Fentanyl

NARCOTICS

1. Fentanyl and Sufentanyl PRESENTER:- Dr. Vishal kumar kandhway

2. INTRODUCTION TO OPIOIDS The word opium is derived from opos , the Greek word for juice, because the drug is derived from the juice of the opium poppy, Papaver somniferum . Opioid refers to all exogenous substances,natural as well as synthetic ,that bind specifically to opiod receptors and produce morphine like effects. Morphine the most well known opioid was isolated in 1803.

3. Classification of Opioids Naturally Occuring Morphine Codeine Papaverine Thebaine Semisynthetic Heroin Dihydromorphone , morphinone Thebaine derivatives (e.g., etorphine , buprenorphine ) Synthetic Morphinan series (e.g., levorphanol , butorphanol ) Diphenylpropylamine series (e.g., methadone) Benzomorphan series (e.g., pentazocine ) Phenylpiperidine series (e.g., meperidine , fentanyl , sufentanil , alfentanil , remifentanil )

4. OPIOID RECEPTORS Classified as- mu, kappa and delta receptors G-protein coupled receptors Location Brain : Locus Ceruleus , Periaqueductal gray matter, rostral ventral medulla Spinal Cord : Interneurons , primary afferent neurons in dorsal horn

5. Receptors u(mu) k ( kappa ) d ( delta ) Analgesia ( supraspinal u1 + spinal u2) Analgesia ( spinal k1 ) Analgesia ( spinal + supraspinal ) Respiratory depression Respiratory depression Respiratory depression Sedation Sedation Affective behaviour Euphoria Dysphoria Reinforcing actions Miosis Miosis Muscular rigidity Physical dependence Proconvulsant Reduced g i motility Reduced g i motility Reduced g i motility

6. MECHANISM OF ACTION Opioids Bind to extracellular domain of GPC receptor Change in receptor shape Activates G protein G protein bound GDP is replaced with GTP which dissociates into two active sub-units.

7. Opening of inward flowing K+ channel Decreased conductance of volatage gated calcium channel Inhibition of adenylate cyclase Leads to decreased neuronal transmission by inhibition of neurotransmitter release.

8. FENTANYL Phenylpiperidine derivative Synthetic opioid agonist 1 st synthesized in 1960 Potent synthetic narcotic with properties similar to those of morphine 50 to 100 times more potent as compared to morphine

9. PHARMCOKINETICS When given i.v . 75% of the dose undergoes first pass pulmonary uptake, limiting the initial amount of drug reaching the systemic circulation. Lipophilic – readily crosses BBB Blood brain equilibrium time : 6 min Rapid onset of action (produces peak analgesia within 5 min of i.v . injection.) Has shorter duration of action – effect starts wearing off after 30–40 min due to redistribution to inactive sites(fat and skeletal muscle)

10. The elimination T ½ of fentanyl is however longer because of its larger volume of distribution. Plasma concentration of the drug is maintained by slow uptake from inactive sites Metabolised by N- demethylation ( norfentanyl is the principal metabolite) in liver by P450 enzyme Excreted by kidney <10% is excreted unchanged

11. Context sensitive half time Is the time required for plasma concentrations of a drug to decrease by 50% after discontinuation of drug administration. It often cannot be predicted by the elimination half-life because it also depends on drug distribution. It helps explain the duration of action of a drug given by infusion after stopping the infusion.

12.  It reflects several pharmacokinetic principles: 1. Longer the duration of infusion - more of the drug will deposit in the body’s tissues until the tissues are completely saturated. 2. Every drug accumulates to differing extents, which is influenced by the physicochemical properties of the drug.

13. 3. Drugs are removed from the blood through two major mechanisms: Distribution: where the drug moves from the blood into the tissues, e.g., fat. Excretion: where the drug is either metabolized (e.g., by the liver) or excreted from the body unchanged (e.g., in urine). Whether or not the metabolites are active is also important.

14. Fentanyl given as T ½ (‘context‐sensitive’) IV bolus 2 minutes 20 minute infusion 8 minutes 30 minute infusion 12 minutes 60 minute infusion 19 minutes 4 hour infusion 2 hours 8 hour infusion 4 hours 12 hour infusion 5 hours

15. Clinical uses 1-2 ug /kg : provide analgesia 2-20 ug /kg : blunts circulatory response to Direct laryngoscopy for tracheal intubation Sudden change in level of surgical stimulation. 50 – 150 ug /kg : produce surgical anaesthesia Advantage Disadvantage Lack myocardial depressent effect Fail to prevent sympathetic response to painful surgical stimulation No histamine release Unpredictable amnestic effect Suppress stress response Post op depression of ventilation

16. 1. Analgesia Intravenous bolus of fentanyl (1-2ug/ kg) produces potent and short lasting analgesia. 2. Balanced anaesthesia Fentanyl is used as a component of balanced anaesthesia To reduce preoperative pain and anxiety To decrease somatic and autonomic response to airway manipulation To improve hemodynamic stability. Reduce requirement for inhaled anaesthetic Immediate post op analgesia

17. 3. Neurolept analgesia Combination of a major tranquilizer (usually the butyrophenone droperidol ) and a potent opioid analgesic ( fentanyl ) to produce a detached, pain-free state of immobilization and insensitivity to pain. It is characterized by analgesia, absence of clinically apparent motor activity, suppression of autonomic reflexes, maintenance of cardiovascular stability, and amnesia in most patients. The addition of an inhaled anesthetic , usually N2O, improves amnesia and has been called neurolept anesthesia .

18. 4 . Total intravenous anaesthesia : An opioid is combined with another drug more likely to provide hypnosis and amnesia. For example, the combination of alfentanil / fentanyl and propofol produces excellent TIVA. Fentanil provides analgesia and hemodynamic stability while blunting responses to noxious stimuli & propofol provides hypnosis and amnesia and is antiemetic. Profound synergism also exists when more than two agents, such as propofol , alfentanil , and midazolam , are combined.

19. The optimal propofol-opioid concentrations that ensure adequate anesthesia and rapid emergence were determined by computer modeling . The optimal propofol concentration decreases in the order of fentanyl > alfentanil > sufentanil >> remifentanil. A shorter contextsensitive half-time allows the administration of greater amounts of opioid (and less propofol ) during anesthesia without creating prolonged opioid effects.

20. 5. Labour analgesia Given by direct I V route only and not by continuous infusion Dosage Initial dose : 0.5-1 ug /kg iv over 1-2 min. Max initial dose should not exceed 100 ug Wait for 5-10 min for effect If further dose are needed, give 0.5-1 ug /kg over 5-10 min until adequate analgesia or max doses are reached. Maximun hourly dose : 2 ug /kg

21. Monitoring Respiratory rate should be monitored prior to and following every dose. Continuous SPo2 monitoring Neither initial or subsequent dose should be administered if RR < 8/min or SPo2 < 94 %. Narcotics administered during active labour will never completely remove pain. Close observation for signs of adverse reaction

22. 6. Break through cancer pain BTcP episode OTFC Onset Rapid and abrupt Onset of analgesia after 5-10 min Peak Peak intensity reached within 3-5 min Peak analgesic effect after 20 min Duration 15 – 30 min 1 – 2 hours

23. Fentanyl is available as- injectable (50 ug / mL ) transdermal patch sublingual / buccal tablet transmucosal film intranasal

24. Transdermal therapeutic system Produces adequate sustained analgesia by maintaining long term plasma concentration for 3 days. Delivers 75 – 100 ug /hr of fentanyl --- 18 hrs to reach peak concentration. Cancer related pain. If applied preoperatively –decreases the dose of parentral opioid required for postop analgesia. s/e acute toxic delirium

25. Oral transmucosal fenatnyl ( OTMF) easy to use Takes advantage of characteristics of the oral mucosa that facilitate rapid absorption large surface area high permeability high vascularity uniform temperature Associated with high bioavailability, due to avoidance of first‐pass metabolism .

26. Film/ lollipop / tablet applied to buccal mucosa. Delivers 5 – 20 ug /kg Decrease preoperative anxiety and facilitate induction of anaesthesia especially in children. S/e : Increased incidence of post op nausea and vomiting. : Decrease in breathing frequency and arterial oxygenation

27. Iontophoresis Is a technique by which drug passage through the skin is augmented by an external electric current. The fentanyl HCl iontophoretic transdermal system is a novel PCA system for the management of acute moderate to severe post operative pain.

28. SIDE EFFECTS OF FENTANYL Respiratory System-Depression of ventillation ( persistent or recurrent ) CVS-Hypotension and bradycardia ( d/t abolishment of carotid sinus mediated baroreceptore reflex ) CNS- Seizure like activity on rapid i.v injection - Increase in ICP in head injury patients ( by 6-9 mmhg ).

29. SUFENTANYL First synthesized in 1974 Has greater affinity for opioid receptors compared to fentanyl explaining its 10 times analgesic potency to that of fentanyl .

30. Pharmacokinetics 60 % first pass pulmonary uptake Lipophilic ( twice that of fentanyl ) Rapid onest of action Redistribution to inactive tissue sites Vd is less due to high protein binding ( 92.5 % ) Also bound to a1-acid glycoprotein

31. Metabolized by N- dealkylation or O- demethylation Metabolite desmethyl sufentanyl has about 10% of the activity of sufentanyl . < 1% excreted unchanged in urine. High lipid solubility of sufentanyl accounts for increased renal tubular reabsoption and increased hepatic extraction and metabolism, hence a normal renal function is important for the clearance of sufentanyl .

32. Context sensitive half time After termination of continuous infusion the decrease in plasma concentration of drug is accelerated not only by metabolism but also by continued redistribution of sufentanyl in to peripheral tissue compartments ----thus have a more favourable recovery profile if used over a long period.

33. SIDE EFFECTS Respiratory depression Skeletal muscle rigidity Hypotension Bradycardia Nausea and vomitting Pruritus

34. ADVANTAGE OVER FENTANYL More potent Better haemodynamic stability than other opioids Post op recovery is rapid Lesser requirement of post-op analgesia

35. References Miller’s Anaesthesia ; 8 th edition Stoelting’s pharmacology and physiology ;5 th edition Bennett D et al. P&T 2005;30:296–301. Chandler S. Am J Hosp Palliat Care 1999;16:489–491 Simmonds MA. Oncology 1999;13:1103–1108

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