Analgesic

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Analgesic Antipyretic Drugs

• Dileep K. Rohra
• Basic Pharmacology Course, Semester 3

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Learning Objectives

• Define the terms analgesic, anti-inflammatory
  antipyretic.
• Differentiate between narcotic non-narcotic
  analgesics.
• Classify the non-narcotic analgesics based on
  their selectivity for cyclooxygenase.
• Discuss the mechanism of action, clinical uses
  and adverse effects of analgesics.

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Definitions

• Anti-inflammatory
• Drug that inhibits inflammation
• Analgesic
• Drug, relieving pain due to multiple causes
• Antipyretic
• Drug which decreases fever

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Peripheral sensitization to pain
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Potential sites of action of analgesics

• At the site of injury
• By interfering with the chemical mediators
  involved in nociception.
• By blocking transmission in peripheral nerves
• Local anesthetics
• By modifying transmission at the dorsal horn
• Some of the actions of opioids antidepressants
  that inhibit axonal reuptake of 5HT
  noradrenaline.
• By interfering with the central appreciation of
  pain or by inhibiting its emotional concomitants
• Important mode of action of the opioids.

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Inflammation
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Antipyretic effect
Normal state
Hypothalamic thermoregulatory centre
PGs
Heat production
Heat lost
Normal temperature
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Antipyretic effect
Hypothalamic thermoregulatory centre
Various pyrogens
PGs
Heat production
Heat lost
Fever
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Antipyretic effect
Hypothalamic thermoregulatory centre
Various pyrogens
PGs
Antipyretics
Heat production
Heat lost
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Biosynthesis of prostaglandins
Membrane Phospholipid
Phospholipase A2
Arachidonic acid
Cyclooxygenase
Prostaglandin G2
Prostaglandin H2
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Two forms of Cyclooxygenase
COX-1 COX-2
Produces PGs that mediate homeostatic functions Produces PGs that mediate inflammation, fever
Constitutive Inducible
Site
Gastric mucosa Kidney Platelets Vascular endothelium Sites of inflammation Brain Kidney
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Nonselective NSAIDs
Selective nonselective NSAIDs
Arachidonic acid
Inflammation
Physiological activation
COX-1
COX-2
(constitutive form)
(inducible form)
PGs for physiological functions
Proinflammatory PGs
Results from inhibition of prostanoids
biosynthesis
COX-2 inhibition
COX-1 inhibition)
Unwanted effects mainly on the GIT kidney,
decrease in platelet aggregation
Ant-iinflammatory, analgesic antipyretic
effects
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Classification of analgesics

• Non-selective NSAIDs Aspirin, Ibuprofen
• Preferential COX-2 inhibiting NSAIDs Nimesulide,
  Meloxicam
• Selective NSAIDs Celecoxib, Rofecoxib,
  Valdecoxib
• Analgesic with poor anti-inflammatory activity
  Paracetamol

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Non-selective NSAIDs

• Aspirin
• Ibuprofen
• Naproxen
• Ketoprofen
• Indomethacin
• Piroxicam
• Mefenamic acid
• Diclofenac

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Aspirin

• Aspirin is the prototype non-selective NSAID.
• Irreversibly acetylates COX causing inhibition of
  PG synthesis.
• Aspirin produce its major analgesic
  anti-inflammatory effects by inhibition of PGE2
  prostacyclin biosynthesis at the site of
  inflammation.

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Aspirin Actions

• Antipyretic
• Fever occurs when the set-point of the
  hypothalamic thermoregulatory centre is elevated.
  This can be caused by PGE2 synthesis, which are
  stimulated when endogenous pyrogen, such as
  cytokines are released from WBC.
• Anti-inflammatory
• Analgesic
• PGE2 is thought to sensitize nerve endings to the
  actions of bradykinin, Histamine other chemical
  mediators released locally by the inflammatory
  process. Thus by decreasing PGE2 synthesis,
  NSAIDs repress the sensation of pain. NSAIDs are
  effective in pain associated with inflammation.

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Aspirin Actions

• Effect on platelets
• TXA2 enhances platelet aggregation. Low doses of
  aspirin can irreversibly inhibit TX production in
  platelets without markedly affecting TX
  production at other sites.
• In overdose
• Aspirin increases respiration by a direct
  stimulating action on the respiratory centre
  also uncouple oxidative phosphorylation leading
  to inefficient cellular respiration, lactic
  acidosis fever.

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Aspirin Actions

• GI effects
• Physiologically, PI inhibits HCl secretion,
  whereas PGE2 PGF2a stimulate synthesis of mucus
  in stomach. In the presence of aspirin, these PGs
  are not synthesized, resulting in increased HCl
  secretion decreased mucus production.
• Kidney
• PGE2 PGI2 maintain renal blood flow. Decreased
  synthesis of PGs can result in retention of Na
  water ? edema.

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Aspirin Clinical uses

• Fever
• Pains associated with inflammation
• Anti-platelet to prevent transient ischemic
  attacks MI.
• Used locally to treat corns

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Aspirin Adverse effects

• Salicylism
• High doses of aspirin cause tinnitus, deafness,
  nausea, vomiting occasionally abdominal pain
  flushing.
• Dyspepsia
• Regular use of aspirin, even in low dose
  frequently causes dyspepsia this is even more
  common when anti-inflammatory doses are used.
  Blood loss from the stomach can be life
  threatening. With prolonged treatment, chronic
  low-grade gastrointestinal blood loss may be
  sufficient to cause iron deficiency anemia.

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Aspirin Adverse effects

• Prolonged BT because of anti-platelet activity
• Should be withdrawn one week before surgery.
• Wheezing, sometimes accompanied by urticaria
  rhinorrhea in aspirin-sensitive asthmatics
• The mechanism of this adverse effect is connected
  with the pharmacological action of aspirin. An
  individual who is aspirin sensitive is
  predictably sensitive to other NSAIDs that share
  its pharmacological effect on COX.

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Aspirin Adverse effects

• Reyes syndrome
• A rare disease of children with high mortality,
  is characterized by hepatic failure
  encephalopathy occurring in the setting of a
  viral illness. It occurs after ingestion of
  aspirin. The cause of this epidemiological
  association is not known.

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Preferential COX-2 inhibitors

• Nimesulide, Meloxicam
• Nonselective but more affinity for COX-2
• Antiinflammatory, analgesic antipyretic
  activity comparable to other NSAIDs
• Adverse effects are similar to nonselective
  NSAIDs but severity incidence is less

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Selective COX-2 inhibitors

• Celecoxib, Rofecoxib, Valdecoxib
• Having advantage of less adverse effects related
  to COX-1 inhibition

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Paracetamol

• Paracetamol is an antipyretic analgesic with
  little, if any, anti-inflammatory properties.
• It has no irritant effect on the gastric mucosa.
• It is useful in pediatrics since, unlike aspirin,
  it has not been associated with Reyes syndrome

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Paracetamol MOA

• Paracetamol inhibits PG biosynthesis in the CNS.
• It is weak antiinflammatory because it has poor
  ability to inhibit COX in the presence of high
  concentration of peroxides, which are found at
  sites of inflammation.
• Now, recent research has shown the presence of a
  new, previously unknown COX-3, found in the brain
  spinal cord, which is selectively inhibited by
  paracetamol. It is now believed that this
  selective inhibition of the enzyme COX-3 explains
  the analgesic antipyretic effects of
  paracetamol without having unwanted
  gastrointestinal side effects.

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Paracetamol Toxicity

• Paracetamol is rapidly metabolized in the liver.
  The major metabolites are sulfates
  glucuronides, which are excreted in the urine.
• When paracetamol is taken in overdose the
  capacity of these conjugating mechanisms is
  increased a reactive metabolite, N-acetyl
  benzoquinone imine (NABQI), is formed by a
  cytochrome P450 - dependent metabolic pathway.
  NABQI is extremely toxic causes hepatocellular
  damage unless inactivated by conjugation with
  reduced glutathione.
• Acetylcysteine is given to reverese
  paracetamol-induced hepatotoxocity, as this
  repletes the supply of reduced glutathione in the
  liver.