of opioids from muscle, lung, fat, and intestine 13)Pain

Answer 14

1) The nucleus solitarius and parabrachial nucleus play an important role in the hemodynamic control of vasopressin secretion. Enkephalin-containing neurons and opioid receptors are distributed in these regions. 2) Opioids can modulate the stress response through receptor-mediated actions on the hypothalamic-pituitary-adrenal axis. 3) Most opioids reduce sympathetic and enhance vagal and parasympathetic tone. 4) Patients who are volume depleted, or individuals depending on high sympathetic tone or exogenous catecholamines to maintain cardiovascular function, are predisposed to hypotension after opioid administration. 5) The predominant and usual effect of opioids on heart rate is bradycardia resulting from stimulation of the central vagal nucleus. Blockade of sympathetic actions may also play a role in opioid-induced bradycardia. 6) Meperidine, in contrast to other opioids, rarely results in bradycardia, but it can cause tachycardia. Tachycardia after meperidine may be related to its structural similarity to atropine.

Answer 15

1) Contractility⇒ morphine decreased the isometric force of contraction in atrial muscles from nonfailing and failing human hearts through a naloxone-insensitive mechanism. Fentanyl produces little or no change in myocardial contractility. Alfentanil, at concentrations achieved in clinical practice, increases contraction in ventricular cells by a mechanism involving an increase in the sensitivity of the contractile apparatus to Ca2+. The negative inotropic effect of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) on ventricular myocytes caused by disruption of sarcoplasmic reticulum Ca2+ handling and Ca2+ transient was reported to be ameliorated by alfentanil, but this response may not be mediated by opioid receptors. 2) Cardiac Rhythm Conduction⇒Opioid-induced bradycardia is primarily mediated by the CNS. However, there is direct effects of opioids on cardiac pacemaker cells. The overall effect of opioid anesthesia is antiarrhythmic.Some of the electrophysiologic actions of opioids resemble those of class III antiarrhythmogenic drugs 3) Myocardial ischemia: fentanyl had antiarrhythmic and antiischemic action with central and peripheral opioid receptor involvement. Opioids can mimic ischemic preconditioning. Opioid receptor stimulation results in a reduction in infarct size similar to that produced by ischemic preconditioning. Although the preconditioning effect of opioids is mediated mainly by the cardiac κ- and δ-opioid receptors, part of the protective effect of remifentanil may be produced by μ-agonist activity outside the heart. The myocardial κ-opioid receptors were demonstrated to mediate cardioprotection by remote preconditioning. Brief cycles of ischemia and reperfusion during the early phase of reperfusion protect the heart from infarction. This phenomenon, termed postconditioning, was shown to be induced by activation of the δ-opioid receptor in the heart. 4)Circulatory Reflexes In an experiment examining baroreceptor reflex responses induced by perfusion of the carotid sinus at predetermined levels, baroreceptor reflexes were well preserved by moderate doses of fentanyl while high doses of fentanyl depressed baroreceptor reflexes. The oculocardiac reflex, which is caused by traction of extraocular muscles during strabismus surgery, was significantly augmented by fentanyl, sufentanil, and remifentanil.

Answer 16

1) morphine causes histamine release and sympathoadrenal activation. Increases in plasma histamine after morphine cause dilation of terminal arterioles and direct positive cardiac chronotropic and inotropic actions. Codeine and meperidine are examples of other opioids that can induce mast cell activation with the release of histamine, probably by a mechanism other than the μ-opioid receptors. 2) The opioids fentanyl, alfentanil, sufentanil, and remifentanil do not produce increases in plasma histamine, subsequently hypotension is less frequent with their administration

Answer 17

The pharmacologically defined opioid receptor subtype μ3 is expressed in human endothelial cells and coupled to vasodilation via nitric oxide (NO) production. Although μ3 is opiate alkaloid sensitive it is insensitive to opioid peptides including peptides previously shown to have affinities for the μ-opioid receptors. Morphine-induced vasodilation may be partially caused by activation of the μ3 receptor.

Answer 18

It has been shown that endogenous opioids contribute to the pathophysiology of hypovolemic shock through central and peripheral sympathetic inhibition and contributes to hypotension during severe hemorrhage

Answer 19

1)opioids generally increase growth hormone, thyroid stimulating hormone, and prolactin 2)decrease luteinizing hormone, testosterone, estradiol, and oxytocin. 3)The effects of opioids on arginine vasopressin and ACTH are conflicting. 4)The primary endocrine disorder that results from opioid misuse is hypogonadism, particularly in males.

Answer 20

1) reduced sympathetic tone and enhanced parasympathetic activity often producing bradycardia 2) minimal changes in cardiac contractility; function generally as an antiarrhythmic; 3) potentially function as cardioprotective agents to reduce the effect of ischemia by mimicking an endogenous opioid-peptide/preconditioning pathway; 4) have no significant effect on the coronary circulation; 5)produce modest vascular smooth muscle relaxation with the exception of a morphine-induced histaminergic mechanism; 6)reduce the surgical stress response through the nervous system and adrenal-pituitary axis—depending on the opioid class.

Answer 21

1) In the locus ceruleus long-term opioid exposure results in inhibition of adenylyl cyclase, reduced activity of protein kinase A, and upregulation of the cyclic AMP pathway 2)Possible mechanisms involve protein kinase signal transduction cascades that link extracellular signals to cellular changes by regulating target gene expression. Central glucocorticoid receptors (GRs) have been implicated in the cellular mechanism of neuronal plasticity that has many cellular steps in common with the mechanism of opioid tolerance. It was shown that the development of tolerance to the antinociceptive effect of morphine was substantially attenuated when the GR antagonist was coadministered with morphine but the GR agonist dexamethasone facilitated the development of morphine tolerance / 3)Cholecystokinin and NMDA-NO system were also shown to be involved in development of acute tolerance to opioids, which is also affected by spinal serotonin activity. 4)It has been suggested that activation of glial cells, including astrocytes and microglia, at the level of the spinal cord plays an important role in the development of opioid tolerance

Answer 22

1) cardiopulmonary problems, renal problems, and anemia. 2) Long-term morphine administration causes adrenal hypertrophy and impairs corticosteroid secretion. Viral and nonviral hepatitis, acquired immunodeficiency syndrome, osteomyelitis, muscle weakness, and neurologic complications may be found in patients suffering from OUD or poly substance use disorder

Answer 23

1. Identification of the population of at-risk patients receiving long-term opioid therapy for various chronic pain situations (musculoskeletal disease, neuropathic conditions, sickle cell disease, HIV-related disease, palliative care), persons recovering in opioid maintenance programs 2. Prevention of withdrawal symptoms and complications 3. Symptomatic treatment of psychological affective disorders such as anxiety 4. Effective analgesic treatment in the acute phase 5. Rehabilitation to an acceptable and suitable maintenance opioid therapy

Answer 24

1)μ-receptor activation causes antidiuresis and decreases electrolyte excretion. κ-receptor stimulation predominantly produces diuresis with little change in electrolyte excretion. Indirect actions may involve inhibiting or altering the secretion of ADH and atrial natriuretic peptide. 2)Intrathecal administration of morphine and sufentanil caused dose-dependent suppression of detrusor contractility and decreased sensation of urge.348 Mean times to recovery of normal lower urinary tract function were 5 and 8 hours after 10 or 30 μg sufentanil and 14 and 20 hours after 0.1 or 0.3 mg morphine, 3)detrusor contraction decreased only after administration of fentanyl and buprenorphine. Urinary retention induced by intravenous infusion of remifentanil, 0.15 μg/kg/min could be reversed by a single intravenous dose of methylnaltrexone 0.3 mg/kg or naloxone 0.01 mg/kg. 4)peripheral mechanisms may play a role in opioid-induced bladder dysfunction 5)anesthesia management using remifentanil may have a renal protective effect in adult patients with chronic kidney disease

Answer 25

1) Decreased gastric motility and emptying ⇒Decreased appetite; increased gastroesophageal reflux 2) Decreased pyloric tone ⇒Nausea and vomiting 3) Decreased enzymatic secretion ⇒Delayed digestion; hard, dry stools 4) Inhibition of small and large bowel propulsion ⇒Delayed absorption of medication; straining; incomplete evacuation; bloating; abdominal distension; constipation 5) Increased fluid and electrolyte absorption ⇒Hard, dry stools 6) Increased nonpropulsive segmental contractions ⇒Spasms; abdominal cramps; pain 7) Increased anal sphincter tone ⇒ .Incomplete evacuation

Answer 26

1) Decreased gastric motility and emptying ⇒Decreased appetite; increased gastroesophageal reflux 2) Decreased pyloric tone ⇒Nausea and vomiting 3) Decreased enzymatic secretion ⇒Delayed digestion; hard, dry stools 4) Inhibition of small and large bowel propulsion ⇒Delayed absorption of medication; straining; incomplete evacuation; bloating; abdominal distension; constipation 5) Increased fluid and electrolyte absorption ⇒Hard, dry stools 6) Increased nonpropulsive segmental contractions ⇒Spasms; abdominal cramps; pain 7) Increased anal sphincter tone ⇒ .Incomplete evacuation

Answer 27

1) Opioid agonists increase biliary duct pressure and sphincter of Oddi (choledochoduodenal sphincter) tone in a dose- and drug-dependent manner through opioid receptor-mediated mechanisms 2) Increases in biliary pressure caused by opioids are, with the exception of meperidine, reversible with naloxone. the regular dose of morphine could increase common bile duct pressure, whereas pethidine had no effect on Oddi’s sphincter motility and tramadol shows inhibited motility of the sphincter of Oddi 3) Opioids produce minimal effects on liver function during anesthesia and surgery but can affect ischemia-reperfusion injury

Answer 28

1) Opioids stimulate the chemoreceptor trigger zone in the area postrema of the medulla possibly through δ-receptors, leading to nausea and vomiting. 2) Alfentanil, compared with approximately equipotent doses of fentanyl and sufentanil, was found in one study to be associated with a lower incidence of PONV 3) Ondansetron, a serotonin type 3 (5-HT3) receptor antagonist, was proved to be effective for postoperative opioid-induced nausea and vomiting 4) Nausea and vomiting after epidural morphine (3 mg) for postcesarean section analgesia could be prevented by dexamethasone (8 mg IV) as efficiently as droperidol (1.25 mg IV).

Answer 29

1) Alfentanil and pethidine have been safely used as analgesics during the harvesting of human oocytes for subsequent in vitro fertilization. 2) Teratogenic actions of opioids, including fentanyl, sufentanil, and alfentanil, at least in animal models, appear to be minimal

Answer 30

Because the fetus is capable of pain perception after the 26th week of gestation, adequate postoperative fetal pain management is essential after fetal surgery

Answer 31

decreases in heart rate variability. Adverse neonatal effects can occur after either morphine or meperidine administration to mothers. Fetal acidosis increases opioid transfer from the mother.

Answer 32

True allergic reactions and systemic anaphylactoid reactions to opioids are rare. More commonly, local reactions caused by preservatives or histamine may occur

Answer 33

The use of fentanyl, sufentanil, and alfentanil during induction of anesthesia can help to prevent increases in intraocular pressure

Answer 34

↓ Splenic and thymic weight (rodents) ↓ T cell viability and proliferative response ↓ T-helper cell function ↓ CD4/CD8 population in vivo ↓ IL1β, IL-2, TNF-α, and IFN-γ (mouse splenocytes) ↓ Th1/Th2 ratio of T-helper cell population (PBMCs) ↓ NK cell activity ↓ Primary antibody response (B cells) ↓ B cells mitogenic response to bacterial LPS ↓ Macrophage activity ↓ TGF-β1 and IL-10 (antiinflammatory cytokines) ↑ T cell apoptosis (NF-κβ and AP-1/NFAT pathways) Inhibition of CD3/28 mAb induced IL-2 transcripts

Answer 35

↓ Number of macrophages available to fight infections ↓ Leucocyte migration ↓ Peritoneal macrophages phagocytosis ↓ Respiratory burst activity and chemotaxis Inhibition of Fc γ receptor mediated phagocytosis ↓ Superoxide production from neutrophils and macrophages Alteration of IL-8 induced neutrophil chemotaxis ↓ Neutrophil cytokines involved in wound healing ↑ Apoptosis of macrophages impairing host defense barrier ↓ Leucocytes endothelial adhesion (intracellular adhesion molecules expression)

Answer 36

↑ Growth hormone, prolactin, and thyroid stimulating hormone secretion in humans May affect the function of the HPA axis (ACTH and CRH) with risk of adrenal insufficiency ↓ Sex hormones [LH and testosterone (hypogonadism)], oxytocin, and estradiol

Answer 37

NF-κβ activation induced by an inflammatory stimulus was inhibited by morphine-induced activation of μ3-opioid receptors in a NO-dependent manner

Answer 38

1) remifentanil, but not sufentanil, alfentanil, or fentanyl, could attenuate activation of human neutrophils exposed to lipopolysaccharides, and decreased activation of intracellular signaling pathways, including p38 and ERK1/2, and expression of proinflammatory cytokines, including TNF-α, IL-6, and IL-8, through a mechanism involving the κ-opioid receptor 2) A prospective study for adult patients who underwent elective colorectal surgery demonstrated that the number of patients who developed surgical site infection was higher after remifentanil-based anesthesia (11.6%) compared with fentanyl-based anesthesia (3.4%).401 A possible reason for this finding may be opioid-induced immunosuppression or opioid withdrawal-induced immunosuppression

Answer 39

1) The opioid growth factor receptor (OGFR) is localized in both the nucleus and the cytoplasm and functions as a receptor for OGF, also known as methionine-enkephalin. OGFR is distinguished from classic opioid receptors (μ, δ, and κ) as not having any role in analgesia but functions as a negative regulator of cell proliferation 2) Epidemiological studies have suggested that patients who receive general anesthesia with opioids have a greater rate of cancer recurrence than patients who receive local or regional anesthetics,402 although there is no direct evidence to support altering anesthetic technique in cancer patients 3) Overexpression of the μ-opioid receptor in human non-small cell lung cancer was suggested to promote tumor growth and progression.404 Furthermore, it was reported that women with A118G genotype of the μ-opioid receptor have decreased breast cancer-specific mortality, suggesting that opioid pathways may be involved in tumor growth

Answer 40

1) Activation of peripheral opioid receptors on primary afferent neurons reduces the excitability of these neurons and suppresses the antidromic release of substance P and calcitonin gene-related peptide, which play an essential role in wound repair. It was shown that topical morphine application significantly reduced the number of myofibroblasts and macrophages in the closing wound. 2) δ-opioid receptors destabilizes intercellular adhesion and promotes the migratory keratinocyte phenotype, which is required for fast wound closure

Answer 41

1) Opioids are weak bases / 2) All opioids are to some extent bound to plasma proteins, including albumin and α1-acid glycoprotein.

Answer 42

1) Morphine is principally metabolized by conjugation in the liver, but the kidney plays a key role in the extrahepatic metabolism of morphine. 2) M3G is the major metabolite of morphine, but does not bind to opioid receptors and possesses little or no analgesic activity. M3G may actually antagonize morphine, and this effect may contribute to both variability in response and resistance to morphine analgesic therapy. M3G was reported to produce seizures in animals and cause allodynia in children. 3) M6G accounts for nearly 10% of morphine metabolite and is a more potent μ-receptor agonist than morphine with a similar duration of action. It was reported that M6G contributes substantially to morphine’s analgesic effects even in patients with normal renal function . In patients with renal insufficiency, 97.6% of the analgesic effect is caused by M6G when morphine is given orally. Especially in patients with renal dysfunction, the accumulation of M6G can lead to an increased incidence of adverse effects, including respiratory depression It appears that M6G is in fact the primary active compound when morphine is administered orally In contrast to the reports suggesting the high potency of M6G, there have been reports showing that short-term intravenous administration of M6G does not provide effective analgesia

Answer 43

1) Approximately 80% of fentanyl is bound to plasma proteins, and significant amounts (40%) are taken up by red blood cells. Fentanyl is relatively long acting, in large part because of this widespread distribution in body tissues. 2) Fentanyl is primarily metabolized in the liver by N-dealkylation and hydroxylation. Metabolites begin to appear in the plasma as early as 1.5 minutes after injection. Norfentanyl, the primary metabolite, is detectable in the urine for up to 48 hours after intravenous fentanyl in humans.

Answer 44

1) Following IV injection, alfentanil plasma concentrations are described by either two-compartment or three-compartment model. Alfentanil is bound to plasma proteins (mostly glycoproteins) in higher proportions (92%) than fentanyl. At physiologic pH, it is mostly (90%) un-ionized because of its relatively low pKa (6.5). Thus, despite more intense protein binding, the diffusible fraction of alfentanil is higher than fentanyl. This explains, in part, its short latency to peak effect after intravenous injection. 2) The main metabolic pathways of alfentanil are similar to those of sufentanil and include oxidative N-dealkylation and O-demethylation, aromatic hydroxylation, and ether glucuronide formation. The degradation products of alfentanil have little, if any, opioid activity. Human alfentanil metabolism may be predominantly, if not exclusively, by cytochrome P-450 3A3/4 (CYP3A3/4)

Answer 45

1) The pharmacokinetic property of sufentanil is adequately described by a three-compartment model. After intravenous injection, first-pass pulmonary extraction, retention, and release are similar to those of fentanyl. The pKa of sufentanil at physiologic pH is the same as that of morphine (8.0), and, therefore, only a small amount (20%) exists in the un-ionized form. Sufentanil is twice as lipid-soluble as fentanyl and is highly bound (93%) to plasma proteins including α1-acid glycoprotein. 2) The major metabolic pathways of sufentanil include N-dealkylation, oxidative O-demethylation, and aromatic hydroxylation. Major metabolites include N-phenylpropanamide

Answer 46

1) Although chemically related to the fentanyl congeners, remifentanil is structurally unique because of its ester linkages. Remifentanil’s ester structure renders it susceptible to hydrolysis by blood- and tissue-nonspecific esterases, resulting in rapid metabolism and rapid reduction of blood concentration after an infusion has stopped. 2) Pharmacokinetic properties of remifentanil are best described by a three-compartment model. Its clearance is several times greater than normal hepatic blood flow, consistent with widespread extrahepatic metabolism. But, remifentanil is not significantly metabolized or sequestered in the lung. 3) It is a weak base with a pKa of 7.07. It is highly lipid-soluble with an octanol/water partition coefficient of 19.9 at pH 7.4. Remifentanil is highly bound (= 70%) to plasma proteins (mostly α1-acid glycoprotein). 4) Its pharmacokinetics is not appreciably influenced by renal or hepatic failure. In blood, remifentanil is metabolized primarily by enzymes within erythrocytes. Remifentanil is not a good substrate for pseudocholinesterase and, therefore, is not influenced by pseudocholinesterase deficiency

Answer 47

1) neonates exhibit a reduced rate of elimination of essentially all opioids. This is presumably due to immature metabolic mechanisms, including the cytochrome P-450 system. The prolonged elimination of opioids observed in the neonatal period quickly normalizes toward adult values within the first year of life. 2) The infusion rate of remifentanil to block somatic and autonomic response to skin incision was almost 2-fold higher in children (2-11 years) than adults (20-60 years). 3) These combined pharmacokinetic and pharmacodynamic changes mandate a reduction in remifentanil dosage by at least 50% or more in the elderly.

Answer 48

Morphine is principally metabolized by conjugation in the liver, and the water-soluble glucuronides (M3G and M6G) are excreted via kidney. The kidney also plays a role in the conjugation of morphine, accounting for nearly 40% of its metabolism.441 Patients with renal failure can develop very high levels of M6G and life-threatening respiratory depression

Answer 49

the main metabolite of meperidine with analgesic and CNS excitatory effect, is subject to renal excretion, the potential CNS toxicity secondary to normeperidine accumulation is especially a concern in patients in renal failure.

Answer 50

1) Morphine pharmacokinetics is relatively unchanged by developing liver disease - substantial compensatory extrahepatic metabolism of morphine / M6G+M3G decreased, clearance of morphine decreased too ⇒ morphine concentration increase. 2) In patients with cirrhosis, the metabolism of meperidine is decreased⇒ accumulation of the parent drug and possible CNS depressive effects similar to hepatic encephalopathy. Although the elimination of normeperidine is decreased⇒ the ratio of normeperidine to meperidine is generally low, and the opioid effects of meperidine usually predominate. 3) The disposition of fentanyl and sufentanil appears to be unaffected in liver diseases

Answer 51

1) CPB demonstrated that the effect of CPB on fentanyl pharmacokinetics is clinically insignificant, 2) normothermic CPB did not significantly affect the clearance of remifentanil, but hypothermic CPB reduced it by an average of 20%, and this was attributed to the effect of temperature on blood and tissue esterase activity

Answer 52

1)It was demonstrated that pH changes influence the protein binding of fentanyl, sufentanil, and alfentanil, resulting in an increase in protein binding with alkalosis and a decrease with acidosis ^ Thus, both intraoperative respiratory alkalosis and respiratory acidosis, especially in the immediate postoperative period, can prolong and exacerbate opioid-induced respiratory depression 2) Analysis with pigs receiving fentanyl suggested that central clearance and central- and second-compartment distribution volumes were significantly reduced in hemorrhagic shock, resulting in higher fentanyl concentrations for any given dosages and prolonged context-sensitive half-time 3) the remifentanil dose should be reduced substantially compared with propofol during total intravenous anesthesia for patients with significant blood loss.

Answer 53

1) Morphine is slow in onset and does not allow rapid titration to effect. 2) Meperidine (50-100 mg IV) produces variable degrees of pain relief and is not always effective in patients with severe pain.

Answer 54

1) IV boluses of fentanyl (1-3 μg/kg), 2) Infusion rates range from 0.01 to 0.05 μg/kg/min\ loading dose of fentanyl (2-6 μg/kg) with a sedative-hypnotic, most commonly thiopental or propofol, and a muscle relaxant. Maintenance of anesthesia can be achieved with low concentrations of potent inhaled anesthetics, and additional fentanyl (intermittent boluses of 25-50 μg every 15-30 minutes or a constant infusion of 0.5-5.0 μg/kg/h). 3) The plasma concentration of fentanyl required for postoperative analgesia was approximately 1.5 ng/mL

Answer 55

1) IV boluses of alfentanil (10-20 μg/kg). 2) Infusion rates 0.25 to 0.75 μg/kg/min, 3) Alfentanil (25-50 μg/kg IV), followed by small titrated sleep doses of any sedative-hyponic (e.g., 50-100 mg sodium thiopental), is usually successful in preventing significant hemodynamic stimulation from laryngoscopy and intubation. 4) The optimum dose of alfentanil, coadministered with 2.5 mg/kg propofol, when inserting a classic laryngeal mask airway was 10 μg/kg

Answer 56

1) IV boluses of sufentanil (0.1-0.3 μg/kg) can produce potent and short-lasting analgesia. 2) Infusion rates 0.0015 to 0.01 μg/kg/min for. sufentanil

Answer 57

1) Infusion rate of remifentanil 0.05 to 0.25 μg/kg/min 2) Very short duration of action of remifentanil mandates that an infusion (0.1-1.0 μg/kg/min) be started prior to or soon after a small bolus dose to ensure sustained opioid effect

Answer 58

1) The recommended doses range from 5 to 20 μg/kg. 2) OTFC should be administered approximately 30 minutes before surgery (or painful procedure) to obtain peak effect. 3) Plasma concentrations after OTFC administration peak at 2.0 ± 0.5 ng/mL, 15 to 30 minutes after OTFC administration, then decline to less than 1 ng/mL an hour later. 4) The systemic bioavailability of OTFC is 50% and reflects both buccal and gastrointestinal absorption.

Answer 59

1) Codeine (methylmorphine) is 6-7 fold less potent as morphine, has a high oral-parenteral potency ratio (2:3), and a plasma half-life of 2 to 3 hours. Codeine has mild to moderate analgesic but strong cough-suppressant properties after oral administration. 2)Cytochrome P450 2D6 (CYP2D6) is the enzyme responsible for O-demethylation of codeine to morphine, and has genetic variants capable of rapid conversion of codeine to morphine in affected children and adults. 3) IV codeine produces profound hypotension and is neither approved nor recommended

Answer 60

1) Oxycodone is a potent analgesic after systemic administration, but its analgesic potency is poor after intrathecal administration. 2) oxycodone is more potent than morphine for visceral pain relief in intravenous patient-controlled postoperative analgesia , 3) the extent and speed of onset of oxycodone-induced respiratory depression was dose-dependent and greater than an equivalent dose of morphine.

Answer 61

1) Meperidine sometimes causes excitation of the CNS, characterized by tremors, muscle twitches and seizures, that are largely due to accumulation of a metabolite, normeperidine. 2) Meperidine has well-known local anesthetic properties. 3) first-pass uptake of meperidine by the lungs is approximately 65%. 4) Meperidine is more highly bound to plasma proteins than is morphine, principally (70%) to α1-acid glycoprotein 5) depends on hepatic blood flow

Answer 62

1) Analgesia produced by levorphanol is mediated via its interactions with μ-, δ-, and κ-opioid receptors. Levorphanol is also an NMDA receptor antagonist. 2) Levorphanol may have particular utility in patients with chronic pain and who demonstrate morphine tolerance

Answer 63

1) Methadone is a potent μ-opioid receptor agonist, with the longest half-life among the clinically used opioids. By virtue of one of methadone’s isomers, it also exerts an inhibitory effect on NMDA receptors, which are implicated in the development of opioid tolerance, hyperalgesia, and chronic pain. 2) methadone inhibits the reuptake of serotonin and norepinephrine, which may play a role in antinociception and mood elevation

Answer 64

1) The action of tramadol to induce analgesia represents the combination of two mechanisms: reuptake inhibition of the noradrenergic serotonergic system and activation of the μ-opioid receptor and to a lesser extent the δ- and κ-opioid receptors⇒ tramadol may also have a direct serotonin-releasing action. 2) Given the analgesic effect of tramadol is only partially reversed by naloxone, its serotonergic and noradrenergic effects likely represent its predominant analgesic action. 3) Tramadol has dose- and time-dependent bactericidal activity against Escherichia coli and Staphylococcus epidermidis, as well as antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. The antibacterial properties of tramadol might be useful for reduction of bacterial infection after regional anesthesia 4) Coadministration of tramadol with proserotonergic medications can result in a hyperserotonergic state, serotonin syndrome, which can be subacute or chronic, and range from mild to severe: In mild cases, patients are afebrile and may report symptoms of diarrhea, tremor, tachycardia, shivering, diaphoresis, or mydriasis. In severe cases, neuromuscular hyperactivity, autonomic hyperactivity, altered mental state, gastrointestinal symptoms, and even death have been reported. Serotonergic medications that can interact with tramadol include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, triptans (e.g., sumatriptan), antipsychotics, anticonvulsants, antiparkinsonian agents, cough and cold medications containing dextromethorphan, herbal products containing St. John’s wort, and medications that inhibit the metabolism of serotonin, such as monoamine oxidase inhibitors.

Answer 65

1) Morphine requirements were significantly less in patients receiving naloxone: naloxone enhanced analgesia⇒ this apparent paradoxic effect of naloxone include enhanced release of endogenous opioids and opioid receptor upregulation. 2) Initial naloxone dose recommendations ranged from 0.4 to 0.8 mg. 3) Onset of action of IV naloxone is rapid (1-2 minutes), and half-life and duration of effect are short, approximately 30 to 60 minutes. 4) If IV access is not available, naloxone, in doses similar to those given IV, is effectively absorbed after intratracheal administration. 5) Reversal with naloxone is limited by high affinity for and slow dissociation from the μ-opioid receptor of buprenorphine, and depends on the buprenorphine dose and the correct naloxone dose window 6) Several mechanisms produce increases in arterial blood pressure, heart rate, and other significant hemodynamic alterations after naloxone reversal of opioids; These include pain, rapid awakening, and sympathetic activation not necessarily due to pain. 7) Opioid reversal may be particularly hazardous in patients with pheochromocytoma or chromaffin tissue tumors. 8) Renarcotization” occurs more frequently after the use of naloxone to reverse longer-acting opioids such as morphine 9)Naloxone infusion 0.25 μg/kg/h prevented the acute opioid tolerance induced by a large dose of remifentanil at 0.30 μg/kg/min, provided a quicker recovery of bowel function 10) ultra-low dose of naloxone (100 ng) to 34 mL of 1.5% lidocaine solution with or without fentanyl in axillary brachial plexus block prolongs the time to first postoperative pain and motor blockade but also lengthens the onset time

Answer 66

1) Naltrexone is a μ-, δ-, and κ-opioid receptor antagonist. 2) It is longer acting than naloxone (plasma half-life of 8-12 vs. 0.5-1.5 hours), and it is active when taken orally

Answer 67

1) Nalmefene has a greater preference for μ- than δ- or κ-receptors. Nalmefene is equipotent to naloxone. 2) Nalmefene is long-acting after oral (0.5-3.0 mg/kg) and parenteral (0.2-2.0 mg/kg) administration. Bioavailability after oral administration is 40% to 50%, and peak plasma concentrations are reached in 1 to 2 hours. The mean terminal elimination half-life of nalmefene is 8.5 hours, compared with 1 hour for naloxone. 3) Prophylactic administration of nalmefene significantly decreased the need for antiemetics and antipruritic medications in patients receiving intravenous PCA with morphine

Answer 68

1) first quaternary ammonium opioid receptor antagonist that does not cross the blood-brain barrier. 2) Delayed gastric emptying induced by 0.09 mg/kg morphine could be attenuated by 0.3 mg/kg methylnaltrexone

Answer 69

1)Gabapentin: Starting dose 100–300 mg/day; titrating up to 1800–3600 mg/day. it does block voltage-gated calcium channels by binding to the α2-δ subunit⇒ reducing calcium influence ⇒reduces the release of glutamate and substance P from primary nociceptive afferents, thereby modulating nociceptive transmission. 2) Pregabalin: Starting dose: 75–150 mg/day; titrating up to 450–600 mg/day. has a high affinity to the α2-δ subunit of voltage-sensitive calcium channels⇒ decreases calcium influx⇒ thereby reducing the release of excitatory neurotransmitters, including glutamate, substance P, and calcitonin gene–related peptide. 3) Zonisamide: Starting dose: 50–100 mg/day; titrating up to 450 mg/day. It blocks both voltage-sensitive sodium channels and N-type calcium channels⇒ modulation of monoamine neurotransmitter release and free radical scavenging 4) Ziconotide: Starting dose: 0.1 μg/h; titrating up to 0.4 μg/h. It potently and selectively blocks N-type voltage-sensitive calcium channels. This drug is approved only for intrathecal use in patients with severe pain who are refractory to other treatment options, 5) Levetiracetam: Starting dose: 250–500 mg/day; titrating up to 2000 mg:/day. it may have effects on several neurotransmitter systems, including dopaminergic, glutamatergic, and GABAergic systems

Answer 70

1) Lidocaine: Used in a lidocaine test: 1 mg/kg via slow intravenous push or drip 2) Mexiletine: Starting dose: 150–300 mg/day; titrating up to 600 mg/day. Mexiletine is an oral lidocaine congener. In many cases, intravenous lidocaine is used as a test to determine whether the intended lidocaine treatment is effective. When a positive response is achieved, oral mexiletine is administered to maintain the therapeutic effect 3) Carbamazepine: Starting dose: 100 mg/day; titrating up to 600 mg/day.A primary mechanism of action of carbamazepine is sodium channel blockade, which decreases spontaneous firing of Aδ-fibers and C-fibers. side effects including aplastic anemia and agranulocytosis. 4) Oxcarbazepine: Starting dose: 150 mg/day; titrating up to 900 mg/day.The most common side effects of oxcarbazepine are dizziness, drowsiness, hypotension, nausea, and asymptomatic mild hyponatremia. 5) Lamotrigine: Starting dose: 25–50 mg/day; titrating up to 250–500 mg/day. It has multiple mechanisms of action, although it also blocks both sodium and calcium channels.Up to 10% of patients may have rashes after taking this medication, with a 3 in 1000 incidence of Stevens-Johnson syndrome. Other side effects are mild dizziness, somnolence, nausea, and constipation. 6) Topiramate: Starting dose: 50–100 mg/day; titrating up to 300–400 mg/day. It has multiple mechanisms of action: block voltage-sensitive/ sodium channels, may potentiate GABA inhibitory action, block voltage-sensitive calcium channels, and inhibit subtypes of glutamate receptors (non-NMDA receptors).Topiramate can cause significant weight loss (up to 7%)

Answer 71

1) Sodium channels can be divided into two general categories based on their sensitivity to tetrodotoxin (TTX ) ; TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) sodium channels. TTX-S sodium channels are expressed mainly in large and medium dorsal root ganglion neurons, whereas TTX-R sodium channels are expressed mainly in small-diameter dorsal root ganglion neurons, including C-afferent neurons. 2) Expression of both TTX-S and TTX-R sodium channels to be altered when peripheral nerves are injured or severed (axotomy)⇒ producing aberrant high-frequency spontaneous ectopic discharges. 3)Sodium channel blockers at a proper dose range are believed to suppress ectopic discharges without blocking normal nerve conduction