Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: hameln pharma plus gmbh, Langes Feld 13, D-31789, Hameln, Germany
Pharmacotherapeutic group: opioid anaesthetics
ATC code: N01AH02 (Alfentanil)
In humans, alfentanil at therapeutic doses has no detrimental effects on myocardial performance. The cardiovascular stability is remarkable both in healthy and poor-risk patients. The only changes seen in blood pressure and heart rate were transient, slight decreases occurring immediately after induction. The incidence and degree of respiratory depression is less and of shorter duration after alfentanil than with fentanyl. Like other opioid analgesics, alfentanil increases the amplitude of the EEG and reduces its frequency. Alfentanil reduces intraocular pressure by about 45%. It blocks increases in plasma cortisol and in plasma antidiuretic and growth hormones throughout surgery, and prevents increases in plasma catecholamines up to, but not during or after, cardiopulmonary bypass in patients undergoing open heart surgery.
Alfentanil is a synthetic opioid with µ-agonist pharmacological effects.
After bolus injections ranging from 2.4 to 125 micrograms/kg, plasma levels in man decay triexponentially with a terminal half life of approx. 90 minutes. Total distribution volume varies from 0.4 to 1.0 l/kg, indicating a limited distribution of alfentanil to the tissues. Plasma clearance, varying from 3.3 to 8.3 ml/kg/min represents approximately one third of liver plasma flow indicating that elimination of alfentanil is not flow dependent. Since only 0.4% of the dose is excreted with the urine as unchanged drug, elimination of alfentanil occurs mainly by metabolism.
These main parameters in patients undergoing surgery are similar to those in healthy volunteers. Only when the drug was given as the sole anaesthetic in a continuous high infusion over about 5 hours was the clearance of alfentanil reduced resulting in a plasma half-life of about 200 minutes, the distribution volume not being markedly changed.
Plasma protein binding of alfentanil is 92%, mainly due to a strong binding to the ‘acute phase’ α1-acid-glycoprotein. It is not bound to the blood cells. Pharmacokinetics were comparable in rats, dogs and man. The elderly show a longer halflife for alfentanil, after IV bolus doses.
The data in children are limited. The values for the pharmacokinetic parameters are shown in the table below.
Pharmacokinetic Parameters of Alfentanil in Paediatric Subjects:
| t1/2β (hr) | CL (mL/kg/min) | Vdss (L/kg) | |
|---|---|---|---|
| Preterm Neonates (0-27 days) Gestational age 25-40 weeks; n=68 | 0.7-8.8 | 0.9-8.4 | 0.3-1.2 |
| Term Neonates (0-27 days) Gestational age: 35-41 weeks; n=18 | 4.1-5.5 | 1.7-3.2 | 0.5-0.8 |
| Infants & Toddlers 28 days – 23 months; n=34 | 0.9-1.2 | 7.7-13.1 | 0.4-1.1 |
| Children 2-11 years; n=32 | 0.7-1.3 | 4.7-10.2 | 0.2-1.0 |
| Adolescents 12-14 years; n=3 | 1.1-1.9 | 5.5-7.4 | 0.3-0.6 |
Note: Data for neonates, infants, and children are given as range of mean values.
CL = clearance, Vdss = volume of distribution at steady state, t1/2β = half-life in the elimination phase.
Protein binding in newborns is 75% and increases in children to 85%.
Pharmacokinetic information on the use of alfentanil in children is limited. Alfentanil is metabolized by CYP3A4. CYP3A4 activity is low in neonates and increases after birth to reach 30 to 40% of adult levels at 1 month of age. Activity of CYPA4 increases further to 45% at 6 months, 80% at 12 months.
After administration of a single intravenous dose of 50 microgram/kg, the terminal half-life in cirrhotic patients is significantly longer than in controls. The volume of distribution remains unchanged. The free fraction of alfentanil increases in cirrhotic patients to 18.5% compared with 11.5% in controls. This increase in free fraction together with a reduction in clearance from 3.06 mL/min/kg in controls to 1.60 mL/min/kg in cirrhotic patients will result in a more prolonged and pronounced effect (see Section 4.4.).
The volume of distribution and clearance of the free fraction is similar in renal failure patients and healthy controls. The free fraction of alfentanil in patients with renal failure is increased to 12.4 to 19% compared with 10.3 to 11% in controls. This may result in an increase in clinical effects of alfentanil (see Section 4.4.).
Preclinical effects observed were only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
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