Transcript Pain, Inflammation, NSAIDs and Analgesics

Pain, Inflammation, NSAIDs and
Analgesics
BY DR KAUKAB AZIM
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Learning Outcomes
By the end of the lecture the student should be able to
• Define and discuss the pathobiology of pain pathways
• Explain the molecular mechanism of action common to all
nonsteroidal antiinflammatory drugs (NSAIDs)
• Describe the pharmacological effects of each drug in each class.
• Describe the pharmacokinetics of salicylates.
• Describe the main adverse effects of the drugs of each class.
• Describe the clinically important drug interactions of the drugs of
each class.
• Describe the principal contraindications of the drugs of each class.
• Describe the main therapeutic uses of NSAIDs and acetaminophen.
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What is inflammation?
• INFLAMMATION – is a reaction to tissue
injury caused by the release of chemical
mediators that cause both vascular
response and the migration of fluids and
cells to the injured site.
• It is a protective mechanism in which the
body attempts to neutralize and destroy
harmful agents at the site of tissue injury
and establish condition for tissue repair.
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What is Pain
Pain: An unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or
described in terms of such damage
Hyperaesthesia (hypersensitivity): Increased sensitivity
to stimulation, excluding the special senses
Hyperalgesia: Increased pain in response to a noxious
stimulus
Allodynia: Pain due to a stimulus that does not normally
produce pain
From the International Association for the Study of Pain
(IASP) definitions (Merskey, and Bogduk 1994)
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Physicians Have a Moral Obligation to Provide
Comfort and Pain Management
Especially for those near the end of life!
• Pain is the most feared complication of illness
• Pain is the second leading complaint in
physicians’ offices
• Often under-diagnosed and under-treated
• Effects on mood, functional status, and quality of
life
• Associated with increased health service use
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18% of Elderly Persons
Take Analgesic Medications Regularly
(daily or more than 3 times a week)
• 71 % take prescription analgesics
– 63% for more than 6 months
• 72% take OTC analgesics
– Median duration more than 5 years
• 26% report side-effects
– 10% were hospitalized
– 41% take medications for side-effects
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Common Causes of Pain In Elderly
Persons
• Osteoarthritis
– back, knee, hip
• Night-time leg cramps
• Claudication
• Neuropathies
– idiopathic, traumatic, diabetic,
herpetic
• Cancer
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Etiological Factors
inflammation/tissue damage/nerve lesions
Pain Mechanism
Pain Sydromes
post-operative/arthritic/back pain/neuropathic
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Mechanisms associated with
peripheral sensitization to pain
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Common actions of the NSAIDs
• Anti-inflammotry effect: modification of
inflammatory reaction
• Analgesic effect: reduction of certain sorts of
pain
• Antipyretic effect: lowering a raised
temperature
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Nonsteroidal antiinflammatory drugs (NSAIDs)
Salicylic acid
derivatives
Propionic
Acetic acid
acid
derivatives
derivatives
Oxicams
Indole
derivatives
Selective
COX-2
inhibitors
-Acetylsalicylic
acid
-Sodium
salicylate
-Diflunisal
-Mesalamine
Ibuprofen
Ketoprofen
Naproxen
Piroxicam
Meloxicam
Indomethacin
Celecoxib
Diclofenac
Ketorolac
Analgesic-antipyretic drug:
Acetaminophen
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Prostaglandins as mediators
√
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▼
–Non-selective (t NSAIDS) inhibit
both isozymes.
–Side effects occur due to inhibition
of COX-1(house keeping” enzyme)
► •With selective COX-2 inhibitors
(Coxibs), chances of GIT toxicity are
less.
•CVS side effects can occur
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Prostanoids actions
• PGI2 (prostacyclin):causes vasodilation and
inhibition of platelets aggregation (used
clinically for primary plumonary hypertension
and inhibition of platelet aggregation in
patients undergoing haemodialysis
• PGD2:causes vaso dilatation and inhibition of
platelet aggregation +relaxation of the GI and
human uterus
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• PGE2:contraction of the bronchial,GIT and uterine
smooth muscle +inhibition of lipolysis and fever(
used clinically for induction of labor; termation of
pregnancy ;post partum haemorrage and prevention
of peptic ulcer
• PGF2α:contraction of the uterine smooth muscle
• Thromboxane A2:causes platelets aggregation and
vasoconstriction
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NSAIDS: Mechanism of action
• Main mechanism: Inhibition of COX
– Reversible (competitive) inhibitors
– Irreversible inactivation (by Aspirin)
– Nonselective COX inhibitors (traditional NSAIDS)
– Selective COX-2 inhibitors (Celecoxib)
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NSAIDS: Effects
• Anti-inflammatory effect
– reverses vasodilation, edema, tenderness
• Analgesic effect
– By preventing PG mediated sensitization of nerve endings
• Antipyretic effect
– Resets the hypothalamic thermostat by decreasing PG
synthesis
– Vasodilation and heat loss
– Do not cause hypothermia
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• Antiplatelet aggregation effect
– Platelets have COX-1
– Aspirin acetylates COX-1 to inhibit its activity in an
“irreversible manner”.
– All other tNSAIDS- reversible inhibitors
– Selective COX-2 inhibitors do not disturb platelet
aggregation at therapeutic doses
– Acetaminophen do not inhibit platelet aggregation
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Common side effects of NSAIDS
• Gastrointestinal:
Nonselective NSAIDS
COX-1 inhibition
↓ gastroprotective PGs
– Gastric irritation, erosions, ulcers, gastric bleeding
– Misoprostol (PGE1) can be used to prevent gastric
ulcers caused by tNSAIDS.
– Selective COX-2 inhibitors are safer.
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• Renal: Sodium water retention, Papillary necrosis
• CVS: ↑ Na and water retention
• Platelet inhibition : bleeding
– Selective COX-2 inhibitors and acetaminophen do not disturb
platelet function.
• CNS: Headache, confusion, seizures
• Hypersensitivity: “Pseudoallergic reaction” (due to
increased leukotrienes)
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Salicylates
• Acetylated salicylate: Aspirin (Acetylsalicylic acid)
• Non-acetylated salicylates: sodium salicylate,
diflunisal, mesalamine (5-ASA)
►Mechanism of action:
– Aspirin: non-selective COX inhibitor;
“Irreversible inhibition” by acetylation.
– Other salicylates: weak COX inhibitors; other
mechanisms are involved.
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Dose dependent effects of Aspirin
Toxic
levels
High
Levels
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Effects of aspirin
• Antiplatelet effect:
– Irreversible inactivation of COX-1 in platelets causes decreased
production of TXA2 (aggregation promoter)
• Platelets (enucleated) cannot regenerate COX; effect lasts for 7-8 days.
– Irreversible inactivation of COX in endothelial cells causes
decreased production of PGI2 (aggregation inhibitor)
• Endothelial cells can regenerate cyclooxygenase in a matter of hrs.
– Net effect is decreased platelet aggregation and increase in
bleeding time.
– Low doses (80-160mg) are enough to inhibit aggregation
without anti-inflammatory effects.
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ANTIPLATELET EFFECT OF APIRIN
Aggregation
inhibitor
Irreversible
inhibition by
Aspirin.
Nucleated
endothelial cells
can regenerate
COX.
COX
Aggregation
promotor
PG I2
COX-1
Irreversible
inhibition by
Aspirin.
Enucleated
platelets cannot
regenerate COX.
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• ↑ Plasma uric acid levels (at low dose)
• ↓ Plasma uric acid levels (at high dose)
• Hyperventilation and compensated alkalosis
(At high levels)
– stimulates respiratory center, ↓ pCO2, Increased
bicarbonate in urine
• Metabolic acidosis: (At toxic levels)
– Accumulation of salicylic acid due to zero order
kinetics at high levels.
– Respiratory center depression; ↑ pCO2
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Salicylates: Adverse effects
• Hypersensitivity reactions
– Pts with asthma, nasal polyps, chronic urticaria are more
susceptible
– Pseudoallergic reaction
– Cross reactivity with other NSAIDS
• Reye’s syndrome: Encephalopathy, hepatotoxicity.
– Do not use aspirin in children with viral fever.
• Salicylism:
Tinnitus, dimness of vision, mental confusion, lassitude,
sweating, hyperventilation, nausea and vomiting, diarrhea
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Salicylate intoxication
–
–
–
–
–
Tinnitus, Nausea and vomiting, abdominal cramps, gastric
bleeding.
Respiratory depression, Acidosis, generalized convulsions.
marked hyperthermia, dehydration.
Skin eruptions, petechial hemorrhages
coma and death (due to respiratory failure)
Treatment: Symptomatic and supportive.
–
–
–
External cooling and I.V. fluids with Na, K, and glucose.
Gastric lavage to remove unabsorbed drug
Forced alkaline diuresis to remove absorbed drug
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Salicylates: Therapeutic uses
• Keratolytic: salicylic acid
• Counterirritant: Methylsalicylate
• Antiinflammatory, analgesic, antipyretic
– Diflunisal: does not enter CNS; no antipyretic effect
Mesalamine (5-ASA):
– inflammatory bowel diseases
Aspirin (Low doses):
– MI, Angina
– Atrial flutter/fibrillation
– Transient ischemic attacks
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Other tNSAIDS
Ibuprofen, Naproxen:
– Widely used NSAID for pain and inflammation
– GIT and CNS side effects are less
Diclofenec
– Inhibits COX and lipooxygenase (to minor extent)
– Decreases free radical production
– Accumulates in synovial fluid
Ketorolac
– Can be administered IV, IM
– Used in postoperative pain
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Indomethacin
• One of the most potent COX inhibitor
–
–
–
–
Inhibits COX
Inhibits Phospholipase A2
Reduces neutrophil migration
Reduces T and B cell proliferation
• Severe side effects (in 1/3rd pts)
– Abdominal pain, diarrhea, GI bleeding
– Frontal headache
– Dizziness, confusion, depression, hallucinations
• Therapeutic Uses:
– Arthritis (osteoarthritis, rheumatoid arthritis, Ankylosing
spondylitis, Gout)
– Closure of ductus arteriosus
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Selective Cox-2 inhibitors
“Coxibs”
• Celecoxib: first selective COX-2 inhibitor
• Potent antiinflammatory, analgesic and antipyretic
activity
• Incidence of GI bleeding and peptic ulcers is lower
than tNSAIDS
• Does not inhibit platelet aggregation
• Increased risk of cardiovascular side effects:
Hypertension, Thrombotic events
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Acetaminophen
• Analgesic and antipyretic agent
– Inhibits COX-3 in CNS… ?
• Lacks significant anti-inflammatory and
antiplatelet activity: very weak COX 1& 2
inhibitor
• Metabolized in the liver
• Toxic doses deplete glutathione
– A metabolite, N-acetyl-p-benzoquinoneimine
accumulates and causes hepatic necrosis.
– Acetylcysteine administered as antidote.
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Acetaminophen: Metabolism
MAJOR
PATHWAY
(Sulphate Conjugation)
MAJOR
PATHWAY
(Glucuronide conjugation)
MINOR
PATHWAY
P450 Enzyme
CYP2E1 and CYP1A2
RENAL EXCRETION
TOXIC METABOLITE
NAPQI
N-acetyl-p-benzoquinone imine)
Therapeutic Doses
Toxic Doses (4gm+)
Glutathione
Available
Glutathione
Depleted
RENAL EXCRETION
Hepatic Necrosis
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Antiinflammatory agents:
Steroids
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Steroids
Duration of
action
Glucocorticoid
activity
Mineralocorticoid
activity
(antiinflammatory)
(Salt retaining)
Short acting
Hydrocortisone
8-12
1
1
Cortisone
8-12
0.8
0.8
Fludrocortisone
8-12
10
Prednisone
12-36
4
0.8
Prednisolone
12-36
4
0.8
Methylprednisolone
12-36
5
0.5
Triamcinolone
12-36
5
0
Betamethasone
24-72
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0
Dexamethasone
24-72
30
0
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Intermediate acting
Long acting
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Glucocorticoids:
Mechanism of action
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Steroids: Antiinflammatory effect
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Therapeutic uses
• Adrenal Uses
• Non-adrenal uses:
– Inflammatory disorders
• Asthma
• Allergies: Allergic rhinitis, Acute allergic reactions
• Autoimmune disorders: RA, SLE, glomerulonephritis
– Carcinomas
– For immunosuppression
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Oral thrush (Candidiasis)
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Other Adverse effects of Glucocorticoids
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•
•
•
•
•
•
•
•
•
•
Cushing like syndrome
Psychosis
Peptic ulcers
Osteoporosis
Aseptic necrosis of hip
Easy bruisability, Purple striae on skin
Visceral fat deposition
Posterior subcapsular cataract, glaucoma
Hirsutism
Increased appetite
Growth retardation in children
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OPIOID ANALGESICS
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History of Opioids
• Opium is extracted from poppy seeds
• Used for thousands of years to produce:
– Euphoria
– Analgesia
– Sedation
– Relief from diarrhea
– Cough suppression
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Mechanism of action
• Activation of peripheral nociceptive fibers causes
release of substance P and other pain-signaling
neurotransmitters from nerve terminals in the dorsal
horn of the spinal cord
• Release of pain-signaling neurotransmitters is
regulated by opioid agonists by acting presynaptically
to inhibit substance P release, causing analgesia
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Molecular Effect of Opioid Receptor Activation
• Reduction or inhibition of neurotransmission, due largely to
opioid-induced presynaptic inhibition of neurotransmitter
release
• Involves changes in transmembrane ion conductance
– Increase potassium conductance (hyperpolarization)
– Inactivation of calcium channels
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Pharmacological Effects
• Sedation and anxiolysis
– Drowsiness and lethargy
– Apathy
– Cognitive impairment
• Depression of respiration
– Main cause of death from opioid overdose
– Combination of opioids and alcohol is especially dangerous
• Cough suppression
– Opioids suppress the “cough center” in the brain
• Pupillary constriction
– pupillary constriction in the presence of analgesics is characteristic of
opioid use
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Pharmacological effects
• Nausea and vomiting
– Stimulation of receptors in an area of the medulla called the
chemoreceptor trigger zone causes nausea and vomiting
– Unpleasant side effect, but not life threatening
• Gastrointestinal symptoms
– Opioids relieve diarrhea as a result of their direct actions on the
intestines
• Other effects
– Opioids can release histamines causing itching or more severe allergic
reactions including bronchoconstriction
– Opioids can affect white blood cell function and immune function
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Three Opioid Receptors
• Mu
• Kappa
• Delta
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Delta Receptor
• It is unclear what delta’s responsible for.
• Delta agonists show poor analgesia and little
addictive potential
• May regulate mu receptor activity
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Mu-Receptor: Two Types
• Mu-1
– Located outside spinal
cord
– Responsible for central
interpretation of pain
• Mu-2
– Located throughout CNS
– Responsible for
respiratory depression,
spinal analgesia, physical
dependence, and
euphoria
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Kappa Receptor
• Only modest analgesia
• Little or no respiratory depression
• Little or no dependence
• Dysphoric effects
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Mu and Kappa Receptor Activation
Response
Mu-1
Mu-2
Kappa
Analgesia
✓
✓
✓
Respiratory
Depression
✓
Euphoria
✓
✓
Dysphoria
Decrease GI
motility
✓
Physical
Dependence
✓
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AGONISTS
Morphine
Heroin
Hydromorphone
Fentanyl
Codeine
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Morphine
• PHARMACOKINETICS
• Routes of administration (preferred)
*Oral
latency to onset –(15 – 60 minutes )
•
* it is also sniffed, swallowed and injected.
•
* duration of action – ( 3 – 6 hours)
•
* First-pass metabolism results in poor
•
availability from oral dosing.
•
* 30% is plasma protein bound
• EFFECTS AND MEDICAL USES
•
*symptomatic relief of moderate to severe pain
•
*relief of certain types of labored breathing
•
*suppression of severe cough (rarely)
•
*suppression of severe diarrhea
•
*AGONIST for mu, kappa, and delta receptors.
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Hydromorphone
• PHARMACOKINETICS
•
*Routes of administration (Preferred)
•
*Oral
•
*latency to onset (15 – 30 minutes)
•
*Intravenous
•
*Duration of Action (3-4 hours)
•
*Peak effect (30-60 minutes)
• PROPERTIES AND EFFECTS
•
* potent analgesic like morphine but is 7-10
•
times as potent in this capacity.
•
*used fequently in surgical settings for moderate to
•
severe pain. (cancer, bone trauma, burns, renal colic.)
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Fentanyl
•
•
Pharmacokinetics
Routes of Administration
* Oral, and transdermal (possibly intravenous)
*Highly lipophilic
*latency to onset (7-15 minutes oral; 12-17 hours
transdermal
*duration of action ( 1-2 hours oral; 72 transdermal)
*80 – 85% plasma protein bound
*90 % metabolized in the liver to inactive metabolites
Other properties
* 80 times the analgesic potency of morphine
and 10 times the analgesic potency of
hydromorphone.
*high efficacy for mu 1 receptors.
*most effective opiate analgesic
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Antagonists
Naloxone
Naltrexone
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Naltrexone
• PHARMACOKINETICS
•
*latency to onset (oral tablet 15-30 min.)
•
*duration of action 24-72 hours
•
*peak effect (6-12 hours)
• STRUCTURAL DISTINCTION
•
*Differs from naloxone insofar as the
•
allyl group on the nitrogen atom is supplanted
•
by a cyclopromethyl group.
• EFFECTS
•
*Reverses the psychotomimetic effects of opiate
•
agonists.
•
* Reverses hypotension and cardiovascular instability
•
secondary to endogeneous endorphins (potent vasodilators)
•
*inhibits Mu, Delta, and Kappa receptors.
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THANK YOU
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