OPIOIDS. Dr S Walton Eastbourne DGH 2012

Size: px

Start display at page:

Download "OPIOIDS. Dr S Walton Eastbourne DGH 2012"

Oliver McLaughlin
5 years ago
Views:

1 OPIOIDS Dr S Walton Eastbourne DGH 2012

2 Learning objectives Terminology Receptors Pharmacology of Opioids Partial Agonist/ antagonist Side effects Bits about some individual drugs

3 Terminology

4 Terminology Opium the sap of the unripe seed pod of Papaver somniferum, referred to as early as 3000 B.C. and found in Spanish burial sites dated 4200 B.C mixture of 20 alkaloids Morphine, Codeine, Papaverine

5 Opiate refers to any agent derived from opium Opioid refers to all substances (exogenous or endogenous) with morphine -like properties The generic term for the class of agents is opioid.

6 Classification Naturally occurring (Alkaloids) derived from the poppy Morphine, Codeine Semisynthetic modification of morphine functional groups Diamorphine, Oxycodone Synthetic Fentanyl, alfentanil, remifentanil, methadone Agonists/partial agonists/mixed agonist antagonist/antagonist

7 Opioid Receptors

8 Opioid receptors Four subtypes named according to pharmacological profiles of compounds that stimulate them or anatomical location International Union of Pharmacology nomenclature µ mu MOP (OP 3) morphine δ delta DOP (OP 1) vas deferens κ kappa KOP (OP 2) ketocyclazocine Nociceptin NOP (OP 4) Nociceptin (orphanin FQ peptide)

9 Opioid receptors All G-protein-coupled receptors All have seven membrane spanning structure with extracellular N terminal and intracellular C terminal Couple to inhibitory G proteins

10 Effect of ligand binding: G protein Inhibition adenylyl cyclase camp Closure of voltage sensitive calcium channelsprevents Ca ++ influx** Stimulation of potassium efflux (hyperpolarisation) Pre synaptic receptor activation inhibition of neurotransmitter release (e.g. substance P, glutamate) Post synaptic receptor activation inhibition of impulse transmission

11 Endogenous Opioid Peptides Three distinct families of peptides have been identified: the enkephalins, the endorphins, and the dynorphins. Each family is derived from a distinct precursor polypeptide These precursors are now designated as proenkephalin (also proenkephalin A) proopiomelanocortin (POMC) and prodynorphin (also proenkephalin B)

12 Receptors Found In Somatosensory cortex Limbic System HIGHER BRAIN PAG MIDBRAIN Rostral ventromedial medulla HIND BRAIN Dorsal horn (substantia gelatinosa) SPINAL CORD

13 Functions Reduction in afferent signaling of pain Pre and post synaptic inhibition of Substance P Enhancement of descending inhibitory pathways on pain pathway Inhibitory descending pathways inhibited by GABA Opioid receptor inhibit GABA release

14 Function of opioid receptors Somatosensory cortex Limbic System PAG? ENHANCE inhibition HIGHER BRAIN MIDBRAIN Rostral ventromedial medulla ENHANCE inhibition HIND BRAIN Dorsal horn (substantia gelatinosa) INHIBIT Pain pathway SPINAL CORD

15 Pharmacology

16 Pharmacokinetics Opioid Terminal t1/2 (h) t1/2α (min) Vd L/kg Cl L/min Rel lipid sol pka % ionised Protein binding Morphine Diamorphine Fentanyl Alfentanil Remifentanil Meperidine

17 Opiate Receptors and effect of Agonist Mu 1 (µ 1 ) Mu 2 (µ 2 ) Kappa analgesia, euphoria constipation, respiratory depression spinal analgesia, dysphoria Delta unknown

18 µ-receptor Binding Affinities Opioids Binding Affinity Sufentanil 0.1 Fentanyl 1.6 Morphine 5.7 Alfentanil 19.0 Meperdine Binding Affinity is measured by the equilibrium inhibition constant (Ki) for [H*] sufentanil (nm). The lower the value of (Ki), the Higher the binding affinity for the µ-receptor.

19 Structure activity relationship Alkaloids are a phenanthrene derivative a 3 ring structure Morphine has an alcoholic gp at 3 6 position MORPHINE

20 Structure activity relationship Codeine change in the methyl group on 3 position substituted for the hydroxyl group Reduces potency CODEINE

21 Structure activity relationship DIAMORPHINE Diamorphine Diacetylmorphine Substitution at 3 and 6 increases lipid solubility Acetyl substitution. Markedly increases lipid solubility Crosses BBB easier More potent

22 Structure activity relationship Naloxone Unsaturated substitutions of methyl gp attached to N associated with antagonist activity

23 Partial agonists Mixed agonists/antagonists Antagonists

24 Dose Response Curves

25 Partial Agonists Less steep dose-response curve than agonists Ceiling effect Concomitant administration of a partial and full agonist reduces (antagonizes) the effect of the full agonist Addictive potential

26 Mixed Agonist-Antagonists have divergent activities at different receptors, acting simultaneously as an agonist at one and an antagonist at another

27 Mixed Agonist-Antagonists Opioid Buprenorphine partial Receptor Type µ κ σ δ Butorphanol antagonist agonist agonist - Nalbuphine antagonist partial agonist - Pentazocine antagonist agonist agonist -

28 Side effects

29 Opioid: Pharmacologic Effects Nausea Sedation Confusion Delirium Hallucination Respiratory depression Pruritus Bradycardia Urinary retention Constipation Myoclonic Jerks Seizures Biliary Spasm

30 Tolerance With continued use, progressively more and more opioid is necessary to produce the same effect Pharmacologic property of a class of agents Incomplete cross tolerance

31 Physical Dependence A state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.. Not synonymous with tolerance or addiction

32 Cold Turkey : Opioid Withdrawal Symptoms of opioid withdrawal: Diaphoresis Lacrimation Coryza Tachycardia Abdominal cramps Nausea Vomiting

33 Respiratory Depression responsiveness of brain stem to pco2 Mu mediated Dose dependent Partial have ceiling effect Causes hypercarbia Displacement of CO2 response curve Anti-tussive effect

34 GI Effects Gastric Gastric Emptying Small intestines: Biliary and pancreatic secretions Peristalsis : H 2 O is absorbed Duodenum > ileum. Large intestines: Peristalsis : Increased H 2 O absorption Etiology of constipation

35 GI: Biliary Tree Effects Biliary tract: spasm, especially of the sphincter of Oddi Reversible by naloxone, nitroglycerin Differential degree of spasm: Fentanyl > morphine

36 Nausea and Vomiting Two mechanisms Stimulation of Chemoreceptor trigger zone Vestibular stimulation

37 Hypnotic effects Mood alteration: limbic system Soporific, but arousal possible even at v large doses EEG resembles sleep: shift to slower waves

38 Pruritus Axial: Limited to the face, nasal ala, trunk interneuron activity ( crosstalk ) DHN More common with neuraxial opiates. Centrally mediated µ effect NOT histamine-related Reversible: Small doses of naloxone Small doses of agonists/antagonists

39 GU Effects Ureteral tone & contraction amplitude Urinary urgency = detrusor spasm. Seen frequently

40 Bits about some individual drugs

41 Morphine: pharmacokinetics Weak base: pka 8 therefore ionised in stomach. Unionised in alkaline environment small bowel and absorbed. Extensive first pass metabolism: 30% reaches systemic circulation. 70% metabolised to M3G. Also M6G: 13x more potent than morphine; similar duration of action Excreted in urine; accumulate in renal failure

42 DIAMORPHINE Diacetylated morphine Pro drug. Rapidly hydrolysed by esterases in plasma to 6-0-acetyl morphine then to morphine 1.5-2x as potent as morphine Extensive first pass metabolism- low oral bioavailability High lipid solubility CH3CO replaces OH of morphine at position 3 and 6. Therefore less risk of delayed resp depression than morphine when used via intrathecal route

43 FENTANYL Tertiary amine which is synthetic phenylpiperidine derivative x more potent than morphine Highly selective µ agonist Highly lipid soluble - rapid onset of action and effective by transdermal patch Short duration of action due to redistribution; secondary peak in plasma concentration Inactive metabolites Less histamine release than morphine Metabolised by N dealkylation to norfentanil then hydroxylated May cause chest wall rigidity

44 ALFENTANIL Synthetic anilopiperidine derivative As fentanyl highly selective µ agonist Less lipid soluble than fentanyl but pka 6.5 therefore 9x more unionised at physiological ph and more rapid onset of action Clearance less than fentanyl (50%)but highly protein bound, Vd smaller (20%)and elimination t1/2 therefore shorter Predominantly metabolised by N dealkylation to noralfentanil, 90% of dose appears in urine

45 REMIFENTANIL Highly potent, ultra short acting opioid Unlimited capacity for metabolism by plasma/tissue esterases - context insensitive half life Low lipid solubility, low Vd and 70% bound to plasma proteins Muscle rigidity and bradycardia

46 TRAMADOL Phenylpiperidine analogue of codeine Racemic mixture of 2 enantiomers µ (δ and κ) receptor agonist and inhibits neuronal reuptake of noradrenaline, potentiates release of serotonin and increases descending inhibition of nociception Hypertension and CNS excitation potentiated with MAOIs Has one active metabolite O-demethyl tramadol Elimination t1/2 doubled in renal/hepatic failure Effective in treatment post op shivering

47 Buprenorphine semi synthetic highly lipophilic high affinity but low intrinsic activity at µ receptor, also κ receptor antagonises effect of morphine, not fully reversed by naloxone prolonged analgesia due to high affinity with receptor, longer duration of action than plasma conc suggest High first pass metabolism, can be given sublingually

48 NALOXONE Short acting competitive opioid antagonist Substituted oxymorphone derivative As hydrochloride 0.02 or 0.04 mg/ml IV/IM/subcutaneous Reverses opioid effects at all receptors; greatest affinity for µ receptor Adverse effects include hypertension, pulmonary oedema, cardiac arrhythmias Acts within 2 min, duration 20 min, note shorter than morphine and high dose fentanyl Alleviates pruritus/ respiratory depression associated with epidural/intrathecal opiates

49 Concept: Equianalgesic Dosing All opioids can be made equipotent or equianalgesic by adjusting for physicochemical and pharmacokinetic differences among individual opioids by correcting for dose and route of administration.

OP01 [Mar96] With regards to pethidine s physical properties: A. It has an octanol coefficient of 10 B. It has a pka of 8.4

Opioid MCQ OP01 [Mar96] With regards to pethidine s physical properties: A. It has an octanol coefficient of 10 B. It has a pka of 8.4 OP02 [Mar96] Which factor does NOT predispose to bradycardia with