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CAUSE OF INFLAMMATION
Inflammation typically represents the response to
tissue injury and includes products of activated mast
calls, leukocytes, and platelets.
The clinical features of inflammation include
1. tumor (edema)
2. rubor (redness)
3. Calor (heat)
4. dolor (pain)
5. loss of function.
Inflammation can be divided into three phases:
a) Acute inflammation
Inflammatory mediators such as histamine are
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
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
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
Antihistamines have little use as general anti-
inflammatory agents. However, antihistamines that block
the H1 receptor are useful in reducing symptoms
attributable to histamine in allergic reactions.
PGs are derived from arachidonic acid. Also can be
generated by inflammatory cells.
PGs exert a multitude of effects in almost every biologic
A. smooth muscle contraction and relaxation
B. vascular permeability
C. renal electrolyte and water transport
D. gastrointestinal (GI) and pancreatic secretion
E. various CNS and autonomic nervous system functions
F. release of hormones
G. Bone resorption
H. Platelet aggregation
PGs are being formed and released at times
when tissue damage and disintegration are
more prominent especially during
PGI2 and PGE2 are potent inducers of
vasodilation and of increased vascular
permeability, which may last for several
PGE2 is pyrogenic, suggesting a mediator
Certain anti-inflammatory drugs that are
potent inhibitors of PG synthesis reduce
experimentally produced inflammation.
All cells except erythrocytes can convert
arachidonic acid to PGs and related
compounds by the action of COX.
A balance between enhancement and
suppression of inflammatory events could be
achieved by local regulation of PG
metabolism because in some systems PGs
have been shown to be either stimulatory or
inhibitory depending on their concentration.
constitutive enzyme: is involved in tissue
inducible enzyme: is responsible for the
production of the prostanoid mediators of
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
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
Drugs that block leukotriene receptors or inhibit leukotriene
synthesis by blocking the enzyme lipoxygenase are used in the
treatment of asthma.
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
Several of these enzymes have the potential to damage
Collagen, elastin, mucopolysaccharides, basement
membrane, and other structural elements may be
Lysosomal proteases cause the production of kinin-like
substance and can generate chemotactic factors for
Delayed allergic reactions may be involved in
some inflammatory processes, especially chronic
processes in which there is a persistent antigenic
stimulus. These reactions are mediated by
factors called cytokines (lymphokines if derived
from lymphocytes), which are produced by
sensitized thymus-dependent lymphocytes, or T
cells, after specific antigenic challenge.
Cytokines that may function in inflammation
related events are:
(1) Interleukins that stimulate the function of T&B cells.
(2) Monocyte chemoattractive protein-1, which
promotes accumulation of monocytes.
(3) Granulocyte/macrophage colony stimulating
(4) Other chemotactic factors that are specific
attractants for neutrophils, macrophages, basophils
(5) Interferon-á, which has antiviral and macrophage
(6) Skin reactive factor, which mimics a delayed
allergic reaction when injected into normal skin.
They have Little involvement in acute inflammatory
responses, but they play a very prominent role in
chronic inflammation and are crucial in the immune
Secretory products include
a) The constituents of lysosomes
b) Reactive metabolites of oxygen
c) Interferon-á, interleukin-1 (IL-1), and TNF-á.
IL-1 is produced by macrophages exposed to bacterial,
viral, and fungal products; antigens; or macrophage
Main role is stimulation of differentiation of a pre–T
lymphocyte population to T cells capable of responding
to an antigen processed and presented by
PAF is a mediator of inflammation produced by
macrophages, mast cells and eosinophils and
PAF initiates various actions:
A. Platelet activation
C. Vascular permeability
D. Neutrophil chemotaxis
E. Discharge of lysosomal enzymes.
7.Mast cell products
Mast cells release numerous inflammatory mediators
2. cytokines (e.g., TNF-á)
Mast cells can become activated by IgE antibodies
that bind to the plasma membrane and sensitize the
mast cell to specific allergens. Several allergic
reactions, including allergic asthma, involve this
Basophiles have many of the same characteristics as
Eosinophils release many enzymes
and toxins that can lead to tissue
Major basic protein is a toxic
substance that can cause tissue
damage and destruction of parasites.
Eosinophils also release leukotrienes
The term kinins refers primarily to two small peptides
that are similar in structure and actions: bradykinin
As with the release of histamine, almost any process
causing tissue injury can trigger the series of events
leading to the production of bradykinin.
Bradykinin exists in plasma as an inactive precursor
(kininogen) and is released in a cascade of
After release, bradykinin is rapidly metabolized by
enzymes present in plasma and tissues.
Bradykinin is a potent but transient vasodilator of
10.Nitric Oxide (NO)
NO plays a regulatory and a pro-inflammatory
role in various inflammatory conditions, including
arthritis, asthma, and inflammatory bowel
Currently approved drugs that target the nitric
oxide system, such as nitroglycerin to treat
angina and the male erectile dysfunction drug
sildenafil (Viagra) increase NO levels.
Analgesics should be used judiciously in dental care as a
temporary measure until the cause of pain has been dealt
The choice of an analgesic should be based on its suitability
for the patient.
Most dental pain is relieved effectively by NSAIDs.
Analgesics are classified as
1. Non-opioid analgesics
2. Opioid analgesics
4. Neuropathic pain agents
5. Antimigraine drugs
For Acute Pain (e.g dental procedures) short term use ≤1
week highly efficacious and safe.
For chronic inflammatory conditions months or years with
doubling the dose often 2-3folds.
NSAIDs lack various undesirable CNS depressant effects that
contribute to the high incidence of drowsiness, dizziness, and
nausea commonly seen with opioid-containing agents.
The development of NSAIDs that are highly selective COX-2
inhibitors seemed to offer a safety advantage regarding some
of the more serious adverse effects seen with long term NSAID
therapy, specifically GI ulcers, perforations, and bleeds.
ANALGESIA , ANTIPYRETIC , ANTI-INFLAMMATORY
Non steroidal anti-inflammatory
Acute renal failure
NSAIDs : anti-platelet—decreases ability of blood to clot
Effects of COX Inhibition by Most
It was first extracted in 1835 from natural sources
and later prepared by chemical synthesis.
Aspirin was synthesized from salicylates
(acetylsalicylic acid) by treating sodium salicylate
with acetyl chloride.
It is one of the most consumed drugs in the world.
Mechanism of action
The efficacy of salicylates and all related NSAIDs as
analgesic, anti-inflammatory, and antipyretic agents
Their ability to inhibit COX activity, preventing the synthesis
and release of COX products, most prominently the PGs
Note : All salicylates and almost all the currently available
NSAIDs, with the exception of the highly selective COX-2
inhibitors, inhibit COX-1 and COX-2.
• Most of these non selective COX inhibiting NSAIDs,
including aspirin, are more potent or at least equipotent
inhibitors of COX-1 which accounts for some of the more
important adverse effects of these drugs.
• Aspirin is an approximately 100-fold more selective inhibitor
of COX-1 than COX-2.
Salicylates may inhibit cell migration and some
functions of neutrophils.
Salicylates Suppress T cell activity Causes
reduction in rheumatoid factor (RF) production.
Other mechanisms contributing to anti-inflammatory
effects include reduced capillary permeability, reduced
antibody production, and alterations in connective
Inhibition of PG synthesis at the site of injury or
inflammation can explain at least some of the analgesic
effect of aspirin. Although PGs themselves do not seem
to cause pain when injected locally, PGE2 and PGF2α
do sensitize pain receptors to other mediators such as
histamine and bradykinin.
In this connection, aspirin and related drugs can
prevent the writhing response elicited by bradykinin
but not that produced by PGs. This finding is
explained by the fact that the salicylates and all other
NSAIDs inhibit the synthesis of PGs induced by
bradykinin but not the binding of PGs to their
receptors. Animal experiments have revealed that
NSAIDs also have central analgesic actions, which
may involve the inhibition of COX or other unknown
mechanisms at the level of the spinal dorsal horn or at
higher levels of the CNS.
Salicylate is distributed throughout most body fluids &
tissues. It can be isolated from spinal, peritoneal, and
synovial fluids; saliva; breast milk; and sweat.
Salicylate freely crosses the placenta from mother to
Half-life of sodium salicylate is 2-3 hours after single
General therapeutic effects
Aspirin has clinically useful analgesic,
antipyretic, antiinflammatory, and
1. Analgesic effect sought and attained with
aspirin is probably caused in many cases by
its anti-inflammatory actions.
Symptomatic relief of acute pain and fever.
Treatment of numerous chronic inflammatory
2. Antipyretic action
• Fever occurs when the set-point of the anterior
hypothalamic thermoregulatory center is elevated.
• This can be caused by PGE2 synthesis, which is
stimulated when an endogenous fever-producing agent
(pyrogen), e.g: cytokine, is released from white cells
that are activated by infection, hypersensitivity,
malignancy, or inflammation.
• The salicylates lower body temperature in patients with
fever by impeding PGE2 synthesis and release.
3. Antiplatelets effects (anticoagulant effect)
Low doses of aspirin can irreversibly inhibit thromboxane (enhances
platelet aggregation) production in platelets.
Because platelets lack nuclei, they cannot synthesize new enzyme, and
the lack of thromboxane persists for the lifetime of the platelet (3-7 days).
As a result of the decrease in TXA2, platelet aggregation is reduced,
producing an anticoagulant effect.
Aspirin also inhibits cyclooxygenase in endothelial cells, resulting in
reduced PGI2 (decreases platelet aggregation) formation
Endothelial cells possess nuclei able to re-synthesize new
cyclooxygenase. Therefore, PGI2 is available for antiplatelet action.
Normal physiologic interaction between PGI2 and TXA2
in platelet and endothelial cell biology
Blood Vessel Wall
Endothelial Cell (COX-2)
Ca2+/vessel smooth muscle constricts
cAMP/vessel smooth muscle relaxes
• Respiratory actions
At therapeutic doses, aspirin increases alveolar ventilation.
Higher doses work directly on the respiratory center in the medulla, resulting in
hyperventilation and respiratory alkalosis that usually is adequately
compensated by the kidney.
At toxic levels, central respiratory paralysis occurs, and respiratory acidosis
results due to continued production of CO2.
• Gastrointestinal effects
Epigastric distress, ulceration, haemorrhage, and iron-deficiency anaemia.
Due to inhibition of PGE2 (stimulate synthesis of protective mucus in both the
stomach and small intestine.
Misoprostol (PGE1-derivative) and the proton-pump inhibitors (lansoprazole,
omeprazole) can also be used for the treatment of an NSAID-induced ulcer.
• Actions on the kidney
Cyclooxygenase inhibitors prevent the synthesis of
PGE2 and PGI2-prostaglandins that are responsible
for maintaining renal blood flow.
Decreased synthesis of prostaglandins can result in
retention of sodium and water and may cause
edema and hyperkalemia in some patients.
1. Acute pain.
It is difficult to separate the analgesic and
Effects of NSAIDs because most painful
conditions have an inflammatory component.
Aspirin is an effective analgesic for almost any type of
acute dental pain.
There is a dose-response for pain relief up to 650 to 1000
mg of aspirin, but increasing the dose beyond these
amounts does not enhance the analgesic effect further
and does INCREASE the likelihood for toxic effects.
One of the early uses of salicylates was in the
treatment of rheumatic fever.
Aspirin markedly reduces the acute inflammatory
components of the disease, such as fever, joint pain,
swelling, and immobility. Salicylates do not affect other
aspects of the disease, however, such as the proliferative
reaction in the myocardium leading to scarring, and they
do not alter the progression of the disease.
Although anti-inflammatory drugs, including
corticosteroids may be used to reduce inflammation,
antibiotic therapy is the major therapeutic strategy.
4.Prophylaxis against platelet aggregation
5. Rheumatoid arthritis.
Salicylates are the drug of choice in the treatment
of rheumatoid arthritis.
In larger dose they suppress the swelling,
immobility and redness of the joints involved.
They produce relief in pain, swelling and morning
stiffness in the rheumatoid arthritis patients.
Absorption, fate, and excretion
When aspirin is taken orally, it is rapidly absorbed from the stomach
and small intestine.
Aspirin is a weak acid, with a pKa of approximately 3.5, which favors
its absorption in the stomach. Most absorption occurs in the small
Half life : Dose-dependent; 2–3 hours for low doses, 15–30
hours for large doses
Because its acetylation of COX in the platelet is irreversible, however,
the full extent of its antiplatelet action depends on the life span of the
platelet (8 days) and not on the short half-life of aspirin.
It is quickly metabolized by gastric and plasma esterases to salicylate
Although some aspirin becomes bound to plasma proteins, 80% to
90% of the salicylate ion is bound for a short time, principally to
The liver is the main site of biotransformation, and conjugation is the
Depend on the overall health of the patient, the length of
dosing, and the total daily intake of drug.
Epigastric distress, nausea, and vomiting.
Aspirin is an acid and at stomach pH, aspirin is
uncharged; consequently, it readily crosses into mucosal
cells, where it ionizes (becomes negatively charged) and
becomes trapped, thus potentially causing direct damage
to the cells.
In toxic doses, salicylates cause respiratory depression.
Allergic reactions include urticaria, skin rash, rhinorrhoea,
asthmatic attack and anaphylactic reactions.
inhibition of platelet aggregation and a prolonged bleeding
aspirin should not be taken for at least 1 week prior to
DISEASE STATE Possible adverse effect of aspirin
Ulcer Internal bleeding , possible haemorrhage
Compromised liver Function
e.g : patients with nasal polyps
Asthmatic attacks resemble allergic
Diabetic High dose may cause hypoglycaemia or
hyperglycaemia (Salicylates may also
increase insulin secretion)
Gout Low plasma increase plasma
high dose decrease plasma
Children < 16 yrs Reye's syndrome **
viral infection (influneza) in adolescent Reye's syndrome
aspirin intolerance Allergic reaction
Reye's Syndrome :
Is primarily a children's disease, although it can occur at
It affects all organs of the body but is most harmful to the
brain and the liver--causing an acute increase of pressure
within the brain and, often, massive accumulations of fat in
the liver and other organs.
The disorder commonly occurs during recovery from a viral
infection, although it can also develop 3 to 5 days after the
onset of the viral illness.
Symptoms of RS include
1. persistent or recurrent vomiting.
3. personality changes such as irritability, disorientation or
confusion delirium, convulsions, and loss of
As analgesic and antipyretic:
0.3-0.6gm, 6-8 hourly
Acute rheumatic fever:
75-100mg/kg/day in divided doses/4-6 days
50mg/kg/day/2-3wks- maintenance dose
Mild-moderate dental pain:
650 to 1000 mg
Acute overdose has a mortality rate of 2%
Chronic overdose more lethal with mortality rate 25% especially in
No antidote for aspirin poisoning.
Acute toxic dose > 150mg/kg
Chronic toxicity of doses of 100mg/kg
Lethal dose >500mg/kg
Overdose/acute salicylate poisoning is characterized by salicylism which
2. vertigo and deafness
4. toxic encephalopathy (agitation, confusion and convulsions followed by
5. dehydration (due to hyperpyrexia, sweating and vomiting),
Treatment of Overdose/Toxicity
i. Gastric lavage.
ii. Intravenous fluid to correct dehydration.
iii. Cold water/alcohol sponges for hyperthermia.
iv. To prevent intracellular potassium loss, potassium is
given along with sodium bicarbonate.
v. For ketoacidosis and hypoglycemia, glucose may be
vi. In severe intoxication, dialysis (peritoneal dialysis
and haemodialysis) may be used.
Diflunisal is a difluorophenyl derivative of salicylic acid with
anti-inflammatory, analgesic, and antipyretic activity.
Although structurally related to salicylates but diflunisal is
not hydrolyzed in vivo to salicylate and is unique among the
Similar to other salicylates, diflunisal blocks the synthesis
of PGs by inhibiting COX.
Diflunisal is approximately 10-fold more potent than aspirin
in suppressing PG formation in rats.
The drug is well absorbed after oral administration, with
peak blood concentrations occurring in 2 to 3 hours. It is
highly bound to plasma protein. Diflunisal has a long
plasma half-life (8 to 12 hours versus 2.5 hours for
salicylate). The drug is excreted in the urine
1. Mild-Moderate pain for osteoarthritis
2. rheumatoid arthritis
3. postoperative dental pain
Because diflunisal has an extended duration of action and a relatively
slow onset of action in acute pain models so the recommended
dosage regimen is a 1000-mg loading dose followed by 500 mg every
8 to 12 hours
1. Nausea and epigastric pain to peptic ulcer and GI bleeding.
2. Diflunisal prolongs the prothrombin time in patients receiving oral
anticoagulants, perhaps by competitive displacement of coumarins
from protein binding sites.
Note: Diflunisal does not penetrate the blood-brain barrier as well as
aspirin does, and diflunisal causes fewer CNS effects, including
For this same reason, it is not used as an antipyretic.
Many NSAIDs chemically unrelated to the salicylates
are now available. They all inhibit COX, but they vary
in their relative potencies against COX-1 and COX-2.
Some NSAIDs may have other anti-inflammatory
actions in addition to inhibiting COX.
For more long-term use, as in the treatment of
rheumatoid arthritis, the choice of an NSAID for
therapy is largely empiric and often based on what
drug is best tolerated and best relieves symptoms in
the individual patient. Most of these drugs are
arylalkanoic or heteroarylalkanoic acid derivatives.
Possess anti-inflammatory property similar to aspirin but
toxicity and adverse effects are fewer and of lesser
These preparations alone and in combination with other
NSAIDs are used for treatment of inflammatory disorders
muscle spasm and rheumatic disorders.
They are all well absorbed orally and are highly bound to
plasma proteins (90-99%).
Metabolized largely in liver
Excreted in urine as well as in bile.
Indication : in rheumatoid and osteoarthritis, ankylosing
spondylitis, mild to moderate pain including
dysmenorrhoea, soft tissue injuries, fractures and
Propionic acid derivatives
first single-entity oral analgesic with a greater peak analgesic
effect more than 650 mg of aspirin.
Anti-inflammatory, analgesic and antipyretic properties.
Fewer side effects than other NSAID but weaker anti-
Ibuprofen administered preoperatively or immediately
postoperatively can delay the onset and lessen the severity of
Dose: 400 to 600 mg every 4 to 6 hours
Maximum daily dose of 2400 mg.
Ibuprofen is a weak organic acid and is highly bound to
plasma albumin. It is extensively metabolized and excreted in
Half life of approximately 2 hours.
BRUFEN, FENBID, DOLARAZ
After oral administration, it is fully Absorbed.
It is 99% bound to plasma proteins and crosses placenta.
Partially metabolized , & the metabolites of naproxen are
excreted in urine.
Naproxen is more efficacious and better tolerated.
It is also longer acting and has the advantage of twice
The sodium salt of naproxen at a 220-mg dose with a
maximum recommended daily dose of 660 mg
Naproxen is more irritating to the GI tract than ibuprofen.
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
Indications: in postoperative pain management in
patients who are unable to consume oral analgesics or
when the pain is severe and injectable opioids are
Adverse effects of propionic
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.
May include headache, dizziness, drowsiness,
vertigo, and visual and auditory disturbances including
Little effect on normal kidneys
NSAIDs Promote Na RETENTION
When renal blood flow is impaired as in:
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.
Name Time to peak
½ life parent
Aspirin 1-2 0.25-0.33
Naproxen 2-4 12-15
Oxaprozin 3-5 42-50
*Sulindac (pro-drug) 2-4 7.8
Ketorolac (inj) .5-1 3.8-8.6
Ibuprofen 1-2 1.8-2.5
Pharmacokinetic Variability of
The selectivity of these so-called coxibs led to roughly a
50% to 60% reduction in serious GI complications—
including symptomatic ulcers and GI bleeds, perforations,
and obstructions compared with standard NSAIDs (e.g.,
ibuprofen, naproxen, diclofenac)
Selective COX-2 Inhibitors
Greater affinity for cyclooxygenase-2
Decreased incidence of negative effects
associated with non-selective COX-inhibitors
Name Time to peak
Celecoxib 3 11
Rofecoxib 2-3 17
Selective COX-2 Inhibitors cont’
4. abdominal pain
6. edema of the lower extremities
Share some of the renal adverse effects of non
selective COX inhibitors and renal toxicity
Hence their use should be restricted to patients who do
not tolerate other NSAIDs
Selective COX-2 Inhibitors cont’
1. Acts on CNS to produce analgesia and antipyretic effect.
2. It also raises the pain threshold.
It has negligible anti-inflammatory action peripherally in
It is poor inhibitor of PG synthesis in peripheral tissues, but
more active on COX in brain.
Paracetamol is given orally and is well absorbed, peak plasma
concentration is reached in 30 to 60 minutes.
Excreted in URINE
Inactivated in LIVER.
Acute toxicity may result in hepatic failure.
Paracetamol is used for the rapid relief of fever, pains and
aches such as headache, earache, toothache, fibrositis,
myalgia, neuralgia, arthralgia, osteoarthritis and postoperative
Para aminophenol Derivatives
The potential for adverse effects from acute or chronic overdose
with the drug.
At therapeutic doses, acetaminophen does not cause nausea,
inhibit platelet aggregation, prolong prothrombin time, or
produce the other side affects associated with the use of aspirin
Allergy to acetaminophen is rare and is generally manifested as
Acetaminophen rarely has been associated with neutropenia,
thrombocytopenia, and pancytopenia.
In contrast to phenacetin, acetaminophen rarely produce
At recommended therapeutic doses (500-1000mg) in
healthy subjects is well tolerated
Hepatic and renal toxicity:
Larger doses (7-10gm) produce extensive hepatocellular
damage and renal tubular necrosis, and may cause death
This is a major problem in paracetamol poisoning
Liver toxicity is due to N-acetyl-P- benzoquinone imine which normally turns
harmless by conjugation with glutathione
Early manifestations are just nausea, vomiting, abdominal pain and live
tenderness with no impairment of consciousness
After 12-18hrs centrilobular hepatic necrosis occurs which may be
accompanied by renal tubular necrosis and hypoglycemia that may progress
Patient is brought early (within 16hrs of ingestion)
Vomiting should be induced or gastric lavage done
Activated charcoal is given orally or through tube to prevent further
Other supportive measures, as needed, should be taken
N- acetylcysteine 150mg/kg should be infused i.v. over 15min, followed by
the same dose i.v. over next 20hrs
Para aminophenol Derivatives
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/
Incidence of adverse reactions is 20%
Adverse effects similar to propionic acid derivatives +
elevation of liver enzymes
Arylacetic acid Derivatives
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,
Dose is 500mg 2-3 times a day
Used in Dysmenorrhoea
Anthranilic acid Derivatives
Diclofenac 1% gel
Ibuprofen 10% gel
Naproxen 10% gel
Ketoprofen 2.5% gel
Flurbiprofen 5% gel
Nimesulide 1% gel
Piroxicam 0.5% gel
• Any natural or synthetic compound
that imitates properties of natural
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.
Alkaloids contained in the resin of the opium poppy
(morphine, codeine, thebaine)
Created from the natural opioids (hydromorphone,
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)
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
LATENCY TO ONSET
i. oral (15-30 minutes)
ii. intranasal (2-3 minutes)
iii. intravenous (15 – 30 seconds)
iv. pulmonary-inhalation (6-12 seconds)
DURATION OF ACTION – anywhere between 4 and 72 hours depending on the
substance in question.
They reduce pain by binding to receptor sites (mainly
mu-receptors) in the central and peripheral nervous
system. After stimulation of receptors they mimic the
effects of naturally occurring opiates that are apart of
the body's own pain relief system.
Processing of pain information is inhibited by a direct
spinal effect at the dorsal horn, which involves
presynaptic inhibition of the release of tachykinins like
Emotional response to pain altered by opioid actions
on the limbic cortex
Act presynaptically to block Ca2+ uptake and
consequently inhibit neurotransmitter release. Opioids
have been shown to inhibit the release of many
neurotransmitters, including substance P,
acetylcholine, norepinephrine, glutamate, and
1. relieve severe pain in acute, chronic and terminal
2. Reduce anxiety
3. Control diarrhea
4. Suppress coughing.
1.Sedation and anxiolysis
Drowsiness and lethargy
Sense of tranquility
2.Depression of respiration
Main cause of death from opioid overdose
Combination of opioids and alcohol is especially
Opioids suppress the “cough center” in the brain
4. Pupillary constriction
pupillary constriction in the presence of analgesics is
characteristic of opioid use
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
Opioids relieve diarrhea as a result of their direct actions on the
Opioids can release histamines causing itching or more severe
allergic reactions including bronchoconstriction
Opioids can affect white blood cell function and immune function
Opoids/Pharmacological Effects cont
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
Physiological dependence occurs when the
drug is necessary for normal physiological
functioning – this is demonstrated by the
Withdrawl reactions are usually the opposite of
the physiological effects produced by the drug
Relaxation and sleep
Decreased blood pressure
Drying of secretions
Reduced sex drive
Flushed and warm skin
Pain and irritability
Dysphoria and depression
Restlessness and insomnia
Fearfulness and hostility
Increased blood pressure
Lacrimation, runny nose
Chilliness and “gooseflesh”
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
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
After awakening, the person is maintained on
orally administered naltrexone to reduce opioid
Routes of administration (preferred)
a. Oral latency to onset –(15 – 60 minutes )
Duration of action :( 3 – 6 hours)
First-pass metabolism results in poor availability
from oral dosing.
30% is plasma protein bound
AGONIST for mu, kappa, and delta receptors.
Side effect :constipation
oral dose; 30-60mg 4-6hrs Max 240mg
Side effect : Nausea, vomiting
opioid effect + enhancement of seratogenic and
less opioid side effects.
psychiatric rxns reported
Dose 50-100mg 4-6hrs.
prompt short term analgesia.
less constipating than morphine less potent analgesic
sc or IM 25-100mg 4-6hrs.
Aspirin and acetaminophen are sometimes combined in proprietary
There is little evidence that either analgesia or antipyresis is enhanced by
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
Combination between NSAIDs or acetaminophen with
NSAIDs/acetaminophen combat pain principally by
interfering with production of biochemical mediators that
cause sensitization of nerve endings at the site of injury or
spinal cord, whereas the opioids alter CNS perception and
reaction to pain.
The clinical significance of the opioids is
1. They provide additional analgesia beyond the ceiling
effect of the NSAID or acetaminophen alone
2. They contribute a centrally mediated sedative effect.
The most effective combinations are those that use the
optimal amount of an aspirin-like drug combined with the
appropriate dose of an opioid analgesic.