Opioids

OPIOIDS Dr.Khalid Al-Jonaieh Demonstrator Anesthesia Department KKUH بسم الله الرحمن الرحيم

Terminology Opiate : used to refer to drugs derived from opium including morphine. Narcotic : not useful in a pharmacologic or clinical context. Affinity : the ability to bind a receptor to produce a stable complex and intrinsic activity. Efficacy : the range in magnitude of an effect produced by a drug receptor combination relative to the maximum possible effect. Potency : the relative dose required to achieve an effect which related to receptor affinity.

Efficacy and Potency described by the dose-effect curve resulting from drug-receptor combination

ENDOGENOUS OPIOIDS AND OPIOID RECEPTORS All of the endogenous opioids are derived from three prohormones : Proenkephalin Prodynorphin Pro-opiomelanocortin ( POMC ) All being with the pentapeptide sequences of {Leu} or {Met}-enkephalin

Proenkephalin Widely distributed throughout the brain, spinal cord, and peripheral sites, particularly the adrenal medulla.

The dynorphin All begin with the [ Leu ]- enkephalin sequence and are widely distributed throughout the brain, spinal cord, and peripheral sites .

Pro-opiomelanocortin The common precursor of β - endorphin, ACTH, and melanocyte - stimulating hormone. The term endorphin is reserved for peptides of the POMC family. The major site of POMC synthesis is the pituitary, but it is also found in the pancreas and placenta .

Receptors The initial classification by Martin of opioid receptors into the three types Based on binding activity of the exogenous ligands Morphine mu (µ) Ketocyclazocine kappa (κ) SKF10,047 sigma ( σ ) Other Opioid receptors identified : Enkephalins delta ( δ ) Endorphin epsilon (ε)

Selectivity Very few endogenous opioids exhibit great selectivity for a single receptor type. Naloxone, the most commonly used opioid antagonist, is not selective for opioid receptor type. Naltrindole ( a δ - opioid receptor antagonist ) Nor - binaltorphimine ( a κ - opioid receptor antagonist ) .

Cellular Level Receptor binding initiates a series of physiologic functions resulting in cellular hyperpolarization and inhibition of neurotransmitter release, effects that are mediated by second messengers . All opioid receptors appear to be coupled to G proteins, which regulate the activity of adenylate cyclase among other functions. G protein interactions, in turn, affect ion channels. Different ion may be involved at different opioid receptor types.

Pharmacokinetics & Pharmacodynamic Pharmacokinetics determines the relationship between drug dose and its concentration at the effect site(s). Pharmacodynamic variables relate the concentration of a drug at its site of action, in this case opioid receptors in the brain and other tissues, and the intensity of its effects.

Pharmacokinetics The processes of absorption, redistribution, biotransformation, and elimination . Compartmental models describe the time course of change in plasma concentration. Opioids used in anesthesia are characterized by two - or three - compartment models. Distribution phase : The early rapid decline in plasma concentration after the peak. Elimination phase : The subsequent slower decline.

Pharmacokinetics Two main mechanisms are responsible for drug elimination biotransformation excretion Opioids are biotransformed in the liver by two types of metabolic processes . Phase I reactions include oxidative and reductive reactions, such as those catalyzed by cytochrome P450 system, and hydrolytic reactions . Phase II reactions involve conjugation of a drug or its metabolite to an endogenous substrate, such as D - glucuronic acid . Remifentanil is metabolized via ester hydrolysis , which is unique for an opioid . With the exceptions of the N -dealkylated metabolite of meperidine and the 6- and possibly 3-glucuronides of morphine, opioid metabolites are generally inactive .

Pharmacokinetics Routes of opioid excretion: Kidneys The biliary system Gut

Pharmacodynamic To reach its effector sites in the central nervous system ( CNS ) , an opioid must cross biologic membranes from the blood to receptors on neuronal cell membranes . The ability of opioids to cross this blood–brain barrier depends on such properties as molecular size ionization lipid solubility protein binding Of these characteristics, lipid solubility and ionization assume major importance in determining the rate of penetration to the CNS .

Pharmacodynamic Lipid solubility is measured as an octanol : water or octanol : buffer partition coefficient . Drug ionization is also an important determinant of lipid solubility. Nonionized drugs are 1,000 to 10,000 times more lipid - soluble than the ionized form . The degree of ionization depends on the pKa of the opioid and the pH of the environment . Plasma protein binding also affects opioid redistribution because only the unbound fraction is free to diffuse across cell membranes . The major plasma proteins to which opioids bind are albumin and α 1-acid glycoprotein.

Morphine Analgesia Effect on MAC of Volatile anesthesia CNS effects Respiratory Depression Cough Reflex Muscle Rigidity Nausea and Vomiting GIT Motility and Secretion Biliary Track Genitourinary Effects Histamine Release Cardiovascular Effects Disposition Kinetics Active Metabolites

Analgesia Morphine analgesia results from complex interactions at a number of discrete sites in the brain, spinal cord, and under certain conditions, peripheral tissues. Involves both µ1 and µ2 opioid effects. Act selectively on neurons that transmit and modulate nociception. Leaving other sensory modalities and motor functions intact .

At the spinal cord level Presynaptically : acts on primary afferent nociceptors to decrease the release of substance P. Postsynaptically : hyperpolarizes postsynaptic neurons in the substantia gelatinosa of the dorsal spinal cord to decrease afferent transmission of nociceptive impulses. Spinal morphine analgesia is mediated by µ 2 - opioid receptors .

At the Supraspinal level Opioid analgesia originates in the periaqueductal gray matter the locus ceruleus nuclei within the medulla notably the nucleus raphe magnus Primarily involves µ1-opioid receptors Microinjections of morphine into any of these regions activate the respective descending modulatory systems to produce profound analgesia Coadministration at the level of the brain and spinal cord increases morphine's analgesic potency nearly tenfold , an effect mediated by µ 2 -opioid receptors

At Peripheral Level An action when acute inflammation is present. By activating peripheral opioid receptors Mediated by µ 3 - opioid receptors . In chronic pain conditions such as neuropathic pain or chronic arthritis, spinal and peripheral receptors may be down - regulated, a state that can decrease morphine analgesia.

Pain Relief The minimum effective analgesic concentration ( MEAC ) of morphine For postoperative pain relief is 10 to 15 ng / mL For more severe pain, plasma morphine concentrations of 30 to 50 ng/mL are needed to achieve adequate analgesia

Effect on MAC of Volatile Anesthetics Decreases MAC of volatile anesthetics in a dose - dependent manner. 1 mg / kg administered with 60% nitrous oxide ( N2O) blocks the adrenergic response to skin incision in 50% of patients, a characteristic called MAC-BAR Epidural morphine 4 mg given 90 minutes prior to incision reduces halothane MAC by nearly 30%.

Other Central Nervous System Effects Cognitive and fine motor impairment Euphoria,dysphoria Sleep disturbances including reduction in rapid eye movement and slow-wave sleep. slowing of EEG, increased voltage and decreased frequency . Pruritus appears to be a µ receptor-mediated effect produced at the level of the medullary dorsal horn. Antipruritic effect mediated by κ receptors & not histamine-mediated.

Hormonal Effects Affect the release of several pituitary hormones, both directly and indirectly Inhibition of corticotropin - releasing factor Inhibition of gonadotropin - releasing hormone Which decreases circulating concentrations of : ACTH β - endorphin follicle - stimulating hormone luteinizing hormone ِ Antidiuretic hormone release is inhibited Prolactin and growth hormone concentrations may be increased by opioids.

Respiratory Depression Produce dose - dependent ventilatory depression. Primarily by decreasing the responsivity of the medullary respiratory center to CO 2 . Similar for young and elderly patients. With increasing morphine doses, periodic breathing resembling Cheyne-Stokes breathing, decreased hypoxic ventilatory drive, and apnea can occur.

Cautions Oxygen desaturation Obstructive apnea Paradoxic breathing Slow respiratory rate Have been reported in asleep patients receiving morphine infusions for postoperative analgesia. Obesity

Cough Reflex Depress by a direct effect on the medullary cough center . Receptors mediating this effect appear to be less stereospecific and less sensitive to naloxone than those responsible for analgesia .

Muscle Rigidity Ex. abdominal muscle rigidity and decrease thoracic compliance Large doses of IV morphine (2 mg/kg infused at 10 mg/min) Increased by the addition of 70% N 2 O Mediated by µ receptors at supraspinal sites. These effects are reduced or eliminated by : naloxone muscle relaxants drugs that facilitate GABA agonist activity such as thiopental and diazepam

Nausea and Vomiting The incidence appears to be similar if you use it as premedication or intraoperative. The incidence appears to be similar what ever the route of administration. including oral, IV, intramuscular, subcutaneous, transmucosal, transdermal, intrathecal, and epidural . Laboratory and clinical studies comparing the incidence or severity of nausea and vomiting have found no differences among opioids in equianalgesic doses. including morphine, hydromorphone, meperidine, fentanyl, sufentanil, alfentanil, and remifentanil .

The vomiting center Receives input from the chemotactic trigger zone ( CTZ ): the area postrema of the medulla pharynx gastrointestinal tract mediastinum visual center The CTZ is rich in opioid, dopamine, serotonin, histamine, and ( muscarinic ) acetylcholine receptors. The CTZ receives input from the vestibular portion of the eighth cranial nerve .

Antiemetic At the level of the vomiting center: High doses of morphine Naloxone Propofol Benzodiazepines Studies suggests that antiemetic effects of morphine are more short-lived than emetic effects. Possible explanation for this observation is that the active metabolite morphine-6-glucuronide accumulates and worsens nausea.

Gastrointestinal Motility and Secretion Mediated by µ - , κ - , and δ - opioid receptors. Inhibit gastric secretion Decrease gastrointestinal motility and propulsion Suppress diarrhea Delayed gastric emptying Decreases lower esophageal sphincter tone

Biliary Tract Increase the tone of the common bile duct and sphincter of Oddi . Symptoms vary from epigastric distress to typical biliary colic and may even mimic angina . Possibly via histamine release. Antagonism of morphine's biliary effects by diphenhydramine supports this hypothesis. Reversed by : Naloxone Atropine Nitroglycerine

Genitourinary Effects Urinary retention. Results in dyssynergia between the bladder detrusor muscle and the urethral sphincter because of a failure of sphincter relaxation . Spinal morphine appears to cause naloxone - reversible urinary retention via µ - and / or δ - , but not κ - opioid receptors .

Histamine Release From circulating basophils. From tissue mast cells in skin and lung. Morphine - mediated histamine release is dose - dependent. Not prevented by pretreatment with naloxone. Suggesting that histamine release is not mediated by opioid receptors . The decrease in peripheral vascular resistance seen with high - dose morphine ( 1 mg / kg ) correlates well with elevated plasma histamine concentration . Fentanyl

Cardiovascular Effects arteriolar and venous dilation. decreased peripheral resistance. inhibition of baroreceptor reflexes. Lead to postural hypotension. Mechanism: histamine release. morphine - mediated central sympatholytic activity. direct action on vascular smooth muscle. Caution : morphine's effect on vascular resistance is greater under conditions of high sympathetic tone . Carefull with Severe Trauma & Cardiac Patients.

Does not suppress myocardial contractility. Produce dose - dependent bradycardia. In clinical anesthesia practice, opioids are often used to prevent tachycardia and reduce myocardial oxygen demand . Patients undergoing cardiovascular surgery who received 1 to 2 mg / kg of morphine experienced minimal changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance . Cautiously in spontaneously breathing patients with head injury or other conditions associated with elevated intracranial pressure.

Disposition Kinetics After IV administration morphine undergoes rapid redistribution Mean redistribution half - time between 1.5 and 4.4 min. pKa: 7.9 Nonionized 23% Clearance: 1050 ml/min Terminal elimination half - life between 1.7 and 3.3 hours. 35% protein bound, mostly to albumin . Its steady - state volume of distribution is large, the range of 3 to 4 L / kg in normal adults . The MEAC is 10-15 ng / mL.

Morphine's major metabolic pathway is hepatic phase II conjugation, to form morphine-3-glucuronide ( M3G ) and morphine-6 β - glucuronide ( M6G ). The rate of hepatic clearance of morphine is high, with a hepatic extraction ratio of 0.7 Extrahepatic sites such as kidney, intestine, and lung. Unchanged morphine in the urine accounts for only about 10% of the dose . A single IV dose, 40% of the dose are excreted in the urine as M3G and and 10% as M6G.

Active Metabolites M6G possesses significant µ receptor affinity and potent antinociceptive activity . Because morphine glucuronides are eliminated by the kidney, morphine should be administered cautiously to patients with renal failure .

Dosage and Administration of Morphine Used mainly as a premedicant and for postoperative analgesia. For adults range from 0.01 to 0.20 mg / kg . When used in a balanced anesthetic technique with N2O, morphine can be given in total doses of up to 3 mg/kg. When combined with other inhalation agents, it should not exceed more than 1 to 2 mg / kg. The morphine dose associated with apparent cardioprotective effect is a single dose of 40 mg, given before cardioplegia and cardiopulmonary bypass .

Extra Info. Because of its hydrophilicity, morphine crosses the blood–brain barrier relatively slowly. Its onset can be observed within 5 minutes peak effects may be delayed for 10 to 40 minutes . This delay makes morphine more difficult to titrate as an anesthetic supplement than the more rapidly acting opioids .

Meperidine A phenylpiperidine derivative. Was the first totally synthetic opioid . It was initially studied as an anticholinergic agent. Last comment about this opioid was Bad-Drug. 3 rd international anesthesia conference .

Analgesia and Effect on MAC of Volatile Anesthetics Potency is about one - tenth that of morphine's. Mediated by µ - opioid receptor activation mostly. Also has moderate affinity for κ - and δ - opioid receptors. The MEAC of meperidine is 200 ng / mL A dose - dependent reduction in the MAC of halothane .

Well - recognized weak local anesthetic properties . Alters nerve conduction and produces analgesia . Neuraxial meperidine may also produce sensory and motor blockade as well as sympatholytic effects that are not seen with other opioids .

Side Effects Therapeutic doses can produce: sedation, pupillary constriction, and euphoria. Very high doses produce CNS excitement and seizures. In equianalgesic doses produce : respiratory depression nausea & vomiting dizziness delay in gastric emptying increase common bile duct pressure

Cardiovascular Effects Not associated with hemodynamic instability. 1 mg / kg in patients with cardiac disease decreased heart rate, cardiac index, and rate–pressure product. High dose depress contractility and significantly more hemodynamic instability than morphine or fentanyl, partially related to histamine release .

Shivering Causes : general and epidural anesthesia fever hypothermia transfusion reactions administration of amphotericin B Eliminates visible shivering prevent the increase of O2 consumption.

Equianalgesic doses of fentanyl (25 µg) and morphine (2.5 mg) did not reduce postoperative shivering Not mediated by µ - opioid receptors . Butorphanol effectively reduces postoperative shivering in a dose of 1 mg Mediated by κ - opioid receptors .

Low doses of naloxone, sufficient to block µ receptors, did not reverse the antishivering effect of meperidine. High - dose naloxone, designed to block both µ and κ receptors, did reverse the antishivering effect. α 1-adrenergic agonists (clonidine 1.5 µg/kg), serotonin antagonists, and propofol, can reduce postoperative shivering. Suggests that a nonopioid mechanism may be involved. Physostigmine 0.04 mg / kg can also prevent postoperative shivering. Suggesting a role for the cholinergic system .

Disposition Kinetics Following IV administration, plasma concentration falls rapidly. Redistribution half - life is 4 to 16 minutes. Its terminal elimination half - life is between 3 and 5 hours. pKa : 8.5 nonionized 7% Moderately lipid soluble. 40 to 70% protein bound mostly to albumin and α1-acid glycoprotein. Large large Vd ss , range of 3.5 to 5 L/kg in adults.

High hepatic extraction ratio. The high clearance rate :10 mL / kg / min. It is N -demethylated in the liver to form normeperidine. Also hydrolyzed to meperidinic acid. Both metabolites may then be conjugated and excreted renally. Normeperidine is pharmacologically active and potentially toxic.

Active Metabolites Normeperidine : pharmacological active. Produce signs of CNS excitation. Mood alterations such as apprehension and restlessness. Neurotoxic effects such as tremors, myoclonus, and seizures. The elimination half - life of the metabolite normeperidine ( 14 to 21 hours ) . Mean plasma normeperidine concentration of 0.81 µg / mL developed seizures even with patients without renal dysfunction.

Dosage and Administration of Meperidine A single IV dose is approximately one - tenth as potent as morphine. IV : a shorter duration of action. IV analgesic doses for adults range from 0.1 to 1 mg / kg. IV doses of 12.5 to 50 mg are effective in reducing postoperative shivering . The total daily dose should not exceed 1,000 mg in 24 hours .

Methadone Primarily a µ agonist. Pharmacologic properties that are similar to morphine . Chemical structure is very different from that of morphine. Pseudopiperidine ring for opioid activity. Because of its long elimination half-life, mostly used for : Long - term pain management Treatment of opioid abstinence syndromes .

Analgesia and Use in Anesthesia The onset of analgesia is rapid, within 10 to 20 minutes. After single doses of up to 10 mg, the duration of analgesia is similar to morphine. Large or repeated parenteral doses, can reach up to 20 hours.

Side Effects Similar in magnitude and frequency to those of morphine . Did not appear to have clinically significant respiratory depression . About 50% experienced nausea or vomiting, which was easily treated with standard antiemetic therapy. Decreases intestinal propulsive activity Biliary spasm.

Disposition Kinetics Mean redistribution half - time is 6 min. Mean terminal elimination T 1/2 is 34 hrs. Well absorbed after an oral dose with bioavailability 90%, and peak plasma concentration at 4 hours. 90% plasma protein. Extensive metabolism in the liver, mostly N -demethylation and cyclization to form pyrrolidines and pyrroline.

Dosage and Administration of Methadone To achieve prolonged postoperative analgesia 20 mg provide analgesia without significant post-OP respiratory depression. Important note: that these long-acting opioids are not currently approved for prophylaxis of postoperative pain.

Fentanyl Structurally related to phenylpiperidines. Clinical potency ratio 50 to 100 times that of morphine . Progressive EEG changes (slow) with a lag of 3 to 5 minutes. Resolution of EEG changes lagged by 10 to 20 minutes after stop of fentanyl infusion.

Analgesia A µ - opioid receptor agonist. Dose - dependent analgesia. Ventilatory depression. Sedation. High doses produce unconsciousness. In post-OP patients, the mean fentanyl dose requirement was 55.8 µg/hr. Mean plasma fentanyl concentration of 1.3 ng / mL reduced experimental pain intensity ratings by 50%.

Use in Anesthesia Reduces the MAC of volatile anesthetics in dose - dependent fashion. A single IV bolus dose of fentanyl 3 µg / kg, given 25 to 30 min prior to incision, reduced both isoflurane and desflurane MAC by 50% . 3 ng / mL provides a 59% reduction of sevoflurane MAC. Combining with propofol is a technique for providing general anesthesia, (TIVA).

The potency index for TIVA is described as the plasma concentration required to prevent a response in 50% ( CP 50 ) or 95% (CP 95 ) of patients to various surgical stimuli. Fentanyl reduces requirements for both volatile agents and propofol by a similar proportion . Spontaneous ventilation returned when the fentanyl concentration dropped to 1.5 to 2 ng / mL .

stress - free anesthesia Fentanyl has been used as the sole agent for anesthesia, a technique that requires a large initial dose of 50 to 150 µg / kg. Significantly blunt the “ stress response ”—that is, hemodynamic and hormonal responses to surgical stimuli—while producing only minimal cardiovascular depression . Disadvantages : early extubation “ fast - track” techniques because of prolonged respiratory depression intraoperative awareness and recall muscle rigidity

Other CNS Effects Increase middle cerebral artery flow. Elevation in ICP. Hypercarbia from fentanyl-induced respiratory depression influence fentanyl ionization and cerebral blood flow and hence the delivery brain tissue. Muscle rigidity. Instructed to deep - breathe during fentanyl induction may experience less rigidity. Seizurelike movements represent as myoclonus. Can activate epileptiform EEG activity in patients having surgery for intractable temporal lobe epilepsy. Pruritus typically presents as facial itching.

Respiratory Depression Respiratory depression expressed as elevation in end-tidal CO 2 a decrease in the slope of the CO 2 response curve decrease minute ventilation at an end-tidal CO 2 of 50 mm Hg (VE 50 ) Greatly increased when it is given in combination with midazolam. Blunts the hypoxic ventilatory drive to a greater extent than the hypercarbic ventilatory drive .

Airway Reflexes Expiration, panting, and coughing decreased, the duration of laryngospasm shortened, in a dose - dependent fashion . These protective reflexes return to baseline rapidly after emergence.

Cardiovascular Effects Concentration - dependent negative inotropic effects. A very high concentration reduced contractility by 50%. In clinical practice up to 75 µg / kg is associated with hemodynamic stability. 7 µg / kg at induction had a slight decrease in heart rate, but no change in mean arterial pressure. 20 µg / kg, decreases 15% in heart rate, MAP, systemic and PVR seen in patients with CAD . Does not prevent the inflammatory effects associated with cardiopulmonary bypass. Does not produce the apparent cardioprotective effects.

Extra Info. Hypertension in response to sternotomy is the most common hemodynamic disturbance during high - dose fentanyl anesthesia and occurs in 40 and 100% in patients receiving 50 to 100 µg / kg . Unlike morphine and meperidine, which induce hypotension, at least in part because of histamine release. The combination of fentanyl and diazepam produces significant cardiovascular depression, increased central venous pressure significantly. Adding 60% N2O to high-dose fentanyl produced a significant decrease in cardiac output and increases in systemic and pulmonary vascular resistance.

Endocrine Effects High - dose fentanyl ( 100 µg / kg ) prevented increases the “ stress response ” during surgery plasma epinephrine Cortisol glucose free fatty acids growth hormone but a lower dose of fentanyl did not . ( 5 µg / kg followed by an infusion of 3 µg / kg / h )

Smooth Muscle and Gastrointestinal Effects Fentanyl, significantly increases common bile duct pressure ( the highest ) Nausea and vomiting Delay gastric emptying Intestinal transit

Disposition Kinetics Fentanyl's extreme lipid solubility. Rapid crossing of biologic membranes. Rapid uptake by highly perfused tissue groups, including the brain, heart, and lung. Thus, after a single bolus dose, the onset of effects is rapid and the duration brief. pKa 8.4 Nonionized 8.5%

The onset within 10 seconds and correlated with a rapid increase in brain tissue fentanyl concentration, which equilibrated with plasma by 1.5 min . Recovery from fentanyl effects started within 5 min and was complete by 60 min . Peak muscle concentration was seen at 5 min . Fat concentration reached a maximum 30 min , because of the limited blood supply to that tissue . With prolonged administration of fentanyl, fat can act as a reservoir of drug .

The terminal elimination half - time ranged from 3.1 to 6.6 hours. Significantly bound to red blood cells: 40%. Blood: plasma partition coefficient of 1. Highly protein bound, 79 to 87%. mostly α1-acid glycoprotein which is pH-dependent. Decrease in pH will increase the proportion of fentanyl that is unbound. Thus, a patient with respiratory acidosis will have a higher proportion of unbound ( active ) fentanyl, which could exacerbate respiratory depression .

Clearance of fentanyl is primarily by rapid and extensive metabolism in the liver . Indicate a high hepatic extraction ratio. Which dependent on liver blood flow . Metabolism is primarily by N -dealkylation to norfentanyl. By hydroxylation of both the parent and norfentanyl. 6% is excreted unchanged in the urine.

Dosage and Administration of Fentanyl Single bolus dose short - acting opioid. Very large doses and multiple doses prolonged respiratory depression and delayed recovery could occur. useful as a sedative / analgesic premedication : 25 to 50 µg IV. A transmucosal delivery system is effective premedicant for pediatric and adult patients as well as an effective treatment for “breakthrough” pain in chronic pain patients, should be administered in a monitored environment .

Intubation Time Fentanyl blunt the hemodynamic response to laryngoscopy and tracheal intubation, which can be particularly severe in patients with hypertension or cardiovascular disease . doses of 1.5 to 5 µg / kg Should be complete approximately 3 min prior to laryngoscopy to maximally blunt hemodynamic responses to tracheal intubation . Administration of up to 3 to 5 µg / kg / hr will allow recovery of spontaneous ventilation at the end of surgery . 0.5 to 2.5 µg / kg every 30 minutes .

cardiac surgery Prevents hemodynamic changes in response to noxious stimuli, can be achieved with: a loading dose of 50 µg/kg, followed by a continuous infusion of 30 µg/kg/hr.

Sufentanil A thienyl derivative of fentanyl. Has a clinical potency ratio 2,000 to 4,000 times that of morphine. Has a clinical potency ratio 10 to 15 times that of fentanyl . EEG changes lagged behind plasma concentration changes by 2 to 3 min , after 4-min sufentanil infusion. Resolution of the EEG changes lagged behind plasma concentration changes by 20 to 30 min .

Analgesia Highly selective µ - opioid receptor agonist. IV infusion rate to adequate postoperative analgesia, mean rate of 8 to 17 µg / hr was required during the first 48 hours .

Use in Anesthesia Decreases the MAC of volatile anesthetics in a dose - dependent manner 70 to 90%. In cardiac surgery, high doses ( 10 to 30 µg / kg ) with oxygen and muscle relaxants are needed. When used as the sole anesthetic agent, even high doses may not completely block the hemodynamic responses to noxious stimuli.

Other CNS Effects Equianalgesic doses of sufentanil and fentanyl produce similar changes in the EEG. With 15 µg / kg, α activity became prominent within a few seconds, and within 3 min, the EEG consisted almost entirely of slow δ activity . 1 to 2 µg / kg, Rigidity and myoclonic activity reported during induction, and on emergence. 0.5 µg / kg was not associated with changes in cerebral blood flow.

In patients with intracranial tumors 1 µg / kg was associated with an elevation in spinal cerebrospinal pressure, a decrease in cerebral perfusion pressure and arterial pressure had dropped significantly.

Respiratory Depression In spontaneously breathing patients anesthetized with 1.5% halothane and N2O, 2.5 µg reduced mean minute ventilation by 50%, and 4 µg reduced mean respiratory rate by 50%. Comparing with fentanyl: Changes in end - tidal CO2 were the same for fentanyl and sufentanil the slope of the ventilatory response to CO2 was depressed to a greater extent by fentanyl.

CVS Effects Produces vasodilation by : A sympatholytic mechanism. A direct smooth muscle effect . 15 µg/kg, decrease in MAP which is used for induction of anesthesia. Combining vecuronium and sufentanil can cause a decrease in MAP during induction and significant bradycardia and sinus arrest, but not with pancuronium.

Endocrine Effects Sufentanil, like fentanyl, reduces the endocrine and metabolic responses to surgery . However, even a large induction dose ( 20 µg / kg ) did not prevent increases in cortisol, catecholamines, glucose, and free fatty acids during and after cardiopulmonary bypass .

Disposition Kinetics Extremely lipophilic. pKa 8 nonionized 20%. Smaller degree of ionization at physiologic Ph. Protein Binding 93% mostly to α1-acid glycoprotein. Vd ss smaller than fentanyl : 1.9 Kg/L. Elimination half - life shorter than that of fentanyl : 2.7 hrs. Plasma concentration drops very rapidly after an IV bolus dose. 98% of the drug is cleared from plasma within 30 minutes after IV bolus dose. Less red cell bound than fentanyl ( 22 compared with 40% ).

Clearance is rapid. As fentanyl high hepatic extraction ratio. Metabolism in the liver is by : N -dealkylation O -demethylation Study show clearance and elimination half - life in patients with cirrhosis are similar to controls.

Dosage and Administration Loss of consciousness is seen with total doses between 1.3 and 2.8 µg / kg . Doses in the range of 0.3 to 1.0 µg / kg given 1 to 3 minutes prior to laryngoscopy can be expected to blunt hemodynamic responses to intubation Balanced anesthesia is maintained with (A)intermittent bolus doses or (B)a continuous infusion A:0.1 to 0.5 µg / kg, mean maintenance requirements of 0.35 µg / kg / hr B:initial bolus of 0.5 µg / kg followed by an infusion of 0.5 µg / kg / hr

Cardiac Anesthesia Can be used as the sole agent. Much higher bolus doses ( 10 µg / kg ) and / or infusion rates ( 0.15 µg / kg / min ) .

Alfentanil A tetrazole derivative of fentanyl. Alfentanil is a µ-opioid receptor agonist and produces typical naloxone-reversible analgesia and side effects such as sedation, nausea, and respiratory depression. Its clinical potency is 10 times that of morphine. Its clinical potency one - fourth to one - tenth that of fentanyl. Peak effect of EEG lagged behind peak plasma concentration by <1 minute. Resolution of effect followed decreasing serum alfentanil concentration by no more than 10 minutes .

Analgesia Following an adequate loading dose, average alfentanil requirements for postoperative analgesia are approximately 10 to 20 µg / kg / hr .

Use in Anesthesia An infusion rate of 8 µg / kg / min, reduced enflurane MAC by 69%. Balance anesthesia : loading dose of 150 µg / kg, followed by an infusion titrated between 25 and 150 µg / kg / hr according to responses to surgical stimuli . Comparing to fentanyl, the duration of even very large doses of alfentanil is short, so repeated doses or a continuous infusion of alfentanil is required . Did not eliminate responses to intubation and intraoperative stimuli in all patients .

Other CNS Effects Produces the typical generalized slowing of the EEG. Increase epileptiform EEG activity in patients with intractable temporal lope epilepsy. Produce intense muscle rigidity 150 to 175 µg/kg Loss of consciousness. Increase CSF pressure in patients with brain tumors, whereas fentanyl does not .

Neurosurgical patients When normocapnia and blood pressure were maintained at baseline. no clinically significant changes in ICP. no evidence of cerebral vasodilation. no evidence of cerebral vasoconstriction. MAP and cerebral perfusion pressure decreased in a dose - dependent fashion.

Respiratory Depression Mild ventilatory depression. increased end - tidal CO2 decreased slope of the CO2 response curve At plasma concentrations associated with 50% reduction in pain intensity, respiratory depression was equivalent for alfentanil, fentanyl, and morphine. Recovery of ventilatory function was faster with alfentanil compared with fentanyl .

Cardiovascular Effects The cardiovascular effects of alfentanil are influenced by preoperative medication, muscle relaxant used, method of administration, and the degree of surgical stimulation. In general, heart rate and MAP are unchanged or slightly decreased during induction with alfentanil 40 to 120 µg / kg. Rapid induction with 150 to 175 µg/kg alfentanil can decrease mean arterial pressure by 15 to 20 torr. With lorazepam premedication or thiopental induction, moderate doses ( 10 to 50 µg / kg ) of alfentanil blunt the cardiovascular and catecholamine responses to laryngoscopy and intubation.

Severe hypotension has been observed when alfentanil is given after 0.125 mg / kg diazepam . Alfentanil can also cause bradycardia. Minimized by premedication with atropine and by the vagolytic effect of pancuronium . Alfentanil 50 µg/kg combined with propofol 1 mg/kg for induction of anesthesia can produce significant bradycardia and hypotension after intubation, but premedication with glycopyrrolate prevents these effects.

Nausea and Vomiting The same incidence of nausea and vomiting as fentanyl. But alfentanil - induced nausea and vomiting resolved more quickly.

Disposition Kinetics Alfentanil pharmacokinetics differs from fentanyl and sufentanil in several respects. Is a weaker base than other opioids . The pKa of alfentanil is 6.8 90% of unbound plasma alfentanil is nonionized at pH 7.4 Volume of distribution is 4 times smaller than fentanyl's. Short terminal elimination half - life. Clearance is just half that of fentanyl.

Smaller volume of distribution is a result of lower lipid solubility high protein binding 92% of alfentanil is protein bound, mostly to α 1-acid glycoprotein. After IV administration, plasma alfentanil concentration falls rapidly; 90% of the administered dose has left the plasma by 30 minutes, mostly because of distribution to highly perfused tissues.

Terminal elimination half - life of 84 to 90 minutes. Clearance of alfentanil, 6.4 mL / kg / min Intermediate hepatic extraction coefficient 32 to 53% which depends on hepatic plasma flow. Mean plasma - brain equilibration half - times : Fentanyl : 6.4 min Sufentanil : 6.2 min Alfentanil : 1.1 min

Alfentanil undergoes N -dealkylation and O -demethylation in the liver to form inactive metabolites. Liver disease can significantly prolong the elimination half - life of alfentanil . Patients with moderate hepatic insufficiency as a result of cirrhosis have reduced binding to α 1-acid glycoprotein and a plasma clearance one-half that of control patients. These changes result in a marked increase in the elimination half-life, 219 min versus 90 min.

Renal disease also decreases alfentanil protein binding, but does not result in decreased plasma clearance or a prolonged terminal elimination half-life. Alfentanil's elimination half-life is prolonged by about 30% in the elderly and appears to be much shorter (about 40 minutes) in children 5 to 8 years old. Obesity is also associated with a 50% decrease in alfentanil clearance and a prolonged (172 minutes) elimination half-life.

The combination of moderate lipid solubility and short elimination half - life suggests that both redistribution and elimination are important in the termination of alfentanil's effects. After a single bolus dose, redistribution will be the most important mechanism. After a very large dose, repeated small doses, or a continuous infusion, elimination will be a more important determinant of the duration of alfentanil's effects .

Dosage and Administration 120 µg / kg produce unconsciousness in 2 to 2.5 minutes, and muscle rigidity. Premedication with a benzodiazepine is associated with: a lower dose requirement, 40 to 50 µg / kg a faster onset of unconsciousness, within 1.5 minutes. hypotension.

Intubation For rapid sequence induction, a bolus dose of 36 µg / kg followed by thiopental and rocuronium can yield ideal intubating conditions within 40 seconds in 95% of patients . A lower dose, 15 µg / kg ( range, 13 to 31 µg / kg ) with sevoflurane and N2O, but without muscle relaxants produced good intubating conditions within 90 seconds in 95% of patients. With propofol 2.5 mg / kg, an alfentanil dose of 10 µg / kg appears optimal for laryngeal mask insertion, but is accompanied by apnea for about 2 minutes .

Brief duration of action. Useful component of general anesthesia in short surgical procedures. Loading doses of 5 to 10 µg/kg provide good analgesia with rapid recovery.

For Long Procedures Its pharmacokinetic properties make it ideal for administration as a continuous infusion. After induction of anesthesia, a loading dose of alfentanil 10 to 50 µg / kg is followed with supplemental bolus doses of 3 to 5 µg / kg as needed. continuous infusion starting at 0.4 to 1.7 µg / kg / min with 60 to 70% N2O or a propofol infusion.

Cardiac Surgery High - dose alfentanil is used as the sole anesthetic agent. Continuous infusion of up to 150 to 600 µg / kg / h . Adjusted according to the patient's responses to stimuli.

Remifentanil A 4-anilidopiperidine with a methyl ester side chain. An ultrashort - acting opioid which is due to metabolism rather than to redistribution. Because its ester side chain is susceptible to metabolism by blood and tissue esterases. Potent, naloxone - reversible µ - selective opioid agonist activity. It does not accumulate with repeated dosing or prolonged infusion.

Analgesia Produces dose - dependent analgesic effects. Analgesic effects of bolus IV doses ( 0.0625 to 2.0 µg / kg ) Bolus doses produced a peak analgesic effect between 1 and 3 minutes and a duration of approximately 10 minutes . Remifentanil is 40 times as potent as alfentanil .

Postoperative analgesia study, 80% of patients got satisfied analgesia with remifentanil infusion of 0.05 to 0.15 µg / kg / min . Remifentanil may offer an alternative for laboring patients in whom regional anesthesia is absolutely contraindicated . PCA with a median effective bolus dose of 0.4 µg / kg ( range, 0.2 to 0.8 µg / kg ) and consumption of 0.066 µg / kg / min ( range, 0.027 to 0.207 µg / kg / min ).

Use in Anesthesia The effect of remifentanil on the MAC of volatile anesthetics is characterized by steep dose - effect or concentration - effect curves. Decreases enflurane and isoflurane MAC in a dose - dependent fashion up to a maximum near 65%. Effects on the MAC - BAR ( requirement for blunting the sympathetic response to skin incision ) of sevoflurane and desflurane in 60% N2O are similar.

12 µg / kg for loss of consciousness. 20 µg / kg, 60% of patients had severe muscle rigidity . Pediatric patients require twice as much as adults ( 0.15 µg / kg / min vs . 0.08 µg / kg / min ) when it is used with propofol for TIVA. Gender differences which female required more in a study with unclear explanation.

For balanced anesthesia, including combination with inhalation agent report similar findings of hemodynamic stability. easy titratability. blunting responses to noxious stimulation permitting rapid recovery. did not alter desflurane's effect on the bispectral index analysis of the EEG.

TIVA Remifentanil is infused as a component of TIVA more frequently than other opioids . Increases in remifentanil dosage to certain level reduced propofol dose requirements. Response to intubation was prevented in 80% of patients by approximately doubling the remifentanil. A small bolus dose of remifentanil (20 µg) given 30 seconds before induction, can reduce the pain of propofol injection.

Cardiac Anesthesia While high - dose remifentanil ( 1 to 2 µg / kg / min ) has been used as a single agent for cardiac anesthesia. It is more commonly administered with propofol or isoflurane for “fast - track cardiac anesthesia. Patients require analgesics very soon after an infusion is stopped. A continuation of remifentanil to transition to postoperative analgesia can avoid early pain and sympathoadrenal stimulation.

Monitored Anesthesia Care Useful during monitored anesthesia care for conscious sedation such as ESWL and colonoscopy. Useful during conjunction with regional anesthesia. When compared with propofol, remifentanil provides better analgesia, but results in more nausea and respiratory depression, whereas propofol causes more oversedation. Times required for discharge are clinically similar . Maintenance of spontaneous respiration during general anesthesia show if low doses of remifentanil are used .

Other CNS Effects Produces effects on the EEG, a concentration - dependent slowing . Produce muscle rigidity, especially with bolus doses. Not affecting intracranial pressure Dose - dependent decreases in MAP . Remifentanil 0.5µg/kg/min plus propofol preserved cerebral autoregulation, whereas isoflurane 1.8% did not.

Motor - Evoked Potentials The ability to monitor motor-evoked potentials (MEPs) is important in many cranial and spinal neurosurgical procedures. All opioids and propofol suppressed MEPs in a dose - dependent fashion. Remifentanil exerted less suppression than the other opioids and propofol . Quality and reproducibility of MEPs was preserved with remifentanil.

Has not been shown to produce seizure activity. Reduce methohexital requirement in patients having electroconvulsive therapy . Remifentanil 1 µg / kg allowed a 50% reduction in methohexital dose, which results in seizure prolongation by 50% .

Respiratory Depression Produces dose - dependent respiratory depression as measured by : increases in end - tidal CO2 decreased oxygen saturation Peak respiratory depression occurred at 5 minutes after each dose of remifentanil and alfentanil. The maximal respiratory depressant effect seen after 2 µg / kg remifentanil was similar to that caused by 32 µg / kg alfentanil .

Recovery from Resp. Depression The duration of respiratory depression, measured as time to return of blood gases to within 10% of baseline values. 10 minutes after 1.5 µg / kg remifentanil 20 minutes after 2 µg / kg remifentanil 30 minutes after 32 µg / kg alfentanil Recovery was rapid, and minute ventilation returned to baseline by 8 minutes after the infusion was stopped for all infusion rates, compared with 61 minutes after stopped of alfentanil infusion.

Hemodynamic Effects Bolus doses >1.0 µg / kg produce brief increases in systolic BP ( 5 to 20 torr ) and heart rate ( 10 to 25 beats / min ). In patients anesthetized, remifentanil ( up to 5 µg / kg ) produces dose - dependent decreases in systolic BP and heart rate around 20% . Attenuated by premedication with glycopyrrolate 0.3 to 0.4 mg and reversed with ephedrine or phenylephrine.

These hemodynamic effects were not mediated by histamine release Transient and easily treated with fluids and downward titration of propofol . A study show : Hypotension : 12% with remifentanil 4% with fentanyl Bradycardia : 2% with remifentanil 1% with fentanyl

Coronary Artery Disease In a comparison of high - dose remifentanil ( 2 µg / kg / min ) and remifentanil 0.5 µg / kg / min plus propofol. Both techniques produced similar changes: 30% drop in mean arterial pressure 25% drop in cardiac index. 30% drop in myocardial blood flow 40% drop in oxygen consumption

Cardiac Surgery Rapid injection of remifentanil 1 µg / kg followed by a continuous infusion at 0.1 to 0.2 µg / kg / min on induction Bradycardia ( heart rate <30 beats / min ) Hypotension ( systolic BP <80 mm Hg ) Hypotension was effectively treated by ephedrine and temporary discontinuation of remifentanil . These severe effects can often be avoided by slower administration ( >60 seconds or longer ) of the loading dose,

Gastrointestinal Effects The incidence of nausea was 44 and 53% for remifentanil and alfentanil, respectively. The incidence of vomiting was 21 and 29% for remifentanil and alfentanil, respectively . With 0.8% isoflurane, nausea occurred in 18 and 20% of patients with remifentanil and alfentanil, respectively. But with propofol reported very low incidence of nausea and vomiting (6 to 22%).

Remifentanil For strabismus surgery in children, vomiting occurred with equal frequency ( 26 to 31% ) with remifentanil, alfentanil, isoflurane, and propofol . Produce dose - dependent nausea and vomiting similar to other short - acting µ - agonist opioids that can be attenuated by propofol . Delays gastric emptying and biliary drainage.

Other Side Effects Postoperative shivering occurred in about 40% of patients. Pruritus in 12% of patients . Psychomotor side effects typical of µ opioids. Dry mouth. Itching. Flushing. Sweating. Turning of the stomach. Miosis. Some of these effects lasted an hour or more after remifentanil administration was stopped .

Disposition Kinetics Remifentanil is an ester functional group that hydrolyzed by blood and tissue nonspecific esterases and results in very rapid metabolism . Because butyrocholinesterase ( pseudocholinesterase ) does not appear to metabolize remifentanil, plasma cholinesterase deficiency and anticholinergic administration do not affect remifentanil clearance . Unlike other opioids, redistribution plays only a minor role in remifentanil clearance .

Has a small volume of distribution, approximately 0.3 to 0.5 L / kg 25 L in adult Clearance, 3 to 5 L / min, is 3 to 4 times normal hepatic blood flow . A rapid distribution phase of 0.9 minutes. Slow distribution half-times 6 minutes. A very short terminal elimination half - life of 9.5 minutes. Doses should be based on lean body mass . pKa 7.26 nonionized 58%.

Dosage and Administration Best administered as a continuous infusion. Repeated bolus doses can be effective. Induction : 0.25–0.5 µg/kg/min or 0.5–1.0 µg/kg . Maintenance : 0.25–0.5 µg/kg/min or 25–50 µg . PACU : 0.05–0.25 µg/kg/min . Monitored Anesthesia Care : 0.01–0.2 µg/kg/min or 12.5–25 µg .

Induction Dosage, Intubation, LMA Placement Unreliability in loss of consciousness and significant muscle rigidity. Remifentanil alone has not been found to be a satisfactory single agent for induction of anesthesia. Bolus doses of >2 µg / kg can drop arterial pressure 20 to 30%. Hemodynamic changes in cardiac patients receiving high - dose infusion are similar to remifentanil plus propofol .

Combined with a potent inhalation agent, a loading dose of 1 µg / kg given slowly ( over 60 seconds ) can provide adequate intubating conditions with hemodynamic stability.

The most commonly reported remifentanil - based regimen for anesthetic induction and laryngoscopy consists of remifentanil 0.5 to 1 µg / kg given over 60 seconds plus propofol 1 to 2 mg / kg , followed by remifentanil infusion of 0.25 to 0.5 µg / kg / min .

Maintenance of General Anesthesia In combination with 70% N2O in O2, remifentanil 0.6 µg/kg/min is generally adequate. A lower infusion rate ( 0.2 to 0.25 µg / kg / min ) is needed when remifentanil is combined with inhalation agents. For TIVA, maintenance infusion rates for remifentanil and propofol are 0.25 to 0.5 µg / kg / min and 75 to 100 µg / kg / min , respectively . If N2O is added, remifentanil infusion rates as low as 0.125 µg/kg/min and propofol infusion of 50 to 75 µg/kg/min can be used.

For elderly patients or those with cardiac disease, a reduction in propofol by about 25% is recommended . Children require higher remifentanil doses to block responses to skin incision.

Cardiac Surgery For high - dose opioid anesthesia for cardiac surgery, the remifentanil infusion is maintained at 1 to 3 µg / kg / min and should be adjusted downward for hypothermia. Adding a low - dose propofol infusion of 50 µg / kg / min to this high infusion rate effectively suppressed responses to skin incision, sternotomy, and aortic cannulation .

A disadvantage of remifentanil Related to its short duration of action. Patients may experience substantial pain on emergence from anesthesia . If moderate - to - severe postoperative pain is anticipated, continuing the remifentanil infusion between 0.05 and 0.15 µg / kg / min . The use of local and regional anesthetic techniques is also effective . Mild postoperative pain is anticipated, intraoperative administration of a NSAID 30 to 60 minutes before the end of surgery.

Monitored Anesthesia Care Used for conscious sedation / analgesia. Used an adjunct for sedation or analgesia during regional anesthesia, or for block placement. During colonoscopy, a continuous remifentanil infusion of 0.2 to 0.25 µg/kg/min , supplemented with small (10-mg) doses of propofol provided good analgesia but mild respiratory depression was common.

ESWT Patients who received low - dose ( 12.5 to 25 µg ) intermittent bolus injection of remifentanil with or without infusion at 0.05 µg / kg / min reported better analgesia than continuous infusion of 0.1 µg / kg / min alone .

Ophthalmologic Surgery Remifentanil 1 µg / kg with or without a subsequent infusion of 0.2 µg / kg / min administered 90 seconds prior to placement of ophthalmologic block resulted in excellent analgesia. 14% of patients who received an infusion experienced respiratory depression.

Regional Anesthesia When used as an adjunct to local or regional anesthesia, a much lower maintenance infusion rate, 0.05 to 0.1 µg / kg / min , provides adequate sedation and analgesia . Finally, the dose requirement of remifentanil for sedation / analgesia is reduced 50% when combined with midazolam or propofol . When 1 to 2 mg of midazolam premedication is given, 0.01 to 0.07 µg / kg / min remifentanil provides good sedation / analgesia.

Partial Agonists and Mixed Agonist–Antagonists Structurally related to morphine . Characterized by binding activity at multiple opioid receptors and their differential effects ( agonist, partial agonist, or antagonist ) . The clinical effect of a partial agonist at the µ - opioid receptor is complex. Administered alone, a partial agonist has a flatter dose - response curve and a lower maximal effect than a full agonist.

The observed effect of the combination of A and B is expressed as a fraction of the maximal effect of the full agonist . As the concentration of the partial agonist increases, the effect of the combination converges on the maximum effect of the partial agonist . When added to a low concentration ( e . g . , [ A ] = 0.25 ) of agonist, the partial agonist increases the response; but when added to a large concentration of the agonist, the response decreases—that is, B acts like an antagonist .

Combined with a low concentration of a full agonist, the effects of the partial agonist are additive up to the maximum effect of the partial agonist . Combined with increasing concentrations ([ A ] = 0.67 to 256 ) of full agonist, the partial agonist will act as an antagonist . These drugs mediate their clinical effects via µ and κ - opioid receptors.

Nalbuphine and butorphanol have been reported to be antagonists at the µ opioid receptor, they do cause respiratory depression, which is not a function of κ agonists . Thus, they appear to have at least partial agonist activity at the µ - opioid receptor .

Receptors µ RECEPTOR: Nalbuphine Butorphanol Buprenorphine Κ RECEPTOR: Nalbuphine Butorphanol

The major role for using them To be in the provision of postoperative analgesia. Used for intraoperative sedation, as adjuncts during general anesthesia. To antagonize some effects of full µ opioid agonists .

Nalbuphine Is a phenanthrene opioid derivative . Classified as a κ agonist and µ antagonist. It is more accurately described as a partial agonist at both κ and µ receptors . 0.5 mg / kg dose reduced enflurane MAC by 8%. This modest MAC reduction, compared with 65% for morphine, suggests nalbuphine may not be a useful adjunct for general anesthesia .

Study Combined with diazepam 0.4 mg / kg and 50% N2O in oxygen, a loading dose of 3 mg/kg was followed by additional doses of 0.25 mg/kg as needed throughout surgery. No significant increases in blood pressure, stress hormones, or histamine were seen. Emergence from anesthesia was uncomplicated.

Side Effects The most common side effect was drowsiness . Respiratory depression. Can precipitate withdrawal symptoms in patients who are physically dependent on opioids .

Comparison with fentanyl Fentanyl was found to better attenuate hypertensive responses to intubation and surgical stimulation . Significant respiratory depression was seen in 8 of 30 patients who received fentanyl; compared with no respiratory depression in the nalbuphine group. Analgesia was similar. Postoperative sedation was common in the nalbuphine group.

Features The respiratory depression mediated by µ - opioid receptors. Has a ceiling effect equivalent to that produced by ~0.4 mg / kg morphine . Analgesia is mediated by both κ and µ receptors . Antagonize the respiratory depressant effects of full agonists while still providing analgesic effects .

Have ceiling analgesic and respiratory depressant effects. Can be as effective as full µ agonists in providing postoperative analgesia . Nalbuphine 5 to 10 mg has also been used to antagonize pruritus induced by epidural and intrathecal morphine . The usual adult dose of nalbuphine is 10 mg as often as every 3 hours .

Butorphanol A morphinan congener. Has partial agonist activity at κ - and µ - opioid receptors. Produced dose - dependent sedation which mediated by κ receptors . Decreases enflurane MAC,11%, at 0.1 mg/kg. Increasing the butorphanol dose 40-fold does not produce a further reduction. Butorphanol and morphine provided equally satisfactory anesthesia .

Produces respiratory depression with a ceiling effect below that of full µ agonists . 3 mg produces respiratory depression approximately equal to that of 10 mg morphine . Its effectiveness in reversing fentanyl - induced respiratory depression (5 µg / kg followed by an infusion of 3 µg/kg/hr) by butorphanol 1 mg only.

Does not produce significant elevation in intrabiliary pressure. Effective in the treatment of postoperative shivering. Antipruritic effect that is blocked by a selective κ antagonist . Reduce morphine - induced pruritus without completely blocking its analgesic effect . Lower incidence of opioid - induced ileus compared with µ - selective opioids.

Extra Info. Use as a sedative as low as 0.5 mg. Treatment of moderate postoperative pain . Single analgesic doses range from 0.5 to 2 mg. Administered as patient - controlled analgesia. Can be administered epidurally and transnasally .

Buprenorphine Highly lipophilic thebaine derivative. A partial µ opioid agonist . At small - to - moderate doses it is 25 to 50 times more potent than morphine . Does not appear to have agonist activity at the κ - opioid receptor. Its slow dissociation from µ receptors, which can lead to prolonged effects not easily antagonized by naloxone .

Bell - shaped dose - response curve such that, at very high doses, it produces progressively less analgesia . 10 or 20 µg / kg buprenorphine during surgery were pain - free postoperatively. 30 or 40 µg / kg had significant postoperative pain .

Have a ceiling effect to its respiratory depressant dose - response curve . Buprenorphine - induced respiratory depression can be prevented by prior naloxone administration. Not easily reversed by naloxone once the effects have been produced . Which require around 5 to 10 mg to antagonize it which maximum occur after 3 hours.

A dose of 0.3 mg buprenorphine reduces CO 2 responsiveness to about 50% of control values. Did not antagonize fentanyl - induced respiratory depression, and appears to increase respiratory rate without antagonizing analgesic effects in slowly administered doses up to 0.5 mg .

Extra Info. Effective in treatment of moderate - to - severe pain. Slow onset. Analgesic duration can be >6 hours . A single dose of 0.3 to 0.4 mg appears to produce analgesia equivalent to 10 mg morphine .

Opioid Antagonists They are competitive inhibitors of the opioid agonists. Effect profile depends on: The type of agonist administered Dose of agonist administered The degree to which physical dependence on the opioid agonist

Naloxone The most widely used opioid antagonist. Structurally related to morphine and oxymorphone. It is a pure antagonist at µ - , κ - , and δ - opioid receptors . Administered to antagonize opioid - induced respiratory depression and sedation .

Naltrexone Long - acting oral agent. Relatively pure antagonist activity .

Mediated by endogenous opioids: reverse “stress analgesia”. antagonize analgesia produced by low-frequency stimulation with acupuncture needles. reverse analgesia produced by placebo medications. Trials in prevention of treatment of opioid - mediated gastrointestinal dysfunction.

Side Effects Producing sudden, severe pain in postoperative patients. Severe hypertension. Tachycardia and ventricular dysrhythmias. Precipitate opioid withdrawal symptoms in opioid-dependent individuals. Acute, sometimes fatal, pulmonary edema even in healthy young patients who have received relatively small doses ( 80 to 500 µg ) .

The Mechanism Pulm. Edema The mechanism for this phenomenon is thought to be centrally mediated catecholamine release, which causes acute pulmonary hypertension. It is also essential to monitor vital signs and oxygenation closely after naloxone is administered to detect occurrence of any of these potentially serious complications.

Very fast onset of action = easy to titrated. Peak effects occur within 1 to 2 minutes. Duration is dose - dependent. Total doses of 0.4 to 0.8 mg last 1 to 4 hours. Suggested incremental doses for IV titration are 20 to 40 µg given every few mins until the patient's ventilation improves, but analgesia is not completely reversed.

Using As Infusion Because naloxone has a short duration of action, respiratory depression may recur if large doses and / or long - acting opioid agonists have been administered . When prolonged ventilatory depression is anticipated, an initial loading dose followed by a naloxone infusion can be used . Infusion rates between 3 and 10 µg / hr have been effective in antagonizing respiratory depression from systemic and epidural opioids .

Use of Opioids in Clinical Anesthesia The goal of opioid premedication is to provide moderate sedation, anxiolysis, and analgesia while maintaining hemodynamic stability . Potential risks of opioid premedication include: Oversedation. Respiratory depression. Nausea and Vomiting .

For induction of anesthesia Opioids are often used to blunt or prevent the hemodynamic responses to tracheal intubation . Opioids with rapid onset of action, such as fentanyl and its derivatives, are appropriate for this use .

During maintenance of general anesthesia Opioid dosage is titrated to the desired effect based on : the surgical stimulus. individual patient characteristics, such as age. volume status. neurologic status. liver dysfunction. other systemic disease states .

Important pharmacokinetic differences among these opioids include volumes of distribution and intercompartmental (distributional) and central (elimination) clearances. A smaller distribution volume tends to shorten recovery time. A reduction in clearance tends to increase recovery time .

The major pharmacodynamic differences among these opioids are potency and the equilibration times between the plasma and the site of drug effect . Equilibration half - times between plasma and effect site are 5 to 6 minutes for fentanyl and sufentanil. Equilibration half - times between plasma and effect site are 1.3 to 1.5 minutes for alfentanil and remifentanil .

The rate of recovery after a continuous infusion will depend on the duration of the infusion as well as the magnitude of decline that is required .

If only a 20% drop in effect site concentration is required, recovery from all three opioids will be rapid, although recovery time increases for fentanyl after 3 hours of drug infusion . If a 50% decrease is required, recovery from sufentanil will be fastest for infusions <6 to 8 hours in duration, but more rapid for alfentanil if infusions are continued for >8 hours .

Context - Sensitive Half - Time Defined as the time required for the drug concentration in the central compartment to decrease by 50%, and demonstrated how this half - time changes as drug infusion duration increases .

Explanation During an infusion, the peripheral ( fast and slow ) compartments begin to “fill up . ” After the infusion is stopped, drug will be eliminated, but will also continue to be redistributed as long as the concentration in a peripheral compartment is lower than that in the central compartment . This leads to a rapid drop in central compartment drug concentration .

When central compartment ( plasma ) concentration drops below that of the peripheral compartment ( s ) , the direction of drug redistribution will reverse and will slow the decline in plasma concentration .

The degree to which redistribution will affect the rate of drug elimination depends on the ratio of the distributional to elimination time constants . Thus, a drug that can rapidly redistribute will have a correspondingly larger contribution from the peripheral compartment ( s ) , and plasma concentration will drop progressively more slowly as infusion duration continues .

Context - sensitive half - times

Opioids

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