Fospropofol: Clinical Pharmacology

Abstract

Sedation in clinical practice extends from minimal sedation to general anaesthesia. Most endoscopic procedures require sedation as it reduces the patient's memory of the events, makes them less anxious, more comfortable and improves the outcome of the procedure. In moderate sedation , patient responds purposefully to verbal or tactile stimulation, does not require airway intervention, has adequate spontaneous ventilation and cardiovascular function is maintained.1 In colonoscopy and flexible bronchoscopy this type of sedation can be utilized Currently intravenous benzodiazepines with opioids are used to provide moderate sedation (midazolam & fentanyl). But, benzodiazepines (BZDs) have several disadvantages like drug-drug interactions (with opioids- CNS depression), high inter-individual metabolic variability ( and long recovery periods. Propofol may be used as an alternative to benzodiazepines because it has rapid onset of action, shorter recovery time, has antiemetic actions and produces better amnesia.2 However the limitations of propofol when used for endoscopic procedures are, narrow therapeutic index, ability to induce general anaesthesia, cause haemodynamic and respiratory depression, lack of a pharmacological antagonist, contamination is easy and has to be avoided in patients with hyperlipidemia(because of its lipid formulation and contains omega 6 fatty acids).3 As a result of these disadvantages, it is not used routinely in endoscopic procedures and hence alternative formulations of the drug were investigated, resulting in the development of fospropofol, a water-soluble prodrug of propofol.1 Both propofol and fospropofol are indicated for use as monitored anaesthesia care (MAC) sedation in adults and fospropofol has been approved for use by US FDA in December 2008. Chemistry The chemical nature of propofol is diisopropyl phenol (Figure 1A). When a phosphate group is added to this molecule, it results in formation of water soluble propofol that does not contain lipids, egg products or preservatives, thereby eliminating the allergic, bacterial infections and hyperlipidemic concerns associated with propofol. The two phosphorylated propofol prodrugs so synthesized were named as propofol phosphate and phosphonooxymethyl propofol4 (Figure 1B, 1C). Figure 1 2,6 diisopropyl phenol molecule (propofol) and prodrug variations Propofol molecule (2,6 -diisopropyl phenol). Propofol phosphate. Phosphonooxymethyl propofol (2,6 diisopropylphen- oxymethyl phosphate). Substitution of hydroxyl by charged phosphate group introduces electronegativity which allows fospropofol to dissolve readily in water, hence does not cross lipid membrane.4 Sodium salt of fospropofol are commonly used. Mechanism of Action Fospropofol gets converted to propofol by endothelial alkaline phosphatases5 Propofol is a agonist at GABAA receptor .It binds to a specific site on the a and 11 subunits of the receptor complex, but not to the GABA binding site. Activation of the GABAA receptor results in increased Cl-conductance and hyperpolarization, thus inhibiting the postsynaptic neuron. It also inhibits the excitatory NMDA glutamate receptors thus decreasing Ca++ entry resulting in postsynaptic inhibition. Above mechanisms results in sedation.6 Pharmacological actions Fospropofol, once metabolized to propofol, is comparable to propofol lipid emulsion, however, the delayed liberation of propofol results in differences in the timing of the pharmacodynamic actions.7 Only liberated drug and not fospropofol exert a CNS effect. The sedative effects are similar to those of propofol emulsion but not equipotent because inactive fospropofol must be converted to propofol. Hence equivalent doses of fospropofol and propofol emulsion will not have similar effects, infact fospropofol has a delayed onset and decreased clinical effect when compared to propofol for producing moderate sedation required for endoscopy procedures. Pharmacokinetics Onset of Action. Fospropofol is administered intravenously. Every 1.86 mg of fospropofol disodium administered results in the molar equivalent of 1 mg of propofol.7 The time dependant enzymatic conversion releases the active drug slowly and thus creates a sedative profile which differs significantly from that of propofol emulsion.4 The onset of sedation occurs after 4-8 min.3 Phase I studies have shown that, 6 and 18 mg/kg intravenous bolus doses have achieved peak plasma concentration [Cmax] at 12 minutes and 8 minutes respectively indicating a dose dependant effect.7 Distribution Fospropofol has a low volume of distribution of 0.33±0.069 L/kg as compared to liberated propofol of 5.8 L/kg. After 6.5mg/kg bolus dose, the mean terminal phase half-life (t1/2) of fospropofol was 48 and 52 minutes in healthy subjects and patients respectively.3 The mean terminal phase half-life of liberated propofol was 2.06 ± 0.77 hours following 6mg/kg bolus, but it does not reflect the duration of sedation due to rapid redistribution.3 Both are 98% protein bound. Propofol readily crosses the placenta and is also found in breast milk but not established for fospropofol.7 Metabolism and Elimination Fospropofol must first be converted to propofol to achieve sedative effects. Alkaline phosphatases present in endothelium and liver are responsible for the enzymatic conversion.8 (Figure 2). Propofol is metabolized to propofol glucuronide and other metabolites in small quantities. The formaldehyde and phosphate plasma concentrations are comparable to endogenous levels.7 Metabolism formaldehyde involves rapid oxidation to formic acid catalyzed by glutathione dependent and independent dehydrogenases in the liver and erythrocytes and therefore there is no increase in serum levels.7 Oxidation to CO2 is the primary means of eliminating excess formate through tetrahydrofolate pathway.9 Serum phosphate levels not shown to reach the toxic concentration and gets excreted through kidney.10 Renal elimination of fospropofol is negligible(<0.02%).7 Figure 2 Metabolism of fospropofol into diisopropyl phenol (propofol), free phosphate, formaldehyde to formate Uses Fospropofol sodium is an intravenous sedative-hypnotic agent indicated for monitored anesthesia care (MAC) sedation in adult patients. The dosing regimen used in studies were based on the age and comorbid conditions as categorised by American Society of Anaesthesiologist.7 Undergoing diagnostic procedures like bronchoscopy, colonoscopy1 7 Minor surgical procedures (arthroscopy, bunionectomy, osteotomy and fasciotomy in carpal tunnel syndrome)11 Adverse reactions Injection was less painful as compared to propofol emulsion. The most common adverse reactions were transient paresthesias (49-74%) and pruritus in 16-28%, mild to moderate in intensity and self limiting.3 The other reported adverse effects were cough, nausea and vomiting. Paresthesia (burning, tingling, stinging) and pruritus in perineal region had occurred within 5 minutes of administration of the initial dose of fospropofol.4 7 The pharmacologic basis of these sensory phenomena is unknown.7 Paresthesia and pruritus may be because of the phosphate ester present in the drug formulations as seen with other phosphate-containing drugs such as dexamethasone phosphate, hydrocortisone phosphate sodium, prednisolone phosphate, fosphenytoin and estramustine phosphate.3 4 12 13 Sedation related adverse effects such as hypoxia, respiratory depression, apnea, loss of purposeful responsiveness and non sedative effects like hypotension were also reported.7 Respiratory adverse effects Respiratory adverse effects are hypoxia, respiratory depression and apnea. Hypoxia was reported in 4% of 455 adult patients but more frequently among patients aged =75 years.7 Use of supplemental oxygen was shown to reduce the risk of hypoxia. Apnea at standard or modified dosing regimen (>65 years) and higher dose of fospropofol was observed in < 1 % and 3 % respectively.5 Airway assistance maneuvers(verbal stimulation, tactile stimulation, jaw thrust, chin lift, suction, and manual ventilation) may be required in the management of respiratory depression, hypoxemia, or apnea. Loss of purposeful responsiveness to Vigorous Tactile or Painful Stimulation : Fospropofol has not been studied for use in general anaesthesia. Release of propofol from fospropofol may cause patients to become unresponsive or minimally responsive to vigorous tactile or painful stimulation indicating patients moving towards deep sedation or general anaesthesia (annexure 1). Their incidence during colonoscopy and bronchoscopy was 4% lasting for 2 to 16 minutes and 16% for 2 to 20 minutes respectively.7 Hence, fospropofol is used for monitored anesthesia care (MAC) sedation in adults undergoing endoscopic procedures. Hypotension Hypotension was observed in 4 % and 6 % of patients with the standard or modified dosing regimen and greater than the recommended dose respectively. Patients with compromised myocardial function, reduced vascular tone or who have reduced intravascular volume may be at an increased risk for hypotension.7 Table 1 Advantages of fospropofol over propofol3 9 14 15 16 17 18 Table 2 Clinical studies The above cardio-respiratory-CNS serious adverse effects during clinical trials were commonly seen in patients undergoing bronchoscopy, because 46% patients were ASA P3 or P4 (high risk) category as compared to colonoscopy (3%) and minor surgical procedures (19%). Specific populations There is no influence of race, gender, renal and concent-rations on the pharmacokinetics of fospropofol or propofol. Fospropofol is not recommended for use in labor, caesarean section deliveries, nursing mothers and patients <18 years as its safety is not yet established.7 There are no adequate and well-controlled studies in pregnant women (Pregnancy Category B.). No dosing adjustments are required for patients with creatinine clearance > 30ml/min5 but data for creatinine clearance < 30 mL/min is not available. Overdose Overdosage of fospropofol can lead to cardiorespiratory depression. Signs of formate toxicity would be similar to those of methanol toxicity and are associated with anion-gap metabolic acidosis because of formic acid, ketonemia, acetonuria, respiratory compromise and blindness. Phosphate could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures.7 Drug Interactions Fospropofol may produce additive cardio-respiratory effects when administered with sedative-hypnotics and opioids but less as compared to propofol emulsion,7 which may be due to the time taken for conversion of fospropofol to propofol, a rate-limiting process. The enzymatic conversion limits immediate release and rapid rise in the blood concentration of propofol, which results in delayed action on the CNS and respiratory depression.4 Precautions Fospropofol should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the diagnostic or therapeutic procedure. Sedated patients should be continuously monitored during sedation and through the recovery process for early signs of hypotension, apnea, airway obstruction, and oxygen desaturation.7 Small doses increased beyond 6mg/kg leads to exponential increase in risk for deep sedation making the 8mg/kg dose a poor choice for moderate sedation.14 During fospropofol anaesthesia, facilities for maintenance of a patent airway, artificial ventilation, supplemental oxygen, and cardiovascular resuscitation must be immediately available. Summary of clinical studies In clinical trials, IV fentanyl was administered 5 min before giving bolus dose of 6.5mg/kg fospropofol with repeated doses of 25% of the original dose every 4 minutes to obtain adequate sedation. Most procedures were completed within half an hour.3 The primary endpoint in the clinical studies was the rate of “sedation success,” defined as the proportion of patients who did not respond readily to their name spoken in a normal tone of voice ( Sedation Scale score of 4 or less) on 3 consecutive measurements taken every 2 minutes, who completed the procedure without the use of alternative sedative medication and without the use of manual or mechanical ventilation.7 (annexure 1) Annexure 1 Modified Observer's Assessment of Alertness/ Sedation Scale Future prospects Clinical trials are in progress to assess the use of fospropofol for Procedural sedation with regional anesthesia block prior to orthopaedic surgery22 For long-term sedation and intravenous anesthesia.23 To sedate patients on ventilator in intensive care unit24 To anesthetize patients during coronary artery catheterization surgery.25 To provide adequate sedation in patients undergoing percutaneous coronary (PC) procedures.26 CONCLUSION Fospropofol, a phosphate ester ater soluble prodrug of propofol has been found to be safe and effective alternative to propofol and midazolam for use in endoscopic and other procedures. The unique pharmacology of fospropofol provides scope for expansion to introduce new drug options for sedation.