55-65-2

Guanethidine is used for severe hypertension when the use of the more generally accepted drugs turns out to be unsuccessful. It is a powerful, long-lasting antihypertensive drug; however, it affects a patient’s blood pressure only in the orthostatic position, and not when lying down.
Guanethidine is a very powerful and long-lasting drug, and its action often lasts 2–3 days after its use has been stopped.

Ismelin,Ciba,US,1960

Antihypertensive.

ChEBI: A member of the class of guanidines in which one of the hydrogens of the amino group has been replaced by a 2-azocan-1-ylethyl group.

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

Guanethidine (Ismelin) is a powerful antihypertensive agent that is quite effective in the treatment of moderate to severe hypertension. It is most frequently used in the treatment of severe hypertension that is resistant to other agents.
Guanethidine exerts its effects at peripheral sympathetic nerve endings following its active transport into the nerve varicosities by the neuronal amine transport system. This is the same uptake system that transports norepinephrine into the varicosity).The accumulation of guanethidine in adrenergic neurons, through an as yet unexplained mechanism, disrupts the process by which action potentials trigger the release of stored norepinephrine and other cotransmitters from nerve terminals. It is this action of guanethidine that is primarily responsible for its antihypertensive properties. Parasympathetic function is not altered, a fact that distinguishes guanethidine from the ganglionic blocking agent.
Guanethidine is suitable for oral use, and this is its usual route of administration. However, absorption from the gastrointestinal tract is variable. The half-life of guanethidine is 5 days, with about one-seventh of the total administered dose eliminated per day. The slow elimination contributes to the cumulative and prolonged effects of the drug.
Guanethidine reduces blood pressure by its ability to diminish vascular tone; both the arterial and venous sides of the circulatory system are involved. The resulting venous pooling contributes to orthostatic hypotension, a prominent feature of guanethidine treatment. The reduction in blood pressure is more prominent when the patient is standing than recumbent.

Guanethidine or guanethidinesulfate [C₁₀H₂₂N₄·H₂SO₄].

Guanethidinehas been classified traditionally as an adrenergic blockingagent because it can prevent the release of norepinephrinefrom postganglionic neurons in response to adrenergic stimulation.Guanethidine and other compounds discussed in thissection have other actions on catecholamine metabolism andcan cause significant depletion of these amines in adrenergicneurons. They do not interfere with release of epinephrinefrom the adrenal medulla.

Unlike adrenoblockers, guanethidine does not act on effector cells. It acts on branched ends of sympathetic peripheral nerve fibers and permeates into the neuron by the same mechanism of reverse uptake that returns norepinephrine from the synaptic cleft to neuron endings. Inside the neuron, guanethidine accumulates and competes with norepinephrine for storage space as granules. With an increase in guanethidine concentration, norepinephrine is replaced and thus the quantity of neurotransmitters capable of being released is reduced. In response to stimulation, the nerve may release guanethidine, which, however, is not an adrenergic receptor stimulant. In addition to this disturbance and the presence of stores of catecholamines in adrenergic nerve endings, guanethidine also acts on the stores of catecholamines in organs such as the heart, spleen, and aorta.Since it does not pass through the blood–brain barrier, it does not act on the central sympathetic neurons.

Guanethidine may aggravate congestive heart failure or actually precipitate failure in patients with marginal cardiac reserve, owing to its ability to produce vascular volume expansion, edema, and a reduced effectiveness of sympathetic cardiac stimulation.
Guanethidine is contraindicated in patients with pheochromocytoma because the drug may release catecholamines from the tumor. The concomitant use of monoamine oxidase (MAO) inhibitors and guanethidine is also to be avoided, since this combined drug treatment eliminates two of the principal mechanisms for terminating the actions of the catecholamines and certain other adrenomimetic drugs, that is, biotransformation and neuronal uptake. Dangerously high concentrations of catecholamines at receptor sites are possible.

Guanethidine, |?-(1-azacyclooctyl)ethylguanidine (12.3.4), is synthesized in the following straightforward manner. Azocine is alkylated by chloracetonitrile, which forms 1-azocinylacetonitrile (12.3.2), which is reduced by lithium aluminum hydride into 1-(2-aminoethyl)azocine (12.3.3). Reacting this with S-methylthiourea gives guanethidine (12.3.4) [77¨C79].