Opioids analgesics and antagonists By S.Bohlooli PhD

Narcotics Those drugs which possess both an analgesic (pain relieving) and sedative properties. (Not Correct term) Opioid refer to drugs in a generic sense, natural or synthetic, with morphine- like actions

Classification of OPIOIDS Natural phenanthrene morphine 10% codeine 0.5% thebaine 0.2% semisynthetic heroin oxymorphone Hydromorphone synthetic Phenylpiperidines (meperidine –fenatnyl) Phenylheptylamines (methadone – levomethadyl ) morphinians (Levorphanol) benzamorphans (pentazocine – dezocine)

Classification of OPIOIDS Strong agonist: Phenanthrenes: morphine, hydromorphone, oxymorphone, heroin Phenylheptylamines: methadone, levomethadyl Phenylpiperidines: meperidine, fentanyl, sufentanyl, alfentanyl, remifetanyl Morphinans: levorphanol Mild to moderate agonists: Phenanthrenes: codeine, oxycodone, dihydrocodeine, hydrocodone Phenylheptylamines: propexyphene Phenylpiperidines: diphenoxylate, difenoxine, loperamide Mixed receptor action: Phenanthrenes: nalbuphine, bupronorphine Morphinans: butorphanol Benzomorphanes: pentazocine, dezocine Miscellaneous: tramadol Opioids antagonists: naloxone, naltrexone, nalmefene

Chemistry Morphine pentacyclic alkaloid (five ring structure) phenolic groups (s/a hydroxyl, alcoholic, OH) at position 3 and 6 modifications at those positions changes pharmacokinetics and potency of drug nitrogen at 16 position (n16) changing it by adding an alkyl group converts it to naloxone (i.e. go from a agonist to an antagonist)

Morphine related opioids

Mepridine related opioids

OPIOID receptors CNS distribution is not uniform 1. cerebral cortex they are at areas concerned with pain receptor locations beginning with highest concentration areas 1. cerebral cortex 2. amygdala 3. septum 4. thalamus 5. hypothalamus 6. midbrain 7. spinal cord

Receptor Stimulation mu Physical dependence Euphoria Analgesia (supraspinal) Respiratory depression

delta sigma kappa Sedation Analgesia (spinal) Miosis analgesia (spinal & supraspinal) release of growth hormone    sigma dysphoria (opposite of euphoria) hallucination (both visual & auditory) respiratory and vasomotor stimulation mydriasis

Opioids’ mechanism of action

Endogenous Opioid Peptides Three distinct families of peptides have been identified: enkephalins endorphins dynorphins the precursors are now designated as: proenkephalin (also proenkephalin A) proopiomelanocortin (POMC) prodynorphin (also proenkephalin B)

Pharmacokinetics of morphine absorption readily absorbed from GI tract, nasal mucosa, lung subcutaneous, intramuscular, and intravenous route distribution Bound & free morphine accumulates in kidney, lung, liver, and spleen CNS is primary site of action (analgesia/sedation)

Pharmacokinetics of morphine metabolism/excretion metabolic transformation in liver conjugation with glucuronic acid excreted by kidney half life is 2.5 to 3 hours (does not persist in body tissue) morphine -3 -glucuronide in main excretion product lose 90% in first day duration of 10 mg dose is 3 to 5 hours

Pharmacokinetics of morphine

Pharmacokinetics of morphine Morphine administration oral morphine not given due to erratic oral availability significant variable first pass effect from person to person and have intraspecies effect (same dose will vary in person day to day) IV morphine acts promptly and its main effect is at the CNS

Pharmacodynamics of Morphine CNS is primary site of action of morphine analgesia sedation euphoria mood change mental cloudiness

Pharmacodynamics of Morphine Morphine analgesia **Changes our reaction and our perception of pain severe cancer pain is tolerated more when person is given morphine relieves all types of pain, but most effective against continuous dull aching pain sharp, stabbing, shooting pain also relieved by morphine

Pharmacodynamics of Morphine Morphine sedation - morphine causes sedation effect, but no loss of consciousness Morphine euphoria sense of well being reason why morphine is abused

Effects of morphine on respiration There is a primary and continuous depression of respiration related to dose decrease rate decrease volume decrease tidal exchange

Pharmacodynamics of Morphine mu receptor activation produces respiratory depression; with increase in dose can cause further respiratory depression CNS becomes less responsive to pCO2 thereby causing a build up of CO2 rhythm and responsiveness causes irregular breathing patterns; one will see periods of apnea

Pharmacodynamics of Morphine nausea and vomiting – Stimulation of CTZ, in brain stem stimulation by stretch receptors causes nausea and vomiting has afferents from gut and ear involved in motion sickness

Pharmacodynamics of Morphine pupil size morphine causes miosis (pinpoint pupils) kappa receptor effect pinpoint pupils still responsive to bright light oculomotor nerve (CN3) is stimulated by kappa receptor site if kappa receptor is blocked, mydriasis from sigma effect will result atropine partially blocks effect indicating parasympathetic system involved

Pharmacodynamics of Morphine Acute overdose High doses (overdose situation) of morphine excitatory and spinal reflexes high doses of many OPIOIDs cause convulsions due to stimulation at sigma receptor

Pharmacodynamics of Morphine Cardiovascular effects Cardiovascular effects of morphine lead to vasodilation, thus a decrease in blood pressure morphine causes the release of histamine and suppression of central adrenergic tone and suppression of reflex vasoconstriction

Pharmacodynamics of Morphine Morphine effects on the gastrointestinal system increase in tone and decrease in mobility leads to constipation decreased concentration of HCl secretion increased tone in stomach, small intestine, and large intestine delay of passage of food (gastric contents) so more reabsorption of water **tolerance does not develop (i.e. same amount of effect each time) to this constipation effect

Pharmacodynamics of Morphine Morphine effects on various smooth muscles biliary tract marked increase in the pressure in the biliary tract 10 fold increase over normal (normal is 20 mm H20 pressure) increase due to contraction of Sphincter of Oddi urinary bladder tone of detrusor muscle increased feel urinary urgency have urinary retention due to increased muscle tone where sphincter closed off bronchial muscle bronchoconstriction can result **contraindicated in asthmatics, particularly before surgery uterus relaxation of uterus can prolong labor

Pharmacodynamics of Morphine Neuroendocrine Effects: inhibit the release of: gonadotropin-releasing hormone (GnRH) corticotropin-releasing factor (CRF), luteinizing hormone (LH) follicle-stimulating hormone (FSH) ACTH, and - endorphin; testosterone cortisol. Secretion of thyrotropin is relatively unaffected.

Tolerance to morphine nausea analgesia sedation respiratory depression cardiovascular euphoric not to: miosis Constipation Convulsive effect

Toxicity of morphine Acute overdose respiratory depression pinpoint pupils (miosis) coma Treatment 1. establish adequate ventilation 2. give OPIOID antagonist (naloxone)

Toxicity of morphine Naloxone it has no agonist activity it displaces morphine from all receptors, reverses all of the effects of morphine its effects are immediate (3-5 min) duration is 30-45 minutes must be reinjected often

Therapeutic uses of morphine relief of pain terminal illness preoperative medications postoperative medications acute pulmonary edema constipating effect cough obstetrical analgesia ?

Drug interactions with Opioids **in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation)

Drug interactions with Opioids OPIOID and phenothiazines produces an additive CNS depression as well as enhancement of the actions of OPIOID (respiratory depression) this combination may also produce a greater incidence of orthostatic hypotension OPIOID and tricyclics antidepressants can produce increased hypotension meperidine and MOA inhibitors results in severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression OPIOID and barbiturates increased clearance morphine and amphetamine enhanced analgesic effect

Codeine change in the methyl group on 3 position of morphine (substituted for the hydroxyl group) one tenth the potency (analgesic properties) of morphine absorbed readily from GI tract the absorption is more regular than morphine and more predictable given orally metabolized like morphine through glucuronic acid physical dependence is necessity of drug so you don't go through withdrawal tolerance and physical dependence is protracted from morphine since potency of codeine is low withdrawal from codeine is mild in relation to morphine antitussive drug for cough

Heroin (diacetylmorphine) at 3 and 6 hydroxy positions, there are acetyl groups instead of hydroxyl groups it is anywhere from 3 to 4 times the analgesic potency of morphine heroin is the most lipophilic of all the OPIOIDs morphine is the least lipophilic of all the OPIOID OPIOID withdrawal is NOT fatal

Heroin (diacetylmorphine) When heroin is ingested, it crosses the blood brain barrier rapidly (morphine crosses slow) where it is hydrolyzed to monoacetyl morphine (acetyl group got cleaved off) and then it is hydrolyzed to morphine making more of the drug in the brain making it 3 to 4 times more potent withdrawal symptoms of heroin similar to morphine, but more intense (rebound effect) mydriasis diarrhea vasoconstriction dysphoria etc.

Hydromorphone Hydromorphone have ketone at 6 hydroxyl position of morphine also strong agonist 9 times more potent than morphine more sedation than morphine so less euphoric feeling so not abused much less constipation does not produce miosis tolerance and physical dependence is more intense than morphine because of its high potency respiratory depression same as morphine

Fentanyl synthetic drug different structure than morphine 80 to 100 times more potent than morphine rapidly acting drug used as preoperative medication short acting (30-45 min) onset of action is 5 minutes very high potency highly abused

Meperidine produced in 1940's same CNS actions as morphine wanted drug with less addictive liability than morphine, but it has same addictive liability as morphine same CNS actions as morphine sedation, analgesia, respiratory depression potency same as morphine unlike morphine: more respiratory depression more bronchoconstriction activity less constipation no antitussive activity **it causes mydriasis (not miosis) toxic effects similar to atropine drug absorbed orally drug most abused by health care professionals due to its availability withdrawal similar to morphine Less sedative ( preferred to morphine in obstetrics)

Methadone pharmacological activity similar to morphine, same potency as morphine long duration of activity absorbed well orally 16 to 20 hour duration of action powerful pain reliever used in maintenance program for narcotic treatment

Diphenoxylate (Lomotil) can be OTC drug now **therapeutic use is antidiarrhea drug meperidine type drug has very little analgesic properties at therapeutic dose no antitussive effect at high doses it has analgesic effects causes respiratory depression and euphoria at high doses

Tramadol Tramadol (ULTRAM) is a synthetic codeine analog that is a weak m-opioid receptor agonist. Part of its analgesic effect is produced by inhibition of uptake of norepinephrine and serotonin. In the treatment of mild-to-moderate pain, tramadol is as effective as morphine or meperidine. However, for the treatment of severe or chronic pain, tramadol is less effective. Tramadol is as effective as meperidine in the treatment of labor pain and may cause less neonatal respiratory depression.

Tramadol Tramadol is 68% bioavailable after a single oral dose and 100% available when administered intramuscularly. Tramadol is supplied as a racemic mixture, which is more effective than either enantiomer alone. The (+)-enantiomer binds to the m receptor and inhibits serotonin uptake. The (-)-enantiomer inhibits norepinephrine uptake and stimulates a2 adrenergic receptors. Analgesia begins within an hour of oral dosing and peaks within 2 to 3 hours. The duration of analgesia is about 6 hours. The maximum recommended daily dose is 400 mg.

Tramadol Common side effects of tramadol include: nausea, vomiting, dizziness, dry mouth, sedation, and headache. Respiratory depression appears to be less than with equianalgesic doses of morphine, and the degree of constipation is less than that seen after equivalent doses of codeine Tramadol can cause seizures However, the use of naloxone increases the risk of seizure. Physical dependence on and abuse of tramadol have been reported. Because of its inhibitory effect on serotonin uptake, tramadol should not be used in patients taking monoamine oxidase (MAO) inhibitors

Antagonism of Morphine three drugs: naloxone, nalmefene and naltrexone (pure antagonist)

Naloxone no analgesic activity at all competitive antagonist at mu, kappa, and sigma receptor displaces morphine and other OPIOID from receptor site reverses all actions of the OPIOID and does it rather quickly it will precipitate withdrawal person on heroin, then naloxone will precipitate withdrawal, but naloxone effects are seen in the first five minutes and it only lasts for 30 minutes: increased blood pressure metabolized same as morphine through glucuronic acid and excreted through kidney

Naltrexone same effect of naloxone except it is used orally so can't use it if for person with acute toxicity long duration of activity single dose block action of heroin effects for 24 hours once stabilized, give patient naltrexone patient get no euphoric effect from heroin so person gets off heroin (negative reinforcement) approved for use by the FDA also used for treatment of alcoholism