ALLERGY

Allergic diseases are a common and increasing cause ofillness, affecting between 15% and 20% of the
populationat some time.
They comprise a range of disorders frommild to life-threatening, and affect many organs.

Definitions

Atopyis :the tendency to produce an exaggerated IgE immuneresponse to otherwise harmless environmental
substances,
An allergic disease :can be defined as theclinical manifestation of this inappropriate IgE immuneresponse.

Pathology of allergy

Normally, the immune system does not make detectableresponses to the many environmental substances
towhich it is exposed daily.

However, in an allergic reaction,initial exposure to an otherwise harmless exogenoussubstance (known as an

allergen) triggers theproduction of specific IgE antibodies by activated Bcells
These IgE antibodies bind to the surfaceof mast cells via high-affinity IgE receptors, a stepthat is not itself
associated with clinical sequelae.
However, upon re-exposure, the allergen binds tomembrane-bound IgE which activates the mast
cells,releasing a variety of mediators (the early phaseresponse).
This type I hypersensitivity reactionis the basis of the symptoms of allergic reactions, whichrange from sneezing
and rhinorrhoea to anaphylaxis

In some patients, the early phase response is followedby persistent activation of mast cells, manifest byongoing
swelling and local inflammation.
This is knownas the late phase reaction and is mediated by basophils,eosinophils and macrophages.

Long-standing or recurrentallergic inflammation may give rise to a chronicinflammatory response characterised

by a complex infiltrateof macrophages, eosinophils and T lymphocytes, inaddition to mast cells and basophils.

Once this has beenestablished, inhibition of mast cell mediators with antihistaminesis clinically ineffective.
Occasionally, mast cell activation may be nonspecificallytriggered through other signals, such asneuropeptides,
anaphylotoxins and bacterial peptides

Summary ;
 the late phase reaction
Long-standing or
----------------------
recurrentallergic
(the early phaseresponse). some patients, the early inflammation
phase response is
------------------- ----------------
followedby persistent
upon re-exposure, the activation of mast cells, may give rise to a
allergen binds manifest byongoing chronicinflammatory
tomembrane-bound IgE swelling and local response characterised by
which activates the mast inflammation. a complex infiltrateof
cells,releasing a variety of macrophages, eosinophils
, it is mediated by
mediators and T lymphocytes,
basophils,eosinophils and
inaddition to mast cells and
macrophages.
basophils

Susceptibility to allergic diseases

The incidence of allergic diseases is increasing.

This trend is largely unexplained but one widely held theoryis the ‘hygiene hypothesis’.
o This proposes that infections in early life are critically important in maturation of theimmune
response and bias the immune system against the development of allergies.
o It is suggested that the high prevalence of allergic disease is the penalty for thedecreased exposure to
infection that has resulted from improvements in sanitation and health care
o .A number of factors predispose to allergic diseases,the strongest of which is a family history.
o A wide arrayof genetic determinants of disease susceptibility havebeen identified, including genes
controlling innateimmune responses, cytokine production, IgE levels andthe ability of the epithelial barrier
to protect againstenvironmental agents.
Contributory environmentalfactors include bacterial and viral infection, pollutantsand cigarette smoke

Presenting problems in allergy

A general approach tothe allergic patient

Clinical assessment
When assessing possible allergic disease, it is importantto identify what the patient means by allergy, as up
to20% of the UK population describe themselves as havinga food allergy, although fewer than 1% have an
IgEmediatedhypersensitivity reaction confirmed on doubleblind challenge.

History
o The nature of symptoms should beestablished and specific triggers identified, along withthe
predictability of a reaction, and the time lag betweenexposure to a potential allergen and onset of
symptoms.
o An allergic reaction usually occurs within minutesof exposure and provokes predictable
symptoms(angioedema, urticaria, wheezing and so on).
o Specificenquiry should be made about other allergic symptoms,past and present, and about family
history of allergicdisease.
o Potential allergens in the home and workplaceshould be identified,
 o a detailed drug history shouldalways be taken, including compliance, side-effects andthe use of
complementary therapies.

Investigations

Skin prick tests These are the mainstay of allergy testing.

A droplet ofdiluted standardised allergen solution is placed on theforearm and the skin is
superficially punctured throughthe droplet with a sterile lancet.
After 15 minutes, a positiveresponse is indicated by a local weal and flareresponse at least
2 mm larger than the negative control.
o A major advantage of skin prick testing is that patientscan clearly see the results,
which may be useful ingaining compliance with avoidance measures.

Disadvantages include:
o the remote risk of a severe allergicreaction, so resuscitation facilities should be
available.
o Results are unreliable in patients with extensive skindisease.
o Antihistamines inhibit the magnitude of theresponse and should be discontinued
before testing; corticosteroidsdo not influence test results.

Specific IgE An alternative to skin prick testing is the quantitationof IgE directed against the putative
tests allergen.

The sensitivity and specificity of specific IgE tests (previouslyknown as radioallergosorbent

tests, RAST) arelower than skin prick tests.
However, IgE tests may bevery useful if skin testing is inappropriate:

for example,
in patients taking antihistamines or those who havesevere skin disease or dermatographism.

o They can alsobe used to test for cross-reactivity between insectvenoms, and post
mortem to identify allergens responsiblefor lethal anaphylaxis.
o There is no indication for testing of specific IgG antibodiesto allergens in the
investigation of allergicdiseases.
Supervised Allergen challenges are usually performed in specialistcentres, and include :
exposure to o bronchial provocation testing,
allergen o nasalchallenge
(challenge test) o food challenge.

These may be particularlyuseful in the investigation of occupational asthma orfood allergy

.Mast cell After a systemic allergic reaction, the circulating levelof mast cell mediators increases
tryptase dramatically

o . Tryptaseis the most stable of these and serum levels peak at1–2 hours.
o Measurement of serum mast cell tryptase isextremely useful in investigating a
possible anaphylacticevent.
o Ideally, measurements should be made at thetime of the reaction, and 3 hours and 24
hours later
.Non-specific
markers of Peripheral blood eosinophilia is common in atopic individuals.
atopic disease: However, eosinophilia of more than 20% or anabsolute eosinophil count over 1.5 × 109/L
total serumIgE should initiatea search for a non-atopic cause
and
eosinophilia Atopy is the most common cause of elevated totalIgE in developed countries. However,
there are manyother causes, including :
1. parasite and helminth infections
 2. lymphoma
3. drug reactionsand
4. Churg–Strauss vasculitis

Moreover, significantallergic disease can occur despite a normal totalIgE level.

Thus total IgE quantitation is not indicated inthe routine investigation of allergic disease.

Management

• Avoidance of the allergen should be rigorouslyattempted, and the advice of specialist dietitiansand
occupational physicians may be required.
• Antihistamines block histamine H1 receptors, therebyinhibiting the effects of histamine release.
Longacting,non-sedating preparations are particularlyuseful for prophylaxis against frequent attacks.
• Corticosteroids down-regulate pro-inflammatorycytokine production. They are highly effective
inallergic disease and, if used topically, their adverseeffects may be minimised.
• Sodium cromoglicate stabilises the mast cellmembrane, inhibiting release of vasoactivemediators. It is
effective as a prophylactic agent inasthma and allergic rhinitis, but has no role in acuteattacks. It is
poorly absorbed and thereforeineffective in the management of food allergies.
• Antigen-specific immunotherapy involves thesequential administration of escalating amounts ofdilute
allergen over a prolonged period of time.
o Itsmechanism of action is unknown, but it is highly effective in the prevention of insect
venomanaphylaxis, and allergic rhinitis secondary to grasspollen
o The traditional route ofadministration is via subcutaneous injections, whichcarry a risk of
anaphylaxis and should only beperformed in specialised centres. More recently,sublingual
immunotherapy has been shown to beeffective in the management of moderate grasspollen allergy, and
clinical trials of immunotherapyfor food allergy are ongoing.
• Omalizumab, a monoclonal antibody against IgE,inhibits the binding of IgE to mast cells andbasophils. It is
effective in moderate and severeallergic asthma and rhinitis.
• Preloaded self-injectable adrenaline (epinephrine) maybe life-saving in acute anaphylaxis.

Anaphylaxis

Anaphylaxis is a potentially life-threatening, systemicallergic reaction caused by the release of histamine andother
vasoactive mediators from mast cells.
The risk ofdeath is increased in patients with pre-existing asthma,particularly if this is poorly controlled, and
when treatmentwith adrenaline (epinephrine) is delayed.

Clinical assessment
The severityof a reaction should be assessed; the time betweenallergen exposure and onset of symptoms
provides aguide.
Enquiry should be made about potential triggers;if these are not immediately obvious, a detailed historyof the
previous 24 hours may be helpful.
The mostcommon triggers are foods, latex, insect venom anddrugs
A history of previous allergic responsesto the offending agent is common.
The route of allergen exposure may influence the principal clinical features ofa reaction; for example, :
o if an allergen is inhaled, themajor symptom is frequently wheezing.

o Features of anaphylaxismay overlap with the direct toxic effects ofdrugs and venoms

Potentiating factors, such as exercise or alcohol, can lower the threshold for an anaphylacticevent
.A number of conditions may mimic anaphylaxis

N.B
o Anaphylactoid reactions result from the nonspecific degranulation of mast cells by drugs, chemicalsor
other triggers and do not involve IgEantibodies.

o The clinical presentations are indistinguishable,and in the acute situation discriminating betweenthem is
unnecessary. However, this may be importantin identifying precipitating factors and
appropriateavoidance measures.

Investigations

o Measurement of serum mast cell tryptase concentrationsis useful to confirm the diagnosis.
o Specific IgE tests maybe preferable to skin prick tests when investigatingpatients with a history of
anaphylaxis.

Management

Anaphylaxis is an acute medical emergency

Individuals who have recovered from an anaphylacticevent should be referred for specialist assessment.
The aim is :
o to identify the trigger factor,
o to educate thepatient regarding avoidance and management of subsequentepisodes, and
o to identify whether specific treatment,such as immunotherapy, is indicated.
If the triggerfactor cannot be identified or cannot be avoided, recurrenceis common.
Patients who have previously experiencedan anaphylactic event should be prescribedself-injectable adrenaline
(epinephrine), and they andtheir families or carers should be instructed on its use

The use of a MedicAlert (or similar) braceletwill increase the likelihood that adrenaline will beadministered in
an emergency.

Issues most pertinent to serious allergy in adolescents

Angioedema

Angioedema is the episodic, localised, non-pitting swellingof submucous or subcutaneous tissues.

This mostfrequently affects:
o the face
o extremities and
o genitalia.
o Involvement of the larynx or tongue maycause life-threatening respiratory tract obstruction, and
o oedema of the intestinal mucosa may cause abdominalpain and distension.

Mechanism
o In most cases, the underlying mechanism is degranulationof mast cells. However, angioedema may
occasionallybe mediated by increased local bradykininconcentration
o Differentiating the mechanismof angioedema is important in determining appropriateinvestigations and
treatment.

Specific allergies

Insect Local non-IgE-mediated reactions to insect stings arecommon and may cause extensive swelling
venom around thesite lasting as long as 7 days.
allergy o These usually do notrequire specific treatment.
o Toxic reactions to venomafter multiple (50–100) simultaneous stings may
mimicanaphylaxis. In addition, exposure to large amounts ofinsect venom frequently
stimulates the production ofIgE antibodies, and thus may be followed by
allergicreactions to single stings.
o Allergic IgE-mediated reactionsvary from mild to life-threatening.
o Antigen-specificimmunotherapy with bee or wasp venom reduces theincidence of
recurrent anaphylaxis from 50–60% to 10%but requires treatment for several years
Peanut Peanut allergy is the most common food-related allergy.
allergy More than 50% of patients present before the age of3 years and some individuals react to
their first knownexposure to peanuts, possibly because of sensitisation bytopical creams.
Peanuts are ubiquitous in the Westerndiet, and every year up to 25% of peanut-
allergicindividuals will experience a reaction as a result of inadvertentexposure

.Birch oral This syndrome is characterised by a combination ofbirch pollen hay fever and local
allergy angioedema after contactwith fresh fruit (especially apples), vegetables and nuts.
syndrome o Cooked fruits and vegetables are tolerated without difficulty.
o It is due to shared or cross-reactive allergenswhich are destroyed by cooking or
digestion, and can beconfirmed by skin prick testing using fresh fruit.
o Severeallergic reactions are unusual.

C1 inhibitor deficiency

Hereditary angioedema Acquired C1 inhibitor deficiency

Hereditary angioedema (HAE), also known as This rare disorder is clinically indistinguishable
inheritedC1 inhibitor deficiency, is an autosomal fromHAE but presents in late adulthood.
dominant disorder caused by decreased production or
activity of C1inhibitor protein. It is associatedwith autoimmune and
lymphoproliferative diseases.
This complement regulatory proteininhibits
spontaneous activation of the classical
complementpathway Treatment of the underlying disorder may induce
remission
C1 inhibitor is also aregulatory protein for the kinin of angioedema.
cascade, activation ofwhich increases local bradykinin
levels and gives rise tolocal pain and swelling.

In HAE, angioedema may be spontaneous or

triggeredby local trauma or infection.
Multiple parts of thebody may be involved,
especially the face, extremities,upper airway and
gastrointestinal tract.

Oedema of theintestinal wall causes severe

abdominal pain.
The mostimportant complication is:
o laryngeal obstruction, oftenassociated with
minor dental procedures, which can befatal.

Course
o Episodes of angioedema are self-limiting
andusually resolve within 48 hours.
o Patients with HAE generallypresent in
adolescence, but may go undiagnosedfor
many years.

A family history can be identified in 80%of cases.

 HAE is not associated with allergic diseases andis
specifically not associated with urticaria.
Acute episodes are always accompanied by lowC4
levels and the diagnosis can be confirmed by
C1inhibitor measurement.

Rx and Px
Prevention is with modifiedandrogens (e.g. danazol),
which increase endogenousproduction of
complement proteins.
Severe acute attacksshould be treated with purified
Cl inhibitor or a bradykininreceptor antagonist
(icatibant).

Microbiology bridges

Hypersensitivity diseases are conditions in which tissue damage is caused by

immune responses. They may result from uncontrolled or excessive responses
against foreign antigens or from a failure of self-tolerance, in which case they
are called autoimmune diseases.
The 2 principal factors which determine the clinical and pathologic consequences
of such conditions are the type of immune response elicited and the nature and
location of the inciting antigen.
What the hypersensitivity reactions have in common:
• The first exposure to the antigen “sensitizes” lymphocytes.
• Subsequent exposures elicit a damaging reaction.
• The response is specific to a particular antigen or a cross-reacting substance.
Hypersensitivity diseases are classifi d on the basis of the effector mechanism
responsible for tissue injury, and 4 types are commonly recognized.
TYPE I (IMMEDIATE) HYPERSENSITIVITY
Type I is the only type of hypersensitivity mediated by IgE antibodies and mast
cells. It is manifested within minutes of the reexposure to an antigen. The IgE response
is the normal protective response against many metazoan parasites, which
are too large to be phagocytized or killed by other cytopathic mechanisms. Approximately
20% of all individuals in the United States, however, display this immune
response against harmless environmental antigens, such as pet dander or
pollen; these responses are called atopic or allergic responses.
The effector cells of the immediate hypersensitivity reaction are mast cells, basophils,
and eosinophils. The soluble substances they release into the site cause the
symptoms of the reaction. Approximately 2-4 hours after the immediate response
to release of these mediators, a late-phase reaction is mediated by products of the
arachidonic acid cascade
These antibodies can cause tissue damage by 3 main mechanisms:
• Opsonization of cells
• Activation of the complement system which recruit neutrophils and
macrophages that cause tissue damage
• Possible binding to normal cellular receptors and interference with their
function
In some types of type II hypersensitivity, complement is activated and/or ADCC
is active (e.g., hemolytic disease of the newborn [HDNB]). In other types, cell
function is altered in the absence of complement activation and ADCC (e.g.,
myasthenia gravis and Graves disease). Eventually, as these diseases progress,
complexes of antigen and antibody may cause localized damage, but they do not
circulate so the damage is localized to the specific issue.
An important example of type II hypersensitivity is HDNB, also known as erythroblastosis
fetalis. In the fetus, this disease is due to transport of IgG specific for one
of the Rhesus (Rh) protein antigens (RhD) across the placenta.
About 85% of people are Rh+. If a pregnant woman is Rh– and the father is Rh+,
there is a chance that the fetus will also be Rh+. Th s situation will pose no problem
in the fi st pregnancy, as the mother’s immune system will not usually encounter
fetal blood cell antigens until placental separation at the time of birth. At
that time, however, Rh+ fetal red blood cells will enter the maternal circulation
and stimulate a T-dependent immune response, eventually resulting in the generation
of memory B cells capable of producing IgG antibody against RhD.
In a subsequent pregnancy with another Rh+ fetus, this maternal IgG can be transported
across the placenta, react with fetal Rh+ red cells, and activate complement,
producing hemolytic disease. Hemolytic disease of the newborn can be prevented
by treating the Rh– mother with RhoGAMTM, a preparation of human anti-RhD
antibody, at 28 weeks of gestation and again within 72 hours after birth. Th s antibody
effectively eliminates the fetal Rh+ cells before they can generate RhD-specific
memory B cells in the mother. Anti-RhD antibody should be given to any
Rh– individual following any termination of pregnancy.
TYPE III (IMMUNE COMPLEX) HYPERSENSITIVITY
The immune complexes that cause disease may involve either self or foreign antigens
bound to antibodies. These immune complexes are filtered out of the circulation in
the small vasculature, so their sites of ultimate damage do not refl ct their sites of
origin. These diseases tend to be systemic, with little tissue or organ specific ty.
TYPE IV (T-CELL–MEDIATED) HYPERSENSITIVITY
T lymphocytes may cause tissue injury by triggering delayed-type hypersensitivity
(DTH) reactions or by directly killing target cells. These reactions are elicited by
CD4+ Th1, Th17 cells, or CD8+ CTLs, which activate macrophages, recruit neutrophils,
and induce inflammation. These T cells may be autoreactive or specifi against foreign protein antigens bound to
tissues. T-cell-mediated tissue injury is
common during the protective immune response against persistent intracellular
microbes.

Pharmacology

HISTAMINE
Histamine is an autacoid present at high levels in the lungs, skin, and gastrointestinal
tract, and is released from mast cells and basophils by type I hypersensitivity
reactions, drugs, venoms, and trauma.
• Histamine receptors are of the serpentine family, with 7 transmembrane–
spanning domains with G-protein–coupled second messenger
effectors.
–– H1 activation
ºº ↑ capillary dilation (via NO) →↓ BP
ºº ↑ capillary permeability →↑ edema
ºº ↑ bronchiolar smooth muscle contraction (via IP3 and
DAG release)
ºº ↑ activation of peripheral nociceptive receptors →↑ pain and
pruritus
ºº ↓ AV nodal conduction
–– H2 activation
ºº ↑ gastric acid secretion →↑ gastrointestinal ulcers
ºº ↑ SA nodal rate, positive inotropism, and automaticity
H1 ANTAGONISTS
• Mechanism of action:
–– H1 antagonists act as competitive antagonists of histamine and therefore
may be ineffective at high levels of histamine.
–– Vary in terms of both pharmacologic and kinetic properties, but all
require hepatic metabolism and most cross the placental barrier.

• Uses:
–– Allergic reactions: hay fever, rhinitis, urticaria
–– Motion sickness, vertigo
–– Nausea and vomiting with pregnancy
–– Preoperative sedation
–– OTC: sleep aids and cold medications
–– Acute EPSs
• Side effects:
–– Extensions of M block and sedation (additive with other CNS
depressants)

Eicosanoids OVERVIEW

• Eicosanoids are cell-regulating polyunsaturated fatty acids primarily

synthesized from arachidonic acid and released by the action of phospholipase
A2 from lipids in cell membranes.
• Eicosanoids are present in low concentrations in most cells but are synthesized
and released “on demand” in response to stimuli, including IgEmediated
reactions, inflammatory mediators, trauma, heat, and toxins.
• Eicosanoids interact with specific receptors, which are G-proteins
coupled to second messenger effector system

LEUKOTRIENES (LTS)
• Formed (via hydroperoxides) from the action of lipoxygenases on arachidonic
acid
–– LTB4:
ºº Mechanism of action: inflammatory mediator → neutrophil chemoattractant;
activates PMNs; ↑ free radical formation → cell damage
–– LTA4, LTC4, and LTD4
ºº Cause anaphylaxis and bronchoconstriction (role in asthma)
• Leukotrienes are “targets” for the following:
–– Glucocorticoids: →↓ phospholipase A2 activity → contributes to both
antiinflammatory and immunosuppressive actions
–– Zileuton: inhibits lipoxygenase →↓ LTs and is used in treatment of asthma
–– Zafirlukast and “–lukasts”: LT-receptor antagonists used in treatment of
asthma
PROSTAGLANDINS (PGS)
• PGs are formed (via endoperoxides) from the actions of cyclooxygenases
(COXs).
• COX 1 is expressed in most tissues, including platelets and stomach,
where it acts to synthesize thromboxane and cytoprotective prostaglandins,
respectively.
• COX 2 is expressed in the brain and kidney and at sites of inflammation.
PGE1
• Drugs:
–– Misoprostol used previously in treatment of NSAID-induced ulcers
(protective action on gastric mucosa)
–– Alprostadil
ºº Maintains patency of ductus arteriosus
ºº Vasodilation; used in male impotence
• Contraindicated in pregnancy, unless used as an abortifacient (misoprostol
in combination with mifepristone)
PGE2
• Mechanism of action: uterine smooth muscle contraction
• Uses: dinoprostone can be used for “cervical ripening” and as abortifacient
PGF2a
• Mechanism of action: uterine and bronchiolar smooth muscle contraction
• Drugs:
–– Carboprost used as abortifacient
–– Latanoprost for treatment of glaucoma (↓ intraocular pressure)

PGI2 (Prostacyclin)
• Platelet stabilizer and vasodilator
• Drug: epoprostenol
• Uses: pulmonary hypertension
PGE2 and PGF2α
• Both ↑ in primary dysmenorrhea
• Therapeutic effects of NSAIDs may be due to inhibition of their synthesis
THROMBOXANES (TXAS)
TXA2
• Platelet aggregator (inhibition of synthesis underlies protective role of
acetylsalicylic acid [ASA] post-MI)
NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS)
• Most NSAIDs are nonselective inhibitors of cyclooxygenases, acting
on both COX 1 and COX 2 isoforms to decrease formation of PGs and
thromboxanes.
• They are analgesic, antipyretic, and antiinflammatory and have antiplatelet
effects.
• Acetylsalicylic acid (ASA) is the prototype of the group, which includes
more than 20 individual drugs.
Acetylsalicylic Acid (ASA; Aspirin)
• Causes irreversible inhibition of COX
• Covalent bond via acetylation of a serine hydroxyl group near the active site
• Actions are dose-dependent:
–– Antiplatelet aggregation. Low dose, the basis for post-MI prophylaxis
and to reduce the risk of recurrent TIAs
–– Analgesia and antipyresis. Moderate dose
–– Antiinflammatory. High doses
–– Uric acid elimination
ºº Low to moderate doses: ↓ tubular secretion → hyperuricemia
ºº High doses: ↓ tubular reabsorption → uricosuria
–– Acid-base and electrolyte balance
ºº Dose-dependent actions
ºº High therapeutic: mild uncoupling of oxidative phosphorylation
→↑ respiration →↓ pCO2 → respiratory alkalosis → renal compensation
→↑ HCO3
– elimination → compensated respiratory alkalosis
(pH = normal, ↓ HCO3
–, ↓ pCO2)

ºº In adults, this can be a stable condition; in children →↑ toxicity.

ºº Toxic doses: inhibits respiratory center →↓ respiration →↑ pCO2
→ respiratory acidosis (↓ pH, ↓ HCO3
–, normalization of pCO2)
plus inhibition of Krebs cycle and severe uncoupling of oxidative
phosphorylation (↓ ATP) → metabolic acidosis, hyperthermia, and
hypokalemia (↓ K+).
• Side effects:
–– Gastrointestinal irritation: gastritis, ulcers, bleeding
–– Salicylism: tinnitus, vertigo, ↓ hearing—often first signs of toxicity
–– Bronchoconstriction: exacerbation of asthma
–– Hypersensitivity, especially the “triad” of asthma, nasal polyps, rhinitis
–– Reye syndrome: encephalopathy
–– ↑ bleeding time (antiplatelet)
–– Chronic use: associated with renal dysfunction
–– Drug interactions: ethanol (↑ gastrointestinal bleeding), OSUs and warfarin
(↑ effects), and uricosurics (↓ effects)
• Aspirin overdose and management:
–– Extensions of the toxic actions described above, plus at high doses vasomotor
collapse occurs, with both respiratory and renal failure.
–– No specific antidote. Management includes gastric lavage (+/– activated
charcoal) plus ventilatory support and symptomatic management
of acid-base and electrolyte imbalance, and the hyperthermia
and resulting dehydration. ↑ urine volume and its alkalinization
facilitate salicylate renal elimination. (Note: ASA follows zero-order
elimination kinetics at toxic doses.)
Other NSAIDs
Types
• Reversible inhibitors of COX 1 and COX 2, with analgesic, antipyretic,
and antiinflammatory actions, include:
–– Ibuprofen
–– Naproxen
–– Indomethacin
–– Ketorolac
–– Sulindac
• Comparisons with ASA:
–– Analgesia: ketorolac > ibuprofen/naproxen > ASA
–– Gastrointestinal irritation: < ASA, but still occurs (consider
misoprostol)
–– Minimal effects on acid-base balance; no effects on uric acid elimination
–– Allergy: common, possible cross-hypersensitivity with ASA
–– Renal: chronic use may cause nephritis, nephritic syndrome, acute failure
(via ↓ formation of PGE2 and PGI2, which normally maintain GFR
and RBF)—does not occur with sulindac

• Specific toxicities:
–– Indomethacin: thrombocytopenia, agranulocytosis, and > CNS effects
–– Sulindac: Stevens-Johnson syndrome, hematotoxicity
Selective COX 2 Inhibitors: Celecoxib
• Compared with conventional NSAIDs, it is no more effective as an antiinflammatory
agent.
• Primary differences are:
–– Less gastrointestinal toxicity
–– Less antiplatelet action
• However, it may possibly exert prothrombotic effects via inhibition of
endothelial cell function (MI and strokes).
• Cross-hypersensitivity between celecoxib and sulfonamides
OTHER DRUGS
Acetaminophen
• Mechanisms
–– No inhibition of COX in peripheral tissues and lacks significant antiinflammatory
effects
–– Equivalent analgesic and antipyretic activity to ASA due to inhibition
of cyclooxygenases in the CNS
• Comparisons with ASA:
–– No antiplatelet action
–– Not implicated in Reye syndrome
–– No effects on uric acid
–– Not bronchospastic (safe in NSAID hypersensitivity and asthmatics)
–– Gastrointestinal distress is minimal at low to moderate doses
• Overdose and management:
–– Hepatotoxicity—Acetaminophen is metabolized mainly by liver glucuronyl
transferase to form the inactive conjugate. A minor pathway
(via P450) results in formation of a reactive metabolite (N-acetylbenzoquinoneimine),
which is inactivated by glutathione (GSH). In overdose
situations, the finite stores of GSH are depleted. Once this happens,
the metabolite reacts with hepatocytes, causing nausea and vomiting,
abdominal pain, and ultimately liver failure due to centrilobular necrosis.
Chronic use of ethanol enhances liver toxicity via induction of P450.
–– Management of the hepatotoxicity: N-acetylcysteine (supplies –SH
groups), preferably within the first 12 hours (N-acetylcysteine is also
used as a mucolytic for cystic fibrosis)

Clinical Correlate
“Tot” Toxicity
Young children are gustatory explorers.Among the compounds responsible fortoxicity in youngsters under the age
of 3years are three items commonly foundin households with “tots”: aspirin,acetaminophen (people know
aboutReye syndrome!), and supplementaryiron tablets
Clinical Correlate
NSAIDs are associated withan increased risk of adversecardiovascular thrombotic eventssuch as MI and stroke.

Bridge to Physiology and

Biochemistry
Platelet Stability and Eicosanoids
Activation of TxA2 receptors →stimulation of phospholipase C →↑PIP2 hydrolysis →↑ IP3 → mobilizationof
bound Ca2+ →↑ free Ca2+ → plateletaggregation.

Activation of PGI2 receptors →stimulation of adenylyl cyclase →↑cAMP →↑ activity of internal Ca2+“pumps” →↓
free Ca2+ → plateletstabilization.