A Textbook of Clinical Pharmacology and Therapeutics

Other humanized monoclonal antibodies used as immuno-
suppressants include:

• Daclizumabandbasilixumab(organ transplant rejection)
  which are anti-IL-2 receptor antibodies, inhibiting IL-2-
  mediated T-cell activation. They have similar toxicities as
  the anti-CD-3 monoclonal antibody, but do not cause
  cytokine release syndrome on first dose.


• Infliximabandetanercept(which bind to TNF-alpha)
  are used in the treatment of refractory rheumatoid
  arthritis and inflammatory bowel disease
  (Chapter 34).


• Natalizumab(an anti-alpha-4 beta-3 integrin monoclonal
  antibody) used in patients with progressive multiple
  sclerosis.

Other drugs that attenuate the immune response include
penicillamine,goldandchloroquine. These drugs are used
in an attempt to modify disease progression in patients with
severe rheumatoid arthritis (Chapter 26).

CHEMICAL MEDIATORS OF THE IMMUNE

RESPONSE AND DRUGS THAT BLOCK

THEIR ACTIONS

Several important therapeutic drugs block the release or action
of mediators of immune reactions.

HISTAMINE

Histamine is widely distributed in the body and is derived
from the decarboxylation of histidine. It is concentrated in
mast-cell and basophil granules. The highest concentrations
are found in the lung, nasal mucous membrane, skin, stomach
and duodenum (i.e. at interfaces between the body and the
outside environment). Histamine is liberated by several basic
drugs (usually when these are given in large quantities intra-
venously), including tubocurarine,morphine,codeine,van-
comycinandsuramin. Histamine controls some local vascular
responses, is a neurotransmitter in the brain, releases gastric
acid (Chapter 34) and contributes to allergic responses. There
are two main types of histamine receptors, H 1 and H 2.

H 1 -RECEPTORS

In humans, stimulation of H 1 -receptors causes dilatation of
small arteries and capillaries, together with increased permea-
bility, which leads to formation of oedema. Histamine induces
vascular endothelium to release nitric oxide, which causes
vasodilatation and lowers systemic blood pressure. Inhaled
histamine induces bronchospasm. In fetal vessels (e.g. the
umbilical artery), histamine causes vasoconstriction. Histamine
contributes to the triple response to mechanical stimulation
of the skin which consists of localized pallor, which gives way
to a wheal (localized oedema caused by increased vessel

permeability and attributable to histamine) surrounded by a

more distant and slowly developing flare (due to arteriolar

dilatation via an axon-reflex mechanism and involving

tachykinins such as substance P, rather than histamine). Local

injection of histamine causes itching and sometimes pain due to

stimulation of peripheral nerves. Inhaled histamine is used as a

challenge to determine bronchial hyperreactivity and assist in

the diagnosis of asthma.

H 2 - AND H 3 -RECEPTORS

H 2 -receptors are principally concerned with the stimulation of

gastric acid release (Chapter 34). Their contribution to most vas-

cular responses is minor, but some (e.g. in the pulmonary vas-

culature) are H 2 -receptor mediated. H 3 -receptors are involved

in neurotransmission.

HYPERSENSITIVITY REACTIONS INVOLVING

HISTAMINE RELEASE

Anaphylactic shock (acute anaphylaxis)

In certain circumstances, injection of an antigen is followed by

the production of reaginic IgE antibodies. These coat mast

cells and basophils, and further exposure to the antigen results

in rapid degranulation with release of histamine and other

mediators, including tachykinins, prostaglandin D 2 and

leukotrienes. Clinically, the patient presents a picture of

shock and collapse with hypotension, bronchospasm and

oropharyngeal-laryngeal oedema, often accompanied by

urticaria and flushing. A similar so-called ‘anaphylactoid reac-

tion’ may occur after the non-IgE-mediated release of media-

tors by x-ray contrast media.

404 CLINICAL IMMUNOPHARMACOLOGY

Key points

Anaphylaxis and anaphylactoid reactions

• Anaphylaxis:
  
  
  • is IgE-mediated hypersensitivity (type-1) that occurs
    in a previously sensitized individual;
  
  
  • its pathophysiology is major cardiovascular and
    respiratory dysfunction due to vasoactive mediator
    release from mast cells;
  
  
  • common causes are penicillins, cephalosporins and
    many other drugs, insect stings and food allergies
    (e.g. strawberries, fish, peanuts).
  
  
  
  


• Anaphylactoid reactions:
  
  
  • are due to drug dose-related pharmacologically
    induced mediator release from mast cells and
    basophils;
  
  
  • common causes include aspirin, NSAIDs and
    radiographic contrast media.
  
  
  
  

Atopy

Some individuals with a hereditary atopic diathesis have a

propensity to develop local allergic reactions if exposed to appro-

priate antigens, causing hay fever, allergic asthma or urticaria.

This is due to antigen combining with mast-cell-associated IgE in

the mucosa of the respiratory tract or the skin.