Aplikasi obat antialergi

&imunosupresi
Introduction
 Manifestation of allergy (Adverse Reactions )
Can be categorized as follows:
• (1) Drug intolerance --- predictable side effect at low
to therapeutic doses due to altered drug metabolism
or end organ hyperacuity
• (2) Idiosyncratic drug reactions
• (3) Immunologic drug reactions (AKA drug allergy)
 Adverse Drug Reactions

Type Example
Drug intolerance Tinnitus after a single
ASA tablet
Idiosyncrasy Glucose 6-phosphate
deficiency: anemia
after antioxidant drugs
Immunologic drug Anaphylaxis from
reactions betalactam antibiotics
Types of Allergic Reactions

• Type I (immediate)
• Type II (cytolytic)
• Type III (immune-complex associated)
• Type IV (delayed)
Types of Allergic Reactions
Type Mechanism Examples

I Anaphylactic (IgE-mediated) Acute anaphylaxis,

urticaria
II Complement dependent Hemolytic anemias,
cytolysis (IgG/IgM) thrombocytopenias,
interstitial nephritis
III Immune complex damage Serum sickness, drug
fever, some cutaneous
eruptions, vasculitis
IV “Delayed” or Cellular Contact dermatitis,
Hypersensitivity ?morbilliform dermatitis
Symptoms of allergic drug reactions

• Skin reactions (80%)

• Anaphylaxis (9 - 15%)
• Respiratory symptoms
(6 - 9%)
• Drug fever (2 - 6%)
 Anaphylaxis versus Anaphylactoid
Reactions
• Anaphylaxis refers to a systemic, immediate
hypersensitivity reaction due to the IgE-mediated
release of mediators from mast cells and basophils.
• Anaphylactoid reactions refer to clinically similar
events as anaphylaxis but are not mediated by IgE.
They cause, via an unknown mechanism, the
degranulation of mast cells and/or basophils.
 Signs and Symptoms of alerrgy
• Urticaria, angioedema, rhinoconjunctivitis, bronchial
asthma, and occasionally anaphylactoid reactions.
• Stevens Johnson syndrome and TEN have been
associated with NSAIDS in 14% and 19% of cases,
respectively.
• The most frequent delayed cutaneous reaction is a
morbilliform exanthem, which usually occurs 1 week
after therapy is begun and can last 2 weeks.
Drugs induced allergy
• Antibiotics
• NSAIDs
• others
Treatment
• Antihistamin
• Imunosupressan/steroid
Tabel 1 Konsep Farmakologi
Kortikosteoid Sistemik
Tabel 2 Dosis Inisial Kortikosteroid per Hari
untuk Orang Dewasa pada Berbagai Dermatosis
Tabel 3 Efek Samping
Penggunaan Kortikosteroid
Sistemik
Antihistamine
Histamine Receptors
• H1 histamine receptor
– Found on smooth muscle, endothelium, and central nervous system
tissue
– Activation results in vasodilatation, bronchoconstriction, smooth
muscle activation, and separation of endothelial cells.
• H2 histamine receptor
– Found on parietal cells of gater/stomach
– Regulates gastric acid secretion
• H3 histamine receptor
– Found in the central nervous system
– Regulates the release of other neurotransmitters
• H4 histamine receptor
– Recently discovered in different parts of the body including organs
of the digestive tract, basophils, and bone marrow cells
 The different Histamine receptors
Location Type of Effect Treatment
receptor
Throughout the body, specifically G-protein coupled, Mediate an increase Allergies, nausea,
H1 in smooth muscles, on vascular linked to in vascular sleep disorders
endothelial cells, in the heart and intercellular Gq, permeability at sites
the CNS which activates of inflammation
phospholipase C induced by histamine

In more specific locations in the G-protein coupled, Increases the release Stomach ulcers
H2 body mainly in gastric parietal linked to of gastric acid
cells, a low level can be found in intercellular Gs
vascular smooth muscle,
neutrophils, CNS, heart, uterus
Found mostly in the CNS, with a G-protein coupled, Neural presynaptic Unknown
H3 high level in the thalamus, possibly linked to receptor, may
caudate nucleus and cortex, also intercellular Gi function to release
a low level detected in small histamine
intestine, testis and prostate.
They were recently discovered in Unknown, most Unknown In addition to
H4 2000. They are widely expressed likely also G- benefiting allergic
conditions, research in
in components of the immune protein coupled
the h4 receptor may
system such as the spleen, lead to the treatment of
thymus and leukocytes. autoimmune diseases.
(rheumatoid arthritis
and IBS)
An Allergic Reaction
• Early phase reaction:
occurs within minutes of
exposure to an allergen
and lasts for 30-90 minutes
• Late phase reaction: begins
4-8 hours later and can last
for several days, often
leading to chronic
inflammatory disease
An Overview of Antihistamines
• Reversible H1 receptor antagonists
• Also considered “Inverse Agonists”
• Block the binding of Histamine to its receptors
• Three generations of Antihistamines
– Each generation improved on the previous one
– Share general characteristics and properties
 First Generation Antihistamines
• Small, lipophilic molecules that could cross the BBB
• Not specific to the H1 receptor
• Groups:
– Ethylenediamines
– Ethanolamines
– Alkylamines
– Piperazines
– Tricyclics
• Common structural features of classical antihistamine
– 2 Aromatic rings
– Connected to a central Carbon, Nitrogen or CO
– Spacer between the central X and the amine
– Usually 2-3 carbons in length
– Linear, ring, branched, saturated or unsaturated
– Amine is substituted with small alkyl groups eg CH3
•
Second Generation Antihistamines
• Modifications of the First Generation Antihistamines
to eliminate side effects resulted in the Second
Generation Antihistamines
• More selective for peripheral H1 receptors
• Examples:
– terfenadine
– loratadine
– cetirizine
– mizolastine
– astemizole
 Third generation H1-receptor
antagonists
• These drugs are derived from second generation antihistamines
• They are either the active enantiomer or metabolite of the second
generation drug designed to have increased efficacy and fewer side
effects
Levocetirizine (Zyzal)
•This drug is the active enantiomer of cetirizine and is
believed to be more effective and have fewer adverse side
effects.
•Also it is not metabolized and is likely to be safer than
other drugs due to a lack of possible drug interactions
(Tillement).
•It does not cross the BBB and does not cause significant
drowsiness
•It has been shown to reduce asthma attacks by 70% in
children
http://en.wikipedia.org/wiki/Image:Levocetirizine.png
 Third generation H1-receptor
antagonists
Deslortadine (Clarinex) Fexofenadine (Allegra)

•It was developed as an alternative

•It is the active metabolite of
to Terfenadine
Lortadine
•Fexofenadine was proven to be
•Even though it is thought to be
more effective and safe
more effective, there is no concrete
evidence to prove this
http://en.wikipedia.org/wiki/Image:Desloratadine.png http://en.wikipedia.org/wiki/Image:Fexofenadine_Structure.png
“Next” Generation Antihistamines
• Metabolite derivatives or active enantiomers of
existing drugs
• Safer, faster acting or more potent than Second
Generation drugs
• Examples:
– Fexofenadine
– Desloratadine
– Levocetirizine
Pharmacokinetics
• Second generation antihistamines H1:
– Relatively rapid onset
– Elimination Half-Lives (t1/2)elmination:
• Loratadine-up to 28 hours
• Fexofenadine-14 hours
• Cetirizine-8 hours
– Children metabolize Cetirizine faster, but rates are
similar for the others
Adverse Reactions
and Side Effects
• First Generation Drugs:
– Anticholinergic CNS interactions
– Gastrointestinal reactions
– Common side effects: sedation, dizziness, tinnitus, blurred vision,
euphoria, lack of coordination, anxiety, insomnia, tremor, nausea and
vomiting, constipation, diarrhea, dry mouth, and dry cough
• Second Generation Drugs:
– Common side effects: drowsiness, fatigue, headache, nausea and dry
mouth
• Side effects are far less common in Second Generation drugs
 The Future of Allergies

• Prevalence that is steadily increasing

worldwide
• Partially attributed to increased awareness and
diagnosis
• Two Theories:
– “Hygiene” Theory
– Increasing Use of Chemicals
Steroid
Pharmacological Actions
• Direct (Intended) Actions
Anti-inflammatory
Anti-allergy
Anti-immunity
• Permissive Actions
• Lipolytic effects
• Effect on bp
• Effect on bronchial muscles
• (e.g.,sympathomimetic amine)
Pharmacological Actions
• Negative feedback mechanism.
• Steroids and drugs designed to mimic them are
directly gene-active.
• Glucocorticoids (e.g., prednisolone) used to suppress
inflammation, allergy and immune responses.
• Anti-inflammatory therapy is used in many illnesses
(e.g., RA,, eye and skin inflammations).
-Useful in, say, tissue transplantation and
lymphopoiesis (leukemias and lymphomas).
 Hypothalamopituitary adrenal (HPA) axis: Negative
Feedback Immune
Stress system:
Circadian altered
rhythm Hypothalamus
Muscle:
CRH Net loss of amino
Posterior Acids (glucose)
Anterior Pituitary Gland
Pituitary Gland Liver:
(-) Deamination of
proteins into amino
ACTH acids,
gluconeogenesis
Glucocorticoids,
Adrenals Catecholamines, (glucose)
etc.. Fat Cells:
Free fatty
acid
Kidney mobilization

Heart rate:
Increased
Pharmacological Actions
• For most clinical purposes, synthetic glucocorticoids
are used because they have a higher affinity for the
receptor, are less activated and have little or no salt-
retaining properties.
• Hydrocortisone used for: orally for replacement
therapy, i.v. for shock and asthma, topically for
eczema (ointment) and enemas (ulcerative colitis).
• Prednisolone the most widely used drug given orally
in inflammation and allergic diseases.
Pharmacological Actions
• Betamethasone and dexamethasone: very potent,
w/o salt-retaining properties; thus, very useful for
high-dose therapies (e.g., cerebral edemas).
• Beclometasone, diproprionate, budesonide: pass
membranes poorly; more active when applied
topically (severe eczema for local anti-inflammatory
effects) than orally; used in asthma, (aerosol).
• Triamcinolone: used for severe asthma and for local
joint inflammation (intra-articular inj.).
Immunosuppressive and anti-allergic actions

• Suppresses all types of hypersensitivity and allergic

phenomenon
• At High dose: Interfere with all steps of
immunological response
• Causes greater suppression of Cell-mediated
immunity (graft rejection and delayed
hypersensitivity)
• Transplant rejection: antigen expression from
grafted tissues, delay revascularization,
sensitisation of T lymphocytes etc.
Tabel 4 Antihistamin H1 Generas Pertama (AH1
sedasi, AH1 klasik, AH1 tradisional)
Tabel 5 Antihistamin H1 Generasi
Kedua (AH1 nonsedasi, AH1
nonklasik)
Tabel 6 Penggolongan Antihistamin H2 (AH2)