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BSC 2017 - with special emphasis on its pharmacology -

Paulo Sá Rodrigues Consultant Anaesthesiologist, Lisbon, Portugal ESA OLA Subcommittee member, EDAIC examiner and translator [email protected] Conflict of interest declaration WHAT DECLARATION Grants/research support/P.I. No conflict Employee No conflict Consultation fees No conflict Honoraria No conflict Speakers bureau No conflict Company sponsored No conflict Stock shareholder No conflict Spouse/partner No conflict Scientific Advisory Board No conflict Other No conflict

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org • Introduction • Structure, receptors, mechanisms of action • Classification, potency, affinity, Emax curves • Pharmacokinetics – global aspects Outline • Pharmacodynamics – CNS effects • Pharmacodynamics – peripheral effects • Clinical Pharmacology of some selected drugs • References

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Short history and etymology

• : • Word derived from opos, the Greek word for juice, • The drug is derived from the juice of the opium poppy . • : • are drugs derived from opium • include the natural products , , and , • Include many semisynthetic drugs derived from them.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Chemical structures of common opioids

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org OPIOIDS act on RECEPTORS

• Distributed throughout • the brain & spinal cord; • and also outside the CNS – vascular tissues, cardia, airway/lung, gut and cells of the immune system. • Rhodopsin family of GPCRs • μ- receptor (MOR), κ- (KOR), δ-opioid receptor (DOR), and orphanin FQ/nociception (NOP) receptor

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org OPIOID RECEPTORS (contd.)

• Upon activation of the receptors , Gi/Gs coupling causing: • Inhibition of adenylyl cyclase activity • Reduced opening of voltage-gated Ca2+ channels • Stimulation of K+ current through GIRKs (G protein-activated inwardly rectifying K+ channels) • Activation of PKC (phosphokinase C) & PLCβ (phospholipase C-β)

From Millers-anesthesia-7th/chapter-27/figure-27-3

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Classification of Opioid Receptors

Adapted from Atcheson R, Lambert DG. Update on opioid receptors. Br J Anaesth 1994;73:132–134.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Opioids: mechanisms of analgesia

• Directly inhibit ascending transmission of nociceptive information from the spinal cord dorsal horn • Activate pain control circuits that descend from the midbrain, via the rostral ventromedial medulla (RVM), to the spinal cord dorsal horn. • The actions of opioids in the bulbospinal pathways are critical to their analgesic efficacy. From: Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior Anesthes. 2011;115(6):1363-1381. doi:10.1097/ALN.0b013e318238bba6

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Opioids: mechanisms of analgesia

• May also produce analgesia through a peripheral mechanism. • Immune cells infiltrating an inflammatory site may release endogenous opioid- like substances that act on opioid receptors located on the primary sensory neuron (disputed).

From: Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior Anesthes. 2011;115(6):1363-1381. doi:10.1097/ALN.0b013e318238bba6

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org • Agents found throughout the body that act on an opioid receptor • All are derived from distinct large precursor proteins - POMC, preproenkephalin, Endogenous preprodynorphin Opioids • Common amino terminal sequence: TYR-GLY-GLY-PHE- (MET OR LEU) • Principally three classes – , endorphins,

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Exogenous Opioids

• Classified according to • Synthesis • Chemical structure • Potency • Receptor binding • Effect at opioid receptors

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org A. Opioid Agonists: Morphine, Codeine, Meperidine, , , Classification , , by B. Opioid Agonist/Antagonist & Partial Agonist: , , receptor , affinity C. Opioid Antagonists: , , , Naltrindole,

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org • According to the strength or potency based on the plasma concentrations at which they

Classification exert their effects (C50 or the plasma of Exogenous concentration causing a 50% effect) • Strong opioids include fentanyl, Opioids sufentanil, and remifentanil. • Weak opioids include codeine and - Strength - tramadol. • An intermediate group includes morphine, methadone, , and buprenorphine.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Opioid potency comparison

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Opioids sigmoid Emax relationships

From clinical-anesthesia-paul-barash-7th/chapter-19/figure-19-4:

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Opioid Pharmacokinetics (PK)

ESA Basic Sciences Course resume Opioids: Physicochemical Properties

• Ionized fraction • Less lipid soluble • Attached to plasma proteins and not available to diffuse to the action site (the receptor) • However - it is the “effective” form of the molecule – the receptor recognizes the ionized form • Base (free) fraction • More lipid soluble – free to diffuse to the action site

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Physicochemical and Pharmacokinetic Data for Commonly Used Opioid Agonists

Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312. t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the central compartment; Vdss volume of distribution at steady state

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org • Modestly absorbed through GI tract -oral, rectal, • Depends on lipophilicity • High first pass metabolism (FPM) • Morphine - ~25% bioavailability by oral route PK: • Codeine & oxycodone – low FPM Absorption • Well absorbed through SC & IM routes • Nasal route – rapid absorption

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org • High concentrations in highly perfused tissues – brain, liver, kidneys & spleen PK: • In chronic administration – Distribution accumulation can take place & opioids are found in the plasma long after their dosage has been stopped

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org PK: Metabolism

• In liver Morphine  morphine-6-glucuronide, morphine-3- glucuronide These have significant activity themselves. • CYP3A4 & CYP2D6 are involved in biotransformation of morphine congeners like , codeine, fentanyl etc Ex: Increased & Decreased activity of CYP2D6 • Remifentanil metabolized within erythrocyte and tissue nonspecific esterases

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org • In kidneys, M6G & M3G are excreted by glomerular filtration. PK: • Chronic renal failure can cause elevated levels of Excretion these metabolites & lead to adverse effects • Seizures • CNS depression

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Context-sensitive half-times for fentanyl, , sufentanil and remifentanil

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Decline of effect site concentrations of different opioids (simulation)

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Pharmacodynamics (PD)

Central Nervous System effects PD: Variability in opioid effects

• Related to • variability in PK-related parameters • Age, weight, body fat, muscle content, renal/liver function, cardiac output, genetic polymorphism, co- medication • Variability in PD parameters • Different opioid sensitivity • Different pain perception

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org PD: Analgesia

• When given to patients in pain • less intense, tolerable, feel more comfortable with relief of distress • Neuropathic pain responds poorly to opioids • Remifentanil may have a sedative and hypnotic effect* • When given to normal patients • Analgesia • Drowsiness • Changes in mood • Mental clouding

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org PD: Opioids as anesthetics

• EEG • High doses produce high-voltage slow (δ) waves that are suggestive of a state consistent with anesthesia • Similar for fentanyl, alfentanil, sufentanil, and remifentanil • Ceiling effect not leading to burst suppression and flat EEG • Evoked potentials • opioids do not appreciably alter sensory evoked potentials (SEPs) elicited at the posterior tibial or median nerve, • SEPs can be used to monitor spinal cord function during anesthesia with opioids.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org PD: Cerebral Blood Flow and Cerebral Metabolic Rate

• modest decreases in the cerebral metabolic rate (CMR) and intracranial pressure • Opioids also decrease cerebral blood flow (CBF) when combined with N2O • However, opioid-induced neuroexcitation and focal seizure activity can cause regional increases in brain metabolism.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org • Respiratory depression: primary cause of morbidity secondary to opioid therapy

PD: CNS 1. Direct depression of rhythm depression generation in ventrolateral medulla 2. Desensitization of brainstem - Respiration - chemoreceptors which normally respond to rising PCO 2 3. Also desensitize the carotid & aortic chemo sensors which usually respond to hypoxia.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org • Direct inhibitory effect on the cough centre of medulla • No loss protective glottic PD: Effect on function Cough • Centrally acting antitussives: • • codeine, • pholcodeine

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Some opioids at a slightly higher doses can produce epileptogenic activity PD: Seizure • Meperidine () • Frank seizures & myoclonus & • Several mechanisms Convulsions • Inhibition of inhibitory interneurons • Direct stimulatory effects • Actions mediated by non-opioid receptors by their metabolites

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Pharmacodynamics (PD)

Peripheral effects Other opioid-related side effects a) Nausea and vomiting b) Smooth muscle effects c) Skeletal muscle effects d) Histamine release e) Puritus f) Pupil effects g) Diffuse CNS effects h) Cardiovascular effects

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Clinical Pharmacology

Of some selected drugs Morphine

• Multiple routes of administration • Slow rise to peak effect • Active metabolite • Morphine-6-glucuronide is Will contribute to effects with chronic dosing especially in renal failure

Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312. t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the central compartment; Vdss volume of distribution at steady state

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Remifentanil

• Potency 50 to 100X morphine • Main features • Rapid onset and offset • Brevity of action (3’ to 5’) • Total metabolism • Rapid recovery • Metabolism by tissue and plasma esterases to inactive metabolites.

Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312. t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the central compartment; Vdss volume of distribution at steady state

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Remifentanil

• Pharmacokinetics • small Vd • rapid clearance (3l/min), and • low interindividual variability • will accumulate less than other opioids. • context-sensitive half- time) nearly independent of the

Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In infusion duration Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312. t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the central compartment; Vdss volume of distribution at steady state

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Alfentanil

• More rapid onset (effect- site equilibration of 1.4 min) – low pKa • Short elim halt-time but long context sensitive half- time • High interindividual variability in metabolism • Elimination prolonged by liver cirrhosis

Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312. t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the central compartment; Vdss volume of distribution at steady state

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Fentanil

• High potency 100x morphine – due to lipid solubility • Large Vdss 3-5 L • Significant first pass pulmonar uptake 75% • Potential for accumulation

Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312. t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the central compartment; Vdss volume of distribution at steady state

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Sufentanil

• High potency 1000x morphine • Large Vd • Significant first pass pulmonar uptake 60% • Potential for accumulation in obese patients (higher Vd) Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312. t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the central compartment; Vdss volume of distribution at steady state

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Pethidine (Meperidine)

• Potent MOR agonist • Used in post op pain, chronic pain of severe degree & post anesthetic shivering • Its metabolite normeperidine is epileptogenic • It can block neuronal uptake of 5HT3 – can cause serotonin syndrome if used with MAO inhibitors & SSRIs • Concurrent use of Antihistaminics & TCAs can cause additive CNS depression

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Effect in the presence of Agonists • Effect on Acute opioid actions: • Increase in respiratory rate & depth • Reversal of dysphoric & Opioid psychotomimetic effects Antagonists • Overshoot phenomenon • Rebound release of catecholamines  tachycardia, hypertension, ventricular arrhythmias

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org Effect in the presence of Agonists • Effect on Opioid dependant patients: • Moderate to severe withdrawal • Depends on the dose of the and also on the degree Antagonists and duration of dependence • & can reverse the GI effects of opioid dependence without making central withdrawal syndrome.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org References

• Opioids in Medicine– A comprehensive Review on the mode of action and the use of analgesia in different pain states; Enno Freye, Spinger, 1997 • Miller’s Anesthesia, 7th edition • Barash Clinical Anesthesia, 7th edition • Stoelting Pharmacology and Physiology in Clinical Practice, 4th edition • http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1934470#6 8016492

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org