1.

Treatment of hereditary angioedema (HAE) consists of prophylaxis, management of

acute attacks, and prophylactic therapy in situations where attacks may occur. Patients
with hypotension due to sequestration of fluid in the extravascular space require
intravascular fluid replacement may require large amounts of intravenous fluids to
maintain hemodynamic stability. Abdominal pain is treated with narcotics. In cases of
serious laryngeal edema causing respiratory obstruction, intubation or tracheostomy
should be performed.

in HAE types I and II, the treatment of choice in acute attacks consists of replacement with
commercially available C1 inhibitor (C1-INH) concentrates [12] or kallikrein inhibitor or, if those
are unavailable, fresh-frozen plasma. In HAE with normal C1 inhibitor levels, infusion of C1-INH
has proven to be ineffective. [22, 23]
For prophylaxis, attenuated androgens are currently the initial mode of treatment. Therapy
should be minimized, balancing disease severity with minimizing adverse effects. The drug most
commonly used is danazol, but all attenuated androgens are useful in treatment. C1-INH
concentrates have become available for prophylaxis and treatment of acute attacks

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1. C1 inhibitor (C1INH) concentrate, derived from human plasma - Functions of C1

inhibitor — C1 inhibitor (C1INH) is an acute-phase reactant and a member of the
"serpin" superfamily of serine protease inhibitors. C1INH is an inhibitor of two
complement pathways (classical and lectin), as well as of the intrinsic coagulation
(contact system) fibrinolytic and kinin-generating pathways. Within these different
pathways, C1INH inhibits several plasma proteases: C1r and C1s, mannose-binding
lectin-associated serine proteases (MASP1 and MASP2), coagulation factor XII
(Hageman factor), coagulation factor XI, plasma kallikrein, and plasmin. The function of
C1INH in the kinin-generating pathway is most directly related to the pathogenesis of
HAE

2. Icatibant (bradykinin B2-receptor antagonist)- The swelling (ie, angioedema,

sometimes called "giant" swelling) that occurs in hereditary angioedema (HAE) results
from excessive production of bradykinin, a potent vasodilatory mediator. Bradykinin also
has important vascular permeability-enhancing effects. During episodes of angioedema
in patients with HAE, plasma bradykinin levels have been shown to be sevenfold higher
than normal [1]. In bradykinin-mediated angioedema, histamine and other mast cell
mediators are not directly involved, which explains the lack of response to
antihistamines and distinguishes this form of angioedema from the histamine-mediated
angioedema that is seen in allergic reactions and urticarial.

3. Ecallantide (recombinant plasma kallekerin inhibitor)- Hereditary

angioedema (HAE) is a rare, autosomal-dominant disorder caused by C1 inhibitor gene
mutation. Patients with HAE experience intermittent attacks of edema affecting the
oropharynx, abdomen, gastrointestinal tract, and limbs. C1 inhibitor is the primary
endogenous inhibitor of the kallikrein-kinin (contact) cascade. Unregulated kallikrein
activation generates bradykinin, the likely mediator of the swelling and pain
characterizing HAE attacks. Ecallantide, a novel, recombinant protein, potently inhibits
kallikrein. This is the first placebo-controlled assessment in human beings of a
therapeutic intervention to improve symptoms of HAE attacks under the hypothesis that
the contact cascade is the putative pathway responsible for HAE pathology.

Until now, there is neither a cure for patients who suffer from HAE attacks nor a therapeutic concept
to prevent these attacks completely.

Furthermore, in many countries there are currently no acute attack treatments available for HAE
patients. Here physicians are therefore limited to providing patients with a short and long term
prophylactic treatment with attenuated androgens (such as Danazol and Oxandrolone) and in some
cases tranexamic acid (such as Cyklokapron).

Acute treatment
The aim of acute treatment is to halt the progression of the edema and alleviate the symptoms. This
applies particularly to episodes affecting the larynx, which can cause death by suffocation if left
untreated.

The recommended options for acute treatment vary from country to country due to the fact that
drugs for specific treatment are not licensed in all countries. In these cases acute treatment may be
limited to more unspecific drugs such as tranexamic acid or even just painkillers.

In countries where it is available, C1-INH concentrate, Icatibant or Ecallantide can be used for the
treatment of acute attacks. Icatibant and Ecallantide must be administered by subcutaneous
injection by a healthcare professional; C1-INH concentrate must be administered intravenously.

Long-term prophylaxis
Long-term prophylaxis is given to patients whose quality of life is clearly reduced by HAE. These are
usually patients who have either very frequent or very painful attacks or are at high risk of
developing laryngeal edema.

Long-term prophylaxis consists mainly of attenuated androgens, synthetically produced derivatives

of the male sex hormone testosterone. They can reduce the number of attacks, but as these
medications are associated with a range of severe side effects, attenuated androgens are generally
reserved for patients suffering from frequent and/or severe symptoms.

In some countries, antifibrinolytic drugs such as tranexamic acid or aminocaproic acid are used as
alternative to androgens.

Short-term prophylaxis
Short-term preventative therapy is recommended for patients undergoing dental procedures or
surgery, which have been known to trigger an attack. One option for short-term prophylaxis consists
of high dose androgen therapy for at least five days prior to surgery and four days afterwards. Where
available, another option is to administer C1-INH concentrate one to two hours prior to surgery.
Treatment of Acute Attacks
Angioedema seen in HAE does not respond to the drugs employed in treating other forms of
urticaria/angioedema such as antihistamines, epinephrine and corticosteroids. While epinephrine, in
particular, may have a transient effect on swelling, it does not alter the course of an attack.

Maintaining airway patency is the primary concern for patients with laryngeal edema. If the airway is
threatened, an experienced physician should intubate the patient. In addition, the capability for
emergency tracheotomy should be readily available. Because gastrointestinal edema usually
involves excruciating pain, frequent vomiting and the potential for hypotension, therapy should
include aggressive fluid replacement and pain management. Clinicians report that Zofran,
Compazine and Phenergan are effective in reducing nausea and vomiting, while morphine or other
narcotics are routinely used to relieve attack related abdominal pain. Some physicians use fresh
frozen plasma in the acute attack setting, but this therapy is considered controversial because in
addition to C1-inhibitor, fresh frozen plasma contains substrates of the complement and kinin
systems that could produce a vasoactive peptide and cause an attack exacerbation.