Guanfacine

Guanfacine is a selective alpha 2A adrenergic agonist. The extended release form is used mainly for attention deficit hyperactivity disorder in children and adolescents; the immediate release form was used for hypertension. It is not widely available in East Africa.

Classification. Selective alpha 2A agonist; centrally acting.

Mechanism. Stimulates postsynaptic alpha 2A receptors in the prefrontal cortex, strengthening working memory and attention, and presynaptic receptors in the brainstem, reducing sympathetic outflow.

Pharmacodynamics. Lowers blood pressure and heart rate in a dose dependent way. Sedation is common in the first weeks. Full effect on attention takes 2 to 4 weeks.

Pharmacokinetics. Extended release peak 5 hours; half life about 18 hours. Metabolised mainly by CYP3A4; excreted in urine. A high fat meal raises exposure by about 40%.

Attention deficit hyperactivity disorder, children 6 to 17 years (extended release).

• Start 1 mg once daily, morning or evening, constant through treatment.

• Increase by 1 mg each week.

• Target dose 0.05 to 0.12 mg/kg daily; usual 1 to 4 mg for ages 6 to 12 and 1 to 7 mg for ages 13 to 17.

• Maximum 4 mg daily for ages 6 to 12 and 7 mg daily for ages 13 to 17 (a ceiling of 0.12 mg/kg also applies).

• Review benefit and need at least yearly. Specialist use.

Hypertension, adult (immediate release, rarely used). 1 mg at bedtime; increase to 2 mg after 3 to 4 weeks; maximum 3 mg daily. Not first line.

Dose adjustments. With strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir), halve the dose; with strong inducers (carbamazepine, rifampicin, phenytoin), consider doubling the dose over 1 to 2 weeks.

Contraindications. Hypersensitivity. Caution in cardiac conduction disorders.

Warnings. Hypotension, bradycardia, syncope and sedation. Rebound hypertension after abrupt withdrawal. Heat exposure and dehydration raise the risk of hypotension. Caution in cardiovascular disease, depression and in those with a history of syncope.

Adverse effects. Somnolence, fatigue, headache, abdominal pain, dry mouth, hypotension, bradycardia, irritability, weight gain.

Interactions. CYP3A4 inhibitors and inducers alter exposure. Valproate: raised valproate levels. Additive hypotension with other antihypertensives. Additive sedation with central depressants. Avoid taking with a high fat meal.

Special groups.

• Pregnancy: avoid unless essential.

• Breastfeeding: no data; avoid.

• Children under 6 years: not established.

• Older adults: not generally prescribed.

• Kidney impairment: severe (eGFR under 30 mL/min): reduce the maximum dose by about one third.

• Liver impairment: reduce the dose; no clear dose advice for severe impairment.

Formulations. Extended release tablets 1, 2, 3 and 4 mg; immediate release tablets 1 mg and 2 mg.

Administration. Swallow whole; do not crush, chew or break. Do not give with a high fat meal. Keep the timing constant.

Baseline. Blood pressure, pulse, ECG if cardiac history, weight, family history of syncope or sudden death.

Monitoring. Blood pressure and pulse before starting, at each dose change and every 3 months; sedation; weight; mood.

Stopping. Taper by no more than 1 mg every 3 to 7 days to avoid rebound hypertension.

Common prescribing errors. Converting between extended release and immediate release products mg for mg; stopping suddenly; combining with a strong CYP3A4 inhibitor without reducing the dose.