1- Hydrazinophtalazine Hydrochloride
Cloridrato de Hidralazina
1.4 Identification numbers
1.4.1 CAS number
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
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
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. PHYSICO-CHEMICAL PROPERTIES
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
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
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
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
A syrup of hydralazine hydrochloride can be prepared
extemporaneously, providing that the guideline
described by Alexander et al (1993) are
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.
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
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).
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)
With the exception of a history of systemic lupus
erythematosus there are no absolute contraindications to
hydralazine use if combined with an adrenergic blocker
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. ROUTES OF ENTRY
Oral ingestion is most likely the most common route of
No data available.
No data available.
No data available.
Poisoning may occur by intravenous administration.
Parenteral therapy is recommended only when the oral route is
No data available.
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 &
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)
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
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. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
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
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).
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).
7.2.1 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
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).
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.,
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).
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
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. TOXICOLOGICAL ANALYSES ETC.
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
220.127.116.11 Toxicological analyses
18.104.22.168 Biomedical analyses
22.214.171.124 Arterial blood gas analysis
126.96.36.199 Haematological analyses
188.8.131.52 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
184.108.40.206 Toxicological analyses
220.127.116.11 Biomedical analyses
18.104.22.168 Arterial blood gas analysis
22.214.171.124 Haematological analyses
126.96.36.199 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
188.8.131.52 Toxicological analyses
184.108.40.206 Biomedical analyses
220.127.116.11 Arterial blood gas analysis
18.104.22.168 Haematological analyses
22.214.171.124 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
126.96.36.199 Simple Qualitative Test(s)
188.8.131.52 Advanced Qualitative Confirmation Test(s)
184.108.40.206 Simple Quantitative Method(s)
220.127.116.11 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
18.104.22.168 Simple Qualitative Test(s)
22.214.171.124 Advanced Qualitative Confirmation Test(s)
126.96.36.199 Simple Quantitative Method(s)
188.8.131.52 Advanced Quantitative Method(s)
184.108.40.206 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
220.127.116.11 Blood, plasma or serum
18.104.22.168 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.
9. CLINICAL EFFECTS
9.1 Acute poisoning
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,
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
No data available.
9.2 Chronic poisoning
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)
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.
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
Severe fall in blood pressure , reflex
tachycardia, palpitations, myocardial ischemia,
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,
Cerebral ischemia as a result of
severe hypotension may be observed. Headache,
numbness, and tingling may occur.
22.214.171.124 Peripheral nervous system
Peripheral neuropathy can be
produced by inhibition of pyridoxine enzyme
126.96.36.199 Autonomic nervous system
Hypotension may lead to sympathetic
stimulation with reflex
188.8.131.52 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.
Nausea, vomiting and diarrhoea.
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).
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
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
No data available
9.4.7 Endocrine and reproductive systems
Hydralazine increases renin secretion.
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).
Pancytopenia and neonatal
A severe lupus-like syndrome may occur as a
consequence of an immunological response to
184.108.40.206 Acid-base disturbances
Lactic acidosis was observed in
acute poisoning with tissue hypoperfusion
(Smith & Ferguson, 1992).
220.127.116.11 Fluid and electrolyte disturbances
Hypokalemia has been described
during hydralazine acute poisoning (Smith &
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
total dose greater than 100 g
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.
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
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
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,
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 &
10.6 Antidote treatment
No specific antidote is available.
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
11. ILLUSTRATIVE CASES
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
11.3 Internal cases
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
No specific antidote is available.
12.2 Specific preventive measures
No data available.
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14. AUTHOR(S), ETC.
Jaderson Socrates Lima, MD; MSc.
Poison Control Center of Rio de Janeiro.
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