Opioid Agonists and Antagonists PDF

OPIOID AGONISTS AND ANTAGONISTS Vaidehi V. Paranjape BVSc, MVSc, MS, DACVAA Department of Small Animal Clinical Sciences VIRGINIA - MARYLAND College of Veterinary Medicine LESSON OBJECTIVES 1. Mechanism of action 2. Classification based on drug-receptor affinity 3. Potency Vs. Efficacy 4. Pharmacody...

OPIOID AGONISTS AND ANTAGONISTS Vaidehi V. Paranjape BVSc, MVSc, MS, DACVAA Department of Small Animal Clinical Sciences VIRGINIA - MARYLAND College of Veterinary Medicine LESSON OBJECTIVES 1. Mechanism of action 2. Classification based on drug-receptor affinity 3. Potency Vs. Efficacy 4. Pharmacodynamic considerations 5. Selection of opioids 6. Opioid reversal 7. Clinical use OPIOID RECEPTOR Serpentine molecule embedded in cell membrane ❖ One terminal ending exposed to extracellular environment ❖ Other terminus is intracellular Mu (m), Kappa (k), Delta (d), and Sigma (s) opioid receptor types OPIOID RECEPTOR Ca2+% Ca2+% K+# Ca2+% NH2$ Ca2+% K+# Ca2+% K+# K+# 7-transmembrane G protein-coupled receptor β" Ca2+ Channel γ" G Protein α" 1" Ca2+% HOOC$ α" + β" K+ Channel 2" K+# γ" cAMP produc on 3" Presynaptic- inhibits neurotransmitter release (ACh, dopamine, norepinephrine, Substance P, and GABA) Postsynaptic- decreases neuronal excitability through hyperpolarization of the cell membrane RECEPTOR SUBTYPES  Mu Receptors Analgesia (supraspinal and spinal) Euphoria, ventilatory depression, bradycardia, urinary retention, physical dependence  Kappa Receptors Analgesia (supraspinal and spinal) Dysphoria, sedation, miosis  Delta Receptors Analgesia (supraspinal and spinal) Ventilatory depression, urinary retention, modulation of mu activity NH2 NH2 β HOOC γ α NH2 β HOOC γ α β HOOC γ α RECEPTOR DISTRIBUTION Tissues Cortex - Brain Diencephalon 1 - Spinal cord Midbrain - Gastrointestinal tract - Urinary tract Medulla - Synovium Spinal cord - Leukocytes - Uterus 2 3 DRUG AFFINITY PURE OPIOID AGONIST Produces dose‐dependent increase in effect until maximum stimulation of receptor achieved Effect increases as dose (or plasma concentration) increases until it plateaus at a maximum effect DRUG AFFINITY PARTIAL OPIOID AGONIST Binding at a given receptor causes an effect that is less pronounced than that of a pure agonist Produces dose‐dependent increase in effect, but plateaus at maximum effect less than maximum effect of a full agonist DRUG AFFINITY OPIOID AGONIST-ANTAGONIST Causes stimulatory effect at one receptor but blocks effect or causes less pronounced effect at another Effects of these drugs depend on previous opioid exposure DRUG AFFINITY OPIOID ANTAGONIST Binds to receptor with high affinity and produces no effect ‘Reverses’ receptor‐mediated effects of agonist by inhibiting binding of agonist & displacing previously bound agonists due to greater receptor affinity of antagonist CLASSIFICATION Full Agonist Morphine, Hydromorphone, Methadone, Oxymorphone, Fentanyl NH2$ α" +" β" Partial Agonist α" +" β" Agonist- Antagonist Butorphanol α" +" β" NH2$ γ" α" β" NH2$ γ" γ" α" Naloxone, Nalmefene, Naltrexone β" k! β" m β" HOOC$ d! γ" α" HOOC$ NH2$ HOOC$ NH2$ γ" α" +" β" NH2$ NH2$ γ" α" NH2$ γ" α" β" γ" α" γ" k! β" HOOC$ d! HOOC$ α" +" β" Antagonist γ" γ" α" γ" γ" α" β" β" k! β" d! HOOC$ HOOC$ m HOOC$ NH2$ γ" α" β" HOOC$ m HOOC$ k! NH2$ γ" α" β" HOOC$ NH2$ Buprenorphine m NH2$ γ" α" d! β" HOOC$ γ" α" Which of the following best describes the opioid and its classification? A. Buprenorphine, full  agonist B. Methadone, partial  agonist C. Fentanyl,  antagonist and  agonist D. Oxymorphone, full  agonist POTENCY Vs EFFICACY Different Potency Different Potency and Efficacy Max Effect Response Response Max Effect Fentanyl Morphine Log Dose Max Effect Buprenorphine Morphine Log Dose PHARMACODYNAMICS Lipophilic and well absorbed IM, SQ, and PO High bioavailability via SQ & IM routes Substantial first pass metabolism results in low oral bioavailability. Transdermal fentanyl: bypasses GI tract & does not lead to first pass hepatic effect; variable absorption Transmucosal buprenorphine: Bypasses first pass metabolism; variable absorption PHARMACODYNAMICS Morphine is hydrophilic, hence best choice for epidural use P-glycoprotein efflux pumps limit CNS effects Limit access across blood brain barrier E.g. Loperamide → reduced central effects Homozygous mutation in MDR1 gene Border Collies, Australian & German Shepherds, Shetland & English Sheepdogs, Whippets Significant central effects Morphine, methadone, fentanyl, buprenorphine, oxycodone PHARMACODYNAMICS Metabolized through hepatic microsomal enzyme systems Morphine – Phase II glucuronidation to morphine‐3‐glucuronide EXCEPTION: Cats (poor glucuronidation; rapidly metabolizes morphine through sulfate conjugation) Elimination through biliary or renal excretion Increased elimination time in geriatric patients Remifentanil metabolism is via plasma esterase CENTRAL NERVOUS SYSTEM EFFECTS 1. Analgesia Inhibition of presynaptic neurotransmitter release & postsynaptic hyperpolarization of neuronal membranes → decreased excitability → decreased transmission within spinal cord Upregulation of supraspinal descending antinociception pathways Epidural → saturate spinal opioid receptors →effects on C‐fiber & A‐δ fiber nociceptors CENTRAL NERVOUS SYSTEM EFFECTS 2. Sedation Dose-dependent sedation; more profound sedation with phenothiazines & alpha-2s 3. Excitation High dose or rapid IV → excitation (high plasma concentration quickly achieved) Cats & horses can exhibit dysphoric/excitatory behavior lasting few hours CENTRAL NERVOUS SYSTEM EFFECTS 4. Dysphoria and Euphoria Vocalizing, thrashing, ataxia, hypersensitivity 5. Thermoregulation Hypothermic response: dogs, rabbits, birds (more profound with phenothiazines, inhalants) Hyperthermic response: cats, horses, ruminants, pigs Cats: hydromorphone, morphine, buprenorphine, butorphanol; up to 5 hours post extubation RESPIRATORY EFFECTS 1. Direct depression of respiratory centers in brainstem Mediated by supra spinal mu2 opioid receptors 2. Decreased responsiveness to increased CO2 3. Dose dependent respiratory depression Caution during increased ICP, lung disease 4. Anti-tussive effects (e.g. Butorphanol, hydrocodone) 5. Panting 6. Opioids cross placenta → respiratory depression of neonates CARDIOVASCULAR EFFECTS 1. Bradycardia Opioid-induced medullary vagal stimulation Second-degree atrioventricular block Anti-muscarinics block or reverse this effect Caution in young patients 2. Minimal effects on myocardial contractility, cardiac output, arterial blood pressure at clinical doses OTHER EFFECTS 1. Propulsive peristaltic contractions decreased Constipation, ileus: concerning in horses & ruminants 2. Non-propulsive peristaltic contractions increased Occasionally causing defecation Dogs > Cats 3. Histamine release E.g. Morphine, Meperidine 4. Nausea and Vomiting Direct stimulation of CTZ, IV < IM route OTHER EFFECTS 5. Urinary effects  effect: increase ADH and natriuretic peptide; decrease urine production;  effect: decrease ADH; diuresis 6. Immune system effects Morphine, fentanyl, codeine, methadone = immunosuppressive 7. Ocular effects Dogs, rabbits, rats → miosis Cats, horses, ruminants → mydriasis Which of the following opioids should be avoided in a dog diagnosed with cutaneous and visceral mast cell tumors? A. Buprenorphine B. Methadone C. Morphine D. Oxymorphone SELECTION OF OPIOIDS 1. Degree of pain 2. Duration of the procedure/pain 3. Sedation requirement 4. Adverse effects 5. Specific species requirements/ limitations 6. Available routes of administration 7. Cost MORPHINE full agonist Analgesia: Severe pain Sedation: Excellent sedation Peak Onset: 15 to 30 minutes Duration: 3 to 4 hours Side Effects: – Histamine release – Mania in cats, horses – Vomiting – Renal disease may impair clearance Routes: SQ, IM, IV, Epidural m HYDROMORPHONE full agonist Analgesia: Severe pain Sedation: Good sedation Peak Onset: 15 minutes Duration: 4 to 6 hours Side Effects: – Vomiting if IM – Less histamine release – Panting in dogs – Hyperthermia in cats Routes: SQ, IM, IV m m METHADONE full agonist Analgesia: Severe pain Sedation: Good sedation NMDA receptor antagonist, think chronic pain!! Peak Onset: 15 minutes Duration: 4 to 6 hours Side Effects: – No histamine release – No vomiting – Panting in dogs Routes: SQ, IM, IV FENTANYL full agonist Analgesia: Severe pain Sedation: Good sedation Peak Onset: 6 to 8 minutes Duration: 30 to 60 minutes Side Effects: – No histamine release – No vomiting – Bradycardia – Chest rigidity (decreased compliance) Routes: IM, IV, Transdermal m BUPRENORPHINE partial agonist Analgesia: Mild to moderate pain Sedation: Minimal sedation Peak Onset: 45 to 90 minutes Duration: 6 to 8 hours Side Effects: – High affinity for receptor – Plateau effect (ceiling effect) – Not effectively reversed with antagonist Routes: PO, Transmucosal, IM, IV m BUTORPHANOL Agonist-antagonist m k Analgesia: Mild pain Sedation: Good sedation Peak Onset: 10 to 15 minutes Duration: 1 to 2 hours Side Effects: – High affinity for receptor – Plateau effect (ceiling effect) – Can reverse effects of pure mu agonists Routes: SQ, IM, IV OPIOID ANTAGONIST Opioid overdose or excessively sedated or obtunded from opioids Reverse both adverse and analgesic effects Effects: Increased alertness, responsiveness, coordination, increased awareness of pain NALOXONE (Prototypical mu antagonist) Onset: 2-5 min 0.01-0.04 mg/kg IV → lasts 20-40 min Watch for recurrence of opioid effects (e.g. resedation) Which of the following opioids will be the best analgesic option in a cat that needs an abdominal explore, but is also presented with hepatic and renal dysfunction? A. Buprenorphine B. Remifentanil C. Methadone D. Morphine CLINICAL USES 1. SYSTEMIC USE: Acute and chronic pain 2. REGIONAL OR LOCAL ADMINISTRATION Epidural Intra-articular Topical application on cornea Adjunct to local anesthetics 3. PARENTERAL SUSTAINED RELEASE: Transdermal Fentanyl and Buprenorphine 4. INJECTABLE SUBCUTANEOUS: Buprenorphine in sustained release polymer (3 day analgesia) or high concentration (24 hour analgesia) CLINICAL USES 5. ORAL OPIOIDS: Codeine, Hydrocodone TRAMADOL ▪ Centrally acting analgesic, atypical opioid ▪ mu opioid agonist, inhibits serotonin & norepinephrine reuptake ▪ 5 to 10 times less potent than morphine ▪ Metabolism to O-desmethyltramadol (M1) via P450 enzyme system → analgesia ▪ Dogs & horses: less M1 metabolite production→ weak analgesia Cats: substantial M1 production → effective analgesia CHAPTER 11 CHAPTER 5