Drugs List

Therapeutic Indications

Uses

Congestive heart failure (resistant to other treatment)
Hypertension - crisis
Moderate to severe hypertension: adjunctive treatment

Contraindications

Aortic stenosis
Cardiac failure secondary to pulmonary disorder
Congestive cardiac failure secondary to mechanical obstruction
Constrictive pericarditis
Dissecting aortic aneurysm
First trimester of pregnancy
Galactosaemia
Hereditary fructose intolerance
High output cardiac failure
Mitral stenosis
Porphyria
Second trimester of pregnancy
Severe tachycardia
Systemic lupus erythematosus
Thyrotoxicosis

Precautions and Warnings

Children under 18 years
Breastfeeding
Cerebrovascular disorder
Glucose-galactose malabsorption syndrome
Hepatic impairment
Ischaemic heart disease
Lactose intolerance
Recent myocardial infarction (until stabilised)
Renal impairment - creatinine clearance below 30 ml/minute
Slow acetylator status
Third trimester of pregnancy

Dose adjustment may be necessary in patients with hepatic impairment
Reduce dose in patients with creatinine clearance below 30ml/min
Advise ability to drive/operate machinery may be affected by side effects
Some formulations contain lactose
Some formulations contain sucrose
Assess risk/benefit of treatment if symptoms of peripheral neuropathy occur
Breastfeeding: Monitor infant for systemic effects of treating the mother
Monitor ANF and urine every 6 months during long term therapy
Monitor closely patient with a history of congestive cardiac failure
Monitor patients on prolonged therapy
Avoid abrupt withdrawal
Discontinue and investigate if symptoms of lupus-like syndrome develop
Discontinue if blood dyscrasia develops
Discontinue if fever occurs
Discontinue treatment if rash occurs
Maintain treatment at the lowest effective dose
Advise patient not to take NSAIDs unless advised by clinician
Hypotensive effects may be potentiated by alcohol

In patients with coronary artery disease, hydralazine should only be given with concurrent beta-blockers or other suitable sympatholytic agents. Patients should be started on beta-blockers a few days before hydralazine therapy commences.

Patients receiving hydralazine may experience a reduction in blood pressure when undergoing surgery. In these situations, adrenaline should not be administered to correct the hypotension as this will enhance the cardiac-accelerating properties of hydralazine.

Prolonged treatment (usually for more than 6 months) may provoke a systemic lupus erythematous (SLE) like syndrome, especially with doses in excess of 100 mg daily. Primary symptoms are likely to be similar to rheumatoid arthritis (arthralgia, fever, anaemia, leucopenia, thrombocytopenia and rash) and are reversible after withdrawal of the drug. In its more severe form it resembles acute SLE (similar manifestations as the milder form plus pleurisy, pleural effusions and pericarditis), and in rare cases renal and ocular involvement have been reported. Early detection and a timely diagnosis with appropriate therapy (i.e. treatment discontinuation and possibly long term treatment with corticosteroids may be required to reverse these changes) are of the utmost importance in this life-threatening illness to prevent more severe complications, which may sometimes be fatal.

Slow acetylators and women have an increased risk of developing a SLE-like syndrome and therefore the dosage should be kept below 100 mg daily where possible and careful monitoring for signs and symptoms suggestive of the syndrome. If symptoms of SLE-like syndrome develop, hydralazine should be gradually withdrawn.

The patient's acetylator status should be monitored before daily doses exceeding 100 mg are recommended.

Rapid acetylators often respond inadequately even to doses of 100 mg daily and therefore the dose can be raised with only a slightly increased risk of SLE like syndrome.

Microhaematuria and/or proteinuria, especially in conjunction with positive ANF titres may indicate the development of immune-complex glomerulonephritis associated with SLE-like syndrome. If these symptoms develop, hydralazine should be withdrawn immediately.

If the discontinuation of hydralazine is necessary, the drug should be withdrawn gradually, except in serious situations such as SLE-like syndrome or blood dyscrasia. This gradual withdrawal reduces the risk of cardiac failure occurring or worsening.

Pregnancy and Lactation

Pregnancy

Hydralazine is contraindicated in the first and second trimesters of pregnancy.

Use hydralazine with caution in the third trimester of pregnancy

The manufacturers state that use of hydralazine in pregnancy before the third trimester should be avoided, but the drug may be considered in later pregnancy if there are no safer alternatives or when the disease itself carries serious risks for the mother or child, e.g. pre-eclampsia and/or eclampsia.

Hydralazine readily crosses the placenta. Serum concentrations in the foetus are equal to or greater than those in the mother (Briggs, 2011).

Only use in later pregnancy if there is no alternative. Caution is advised although there have been few adverse effects in human pregnancy reported to date. Experience in the third trimester is extensive. However, neonatal thrombocytopaenia and bleeding secondary to maternal ingestion of hydralazine has been reported infants of mothers who had consumed hydralazine daily throughout the third trimester. Other reports of symptomatic neonatal thrombocytopenia, leucopenia, petechial bleeding and haematomas have been reported after prenatal exposure (Schaefer, 2007). Therefore, chronic use should be reserved for refractory patients.

There is a possibility that systemic vasodilation may be accompanied by decreased placental perfusion resulting in foetal/neonatal bradycardia (Schaefer, 2007).

Hydralazine has been found to be teratogenic in mice, producing cleft palate and other bony malformations in doses ranging from 20 to 120 mg/kg (20 to 30 times the maximum human daily dose. It was found not to be teratogenic in rats or rabbits.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Use hydralazine with caution in breastfeeding.

Where hydralazine treatment is essential for breastfeeding mothers, they may receive therapy and the infant should be observed for possible adverse effects of hypotension, sedation and weakness.

Hydralazine is excreted into breastmilk and has been reported to achieve a milk: plasma ratio of 1.4. So far there are no reports that have shown adverse effects on the infant. Caution is advised and if used during breastfeeding, infants should be monitored. Schaefer (2007) concludes that hydralazine is among the antihypertensives of choice during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abnormal liver function
Acute renal failure
Agitation
Agranulocytosis
Anaemia
Anginal pain
Anorexia
Anxiety
Arthralgia
Blood disorders
Cardiac failure
Conjunctivitis
Depression
Diarrhoea
Dizziness
Dyspnoea
Eosinophilia
Exophthalmos
Fever
Fluid retention
Flushing
Gastro-intestinal disturbances
Glomerulonephritis
Haematuria
Haemolytic anaemia
Hallucinations
Headache
Hepatitis
Hepatomegaly
Hypersensitivity reactions
Hypertension (paradoxical)
Hypotension
Increased lacrimation
Jaundice
Joint swelling
Leucocytosis
Leucopenia
Lupus erythematosus-like syndrome
Lymphadenopathy
Malaise
Myalgia
Nasal congestion
Nausea
Neutropenia
Ocular changes
Oedema
Orthostatic hypotension
Palpitations
Pancytopenia
Paraesthesia
Paralytic ileus
Peripheral neuritis
Pleuritic pain
Polyneuritis
Proteinuria
Pruritus
Purpura
Rash
Serum creatinine increased
Splenomegaly
Tachycardia
Thrombocytopenia
Thrombocytopenic purpura
Urinary retention
Urticaria
Vasculitis
Vomiting
Weight loss

Presentation

Oral formulations of hydralazine

Drugs List

Therapeutic Indications

Uses

Congestive heart failure (resistant to other treatment)
Hypertension - crisis
Moderate to severe hypertension: adjunctive treatment

Dosage

Adults

Elderly

Children

Neonates

Patients with Renal Impairment

Patients with Hepatic Impairment

Contraindications

Aortic stenosis
Cardiac failure secondary to pulmonary disorder
Congestive cardiac failure secondary to mechanical obstruction
Constrictive pericarditis
Dissecting aortic aneurysm
First trimester of pregnancy
Galactosaemia
Hereditary fructose intolerance
High output cardiac failure
Mitral stenosis
Porphyria
Second trimester of pregnancy
Severe tachycardia
Systemic lupus erythematosus
Thyrotoxicosis

Precautions and Warnings

Children under 18 years
Breastfeeding
Cerebrovascular disorder
Glucose-galactose malabsorption syndrome
Hepatic impairment
Ischaemic heart disease
Lactose intolerance
Recent myocardial infarction (until stabilised)
Renal impairment - creatinine clearance below 30 ml/minute
Slow acetylator status
Third trimester of pregnancy

Dose adjustment may be necessary in patients with hepatic impairment
Reduce dose in patients with creatinine clearance below 30ml/min
Advise ability to drive/operate machinery may be affected by side effects
Some formulations contain lactose
Some formulations contain sucrose
Assess risk/benefit of treatment if symptoms of peripheral neuropathy occur
Breastfeeding: Monitor infant for systemic effects of treating the mother
Monitor ANF and urine every 6 months during long term therapy
Monitor closely patient with a history of congestive cardiac failure
Monitor patients on prolonged therapy
Avoid abrupt withdrawal
Discontinue and investigate if symptoms of lupus-like syndrome develop
Discontinue if blood dyscrasia develops
Discontinue if fever occurs
Discontinue treatment if rash occurs
Maintain treatment at the lowest effective dose
Advise patient not to take NSAIDs unless advised by clinician
Hypotensive effects may be potentiated by alcohol

In patients with coronary artery disease, hydralazine should only be given with concurrent beta-blockers or other suitable sympatholytic agents. Patients should be started on beta-blockers a few days before hydralazine therapy commences.

Patients receiving hydralazine may experience a reduction in blood pressure when undergoing surgery. In these situations, adrenaline should not be administered to correct the hypotension as this will enhance the cardiac-accelerating properties of hydralazine.

Prolonged treatment (usually for more than 6 months) may provoke a systemic lupus erythematous (SLE) like syndrome, especially with doses in excess of 100 mg daily. Primary symptoms are likely to be similar to rheumatoid arthritis (arthralgia, fever, anaemia, leucopenia, thrombocytopenia and rash) and are reversible after withdrawal of the drug. In its more severe form it resembles acute SLE (similar manifestations as the milder form plus pleurisy, pleural effusions and pericarditis), and in rare cases renal and ocular involvement have been reported. Early detection and a timely diagnosis with appropriate therapy (i.e. treatment discontinuation and possibly long term treatment with corticosteroids may be required to reverse these changes) are of the utmost importance in this life-threatening illness to prevent more severe complications, which may sometimes be fatal.

Slow acetylators and women have an increased risk of developing a SLE-like syndrome and therefore the dosage should be kept below 100 mg daily where possible and careful monitoring for signs and symptoms suggestive of the syndrome. If symptoms of SLE-like syndrome develop, hydralazine should be gradually withdrawn.

The patient's acetylator status should be monitored before daily doses exceeding 100 mg are recommended.

Rapid acetylators often respond inadequately even to doses of 100 mg daily and therefore the dose can be raised with only a slightly increased risk of SLE like syndrome.

Microhaematuria and/or proteinuria, especially in conjunction with positive ANF titres may indicate the development of immune-complex glomerulonephritis associated with SLE-like syndrome. If these symptoms develop, hydralazine should be withdrawn immediately.

If the discontinuation of hydralazine is necessary, the drug should be withdrawn gradually, except in serious situations such as SLE-like syndrome or blood dyscrasia. This gradual withdrawal reduces the risk of cardiac failure occurring or worsening.

Pregnancy and Lactation

Pregnancy

Hydralazine is contraindicated in the first and second trimesters of pregnancy.

Use hydralazine with caution in the third trimester of pregnancy

The manufacturers state that use of hydralazine in pregnancy before the third trimester should be avoided, but the drug may be considered in later pregnancy if there are no safer alternatives or when the disease itself carries serious risks for the mother or child, e.g. pre-eclampsia and/or eclampsia.

Hydralazine readily crosses the placenta. Serum concentrations in the foetus are equal to or greater than those in the mother (Briggs, 2011).

Only use in later pregnancy if there is no alternative. Caution is advised although there have been few adverse effects in human pregnancy reported to date. Experience in the third trimester is extensive. However, neonatal thrombocytopaenia and bleeding secondary to maternal ingestion of hydralazine has been reported infants of mothers who had consumed hydralazine daily throughout the third trimester. Other reports of symptomatic neonatal thrombocytopenia, leucopenia, petechial bleeding and haematomas have been reported after prenatal exposure (Schaefer, 2007). Therefore, chronic use should be reserved for refractory patients.

There is a possibility that systemic vasodilation may be accompanied by decreased placental perfusion resulting in foetal/neonatal bradycardia (Schaefer, 2007).

Hydralazine has been found to be teratogenic in mice, producing cleft palate and other bony malformations in doses ranging from 20 to 120 mg/kg (20 to 30 times the maximum human daily dose. It was found not to be teratogenic in rats or rabbits.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Use hydralazine with caution in breastfeeding.

Where hydralazine treatment is essential for breastfeeding mothers, they may receive therapy and the infant should be observed for possible adverse effects of hypotension, sedation and weakness.

Hydralazine is excreted into breastmilk and has been reported to achieve a milk: plasma ratio of 1.4. So far there are no reports that have shown adverse effects on the infant. Caution is advised and if used during breastfeeding, infants should be monitored. Schaefer (2007) concludes that hydralazine is among the antihypertensives of choice during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abnormal liver function
Acute renal failure
Agitation
Agranulocytosis
Anaemia
Anginal pain
Anorexia
Anxiety
Arthralgia
Blood disorders
Cardiac failure
Conjunctivitis
Depression
Diarrhoea
Dizziness
Dyspnoea
Eosinophilia
Exophthalmos
Fever
Fluid retention
Flushing
Gastro-intestinal disturbances
Glomerulonephritis
Haematuria
Haemolytic anaemia
Hallucinations
Headache
Hepatitis
Hepatomegaly
Hypersensitivity reactions
Hypertension (paradoxical)
Hypotension
Increased lacrimation
Jaundice
Joint swelling
Leucocytosis
Leucopenia
Lupus erythematosus-like syndrome
Lymphadenopathy
Malaise
Myalgia
Nasal congestion
Nausea
Neutropenia
Ocular changes
Oedema
Orthostatic hypotension
Palpitations
Pancytopenia
Paraesthesia
Paralytic ileus
Peripheral neuritis
Pleuritic pain
Polyneuritis
Proteinuria
Pruritus
Purpura
Rash
Serum creatinine increased
Splenomegaly
Tachycardia
Thrombocytopenia
Thrombocytopenic purpura
Urinary retention
Urticaria
Vasculitis
Vomiting
Weight loss

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review: January 2016

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

Summary of Product Characteristics: Apresoline Tablets 25mg. Amdipharm Mercury Company Ltd. Revised September 2013.

Summary of Product Characteristics: Hydralazine Tablets BP 25mg. Actavis UK Ltd. Revised January 2015.
Summary of Product Characteristics: Hydralazine Tablets BP 50mg. Actavis UK Ltd. Revised January 2015.

The Renal Drug Handbook. Fourth Edition (2014) ed. Ashley, C and Dunleavy, A, Radcliffe Publishing Ltd, London.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 25 August 2017

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~MM5Uti:1
Hydralazine. Last revised: 10 March, 2015
Last accessed: 20 January, 2016