Drugs

Question 1

Propofol , Dose

Answer 1

Dose: 1 to 2.5 mg/kg, Older age: 1 to 1.5 mg/kg, Hypovolemia or hemodynamic compromise: ≤1 mg/kg
.

Question 2

Propofol, Advantages

Answer 2

Rapid onset and offset

Antiemetic properties

Antipruritic properties

Bronchodilation

Anticonvulsant properties

Decreases CMRO2, CBF, and ICP

Question 3

Propofol / Potential adverse effects

Answer 3

Dose-dependent hypotension

Dose-dependent respiratory depression

Pain during injection

Microbial contamination risk

Rare anaphylaxis in patients with allergy to its soybean oil emulsion with egg phosphatide

Question 4

Etomidate / Dose

Answer 4

0.15 to 0.3 mg/kg

Presence of profound hypotension: 0.1 to 0.15 mg/kg

Question 5

Etomidate/advantages

Answer 5

Rapid onset and offset

Hemodynamic stability with no changes in BP, HR, or CO

Anticonvulsant properties

Decreases CMRO2, CBF, and ICP

Question 6

Etomidate / Potential adverse effects

Answer 6

High incidence of PONV

Pain during injection

Involuntary myoclonic movements

Absence of analgesic effects

Transient acute adrenocortical suppression

Mild increases in airway resistance

Question 7

Ketamine / Dose

Answer 7

1 to 2 mg/kg

Chronic use of tricyclic antidepressants: 1 mg/kg

Presence of profound hypotension: 0.5 to 1 mg/kg

Intramuscular dose: 4 to 6 mg/kg

Question 8

Ketamine / Advantages

Answer 8

Rapid onset
Increases BP, HR, and CO in most patients
Profound analgesic properties
Bronchodilation
Maintains airway reflexes and respiratory drive
Intramuscular route available if IV access lost

Question 9

Ketamin/ Potential adverse effects

Answer 9

• .Cardiovascular effects
  Increases myocardial oxygen demand due to increases in HR, BP, and CO
  Increases pulmonary arterial pressure (PAP)
  Potentiates cardiovascular toxicity of cocaine or tricyclic antidepressants
  Exacerbates hypertension, tachycardia, and arrhythmias in pheochromocytoma
  Direct mild myocardial depressant effects
  Neurologic effects

Psychotomimetic effects (hallucinations, nightmares, vivid dreams)
Increases CBF and ICP; may increase CMRO2
Unique EEG effects may result in misinterpretation of BIS and other processed EEG values
Other effects

Increases salivation

Question 10

Methohexital

Answer 10

Induction for electroconvulsive therapy (ECT) because it activates seizure foci.
1) dose 1.5 mg/kg
2) advantages: Lowers seizure threshold, facilitating ECT
Decreases CMRO2, CBF, and ICP
3) potential adverse effects: Limited availability
Dose-dependent hypotension
Dose-dependent respiratory depression
Involuntary myoclonic movements
Pain during injection
Contraindicated in patients with porphyria

Question 11

Propofol/mechanism of action

Answer 11

Its primary mechanism of action is activation of the gamma-aminobutyric acidA(GABAA) receptor complex, the chief inhibitory neurotransmitter of the central nervous system. Propofol is also an antagonist of the N-methyl-D-aspartate (NMDA) receptor.

Question 12

• Propofol / Pharmacokinetic

Answer 12

Propofolis highly lipid soluble with formulation in an aqueous emulsion containing egg phosphatide, soybean oil, and glycerol. Its onset of action is very rapid due to high lipid-solubility.
The half-life of equilibration between plasma and effect site (the brain) is 1.5 to 2.6 minutes .
. Duration of action is short (two to eight minutes), as propofol is rapidly redistributed from the brain into a very large volume of distribution in other tissues (3 to 12 L/kg)
Most of the drug is conjugated in the liver and the resulting inactive metabolites are eliminated by the kidneys. Clearance ofpropofolis very rapid (20 to 30 mL/kg/minute), in excess of liver blood flow, suggesting extrahepatic metabolism .
Although propofol has a long terminal elimination half-life of 4 to 30 hours, actual plasma concentrations remain low throughout this time period after administration of a typical induction dose

’

Question 13

Etomidate / mechanism of
actions .

Answer 13

It is an imidazole derivative that acts directly on the gamma-aminobutyric acidA (GABAA) receptor complex to block neuroexcitation and produce anesthesia.

Question 14

Naturally opioid

Answer 14

Morphine, codeine, papaverine, thebaine

Question 15

Semisynthetic opioids

Answer 15

Heroin,
dihydromorphone, morphinone,
thebaine derivatives (etorphine, buprenorphine)

Question 16

Synthetic opioids

Answer 16

Morphinan derivatives (levorphanol,butorphanol)
Diphenylpropylamine derivatives (methadone)
Benzomorphan (pentazocine)
Phenylpiperidine derivatives (meperidine, fentanyl, sufentanil, alfentanil, remifentanil)

Question 17

Types of opioids receptors

Answer 17

Мю, дельта, каппа, nociceptine/orphanin

Question 18

Mu - opioids receptors

Answer 18

1).Mu1,2,3 receptors (MOR) bind to endogenous ligands - beta-endorphin, endomorphin 1 and 2 with proopiomelanocortin (POMC) being the precursor.:
The mu-1 receptor is responsible for analgesia and dependence.
IThe mu-2 receptor is vital for euphoria, dependence, respiratory depression, miosis, decreased digestive tract motility/constipation
Mu-3 receptor causes vasodilation.
2)Agonist : Morphine, Fentanyl, DAMGO
3)Antagonist: Naloxone, Naltrexone
4) CNS (brain+spinal cord), gastrointestinal system, peripheral sensory nerves

Question 19

Kappa opioid receptors

Answer 19

1) .Kappa receptors (KOR) bind to dynorphin A and B (Prodynorphin as the precursor).Endogenous ligand: Dynorphin. They provide analgesia, diuresis, and dysphoria.
2)Agonist: Buprenorphine, Pentazocine, U50488H
3)Antagonist: Naloxone, NorBNI (norbinaltorphimine)
4)CNS+PNS

Question 20

Delta- opioids receptors

Answer 20

1) Delta receptors (DOR) bind to enkephalins (precursor being Proenkephalin).Endagenu ligand: Leu-enkephalin, Met-enkephalin.They play a role in analgesia and reduction in gastric motility.
2) Agonist: DPDPE [D-penicillamine2, D-penicillamine5]enkephalin, Deltorphin
3) Antagonist: Naloxone, Naltrindole
4) Brain+PNS

Question 21

Nociceptive opioid receptors

Answer 21

Nociceptin receptors (NOR) bind to nociceptin/orphanin FQ (Pre-pronociceptin is the precursor) causing analgesia and hyperalgesia (depending on the concentration)
Endogenous ligand: Nociceptin
There are in CNS

Question 22

Intracellular signal transduction mechanisms linked with the opioid receptors

Answer 22

1) Agonist bind with opioids receptors (7 transmembrane G-proteine coupled receptor)
2) activation g protein
3) suppressed activity of adenylate cyclase, voltage dependent calcium (Ca2+) channels
4) inward rectifier potassium channels (from cell)
5) activated mitogen-activated protein kinase (MAPK) cascade
6) Result: hyperpolarization of neurons, Reduced neurotransmitter release, reduced intracellular cAMP

Question 23

Biased agonism of opioid receptors

Answer 23

1) G i/o- signaling pathway mediate analgesic action of morphine
2) beta-arrestin signaling results in unwanted side effects: euphoria, addiction, respiratory depression and gastrointestinal effects

Question 24

Effects of opioid for consciousness

Answer 24

Injection of morphine to the substantia innominata or intravenous morphine administration significantly decreased acetylcholine release within the prefrontal cortex

Question 25

Hallucinations attributed to opioids

Answer 25

1) Auditory
2) Visual
3) Tactile

Question 26

Hallucination by opioid

Answer 26

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

Question 27

CBF and CMR with opioids

Answer 27

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

Question 28

Opioid- induced muscle regidity

Answer 28

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.

Question 29

Potential Problems Associated With Opioid-Induced Rigidity

Answer 29

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

Question 30

seizure activity, associated with opioids

Answer 30

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.

Question 31

Pupil size and opioides

Answer 31

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

Question 32

Opioid-induced pruritis

Answer 32

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)

Question 33

Opioid-Induced Hyperalgesia

Answer 33

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

Question 34

Respiratory effects of opioid

Answer 34

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).

Question 35

Causes of respiratory depression by opioids

Answer 35

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.

Question 36

Fentanyl-induced respiratory disorders

Answer 36

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

Question 37

Factors Increasing the Magnitude and/or Duration of Opioid-Induced Respiratory Depression

Answer 37

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

Question 38

Cardiovascular Effects of Opioids : Neurologic Mechanisms

Answer 38

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.

Question 39

Cardiovascular Effects of Opioids: Cardiac mechanisms

Answer 39

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.

Question 40

Cardiovasculare effect of opioids : Histamine release

Answer 40

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

Question 41

Cardiovasculare effects of opioids : Vascular mechanism

Answer 41

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.

Question 42

Opioids in Shock

Answer 42

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

Question 43

Endocrinologic Effects of Opioids

Answer 43

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.

Question 44

the mechanisms underlying the ability of opioids to provide perioperative cardiovascular stability

Answer 44

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.

Question 45

What is help to drive opioid dependence and tolerance

Answer 45

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

Question 46

Complications in opioid-addicted patients

Answer 46

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

Question 47

Goals of Acute Pain Management in Opioid-Dependent Patients

Answer 47

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

Question 48

Renal and Urodynamic Effects of Opioids

Answer 48

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

Question 49

Effects of Opioids on the Gastrointestinal Tract

Answer 49

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

Question 50

Effects of Opioids on the Gastrointestinal Tract

Answer 50

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

Question 51

Biliary and Hepatic Effects of opioid

Answer 51

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

Question 52

Nausea and vomiting and opioid

Answer 52

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).

Question 53

the harvesting of human oocytes for subsequent invitro fertilization and opioid

Answer 53

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

Question 54

fetal Surgery and opioid

Answer 54

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

Question 55

Fetal manifestations of maternal opioid administration

Answer 55

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.

Question 56

Opioid associated Anaphylactoid Reactions

Answer 56

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

Question 57

Intraocular pressure and opioid

Answer 57

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

Question 58

effects of opioid on adaptive immunity

Answer 58

↓ Splenic and thymic weight (rodents)
↓ T cell viability and proliferative response
↓ T-helper cell function
↓ CD4/CD8 population invivo
↓ 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

Question 59

Effects of opioid on innate immutiny

Answer 59

↓ 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)

Question 60

Influence of opioids on neuroendocrine system

Answer 60

↑ 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

Question 61

potential mechanism for the immunosuppressive effects of morphine

Answer 61

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

Question 62

effects of opioids on neutrophils

Answer 62

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

Question 63

Cancer Progression and opioids

Answer 63

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

Question 64

Wound Healing and opioids

Answer 64

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

Question 65

Physicochemical Properties of opioids

Answer 65

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

Question 66

Pharmacokinetic of morphine

Answer 66

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

Question 67

Pharmacokinetic of fentanyl

Answer 67

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.

Question 68

Pharmacokinetic of alfentanil

Answer 68

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)

Question 69

Pharmacokinetic of sufentanil

Answer 69

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

Question 70

Pharmacokinetic of ramifentanyl

Answer 70

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

Question 71

Age and pharmacokinetic of opioids

Answer 71

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.

Question 72

Renal failure and morphine

Answer 72

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

Question 73

Meperidine and renal failure

Answer 73

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.

Question 74

Hepatic failure and opioids

Answer 74

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

Question 75

Cardiopulmonary bypass and opioid

Answer 75

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

Question 76

pH and opioids

Answer 76

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.

Question 77

Titration of Meperedine

Answer 77

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.

Question 78

Titration of fentanyl

Answer 78

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

Question 79

Titration of alfentanyl

Answer 79

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

Question 80

Titration of suffertanyl

Answer 80

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

Question 81

Titration of remifentanyl

Answer 81

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

Question 82

Oral transmucosal fentanyl citrate (OTFC)

Answer 82

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.

Question 83

Codeine

Answer 83

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

Question 84

Oxycodone

Answer 84

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.

Question 85

Meperidine

Answer 85

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

Question 86

Levophranone

Answer 86

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

Question 87

Methadone

Answer 87

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

Question 88

Tramadol

Answer 88

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.

Question 89

Naloxone

Answer 89

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

Question 90

Naltrexone

Answer 90

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

Question 91

Nalmefene

Answer 91

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

Question 92

Methylnaltrexone

Answer 92

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

Question 93

Calcium Channel Blockers as Pain Medications

Answer 93

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

Question 94

Sodium Channel Blockers as Pain Medications

Answer 94

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%)

Question 95

Sodium Channel Blockers | Type , mechanism

Answer 95

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