Guanfacine

Guanfacine is a antihypertensive agent belonging to centrally acting alpha 2a-adrenergic receptor agonists.

Guanfacine is approved for the treatment of hypertension. It is also used to treat ADHD as monotherapy or as adjunctive therapy to a psychostimulant, Tourette syndrome or tic disorders.

Guanfacine is rapidly absorbed and its bioavailability is approx 80%.It is extensively distributed in tissues with plasma protein binding of approx 70%. It is rapidly metabolised in liver via CYP3A4/5-mediated oxidation, w/ subsequent sulfation and glucuronidation. It is excreted via urine, as unchanged drug (approx 50%) and metabolites with elimination half-life of about 10-30 hr.

The common side effects associated with Guanfacine include bradycardia, bronchospasm, hypotension, blurred vision, palpitations, blurred vision, chest pain, edema, diarrhea, etc.

Guanfacine is available in the form of dosage forms as tablet.

Guanfacine is available in Australia, India, Canada, USA

Guanfacine belonging to the Centrally acting alpha 2a-adrenergic receptor agonists., acts as a antihypertensive agent. Guanfacine works by stimulating alpha2 adrenergic receptors in brain. This stimulation reduces the nerve impulses from the vasomotor center (located in the medulla oblongata of the brain) to the heart and blood vessels. As a result, the heart rate reduces and blood vessels dilate (widen), reducing how hard heart has to work to pump around the body, which lowers blood pressure.

Guanfacine stimulates postsynaptic alpha-2A adrenergic receptors so it inhibits the production of cAMP and closes HCN channels enhancing the effectiveness of the signal of the pyramidal neurons of the prefrontal cortex (PFC), thus improving working memory and attention.

The onset of action of Guanfacine occurs within 30- 60 minutes.

The Duration of Action for Guanfacine is 17 hours.

The Tmax was found within 1-2 hour and Cmax in blood reached 2.5±0.6ng/mL

Guanfacine is available in the form of tablets.

Guanfacine tablets are taken orally by mouth with or without water.

Guanfacine is approved for the treatment of hypertension. It is also used to treat ADHD as monotherapy or as adjunctive therapy to a psychostimulant, Tourette syndrome or tic disorders.

Guanfacine stimulates postsynaptic alpha-2A adrenergic receptors so it inhibits the production of cAMP and closes HCN channels enhancing the effectiveness of the signal of the pyramidal neurons of the prefrontal cortex (PFC), thus improving working memory and attention.

Guanfacine is approved for use in the following clinical indications:

● Hypertension

1 mg administered orally once daily at bedtime at first. Although the majority of the benefit of guanfacine on blood pressure is evident at 1 mg/day, a dose of 2 mg taken orally once day may be given if outcomes after 3 to 4 weeks of therapy are unsatisfactory. Although higher daily doses have been utilised, oral doses above 3 mg/day cause a considerable increase in adverse effects. 3 to 4 mg maximum given orally once per day. A thiazide diuretic or some additional medication may be administered if the therapeutic response is insufficient. Don't stop your therapy abruptly.

Although not approved, there have been certain off-label uses documented for Guanfacine These include:

• Attention Deficit Hyperactivity Disorder (ADHD)

For Extended Release tablet

Initially, 1 mg was taken orally once per day at the same time (morning or evening). Depending on the clinical response and tolerability, titrate no more than 1 mg/week.

Orally administered dose range: 0.05 to 0.12 mg/kg/day.

Estimated weight-based target doses: Weight 25 to 33.9 kg = 2 to 3 mg/day taken orally; Weight 34 to 41.4 kg = 2 to 4 mg/day taken orally; Weight 41.5 to 49.4 kg = 3 to 5 mg/day taken orally; Weight 49.5 to 58.4 kg = 3 to 6 mg/day taken orally; Weight 58.5 to 91 kg = 4 to 7 mg/day taken orally. Weight more than 91 kg: 5 to 7 mg/day taken orally.

Age Based Maximum: Do not exceed 4 mg/day taken orally for children 6 to 12 years; do not exceed 7 mg/day taken orally For teenagers aged 13 to 17, the maximum daily oral dose should not exceed 7 mg; adjunctive trials on doses higher than 4 mg have not been conducted. Reevaluate effectiveness on a regular basis, adjusting the weight-based dosage as necessary. Consider avoiding the coadministration of some medications or adjusting dosages; look into drug interactions. Don't mix up immediate-release (IR) and extended-release (ER) medications on a mg-per-mg basis; instead, stop taking IR guanfacine and start titrating with the ER medication as directed above if you're switching from IR.

Missed doses: Restart therapy at the previous maintenance dose and take into consideration titration for tolerance if the patient misses two or more doses in a row.

Discontinuation: Do not abruptly discontinue. To prevent rebound hypertension, taper the daily dose by no more than 1 mg every 3 to 7 days. Blood pressure and pulse should be then monitored when cutting the dose or stopping it altogether.

For Immediate Release Tablet

The ideal dosage has not been determined. A positive impact may be possible with oral administration of 0.25 to 2 mg per day in split dosages, according to limited research. In a modest crossover research, 17 adult patients received guanfacine, dextroamphetamine, and placebo treatments alternately for two weeks, with a four-day washout period in between. Guanfacine was first administered orally once daily in the morning at a dose of 0.25 mg, and it was then gradually raised by 0.25 mg every other day or as tolerated. The maximum daily dosage was 2 mg, while the average (SD) dose was 1.1 mg (0.6 mg). Guanfacine's effects lasted for roughly 6.9 hours. Using the DSM-IV ADHD Behavior Checklist (Adults), both medications showed comparable improvements in the severity of ADHD symptoms; the Stroop test also revealed favourable pharmacological effects.

• For the treatment of Tourette’s Syndrome

For Immediate release tablet

Initially, 0.5 to 1 mg/day taken orally, then titrate gradually according to blood pressure and heart rate.

Usual dosage range: 0.5 mg to 3 mg/day taken orally per evidence-based guidelines (strong recommendation, moderate-quality evidence).

Max: 4 mg/day taken orally. Guanfacine may be more likely than a placebo to lessen the intensity of tics in people with Tourette's syndrome or other chronic tic disorders; consider the advantages of therapy vs the dangers, according to the American Academy of Neurology practise recommendation (e.g., sedation, hypotension). Guanfacine may help persons who have ADHD and attention deficit hyperactivity disorder (ADHD) together.

For Extended Release tablet

1 mg given orally once day at first. Titrate based on blood pressure and heart rate in increments of not more than 1 mg/week.

1 to 4 mg administered orally once per day is the typical dose range. Maximum oral dose per day: 4 mg. Guanfacine may be more likely than a placebo to lessen the intensity of tics in people with Tourette's syndrome or other chronic tic disorders; consider the advantages of therapy vs the dangers, according to the American Academy of Neurology practise recommendation (e.g., sedation, hypotension). Guanfacine may help persons who have ADHD and attention deficit hyperactivity disorder (ADHD) together.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Guanfacine is available in tablets in strengths of 1 and 2 mg

Guanfacine is available in the form of Tablets.

In perioperative, postoperative, or other urgent situations when short-term control of ventricular rate with a short-acting drug is preferred, guanfacine should be used to treat the quick control of ventricular rate in patients with atrial fibrillation or atrial flutter.. Also used in the no compensatory sinus tachycardia where the rapid heart rate requires specific intervention.

Hypertension:

Supraventricular tachycardia: Alcohol, coffee and its derivative, Chocolates, and Stimulants.

Migraine: Some commonly triggered diets include: Baked food with yeast, such as sourdough bread, bagels, doughnuts, coffee cake, Chocolate, Cultured dairy products (like yogurt and 0kefir), Tomatoes, Vegetables like onions, pea pods, some beans, corn, and sauerkraut, Vinegar and Alcohol must be avoided.

The low-salt Dietary Approaches to Stop Hypertension (DASH) diet has been found to reduce blood pressure. Sometimes, its effects on blood pressure only become apparent after a few weeks.

Atrial Fibrillation: Certain meals have been found to raise the risk of cardiac problems and have a detrimental impact on heart health. A higher risk of heart disease has been associated with diets heavy in processed foods, such as fast food, and products with added sugar, such as soda and sweet baked goods. Additionally, they can result in additional detrimental health effects like weight gain, diabetes, cognitive loss, and some types of cancer.

The food limitation should be tailored to the patient's needs.

Guanfacine may be contraindicated in the following:

● Guanfacine ER is contraindicated in patients with a known hypersensitivity to guanfacine or to any component of the product. Precautions are advised for those with a history of bradycardia, cardiovascular disease, heart block, hypotension, and syncope.

● To avoid the risk of rebound hypertension, patients should not stop therapy abruptly. The concomitant use of alcohol and other known depressants, as well as other guanfacine-containing drugs (e.g., Tenex) should be avoided.

● Patients should not drive or operate heavy equipment until they know how they respond to guanfacine ER. The safety and efficacy of the drug have not been established in children younger than six years of age. It is unknown whether the drug is effective if used for longer than nine weeks.

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

Hypotension:

Blood pressure and heart rate can decrease during guanfacine treatment in a dose-dependent manner. Over the course of treatment, decreases became less noticeable. There have been cases of syncope and orthostatic hypotension. Measure heart rate and blood pressure before starting therapy, after increasing the dose, and on occasion while receiving therapy. In patients who have experienced syncope in the past, have a history of hypotension, heart block, bradycardia, cardiovascular disease, or who may be at risk for syncope due to hypotension, orthostatic hypotension, bradycardia, or dehydration, use guanfacine with caution. In patients receiving antihypertensives or other medications that can lower blood pressure or heart rate or raise the risk of syncope concurrently, use guanfacine with extreme caution. Encourage patients not to become dehydrated.

PRECAUTIONS

General

Because the acid metabolite of Guanfacine is primarily excreted unchanged by the kidney, Guanfacine should be administer with caution to patients having impaired renal function. The elimination half-life of acid metabolite was prolonged ten-fold, and the plasma level was considerably elevated in the patients with end-stage renal disease.

Consumption of alcohol is not recommended while receiving the medicine as it may increase the risk of adverse effects and lowers the blood pressure.

Guanfacine use in breast feeding patient is not recommended.

Teratogenicity studies in rats at intravenous dosages of Guanfacine up to 3000 mcg/kg/min (3 mg/kg/min) (ten times the maximum human maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity, or teratogenicity, while a dosage of 10,000 mcg/kg/min (10 mg/kg/min) produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min (1 mg/kg/min) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while 2500 mcg/kg/min (2.5 mg/kg/min) produced minimal maternal toxicity and increased fetal resorptions. Although there are no adequate and well-controlled studies in pregnant women, use of Guanfacine in the last trimester of pregnancy or during labor or delivery has been reported to cause fetal bradycardia, which continued after termination of drug infusion. Guanfacine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Avoid consuming grapefruit or grapefruit juice during treatment with Guanfacine, as it may increase blood levels and effects of the medication. This may cause blood pressure to fall excessively, especially when you rise from a sitting or lying position.

Pleurisy Root: Pleurisy roots are not recommended with most heart medications due to the cardiac glycoside content of the root.

The adverse reactions related to molecule Guanfacine can be categorized as follows:

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripherial ischemia, infusion site reaction such as blistering /necrosis/ thrombophlebitis.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Guanfacine is briefly summarized here.

There was a three-fold increase in the area-under-the-curve (AUC) concentration of guanfacine when it was given with ketoconazole, Nizoral, Janssen. Caution should be used when guanfacine ER is given with other CYP 3A4 and 3A5 inhibitors such as ketoconazole. Patients should be monitored for hypotension, bradycardia, and sedation. Dose adjustments may be needed if guanfacine ER is taken with a CYP 3A4 inducer because the AUC concentration of guanfacine ER is decreased by 70%.

Patients should be monitored for potential CNS side effects when guanfacine ER is given with valproic acid because of increased concentrations of valproic acid with coadministration. Potential additive pharmacodynamic effects (e.g., hypotension and syncope) must be monitored when guanfacine ER is taken with other antihypertensive agents. Sedation and somnolence may be experienced if guanfacine ER is taken with alcohol, sedatives, hypnotics, benzodiazepines, barbiturates, or antipsychotic agents.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Overall, there are no distinctions between elderly and younger patients in terms of safety or efficacy.

Symptoms:

A Guanfacine overdose can have a wide range of side effects. Bradycardia, any degree of AV block, full AV dissociation, decreased contractility, cardiogenic shock, asystole, and pulseless electrical activity are just a few examples of the cardiac symptoms of poisoning. Respiratory abnormalities, seizures, coma, and mental health symptoms are only a few examples of the neurologic symptoms of poisoning. Bronchitis, gastro-intestinal mesenteric ischemia, and peripheral cyanosis are some other signs of poisoning.Since Guanfacine has a very short half-life (9 minutes), toxicity should be treated by discontinuing the Guanfacine infusion.

Management:

Acute toxicity is often self-limited and is treated supportively. Toxicity that results in bradycardia should be treated by atropine, pacing, and other anticholinergic agents. Cardiogenic shock can be treated with inotropic agents like dobutamine, dopamine, and isoproterenol. Bronchospasms, even though rare, should be treated with a beta-2 agonist, such as albuterol

Pharmacodynamics:

Guanfacine is absorbed orally, with a bioavailability of 80%. It is taken once daily, usually in the morning, but it should not be taken with high-fat meals. The drug is approximately 70% bound to plasma proteins, and it is widely distributed throughout body, with a volume of distribution (V_d) of 6.3 L/kg (276–347 L). Fifty percent of the drug is metabolized in the liver, primarily to the glucuronide and sulfate of 3-hydroxyguanfacine, oxidized mercapturic acid derivatives, and other minor metabolites

Pharmacokinetics:

• Absorption:

Guanfacine is 80% orally bioavailable. 1mg immediate release oral guanfacine reaches a C_max of 2.5±0.6ng/mL with a T_max of 3.0h and an AUC of 56±15ng*h/mL. 1mg extended release oral guanfacine reaches a C_max of 1.0±0.3ng/mL with a T_max of 6.0h and an AUC of 32±9ng*h/mL.

● Metabolism:

Guanfacine is oxidized by CYP3A4 to it's main metabolite, 3-hydroxyguanfacine. 3-hydroxyguanfacine is then either glucuronidated or sulphated

● Elimination:

Guanfacine is 57.0±32.0% eliminated in the urine in patients with normal renal function. Patients with a glomerular filtration rate (GFR) of 10-30mL/min eliminate 14.0±9.0% of a dose in the urine, while patients with a GFR of <1mL/min eliminate 7.5±2.4% of a dose in the urine.

• https://go.drugbank.com/indications/DBCOND0056178
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022037s009lbl.pdf
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935643/#__sec10title Inbo
• https://reference.medscape.com/drug/intuniv-tenex-guanfacine-342384