Professional Documents
Culture Documents
Inflammation
and
Anti-inflammatory Drugs
b) Subacute inflammation
Inflammatory cells migrate and invade the site.
PGs, leukotrienes, platelet-activating factor (PAF), and
cytokines are prominent in this stage.
c) chronic inflammation.
lymphocytic phase of injury cleansing and repair.
Cytokines, especially interleukins and tumor necrosis
factor-α (TNF-α), are prominent in this stage .
In reality these phases are not distinct entities.
Components of the subacute phase participate in
the acute inflammatory process, and acute
inflammatory mediators are present in chronic
inflammatory disorders.
1 Tissue mediators
Histamine
Prostaglandins
Leukotrines
Lysosomal products
Lymphocyte products
Macrophage products
Mast cell products
Eosinophile products
Plasma protein derived Mediators
Nitric Oxide
Tissue Mediators
1. Histamine
Histamine is the first mediator which has a role in
the inflammatory process.
Most of the histamine is stored in mast cells and
basophilic granules, only some of it exists as free
active in tissues.
Various physical and chemical stimuli -antigens,
complement fragments, or simple mechanical
trauma- causes extrusion of the granules and
release of active histamine into the extracellular
fluid.
Histamine causes:
I. dilation of vessels of the microcirculation
II. Marked but transient, increase in the permeability of
capillaries and post-capillary venules.
The histamine content of tissue fluid at the site of injury
increases within minutes after the insult and then
decreases gradually.
COX-1:
constitutive enzyme: is involved in tissue
homeostasis.
COX-2:
inducible enzyme: is responsible for the
production of the prostanoid mediators of
inflammation
COX Enzyme:Prostaglandin Effects
COX-1: beneficial COX-2: harmful
Kidney vasodilation
3.Leukotrienes
The ability of cells to produce leukotrienes seems to be limited to
the lung, leukocytes, blood vessels, and epicardium.
Leukotrienes C4 and D4 are constrictors of bronchial smooth
muscle
More potent than histamine-they increase vascular permeability
Leukotriene B4 can enhance chemotactic and chemokinetic
responses in human neutrophils, monocytes, and eosinophils
They are involved in localized inflammatory processes and in
asthma.
Drugs that block leukotriene receptors or inhibit leukotriene
synthesis by blocking the enzyme lipoxygenase are used in the
treatment of asthma.
4.Lysosomal products
During phagocytosis of bacteria or foreign material by
neutrophils, the contents of lysosomes are released into
the extracellular environment.
Cationic proteins released contribute to the inflammatory
process by triggering mast cell degranulation increased
vascular permeability
Several of these enzymes have the potential to damage
host tissues.
Collagen, elastin, mucopolysaccharides, basement
membrane, and other structural elements may be
degraded.
Lysosomal proteases cause the production of kinin-like
substance and can generate chemotactic factors for
5.Lymphocyte products
Major Actions:
ANALGESIA , ANTIPYRETIC , ANTI-INFLAMMATORY
Except acetaminophen
Effects of COX Inhibition by Most
NSAIDS
COX-1 COX-2
Arachidonic acid
Arachidonic acid
PGH2
PGH2
Prostacyclin (PGI2)
Thromboxane (TXA2)
• Gastrointestinal effects
Epigastric distress, ulceration, haemorrhage, and iron-deficiency anaemia.
• GIT
NO PAIN
3.Ketorolac
Ketorolac was the first injectable NSAID approved in
the United States.
Also available in tablet form for oral use, but only after
initial intramuscular or intravenous injection.
The total course of therapy with ketorolac not exceed 5
days. Because the drug’s high incidence of GI
ulceration and bleeding complications compared with
other NSAIDs.
Indications: in postoperative pain management in
patients who are unable to consume oral analgesics or
when the pain is severe and injectable opioids are
contraindicated.
Adverse effects of propionic
acid
Although the incidence with some propionic acid
disturbances (epigastric pain, nausea, vomiting, gastric
bleeding, and constipation or diarrhea) can occur.
These drugs should be used with caution in patients with
a history of peptic or duodenal ulcer.
Long-term, high-dose administration for arthritic conditions
is far more likely to produce serious adverse events than
short-term administration for acute pain.
CNS effects
May include headache, dizziness, drowsiness,
vertigo, and visual and auditory disturbances including
tinnitus.
Renal Effects
Little effect on normal kidneys
NSAIDs Promote Na RETENTION
When renal blood flow is impaired as in:
Heart failure
Dehydration
Kidney disease
Normal aging
Skin rashes are common, and immediate allergic
reactions have been reported
Increased risk of GI bleeding when these drugs and other
NSAIDs are taken concomitantly with antidepressants of
the selective serotonin reuptake inhibitor (SSRI) class.
Pharmacokinetic Variability of
Non-Selective COX-Inhibitors
Name Time to peak ½ life parent
(hours) ½ life*active
Aspirin 1-2 0.25-0.33
(*3-10 L-H)
Naproxen 2-4 12-15
Oxaprozin 3-5 42-50
*Sulindac (pro-drug) 2-4 7.8
(*16.4)
Ketorolac (inj) .5-1 3.8-8.6
Ibuprofen 1-2 1.8-2.5
Selective COX-2 Inhibitors
Examples are
A. Celecoxib
B. rofecoxib,
C. Valdecoxib
D. KETOROLAC
E. NIMESULIDE
F. NABUMETONE
Rofecoxib 2-3 17
Selective COX-2 Inhibitors cont’
Adverse effects:
1. nausea
2. vomiting
3. dyspepsia
4. abdominal pain
5. diarrhoea
6. edema of the lower extremities
Specific:
N- acetylcysteine 150mg/kg should be infused i.v. over 15min, followed by
the same dose i.v. over next 20hrs
Arylacetic acid Derivatives
Diclofenac:
Probably has greater activity than other NSAIDs
Extensively bound to plasma proteins, t1/2 is 1-2hrs
Accumulates in the synovial fluid- probably responsible for its
longer duration of action than its t1/2
Incidence of adverse reactions is 20%
Adverse effects similar to propionic acid derivatives +
elevation of liver enzymes
Anthranilic acid Derivatives
(Fenamates)
Mefenamic acid:
Useful in chronic and dull aching pains
No advantages over other NSAIDs
Weaker analgesic than aspirin
Adverse reactions include gastric upset,
diarrhoea, dizziness, headache, skin rashes,
hemolytic anemia
Dose is 500mg 2-3 times a day
Used in Dysmenorrhoea
Topical NSAIDs
Diclofenac 1% gel
Ibuprofen 10% gel
Naproxen 10% gel
Ketoprofen 2.5% gel
Flurbiprofen 5% gel
Nimesulide 1% gel
Piroxicam 0.5% gel
Opoids
DEFINITION:
• Any natural or synthetic compound
that imitates properties of natural
narcotics
Is an analgesic that works by binding
to opioid receptors, which are found
principally in the central nervous
system and the gastrointestinal tract.
The receptors mediate both the
beneficial effects, and the
undesirable side effects.
Examples
Morphine
Heroin
Hydromorphone
Fentanyl
Codeine
Opoids/ CLASSIFICATION
Natural opiates
Alkaloids contained in the resin of the opium poppy
(morphine, codeine, thebaine)
Semi-synthetic opiates
Created from the natural opioids (hydromorphone,
hydrocodone, oxycodone,oxymorphone,
desomorphine, diacetylmorphine (Heroin)
Fully synthetic opioids
Created from chemical compounds (fentanyl,
pethidine, methadone, tramadol and propoxyphene)
Endogenous opioid peptides
Produced naturally in the body (endorphins,
enkephalins, dynorphins, and endomorphins)
Opoids/PHARMACOKINETICS
Distribution - Widely distributed throughout body tissue; concentration in kidney,
liver and spleen is higher than that in plasma.
Only a small fraction enters brain rather slowly.
Morphine crosses placenta.
Metabolism - Extensively in the liver.
Excretion - Metabolites are excreted by the kidneys. A small fraction is excreted
in stool through the biliary tract.
Routes of administration - Oral, Transmucosal, I.V (most rapid acting), I.M and
S.C
LATENCY TO ONSET
i. oral (15-30 minutes)
ii. intranasal (2-3 minutes)
iii. intravenous (15 – 30 seconds)
iv. pulmonary-inhalation (6-12 seconds)
2.Depression of respiration
Main cause of death from opioid overdose
Combination of opioids and alcohol is especially
dangerous
3.Cough suppression
Opioids suppress the “cough center” in the brain
4. Pupillary constriction
pupillary constriction in the presence of analgesics is
characteristic of opioid use
Opoids/Pharmacological Effects cont
5.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
6.Gastrointestinal symptoms
Opioids relieve diarrhea as a result of their direct actions on the
intestines
7.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
Opoids
Tolerance and Dependence
Tolerance
Tolerance is a diminished responsiveness to the
drug’s action that is seen with many compounds
Tolerance can be demonstrated by a decreased
effect from a constant dose of drug or by an
increase in the minimum drug dose required to
produce a given level of effect
Physiological tolerance involves changes in the
binding of a drug to receptors or changes in
receptor transductional processes related to the
drug of action
This type of tolerance occurs in opioids
Dependence
Physiological dependence occurs when the
drug is necessary for normal physiological
functioning – this is demonstrated by the
withdrawl reactions
Withdrawl reactions are usually the opposite of
the physiological effects produced by the drug
Withdrawl Reactions
Acute Action Withdrawl Sign
Analgesia Pain and irritability
Respiratory Depression Hyperventilation
Euphoria Dysphoria and depression
Relaxation and sleep Restlessness and insomnia
Tranquilization Fearfulness and hostility
Decreased blood pressure Increased blood pressure
Constipation Diarrhea
Pupillary constriction Pupillary dilation
Hypothermia Hyperthermia
Drying of secretions Lacrimation, runny nose
Reduced sex drive Spontaneous ejaculation
Flushed and warm skin Chilliness and “gooseflesh”
Dependence continued
Acute withdrawl can be easily precipitated in drug
dependent individuals by injecting an opioid
antagonist such as naloxone or naltrexone –
rapid opioid detoxification or rapid anesthesia
aided detoxification
The objective is to enable the patient to tolerate
high doses of an opioid antagonist and undergo
complete detox in a matter of hours while
unconscious
After awakening, the person is maintained on
orally administered naltrexone to reduce opioid
craving
1.Morphine
PHARMACOKINETICS
Routes of administration (preferred)
a. Oral latency to onset –(15 – 60 minutes )
b.sniffed
c. injected.
3. Dihydrocodeine
30-60mg 4-6hrs
Side effect : Nausea, vomiting
4.Tramadol
opioid effect + enhancement of seratogenic and
androgenic pathways.
less opioid side effects.
psychiatric rxns reported
Dose 50-100mg 4-6hrs.
5. Pethidine
prompt short term analgesia.
less constipating than morphine less potent analgesic
50-150mg 4-6hrs.
sc or IM 25-100mg 4-6hrs.
COMBINATION ANALGESICS
Nonopioids
Aspirin and acetaminophen are sometimes combined in proprietary
compounds.
There is little evidence that either analgesia or antipyresis is enhanced by
this combination.
A ceiling effect still occurs when the total amount of aspirin and
acetaminophen approaches 1 g.
In pain following impacted third molar surgery, the combination of 100 mg
of enteric-coated diclofenac with 1000 mg of acetaminophen provides a
superior analgesic effect than either drug alone or combination of 1000
mg of acetaminophen plus 60 mg of codeine.
Many of these combinations also contain caffeine. Caffeine is considered
to be an analgesic adjuvant.
Caffeine doesn't seem to have analgesic effects when used alone. When
65to 100 mg of caffeine is combined with traditional analgeics (aspirin,
acetaminophen, or ibuprofen), it improves their analgesic efficacy.
Opioid and Nonopioid Analgesics