Download - Pain, Inflammation, NSAIDs and Analgesics
Pain, Inflammation, NSAIDs and Analgesics
BY DR KAUKAB AZIM
Learning OutcomesBy 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.
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.
What is PainPain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damageHyperaesthesia (hypersensitivity): Increased sensitivity to stimulation, excluding the special sensesHyperalgesia: Increased pain in response to a noxious stimulusAllodynia: Pain due to a stimulus that does not normally produce painFrom the International Association for the Study of Pain (IASP) definitions (Merskey, and Bogduk 1994)
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
18% of Elderly PersonsTake 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
Common Causes of Pain In Elderly Persons
• Osteoarthritis– back, knee, hip
• Night-time leg cramps• Claudication• Neuropathies
– idiopathic, traumatic, diabetic, herpetic• Cancer
Pain Receptors
Pain Intensity
Proportional to number of receptors stimulated
Pain Pathway
Pain Mechanism
Etiological Factorsinflammation/tissue damage/nerve lesions
Pain Sydromespost-operative/arthritic/back pain/neuropathic
Mechanisms associated with peripheral sensitization to pain
Nonsteroidal antiinflammatory drugs (NSAIDs)
Salicylic acid derivatives
Propionic acid derivatives
Acetic acid derivatives
Oxicams Indole derivatives
Selective COX-2 inhibitors
-Acetylsalicylic acid
-Sodiumsalicylate-Diflunisal-Mesalamine
IbuprofenKetoprofenNaproxen
DiclofenacKetorolac
PiroxicamMeloxicam
Indomethacin Celecoxib
Analgesic-antipyretic drug:Acetaminophen
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Prostaglandins as mediators
√
–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
►
▼
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)
• 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
NSAIDS: Effects
• 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
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.
• 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)
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.
Dose dependent effects of Aspirin
Toxic levels
High Levels
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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COX-1
COX PG I2
Aggregation inhibitor
Aggregation promotor
Irreversible inhibition by Aspirin.
Enucleated platelets cannot regenerate COX.
Irreversible inhibition by Aspirin.
Nucleated endothelial cells can regenerate COX.
ANTIPLATELET EFFECT OF APIRIN
• ↑ 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
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, sweating, hyperventilation, nausea and vomiting, diarrhea
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
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
Other tNSAIDSIbuprofen, 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
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
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
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.
Acetaminophen: MetabolismMINOR
PATHWAYP450 Enzyme
CYP2E1 and CYP1A2
MAJORPATHWAY
(Sulphate Conjugation)
MAJORPATHWAY
(Glucuronide conjugation)
RENAL EXCRETIONTOXIC METABOLITE
NAPQIN-acetyl-p-benzo-
quinone imine)
Toxic Doses (4gm+)Therapeutic Doses
GlutathioneAvailable
GlutathioneDepleted
RENAL EXCRETION Hepatic Necrosis
Antiinflammatory agents:
Steroids
Steroids Duration of action
Glucocorticoid activity
(antiinflammatory)
Mineralocorticoid activity
(Salt retaining)
Short actingHydrocortisone 8-12 1 1
Cortisone 8-12 0.8 0.8
Fludrocortisone 8-12 10 125Intermediate actingPrednisone 12-36 4 0.8
Prednisolone 12-36 4 0.8
Methylprednisolone 12-36 5 0.5
Triamcinolone 12-36 5 0Long actingBetamethasone 24-72 35 0Dexamethasone 24-72 30 0
Glucocorticoids: Mechanism of action
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Steroids: Antiinflammatory effect
Therapeutic uses
• Adrenal Uses• Non-adrenal uses:
– Inflammatory disorders• Asthma• Allergies: Allergic rhinitis, Acute allergic reactions• Autoimmune disorders: RA, SLE, glomerulonephritis
– Carcinomas– For immunosuppression
Oral thrush (Candidiasis)
Other Adverse effects of Glucocorticoids
• 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
OPIOID ANALGESICS
History of Opioids
• Opium is extracted from poppy seeds
• Used for thousands of years to produce:– Euphoria– Analgesia– Sedation– Relief from diarrhea– Cough suppression
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
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
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
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
Three Opioid Receptors
• Mu
• Kappa
• Delta
Delta Receptor
• It is unclear what delta’s responsible for.• Delta agonists show poor analgesia and little
addictive potential• May regulate mu receptor activity
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
Kappa Receptor
• Only modest analgesia• Little or no respiratory depression
• Little or no dependence • Dysphoric effects
Mu and Kappa Receptor Activation
Response Mu-1 Mu-2 Kappa
Analgesia ✓ ✓ ✓Respiratory Depression ✓
Euphoria ✓Dysphoria ✓
Decrease GI motility ✓Physical
Dependence ✓
AGONISTS
MorphineHeroin
HydromorphoneFentanylCodeine
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.
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.)
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
Antagonists
NaloxoneNaltrexone
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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