1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance Colour State/Form Description
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data Adults Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s) Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis Blood, plasma or serum Urine Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomed. investigations etc.
   8.5 Overall Interpretation etc.
   8.6 References
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological CNS Peripheral nervous system Autonomic nervous system Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary Renal Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic Acid-base disturbances Fluid and electrolyte disturbances Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures etc.
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
    1.  NAME
        1.1  Substance
                      Hydralazine Hydrochloride
        1.2  Group
                      Vasodilator; Antihypertensive
        1.3  Synonyms
                      Hydralazine Hydrochloride
                      1- Hydrazinophatalazine
                      1- Hydrazinophtalazine Hydrochloride
                      CIBA 5968
                      Hydralazini Hydrochloridum
                      Cloridrato de Hidralazina
        1.4  Identification numbers
             1.4.1  CAS number
                    Hydralazine (86-54-4) 
                    Hydralazine Hydrochloride (304-20-1) 
             1.4.2  Other numbers
        1.5  Brand names, Trade names
             Hydralazine Hydrochloride Injection USP 23, 
             Hydralazine Hydrochloride Tablets USP 23, 
             Hydralazine Injection BP 1993, 
             Hydralazine Tablets BP 1993, 
        1.6  Manufacturers, Importers
                       CIBA (Novarte).
    2.  SUMMARY
        2.1  Main risks and target organs
             Hypotension, sinus tachycardia, palpitations, sweating, 
             flushing, and headache are the most commonly reported side 
             effects. Severe hypotension may result in myocardial and/or 
             cerebral ischemia. Congestive heart failure, peripheral 
             neuropathy, paresthesia, hepatotoxicity, drug fever, nausea, 
             vomiting and diarrhea are also possible side effects but are 
             most commonly related to chronic use . A lupus-like syndrome 
             may be seen in 15 per cent of patients taking 400 mg or more 
             of hydralazine daily. A higher percentage of patients develop 
             circulating antinuclear antibodies. This syndrome is less 
             common in patients who receive less than 200 mg per day.
             The cardiovascular system is mainly affected by hydralazine. 
             The nervous system , the liver, the gastrointestinal and the 
             immunologic systems are also target organs.
        2.2  Summary of clinical effects
             Signs and symptoms of poisoning depends on the dose 
             taken and the time of exposure. These include severe 
             hypotension, reflex tachycardia, palpitations, cardiac 
             arrhythmias, syncope, sweating, cerebral and/or myocardial 
             ischemia, headache and dizziness.  Nausea, vomiting and 
             diarrhoea are also observed. 
             Hypokalemia and lactic acidosis can occur. Ten to twenty per 
             cent of patients taking 400 mg or more of hydralazine can be 
             affected by a lupus-like syndrome.  This effect is almost 
             exclusively seen in slow acetylators.  Chronic use may also 
             lead to fluid retention, peripheral neuropathy and 
        2.3  Diagnosis
             Diagnosis is based on the patient's history and the 
             signs and symptoms of hydralazine exposure.  Hypotension, 
             reflex tachycardia, syncope, sweating, headache, cardiac 
             arrhythmias, cerebral and/or  myocardial ischemia are the 
             main observed effects.
        2.4  First aid measures and management principles
             Monitor vital signs. In severe cases, cardiovascular 
             function should be continuously monitored and the patient 
             should be admitted in a intensive care unit. Airway 
             protection in alert patients can be done by assuming a 
             Trendelenburg with left lateral decubitus position.  An 
             endotracheal tube may be necessary if the patient is obtunded 
             or unconscious.  Correct hypotension with intravenous 
             Administer vasopressors if necessary. Avoid the 
             administration of beta-adrenergic agents such as epinephrine 
             or isoproterenol because of the increased  risk of 
             hydralazine-induced myocardial isquemia.
             GI decontamination by emesis may be used. It is probably more 
             efficient if performed in the first 30 minutes of ingestion. 
             Activated charcoal with water, sorbitol, or a saline 
             cathartic is also indicated. The severity of the intoxication 
             and prognosis are also based on the clinical findings.
        3.1  Origin of the substance
             A synthetic compound prepared by action of hydrazine 
             hydrate on 1-chloro or 1-phenoxyphtalazine
             (The Index Merck, 1996).
        3.2  Chemical structure
             Hydralazine; Hydrallazine; 1- hydrazinophtalazine : C8H8N4.
             Hydralazine Hydrochloride: C8H8N4.HCl.
        3.3  Physical properties
             3.3.1  Properties of the substance
                             A white to off-white substance 
                             (Clark's,1986; Martindale,1995).
                             Crystalline powder.
                             An odourless to almost odourless 
                             compound. Solubilities are: soluble in water 
                             (1 in 25), slightly soluble in ethanol (1 in 
                             500) and in methanol; practically insoluble 
                             in ether or chloroform. (B.P., U.S.P.). A 2 % 
                             solution in water has a pH of 3.5 to 4.2. pKa 
                             0.5, 7.1.
                             Colour test: Nessler's Reagent-black. 
                             Thin-layer Chromatography: System TA-Rf 38, 
                             system TC-Rf11, (Acidified iodoplatination 
                             solution, positive). Gas Chromatography: 
                             System GA-RI 1528.
                             Ultraviolet Spectrum: principal peaks at wave 
                             numbers 1665, 790, 1582, 1000,810, 1175 
                             (hydralazine hydrochloride, K Br disk).
                             Mass spectrum: principal peaks at m/z 160, 
                             103, 89, 131, 115, 76, 161, 104 
                             (Clark's, 1986).
             3.3.2  Properties of the locally available formulation
                    No data available.
        3.4  Other characteristics
             3.4.1  Shelf-life of the substance
                    No data available.
             3.4.2  Shelf-life of the locally available formulation
                    No data available.
             3.4.3  Storage conditions
                    Oral tablets: stored in light proof and air 
                    tight containers, between 15°C and 40°C (59 to 104 
                    Ampules should be kept between the same temperatures 
                    described above and should not be frozen.
                    Solutions containing glucose, fructose, lactose and 
                    maltose reduce the stability of the drug (Das Gupta et 
                    al., 1986). Therefore, administration in solution 
                    containing glucose is inadvisable. Furthermore, 
                    solutions for injections deteriorate on storage and 
                    must be used immediately after preparation 
                    (Martindale, 1995)  However, solutions containing 
                    mannitol or sorbitol are stable, with less than 10% of 
                    hydralazine degradation after 21 days (Das Gupta et 
                    al. 1986).  Alterations in colour are seen in most 
                    infusion fluids which are not indications of any 
                    alteration in potency if temperature conditions are 
                    maintained at 30°C or lower. If stored in a syringe, 
                    hydralazine solutions may also have alterations in 
                    colour. A reaction with metals is also possible. 
                    Therefore, a non-metal filter should be used in the 
                    preparation of the injection and thus administered as 
                    soon as possible to avoid a reaction with the needle 
                    (Enderlin, 1984).
                    A syrup of hydralazine hydrochloride can be prepared 
                    extemporaneously, providing that the guideline 
                    described by Alexander et al (1993) are 
             3.4.4  Bioavailability
                    Hydralazine bioavailability is variable, 
                    ranging from 50 to 90% of a single oral dose. 
                    Depending on the dose, peak plasma levels occur from 
                    0.3 to 1.0 hour after a single oral dose (Shepherd et 
                    al.,1980; Ludden et al., 1982). With increasing oral 
                    dose, there is a non-proportional increase in the 
                    hydralazine plasma levels. A saturation in the 
                    metabolic pathways (gut; liver) may be responsible for 
                    this phenomenon (Shepherd et al., 1984b).  Hydralazine 
                    undergoes first-pass metabolism which is determined by 
                    the acetylator phenotype. Therefore, different 
                    bioavailability patterns are expected: it is greater 
                    in slow acetylators than in fast acetylators. Food may 
                    interfere with hydralazine bioavailability.  It has 
                    been demonstrated that plasma levels and area under 
                    the curve bioavailability is reduced up to 46 % if the 
                    drug is administered 45 minutes after a meal (Shepherd 
                    et al, a).
             3.4.5  Specific properties and composition
                    No data available.
    4.  USES
        4.1  Indications
             4.1.1  Indications
             4.1.2  Description
                    Hydralazine is used to treat arterial 
                    hypertension (primary; malignant; pulmonary; 
                    pree-eclampsia and eclampsia), congestive heart 
                    failure, pulmonary hypertension in chronic obstructive 
                    pulmonary disease, and aortic regurgitation (McFadden 
                    & Braunwald, 1992; Gallager et al, 1994 ; Oates, 
                    1995).  Some benefit may be seen if used in primary 
                    oesophageal motility disorders (Mellow, 1982) and 
                    psoriasis (Isaac, 1982). Recent observations indicate 
                    that it can be used to withdraw patients from 
                    dobutamine in severe congestive heart failure (Binkley 
                    et al, 1991). Infants with chronic heart failure and 
                    left-to-right shunts may experience some benefit with 
                    hydralazine use (Artman et al., 1984).
        4.2  Therapeutic dosage
             4.2.1  Adults
                    There is no clear relationship between dose and 
                    response for hydralazine's antihypertensive effect. 
                    Furthermore, besides being ineffective as a single 
                    agent to treat hypertension, little evidence exists 
                    concerning the relationship between the dose or plasma 
                    levels and the drug's antihypertensive effect (Jounela 
                    et al., 1975; Johnston, 1992).
                    The dose range varies from 10 mg four times a day for 
                    the first 2 to 4 days, increasing to 25 mg 4 times a 
                    day for the remainder of the first week.  For the 
                    subsequent weeks, it may be necessary to increase the 
                    dose up to 50 mg 4 times a day.  After a 
                    antihypertensive effect is seen, titration of the dose 
                    downward to the minimal effective dose is recommended. 
                    In patients who cannot tolerate other antihypertensive 
                    agents a dose of 400 mg or more may be effective 
                    (Barker, 1995).  After initial stabilization with 
                    multiple daily doses a twice daily dosage regimen can 
                    be effective.  Slow acetylators need a lower dose. 
                    Concurrent administration of a beta-blocker to 
                    overcome the reflex activation of the sympathetic 
                    nervous system and a diuretic to reduce fluid 
                    retention, produces a more effective vasodilation with 
                    minimal side effects (Johnston, 1992; Kaplan, 1992). 
                    For heart failure recommended doses are higher (up to 
                    800 mg daily or more), vary from one patient to 
                    another and require individualization (Packer et al., 
                    As a rule 10 to 100 mg four times a day can be 
                    effective (Smith et al., 1992).
             4.2.2  Children
                    The oral dose ranges from 0.75 to 7.5 mg/kg/day 
                    (every 6 to 8h) or 1 to 3 mg/kg/day (every 12 h). 
                    Intravenous administration requires 0.8 to 3.0 
                    mg/kg/day (every 4 to 6 h) (Friedman, 1992)
        4.3  Contraindications
             With the exception of a history of systemic lupus 
             erythematosus there are no absolute contraindications to 
             hydralazine use if combined with an adrenergic blocker 
             (Barker, 1995).
             Relative Contraindications
             Hydralazine should be used cautiously in patients with 
             dissecting aortic aneurysm, heart failure with high output, 
             cor pulmonale or myocardial insufficiency caused by 
             mechanical obstruction due to valvular diseases.  It should 
             also be used with caution in patients with coronary and/or 
             cerebrovascular diseases because of increased ischemia 
             (Reynolds, 1995). Renal failure requires dose adjustment to 
             20 to 40 mg  (every 6 to 8 h) despite the acetylator 
             phenotype (St. Peter & Halstenson, 1994).  In geriatric 
             patients it is wise to start with lower doses (about one-half 
             of the adult normal dose), with subsequent titration. 
             Postural hypotension and other side effects are more common 
             in old people (Grahame-Smith & Aronson, 1992).
        5.1  Oral
             Oral ingestion is most likely the most common route of 
        5.2  Inhalation
             No data available.
        5.3  Dermal
             No data available.
        5.4  Eye
             No data available.
        5.5  Parenteral
             Poisoning may occur by intravenous administration. 
             Parenteral therapy is recommended only when the oral route is 
             not feasible.
        5.6  Other
             No data available.
    6.  KINETICS
        6.1  Absorption by route of exposure
             By the oral route, hydralazine absorption is variable 
             and ranges from 50 to 90 % (Talseth, 1977).  Bioavailability 
             is greater in slow compared to fast acetylators. (Zacest & 
             Koch-Weser, 1972) Increasing the dose, there is a 
             non-proportional increase in the serum levels, possibly 
             because of saturation in the metabolic pathways of 
             hydralazine (Shepherd, 1984). 
             Peak plasma levels are achieved in about  60  minutes after 
             ingestion (Ludden et al., 1982).  The maximum hypotensive 
             effect occurs from 2 to 4 hours after ingestion and may 
             persist for up to 24 hours (Barker, 1995).
        6.2  Distribution by route of exposure
             Binding to plasma proteins is reported to be greater 
             than 87 % (Pastan & Braunwald, 1992). Hydralazine can be 
             found in high concentrations in liver, kidneys, lungs, 
             adrenals and arteries (Ludden et al. ,1982; Johnston, 1992). 
             Volume of distribution (Vd) is 0.5 to 0.9 L/kg.  In renal 
             failure Vd can increase to 7 to 16 L/kg (St. Peter & 
             Halstenson, 1994).
        6.3  Biological half-life by route of exposure
             Biological half-life is about 3 to 4 hours and is not 
             related to the rate of acetylation (Grahame-Smith & Aronson, 
             1992; Ziegler & Ruiz-Ramon, 1994).  However, the half-life of 
             its antihypertensive effect may last up to 100 hours (Ziegler 
             & Ruiz-Ramon, 1994).  The effects may be prolonged with renal 
             failure. (Reynolds, 1995)
        6.4  Metabolism
             Hydralazine undergoes first pass metabolism by 
             acetylation which is genetically determined.(Koch-Weser, 
             1976).  The gastro-intestinal mucosa and the liver are the 
             main sites of this saturable metabolic pathway.  The major 
             metabolites are: MTP; the acetylation product 
             (3-methyl-1,2,4-triazolo-(3,4a)phtalazine); HPH hidralazine 
             piruvic acid hidrazone), which is the major plasma 
             metabolite; N-AcHPZ (4-(2-acetylhydrazino) phtalazin-1-one, 
             which is  mostly found in the urine and 3-OHMTP 
             (3-hydroxymethyl-1,2,4-triazolo(3,4a) phtalazine (Clark's, 
             1986). Systemic metabolism is dependent on hydroxylation 
             followed by conjugation with glucuronic acid in the liver, 
             which is not dependent on the rate of acetylation. Therefore, 
             the half-life does not differ very much between slow and fast 
             acetylators (Grahame-Smith & Aronson, 1992).
             Biotransformation of xenobiotics containing an aromatic amine 
             or a hydrazine group by N-acetylation is dependent on the 
             N-acetyltransferases enzymes which in humans are expressed by 
             only two different enzymes, known as NAT1 and NAT2. Genetic 
             polymorphism determines a reduction in the activity/stability 
             of the NAT2 enzyme which is observed in slow acetylators 
             (Parkinson, 1996).
             The incidence of slow acetylator phenotype is about 5 to 10% 
             in Asians, 50% in Americans (both white and blacks), and 60 
             to 70% in Northern Europeans. (Benet et al. 1995).
        6.5  Elimination by route of exposure
             About 65% of the total dose is excreted in the urine in 
             24 hours.  Slow acetylators eliminate 15 to 20% as N-AcHPZ 
             and 10% as conjugated 3-OHMTP.  In fast acetylators, 30% is 
             excreted in the urine as N-AcHPZ, as well as 10 to 30% as 
             conjugated 3-OHMTP.  The fecal contend of hydralazine is 
             about 10% of the dose (Clark's, 1986).
        7.1  Mode of action
             7.1.1  Toxicodynamics
                    Hydralazine is a potent arteriolar vasodilator 
                    by producing relaxation of vascular smooth muscle. 
                    The vasodilation is most marked in the splanchnic, 
                    coronary, cerebral and renal arterial beds.  Some of 
                    the symptoms may be caused by vasodilation and 
                    histaminic effects. Iron chelation may lead to anemia. 
                    (Alarcon-Segovia et al, 1967)
                    A hydralazine-DNA pyrimidine interaction resulting in 
                    immune responses to hydralazine and  nuclear antigens 
                    in which antibodies to native DNA occur can explain 
                    the hydralazine-induced lupus erythematosus (Hahn et 
                    al., 1972; Dubrof & Reid, 1980).  Recent observations 
                    have demonstrated that in the presence of metal ions 
                    or peroxidase hydrogen peroxide, hydralazine increased 
                    free radical production and site-specific DNA-damage. 
                    It was suggested that this could be a possible 
                    explanation for hydralazine-induced lupus, mutation 
                    and  cancer.
                    Slow acetylators produce hydralazine degradation to 
                    phtalazine through the intermediate of 
                    nitrogen-centered free radical  and carbon centered 
                    free-radicals (Yamamoto & Kawanishi, 1991).  On the 
                    other hand, Runge-Morris & Novak (1993) have found 
                    that in human red blood cells, hydralazine increases 
                    hydrogen peroxide production and proteolysis.  These 
                    authors have suggested that this phenomena may lead to 
                    morphological alterations or to the release of novel 
                    antigenic protein determinants, leading to the 
                    recognition of damaged cells by the immune system 
                    which may in turn be responsible for the auto-immune 
                    disease. Some other experimental data could also lead 
                    to the hypothesis that hydralazine and others 
                    xenobiotics containing a hydrazine function, react 
                    with H2O2 to generate free-radicals, damage proteins 
                    and stimulate proteolysis (Runge-Morris et al., 1994). 
                    Studying sera from 25 patients taking hydralazine, 
                    Thomas et al. (1993) found that 82% of these patients 
                    had anti-(Z-DNA) antibodies, suggesting that 
                    drug-induced lupus could be involved in the induction 
                    and stabilization of Z-DNA. However it has been 
                    demonstrated that some hydralazine-induced 
                    conformational and structural changes in DNA can be 
                    achieved only at high concentrations (Mathison et al. 
                    1994; Martelli et al., 1995).
                    As far as the hydralazine-induced lupus syndrome is 
                    concerned, since it was initially described by Dustan 
                    et al (1954) as a rheumatic and febrile disease and by 
                    Perry & Schroeder (1954) as a collagen simulating 
                    disease, it has become evident that this syndrome is 
                    indistinguishable from that of systemic lupus 
                    erythematous (Alarcon-Segovia et al., 1965).  Since 
                    then, it has been confirmed by several observations 
                    that anti-nuclear antibodies are almost always seen in 
                    the patients affected with the disease.  These 
                    antibodies may persists for up to nine years after 
                    hydralazine exposure (Condemi et al., 1967).
                    A relationship between the phenotype acetylator 
                    activity to the antinuclear antibodies production and 
                    toxic symptoms in hypertensive patients was 
                    demonstrated by Perry et al. (1970). Slow acetylator 
                    Caucasian peopole are at higher risk (Hahn et al., 
                    Long term and high doses may increase the possibility 
                    of this kind of toxicity (Perry, 1973), which can also 
                    be observed at lower doses (Cameron & Ramsey, 1984). 
                    Patients at risk of developing late toxicity to 
                    hydralazine include those with initial accelerated 
                    hypertension, previous positive antinuclear 
                    antibodies, coexisting autoimmune disease and a total 
                    dose of more than 100 g (Brooks & Pauley,1980). 
                    Patients with an itchy maculopular and pruritic 
                    eruption or a erythematous rash while taking 
                    hydralazine should be evaluated for the lupus-like 
                    syndrome (Finlay et al., 1981).  A possible 
                    association with the HLA-DR4 histocompatibility 
                    complex system was suggested but could not be 
                    confirmed (Batchelor et al, 1980; Christophidis, 1984; 
                    Brand et al., 1984).
                    More recently, it has also been demonstrated that 
                    hydralazine can stimulate the production of antibodies 
                    against elastase and myeloperoxidase, inhibiting the 
                    activity of the latter (Hanson & Nassberger, 1993). 
                    Furthermore, oxidation of hydralazine by HOCl, 
                    produced by activated leukocytes leads to a reactive 
                    intermediate, which binds covalently to the leukocytes 
                    (Hofstra & Uetrecht, 1993). Based on these and other 
                    observations, it has been proposed that hydralazine 
                    and other lupus-inducing drugs are only cytotoxic in 
                    the presence of activated neutrophils and that these 
                    drugs are transformed to cytotoxic agents by the 
                    leukocytes, with hydrogen peroxide being necessary for 
                    this transformation (Jiang et al., 1994).
             7.1.2  Pharmacodynamics
                    The mechanism of action of the vasodilation 
                    induced by hydralazine is not yet well understood. 
                    Recent observations suggest that it inhibits calcium 
                    release of the vascular smooth muscle sarcoplasmic 
                    reticulum by blocking the inositol trisphosphate 
                    (IP3)-induced calcium release, therefore reducing 
                    calcium turnover inside the cell (Gurney & Allam, 
                    1995).  The  resultant vasodilation reduces cardiac 
                    afterload, increasing cardiac function in patients 
                    with heart failure. However, some evidence exists 
                    concerning a direct action in the myocardium by an 
                    increase in calcium influx through the sarcolemma. 
                    This may be partially due to the stimulation of the 
                    beta-adrenoreceptors (Azuma et al. 1987).
        7.2  Toxicity
             7.2.1  Human data
                             Adverse effects are described even 
                             within the therapeutic range, conversely 
                             patients may tolerate up to 800 mg or more 
                             daily. The severity of hydralazine poisoning 
                             should be determined by the clinical 
                             findings.  Hydralazine poisonings are 
                             believed to be very uncommon.
                             No data available.
             7.2.2  Relevant animal data
                    Neither the minimal toxic doses nor the lethal 
                    dose have yet been established. 
                    Combined with prenalterol, hydralazine exhibits a 
                    cardiotoxic effect by enhancing myocardial necrosis in 
                    rats (Joseph & Balazs, 1986).  This effect could not 
                    be reproduced in rabbits.
             7.2.3  Relevant in vitro data
                    No data available
        7.3  Carcinogenicity
             Hydralazine has been associated with the appearance 
             oflung tumorigenesis in mice (Drozdz et al, 1987)   However, 
             little information can be found to establish a causal 
             relationship between hydralazine use and the development of 
             cancer.  A study describing a large number of patients found 
             no evidence that hydralazine alters the risk of gut and lung 
             cancer (Kaufman et al., 1989).
        7.4  Teratogenicity
             Hydralazine readily crosses the placental blood-barrier 
             but has no effect on the placental circulation (Gudmundsson 
             et al., 1995).  It has minimal effects on isolated human 
             umbilical vessels (Belfort et al, 1995).
             In mice and rabbits, hydralazine can produce skeletal 
             malformations due to its effect on the collagen synthesis. 
             When given to pregnant rats in doses non-toxic to the mother, 
             hydralazine does not have teratogenic or fetotoxic effects 
             (Pryde et al., 1993).  However, human data have demonstrated 
             that there is no increased risk of congenital malformations 
             in the offspring of women treated with hydralazine, even 
             during the first trimester of pregnancy  (Briggs et al, 
             Some cases of  hydralazine-induced neonatal thrombocytopenia 
             with increased risk of bleeding were reported to the Swedish 
             Adverse Drug Reaction Committee (Widerlov et al., 
        7.5  Mutagenicity
             Hydralazine can induce structural and/or conformational 
             changes in DNA (see toxicodynamics).  It has a clastogenic 
             effect in the liver which can be the main target site of 
             genotoxicity.(Martelli et al., 1995).
        7.6  Interactions
             Indomethacin may produce a clinically important decrease 
             in the hypotensive effects of hydralazine, however, such 
             effects have been demonstrated only in healthy volunteers 
             (Cinquegrani & Liang, 1986).
             Some pharmacokinetic interactions have been described with 
             the concomitant administration of hydralazine and 
             beta-blockers.  Increased bioavailability of propranolol 
             (Schneck & Vary, 1984), and of metoprolol (Lindeberg & Holm, 
             1988),  (Byrne et al., 1984) were observed in these 
             circumstances.  This interaction was not seen with a 
             sustained release preparation of propranolol.
             Pyridoxine can reverse the neuropathy produced by hydralazine 
             (Raskin & Fishman, 1965).
             Severe hypotensive sequelae of combined diazoxide and 
             hydralazine therapy was observed in some patients (Henrich et 
             al., 1977).
             Beta-blockers can reduce the side effects produced by 
             sympathetic stimulation when hydralazine is clinically used 
             to treat hypertension (Johnston, 1992).  However, when used 
             in pregnancy associated with propranolol, some negative 
             effects on fetal development may occur.  These effects are 
             not seen with the combination of pindolol and hydralazine 
             (Paran et al., 1995). Combined with propranolol, there may be 
             a reduction in the activity of lipoprotein lipase activity, 
             and alteration of the lipid profile (Marotta et al, 1995)
             Organic nitrates when associated with hydralazine may have 
             beneficial effects in patients with long-standing mitral 
             regurgitation (Roth et al., 1993).  In patients with heart 
             failure, the combination of hydralazine and dinitrate 
             isosorbide has a better survival rate compared to placebo 
             (Loeb et al, 1993)
        7.7  Main adverse effects
             Hypotension, syncope, headache, myocardial and/or 
             cerebral ischemia, flushing, nasal congestion, angina 
             pectoris, fluid retention, edema of the lower extremities, 
             palpitations, tachycardia, nausea and vomiting.  Myocardial 
             infarction and sudden death can occur.  Antinuclear 
             antibodies and lupus-like syndrome may occur.
        8.1  Material sampling plan
             8.1.1  Sampling and specimen collection
            Toxicological analyses
            Biomedical analyses
            Arterial blood gas analysis
            Haematological analyses
            Other (unspecified) analyses
             8.1.2  Storage of laboratory samples and specimens
            Toxicological analyses
            Biomedical analyses
            Arterial blood gas analysis
            Haematological analyses
            Other (unspecified) analyses
             8.1.3  Transport of laboratory samples and specimens
            Toxicological analyses
            Biomedical analyses
            Arterial blood gas analysis
            Haematological analyses
            Other (unspecified) analyses
        8.2  Toxicological Analyses and Their Interpretation
             8.2.1  Tests on toxic ingredient(s) of material
            Simple Qualitative Test(s)
            Advanced Qualitative Confirmation Test(s)
            Simple Quantitative Method(s)
            Advanced Quantitative Method(s)
             8.2.2  Tests for biological specimens
            Simple Qualitative Test(s)
            Advanced Qualitative Confirmation Test(s)
            Simple Quantitative Method(s)
            Advanced Quantitative Method(s)
            Other Dedicated Method(s)
             8.2.3  Interpretation of toxicological analyses
        8.3  Biomedical investigations and their interpretation
             8.3.1  Biochemical analysis
            Blood, plasma or serum
            Other fluids
             8.3.2  Arterial blood gas analyses
             8.3.3  Haematological analyses
             8.3.4  Interpretation of biomedical investigations
        8.4  Other biomed. investigations etc.
        8.5  Overall Interpretation etc.
        8.6  References
        9.1  Acute poisoning
             9.1.1  Ingestion
                    Acute poisoning may be characterized by the 
                    following signs and symptoms: hypotension with a 
                    remarkable fall in blood pressure and reflex 
                    tachycardia, possibly with syncope; myocardial and/or 
                    cerebral ischemia may follow; headache, flushing, 
                    nausea and vomiting, nasal congestion, conjunctival 
                    injection, edema of lower extremities.  Cardiovascular 
                    changes may include palpitations, exacerbation of 
                    coronary insufficiency, ischemic changes by 
                    electrocardiogram, angina pectoris, myocardial 
                    infarction and sudden death may occur. These signs and 
                    symptoms may appear from 30 minutes to 2 hours after 
                    ingestion, depending on the amount taken 
                    (Alarcon-Segovia et al, 1967; Smith & Ferguson, 
             9.1.2  Inhalation
                    No data available.
             9.1.3  Skin exposure
                    No data available 
             9.1.4  Eye contact
                    No data available. 
             9.1.5  Parenteral exposure
                    Depending on the dose, parenteral 
                    administration of hydralazine may result in more rapid 
                    and intense poisoning.  The signs and symptoms are 
                    expected to be the same as those observed after 
             9.1.6  Other
                    No data available.
        9.2  Chronic poisoning
             9.2.1  Ingestion
                    The hydralazine-induced lupus like syndrome is 
                    more commonly related to the chronic ingestion of the 
                    drug. (Alarcon-Segovia et al, 1967)  Asthma produced 
                    by continuous ingestion of hydralazine has been 
                    described. (Perrin et al, 1990)  Peripheral neuropathy 
                    with the symptoms of numbness, tingling, peripheral 
                    neuropathy may also occur.  Anemia has been described 
                    in a single report, as has anxiety, depression, and 
                    psychosis. (Alarcon-Segovia et al, 1967)
             9.2.2  Inhalation
                    No data available
             9.2.3  Skin exposure
                    No data available
             9.2.4  Eye contact
                    No data available
             9.2.5  Parenteral exposure
                    Would be expected to be similar to oral 
                    ingestion, however, no data is available.
             9.2.6  Other
                    No data available
        9.3  Course, prognosis, cause of death
             The clinical features of acute poisoning are mainly due 
             to the fall in blood pressure. The severity of symptoms is 
             determined by the amount ingested, time of exposure as well 
             as the interval between exposure  and the beginning of the 
             medical treatment of the poisoning.  These parameters should 
             be used to evaluate course and prognosis. Death may result 
             from shock, myocardial infarction, cerebral ischemia with 
             associated stroke, or renal failure.
        9.4  Systematic description of clinical effects
             9.4.1  Cardiovascular
                    Severe fall in blood pressure , reflex 
                    tachycardia, palpitations, myocardial ischemia, 
                    cerebral ischemia.
             9.4.2  Respiratory
                    A paradoxical effect, with an increase in 
                    pulmonary pressure, was observed in patients with 
                    primary pulmonary hypertension (Kronzon et al., 1982). 
                    One case of asthma has been described. (Perrin et al, 
             9.4.3  Neurological
                             Cerebral ischemia as a result of 
                             severe hypotension may be observed. Headache, 
                             numbness, and tingling may occur.
            Peripheral nervous system
                             Peripheral neuropathy can be 
                             produced by inhibition of pyridoxine enzyme 
            Autonomic nervous system
                             Hypotension may lead to sympathetic 
                             stimulation with reflex 
            Skeletal and smooth muscle
                             Myalgias have been described in a 
                             patient with hydralazine-induced hepatitis 
                             (Foster, 1980).  Arthritis may be seen in 
                             patients with lupus-like syndrome.
             9.4.4  Gastrointestinal
                    Nausea, vomiting and diarrhoea.
             9.4.5  Hepatic
                    Liver damage may be induced by hydralazine use 
                    and the clinical/laboratorial presentation has been 
                    described as transient granulomas (Jori & Peschle, 
                    1973) acute hepatitis (Bartoli et al., 1979; Barnett 
                    et al., 1980; Foster, 1980; Itoh et al., 1980), 
                    cholangitis (Myers & Augur, 1984), and cholestasis 
                    with pancytopenia (Stewart et al., 1981). 
                    Hydralazine-induced cholestatic jaundice was also 
                    described in a patient receiving oral and parenteral 
                    hydralazine after liver transplantation (Shaefer et 
                    al., 1989).  The granulomatous reactions produced by 
                    hydralazine are defined as noncaseating granulomas 
                    resembling sarcoidosis and may be also induced by 
                    other drugs (Lee, 1995).
                    A clastogenic effect was observed in liver cells 
                    (Martelli et al, 1995).
             9.4.6  Urinary
                             Hydralazine produced an increase on 
                             renin secretion when administered in patients 
                             with hypertension associated with unilateral 
                             renal stenosis (Huvos et al., 1965). This 
                             effect has been seen in normotensive 
                             individuals and patients with essential 
                             hypertension (Ueda et al., 1968).  Rapidly 
                             progressive glomerulonephritis has been 
                             observed in some patients after hydralazine 
                             use, which improves after hydralazine 
                             withdrawal (Bjorck et al, 1983). The clinical 
                             picture common to these patients was 
                             microscopic hematuria, anemia, and high ESR. 
                             The histological picture is characterized by 
                             segmental necrosis of the glomeruli and 
                             extracapillary proliferation. 
                             Immunoflourescence is positive.  Electron 
                             microscopy may reveal deposits in the 
                             glomeruli (Bjorck et al. 1985). Rapid and 
                             slow acetylators are affected with equal 
                             frequency and urine should be tested during 
                             hydralazine use irrespective to the 
                             acetylator phenotype, genotype or sex (Bjorck 
                             et el., 1985). Recent observations suggest 
                             that these autoimmune reactions can be also 
                             be characterized by antibodies to neutrophil 
                             granulocyte myeloperoxidase and elastase 
                             (Nessberger et al., 1991).  These and other 
                             antibodies can be used as markers of organ 
                             damage produced by  hydralazine (Almroth et 
                             al., 1992). 
                             No data available
             9.4.7  Endocrine and reproductive systems
                    Hydralazine increases renin secretion.
             9.4.8  Dermatological
                    Skin rash, vasculitis and extensive skin 
                    ulceration may be seen (Brooks & Pauley, 1980)
             9.4.9  Eye, ear, nose, throat: local effects
                    Retinal vasculitis can be seen in patients with 
                    lupus-like syndrome (Doherty et al., 1985).
             9.4.10 Haematological
                    Pancytopenia and neonatal 
             9.4.11 Immunological
                    A severe lupus-like syndrome may occur as a 
                    consequence of an immunological response to 
             9.4.12 Metabolic
           Acid-base disturbances
                             Lactic acidosis was observed in 
                             acute poisoning with tissue hypoperfusion 
                             (Smith & Ferguson, 1992).
           Fluid and electrolyte disturbances
                             Hypokalemia has been described 
                             during hydralazine acute poisoning (Smith & 
                             Ferguson, 1992).
                             Hypertension have been described by 
                             Webb and White (1980) as a paradoxical effect 
                             of hydralazine in a patient with hypertension 
                             secondary to renal stenosis.
             9.4.13 Allergic reactions
                    No data available
             9.4.14 Other clinical effects
                    No data available.
             9.4.15 Special risks
                    Risk factors for the development of the 
                    lupus-like syndrome include: 
                         slow acetylator Caucasian
                         long term use 
                         the development of antinuclear antibodies
                         coexistent autoimmune 
                         total dose greater than 100 g
        9.5  Other
             Hypotension with the consequences of tissue 
             hypoperfusion, the lupus-like syndrome, peripheral neuropathy 
             and hepatotoxicity are the primary  toxic effects of 
             hydralazine.  With acute poisonings, the concern is 
             cardiovascular and toxicity results from hypotension.
        9.6  Summary
        10.1 General principles
             Treatment should be based on the support of the 
             cardiovascular function to ensure adequate blood perfusion. 
             Patients with severe hypotension, myocardial and/or cerebral 
             ischemia should be admitted to an intensive care unit. 
             Monitor vital signs, cardiovascular and renal functions. 
             Assuming a Trendelenburg position with left lateral decubitus 
             can protect respiratory airways and endotracheal tube can be 
             adopted in unconscious patients.  Correct hypotension with 
             intravenous fluids and if necessary administer vasopressors. 
             Epinephrine and isoproterenol (adrenalin and isoprenaline) 
             should be avoided due to the risk of myocardial ischemia. 
             Gastrointestinal decontamination by emesis can be performed, 
             it is more efficient in the first 30 minutes after ingestion, 
             is controversial, and should be carefully considered 
             depending on the patient's condition and health care 
             facilities available.  Gastric lavage and the administration 
             of activated charcoal are also indicated.
        10.2 Relevant laboratory analyses
             10.2.1 Sample collection
                    Laboratory analysis is not considered 
                    clinically useful in the management of hydralazine 
                    poisoning.  Samples of blood and urine may be 
                    collected for analysis.
             10.2.2 Biomedical analysis
                    Total blood count, BUN, acid-base status, and 
                    electrolytes may be clinically useful.  Renal and 
                    liver function tests may be required if hypotension 
                    occurs, or there is clinical evidence of 
             10.2.3 Toxicological analysis
             10.2.4 Other investigations
                    The EKG is useful in acute poisoning to assess 
                    the possibility of myocardial ischemia or arrhythmias. 
                     The anti-nuclear antibodies may be of use in the 
                    lupus syndrome.
        10.3 Life supportive procedures etc.
             Maintenance of a clear airway and respiratory function; 
             evaluation of the cardiologic and haemodynamic status, 
             neurological and renal function conditions are mandatory. 
             Monitor blood pressure, heart rate, respiratory rate, and 
             EKG. To correct hypotension, patient should be placed in a 
             Trendelenburg position.  Isotonic saline solutions should be 
             administrated by intravenous infusion at standard maintenance 
             therapy.  For both adults and children, 100 ml/kg/24 hours is 
             administered for the first 10 kg of body weight, 50 ml/kg/24 
             hours for the next 10 kg of body weight, and 20 ml/kg/24 
             hours for each additional kilogram of body weight (Warren, 
             1991).  The standard maintenance solution recommended by most 
             clinicians after correction of hypotension is 5% 
             dextrose/0.2% (NaCl), with 10 to 20 mEq potassium chloride 
             added per liter.  The electrolytes can be adjusted according 
             to the blood measurements (Warren, 1991).
             If the patient is not responsive to these measures, 
             vasopressor treatment should be instituted  with dopamine, 
             followed by norepinephrine (noradrenalin) if required. 
             Dopamine is administered as follows: initial dose: 2.5 
             ug/kg/min constant IV infusion; titrate dose to clinical 
             response up to 15 ug/kg/min. Occasionally higher doses are 
             necessary. End points to evaluate treatment are cardiac 
             output, pulmonary wedge pressure, restoration of blood 
             pressure between normal range, and urine output. 
             Norepinephrine can be administered at a loading dose of 8-12 
             ug IV (child : 0.1-0.2 ug/kg/min). Titrate constant infusion 
             starting at 2 ug/min. End points are adequate blood pressure 
             and perfusion, cardiac arrhythmias, decreased urine output 
             (Saunders, 1991).
        10.4 Decontamination
             Attempts to decrease absorption from the GI tract may 
             be beneficial. Whether or not to induce emesis with ipecac 
             syrup should be carefully considered. Syrup of Ipecac is most 
             efficient if performed as soon as possible after ingestion. 
             For this reason it is mainly indicated in pediatric 
             ingestions managed immediately at home, following telephone 
             contact to the poison center. It can also be used in 
             emergency departments, mainly in children, soon after an 
             ingestion (Perrone et al., 1994).  Syrup of Ipecac can be 
             administered in a dose of 15 ml by oral route to children 
             (aged 1 to 12 years) and 30 ml in older children and adults. 
             Dose can be repeated twice if vomiting does not occur in the 
             next 30 min an addition of a small volume fluids may improve 
             the ipecac effect (Perrone et al., 1994; Howland, 1994). 
             Orogastric lavage can be indicated if patients presents to 
             the emergency department obtunded, unconscious, depressed gag 
             reflex, needing orotracheal intubation or when rapid 
             deterioration of the mental status and/or haemodynamics are 
             expected (Perrone et al.,1994).  It is performed with a 
             orogastric tube (adult: 36 to 42 French; Children: 24 to 32 
             French).  Fluids used for gastric lavage include lukewarm tap 
             water or saline (150 to 200 ml per wash; children of less 
             than five years 50 to 100 ml per wash), repeated until the 
             liquid return is clear. The material can be stored for 
             toxicological analysis, if needed.
             Activated charcoal can be safely used after performing 
             gastric lavage. As a rule, a dose of  0.5-1.0 g/kg is 
             appropriate as initial dose. Dose can be increased to 1.5-2.0 
             g/kg in massive ingestions (Smilkstein & Flomenbaun, 
        10.5 Elimination
             No evidence exists to suggest that measures to increase 
             urine output (forced diuresis) in hydralazine poisoning 
             would be useful.  Hydralazine is not significantly removed by 
             either hemodialysis or peritoneal dialysis (St. Peter & 
             Halstenson, 1994).
        10.6 Antidote treatment
             10.6.1 Adults
                    No specific antidote is available.
             10.6.2 Children
                    No specific antidote is available.
        10.7 Management discussion
             Administration of cathartics as well as whole-bowel 
             irrigation is of no proven value in the treatment of 
             hydralazine poisoning. Furthermore side effects as 
             hypocalcemia, hypophosphatemia and hypokalemia may follow 
             these procedures.
        11.1 Case reports from literature
             Smith and Ferguson (1992) reported a case of 
             hydralazine poisoning in an suicide attempt by a 27-years-old 
             woman mixed with ethanol intoxication.  Marked ECG St segment 
             depression was observed. The patient had mild hypotension and 
             acidemia. ECG was suggestive of myocardial ischemia. 
             Metabolic and ECG abnormalities were corrected by 
             conservative treatment in a intensive care unit.
             On the other hand, sudden withdrawal of hydralazine used 
             hronically for reduction of afterload in a patient 
             preipitated severe congestive heart failure (Black & Mehta, 
             Pericardial tamponade caused by the development of 
             pericarditis was described in a patient treated with 
             hydralazine, with clinical and laboratorial evidence of 
             lupus-like syndrome.  Treatment with prednisone produced 
             dramatic amelioration (Carey et al, 1973).
        11.2 Internally extracted data on cases
             The Poison Control Center of Rio de Janeiro recorded 8 
             cases of hydralazine exposure during an eight year period. 
             Five children and three adults ingested unknown amounts of 
             hydralazine, either by accident or as a suicide attempt, 
             respectively.  One patient presented with hypotension . No 
             deaths occurred.
        11.3 Internal cases
        12.1 Availability of antidotes
             No specific antidote is available.
        12.2 Specific preventive measures
             No data available.
        12.3 Other
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    14. AUTHOR(S), ETC.
        Jaderson Socrates Lima, MD; MSc. 
        Poison Control Center of Rio de Janeiro.
        University Hospital
        Federal University of Rio de Janeiro.
        Av. Brig. Trompovsky, s/n - SSn02
        21940-590 - Ilha do Fundao -
        Rio de Janeiro - Brazil.
        Reviewed at INTOX 9, Cardif, Wales, Sept, 1996

    See Also:
       Toxicological Abbreviations
       Hydralazine  (IARC Summary & Evaluation, Supplement7, 1987)