Administration routes intrathecal

Parenteral is defined as situated or occurring outside the intestine, and especially introduced otherwise than by way of the intestines —pertaining to essentially any administration route other than enteral. This field is obviously too broad for an adequate focus in one book, let alone one chapter. Many have nonetheless used the term synonymously with injectable drug delivery. We restrict ourselves to this latter usage. This would thus include intravenous, intramuscular, subcutaneous, intrathecal, and subdural injection. In this chapter we discuss the theoretical and practical aspects of solubilizing small molecules for injectable formulation development and will examine the role of surfactants and other excipients in more recent parenteral delivery systems such as liposomes, solid-drug nanoparticles and particulate carriers. 

Drug administration route An obstructed catheter connection pin discovered during intrathecal baclofen pump exchange caused increased intrathecal drug dosage requirements and eventually oral baclofen was required [51 ]. 

Fig. 13.2 Epidural and intrathecal administration route. Source Recepteerkunde 2009, KNMP...

An example of calculating the limits for endotoxins A morphine containing injection solution with the strength of 100 mg/5 mL has been prepared. Because the product will be administered parenterally a bacterial endotoxins test has to be performed. Therefore the administration route has to be known is this intravenous or intrathecal or epidural. For endotoxins in intravenous administration the requirement is maximally 5 EU/kg body weight during 1 h. Based on a body weight of 70 kg this means 350 EU/h. Secondly the maximal dose (in volume of the product per hour) will determine the actual limit. This depends on the need of the patient as well. If he needs the full 5 mL, this makes the requirement for the product to be 350 EU/5 mL = 70 EU/mL. 

Opioids maybe administered in a variety of routes including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, intravenous, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so intravenous or subcutaneous administration maybe preferred if more rapid relief is desired. Intramuscular injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but may also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the intravenous route, but less frequently by the subcutaneous or epidural route. 

The major routes of parenteral administration of drugs are subcutaneous, intramuscular, and intravenous. Other more specialized routes are intrathecal, in-tracistemal, intra-arterial, intraspinal, intraepidural, and intradermal. The intradermal route is not typically used to achieve systemic drug effects. The major routes will be discussed separately. Definitions of the more specialized routes, along with additional information concerning needle sizes, volumes typically administered, formulation constraints, and types of medication administered, are summarized in Table 1. 

However, for certain routes of injection, such as intrathecal, intraocular, or into any part of the brain, isotonicity and physiological pH are critical in order to minimize potential nerve damage. Absence of preservatives is also critical for these routes of administration for the same reason. 

With increased meningeal inflammation, there will be greater antibiotic penetration (Table 36-3). Problems ofCSF penetration maybe overcome by direct instillation of antibiotics by intrathecal, intracisternal, or intraventricular routes of administration (Table 36-4). 

Morphine is often the choice in this category (1) multiple products available (2) multiple route of administration options, such as oral, rectal. IM. SC. IV. epidural, and intrathecal and (3) a known eqiipotency between these routes that allows a much easier transition. 

Only the first three are discussed in any detail here. Most of these routes of administration place a drug directly or indirectly into systemic circulation. There are a number of these routes, however, by which the drug exerts a local effect, in which case most of the drug does not enter systemic circulation (e.g., intrathecal, intraventricular, intraocular, intraracistemal). Certain routes of administration may exert both local and systemic effects depending on the characteristics of the drug and excipients (e.g., subcutaneous). 

Incidents of vincristine overdosage have been reported relatively frequently in the medical literature. Some of these have involved inadvertent administration of the intravenous formulation into the central nervous system by the intrathecal route this produces devastating results by a combination of chemical damage to sensitive neuronal tissue as well as biochemical perturbations. Two representative cases of vincristine overdose were described (46) involving administration of vincristine to patients scheduled to receive vinblastine. In one patient toxicity initially involved vomiting and diarrhea with subsequent constipation and paralytic ileus (inhibition of motor activity in the small intestine). Muscle pain... 

Astromorph PF, Duramorph, Infumorph - Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose. 

Intrathecal Management of severe spasticity of spinal cord origin in patients who are unresponsive to oral baclofen therapy or experience intolerable CNS side effects at effective doses. Intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in implantable pumps approved by the FDA specifically for the administration of baclofen into the intrathecal space. 

IV administration - Administer by IV infusion only, slowly over a period of 60 minutes or more (750 mg over 90 minutes). Avoid rapid or bolus IV infusion. Do not administer by IM, intrathecal, intraperitoneal, or subcutaneous routes. Single-use vials require dilution prior to administration. 

Ziconotide is a non-opioid, non-NSAID, non-local anesthetic used for the amelioration of chronic pain. In December 2004 the FDA approved ziconotide for intrathecal administration. The drug is derived from a marine snail toxin. Its mechanism of action has not yet been elucidated. Due to serious side effects or lack of efficacy when delivered through more conventional routes ziconotide must be administered in-trathecally. It s use is considered appropriate only for management of severe chronic pain in patients for whom intrathecal therapy is indicated. 

Other routes of administration can be employed in certain situations. Methotrexate and cytarabine are given intrathecally or intraventricularly to prevent relapses in the meninges in acute lymphocytic leukemia and to treat carcinomatous meningitis. Thiotepa and bleomycin have been administered by intravesical instillation to treat early bladder cancers. Fluorouracil can be applied topically for certain skin cancers. 

Some of the dosage formulations available for protein pharmaceuticals are listed in Table 5.7. An examination of Table 5.7 reveals that no protein drug up until this time has been formulated for oral administration. Most protein drugs are administered by means of injection (parenteral administration). Parenteral administration includes intravenous, intra-arterial, intracardiac, intraspinal or intrathecal, intramuscular, intrasynovial, intracuta-neous or intradermal, subcutaneous injections, and injection directly into a dermal lesion (e.g., a wart). The parenteral route of administration requires a much higher standard of purity and sterility than oral administration. It also may require trained... 

Most therapeutic proteins and peptides are formulated as solution or suspensions for injection (i.e., intravenous, subcutaneous, intramuscular, intraperitoneal, intravitreal, or intrathecal). These routes of administration are described in Table 5.5. Parenteral administration provides a more predictable therapeutic profile than oral administra-... 

Side effects and complications tend to be higher with the intrathecal than the epidural route. A common side effect is pruritus, the incidence of which is higher with intrathecal than with epidural administration. It is dose-dependent, with an incidence of about 10% after epidural morphine 5 mg. The risk of severe, distressing itching is about 1%. Pruritus may be related to cephalad spread of morphine... 

Dosages and routes of administration Diamorphine is given by the oral as well as by parenteral (i.m., s.c) or intrathecal routes. Diamorphine is about twice as potent as morphine. The parenteral doses are 5-10 mg every 4 h, oral doses are up to two-fold higher. 

Dosages and routes of administration Morphine is available in different salt forms but the hydrochloride and sulfate (Vermeire and Remon, 1999) are used preferentially. The compound can be administered by the oral, parenteral or intraspinal route. Oral application is preferred for chronic pain treatment and various slow release forms have been developed to reduce the administration frequency to 2-3 times per day (Bourke et al., 2000). Parenteral morphine is used in intravenous or intramuscular doses of 10 mg, mostly for postoperative pain and self-administration devices are available for patient-controlled analgesia (PCA). Morphine is additionally used for intraspinal (epidural or intrathecal) administration. Morphine is absorbed reasonably well in the lower gastrointestinal tract and can be given as suppositories. 

Most muscle relaxants are absorbed fairly easily from the gastrointestinal tract, and the oral route is the most frequent method of drug administration. In cases of severe spasms, certain drugs such as methocarbamol and orphenadrine can be injected intramuscularly or intravenously to permit a more rapid effect. Likewise, diazepam and dantrolene can be injected to treat spasticity if the situation warrants a faster onset. As discussed earlier, continuous intrathecal baclofen administration may be used in certain patients with severe spasticity, and local injection of botulinum toxin is a possible strategy for treating focal dystonias and spasticity. Metabolism of muscle relaxants is usually accomplished by hepatic microsomal enzymes and the metabolite or intact drug is excreted through the kidneys. 

Amphotericin B has been used intrathecally in patients with coccidioidal or cryptococcal meningitis. The side effects associated with this route of administration are headache, paraesthesia, nerve palsy, and visual impairment. To treat coccidioidal arthritis, amphotericin B may be injected intraarticularly (Figure 45.2). 

Methotrexate is administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55-3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action. 

Route of Administration. An application for a change in the route of administration, such as a change from an intravenous to intrathecal route. 

As indicated in Table 2.1, drugs may be injected into veins, muscles, subcutaneous tissue, arteries, or into the subarachnoid space of the spinal canal (intrathecal). For obvious reasons, intraarterial and intrathecal injections are reserved for specialized drug administration requirements, such as regional perfusion of a tumor with a toxic drug or induction of spinal anesthesia, respectively. Therefore, the more routine injection routes are intravenous (IV), intramuscular (IM), and subcutaneous (SC). Because these three modalities involve skin puncture, they carry the risks of infection, pain, and local irritation. 

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