Description
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.
Chemical Properties
GUANETHIDINE SULFATE is colourless, crystalline powder
Originator
Ismelin,Ciba,US,1960
Uses
Guanethidine Monosulfate acts as an antihypertensive; antiglaucoma
Definition
ChEBI: A organic sulfate salt obtained from guanethidine and sulfuric acid in a 1:1 ratio.
Manufacturing Process
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).
brand name
Ismelin (Novartis).
Therapeutic Function
Antihypertensive
General Description
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.
Mechanism of action
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.
Pharmacokinetics
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.
Clinical Use
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.
Side effects
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.
Drug interactions
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.
References
[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
