Opioid Flashcards
Enkephalins
Endogenous opioid
Precursor: proenkephalin
Leucine and methionine enkephalins have wide CNS distribution (especially in interneurons, including those in pain pathways)
Most selective for delta receptor and somewhat for Mu
Work on presynaptic and postsynaptic Mu opioid receptors- hyperpolarization
Opioid Pharmacology
Analgesia- most are full agonists and equally effective except codeine and propoxyphene and decrease perception and appreciation of pain
Cough Suppression- codeine and dextromethorphan; directly suppress the brainstem cough centers but may not be mediated by opiate receptors
Anti diarrheal effect and constipation- central and peripheral effects, Mu receptors on GI nerves
Euphoria (rush, high)
Sedation
Respiratory Depression- most serious side effect; decrease in sensitivity of brainstem chemoreceptors to CO2
Nausea- stimulation of chemical trigger zone in area postrema and more when standing
Endocrine effects- decrease LH (Mu effect) and increased ADH secretion- Mu and decrease ADH- kappa
Pupillae constriction- miosis (stimulation of EW nucleus of occulomotor and no tolerance possible)
Peripheral Vasodilation, reduced peripheral resistance, inhibition of baroreceptors reflex- Orthostatic hypotension fainting possible when supine patients assume head up position (release of histamine to cause vasodilation and blunting of vasoconstriction in response to increased Pco2)
Functional affects of acute and chronic opioid use
Desensitization (acute tolerance)- minute to hours; mediated by receptor phosphorylization and then internalization (agonist dependent to enkephalins cause rapid but morphine no internalization); uncoupling from G -protein
Tolerance: (days to weeks) right shift in dose-effect curve (need higher dose for same effect) and reversible with removal of the drug
Incomplete cross-tolerance (if on morphine for many years then substitute another drug- get only some tolerance to new drug)
Effects- rapid (nausea and vomiting), more gradual (analgesia, euphoria, respiratory depression, endocrine), Little or none (miosis, constipation)
Dependence: state of adaptation and revealed by drug withdrawal or antagonist treatment, withdrawal produces opposite symptoms of acute exposure (somatomotor and autonomic outflow increased and get hyperalgesia, hyperthermia, pupillary dilation and aversion)
Addiction- not same as dependence, compulsive use and overwhelming involvement with procurement and use, drug seeking/taking occurs in spite of adverse consequences
Effects of Opioid Drugs
Analgesia Cough suppression Anti diarrheal/constipation Resp depression Peripheral vasodilation, reduced peripheral resistance, inhibition of baroreceptors reflexes Nausea Pupillary constriction Sedation Euphoria Endocrine effects Increased biliary pressure
Fentanyl
Selective at Mu receptor No release of histamine from mast cells Structurally related to meperidine 100 times as potent as mrophoine Short acting- 1 to 1.5 hours Available in injectable form and transdermal patches
Suboxone
Buprenorphine plus Naloxone
Naloxone
Non selective antagonists with most activity at Mu and less for Kappa and less at Delta (works at all 3)
Poor bioavailability
Much greater activity parenterally than orally
Short duration: 1-2 hours
Used: to treat opioid overdoses (rapidly reversed even if on the verge of death) and start with small doses and titrated up; also used in drug diversion (oral/sublingual preparations of opioid agonists or partial agonists to prevent euphoria when injected)
Combined with opioids to decrease parenteral abuse liability
Component of newer treatment for addiction- suboxone
Treatment of Opioid abuse
Methadone (slow acting Mu agonist-orally)
Suboxone (buprenorphine/naloxone- sublingual)
Naltrexone (overtime see craving opioid and drugs like alcohol so reduce this craving)
Symptoms: euphoria, craving, drug seeking behavior, withdrawal, low in clinical settings
Salvinorin A (Salvia)
High selective at Kappa receptor
Oxycodone
More efficacious and useful for moderate to sever pain
Abuse problems
Available as sustained release oral preparation
Meperidine
A phenylpiperidine
Shorter duration of analgesia than morphine
Forms toxic metabolite, normeperidine that can accumulate with frequent use
Interact with MAO inhibitor
Endorphins
Endogenous opioid
Precursor is POmC
Beta endorphin in hypothalamus and nucleus tract us solitaries
Also in anterior pituitary: co-released with ACTH during stress
Highly selective at both Mu and Delta receptors
Dextromethorphan
D-isomer of levorphanol
Not a Mu agonist
Cough suppressant
NMDA receptor antagonist
Nalbuphine
Antagonist of Mu and agonist at Kappa
Similar in efficacy and potency to morphine
Little europhoria and low abuse potential
Can precipitate withdrawal in opiate dependent patients
Available only by injection
Hydromorphone
Agonist at opioid receptor
2-3 times as potent as morphine
Opioid Pharmacokinetics
Oral absorption and bioavailability varies y compound (poor for morphine and naloxone where oral potency is 1/3 of parenteral)
Onset of action related to lipophilicity
Duration of action relegated to both lipophilicity and elimination rate
Ultimately metabolized by liver to more polar and less active metabolites
Tramadol
Weak Mu agonist
Block NE and serotonin uptake
Mild and moderate pain
Available for oral use including sustained release preparation
Dynorphins
Precursor: prodynorphin
Dynorphin A co-localized with vasopressin in magno cellular cells of hypothalamus and posterior pituitary
Shorter dystrophies have wide CNS distribution; some are associated with pain pathways, especially in the spinal cord
Most selective for Kappa receptors and some at Mu receptor
Tyr-Gly-Gly-Phe-Met (consensus sequence)
Hydrocodone
Moderate to severe pain
Often in combination with NSAIDs or acetaminophen
Available as sustained release oral preparation- Major abuse problem
Codeine
Low selectivity at Mu and Delta
Cough suppression
Converted to active drug by metabolism to morphogenetic
For mild to moderate pain and morphine like efficacy not achievable
Used with aspirin or acetaminophen
Morphine
Selective at Mu
Poor oral bioavailability
Low oral to parenteral potency- 1/3 bioavailability
Available as injectable, oral and oral sustained and suppository form
Duration of analgesia is 4-5 hours
Buprenorphine
Mixed action (stimulation of receptors but not to same degree as full agonist)
Partial agonist at Mu opioid receptor (25 to 50 times greater potency than morphine)
Antagonist at kappa receptor
Help people with opioid dependence problems (not used clinically)
Used to treat moderate to severe pain and a transdermal patch is available
Orally combined with naloxone (antagonist at all three opioid receptors) and is used to treat opioid dependence - Suboxone=Naloxone and Oral buprenorphine
Proxyphene
Agonist of opioid receptor
Withdrawn from US market because of cardiac arrhythmias
Methadone
Full agonist at Mu opioid receptor
Wean people off of the other drugs like heroine and morphine
Good bioavailability and absoprtion
Chemically a phenylheptylamine
Longer duration of action
Equipment with morphine
Used in treatment of opioid abuse and chronic pain
