HYDRALAZINE HCL

Chemistry - A phthalazine-derivative antihypertensive/vasodilating agent, hydralazine HCl occursas an odorless, white to off-white crystalline powder with a melting point between 270 - 280°C anda pKa of 7.3. One gram is soluble in approximately 25 ml of water or 500 ml of alcohol. Thecommercially available injection has a pH of 3.4 - 4. Hydralazine may also be known as
Hydrallazine.

Storage, Stability, Compatibility

Hydralazine tablets should be stored in tight, light resistantcontainers at room temperature. The injectable product should be stored at room temperature; avoidrefrigeration or freezing.
When mixed with most infusion solutions a color change can occur which does not necessarilyindicate a loss in potency (if occured over 8-12 hours).
Hydralazine is reported to be compatible with the following infusion solutions/drugs: dextrose-Ringer's combinations, dextrose-saline combinations, Ringer's injection, lactated Ringer's injection, sodium chloride solutions, and dobutamine HCl.
Hydralazine is reported to be incompatible with 10% dextrose or fructose and is reported to beincompatible with the following drugs: aminophylline, ampicillin sodium, chlorothiazide sodium, edetate calcium disodium, hydrocortisone sodium succinate, mephentermine sulfate, methohexitalsodium, phenobarbital sodium, verapamil HCl. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluents used and it is suggested to consult specialized referencesfor more specific information.

Pharmacology - HYDRALAZINE HCL

Hydralazine has direct action on vascular smooth muscle and reduces peripheralresistance and blood pressure. It is believed that hydralazine acts by altering cellular calciummetabolism in smooth muscle, thereby interfering with calcium movements and preventing theinitiation and maintenance of the contractile state. Hydralazine has more effect on arterioles than onveins.
In patients with CHF, hydralazine significantly increases cardiac output and decreases systemicvascular resistance. Cardiac rate may be slightly increased or unchanged, while blood pressure, pulmonary venous pressure, and right atrial pressure may be decreased or unchanged.
When used to treat hypertensive patients (without CHF), increased heart rate, cardiac output andstroke volume can be noted. The renin-angiotensin system can be activated with a resultant increasein sodium and water retention if not given with diuretics or sympathetic blocking drugs.
Parenteral hydralazine administration can cause respiratory stimulation.
Uses, Indications - Primary use of hydralazine at the present time in veterinary medicine is as anafterload reducer for the adjunctive treatment in CHF in small animals, particularly if mitral valveinsufficiency is the primary cause. It is also used to treat systemic hypertension.

Pharmacokinetics - HYDRALAZINE HCL

In dogs, hydralazine is rapidly absorbed after oral administration with anonset of action within one hour and peak effects at 3-5 hours. There is a high first-pass effect afteroral administration. The presence of food may enhance the bioavailability of hydralazine tablets.
Hydralazine is widely distributed in body tissues. In humans, approximately 85% of the drug inthe blood is bound to plasma proteins. Hydralazine crosses the placenta and very small amounts areexcreted into the milk.
Hydralazine is extensively metabolized in the liver and approximately 15% is excreted unchangedin the urine. The half-life in humans is usually 2-4 hours, but may be as long as 8 hours. Thepharmacokinetic parameters for this drug in veterinary species was not located, but the duration ofaction of hydralazine in dogs after oral administration is reportedly 11-13 hours.
Contraindications/Precautions - Hydralazine is contraindicated in patients hypersensitive to itand in those with coronary artery disease. The drug is listed as contraindicated in human patientswith mitral valvular rheumatic disease, but it has been recommended to be used in small animalpatients with mitral valve insufficiency. It is recommended not to use the drug in patients withhypovolemia or preexisting hypotension.
Hydralazine should be used with caution in patients with severe renal disease or intracerebral bleeding. In humans, a syndrome resembling systemic lupus erythematosis (SLE) has been documented after hydralazine use. While this syndrome has not been documented in veterinary patients, the drug should be used with caution in patients with preexisting autoimmune diseases.

Adverse Effects, Warnings

The most prevalent adverse effects seen in small animals include:hypotension, tachycardia, sodium/water retention (if not given concurrently with a diuretic), and GIdistress (vomiting, diarrhea). Initially, transient weakness and lethargy can be seen, but usuallyresolve in 3-4 days. Other adverse effects documented in humans which could occur, include an
SLE-like syndrome, lacrimation, conjunctivitis, peripheral neuritis, blood dyscrasias, urinaryretention, constipation and hypersensitivity reactions.
Tachycardias may be treated with concomitant digitalis treatment or a beta-blocker (Caution: betablockers may reduce cardiac performance).
Overdosage - Overdoses may be characterized by severe hypotension, tachycardia or other arrhythmias, skin flushing, and myocardial ischemia. Cardiovascular system support is the primarytreatment modality. Evacuate gastric contents and administer activated charcoal using standardprecautionary measures if the ingestion was recent and if cardiovascular status has been stabilized.
Treat shock using volume expanders without using pressor agents if possible. If a pressor agent isrequired to maintain blood pressure, the use of a minimally arrhythmogenic agent (e.g., phenylephrine or methoxamine) is recommended. Digitalis agents may be required. Monitor bloodpressure and renal function diligently.

Drug Interactions

Sympathomimetics (e.g., phenylpropanolamine) may cause additive tachycardia.
Hydralazine may enhance the oral absorption of propranolol (or other beta-blockers). Other antihypertensive agents may cause additive hypotension. The pressor response to epinephrine may be reduced by hydralazine.