Intrathecal drug administration

Administration of dmgs in solution by intrathecal catheter provides an opportunity to delivery drugs to the brain and spinal cord. 

The intrathecal route is more invasive than i.v, i.m. or s.c routes. Both percutaneously implanted catheters and subcutaneously implantable pumps have heen used to reduce the risk of infection on repeated puncture. 

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Intrathecal Drug administration into the cerebrospinal fluid of the spinal cord. 

Combinations of amphotericin-B with flucytosine are sometimes used to reduce the occurrence of resistance. Amphotericin-B is not absorbed from the gastrointestinal tract which necessitates intravenous administration. It is 90% protein bound and widely distributed, except for the CNS. For the treatment of fungal meningitis therefore only intrathecal drug administrations can be effective. Amphotericin-B is eliminated very slowly in urine, mainly in an inactive form, with an elimination half-life of about 24 hours which can increase to up to 15 days with repeated doses. 

Central nervous system toxicity is unusual with vinca alkaloids, because they do not readily cross the blood-brain barrier. However, fatal myeloencephalopathy can occur a few hours after accidental intrathecal drug administration (58,59), with severe bilateral leg pain, and over the next 36 hours progressive leg weakness, urinary retention, meningism, fever, and somnolence. Other effects include absence of deep tendon and gag reflexes and disappearance of rectal tone. In spite of high-dose folinic acid rescue, patients became comatose, for example by the fourth day after injection, with loss of brain stem function a few days later. 

Figure 9.56 Anatomical structures and pathways of drug movement important in intrathecal drug administration the lower part (sacral, lumbar) of the spinal cord is shown in this diagram.

Ease of use preservative-free morphine should be administered by or under the direction of a physician experienced in the techniques and familiar with the patient management problems associated with epidural or intrathecal drug administration. 

Monocytic oligocytosis and monocytic pleocytosis—in multiple sclerosis this is practically always a reactive manifestation after administration of intrathecal drugs. 

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. 

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. 

In neither of the last two cases was there motor blockade or neonatal sequelae. Such adverse effects can be caused by sufentanil, bupivacaine, or both. Regardless of which drug caused these events, the intrathecal administration of a hypobaric solution to a patient in the sitting position might have contributed, since rostral spread of intrathecal drugs is accelerated in this setting. The use of smaller doses of sufentanil (2.5 or 5 micrograms) will also prevent such adverse effects. 

Parenteral (injected) administration of drugs provides a solution to many problems associated with the oral delivery route. A drug injected into the blood circulation is considered to be completely bioavail-able thaefore, the quantity of the surfactants and otha inactive excipients in intravenous dosage forms are usually strictly limited. The most common alternative routes of parenteral drug administration are intramuscular or subcutaneous injections [2], Several otha injection routes are available to elicit rapid local reaction, such as intrathecal, intraarticular, and intracardiac. 

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 ]. 

Like all opioid analgesics, intrathecal morphine may cause severe hypotension in a patient whose ability to maintain blood pressure is already compromised by hypovolemia or concurrent drug administration. 

The drug is metabolized rapidly in the liver, kidney, intestinal mucosa, and even red blood cells. Therefore it has a plasma half-life of only 10 min after bolus intravenous application. The major metabolite, uracil arabinoside (ara-U), can be detected in the blood shortly after cytarabine administration. About 80% of the dose is excreted in the urine within 24 h, with less than 10% appearing as cytarabine the remainder is ara-U. After continuous infusion, cytarabine levels in the liquor (cerebro-spinal fluid) approach 40% of that in plasma. Continuous infusion schedules allow maximal efficiency, with uptake peaks of 5-7 pM. It can be administered intrathecally as an alternative to methotrexate. 

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. 

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). 

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. 

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 of the ester-linked local anaesthetics are rapidly hydrolysed by plasma cholinesterases and liver esterases. Because the cerebrospinal fluid contains little or no esterase, intrathecal administration of these drugs produces a prolonged effect, which persists until the agent is absorbed into the bloodstream. 

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