Term
Side effects of opioid analgesics
CNS Effects |
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Definition
Euphoria: increased release of dopamine
Sedation: with mental clouding; unclear mechanism
Respiratory depression: direct actions in brainstem
depressed breathing and response to carbon dioxide challenge
Cough suppression: actions in medulla cough center; accumulation of secretions
Miosis: pupil constriction by excitation of Edinger-Westphal nucleus
Truncal rigidity: increased muscle tone can interfere with ventilation, most apparent with high i.v. dose of lipid soluble opioids fentanyl
Nausea and vomiting: activation of brainstem chemoreceptor trigger zone in area postrema; ambulation increases nausea (vestibular influence)
Hyperthermia: modulation of hypothalamic regions
Restlessness, hyperactivity, convulsions: sometimes due to metabolites |
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Term
Side effects of opioid analgesics
Peripheral Effects |
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Definition
Cardiovascular: no significant direct effects; hypotension during stress, peripheral vasodilation, orthostatic hypotension
Gastrointestinal tract: constipation due to decreased motility and increased tone due to opioid receptors in GI tract
Biliary tract: biliary colic; contract biliary smooth muscle and sphincter of Oddi; reflux of biliary secretions, elevated plasma amylase and lipase
Renal: depressed renal function, and antidiuretic. Increased sphincter tone may lead to urinary retention (bad for gallstones)
Uterus: decreased uterine tone, prolonged labor
Pruritus: flushing and warming of skin, sweating, itching caused by peripheral histamine release
Immune system: reduced immune function
Endocrine: inhibition of lutenizing hormone release, increased release of antidiuretic hormone and prolactin |
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Term
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Definition
Phenanthrenes
*Strong Opioid Agonist
Prototypical MOR opioid analgesic
Synthesis difficult, most obtained from poppy
Hydrophilic, poor lipid solubility, ~2hr half-life
slower absorption and CNS entry
Oral administration: first-pass metabolism, 25% bioavailability
Less effective than parenteral, but easier
Metabolism: CYP450, mostly glucuronidation
morphine-3 and morphine-6 glucuronide (2x potent)
Sustained release formulation used for 8-12 hour analgesia
Effects: analgesia, sedation, euphoria (sometimes dysphoria)
Major side effect: respiratory depression --> respiratory arrest
High potential for abuse
Drug interactions: MAO inhibitors, alcohol
*Also useful for MI pain (anxiolytic and sedating), epidural anesthesia (long-lasting), cancer pain |
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Term
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Definition
Phenylpiperidines
*Strong Opioid Agonist
Very potent MOR agonist (~100X morphine)
*Highly lipophilic, faster absorption and CNS entry
Multiple routes available
parenteral; i.v., epidural and intrathecal (acute and chronic)
oral mucosa: lozenge lollipop discontinued in US
transdermal patches for 72 hour analgesia
Useful as general anesthetic (combined with droperidol)
Greater hemodynamic stability - no histamine release
Derivatives sufentanil, alfentanil
anesthetic adjuvants, epidural
Less nausea, more muscle rigidity
several drug interactions (e.g. aprepitant, antibiotics, diltiazem, verapamil) |
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Term
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Definition
Phenylpiperidines
*Strong Opioid Agonist
1/5 morphine potency
1/4 morphine duration
no cough suppression, less constipation, no labor prolongation
*OB/Surg analgesia, Mod-severe pain
-The drug is converted to a non-analgesic, but pro-convulsant, metabolite normeperidine that can become problematic with long-term usage. Accordingly, meperidine is primarily used for the short-term treatment of acute pain syndromes.
MOR agonist
Less potent and shorter acting than morphine
faster onset (~10 min); duration (1.5-3 hr)
Unusual profile compared to morphine
does not prolong labor
not antitussive
less constipation
Not recommended for chronic pain (>48 hours)
toxic metabolite normeperidine can accumulate
dysphoria, irritability, tremors, myoclonus and seizures
Interaction with MAOIs to produce cerebral edema (5-HT syndrome)
Anti-muscarinic activity can lead to tachycardia
should not be used for MI |
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Term
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Definition
Phenylheptylamines
*Strong Opioid Agonist
Potent MOR agonist, racemic mix also blocks NMDAR
Use for analgesia, instead of only heroin addiction
Better oral bioavailability than morphine
Long-lasting; long half-life (25-52 hours)
Strong binding to protein-->accumulation; maintained low concentration when discontinued
Milder, but more prolonged withdrawal than morphine
*If taken as prescribed, minimal euphoria and prevents withdrawal Sx
Risk of opioid overdose if heroin use while taking methadone |
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Term
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Definition
Phenanthrenes
*Mild to Moderate Opioid Agonist
Mild-moderate pain, cough suppression
Excellent oral bioavailability, ~60%
Less first-pass metabolism
Itself is weak MOR agonist, but metabolized to morphine
~10% of population have polymorphism of CYP2D6, do not effectively convert codeine to morphine
metabolism by CYP450 system may lead to drug-drug interactions
Useful as antitussive; doses exert minimal side effects
Histamine release - intching
Usually used with acetaminophen or aspirin for pain relief |
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Term
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Definition
Phenanthrenes
*Moderate Opioid Agonist
Used for mild to moderate pain (1990’s)
MOR receptor agonist
can be fairly potent agonist
Better oral bioavailability than morphine
Used in lower doses in combination with aspirin or acetaminophen; synergistic pain relief (Percodan or Percocet)
Metabolism by CYP450, CYP2D6 system - potential drug interactions
Widespread abuse of sustained release OxyContin
search for non-abused formulations |
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Term
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Definition
*Moderate Opioid Agonist
Used for mild to moderate pain (1940’s)
MOR receptor agonist
Similar to oxycodone, little shorter duration of analgesia
Used in lower doses in combination with ibuprofen or acetaminophen; synergistic pain relief (Vicoprofen, Vicodin)
VI x stronger than codeine orally
Metabolism by CYP450, CYP2D6 system - potential drug interactions
Among most commonly prescribed drugs |
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Term
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Definition
Phenylheptylamines
*Moderate Opioid Agonist
Useful for mild to moderate pain
MOR agonist chemically related to methadone
Orally less potent than codeine
combined with aspirin, effective analgesia
sometimes used because of overconcern of abuse liability of codeine
Adverse interactions with alcohol and sedatives can be fatal
Irritant when i.v. or subcutaneous
Toxic psychosis, pulmonary edema, cardiotoxicity
Reduced use because other equally efficacious medications available without adverse interactions
Risk of fatal overdose prompted FDA requirement for stronger warning |
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Term
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Definition
Benzomorphans
*Mixed opioid agonist-antagonists
Useful for moderate pain
Only for patients not using other opioids
Ceiling effects for analgesia and respiratory depression
similar to butorphanol
Pharmacology unlike morphine
KOR agonist
Weak MOR antagonist/partial agonist
Formulated with naloxone
if injected i.v., naloxone prevents euphoria
if taken orally, naloxone metabolized before pentazocine reaches CNS
Less nausea than morphine
sedation, sweating, dizziness, psychotomimetic effects, anxiety, increased HR/BP
The combination of pentazocine with the antihistamine tripelennamine (“Ts and blues”) produces heroin-like subjective effects and has been a drug abuse problem in the past. |
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Term
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Definition
Morphinans
*Mixed opioid agonist-antagonists |
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Term
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Definition
Phenanthrenes
Mixed agonist-antagonists and partial agonists
More potent analgesic than morphine
Slower onset and longer duration
Highly lipophilic
Pharmacology
KOR antagonist
High affinity MOR partial agonist, slow dissociation
more resistant to naloxone reversal
Greater sedation and less respiratory depression
Antagonizes respiratory depression caused by fentanyl
Mild morphine-like withdrawal syndrome
Useful for treatment of addiction:
Low abuse liability, but decreases cravings |
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Term
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Definition
Phenanthrenes
Mixed agonist-antagonists and partial agonists |
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Term
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Definition
Phenanthrenes
*Opioid Antagonists
Fast onset (minutes) and offset (1-2 hr)
Multiple injections may be needed to treat overdose
Minimal oral bioavailability
almost complete first-pass metabolism
If given alone to opioid-naïve, little effect |
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Term
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Definition
Phenanthrenes
*Opioid Antagonists
More potent than naloxone
Longer duration of action (half-life 10 hours, effects days)
Greater oral bioavailability
Helpful in drug addiction
alcohol dependence, reduced heroin-seeking |
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Term
Interactions and contraindications
of opioid analgesics |
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Definition
Contraindications
full agonist + partial agonist withdrawal
head injuries: CO2 retention cerebral vasodilation, intracranial pressure
pregnancy: physical dependence in infant
impaired hepatic or renal function: accumulation of drug or metabolite
impaired pulmonary function (emphysema, severe obesity)
depressant properties respiratory failure
endocrine disease: exaggerated response to opioids
Interactions
MAO Inhibitors: hyperpyrexic coma, hypertension
antipsychotic tranquilizers: increased sedation; increased cardiovascular effects
sedative-hypnotics: increased CNS depression |
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