Newer drug delivery systems in anesthesia

Advantages of drug delivery system

1. Increases bioavailability

2. Can be used for long-term treatments of chronic illness

3. Sustained maintenance of plasma drug levels

4. Decreased adverse drug effects[1,2]

5. Decrease in the total amount of drugs required thus reducing side effects

6. Improved patient compliance due to reduction in number and frequency of doses required

7. There is less damage sustained by normal tissue due to targeted drug delivery

8. Reduction in cost by developing newer delivery systems for existing molecules.[3,4]

Intranasal drug delivery

In addition to being convenient and painless, there is no reduction in bioavailability of drugs administered nasally.[5] Direct deliveries to the cerebrospinal fluid due to nose-brain pathway reduce the onset time. Highly lipophilic drugs of low molecular weight easily cross the nasal mucosa.[6,7,8,9] It does not require coupling with carrier nor any modification of therapeutic agent.[5] To avoid runoff, 0.25–0.3 ml of concentrated drug per nostril is used. One of the limitations is that in patients with bloody nose or increased mucus production there may be decreased absorption. Intranasal drug takes about 3–5 min to be absorbed, and drug levels achieved rarely cause respiratory depression. However, sufentanil is an exception where toxic levels can reach very rapidly.[10]

Pulmonary drug delivery system

Metered dose inhalers, nebulizers, and dry powder inhalers are used for pulmonary drug delivery.[11] They offer several advantages including a larger surface area and closer proximity to blood flow.[11,12] Lower doses can be used thus avoiding systemic toxicity. However, disadvantages include shorter duration and only 10–40% of the drugs delivered become available for systemic absorption, and to overcome this limitation, nanoparticles have been developed. There has been a constant endeavor to deliver opioids by inhalation route.[13] Bioavailability of fentanyl when administered by this route has been found to be 20%.[14,15] Iloprost, a newer prostacyclin analog used to treat pulmonary hypertension, has a very short half-life requiring frequent dosing regimens. Thus, to improve patient compliance an aerosolized controlled release formulation is an available alternative.[10,16,17] The use of pulmonary DDS using colloidal carrier systems has more physiological components.[18] The drugs used to treat asthma and certain lung infections as well as inhaled insulin are also being developed with newer technology using carriers.[19,20]

Buccal mucosal drug delivery system

In addition to ease of administration, it avoids the first pass effect and presystemic elimination.[21,22] Toxicity or undesired side effects are significantly reduced. Drugs for chronic pain management and breakthrough pains[23] including fentanyl (lozenges, tablets, and films)[24] and buprenorphine hydrochloride (tablets) are available for delivery through this route. The buccal mucosa is less permeable with a large immobile surface which results in slower onset and is more suitable for sustained release preparations, whereas sublingual drug delivery has a more dramatic onset.[25,26,27]

Intra-articular drug delivery

The size of the drug molecule has to be 3–5 μ. The residence time of drugs in intra-articular tissues may be prolonged by microspheres that are designed to improve their uptake by the synovium.[28]

Transdermal drug delivery system

Fentanyl, clonidine, glyceryl trinitrate, lisuride, and buprenorphine are available as transdermal preparations. Advantage of this route is, it avoids first pass metabolism and large variations in plasma drug concentrations.[29] Decreased gastrointestinal side effect improves compliance.[3] Constant drug levels are maintained which avoids ups and downs in plasma concentration levels seen with oral and parenteral route.[30] The stratum corneum is the greatest barrier to transport of drugs; hence, drugs need to be lipid soluble and have a low molecular weight.[3,31,32] Factors such as drug permeability, molecular weight, total body clearance, and therapeutic plasma concentrations have to be taken into consideration when calculating transdermal doses.[33] Reservoir patch and matrix patch are the two types of patches [Figure 1].[33,34,35]

Fentanyl patches are of the matrix design from which a constant amount of drug is released per unit time. The diffusion occurs at a constant rate in the direction of the lower concentration. After application of patch, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers.[34,36] Plasma fentanyl concentrations gradually increase following initial application. A steady-state serum concentration is reached between 12 and 24 h and remains relatively constant, with some fluctuation, for the remainder of the 72 h application period.[37] By the end of the second 72 h application, serum concentration remains nearly steady and this is maintained during subsequent applications of a patch of the same size. The fentanyl patches are available to deliver the drug at a constant rate of 25, 50, 75, and 100 μg/h spread over a period of 72 h.[38] The elimination half-life after patch removal is 13–22 h due to slow release of the fentanyl from skin depots. Thus, in cases of adverse effects, the patient needs to be monitored for a further period of 24 h after removal of the patch. The most frequent side effects observed are nausea, vomiting, and constipation. Less frequent ones include hypoventilation and rash at application site.[39]

A newer patient-controlled fentanyl transdermal system, the size of a credit card has been designed, which has to be worn on the upper arm or the chest. Iontophoresis is utilized to deliver fixed drug boluses.[40] There is no background infusion and also passive absorption of the drug is negligible.[35,40,41] Ahmad et al. compared intravenous patient-controlled analgesia morphine with fentanyl iontophoretic transdermal system and found the latter to be associated with lesser analgesic gaps.[42,43]

Although the transdermal delivery of drug is the most patient compliant mode of delivery only lipophilic, low molecular weight drugs can be delivered by this route.[44,45] To overcome this shortcoming, second and third generation DDS has been developed. In the second generation, enhancers are incorporated into the DDS, to reversibly disrupt the stratum corneum and thus promote the transfer of lesser lipid soluble drugs. In case of hydrophilic drugs, active energy-dependent methods have been used to drive drug across. This can be achieved using eutectic mixtures of local anesthetics, controlled heat, magnetophoresis, iontophoresis,[46,47] electroporation, or sonophoresis.[48] Using iontophoresis dermal anesthesia with lignocaine can be achieved.[49,50] The effect can be enhanced by adding adrenaline. Controlled release preparations of tramadol and buprenorphine are available. Beta blocker delivered in this way synchronized with continuous Holter monitoring is a novel application.[51]

Liposomes

Liposomes are nanovesicles encapsulated in phospholipid bilayer. They are biodegradable, nontoxic, and nonimmunogenic thus making them favorable carriers for drug delivery. Although major advances of liposomal drugs are in anticancer treatment, efficiency of anesthetic drugs can also be enhanced. Multimodal approach to postoperative pain management is the key to early recovery. One of the major limitations to the array of local anesthetics available is their relative short duration of action and the risk of systemic toxicity. Liposomal bupivacaine is an important advance in the delivery of local anesthetics formulations.[52] Up to 96 h of therapeutically active concentration can be achieved after single administration with delay in peak plasma concentrations.[53] However, phase 3 trials need to be conducted before they can be used in clinical practice for field blocks.[54] Liposomal formulation of epidural morphine DepoDur can provide up to 2 days of analgesia.[55,56] This was also confirmed in a study by Viscusi et al. using extended release morphine.[56] Liposomal encapsulated inhaled fentanyl having onset of action similar to intravenous preparation is also being developed[57] Liposomal drugs though in clinical research since last 50 years have not made much strides in clinical practice due to the various hurdles faced in quality assurance and costs. Furthermore, clinical trials related to them are more complex than conventional molecules.[58]

Transient targeted thromboprophylaxis

Thromboprophylaxis in the immediate postoperative period has always remained a gray area. Bleeding in the postoperative period is a real danger and at the same time thrombosis risk is also highest during this period when the patient is immobile. The novel DDS for thromboprophylaxis includes flow sensitive nanoparticles which are coated with tissue plasminogen activator (tPA) which release it at the site of clot.[59,60,61,62,63]

Target-controlled infusion pumps (open-loop)

In the routine practice in drug dose calculations, age, sex, or creatinine clearance is unaccounted for due to complex calculations.[74] The distribution of the drug to the peripheral tissues must be taken into account and only after there is equilibrium with the peripheral tissue can clearance be taken for calculation.

Pharmacokinetic simulation of certain opioids has shown that initial boluses usually result in drug concentrations far in excess than that is in the therapeutic range, and subsequent boluses result in the drug concentration periodically falling in the subtherapeutic range. Ideally, the drug concentration should always be in the therapeutic range which can be achieved by continuous infusions. However, the currently available sophisticated infusion pumps fall short of the convenience and accuracy of volatile anesthetic agents the delivery of which is guided by the minimum alveolar concentration.[75,76] Development of infusion devices for intravenous drugs which are the prototype of the vaporizers would be desirable.[77,78,79]

A step toward this goal is the development of target-controlled infusion (TCI) devices. In open-loop system, the plasma or the drug concentrations at the site of effect are calculated using a computer and the knowledge of the pharmacokinetic and the pharmacodynamic models of the drug.[76,80] Conventional infusion pumps result in continuous drug uptake, whereas TCI pumps gradually decrease the rate of drug delivery based on the pharmacokinetics of the drug. In TCI, the anesthesiologist sets desired target concentration, and the computer calculates the infusion rate that is required to deliver the necessary target concentration [Figure 3].

Measurements obtained from clinical studies in various subgroups are used to first formulate the pharmacokinetic profile of the drug which is then fed into the computer system. The drug delivery in TCI pumps is based on bolus elimination and transfer principle.[76] The initial bolus is given to reach the target concentration followed by infusion rate that replaces the amount of drug that is eliminated and the drug that is transferred to the peripheral tissue using an exponentially decreasing infusion rate. At present, only models for propofol, fentanyl, sufentanil, alfentanil, and remifentanil are available.[74] Using pharmacokinetic data models for dexmedetomidine are also in the process of being developed.[81]

Paedfusor TCI for pediatric use has shown promising results in cardiac surgery.[82] Pediatric TCI models currently available can be used in healthy children over 3 years of age. However, further research is needed to develop a system for optimal drug delivery in children.

Closed-loop systems

The closed-loop systems have real-time monitoring of the patients’ variables such as muscle relaxation, hypnosis,[83] analgesia, and a computer-controlled feedback mechanism which precisely delivers the drugs based on these parameters.[76] Muscle relaxation is monitored using peripheral nerve stimulator and recording the responses using accelerograph.[84] Hypnosis is monitored using the bispectral (BIS) monitor and a BIS index between 40 and 60 is generally advised as adequate hypnosis for general anaesthesia.[85,86,87,88,89,90,91,92] The most challenging parameter to monitor is the adequacy of analgesia as there are no objective parameters to verify. Since a surgical stimulus results in strong sympathetic activation, physical parameters such as heart rate and blood pressure can be used to monitor the level of analgesia.[93,94] Newer parameter, heart rate variability, has been used to quantify the degree of analgesia.[95] Hence, these patient parameters are fed to the computer which in turn using the inbuilt drug pharmacodynamic data adjusts the dose of intravenous drugs. Postoperative delivery of sedative doses of propofol after cardiac surgeries can also be delivered more precisely using closed-loop system.[88,96] With robotic surgery being the norm of the day, closed-loop anesthesia can be compared to pharmacological robot.[97] Teleanesthesia is also not far away where not only the patient's fitness will be done by distant preoperative assessment but also anesthesia will be provided at distant locations.[98]

Pitfalls of drug delivery system

1. Final drug product could turn out to be costly when high-end technology is being used

2. Toxicity of the various carriers

3. Lack of knowledge about the degradation products

4. Trained staff to administer personalized treatment and to use various DDS

5. Patient compliance may be affected due to complex devices.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.