Guanadrel Sulfate

Description

Guanadrel sulfate is an antihypertensive belonging to the class of adrenergic neuron blocking drugs. It diminishes sympathetic vasoconstriction by inhibiting norepinephrine storage and release from neuronal storage sites. It appears similar in effectiveness and side effect profile to its structural relative guanethidine.

Originator

Cutter (USA)

Manufacturing Process

A mixture of 10.5 g of 1,4-dioxaspiro[4.5]decane-2-methylamine and 8.6 g of 2-methyl-2-thiopseudourea sulfate in 40 ml of water was heated on the steam bath for 4 hours during which 2.0 g of methylmercaptan was collected in a dry ice bath connected to the reaction flask through a water cooled reflux condenser. The reaction mixture was then evaporated at 15 mm pressure to a solid residue which was then dissolved in 80 ml of 50/50 methanol-ethanol. The solution was filtered and evaporated to approximately 50 ml volume and allowed to cool and crystallize, giving a crop melting at 213.5°C to 215°C of 1,4-dioxaspiro[4.5]decan-2-ylmethyl)-guanidine sulfate.

brand name

HYLOREL

Therapeutic Function

Antihypertensive

Mechanism of action

Guanadrel, like guanethidine, produces a selective block of efferent, peripheral sympathetic pathways by replacing and depleting norepinephrine stores from adrenergic nerve endings, thus preventing the release of norepinephrine from adrenergic nerve endings in response to sympathetic nerve stimulation. Unlike guanethidine, it does not release norepinephrine from the adrenal medulla and reportedly depletes norepinephrine stores in the GI tract to a lesser extent than guanethidine does. Guanadrel decreases systolic blood pressure more than diastolic blood pressure.

Pharmacokinetics

Guanadrel, unlike guanethidine, is rapidly and almost completely absorbed following oral administration. Following oral administration, its peak plasma concentrations usually are achieved in approximately 2 hours, and its hypotensive effect usually has an onset of 0.5 to 2.0 hours, with peak activity at 4 to 6 hours and a duration of action of 4 to 14 hours. Approximately 20% of guanadrel is bound to plasma proteins, and little, if any, of the drug crosses the blood-brain barrier or distributes into the eye. Guanadrel has a plasma half-life of approximately 2 hours and an elimination half-life of approximately 10 to 12 hours in patients with normal renal function. Approximately 40 to 50% of guanadrel is metabolized in the liver to 2,3-dihydroxypropylguanidine and several unidentified metabolites, which are excreted principally in the urine. Unlike guanethidine, approximately 85% of an oral dose of the drug is excreted in the urine within 24 hours, with 40 to 50% of the dose excreted in the urine unchanged. In patients with impaired renal function, the half-life of guanadrel is prolonged, and apparent total body clearance and renal clearances are decreased.

Clinical Use

Guanadrel is used in the management of hypertension, and its efficacy is similar to that of guanethidine. Guanadrel generally is considered to be a step 2 drug and is reserved for patients who fail to respond to therapy with a step 1 drug or for cases requiring more prompt or aggressive therapy. Postural and postexercise hypotension is common in patients receiving guanadrel, and it also is likely that heat-induced vasodilation will augment its hypotensive effect. There is a possibility that geriatric patients may not tolerate the postural hypotensive effects of guanadrel. Being a peripheral adrenergic neuron blocking drug, guanadrel shares the toxic potentials of guanethidine, and the usual precautions of this drug should be observed.

Side Effects

Overall, the frequency of adverse effects produced by guanadrel is similar or less than those produced by guanethidine and by methyldopa. In patients with impaired renal function, the elimination half-life of unmetabolized guanadrel is prolonged and its clearance decreased, thus increasing the incidence of adverse effects if the usual dosage is maintained in these patients.

Drug interactions

Being a peripheral adrenergic neuron blocking drug, guanadrel shares the same potential for drug interactions as guanethidine, and the usual precautions of this drug should be observed.