Section 1 - CHEMICAL PRODUCT AND COMPANY IDENTIFICATION

PRODUCT NAME

ZAPRINAST

NFPA

PRODUCT USE

Given by mouth for prophylaxis of asthma. A phosphodiesterase inhibitor. The
parasympathetic nervous system, when stimulated, induces smooth muscle relaxation,
resulting in a larger artery. Upon certain types of stimulation (for example, allergic or
sexual) the terminal of the axons of the parasympathetic nerves release mononitrogen
monoxide (NO) which diffuses into the smooth muscles which line the arteries. This, in
turn, binds to adenine and guanylate cyclase, enzymes which thus activated, convert the
nucleotides adenine and guanosine triphosphate (ATP and GTP respectively) to their cyclic
monophosphate counterparts, cAMP and cGMP. These cyclic nucleotides induce the relaxation
of smooth muscle cells, producing dilation. A super- family of enzymes, described as
phosphodiesterases, cleave cyclic nucleotides (cAMP and cGMP) thus reversing smooth muscle
relaxation; these enzymes occur in multiple forms (isozymes) which catalyze the same
chemical reaction. The so- called PDEIs (phosphodiesterase inhibitors) generally produce
arterial dilation (and bronchodilation) and some are used in the treatment of certain
respiratory disease (such as asthma). In general, isozyme- specific inhibitors are
referred to as second- generation inhibitors. They are represented by a variety of
synthetic drugs as well as naturally occurring agents such as the xanthines (found in
coffee and tea) and the alkaloid, papaverine. PDEs are divided into two major classes, I
and II which have no recognizable sequence similarity. Class I includes all known
mammalian PDEs. Some PDEs are highly specific for hydrolysis of cAMP (PDE- IV , PDE- VII,
PDE- VIII, also described as PDE4 etc.), some are highly cGMP- specific (PDE- V, PDE- VI,
PDE- IX) and some have mixed specificity (PDE- I, PDE- II, PDE- III, PDE- X). All
mammalian PDEs are dimeric. Activators of PDEs appear to relieve the influence of
autoinhibitory domains located within the enzyme structure. Side- effects of treatment
with PDEIs, often are specific to the nature of inhibition. For example, the use of PDE-
III- specific agents have a tendency to produce tachycardia (elevated heart- rates,
typically exceeding 100 beats per minute). PDE- IV, the primary isozyme located in
inflammatory cells associated with bronchial asthma have been targeted by PDE- IV-
specific inhibitors; atopic dermatitis is also treated with this family of inhibitors.
Some PDE- IV- specific agents (such as rolipram) produce central nervous system side-
effects. Type- V inhibitors (typically dipyridamole) have been used as vasodilators of the
coronary circulation, increasing blood flow to a weakened heart, in part, because they
inhibit thrombo- embolism (it has been shown that increased cAMP and cGMP levels reduce
platelet aggregation, reducing the size of clots). cGMP- PDE- specific agents (those
mimicking the action of cGMP and thus acting as substrates for several isozymes, in a
specific manner) are generally targeted towards angina, hypertension, congestive heart
failure, atherosclerosis, peripheral vascular disease, stroke, bronchitis, asthma,
glaucoma and irritable bowel syndrome. One of these, a synthetic vasodilator, Sildenafil
(Viagra) was found to produce unexpected side- effects, namely formation and maintenance
of penile erection. The effect of this drug on the corpus cavernosal smooth muscle of the
penis is now established; PDE- V has been identified as the primary isoenzyme associated
with relaxation of the arteries of the this muscle. A side- effect of Viagra treatment
involves substrate binding to PDE- VI, the predominant PDE found in the retina. Patients
occasionally complain about altered colour perception and/or increased sensitivity to
light (photophobia). This " blue haze" showed a dose- related effect, probably restricted
to the blue- green part of the spectrum. Cardiovascular effects have also been noted with
Viagra especially amongst patients receiving nitric oxide donators (e.g nitroglycerin,
isosorbide mononitrate and pentaerythritol) for hypertension and heart disease. These
drugs produce a synergistic effect resulting in unexpectedly high levels of cGMP; this
often results in a catastrophic drop in systemic blood pressure (due to vasodilation)
producing a continuum of symptoms ranging from mild dizziness or light- headedness,
fainting upon standing, or even a heart attack or stroke.

SYNONYMS

C13-H13-N5-O2, "1, 4-dihydro-5-(2-propoxyphenyl)-1, 2, 3-triazolo[4, 5-d]pyrimidin-7-one",
"1, 4-dihydro-5-(2-propoxyphenyl)-1, 2, 3-triazolo[4, 5-d]pyrimidin-7-one", M&B-22948,
"anti-allergic agent", anti-asthmatic, "phosphodiesterase inhibitor (PDEI-V)"

Section 2 - HAZARDS IDENTIFICATION

CANADIAN WHMIS SYMBOLS

None

EMERGENCY OVERVIEW

RISK

POTENTIAL HEALTH EFFECTS

ACUTE HEALTH EFFECTS

SWALLOWED

  Although ingestion is not thought to produce harmful effects, the material may still be damaging to the health of the individual following ingestion, especially where pre-  existing organ (e.g. liver, kidney) damage is evident. Present definitions of harmful or toxic substances are generally based on doses producing mortality (death) rather than those producing morbidity (disease, ill-health). Gastrointestinal tract discomfort may produce nausea and vomiting. In an occupational setting however, ingestion of insignificant quantities is not thought to be cause for concern.  Considered an unlikely route of entry in commercial/industrial environments.  The material may produce biochemical inhibition of the enzyme, phosphodiesterase. Several families of drug (including xanthines, papaverine, bipyridines, imidazolines, imidazolones, dihydropyridazinones, dihydroquinilones, pyrrolidinones) produce this effect. Synthetic inhibitors of these types, (PDEIs), may produce a wide range of adverse effects in a clinical setting. These include tachycardia (elevated pulse rate), decreased blood pressure (hypotension), central nervous system effects, altered colour perception (a blue-green haze persists), an increased sensitivity to light (photophobia), dizziness, light-headedness, fainting, nausea, vomiting and diarrhoea, dyspepsia (upset stomach), facial flushing, nasal congestion, urinary tract infection, skin rash, muscle aches in the pelvic area and, rarely, heart attack or even stroke. Other reported effects include hepatotoxicity, especially in long-term treatment, dose-dependent thrombocytopenia, cardiac arrhythmia, headache, fever, chest pain and hypersensitivity reactions.  .  

EYE

  Although the material is not thought to be an irritant, direct contact with the eye may produce transient discomfort characterized by tearing or conjunctival redness (as with windburn).  

SKIN

  The material is not thought to produce adverse health effects or skin irritation following contact (as classified using animal models). Nevertheless, good hygiene practice requires that exposure be kept to a minimum and that suitable gloves be used in an occupational setting.  

INHALED

  The material is not thought to produce adverse health effects or irritation of the respiratory tract (as classified using animal models). Nevertheless, good hygiene practice requires that exposure be kept to a minimum and that suitable control measures be used in an occupational setting.  Persons with impaired respiratory function, airway diseases and conditions such as emphysema or chronic bronchitis, may incur further disability if excessive concentrations of particulate are inhaled.  

CHRONIC HEALTH EFFECTS

  Principal routes of exposure are usually by skin contact/absorption and inhalation of generated dust.  No human exposure data available. For this reason health effects described are based on experience with chemically related materials.  As with any chemical product, contact with unprotected bare skin; inhalation of vapor, mist or dust in work place atmosphere; or ingestion in any form, should be avoided by observing good occupational work practice.