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Kinetic and clinical observations in cyanotic children on propranolol therapy
Insights
This study examined propranolol in cyanotic children, finding plasma concentrations correlate with reduced heart rate. Withdrawal showed propranolol
Area of Science:
- Pharmacology
- Pediatric Cardiology
Background:
- Cyanotic children often require long-term propranolol therapy.
- Understanding propranolol pharmacokinetics and pharmacodynamics is crucial for effective treatment.
Purpose of the Study:
- To determine the pharmacokinetics of propranolol and its metabolite 4-hydroxypropranolol.
- To assess heart rate and blood pressure responses to propranolol therapy and withdrawal.
- To establish relationships between propranolol dosage, plasma concentrations, and physiological effects.
Main Methods:
- Kinetics of propranolol and 4-hydroxypropranolol were measured.
- Heart rate and blood pressure were monitored in five cyanotic children.
- Data were analyzed for correlations between dose, plasma concentration, and physiological responses before and after drug withdrawal.
Main Results:
- Propranolol plasma concentrations showed a linear relationship with dose above 1.8 mg/kg/day.
- A strong correlation existed between propranolol concentrations and heart rate reduction, with maximal effect around 80-100 ng/ml.
- 4-hydroxypropranolol plasma concentrations were inversely related to dose.
- Propranolol half-life ranged from 3.9 to 6.4 hr and correlated with hemoglobin levels.
- Heart rates normalized approximately 36 hours after propranolol withdrawal; blood pressure changes were minimal.
Conclusions:
- Propranolol dosage directly influences plasma concentrations and heart rate reduction in cyanotic children.
- The metabolite 4-hydroxypropranolol exhibits different concentration-dose dynamics.
- Propranolol withdrawal leads to a predictable decline in plasma levels and a return to baseline heart rate.
Abstract:
The kinetics of propranolol and its metabolite 4-hydroxypropranolol were determined together with heart rate and blood pressure responses in five cyanotic children on long-term propranolol therapy and after abrupt withdrawal. The daily dose range of propranolol was 2.4 to 4.4 mg/kg. Mean steady-state plasma propranolol concentrations, 16.5 to 114 ng/ml, were linearly related to dose (r = 0.93; p < 0.02) above a threshold dose of 1.8 mg/kg/day. There was excellent correlation (r = 0.96; p = 0.01) between concentrations and reduction in heart rate (delta HR, 14 to 27.5 beats/min), which also suggested a maximum heart rate response at plasma propranolol concentrations of 80 to 100 ng/ml. There was an inverse relationship between the plasma concentrations of 4-hydroxypropranolol and dose. On abrupt withdrawal of long-term propranolol therapy, plasma levels declined with a propranolol half-life (t1/2) of 3.9 to 6.4 hr, which correlated with the hemoglobin value. The 4-hydroxypropranolol t1/2 was 5.2 to 7.5 hr. Heart rates returned to normal after approximately 36 hr. Changes in blood pressure were minimal.