Guanethidine

Guanethidine is an antihypertensive agent belonging to the adrenergic neuron blocker class.

Guanethidine is approved for the treatment of moderate and severe hypertension, either alone or as an adjunct. It is also used for the treatment of renal hypertension including that secondary to pyelonephritis, renal amyloidosis, and renal artery stenosis.

Guanethidine appeared to be absorbed continuously over a period of at least 12 hours after oral administration. Following its absorption, guanethidine is metabolized to the guanethidine N-oxide and 2-(6-carboxyhexylamino) ethyl guanidine. These metabolites have less than one-tenth of the pharmacological activity of guanethidine. The metabolism of guanethidine was much more extensive after oral than after intramuscular administration, suggesting that an appreciable fraction of absorbed drug was metabolized during its first pass through the liver.

Guanethidine is converted by the liver to three metabolites, which are excreted in the urine.

The common side effects associated with Guanethidine include nausea, vomiting, diarrhea, loss of appetite; headache, dizziness, drowsiness; breast tenderness or swelling; itching or rash; stuffy nose, nosebleeds, etc.

Guanethidine is available in the form of dosage forms such as tablets and injection.

Guanethidine is available in India, China, UK, Sweden, Australia.

• Guanethidine, belonging to the adrenergic neuron blocker, acts as an antihypertensive agent. Guanethidine works by controlling nerve impulses along certain nerve pathways. As a result, it relaxes blood vessels so that blood passes through them more easily. This helps to lower blood pressure.
• Guanethidine is transported across sympathetic nerve membrane by the same mechanism that transports norepinephrine itself, and uptake is essential for drug's action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine. It may also inhibit the release of granules by decreasing norepinephrine.
• The onset of action of Guanethidine occurs within 30 minutes.
• The Duration of Action for Guanethidine in the body is 9-10 days.
• The Tmax was found within 1-2 hours following the administration of Guanethidine and the Cmax was 3.6 + 1.6 ng/ml/hr.

Guanethidine is available in the form of tablets and Injections

• Tablets:

Guanethidine tablets are to be swallowed whole with water. Guanethidine comes as a tablet to be taken by mouth. It is usually taken two times a day.

• Injection:

Hold it firmly about an inch away (2.54 cm) from muscle. In the other hand, hold the needle at a 90-degree angle and insert it quickly and deeply enough to penetrate your muscle. Inject the medication. If there is no blood in the syringe, push on the plunger to inject the medication slowly into the muscle.

Guanethidine is an antihypertensive agent belonging to the adrenergic neuron blocker class.

Guanethidine is approved for the treatment of moderate and severe hypertension, either alone or as an adjunct. It is also used for the treatment of renal hypertension including that secondary to pyelonephritis, renal amyloidosis, and renal artery stenosis.

Guanethidine acts at the sympathetic neuroeffector junction by inhibiting or interfering with the release and/or distribution of norepinephrine. Guanethidine at the nerve terminal blocks the release of noradrenaline in response to an action potential. In contrast to ganglionic blocking agents, Guanethidine suppresses equally the responses mediated by alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade.

Guanethidine is approved for use in the following clinical indications.

• Hypertension:

Use alone or as an adjunct to treat severe hypertension.

Although not approved there have been several off-label indication documented for Guanethidine, which include treatment in renal hypertension, including that secondary to pyelonephritis, renal amyloidosis, and renal artery stenosis.

Guanethidine is available in the form of tablets and injections.

• Hypertension:

Initial dose: 10 mg orally once a day (25 mg to 50 mg if hospitalized).

Maintenance dose: 25 mg to 50 mg orally once a day.

• Hypertension Emergency:

Loading dose: 25 mg to 50 mg orally 3 times a day at 6 hour intervals over 1 to 3 days. The nighttime dose is omitted.

• Ambulatory Patients:

Initial doses should be small (10 mg) and increased gradually, depending on the patient response. Guanethidine monosulfate has a long duration of action; therefore, dosage increases should not be made more often than every 5-7 days unless the patient is hospitalized. Blood pressure should be measured in the supine position, after standing for 10 minutes, and immediately after exercise if feasible. Dosage may be increased only if there has been no reduce in standing blood pressure from previous levels. The average daily dose is 25-50 mg; only one dose per day is usually required.

Guanethidine can be administered orally before/ after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Guanethidine is available in the form of tablets and injection.

Guanethidine is approved for the treatment of moderate and severe hypertension, either alone or as an adjunct. It is also used for the treatment of renal hypertension, including that secondary to pyelonephritis, renal amyloidosis, and renal artery stenosis.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per patient requirements

Guanethidine may be contraindicated in the following:

Phaeochromocytoma, heart failure unrelated to hypertension. Concomitant use or within two weeks of MAOIs.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

Guanethidine is a potent drug, and its use can lead to the disturbing and serious clinical problems. Before prescribing, physicians should familiarize themselves with details of its use and warn patients not to deviate from instructions.

Precautions:

General:

Dosage requirements may be reduced in the presence of a fever.

• Special care should be exercised when treating patients with a history of bronchial asthma; asthmatic patients are more apt to be hypersensitive to catecholamine depletion, and their condition may be aggravated.
• The effects of guanethidine monosulfate are cumulative over long periods; initial doses should be small and increased gradually in small increments.
• Guanethidine monosulfate should be used very cautiously in hypertensive patients with: renal disease and nitrogen retention or rising BUN levels, since decreased blood pressure may further compromise renal function; coronary insufficiency or recent myocardial infarction, and cerebrovascular disease, especially with encephalopathy.
• Guanethidine monosulfate should not be given to patients with severe cardiac failure except with extreme caution since guanethidine monosulfate may interfere with the compensatory role of the adrenergic system in producing circulatory adjustment in patients with congestive heart failure.
• Patients with incipient cardiac decompensation should be watched for weight gain or edema, which may be averted by the concomitant administration of a thiazide.
• Guanethidine monosulfate should be used cautiously in patients with a history of peptic ulcer or other chronic disorders that may be aggravated by a relative increase in parasympathetic tone.

Ginseng: Intake of ginseng while taking guanethidine will reduce the effectiveness of guanethidine. Ginseng is found to increase the blood pressure and therefore should be avoided with antihypertensive medications.

The adverse reactions related to molecule Guanethidine can be categorized as

• Common Adverse effects:

Bradycardia, headache, Dizziness, fatigue etc.

• Less Common adverse effect:

Nervousness, Elevated liver enzymes, joint paint, edema, vivid dreams, abdominal discomfort, nausea, muscle cramps, paresthesias, bradycardia, cold extremities, hypotension, palpitations, syncope, Anxiety, lethargy, diarrhea, vomiting, Pruritus, drug-induced Parkinson’s disease

• Rare adverse effects:

Heart failure, optic atrophy, bronchospasm, depression, decreased exercise tolerance, Gynecomastia,enon, etc.

The clinically relevant drug interactions of Guanethidine is briefly summarized here:

• Concurrent use of Guanethidine rauwolfia derivatives may cause excessive postural hypotension, bradycardia, and mental depression.
• Thiazide diuretics enhance the antihypertensive action of Guanethidine
• Amphetamine:  like compounds, stimulants (e.g., ephedrine,methylphenidate), tricyclic antidepressants (e.g., amitriptyline, imipramine, desipramine) and other psychopharmacologic agents (e.g., phenothiazines and related compounds), as well as oral contraceptives, may reduce the hypotensive effect of Guanethidine.
• MAO inhibitors should be discontinued for at least 1 week before starting therapy with Guanethidine.

The common side of Guanethidine includes the following:

Fatigue, Nasal Congestion, upset stomach, headache, depression, dizziness, nausea, etc.

The use of Guanethidine should be prudent in the following group of special populations:

Pregnancy

• Pregnancy Category C (FDA):

Animal reproduction studies have not been conducted with Guanethidine. It is also not known that Guanethidine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Guanethidine should be given to pregnant woman only if clearly needed.

Nursing Mothers:

Guanethidine (guanethidine monosulfate) is excreted in breast milk in very small quantity. Caution should be exercised when Guanethidine (guanethidine monosulfate) is administered to a nursing woman.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

Pharmacodynamics:

• Guanethidine acts at the sympathetic neuroeffector junction by inhibiting or interfering with the release and/or distribution of the chemical mediator (presumably the catecholamine norepinephrine), rather than acting at the effector cell by inhibiting the association of the transmitter with its receptors. In contrast to ganglionic blocking agents, Guanethidine equally the responses mediated by alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade. Since sympathetic blockade results in modest decreases in peripheral resistance and cardiac output, Guanethidine lowers blood pressure in the supine position. It further reduces blood pressure by decreasing the degree of vasoconstriction that normally results from reflex sympathetic nervous activity upon assumption of the upright posture, thus reducing venous return and cardiac output more. The inhibition of sympathetic venoconstrictive mechanisms results in venous pooling of blood. Therefore, the effect of Guanethidine is especially pronounced when the patient is standing. Both the systolic and diastolic pressures are reduced.
• Other actions at the sympathetic nerve terminal include depletion of norepinephrine. Once it gains access to the neuron, Guanethidine accumulates within the intraneuronal storage vesicles and causes depletion of norepinephrine stores within the nerve terminal. Prolonged oral administration of Guanethidine produces a denervation sensitivity of the neuroeffector junction, probably resulting from the chronic reduction in norepinephrine released by the sympathetic nerve endings. Systemic responses to catecholamines released from the adrenal medulla are not prevented and may even be augmented as a result of this denervation sensitivity. A paradoxical hypertensive crisis may occur if Guanethidine is given to patients with pheochromocytoma or if norepinephrine is given to a patient receiving the drug.
• Due to its poor lipid solubility, Guanethidine does not readily cross the blood-brain barrier. In contrast to most neural blocking agents, Guanethidine appear to suppress plasma renin activity in many patients.

Pharmacokinetics:

• Absorption:

Guanethidine appeared to be absorbed continuously over a period of at least 12 hr after oral administration.

• Metabolism:

Following its absorption, guanethidine is metabolised to guanethidine N-oxide and 2-(6-carboxyhexylamino) ethyl guanidine. These metabolites have less than one-tenth of the pharmacological activity of guanethidine. The metabolism of guanethidine was much more extensive after oral than after intramuscular administration suggesting that an appreciable fraction of absorbed drug was metabolised during its first pass through the liver.

• Excretion:

After chronic oral administration, the initial phase of elimination with a half-life of 1.5 days is followed by a second phase of elimination with a half-life of 4-8 days. The renal clearance of guanethidine is 56 ml/min. guanethidine monosulfate is converted by the liver to three metabolites, which are excreted in the urine.

1. https://www.webmd.com/drugs/2/drug-2471/guanethidine-hydrochlorothiazide-oral/details/list-contraindications
2. https://www.mayoclinic.org/drugs-supplements/guanethidine-oral-route/precautions/drg-20067754
3. https://www.medindia.net/doctors/drug_information/guanethidine_monosulfate.htm#Warning
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