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• PRODUCED IN ONE ORGAN AND ARE TRANSPORTED VIA THE LYMPH SYSTEM
• ALL OCCUR (MADE) NATURALLY IN THE BODY.
OCCUR NATURALLY IN THE BODY
Terms & DefinitionsAutacoids - Examples:
Prostaglandins – lipids that are synthesized locally by inflammatory stimuli –↑↑ PAIN receptors
Thromboxanes (a vasoconstrictor and a potent hypertensive agent, and facilitates platelet aggregation [clotting]).
Leukotrienes (Inflammatory molecules; precursor of prostaglandins)
“-kinins” - messengers
NON OPIOID ANALGESICS ARE ALSO CALLED:NONNARCOTIC, PERIPHERAL, MILD, AND ANTIPYRETIC (AGENTS THAT REDUCE FEVER)
OPIOID ANALGESICS ARE ALSO CALLED: NARCOTIC, CENTRAL, OR STRONG ANALGESICS.
NON-OPIODS
1. Nonopioids (nonnarcotics) Act primarily at the:
peripheral nerve endings
Inhibit prostaglandin synthesis (regulating the contraction and relaxation of smooth muscle tissue)
Not effective for severe pain
3 subgroups:• Salicylates (aspirin-like group)
• NSAIDs • Acetaminophen
2. Opioids (narcotics)Act primarily within the:
central nervous system
Depress the central nervous system
Effective for severe pain
Examples: Morphine, Codeine, Agents in cough suppressants
We will discuss this area more in the next chapter
Difference is in their site of action
Classification of Analgesic Agents
Difference in their mode of action
ASPIRIN IS THE MOST USEFUL AND COMMON SALICYLATE TO REDUCE PAIN
(ANALGESIC ACTION)
ACETYL SALICYLIC ACID (ASA) – THE CHEMICAL NAME FOR ASPIRIN
SALICYLATES
Salicylates
• Aspirin belongs to a class of medications called nonsteroidal antiinflammatory drugs (NSAIDs). – Aspirin and other NSAIDs, for example, ibuprofen
(eg. Motrin, Advil) and naproxen (eg. Aleve), are widely used to treat fever (antipyretic action), pain (analgesic action), and inflammatory (anti-inflammatory action) conditions such as arthritis
– Aspirin is also known for its anti-platelet action
ASA
• Aspirin have: –anti-inflammatory, –antipyretic, –analgesic, and –antiplatelet actions.
• These actions are related to the ability to inhibit prostaglandin synthesis
Salicylates:
MECHANISM OF ACTION
Whereas, Acetaminophen drugs have only antipyretic &
analgesic actions.
ASA
• Aspirin inhibits cyclo-oxy-genase (COX) to block production of prostaglandins
• Prostaglandins can sensitize pain receptors to substances such as BRADYKININ (SEE NOTE)
–A reduction in prostaglandins results in a reduction in pain
Salicylates:
MECHANISM OF ACTION
ASA
3. Reye’s Syndrome• Associated with use of aspirin in children &
adolescents who took it when they had the chickenpox or influenza
• Fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver.
• ACETAMINOPHEN and NSAIDs are now used for fever (antipyretic action) or pain (analgesic action) in pediatric and adolescents to reduce the chances of Reye’s Syndrome
Salicylates:
ADVERSE REACTIONS
NSAIDs• A rapidly growing group with important
application in dentistry– Mechanism of action and many of their
pharmacologic effects and adverse reactions resemble aspirin
• Many authors agree that the NSAIDs are the most useful drug group for the treatment of dental pain.– Most are available without a prescription.
NSAIDs
• Most NSAIDs peak in about 1-2 hours–Well absorbed orally and food reduces
the rate but not the extent of absorption
• Metabolized in liver, excreted in kidneys
PHARMACOKINETICS
NSAIDs
• have a significant anti-inflammatory effect
• Similar as aspirin:–analgesic–antipyretic –anti-inflammatory
• They inhibit prostaglandin synthesis
PHARMACOLOGIC EFFECTS
NSAIDS ARE NOT ADDICTING, TOLERANCE DOES NOT DEVELOP, AND NO
WITHDRAWAL SYNDROME CAN BE INDUCED.
NO!
NSAIDs
7. Pregnancy and Nursing
• Contraindicated in pregnancy; • Like aspirin, NSAIDs given late in pregnancy
can prolong gestation• IBUPROFEN is drug of choice for nursing
ADVERSE REACTIONS
IN USUAL PRESCRIPTION DOSES, NSAIDS CAN BE SHOWN TO BE STATISTICALLY
SIGNIFICANTLY BETTER THAN CODEINE ALONE, ASPIRIN, ACETAMINOPHEN, OR
PLACEBO.
400MG
NSAIDs
• NSAIDs should be used with caution in patients with:
1. asthma2. cardiovascular disease3. Renal diseases with fluid retention 4. coagulation problems5. peptic ulcer disease6. ulcerative colitis
CONTRAINDICATIONS & CAUTIONS
Contraindicated in pregnancy
Acetaminophen
• Used as an analgesic and antipyretic in children and adults when aspirin is contraindicated
• Has no anti-inflammatory action
Acetaminophen
• Rapidly and completely absorbed from the GI tract
• Peak plasma level in 1 – 3 hours• Half life of 1 to 4 hours• Metabolized by the liver• Excreted by the kidneys in 24 hours• When large doses are ingested, an intermediate
metabolite is produced that is thought to be hepatotoxic and possibly nephrotoxic.
.
PHARMACOKINETICS
Acetaminophen
• Acetaminophen is used as an:
–Analgesic agent (↓ pain)–Antipyretic agent (↓ fever)
USES
Acetaminophen
• Used when hypersensitivity to aspirin or for patients experiencing aspirin-gastric induced irritation.
• Used as an antipyretic instead of aspirin for young children; due to aspirin’s association with Reye’s syndrome.
• Can be used in all stages of pregnancy (always ask doctor)
USES
Drugs Used to Treat Gout
Allopurinol (Zyloprim)• used in PREVENTION of a gout attack.
– Inhibits the synthesis of uric acid– Also used in patients receiving either
chemotherapy or irradiation – If a pruritic rash should occur, the drug
should be promptly discontinuedProbenecid (Benemid)
• used in PREVENTION of a gout attack.– Is an uricosuric drug that increases uric acid
excretion in the urine
AT FIRST REFERRED TO DRUGS THAT ARE DERIVATIVES OF OPIUM POPPY
OPIOID OR NARCOTIC ANALGESICS ARE USED TO MANAGE DENTAL PAIN IN
PATIENTS IN WHOM NSAIDS ARE CONTRAINDICATED
MODERATE TO SEVERE PAIN
1. Mechanism of action at the receptor site:
53
CLASSIFICATION-THREE GROUPS-
GROUP SUBGROUP EXAMPLE
OPIOID AGONISTS
morphine, codeine
MIXED OPIOIDS
AGONIST-ANTAGONISTS
PARTIAL AGONIST
pentazocine
buprenorphine
ANTAGONISTS Naloxone
54
CLASSIFICATION: CHEMICAL STRUCTURE
BOX 6-1 OPIOD ANALGESIC AGENTS BY STRUCTURE GROUP
MORPHINE AND CODEINE(Largest Group)
• hydromorphone (Dilaudid) agonist• hydrocodone (in Vicodin) agonist• dihydrocodeine (in Synalgos-DC)• oxycodone (in Percodan, Percocet, Tylox) agonist
METHADONE • methadone (Dolophine) agonist• propoxyphene (Darvon) agonist
MORPHINAN • butorphanol (Stadol) agonist-antagonist• pentazocine (in Talwin-NX) agonist-antagonist
MEPERIDINE • meperidine (Demerol) agonist• fentanyl (Sublimaze) agonist• diphenoxylate (in Lomotil)
OTHER • buprenorphine (Buprenex, Subutex) partial agonist
Do not give any of these drugs if the patient has an
allergy to morphine or codeine
57
DRUG NAME (SOME EXAMPLES)
COMMENTS SCHEDULE FOR
CONTROLLED
SUBSTANCE
STRONGEST
MORPHINE Standard agent; prototype
II
MERPERIDENE (Demerol)
Abused by professionals
II
INTERMEDIATE
OXYCODONE (in Percocet)
Popular with addicts ‘shopping’ for opioids
II
WEAKEST
HYDROCODONE (in Vicodin)
III
CODEINE (in Tylenol#3)
#2=15mg; #3-30mg; #4=60mg
III
OPIOIDS BIND TO RECEPTORS IN BOTH THE CENTRAL NERVOUS SYSTEM (CNS) AND THE SPINAL CORD, PRODUCING AN ALTERED PERCEPTION OF REACTION TO
PAIN
PERIPHERAL NERVE ENDINGS
NATURAL OPIOIDS (ALSO CALLED ENDOGENOUS OPIOIDS) , INCLUDE:
ENKEPHALINSENDORPHINSDYNORPHINS
THESE ARE THE CHEMICALS THAT MAKE SURE WE CAN FUNCTION DURING ACCIDENTS,
L IKE AFTER BREAKING OUR LEG…
RELIEVE PAIN AND RELAXATION
1. Enkephalins
2. Endorphins
3. Dynorphins
All 3 have opioid-like action and are found in the body.They are naturally occurring peptides that possess
analgesic action and addiction potential62
The Discovery of 3 Groups of Endogenous Substances
Probably function as
neurotransmitters, although their
exact function has not been
elucidated.
reduces pain & positively affects mood.
stimulates delta() receptor
stimulates the kappa ()-receptor
MECHANISM OF ACTION
THE DOSING INTERVALS OF MOST OPIOIDS ARE BETWEEN 4-6 HOURS; THE
USUAL DOSE DEPENDS ON THE DRUG.
DURATION – NECESSITATES DOSING EVERY 4 -6 HOURS
WITHIN 1 HOUR
UNDERGOES FIRST PASS METABOLISM IN THE LIVER AND INTESTINE, REDUCING
ITS BIOAVAILABILITY.
REDUCES THE BIOAVAILABILITY
Distribution:Oral bioavailability of opioids is primarily limited by first pass metabolism.
Undergoes first pass metabolism in the liver and intestine, reducing its bioavailability.
Degree of first pass differs among individuals.May cause respiratory depression in fetus when mother is given opioids near term.
67
PHARMACOKINETICS
Excretion:Most opioids are excreted through the kidneys, but this action does not selectively affect their availability after oral administration.
Metabolized opioids and the unchanged drug are excreted in the urine.
68
A.D.M.EPHARMACOKINETICS
A PHARMACOLOGIC EFFECT MAY ALSO BE AN ADVERSE REACTION, DEPENDING ON
THE CLINICAL USE OF THE AGENT.
TRUE
• MORPHINE IS THE OPIOID AGONIST BY WHICH ALL OTHERS ARE MEASURED.
• STRONGEST CAN RELIEVE SEVERE PAIN WHILE WEAKER AGENTS MIXED WITH
NON-OPIOIDS ARE EQUIVALENT TO NSAIDS.
THE STRONGEST
Aspirin (ASA) and ibuprofen (NSAID) are analgesic, antipyretic, and antiinflammatory, and they inhibit platelet aggregation.
Acetaminophen is analgesic and antipyretic.
Codeine is analgesic.73
AnalgesiaPHARMACOLOGI
C EFFECTS
What do aspirin, acetaminophen, ibuprofen, and codeine have in common?
Opioid analgesics ↑ smooth muscle tone and ↓ propulsive contractions and motility (some opioids have constipation as a side effect).
Useful for treating diarrhea.
Example: diphenoxylate (in Lomotil)
76
Gastrointestinal Effects
Opioids are not used for depression, infections, or hypertension
PHARMACOLOGIC EFFECTS
Combining an opioid with a nonopioid analgesic produces an additive analgesic
effect with fewer adverse reactions.
77
ADVERSE REACTIONSTRUE or FALSE
TRUE
These agents work at two different levels on pain and produce an additive analgesic effect. In
combination products, lower doses of each analgesic may be used, and a potential exists for a reduction in
adverse reactions.
THE RATE AND DEPTH OF BREATHING ARE REDUCED.
THE DEPRESSION IS RELATED TO A DECREASE IN THE SENSITIVITY OF THE
BRAINSTEM TO CARBON DIOXIDE.
DEPRESS THE RESPIRATORY CENTER IN A DOSE RELATED
MANNER
80
Respiratory Depression (RP)
Not a problem with usual doses
in normal patients
RP is usually the cause of
death with an overdose
ADVERSE REACTIONS
81
Nausea and EmesisAnalgesic doses of opioids often produce nausea and vomiting.
Result of their direct stimulation of the chemoreceptor trigger zone (CTZ) located in the medulla.
Repeated administration of regular doses can prevent vomiting at the vomiting center (VC).
ADVERSE REACTIONS
88
Biliary Tract Constriction
Opioids may constrict the biliary duct, causing biliary colic (bile duct obstruction leading to gall stones).
ADVERSE REACTIONS
Importance in patients passing gallstones who are being treated with opioids.
NOT TERATOGENIC, BUT MAY PROLONG LABOR OR DEPRESS FETAL RESPIRATION
IF GIVEN NEAR TERM..
NOT USUALLY A PROBLEM WITH MOTHER’S MILK WITH THERAPEUTIC
DOSES.
THE INFANT MAY HAVE DEPRESSED RESPIRATION AND
WITHDRAWL SYMPTOMS
92
ADVERSE REACTIONS
AddictionThe degree of addiction potential is proportional to analgesic strength.
An addict will develop tolerance to the effects of opioids, EXCEPT for miosis and constipation.
93
AddictionSince the duration of use in dentistry is usually short – addiction for dentistry does not pose a problem
NSAIDs should be used to control dental pain in the addict.
AN ADVANTAGE OF NSAIDs OVER OPIOIDS:
NSAIDs are not addictive, tolerance does not develop, and no withdrawal syndrome can be
induced.
ADVERSE REACTIONS
TERMED ‘SHOPPERS’ THE CLIENT IS LOOKING FOR A SPECIFIC OPIOD.
KEEP IN MIND – THIS ISNT ALWAYS THE CASE…LOOK FOR OTHER SIGNS NOT JUST
ONE
OPIOD ADDICT
96
Addiction: Identification of an Addict
The “shoppers” - What to look for:Asks for the opioid analgesic by name and says that this is the only drug that
works for them.Claims allergies to NSAIDs .Cancels dental appointment but still requests the opioid analgesic even
though they will be “out of town on business”.Experiences pain for days after scaling and root planingMoves from office to office because “others don’t understand”.Claims a “low pain threshold”.Needs refills several days after a procedure without complications.Calls with a request for an opioid analgesic just as the office is closing or after
hours.
ADVERSE REACTIONS
MAINTAINING PATIENTS ON HIGH DOSES OF METHADONE (METHADONE
MAINTENANCE) .
USED TO TREAT OPIOD ADDICTION AND WITHDRAWL
99
Addiction: 4 Treatment
OptionsAddiction, overdose, and withdrawal can be treated with opioid antagonists
1. Substituting addict with oral opioid (methadone).2. Going cold turkey and using medication such as
phenothiazines, clonidine or benzodiazepines (to alleviate symptoms of withdrawal).
3. Maintaining patients on high doses of methadone (methadone maintenance).
4. Administering an orally effective, long-acting antagonist Naltrexone (Trexan).
ADVERSE REACTIONS
100
Addiction: Treatment Options Example: The Heroin Addict
The following drugs can be used to treat heroin addiction
ADVERSE REACTIONS
METHADONE, is used by substituting methadone for heroin and then tapering
off or maintaining the addict on oral methadone.
NALTREXONE, a long-acting opioid antagonist, is used to block the action of
usual doses of opioid administered illegally
MOST COMMON TYPES OF TRUE ALLERGIC REACTIONS TO OPIOIDS IS
DERMATOLOGIC IN NATURE.
DUE TO THE HISTAMINE-RELEASING PROPERTIES OF OPIOID ANALGESICS.
INCLUDES SKIN RASHES AND URTICARIA.GI SIDE EFFECTS ARE OFTEN REPORTED.
NO
103
A patient with a true allergy to codeine
should NOT be given an analgesic in that group
This includes:
oxycodone hydromorphone, hydrocodone, and dihydrocodone
Because they are all members of the same
morphine and codeine group.
The prototype opioid agonist which other opioids are measured
107
Agonists: MorphineSPECIFIC OPIODS
Parenterally: used to control postoperative pain
Orally: used primarily in the treatment of cancer
Used alone or combined with aspirin (in Percodan) or acetaminophen (in Percocet, Tylox) with fewer adverse reactions.
For moderate to severe pain.
It is located in the middle of the chart for strength value.
108
Agonists: OxycodoneSPECIFIC OPIODS
Weak opioid analgesic with fewer adverse reactions.
Less potential for abuse. Combination of Hydrocodone (5mg) with acetaminophen (500mg) is recommended for the majority of dental patients with pain
109
Agonists: HydrocodoneSPECIFIC OPIODS
In Vicodin, it has been reported as being safe to use when breastfeeding
MOST COMMONLY USED OPIOID IN DENTISTRY AND IS OFTEN COMBINED
WITH ACETAMINOPHEN (TYLENOL #3) FOR ORAL ADMINISTRATION
CODEINE
Favorite drug of abuse for medical personnel; 100mg meperidine=10mg morphine.
For acute management of moderate to severe pain.
Poor choice for oral use because it has a high first pass effect; short duration of action.
Less constipating, and without miosis or cough suppression.
EXAMPLE: meperidine HCl (Demerol)
112
Agonists: MeperidineSPECIFIC OPIODS
An orally effective opioid, reserved for management of severe pain.
More potent than morphineSimilar adverse reactions to morphine.Favourite of the addicts because of its high strength; requires careful monitoring.
EXAMPLE: Dilaudid
115
Agonists: HydromorphoneSPECIFIC OPIODS
116
Agonists: Methadone
SPECIFIC OPIODS
Methadone is used either to withdraw the patient gradually or for
methadone maintenance. Because it has a longer duration of action, withdrawal from methadone is
easier than from heroin. Because it is an
opioid analgesic, however, the risk for
dependence still exists.
Used primarily to treat any opioid
addicts (eg. Heroin addicts)
Similar to morphine.
Slower onset and longer duration of action.
EXAMPLE: Dolophine
117
Antagonists SPECIFIC OPIODS
Naloxone will block the therapeutic and toxic actions of opioids
Methadone is an opioid used in treatment of addiction, but will exacerbate symptoms of an opioid overdose.
An pure opioid antagonist that is active parenterally.
Drug of choice for treating agonist or mixed opioid overdoses.
naloxone (Narcan)
Few studies have confirmed its efficacy:Binds with mu (μ) opioid receptors; inhibits reuptake of serotonin and norepinephrine,
and modifies ascending pain pathways.
Its analgesic efficacy is equivalent to that of codeine.Side effects can include: miosis and CNS effects, such as
dizziness, headache and stimulation and GI tract effects include nausea, diarrhea, constipation and vomiting.
Is moving up the top 200 most prescribed drugs.
120
SPECIFIC OPIODSTramadol (Ultram)
Most dental pain can be managed with NSAIDs.
If NSAIDs are contraindicated - the DDS has a wide variety of opioids to choose from.
Eg. Beginning with codeine or hydrocodone combinations, and progressing to oxycodone combinations.
Only in rare cases and for short periods of time (approx. 1-2 days) should stronger opioids be prescribed for outpatient dental pain.
121
DENTAL USE OF OPIODS
Opioids are considered first-line therapy for:Pain associated with procedures (bone marrow biopsy)Pain due to trauma or cancer (burns)Visceral pain (appendicitis)
Majority used to relieve acute or chronic pain.Few, such as fentanyl (Sublimaze, Duragesic), alfentanil (Alfenta), and sufentanil (Sufenta), are primarily indicated for preoperative sedation to reduce patient apprehension.
Also used to suppress cough and treat diarrhea
124
REVIEW: USE OF OPIODS
Recommended