Upload
hiwa-k-saaed
View
223
Download
1
Embed Size (px)
Citation preview
7/31/2019 Opioids Pharmacology
1/50
Click to edit Master subtitle style
8/3/12
Analgesics in DentistryOpioids
PharmacologyHiwa K. Saaed PhD
Pharmacology & ToxicologyCollege of Pharmacy
University of Sulaimani 11
7/31/2019 Opioids Pharmacology
2/50
8/3/12
Analgesic
Analgesic an agent that selectivelyrelieves pain by acting in the CNS oron peripheral pain mechanisms, withoutsignificantly altering the consciousness
Pain is:
acute or chronic
Consequence of complex neurochemicalprocesses
Subjective: perceptive and descriptive
22
7/31/2019 Opioids Pharmacology
3/50
8/3/12
Analgesic
Alleviation of pain depend on its type
Headache, arthritic pain Rx NSAIDs
Neurogenic pain Rx TCA Amitriptyline or
SSRI Fluoxetine
Severe or chronic malignant pain Rx Opiodsare DOC
33
7/31/2019 Opioids Pharmacology
4/50
8/3/12
History / Definitions
Ancient Egypt papyrus records reported theuse of opium for pain Relief
Opium mixture of alkaloids from the poppyseed
Opiates naturally occurring alkaloids suchas morphine or codeine obtained from the
juice of the opium poppy
Opioid broad term to describe all naturalor synthetic compounds that work at theopioid receptors and produce morphine-likeeffects 44
7/31/2019 Opioids Pharmacology
5/50
8/3/12
Endogenous Opioid peptidesneurotransmitters
endorphin, enkephalins & dynorphins
Opiods act by binding to specific opioidreceptors in the CNS to produce the actionof endogenous peptide neurotransmitters
55
7/31/2019 Opioids Pharmacology
6/50
8/3/12
Opioid Classifications
Chemistry Natural Semisynthetic Synthetic
OPIOIDRECEPTOR
Mu( ) Kappa( ) Delta ( )
INTRINSICACTIVITY
Agonists Antagonists Mixed Agonistsand Antagonists
66
7/31/2019 Opioids Pharmacology
7/508/3/12
Opioid Classifications
Opioids can further be classified by their actions:
agonist,
or partial/weak agonist,
or antagonist Mixed agonist/antagonist
An agonist has both affinity and efficacy
An antagonist has affinity but no efficacy
A partial or weak agonist has affinity, butonly partial efficacy
Compounds can have differing degrees of affinity
and efficacy at these various receptors 77
7/31/2019 Opioids Pharmacology
8/508/3/12
Opioid receptorsMu( ), Kappa( ), Delta ( )
Opioids interact with:
receptors on the membranes of certain
cells in the CNS,
on nerve terminals in the periphery
on cells of the gastrointestinal tract and
the anatomic regions urinary bladder.
88
7/31/2019 Opioids Pharmacology
9/508/3/12
Opioid receptors
Analgesic properties are mediated:
mainly via receptors and receptors of the dorsal horn of the
spinal cord.
Enkephalins interact more selectivelywith the receptors in the periphery.
99
7/31/2019 Opioids Pharmacology
10/508/3/12
Endogenous opioid receptors
MuAnalgesia (supraspinal)MiosisRespiratory depressionEuphoriaPhysical dependenceDecrease GIT motility
KappaSpinal analgesiaSedationmiosis
Deltaanalgesia (spinal &supraspinal)release ofgrowth hormoneAffective behaviorPresent in limbic system
Sigma#DysphoraHallucination (both visual &auditory)Respiratory and vasomotorstimulationmydriasis#less specific bind with nonopioid agent e.g hallucinogen
10
7/31/2019 Opioids Pharmacology
11/508/3/12
Mechanism ofAction
All are G-protein coupledreceptors and inhibitadenylate cyclase.
They are also involved inpostsynaptichyperpolarization:
(increasing K+ efflux)
or reducing presynaptic Ca++ influx;
thus inhibits neuronalactivity.
11
7/31/2019 Opioids Pharmacology
12/508/3/12
Receptor distribution
High densities of opioid receptors on peripheralnerve fibers, immune cells and five general areasof the CNS:
1. Brainstem: respiration, cough, nausea &vomiting, BP, papillary diameter and stomachsecretion.
2. Medial thalamus: mediating poorly localized
deep pain3. Spinal cord: in the substantia gelatinosa areinvolved in the receipt & integration on sensoryinput leading to the attenuation of painful
afferent stimuli. 12
7/31/2019 Opioids Pharmacology
13/508/3/12
Receptor distribution
4. Hypothalamus: neuroendocrine secretion.
5. Limbic system: the greatest concentrationin the amygdale, a major role in emotional
behavior & response and little analgesiceffect.
6. Periphery: they inhibit Ca+2 dependentrelease of excitatory, pro-inflammatorysubstances (substance P)
7. Immune cells: undetermined.
13
7/31/2019 Opioids Pharmacology
14/508/3/12
Opioids
Strong
Alfentanil
Fentanyl
Heroin
Meperidine
Methadone
Morphine
Oxycodone
Remifentanil
Sufentanil 14
7/31/2019 Opioids Pharmacology
15/50
Opioid Agonists
The strongest naturally occurring analgesic drugsare 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.
7/31/2019 Opioids Pharmacology
16/508/3/12
Morphine
Exert its effects through interaction with central &peripheral opioid receptors, binding results inhyperpolarization, inhibition of nerve firing andpresynaptic inhibition of transmitter release
Acts at the receptors in lamina I & II of thesubstantia gelatinosa of the cord and decreases therelease of substance P,
it also inhibits the release of excitatory transmitters
from nociceptive nerve terminals centrally and inthe cord
16
7/31/2019 Opioids Pharmacology
17/508/3/12
Morphine Pharmacological
Actions-Analgesia: Opioids cause pain relief by both
raising the pain threshold at the spinal cord level
altering the central perception of pain; awarenessof pain remains but it loses its unpleasant
character
Euphoria:
Opioids produce a sense of contentment and wellbeing, this may be related to stimulation of theventral tegmental tract
Respiration:
Opioids cause respiratory depression by decreasing
the sensitivity of central respiratory neurons to17
7/31/2019 Opioids Pharmacology
18/50
8/3/12
MorphinePharmacological Actions-
Suppression of cough reflex:
Antitussive properties do not correlate
with analgesic or respiratory depressioneffects; this appears mediated via adifferent receptor complex
Miosis:
Results from stimulation of and
receptors located in the Edinger 18
M hi
7/31/2019 Opioids Pharmacology
19/50
8/3/12
MorphinePharmacological
Actions-Emesis:Opioids directly stimulate the
chemoreceptor trigger zone in the areapostrema that causes vomiting
GI tract:
Opioids relieve diarrhea by decreasinggut motility and increasing the tone ofintestinal smooth muscle
Constipation is also resistant totolerance 19
7/31/2019 Opioids Pharmacology
20/50
8/3/12
MorphinePharmacological
Actions-Histamine release:
Morphine causes mast celldegranulation, the release of histamine
causing urticaria, itching, diaphoresisand vasodilation
In asthmatics it may precipitate
bronchospasmHormonal Actions:o
inhibits the release of GnRH, CRH
and deceases the release of LH, FSH &20
M hi
7/31/2019 Opioids Pharmacology
21/50
8/3/12
MorphineTherapeutic
Uses Analgesia:
Few drugs are as effective as morphine for
the relief of pain Treatment of Diarrhea
Anti tussive:
codeine and dextromethorphanarecongeners with greater antitussive effects
Acute Pulmonary Edema:
IV morphine dramatically relieves the21
7/31/2019 Opioids Pharmacology
22/50
8/3/12
MorphinePharmacokinetics
Administration: Morphine is poorly absorbed orally; codeine
is a much more effective oral analgesic
Both undergo extensive first passmetabolism in the liver. Inhalation is aneffective route but has found favor onlywith non medicinal administration
Implantable morphine pumps are also nowuse for chronic pain
Distribution:
Morphine readily enters all body tissues22
7/31/2019 Opioids Pharmacology
23/50
8/3/12
MorphinePharmacokinetics
Metabolism:
Conjugated in the liver,
morphine6 glucuronide is a much morepotent analgesic;
however morphine 3 glucuronide is less analgesic
Both are excreted in the urine
with small amounts excreted in the bile
Hepatic & renal dysfunction both prolongthe normal 4 6 hour duration of action 23
7/31/2019 Opioids Pharmacology
24/50
8/3/12
MorphinePharmacokinetics
Note: A patient's age can influence theresponse to morphine.
Elderly patients are more sensitive tothe analgesic effects of the drug,possibly due to decreased metabolismor other factors, such as decreased lean
body mass, renal function, etc. Theyshould be treated with lower doses.
Neonates should not receive morphine
because of their low conjugating 24
7/31/2019 Opioids Pharmacology
25/50
8/3/12
MorphineAdverse Effects
Severe respiratory depression ( , and receptors)
Constipation (variable, and receptors)
Nausea and vomiting
Pupillary constriction ( / receptors)
Caution must be exercised whenopiates are used in those with liver or
renal failure 25
7/31/2019 Opioids Pharmacology
26/50
8/3/12
MorphineAdverse Effects
In BPH, morphine cause acute urinaryretension
Patients with adrenal insufficiency ormyxedema may experience extendedand increased effects from the opioids.Morphine should be used with
cautiously in patients with bronchialasthma or liver failure.
Note: Many of the effects above can be
inhibited by opioid receptor antagonists26
orp ne
7/31/2019 Opioids Pharmacology
27/50
8/3/12
orp neTolerance &
Physical
Dependence Repeated use produces tolerance to the
effects of respiratory depression,analgesia, euphoria and sedation
Tolerance does not develop to miosisand constipation
Physical & psychological dependencereadily occurs
Withdrawal induces a syndromeassociated with autonomic, motor ands cholo ical res onses that are 27
7/31/2019 Opioids Pharmacology
28/50
8/3/12
Opioid withdrawal syndrome
28
7/31/2019 Opioids Pharmacology
29/50
8/3/12
comparison of the maximum Efficacy versusAddiction / Abuse Potential of Various
Opioids
Detoxification of heroin-or morphine-dependentindividuals is usually
accomplished throughthe oral administrationof
methadone,
buprenorphine, or
clonidine.
29
7/31/2019 Opioids Pharmacology
30/50
8/3/12
Drug interactions:
The depressant actions of morphine areenhanced by phenothiazines, MAOIs,and TCAs.
Low doses of amphetamine inexplicablyenhance analgesia, as doeshydroxyzine.
30
7/31/2019 Opioids Pharmacology
31/50
8/3/12
Meperidine Pethidine ( ,)
A synthetic opioid structurally unrelatedto morphine
Mechanism:
It binds to receptors with some bindingat receptors
Actions:
Causes respiratory depression similar tomorphine, but less urine retention
no significant CV effect when given orally.
IV administration produces a decrease in31
7/31/2019 Opioids Pharmacology
32/50
8/3/12
Meperidine
Therapeutic uses:
Severe acute pain
Lacks antitussive activity No anti diarrhea;
Obstetrics; Produces less smooth musclecontraction/ spasm than morphine
Pharmacokinetics:
Well absorbed form the GI tract; it is mostoften given IM
32
7/31/2019 Opioids Pharmacology
33/50
8/3/12
Meperidine-Adverseeffects:
With large repeated doses normeperidine(demethylated meperidine) accumulatescausing
anxiety, muscle tremors and convulsions
Causes papillary dilation (vs. miosis withmorphine) in large doses
Hyperactive reflexes
Severe hypotension when admin.postop.
+neurole tics: enhanced de ression33
7/31/2019 Opioids Pharmacology
34/50
8/3/12
Methadone ( )
This is a synthetic orally effective opioidthat
is equipotent to morphine
but induces less euphoria
has a longer duration of action
Mechanism of action: Binds to the receptor.
Actions:
An equipotent analgesic to morphine 34
7/31/2019 Opioids Pharmacology
35/50
8/3/12
Methadone
Therapeutic uses:
Used for controlled withdrawal from heroin& morphine
Self addictive but the withdrawal syndromeis somewhat milder but more protractedthan with other opioids
Pharmacokinetics:
Readily absorbed orally, t1/2 24hrs
Highly protein bound so remains in tissuesfor a prolonged period.
Transformed in the liver and excreted b35
7/31/2019 Opioids Pharmacology
36/50
8/3/12
Fentanyl
Chemically related to meperidine butmiosis
has 100 times the analgesic potency of
morphine; used in anesthesia and asanalgesia postop & during labor
Highly lipophilic: elimination half life is
longer than morphines as redistributionoccurs
Rapid onset of action and a short
duration (15 30 minutes) 36
7/31/2019 Opioids Pharmacology
37/50
8/3/12
Fentanyl
Like morphine fentanyl causes miosis(vs. mydriasis)
Particular risk of the transmucosal ortransdermal routes is respiratorydepression; these delivery routes createa reservoir of drug in the skin or
mucosa. Hence, the onset is delayed 12hours, and the offset is prolonged
Fentanyl is often used during cardiac
surgery because of its negligible effects37
7/31/2019 Opioids Pharmacology
38/50
8/3/12
Fentanyl derivative
Adverse effects of fentanyl are similar tothose of other -receptor agonists.
Because of life-threatening
hypoventilation, the fentanyl patch iscontraindicated in the management ofacute and postoperative pain or painthat can be ameliorated with otheranalgesics.
Sufentanil, Alfentanil & Remifentanil arerelated to fentanyl they differ in their
potency and metabolic disposition. 38
7/31/2019 Opioids Pharmacology
39/50
8/3/12
Heroin
Heroin is produced by the diacetylationof morphine which results in a three foldincrease in its potency
Acetylation allows it to cross the BBBmuch more rapidly yielding a morepronounced euphoria
May be used IV or smoked, both allowfor rapid distribution,
heroin is metabolized to morphine
No medical indication for its use in the39
7/31/2019 Opioids Pharmacology
40/50
8/3/12
oxycodone
is a semisynthetic derivative ofmorphine.
It is orally active and is sometimes
formulated with aspirin oracetaminophen.
It is used to treat moderate to severe
pain and has many properties in commonwith morphine.
Oxycodone is metabolized to productswith lower analgesic activity.
40
7/31/2019 Opioids Pharmacology
41/50
8/3/12
Moderate/Weak Agonists
CodeineConverted to morphine thus:
Much less analgesic than morphine
Less euphoria and has much lowerabuse potential and rarely producesphysical dependence
An effective oral analgesic
Does possess significant anti tussiveeffects at sub analgesic doses
Often formulated with either 41
7/31/2019 Opioids Pharmacology
42/50
8/3/12
Moderate/Weak AgonistsPropoxyphene
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 twicedose)
Often formulated with another over the counter analgesic; combination has greater effect than either
drug aloneToxic doses may produce cardio and pulmonary
toxicity particularly when taken in combination withalcohol and/or sedatives in addition to CNSdepression
O ioid anta onists can reverse the ulmonar and42
7/31/2019 Opioids Pharmacology
43/50
8/3/12
Mixed Agonists Antagonists& Partial Agonists
Pentazocine
Buprenorphine
Butorphanol
Nalbuphine
Drugs that stimulate one receptor but
block another
Effects of these drugs depend on previousexposure to opioids
Nave patients drugs act as agonists;43
7/31/2019 Opioids Pharmacology
44/50
8/3/12
Pentazocine
Pentazocine acts as an agonist on kreceptors and is a weak antagonist at and delta receptors.
Pentazocine promotes analgesia byactivating receptors in the spinal cord,and it is used to relieve moderate pain.
It may be administered either orally orparenterally.
Pentazocine produces less euphoria
compared to morphine. 44
7/31/2019 Opioids Pharmacology
45/50
8/3/12
Pentazocine
In angina, pentazocine increases themean aortic pressure and pulmonaryarterial pressure and, thus, increasesthe work of the heart.
The drug decreases renal plasma flow.
Despite its antagonist action,pentazocine does not antagonize therespiratory depression of morphine,
but it can precipitate a withdrawalsyndrome in a morphine abuser.
Tolerance and dependence develop on45
Mixed Agonists
7/31/2019 Opioids Pharmacology
46/50
8/3/12
Mixed AgonistsAntagonists & Partial
AgonistsBuprenorphine
A partial agonist at receptors
producing morphine like effects innave users but precipitating withdrawalin morphine dependents
Metabolized in the liver and excreted inthe urine and bile
May be taken sublingually or parenteraland possess a long duration of action
46
7/31/2019 Opioids Pharmacology
47/50
8/3/12
Buprenorphine
Main use is in opioid detoxification asits withdrawal syndrome appears less
severe and of shorter duration thanmethadone
Available outside of the specialized
clinic allowed to dispense methadonefor opiate withdrawal
47
7/31/2019 Opioids Pharmacology
48/50
8/3/12
Antagonists
Bind with high affinity to the , & receptors but fail to activate thereceptor
In normal individuals, these agentsproduce no effect but in those withopiates present, they induce an acute
withdrawal syndromeNaloxone
Reverses the coma and respiratory
depression associated with opioid 48
7/31/2019 Opioids Pharmacology
49/50
8/3/12
Antagonists
Naltrexone (hepatotoxic)
Similar actions as naloxone but an oralagent with a much longer duration ofaction
Single dose able to antagonize theeffects of heroin for up to 48 hours
Nalmefene
is a parenteral opioid antagonist withactions similar to that of naloxone and
naltrexone. 49
7/31/2019 Opioids Pharmacology
50/50