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39 Cards in this Set

  • Front
  • Back
Receptor Types
- 3 major classes: miu, delta, and kappa
- they are G-protein linked receptors, coupled to inhibition of adenylyl cyclase, activation of receptor-operated potassium channels, and suppression of voltage-operated Ca channels
- analgesia, euphoria, resp depression, and physiological dependance result from activation of miu receptors
Cellular Actions of Opioids
2 actions

1. close voltage-gated Ca channels on PRESYNAPTIC nerve terminals --> reduce NT release

2. open K channels --> hyperpolarization --> inhibition of POSTSYNAPTIC neurons
Analgesic Effects of Opioids
arise from their ability to directly inhibit the ascending transmission of nociceptive info from the spinal cord dorsal horn and to indirectly activate pain-inhibitory circuits
Spinal Analgesia
- all three types of receptors present in dorsal horn of spinal cord (pain tranmission neurons) and presynaptically on the primary afferents relaying the pain
- Actions: inhibit release of excitatory NT (substance P and glutamate) from primary afferents; directly inhibit dorsal horn pain transmission
- thus spinal analgesics provide regional analgesic effects while min the unwanted resp depression, nausea/vomit, and sedation that occur from supraspinal axns
Supraspinal Analgesia
- pain-inhibitory descending neurons send processes to spinal cord and inhibit pain transmission neurons
- activated by opioids resulting from the inhibition of inhibitory neurons
Peripheral Analgesia
- there are opioid miu receptors on peripheral terminals of sensory neurons
- stimulation of peripheral miu receptors decreases sensory neuron activity and NT release
CNS Effects of Opioids
- Analgesia
- Euphoria
- Sedation and drowsiness (ameliorated w/ amphetamine, methylphenidate, or modafil)
- Resp depression
- Cough suppression
- Miosis
- Truncal rigidity (axn at supraspinal levels)
- Nausea and vomiting (CTZ)
Peripheral Effects of Opioids
- Hypotension (inhibition of vasomotor centre in brainstem causing vasodilation, inhibit baroreceptor reflex, increase histamine)
- GIT - constipation
- Biliary tract - contract biliary SM
- Gentourinary tract - dec renal plasma flow --> depressed renal fxn
- Uterus - prolong labor
- Neuroendocrine - stimulate release of ADH, PRL, and somatotropin, and inhibit LH)
- Pruritis
Metabolism of Opioids
- opioids converted to polar metabolites (mostly glucuronides) that are excreted by the kidneys
- morphine --> M3G (neuroexcitatory) + M6G (active metabolite w/ analgesic potency 4-6x that of parent compound) [both cant cross BBB so not sig in CNS effects]
- Heroin --> morphine --> glucuronic acid
- Acc of meperidine and normeperidine may occur in pts w/ dec renal fxn; in high doses normeperidine --> seizures
- Fentanyl met by CYP3A4
- Codeine, oxycodone, and hydrocodone met by CYP2D6 --> prod of metabolites of greater potency (ex: codeins --> morphine)
Genetic polymorphisms of CYP2D6
- linked to variation in analgesic response seen among pts
- codeine --> morphine important b/c codeine has low affinity for opioid receptors
Clinical Uses of Opioid Analgesics
- Analgesia (mod-severe pain)
- Acute pulmonary edema - IV morphine (dyspnea from pulmonary edema assoc w/ LVF)
- Cough - dextrometorphan, codeine, levopropoxyphine, noscapine
- Diarrhea - loperamide, diphenoxylate; if diarrhea b/c of infection, chemotherapy indicated
- Shivering - meperidine (axn on alpha-2 adrenoceptors)
- Anesthesia - premedicant drug (sedative, anxiolytic, analgesic); intraoperative; regional analgesic (admin into epidural/subarachnoid)
Adverse Effects of Opioid Analgesics
- Resp depression
- Nausea
- Constipation
- Urinary retention
- Hypotension
- Sedation
- Drowsiness
- Miosis
Tolerance, Dependence, Addiction
- frequent admin --> loss of effectiveness (tolerance)
- physio. dependance --> occurrence of w/drawal or abstinence syndrome
- addiction - euphoria, indiff to stimuli, and sedation esp when given IV promote compulsive use
Contraindications/Cautions in Therapy
- Combining full agonist with partial agonist opioids should be avoided
- Pts w/ head injuries (CO2 retention --> cerebral vasodilation)
- Pregnancy (fetal w/drawal sx)
- Pts w/ impaired pulmonary fxn
- Pts w/ impaired hepatic fxn
- Pts w/ impaired renal fxn (half-life of opioids can be prolonged)
- Pts w/ endocrine disease (adrenal insufficiency or hypothyroidism --> prolonged/exaggerated response)
Drug Interactions
- Sedative-hypnotics = increased CND depression (esp resp)
- Antipsychotics = increased sedation and accentuated CV effects
- MAO inhibitors - meperedine + MAOI = life-threatening rxn (excitement, muscle rigidity, hyperthermia, unconsciousness) [similar rxns seen w/ tramadol + MAOI]
Strong Agonists
Morphine
Hydromorphine and Oxymorphone
Heroin
Meperidine
Fentanyl
Methadone
Levorphanol (closley parallel morphine)
Morphine
- High affinity for miu receptors and low affinity for delta and kappa receptors
- standard tx
Hydromorphone and Oxymorphone
- strong agonists useful in treating severe pain
Heroin
- rapidly hydrolyzed --> 6-MAM --> morphine
- both heroin and 6-MAM are more liposoluble than morphine and enter the brain more readily
- morphine and 6-MAM are responsible for pharmacological actions of heroin
Meperidine
- predom miu receptor agonist
- has significant antimuscarinic effects, which may be a contraindication if tachycardia would be a problem
- negative inotropic action on heart
- large doses = tremors, muscle twitches, dilated pupils, hyperactive reflexes, convulsions (b/c of acc of normeperidine which has a half-life of 15-20 hrs compared to 3 hrs for meperidine)
- decreased renal or hepatic fxn increases likelihood of toxicity
Meperidine - Drug Interactions
Serotonin syndrome - delirium, hyperthermia, headache, rigidity, convulsions, coma, death
- rxn may be due to ability of meperidine to block neuronal reuptake of serotonin and resulting serotonergic overactivity
- so meperidine should NOT be used in pts taking other serotonergic agents such as MAOI
Fentanyl
- primarily a miu agonist
- rapid onset; short duration of action
- also includes sufentanil, alfentanil, remifentanil
- fentanyl = 100x more potent than morphine; sufentanil = 1000x
- fentanyl and sufentanil --> anesthetic adjuvants, chronic pain tx
- transdermal patch available, oral transmucosal formation (pain in cancer pts), effervescent buccal tablet
Methadone
- synthetic, orally effective, equal in potency to morphine, BUT LESS EUPHORIA and LONGER duration of action
- miu receptor agonist, NMDA receptor antagonist, and a serotonin and NE reuptake inhibitor
- effective analgesic activity, efficacy by oral route, extended duration of action in suppressing w/drawal sx of pts w/ physical dependence, tendency to show persistent effects w/ repeated admin
- useful drug for detox and maint. of chronic relapsing heroin addict
- no active metabolites so useful in pts w/ renal insufficiency
Methadone - Adverse effects, Uses and Related Compounds
- AE: dose-related QT prolong; torsades de pointes, death
- Uses: relief of chronic pain, tx of opioid abstinence syndromes, tx of heroin users
- Related compound: levomethadyl acetate (even longer half-life than methadone)
Mild to Moderate Agonists
Codeine, Oxycodone, & Hydrocodone
Propoxyphene
Tramadol
Codeine, Oxycodone, & Hydrocodone
- less efficacious than morphine
- rarely used alone; combined w/ aspirin, acetaminophen, and others
- analgesic effect of codeine bc of its conversion to morphine by CYP2D6
- codeine's antitussive axns may involve distinct receptors binding codeine itself
Propoxyphene
- primarily miu receptors
- dextro isomer = analgesic for mild to mod pain
- levo isomer = antitussive
- weaker than codeine (need twice the dose for same effect)
- AE: increased risk of seizures and cardiac conduction abnormalities so should be avoided in elderly
- metabolized --> norpropoxyphene (longer half-life, acc = toxicity)
- controlled substance
Tramadol
- weak miu agonist, NE/serotonin reuptake inhibitor
- useful in neuropathic pain
- inc risk of seizures in pts w/ seizure disorder and those taking medications that lower seizure threshold
- tramadol + serotonergic drug (eg serotonin reuptake inhibitor, TCA, MAOI) should be avoided b/c --> serotonin syndrome
Antimotility Agents
Diphenoxylate and Loperamide
-tx of diarrhea
- miu or delta receptors on enteric nerves, epithelial cells, and muscle
Diphenoxylate
- not used for analgesia
- tx of diarrhea
- schedule V (minimal control b/c abuse is remote)
Loperamide
- potential for abuse is very low b/c of its limited access to brain
- control diarrhea
- available over-the-counter
Mixed Agonist-Antagonist
Pentazocine, Butorphanol, Nalbuphine, Buprenoprhine
- potent analgesics in opioid-naive pts but precipitate w/drawal in pts who are physically dependent on opioids
- poor choice for pts w/ severe pain or as a routine analgesic b/c dosing is limited by a ceiling effect
Pentazocine, Butorphanol, Nalbuphine
Pentazocine: kappa agonist and a miu antagonist/partial agonist

Butorphanol: kappa agonist and a miu antagonist/partial agonist

Nalbuphine: kappa agonist and a miu antagonist

All 3: psychotomimetic effects
Buprenorphine
- partial miu agonist and kappa antagonist
- management of opioid addiction
- tx initiated w/ buprenorphine alone and then with adding naloxone to minimize abuse potential
- pychotomimetic effects uncommon
Caution for Mixed Agonist-Antagonist
- care should be taken not to administer any partial agonist or drug w/ mixed opioid receptor actions to pts receiving pure agonist drugs b/c of the unpredictability of both drugs' effects: reduction of analgesia or precipitation of an explosive abstinence syndrome can result
Opioid Antagonists
Naloxone, Naltrexone, and Nalmefene
Naloxone, Naltrexone, and Nalmefene
- high affinity for miu receptors
- lower afffinity for kappa and delta but can reverse the action of agonists at kappa and delta receptors
- Naloxone = tx of acute opioid overdose
- Naltrexone = long duration of action so is proposed as maint drug for addicts in tx programs
- Naltrexone decreases craving for alcohol in chronic alcoholics
Antitussives
- opioid analgesic --> suppression of cough
- different receptors than those assoc with other actions of opioids
- Dextrometorphan, codeine, levopropoxyphene, noscapine
- should be used w/ caution in pts taking MAOIs
Dextrometorphan

Codeine

Levopropoxyphene
Dextrometorphan - dextro isomer of a derivative of levorphanol

Codeine - useful antitussive at doses lower than those required for analgesia

Levopropoxyphene - isomer of weak opioid agonist dextropropoxyphene