Nervous System- Opioids By Schriefer

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Nervous System- Opioids by Schriefer

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Nervous System- Opioids by Schriefer

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Treatment of pain.

low dose vs high dose opioids

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Treatment of pain:
-Eliminate cause
-Interrupt pain pathways
-Alter perception or reaction to pain

Opioid analgesics are more effective against slow than fast pain

At low dose, opioid drugs markedly ↑ ability to tolerate pain, while at high dose can interfere with the detection of pain

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narcotic, opiate, opiods

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Narcotic
Drug that can cause dependence – obsolete medical term; still used legally

Opiate
Drugs derived from opium, or semi-synthetic congeners of morphine

Opioids
Drugs that bind to opioid receptors, may not possess morphine-like properties; broadest term

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describe opioid receptors and subtypes

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Characteristics:
Highly specific, high affinity binding sites
Receptors subtypes
mu (μ) – euphoria, analgesia, physical dependence, respiratory depression; **most important! most effective.
kappa (κ) – miosis, analgesia of pentazocine, sedation; mainly in spinal cord; DYSPHORIA!
delta (δ) similar to μ receptors, enkephalins natural agonists; mediate neuro-endocrine effects; we have no drugs to affect these; dont worry
N/OFQ (pro-orphanin) – newest opioid receptor; orphanin natural agonists

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Cellular Mechanism of Action

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Opioid receptors are linked to G proteins. Activation of Gi leads to decreased cAMP and

Closure of voltage-gated Ca2+ channels on presynaptic nerve terminals, which decreases neurotransmitter release. Transmitters affected include Ach, NE, glutamate, serotonin, and substance P.
--A new analgesic, ziconotide (Prialt), blocks neuronal N-type calcium channels and mimics this effect of opioids. Approved for chronic pain. Is NOT an opioid.
--May cause psychotic-like symptoms.

Opening of K+ channels causing hyperpolarization (inhibition) of postsynaptic neurons.

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Classification of Agents:

agonists, opium derivatives, synthetic opioids

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1. Agonists
2. Opium derivatives
-Morphine
-Codeine
-Heroin (semi-synthetic)
-Hydromorphone (Dilaudid), Oxymorphone (Opana) – semisynthetic derivatives of morphine
-Hydrocodone (Vicodin), oxycodone (Percodan; Oxycontin) – semisynthetic derivatives of codeine
3. Synthetic opioids
-Meperidine (Demerol) me per’ i deen
-Methadone (Dolophine) meth’ a done
-Propoxyphene (Darvon) proe pox’ i feen
-Levorphanol (Levo-Dromoran) lee vor’ fa nole

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Opioid Antagonists, and agonist-antagonists

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Opioid antagonists:

-Drugs that bind to opioid receptors. May antagonize (pure antagonists) or partially stimulate (partial agonists).

-Agonist – antagonists (partial agonists)
Pentazocine (Talwin) pen taz’ oh seen
Buprenorphine (Buprenex) byoo pre nor’ feen
Butorphanol (Stadol) byoo tor’ fa nole
Nalbuphine (Nubain) nal’ byoo feen

when you give it alone, it's an agonist (not a strong one)
when you give it with a full agonist, it acts more like an antagonist.
Don't mix a full agonist with a partial agonist!

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Pure antagonists

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Naloxone (Narcan) nal ox’ one
Naltrexone (ReVia) nal trex’ one
Nalmefine (Revex) nal’ me feen

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pentazocine

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partial agonist at mu receptors, and major effect agonist at kappa receptors.

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naloxone

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antagonist at mu, kappa, and delta

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Morphine

L-isomers are active form
Extract of Papaver somniferum; chief phenanthrene alkaloid in opium
Standard analgesic for moderate to severe pain

CNS effects? behavioral effects? emetic effects? antitussive?

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CNS effects:
Analgesia
-Selective on pain; Interferes with forebrain mechanisms for affective reaction to pain; Inhibits conduction; Action mediated via receptors in dorsal horn of spinal cord, periaqueductal gray, dorsal raphe nuclei, and limbic regions

Behavioral effects: dysphoria as initial experience followed by euphoria – major contributor to abuse liability as well as relief of pain and anxiety
Sedation, drowsiness, and mental clouding
Emetic: direct stimulation of CTZ followed by depression
Antitussive: direct action on medulla to suppress cough reflex

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respiration and the drawbacks

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Respiratory depression: ↓ sensitivity of respiratory center to CO2 drive. ↓ both rate and depth of respiration. Overdose-death by respiratory failure.
Hypothalamus – slightly ↓ body temperature - ↓ ACTH, FSH, LH, TSH
*Miosis
Trunchal rigidity at high dose
Excitatory effect at high doses, e.g., convulsion (morphine-3-glucuronide)

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Peripheral actions: GI, Biliary, Urinary tracts

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GI tract - ↑ tone, ↓ peristalsis – constipation (need to prevent and/or treat constipation in patients taking opioids)
Biliary tract – gall bladder or bile duct spasm due to ↑ biliary pressure
Urinary tract - ↑ muscle tone → ↓ urinary output

Cardiovascular system – peripheral vasodilation and orthostatic hypotension as a result of CNS actions, and histamine release.
Cerebral vasodilation, ↑ CSF pressure
Indirect effect due to histamine release
-Itching, sweating, redness of eyes; Bronchoconstriction, ↓ bronchial secretions
Immunologic – suppression of function of NK cells. However, blocking pain with opioids may reverse pain-induced suprression of immune function.

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Morphine and derivatives Pharmacokinetics

alternative routes of administration

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Absorption:
-i.m. or s.c.: rapid absorption; peak plasma level within 30 min
-p.o.: rapid absorption; significant first pass effect, relatively low oral/parenteral ratio. Various oral forms available (prolonged release), eg MS-contin, Aviza and Kadian, Embeda (mor + nltx).

Alternative routes of administration – an attempt to maximize benefit and minimize side effects
Patient controlled analgesia (PCA)
Epidural
Transdermal
Transmucosal
Intra-articular

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Pharmacokinetics, metabolism, distribution, excretion

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Metabolism:
-Rapidly conjugated with glucuronide in liver and intestine. 90% may be metabolized during the first pass through the liver after an oral dose
-Morphine-6-glucuronide (active metabolite). Contributes significantly to -analgesia when morphine given chronically by oral route
-Morphine-3-glucuronide causes dysphoric side effects

Distribution – widely distributed. Crosses placenta. Relatively little gets into the brain.
Excretion – 90% via kidney (as glucuronide); 10% in feces via bile

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Acute toxic symptoms

what's the triad? what's the treatment?

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Acute toxic symptoms:
Triad of coma, pinpoint pupils, respiratory depression

Treatment:
Maintain respiration
Opioid antagonist, preferably i.v. naloxone (may precipitate withdrawal symptoms)

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Morphine Pharmacology,

Drug interactions

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Drug interactions:
-Depressant effects may be prolonged or exaggerated by CNS depressants: phenothiazines, MAOI, tricyclic antidepressants, cimetidine
-Amphetamine in small dose may enhance morphine effect

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Contraindications/cautions

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Contraindications/cautions:
Bronchial asthma
Emphysema
Liver damage
Head injuries
Acute alcohol use- potentiation of CNS depression
Previous addiction
Convulsive disorders- caution, not contraindication
Abdominal pain of unknown origin

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Morphine Derivative:

Heroin – (3,6-diacetylmorphine)

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Similar to morphine pharmacologically. Faster onset of action. Greater euphoric effect after IV administration, since it crosses the blood-brain barrier easier than morphine
Metabolized to morphine
Analgesic equivalent: 3 mg heroin = 10 mg morphine

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Codeine – 0-methylated morphine (3-methylmorphine)


what must it be metabolized into for it to be fully activated?

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Codeine – 0-methylated morphine (3-methylmorphine)
Relatively effective orally; must be metabolized to morphine (by Cyt 2D6) to be fully active – 7% of Caucasians lack this enzyme.
Useful for mild to moderate pain (in combination with aspirin or acetominophen); antitussive

Less potent than morphine
Analgesic equivalent
32-65 mg orally = 650 mg aspirin
120-130 mg s.c. = 10 mg morphine s.c.
Lower abuse potential, lesser constipation, sedation, respiratory depression than morphine. Relatively mild withdrawal symptoms.

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“Morphones” – similar in efficacy to morphine
“Codones” – a little more efficacy than codeine

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“Morphones” – similar in efficacy to morphine
“Codones” – a little more efficacy than codeine

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Meperidine (Demerol)

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Actions similar to morphine except for the following differences:
-Analgesia: meperidine has a faster onset, shorter duration, and is less potent
-No antitussive activity
-Less constipation
-“Conventional wisdom” suggests that meperidine produces less biliary spasm than morphine, but there is no evidence to support this
-Lesser degree of respiratory depression in fetus and does not inhibit uterine contraction
-Less addiction liability than morphine
-More effective than morphine after oral administration
-Metabolite normeperidine is a stimulant. Normeperidine accumulates with repeated doses.
-High doses – atropine-like toxicity: CNS excitation, convulsions (antagonized by diazepam only)
-Meperidine should not be used in patients receiving MAOI – potential for serotonin syndrome (severe restlessness, fever, and hypertension). Meperidine blocks 5HT reuptake.

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Meperidine and Congeners:

Fentanyl

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short duration; 80-100 x more potent than morphine. Available in a transdermal patch (Duragesic) which provides long lasting (48-72 hrs.) pain relief; buccal fentanyl (Actiq, Fentora) used for breakthrough pain. Several congeners of fentanyl used in anesthesia.

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Opioids for Diarrhea:

Diphenoxylate

Loperamide

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Diphenoxylate: Combined with atropine (Lomotil) is used to treat diarrhea.

Loperamide (Imodium): effective antidiarrheal drug with little abuse potential

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Other Synthetic Opioids:

Methadone

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Methadone (Dolophine)
Primarily a μ agonist with actions similar to morphine except
Greater oral effectiveness
Extended duration of action in suppressing withdrawal
Slow onset. Long duration (T1/2 22 hr) may accumulate

stretched out morphine (acts for a longer period of time)

Tolerance develops more slowly. Withdrawal syndrome is long and relatively mild – basis of “methadone detoxification”; wean addicts off of other narcotics with oral methadone for a few weeks.
May cause torsades de pointes. Use with caution in patient at risk for arrhythmias.
Low cost so payers are encouraging its use. Most physicians unfamiliar with dosing – be careful! There has been a large increase in overdoses.

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Other Synthetic Opioids:

Propoxyphene (Darvon)

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Weak analgesic
Only administered orally
Overly prescribed propoxyphene has been involved in many drug-related deaths (mostly suicides). Overdose – seizures, toxic psychosis


DON'T USE IT.
no better than aspirin but can cause seizures and toxic psychosis

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Tramadol (tra ma dol; Ultram)

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Tramadol (tra ma dol; Ultram) – not strictly an opioid analgesic. Does produce a portion of its action by binding to μ receptors.

Also inhibits NE and 5HT reuptake (makes it a better pain reliever)

Risk of seizures.

Tapentadol (Nucynta) – similar to tramadol but more effective (more NE effect)

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high, moderate, minimal/no tolerance

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High Degree of Tolerance:
AnalgesiaEuphoria, dysphoria, Mental Clouding, Sedation, Respiratory depression, Antidiuresis, Nausea and vomiting, Cough suppression

Moderate:
bradycardia

Minimal/no:
miosis, constipation, convulsions, antagonist actions

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mechanism of tolerance

physical dependence

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Tolerance:
Mechanism – uncertain, but possibly due to changes in the activity of adenylyl cyclase, plus receptor uncoupling and changes in receptor recycling
-The degree of tolerance is related to dose, frequency, and duration of drug use
-There is cross tolerance among the opioids, but not to other drugs, e.g., barbiturates

Physical dependence:
-The degree of physical dependence is related to the amount, frequency, and duration of drug use
-Abrupt termination of drug use or the injection of an opioid antagonist precipitates a characteristic withdrawal syndrome

Abuse liability: Dependent mainly on the degree to which it induces euphoria

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Mixed Agonist-Antagonists (Partial Agonists):

Pentazocine and related compounds
Drugs
Pentazocine (Talwin)
Dezocine (Dalgan)
Butorphanol (Stadol)
Buprenorphene (Temgesic)
Nalbuphine (Nubain)

pentazocine's action is at which type of receptor? what happens at high doses?

what happens at high doses?

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pentazocine is the prototype.produces analgesia, sedation, and respiratory depression
Pentazocine analgesia probably produced by an action at spinal κ receptors – adequate for moderate pain
Produces limited respiratory depression
High doses produce dysphoria and psychotomimetic effects

High doses also produce cardiovascular effects different from morphine, i.e., ↑ BP and ↑ HR
Has μ partial agonist/antagonist action. Can precipitate withdrawal in morphine/heroin dependent individuals
Tolerance develops to analgesia and behavioral effects

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Pure Opioid Antagonists:

Naloxone (Narcan): used parenterally only, T ½ about 1 hour
Naltrexone (Revia): Orally effective, longer acting; Vivitrol, monthly IM injection.
Nalmefene (Revex): Long acting injectable form
Methylnaltrexone (Relistor): SC
Alvimopan (Entereg): oral

what are they used for?

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Antagonize all depressant effects of all opioid agonists and mixed agonist-antagonists. No effect of their own.

Use:
Treat opioid overdose toxicity
Reverse opioid-induced anesthesia
Precipitate the withdrawal syndrome in addicts. Low dose should be used.
Maintain abstinence

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Naltrexone in alcoholism

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some studies suggest that oral naltrexone may block pleasurable effects of alcohol consumption, and decrease alcohol use. Others have found naltrexone to be no better than placebo. Compliance may explain these differences. A recent study with depot naltrexone (Vivitrol) showed a positive effect.

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New Opioid Antagonists:

what does methynaltrexone do?

what about alvimopan?

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Methylnaltrexone reverses opioid-induced constipation but not analgesia (doesn’t enter CNS). Used for patients receiving chronic opioids.

Alvimopan used to treat post-op ileus; given before and after bowel resection.

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which drugs for moderate/severe pain? what about mild/moderate?

what do you use for chronic non-cancer pain?

pain of terminal illness/cancer?

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Moderate/severe pain: morphine, meperidine, methadone, fentanyl patch

Mild/moderate: codeine, oxycodone, pentazocine alone or in combination with aspirin, ibuprofen or acetaminophen

Chronic non-cancer pain – methadone use increasing. Legal concerns make use of opioids for chronic pain problematic. New clinical guidelines.

Pain of terminal illness/cancer – may require large doses of potent opioids. Patients will likely become physically dependent, but remember this is not the same as addiction. Morphine, Oxycontin, transdermal fentanyl.

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Preanesthetic medication?

therapy of emergency states?
acute pulmonary edema or MI?

Antitussive?

antidiarrheal?

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Preanesthetic medication: Morphine or meperidine

Therapy of emergency states
Acute pulmonary edema: morphine IV (concern of resp. depression side fx)
Myocardial infarct: morphine (decrease o2 demand of heart tissue...less work that the heart has to pump)

Antitussive: codeine at doses lower than for analgesia. Dextromethorphan OTC, but recent studies suggest it is no more effective than placebo.

Antidiarrheal:
Diphenoxylate + atropine (Lomotil)
Loperamide (Imodium)