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Analgesic
Analgesic an agent that selectively relieves pain by acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness Pain is:
acute or chronic Consequence of complex neurochemical
processes
Subjective: perceptive and descriptive
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Analgesic
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History / Definitions
Ancient Egypt papyrus records reported the use of opium for pain Relief
Opium mixture of alkaloids from the poppy
seed
Opiates naturally occurring alkaloids such
or synthetic compounds that work at the opioid receptors and produce morphine-like effects 8/3/12 44
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Opioid Classifications
Chemistry OPIOID RECEPTOR INTRINSIC ACTIVITY
Natural Mu() Agonists Semisynthetic Synthetic Kappa() Antagonists Delta () Mixed Agonists and Antagonists
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Opioid Classifications
An agonist has both affinity and efficacy An antagonist has affinity but no efficacy A partial or weak agonist has affinity, but only partial efficacy Compounds can have differing degrees of affinity and efficacy at these various receptors
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Opioid receptors
Mu(), Kappa(), Delta ()
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Opioid receptors
Analgesic
spinal cord. Enkephalins interact more selectively with the receptors in the periphery.
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Sigma# Dysphora Hallucination (both visual & auditory) Respiratory and vasomotor stimulation mydriasis #less specific bind with non opioid agent e.g hallucinogen
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Mechanism of Action
All are G-protein coupled receptors and inhibit adenylate cyclase. They are also involved in postsynaptic hyperpolarization: (increasing K+ efflux) or reducing presynaptic Ca+ + influx;
Receptor distribution
High densities of opioid receptors on peripheral nerve fibers, immune cells and five general areas of the CNS: 1. Brainstem: respiration, cough, nausea & vomiting, BP, papillary diameter and stomach secretion. 2. Medial thalamus: mediating poorly localized deep pain 3. Spinal cord: in the substantia gelatinosa are involved in the receipt & integration on sensory input leading to the attenuation of painful afferent stimuli.
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Receptor distribution
4. Hypothalamus: neuroendocrine secretion. 5. Limbic system: the greatest concentration in the amygdale, a major role in emotional behavior & response and little analgesic effect. 6. Periphery: they inhibit Ca+2 dependent release of excitatory, pro-inflammatory substances (substance P) 7. Immune cells: undetermined.
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Opioids
Strong
Opioid Agonists
The strongest naturally occurring analgesic drugs are found in opium from the poppy flower, morphine and less potent codeine. These drugs show a high affinity for the receptor and less affinity for the and receptors.
Morphine
Exert its effects through interaction with central & peripheral opioid receptors, binding results in hyperpolarization, inhibition of nerve firing and presynaptic inhibition of transmitter release Acts at the receptors in lamina I & II of the substantia gelatinosa of the cord and decreases the release of substance P, it also inhibits the release of excitatory transmitters from nociceptive nerve terminals centrally and in the cord
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raising the pain threshold at the spinal cord level altering the central perception of pain; awareness of pain remains but it loses its unpleasant character Opioids produce a sense of contentment and well being, this may be related to stimulation of the ventral tegmental tract Opioids cause respiratory depression by decreasing the sensitivity of central respiratory neurons to
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Euphoria:
Respiration:
properties do not correlate with analgesic or respiratory depression effects; this appears mediated via a different receptor complex
Miosis:
Results
Emesis:
Opioids
directly stimulate the chemoreceptor trigger zone in the area postrema that causes vomiting relieve diarrhea by decreasing gut motility and increasing the tone of intestinal smooth muscle is also resistant to
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GI tract:
Opioids
Constipation
tolerance
Histamine release:
Morphine
causes mast cell degranulation, the release of histamine causing urticaria, itching, diaphoresis and vasodilation asthmatics it may precipitate bronchospasm the release of GnRH, CRH
In
Hormonal Actions:o
inhibits and
8/3/12 20 deceases the release of LH, FSH &
Analgesia:
Few drugs are as effective as morphine for
of Diarrhea
Anti tussive:
Pulmonary Edema:
Morphine Pharmacokinetics
Administration:
metabolism in the liver. Inhalation is an effective route but has found favor only with nonmedicinal administration
Implantable morphine pumps are also now
Distribution:
Morphine Pharmacokinetics
Metabolism:
potent analgesic;
however morphine3glucuronide is less
analgesic
Both are excreted in the urine with small amounts excreted in the bile Hepatic & renal dysfunction both prolong
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Morphine Pharmacokinetics
Note:
A patient's age can influence the response to morphine. patients are more sensitive to the analgesic effects of the drug, possibly due to decreased metabolism or other factors, such as decreased lean body mass, renal function, etc. They should be treated with lower doses. should not receive morphine because of their low conjugating 8/3/12 24
Elderly
Neonates
Constipation Nausea
Pupillary Caution
must be exercised when opiates are used in those with liver or renal failure 8/3/12 25
BPH, morphine cause acute urinary retension with adrenal insufficiency or myxedema may experience extended and increased effects from the opioids. Morphine should be used with cautiously in patients with bronchial asthma or liver failure. Many of the effects above can be inhibited by opioid receptor antagonists 8/3/12 26
Patients
Note:
Repeated
use produces tolerance to the effects of respiratory depression, analgesia, euphoria and sedation does not develop to miosis and constipation & psychological dependence readily occurs induces a syndrome associated with autonomic, motor and 8/3/12 psychological responses that are 27
Tolerance Physical
Withdrawal
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comparison of the maximum Efficacy versus Addiction/ Abuse Potential of Various Opioids
Detoxification
Drug interactions:
The
depressant actions of morphine are enhanced by phenothiazines, MAOIs, and TCAs. doses of amphetamine inexplicably enhance analgesia, as does hydroxyzine.
Low
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Meperidine Pethidine (, )
Mechanism:
at receptors
Actions:
Meperidine
Therapeutic
uses:
Severe acute pain Lacks antitussive activity No anti diarrhea; Obstetrics; Produces less smooth muscle
often given IM
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Meperidine-Adverse effects:
papillary dilation (vs. miosis with morphine) in large doses reflexes hypotension when admin.
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Hyperactive Severe
postop.
+neuroleptics:
Methadone ()
This
that
is equipotent to morphine but induces less euphoria has a longer duration of action
Mechanism Actions:
of action:
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Methadone
Therapeutic
uses:
& morphine
Readily absorbed orally, t1/2 24hrs Highly protein bound so remains in tissues
Fentanyl
Chemically
miosis
has
100 times the analgesic potency of morphine; used in anesthesia and as analgesia postop & during labor lipophilic: elimination halflife is longer than morphines as redistribution occurs onset of action and a short duration (1530 minutes)
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Highly
Rapid
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Fentanyl
Like
morphine fentanyl causes miosis (vs. mydriasis) risk of the transmucosal or transdermal routes is respiratory depression; these delivery routes create a reservoir of drug in the skin or mucosa. Hence, the onset is delayed 12 hours, and the offset is prolonged is often used during cardiac surgery because of its negligible effects 8/3/12 37
Particular
Fentanyl
Fentanyl derivative
Adverse
effects of fentanyl are similar to those of other -receptor agonists. of life-threatening hypoventilation, the fentanyl patch is contraindicated in the management of acute and postoperative pain or pain that can be ameliorated with other analgesics. Alfentanil & Remifentanil are related to fentanyl they differ in their potency and metabolic disposition. 38 8/3/12
Because
Sufentanil,
Heroin
Heroin
is produced by the diacetylation of morphine which results in a three fold increase in its potency allows it to cross the BBB much more rapidly yielding a more pronounced euphoria be used IV or smoked, both allow for rapid distribution, is metabolized to morphine medical indication for its use in the 8/3/12 39
Acetylation
May
heroin No
oxycodone
is It
a semisynthetic derivative of morphine. is orally active and is sometimes formulated with aspirin or acetaminophen. is used to treat moderate to severe pain and has many properties in common with morphine. is metabolized to products with lower analgesic activity.
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It
Oxycodone
Moderate/WeakAgonists
Codeine Converted Much Less
to morphine thus:
euphoria and has much lower abuse potential and rarely produces physical dependence effective oral analgesic possess significant antitussive effects at subanalgesic doses
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An
Does
Often
Moderate/WeakAgonists
Propoxyphene
Derivative of methadone, dextro isomer is analgesic, levo isomer is antitussive Used for mild to moderate pain; its opioid dose equipotency is about half of codeine (require twice dose) Often formulated with another overthecounter analgesic; combination has greater effect than either drug alone Toxic doses may produce cardio and pulmonary toxicity particularly when taken in combination with alcohol and/or sedatives in addition to CNS depression
8/3/12 42 Opioid antagonists can reverse the pulmonary and
block another
exposure to opioids
Pentazocine
Pentazocine
acts as an agonist on k receptors and is a weak antagonist at and delta receptors. promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain. may be administered either orally or parenterally. produces less euphoria compared to morphine. 8/3/12 44
Pentazocine
It
Pentazocine
Pentazocine
In
angina, pentazocine increases the mean aortic pressure and pulmonary arterial pressure and, thus, increases the work of the heart. drug decreases renal plasma flow. its antagonist action, pentazocine does not antagonize the respiratory depression of morphine, it can precipitate a withdrawal syndrome in a morphine abuser. 8/3/12 Tolerance and dependence develop 45 on
The
Despite
but
partial agonist at receptors producing morphinelike effects in nave users but precipitating withdrawal in morphine dependents in the liver and excreted in the urine and bile be taken sublingually or parenteral and possess a long duration of action
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Metabolized May
Buprenorphine
Main
use is in opioid detoxification as its withdrawal syndrome appears less severe and of shorter duration than methadone outside of the specialized clinic allowed to dispense methadone for opiate withdrawal
Available
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Antagonists
Bind
with high affinity to the , & receptors but fail to activate the receptor normal individuals, these agents produce no effect but in those with opiates present, they induce an acute withdrawal syndrome the coma and respiratory depression associated with opioid
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In
Naloxone Reverses
48
Antagonists
Naltrexone (hepatotoxic)
Similar
actions as naloxone but an oral agent with a much longer duration of action dose able to antagonize the effects of heroin for up to 48 hours a parenteral opioid antagonist with actions similar to that of naloxone and 8/3/12 49 naltrexone.
Single
Nalmefene
is
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