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Pain, Inflammation, NSAIDs and Analgesics

BY DR KAUKAB AZIM

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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.

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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 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)

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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 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

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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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Pain Receptors

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Pain Intensity

Proportional to number of receptors stimulated

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Pain Pathway

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Pain Mechanism

Etiological Factorsinflammation/tissue damage/nerve lesions

Pain Sydromespost-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 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

√

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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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• 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

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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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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

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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 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

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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: 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

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Antiinflammatory agents:

Steroids

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Steroids Duration of action

Glucocorticoid activity

(antiinflammatory)

Mineralocorticoid activity

(Salt retaining)

Short acting

Hydrocortisone 8-12 1 1

Cortisone 8-12 0.8 0.8

Fludrocortisone 8-12 10 125

Intermediate acting

Prednisone 12-36 4 0.8

Prednisolone 12-36 4 0.8

Methylprednisolone 12-36 5 0.5

Triamcinolone 12-36 5 0

Long acting

Betamethasone 24-72 35 0

Dexamethasone 24-72 30 0

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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

• 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

MorphineHeroin

HydromorphoneFentanylCodeine

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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

NaloxoneNaltrexone

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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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