Mechanism of action of Guanfacine

Mechanism of Action of Guanfacine

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Introduction

Guanfacine is a selective α₂A‑adrenergic receptor agonist used in treating ADHD and for managing hypertension. It enhances prefrontal cortex functioning by activating postsynaptic α₂A receptors, resulting in improved attention, impulse control, and reduced sympathetic tone.

Step-by-Step Mechanism of Action

  1. Selective α₂A Receptor Agonism
    Guanfacine binds preferentially to α₂A receptors in the prefrontal cortex.
  2. Inhibition of cAMP Signaling
    This activation reduces cAMP production, closing HCN and KCNQ potassium channels.
  3. Increased Neuronal Firing Efficiency
    Stabilization of membrane potentials fosters enhanced neuronal signaling for working memory and attention.
  4. Reduced Sympathetic Output
    In the brainstem, α₂A activation diminishes sympathetic activity, lowering heart rate and blood pressure.
  5. Clinical Improvement in ADHD
    Enhanced prefrontal regulation improves attention span, decreases distractibility, and reduces impulsivity.
Mechanism of action of Guanfacine flowchart
Guanfacine mechanism of action flowchart

Pharmacokinetic Parameters

ParameterValue
Bioavailability~70–80% (oral)
Time to Peak (Tₘₐₓ)~1–4 hours
Half‑Life~17 hours
Protein Binding~70%
MetabolismHepatic via CYP3A4
Excretion~60% renal, ~20% fecal

Clinical Uses

  • ADHD (especially inattentive and hyperactive subtypes)
  • Adjunctive therapy in ADHD when stimulants are inadequate
  • Off-label: management of PTSD, tic disorders, insomnia

Adverse Effects

  • Drowsiness, sedation
  • Dry mouth
  • Hypotension, bradycardia
  • Headache, fatigue
  • Rare: rebound hypertension upon abrupt discontinuation

Comparative Analysis

FeatureGuanfacine ERClonidine (α₂ agonist)
Receptor Selectivityα₂A‑selectiveNon‑selective α₂
Sedation RiskLower sedationHigher sedation/hypotension
DurationOnce-daily dosingMultiple daily doses required
ADHD Symptom EffectImproves attention and impulse controlMore sedation-focused effect

MCQs

1. Guanfacine primarily acts as an agonist at which receptor?
A. β₁‑adrenergic
B. α₂A‑adrenergic
C. α₁‑adrenergic
D. α₂B‑adrenergic
Answer: B

2. In the prefrontal cortex, guanfacine reduces:
A. cGMP
B. cAMP
C. IP₃
D. DAG
Answer: B

3. The pharmacodynamic effect on neuronal firing is:
A. Increased membrane leak conductance
B. Stabilization of neuronal firing
C. Increased HCN channel activity
D. Inhibition of calcium influx
Answer: B

4. Guanfacine lowers blood pressure through:
A. α₁ blockade
B. Reduced sympathetic tone
C. β₂ antagonism
D. Vasodilatory prostaglandins
Answer: B

5. Compared with clonidine, guanfacine has:
A. More sedation
B. Greater prefrontal selectivity
C. Higher rebound hypertension risk
D. Shorter duration
Answer: B

6. What is the half-life of guanfacine?
A. 6 hours
B. 17 hours
C. 5 hours
D. 24 hours
Answer: B

7. Which enzyme metabolizes guanfacine?
A. CYP2D6
B. CYP3A4
C. CYP2C9
D. CYP1A2
Answer: B

8. A key side effect in children is:
A. Weight gain
B. Sedation
C. Incontinence
D. Tachycardia
Answer: B

9. Rebound hypertension may occur if guanfacine is:
A. Taken with food
B. Stopped abruptly
C. Combined with stimulants
D. Dosed nightly
Answer: B

10. Guanfacine’s ADHD efficacy is mainly due to:
A. Dopamine reuptake inhibition
B. Serotonin blockade
C. Prefrontal cortex modulation
D. GABA receptor activation
Answer: C

FAQs

1. Is guanfacine a stimulant?
No. It is a non-stimulant α₂A-agonist that improves PFC function.

2. Can it be used alone for ADHD?
Yes, or as an adjunct when stimulants alone are insufficient.

3. Does it cause sleepiness?
Yes, particularly when starting or increasing dosage.

4. Is withdrawal a concern?
Yes—gradual tapering is recommended to avoid rebound hypertension.

5. Is it safe for children?
It is FDA-approved for ADHD in pediatric patients and is well-tolerated.

References

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