Alfenta

ALFENTA Info



Alfenta bentley notes



Alfenta Info [] official fda site

__Katsung__ Alfentanil (generic, Alfenta) - Parenteral: 0.5 mg/mL for injection (pg 705 CH31) Phenylpiperidines Fentanyl is one of the most widely used agents in the family of synthetic opioids. The fentanyl subgroup now includes sufentanil, alfentanil, and remifentanil in addition to the parent compound, fentanyl. These opioids differ mainly in their potency and biodisposition. Sufentanil is five to seven times more potent than fentanyl. Alfentanil is considerably less potent than fentanyl, but acts more rapidly and has a markedly shorter duration of action. Remifentanil is metabolized very rapidly by blood and nonspecific tissue esterases, making its pharmacokinetic and pharmacodynamic half-lives extremely short. Such properties are useful when these compounds are used in anesthesia practice. Although fentanyl is now the predominant analgesic in the phenylpiperidine class, meperidine continues to be used. This older opioid has significant antimuscarinic effects, which may be a contraindication if tachycardia would be a problem. Meperidine is also reported to have a negative inotropic action on the heart. In addition, it has the potential for producing seizures secondary to accumulation of its metabolite, normeperidine, in patients receiving high doses or with concurrent renal failure. Given this undesirable profile, use of meperidine as a first-line analgesic is becoming increasingly rare. (pg 691 CH31) CYP 34A (pg 81 CH4) Itraconazole – inhibits metabolism of alfenta (pg92 CH4) (pg 681 CH31) Hepatic oxidative metabolism is the primary route of degradation of the phenylpiperidine opioids (meperidine, fentanyl, alfentanil, sufentanil) and eventually leaves only small quantities of the parent compound unchanged for excretion. (pg 682 CH31) TRUNCAL RIGIDITY An intensification of tone in the large trunk muscles has been noted with a number of opioids. It was originally believed that truncal rigidity involved a spinal cord action of these drugs, but there is now evidence that it results from an action at supraspinal levels. Truncal rigidity reduces thoracic compliance and thus interferes with ventilation. The effect is most apparent when high doses of the highly lipid-soluble opioids (eg, fentanyl, sufentanil, alfentanil, remifentanil) are rapidly administered intravenously. Truncal rigidity may be overcome by administration of an opioid antagonist, which of course will also antagonize the analgesic action of the opioid. Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents. (pg 691 CH31) Schedule II (pg 1413)

__Lippincott’s Illustrated Review of Pharmacology__ E. Sufentanil, alfentanil, and remifentanil Three drugs related to fentanylâ!”sufentanil [soo-FEN-ta-nil], alfentanil [al-FEN-ta- nil], and remifentanil [rem-i FEN-ta-nil]â!”differ in their potency and metabolic disposition. Sufentanil is even more potent than fentanyl, whereas the other two are less potent but much shorter-acting.

__Stoelting and Hiller__ Cytochrome P-450 Enzymes (pg 14) The enzymes of the cytochrome P-450 (CYP) system, a superfamily of membrane-bound heme proteins, catalyze the metabolism of endogenous compounds. P-450 3A4 is the most abundantly expressed P-450 isoform, comprising 20% to 60% of total P-450 activity. P-450 3A4/5 is considered to be responsible for metabolizing more than one half of all currently available drugs, including opioids (alfentanil, sufentanil, fentanyl), benzodiazepines, local anesthetics (lidocaine, ropivacaine), immunosuppressants (cyclosporine), and antihistamines (terfenadine). (pg 20) Synthetic Opioids Fentanyl, sufentanil, alfentanil, and remifentanil are semisynthetic opioids that are widely used to supplement general anesthesia or as primary anesthetic drugs in very high doses during cardiac surgery. The major pharmacodynamic differences between these drugs are potency and rate of equilibration between the plasma and the site of drug effect (biophase). (pg 72) Pharmacokinetics Morphine is usually administered intravenously in the perioperative period, thus eliminating the unpredictable influence of drug absorption. The peak effect (equilibration time between the blood and brain) after the intravenous administration of morphine is delayed, compared with opioids such as fentanyl and alfentanil, and requires about 15 to 30 minutes (Table 3-5). Plasma morphine concentrations after rap id intravenous injections do not correlate closely with the opioid's pharmacologic activity. Presumably, this discrepancy reflects a delay in the penetration of morphine across the blood-brain barrier. Only a small amount of administered morphine gains access to the CNS. It is estimated that <0.1% of morphine that is administered intravenously has entered the CNS at the time of peak plasma concentrations. (pg 79) (pg 80) Alfentanil Alfentanil is an analog of fentanyl that is less potent (one-fifth to one-tenth) and has one-third the duration of action of fentanyl (see Fig. 3-1). A unique advantage of alfentanil compared with fentanyl and sufentanil is the more rapid onset of action (rapid effect-site equilibration) after the intravenous administration of alfentanil. The effect-site equilibration time for alfentanil is 1.4 minutes, compared with 6.8 and 6.2 minutes for fentanyl and sufentanil, respectively. Pharmacokinetics (see Table 3-5) The rapid effect-site equilibration characteristic of alfentanil is a result of the low pK of this opioid, so that nearly 90% of the drug exists in the nonionized form at physiologic pH. The nonionized fraction readily crosses the blood-brain barrier. The rapid peak effect of alfentanil at the brain is useful when an opioid is required to blunt the response to a single, brief stimulus, such as tracheal intubation or the performance of a retrobulbar block. Metabolism Noralfentanil is the major metabolite recovered in urine, with <0.5% of an administered dose of alfentanil being excreted unchanged. The efficiency of hepatic metabolism is emphasized by a clearance of about 96% of alfentanil from the plasma within 60 minutes of its administration. Population variability in P-450 3A4 (CYP3A) activity is the most likely mechanistic explanation for the interindividual variability in alfentanil disposition. Context-Sensitive Half-Time The context-sensitive half-time of alfentanil is longer than that of sufentanil for infusions up to 8 hours in duration (see Fig. 3-2). The Vd of alfentanil equilibrates rapidly, and peripheral distribution of the drug away from the plasma is not a significant contributor to the decrease in its plasma concentration after discontinuation of the alfentanil infusion. Clinical Uses Alfentanil has a rapid onset and offset of intense analgesia, reflecting its very prompt effect-site equilibration. This characteristic of alfentanil is used to provide analgesia when the noxious stimulation is acute, but transient, as associated with laryngoscopy and tracheal intubation and the performance of a retrobulbar block. For example, the administration of alfentanil, 15 Â!g/kg IV, about 90 seconds before beginning direct laryngoscopy is effective in blunting the systemic blood pressure and heart rate response to tracheal intubation. Alfentanil, 150 to 300 Â!g/kg IV, administered rapidly, produces unconsciousness in about 45 seconds. After this induction, the maintenance of anesthesia can be provided with a continuous infusion of alfentanil, 25 to 150 Â!g/kg per hour, combined with an inhaled drug. Alfentanil increases biliary tract pressures similarly to fentanyl, but the duration of this increase is shorter than that produced by fentanyl. (pg 89) Derivatives of meperidine (fentanyl, sufentanil, alfentanil) have been associated with adverse reactions in patients treated with MAO inhibitors. (pg 339)

__Opioid receptor signaling__ Following binding of a ligand to the opioid receptor a conformational change in the three-dimensional structure of the receptor will occur so that the ligand-receptor complex reaches a state of high affinity for intracellular G a /Gp Y heterotrimeric G proteins [28]. This promotes a GDP/GTP exchange, resulting in receptor binding of the G-, subunit and liberation of the Gp y subunit. G a GTP and Gp Y target intracellular effectors including adenylate cyclases and Ca 2 + /K + ion channels, respectively (Fig. 31.5). In particular, inhibitory G, /i/o subunits show a preference for opioid receptors, resulting in reduced intracellular cAMP levels, inhibition of Ca 21 current, and increase in extracellular K + current [28]. This will finally lead to a decrease in the neuronal excitation and to an inhibition of neurotransmitter and/or neuropetide release. Hydrolysis of GTP to GDP returns the receptor-bound G a subunit to its inactive state and subsequent dissociation. On the intracellular side of the opioid receptor the third intracellular loop and the carboxy terminal are mainly responsible for binding of the ( j y subunit. Since there are also several putative phosphorylation sites as targets for different intracellular kinases, phosphorylation of the opioid receptor will interfere with the effective G-protein coupling of the receptor, a condition that has been described for the phenomenon of opioid tolerance (see below). According to their ability to initiate such G-protein coupling of opioid receptors, their ligands are classified into full opioid agonists, partial agonists, antagonists, and mixed agonist-antagonists (Table 31.3). Opioid agonists elicit typical opioid effects via a reversible receptor G-protein coupling. Full opioid agonists (e.g., fentanyl, sufentanil) are highly potent and require only little receptor occupancy for maximal response. Partial opioid agonists (e.g., buprenorphine) require a higher receptor occupancy for maximal efficacy, which is usually lower than that of the full agonists.
 * From Anesthetic Pharmacology**

__Mechanisms of analgesic actions__ A comparison of p-opioid receptor binding and mRNA expression in the brain identified overlapping areas of high opioid receptor density as possible central sites of analgesic actions such as the thalamus, hypothalamus, insular cortex, amygdala, cingulate gyrus, locus coeruleus, and periaqueductal gray [29], This was confirmed by visualization of central opioid receptors with p-, 8-, and K-opioid receptor-specific immunohistochemistry [30], More recently, functional imaging studies such as fMRI and PET scans in humans showed similar results using specific pain paradigms and radiolabeled opioid ligands (e.g., n C-carfentanil). An opioid-specific reduction in pain-induced brain activity was mainly observed in the thalamus, insula, and both anterior and posterior cingulate cortex [31-33]. More interestingly, a specific pain paradigm triggered the activation of the endogenous opioid peptide system in humans, which resulted in a competitive displacement of radiolabeled opioid ligands in the above-mentioned brain areas [34,35], Opioid actions within the CNS are well characterized at the locus coeruleus, the periaquaeductal gray (PAG), and the ventral tegmental area, in which a high density and overlap of both opioid receptors and opioid peptides can be identified [36] (Fig. 31.6). In the PAG area administered exogenous opioids bind to opioid receptors and activate descending inhibitory pathways that project to the dorsal horn of the spinal cord to inhibit nociceptive processing [36]. These descending inhibitory pathways are also stimulated by a release of endogenous opioid peptides following certain stressful stimuli. At the level of the spinal cord a high density of opioidreceptor binding sites has been demonstrated within the dorsal horn [37] (Fig. 31.6). Consistently, p-, §-, and K-opioid receptor- specific immunohistochemistry showed distribution in laminae I and II of the spinal cord [30], These opioid receptors are located both presynaptically on central nerve terminals of peripheral sensory neurons and postsynaptically on secondorder spinal cord neurons. Interestingly, a surgical ablation of the incoming sensory neurons (i.e., rhizotomy) leads to a 50% up to 70% loss of presynaptic opioid receptor binding sites [37]. Functional studies show that intrathecal opioids inhibit the Ca 2 influx of incoming peripheral sensory neurons [28,38] and the subsequent spinal release of glutamate and neuropeptides such as substance P [39], In addition, postsynaptic opioid receptors open G-protein-coupled inwardly rectifying K ! (GIRK) channels and hyperpolarize the membrane [40,41], These two mechanisms may underlie the potent endogenous opioid peptides [54], Recent evidence shows that [3-endorphin, enkephalin, and dynorphin and their respective precursors colocalize with processing enzymes in these immune cells, resulting in the vesicular accumulation of peptide end-products [55]. Trigger substances, such as CRH, initiate the Ca 2+ -dependent release of these opioid peptides, which play a role in stress-induced analgesic effects [56,57].