645-43-2

Guanethidine is an antihypertensive compound that competes with norepinephrine for transport into presynaptic terminals of adrenergic neurons by the norepinephrine transporter. Once guanethidine has entered the nerve, it becomes concentrated in synaptic vesicles, depleting endogenous norepinephrine, and thus, reducing the release of norepinephrine in response to action potentials. Guanethidine’s actions are restricted to peripheral nerve terminals because its basic guanidine group does not allow passage through the blood brain barrier. Its use has been explored in the relief of chronic pain caused by complex regional pain syndrome.

GUANETHIDINE SULFATE is colourless, crystalline powder

Ismelin,Ciba,US,1960

Antihypertensive.

ChEBI: A organic sulfate salt obtained from guanethidine and sulfuric acid in a 1:1 ratio.

13.6 grams of chloroacetyl guanide is added while stirring to a solution of 22.6 grams of heptamethylene imine in 200 ml of benzene. After warming for 1 hour, and then cooling, the solution is filtered and the filtrate concentrated under reduced pressure. The residue, containing the 2-(1-N,N-heptamethylene-imino)-aceticacid guanide, is suspended in tetrahydrofuran and added to a refluxing solution of 6 grams of lithium aluminum hydride in tetrahydrofuran. After completion of the reaction, the excess of lithium aluminum hydride is decomposed by adding water, then aqueous sodium hydroxide. The solid material is filtered off, the filtrate is acidified with sulfuric acid and the 2-(1-N,N-heptamethylene-imino)-ethyl-guanidine sulfate can be recovered and recrystallized from aqueous ethanol, MP 276° to 281°C (with decomposition).

Ismelin (Novartis).

Antihypertensive

Guanethidinemonosulfate, [2-(hexahydro-1 (2H)-azocinyl)ethyl]guanidinesulfate (Ismelin sulfate), is a white, crystalline materialthat is very soluble in water. It was one of a series ofguanidine compounds prepared in the search for potent antitrypanosomalagents. There is an absence of CNS effects,such as depression, because the drug is highly polar anddoes not easily cross the blood-brain barrier. Guanethidinemonosulfate produces a gradual, prolonged fall in bloodpressure. Usually, 2 to 7 days of therapy are required beforethe peak effect is reached, and usually, this peak effectis maintained for 3 or 4 days. Then, if the drug is discontinued,the blood pressure returns to pretreatment levelsover a period of 1 to 3 weeks. Because of this slow onsetand prolonged duration of action, only a single daily doseis needed.

Guanethidine is an adrenergic neuronal blocking agent that produces a selective block of peripheral sympathetic pathways by replacing and depleting norepinephrine stores from adrenergic nerve endings, but not from the adrenal medulla. It prevents the release of norepinephrine from adrenergic nerve endings in response to sympathetic nerve stimulation. The chronic administration of guanethidine results in an increased sensitivity of these effector cells to catecholamines. Following the oral administration of usual doses of guanethidine, depletion of the catecholamine stores from adrenergic nerve endings occurs at a very slow rate, producing a more gradual and prolonged fall in systolic blood pressure than in diastolic pressure. Associated with the decrease in blood pressure is an increase in sodium and water retention and expansion of plasma volume (edema). If a diuretic is not administered concurrently with guanethidine, tolerance to the antihypertensive effect of the guanethidine during prolonged therapy can result.

Guanethidine is incompletely absorbed from the GI tract and is metabolized in the liver to several metabolites, including guanethidine N-oxide (from flavin mononucleotide). These metabolites of guanethidine are excreted in the urine and have less than 10% of its hypotensive activity. The amount of drug that reaches the systemic circulation after oral administration is highly variable from patient to patient and may range from 3 to 50% of a dose. Guanethidine accumulates in the neurons with an elimination half-life of 5 days.

Guanethidine monosulfate is metabolized by microsomalenzymes to 2-(6-carboxyhexylamino)ethylguanidine andguanethidine N-oxide . Both metabolites havevery weak antihypertensive properties. Guanethidine monosulfateis taken up by the amine pump located on theneuronal membrane and retained in the nerve, displacingnorepinephrine from its storage sites in the neuronal granules.The displaced norepinephrine is metabolized to homovanillicacid by mitochondrial MAO, depleting the nerveending of the neurotransmitter. The usefulness of guanethidinemonosulfate also resides in the fact that once it is takenup by the nerve, it produces a sympathetic blockade by inhibitingrelease of nonepinephrine that would occur on neuronalmembrane response to stimulation29 by the nerveaction potential. Guanethidine monosulfate stored in thegranules is released by the nerve action potential but hasvery low intrinsic activity for the adrenergic receptors on thepostjunctional membrane. Moderate doses for a prolongedperiod or large doses may produce undesirable side effectsby causing neuromuscular blockade and adrenergic nerveconduction blockade.

Adverse effects of guanethidine frequently are dose related, including dizziness, weakness, lassitude, and syncope resulting from postural or postexercise hypotension. A hot environment (i.e., a hot bath) may aggravate postural hypotension. Patients should be warned about possible orthostatic hypotension and about the effect of rapid postural changes on blood pressure (e.g., arising in the morning) that may cause fainting, especially during the initial period of dosage adjustment. Sodium retention (edema) usually is controlled by the coadministration of a diuretic.

Diuretics and other hypotensive drugs can potentiate the hypotensive effects of guanethidine. Reportedly, MAO inhibitors antagonize the hypotensive effect of guanethidine. Oral sympathomimetic, nasal decongestants, and other vasopressor agents should be used cautiously in patients receiving guanethidine, because guanethidine may potentiate their pressor effects. The mydriatic response to ophthalmic administration of phenylephrine is markedly increased in patients receiving guanethidine either ophthalmically or orally.
Tricyclic antidepressants and some phenothiazines block the uptake of guanethidine into adrenergic neurons and, thus, prevent the hypotensive activity of guanethidine. Orthostatic hypotension may be increased by concomitant administration of alcohol with guanethidine, and patients receiving guanethidine should be cautioned to limit alcohol intake.

Store at -20°C

[1] J G GERBER  A S N  C R Freed. Antihypertensive pharmacology.[J]. The Western journal of medicine, 1980, 132 5: 430-439.
[2] J. LIVINGSTONE R M A. Intravenous regional guanethidine blockade in the treatment of post-traumatic complex regional pain syndrome type 1 (algodystrophy) of the hand.[J]. Journal of Bone and Joint Surgery-british Volume, 2002, 48 1: 380-386. DOI: 10.1302/0301-620x.84b3.11901