Hydralazine

Hydralazine (apresoline) is a direct-acting smooth muscle relaxant used to treat hypertension by acting as a vasodilator primarily in arteries and arterioles. By relaxing vascular smooth muscle, vasodilators act to decrease peripheral resistance, thereby lowering blood pressure and decreasing afterload.

However, this only has a short term effect on blood pressure, as the system will reset to the previous, high blood pressure necessary to maintain pressure in the kidney necessary for natriuresis. The long term effect of antihypertensive drugs comes from their effects on the pressure natriuresis curve.

It belongs to the hydrazinophthalazine class of drugs.

Medical use
Hydralazine is not used as a primary drug for treating hypertension because it elicits a reflex sympathetic stimulation of the heart (the baroreceptor reflex). The sympathetic stimulation may increase heart rate and cardiac output, and in patients with coronary artery disease may cause angina pectoris or myocardial infarction. Hydralazine may also increase plasma renin concentration, resulting in fluid retention. In order to prevent these undesirable side-effects, hydralazine is usually prescribed in combination with a beta-blocker (e.g., propranolol) and a diuretic. In the UK, labetalol tends to be the first line beta-blocker.

Hydralazine is used to treat severe hypertension, but again, it is not a first-line therapy for essential hypertension. However, hydralazine is the first-line therapy for hypertension in pregnancy, with methyldopa. It has also been used successfully as a treatment for myelodysplastic syndrome in its capacity as a DNA methyltransferase inhibitor.

Pre-clinical research
Multiple sclerosis: Due to its ability to damage myelin nerve sheaths, acrolein may be a factor in the development of multiple sclerosis. Hydralazine, a known scavenger of acrolein, was found to reduce myelin damage and significantly improve behavioral outcomes in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis).

Side effects
Very common (>10% frequency) side effects include:
 * Headache
 * High heart rate
 * Palpitations

Common (1-10% frequency) side-effects include:


 * Flushing
 * Hypotension
 * Anginal symptoms
 * Joint ache
 * Positive test for ANF
 * Gastrointestinal disturbances
 * Diarrhoea
 * Nausea
 * Vomiting


 * Joint swelling
 * Muscle aches


 * Oedema (sodium and water retention)

Uncommon (0.1-1% frequency) side effects include:


 * Nasal congestion
 * Heart failure
 * Dizziness
 * Rash
 * Lupus-like syndrome
 * Protein in the urine
 * Increased plasma creatinine
 * Blood in the urine
 * Glomerulonephritis
 * Jaundice
 * Liver enlargement
 * Hepatitis
 * Agitation
 * Weight loss
 * Appetite loss
 * Anxiety
 * Blood dyscrasias


 * Increased lacrimation
 * Conjunctivitis
 * Nasal congestion
 * Dyspnoea
 * Pleural pain
 * Fever
 * Malaise
 * Hypersensitivity reactions

Rare (<0.1% frequency) side effects include:


 * Paradoxical pressor responses


 * Pins and needles (might be reversed by pyridoxine administration)
 * Peripheral neuritis
 * Polyneuritis
 * Tremor
 * Paralysed bowel
 * Acute kidney failure
 * Urinary retention
 * Depression
 * Hallucinations
 * Haemolytic anaemia
 * Leucocytosis
 * Lymphadenopathy
 * Pancytopenia
 * Splenomegaly
 * Agranulocytosis
 * Exophthalmos
 * Retroperitoneal fibrosis

Contraindications
Contraindications include:

mitral stenosis or constrictive pericarditis).
 * Known hypersensitivity to hydralazine or dihydralazine.
 * Idiopathic systemic lupus erythematosus (SLE) and related diseases.
 * Severe tachycardia and heart failure with a high cardiac output (e.g. in thyrotoxicosis).
 * Myocardial insufficiency due to mechanical obstruction (e.g. in the presence of aortic or
 * Isolated right-ventricular heart failure due to pulmonary hypertension (cor pulmonale).
 * Dissecting aortic aneurysm

Interactions
It may potentiate the antihypertensive effects of the following medications:


 * Vasodilators
 * Calcium antagonists
 * ACE inhibitors
 * Diuretics
 * Antihypertensives
 * Tricyclic antidepressants
 * Major tranquillisers
 * Ethanol (alcohol)
 * Diazoxide

Drugs subject to a strong first-pass effect such as beta-blockers may increase the bioavailability of hydralazine. Epinephrine (adrenaline)'s heart rate-accelerating effects are increased by hydralazine and hence may lead to toxicity.

Mechanism of action
Hydralazine binds to and activates gated potassium channels on vascular smooth muscle. The result is an efflux of potassium and a subsequent hyperpolarization of the cell. This prevents calcium-mediated activation and constriction of the smooth muscle, resulting in vasodilation. However, this induced vasodilation triggers the baroreflex resulting in tachycardia and vasoconstriction. Hydralazine is therefore not a great candidate for control of hypertension alone. It is often co-administered with a beta blocker to mitigate the effects of the baroreflex.

Hydralazine requires the endothelium to provide NO (nitric oxide. ) thus only provides the effects of NO in vivo with functional endothelium. It will not work to vasodilate in vitro in an isolated blood vessel.

Activation of hypoxia-inducible factors has been suggested as a mechanism.