Chapter 9. Pharmacology for the Orthopaedic Physical Therapist

At the completion of this chapter, the reader will be able to:

1. Differentiate between pharmacokinetics and pharmacodynamics.

2. Describe the process behind drug development, regulation, and distribution.

3. Describe controlled substances and their potential for abuse.

4. Recognize the three different names used for drugs.

5. Describe the various modes of action of drugs.

6. Describe the various drug receptor sites within the body.

7. Outline the different administration routes used for drug delivery.

8. Understand the potential effects of physical agents and exercise on drug delivery.

Physical therapists in many states are now positioned to provide care for patients prior to physician intervention. Although the dispensing of medications is out of the scope of practice for a physical therapist, questioning the patient about prescribed medication use can reveal medical conditions that the patient might not consider related to his or her present problem.1 As physical therapists attempt to account for the effects of their interventions, it becomes apparent that they must also understand the effect and potential interactions of all available and reasonable resources, including pharmacological interventions, offered by other members of the health-care team.1 Drug therapy is one of the mainstays of modern treatments and physical therapists often encounter patients who are taking various medications. These medications may be administered to treat preexisting conditions that are not directly related to the condition being treated with physical therapy but can nonetheless have an impact on the patient's response to rehabilitation.2 Medications also can have an impact on clinical findings and on the success of an intervention.3 For example:

• Pain medications, muscle relaxants, and nonsteroidal anti-inflammatory drugs (NSAIDs) can mask signs and symptoms, thereby affecting examination findings and increasing the potential for injury during the performance of prescribed exercises.4 However, if the patient has a significant amount of pain, appropriate use of these medications may enhance treatment, allowing a more rapid progression than would otherwise be possible. However, as the patient improves, the need for this medication should lessen.
• Certain medications can produce changes in musculoskeletal structures. For example, prolonged use of corticosteroids may produce osteoporosis and weakening of connective tissues.5
• A patient undergoing anticoagulant therapy has a reduced clotting ability and is more susceptible to bruising or hemarthrosis. It is worth remembering that aspirin and aspirin-based products have an anticoagulant effect.

Pharmacology is the broad area of study that deals with how chemical substances affect living tissue on a molecular level and how drugs affect specific patient populations (Table 9-1). The Guide to Physical Therapist Practice6 identifies clinical pharmacology as an essential component of appropriate patient monitoring, modality delivery, and communication among medical professionals. It is important for the physical therapist to have a working knowledge of pharmacology because of the number of drugs currently on the market and the number of physical therapy patients that are likely to have been prescribed medications. The prescription-drug-writing privileges exercised by select military therapists and the evolution of the physical therapy profession promote consideration of an expanded pharmacological role in physical therapy practice.7 While the importance of a pharmacologically integrated approach to comprehensive patient management cannot be over emphasized, it is worth remembering that while some drugs can enhance physical therapy interventions, many can have negative consequences.

Pharmacokinetics is the study of the physicochemical factors involved as the body absorbs, distributes, metabolizes, and eliminates a drug. To have a desirable effect, drugs must have the appropriate concentration at the site of action. Absorption is the process by which a drug is made available to the body fluids that distribute the drug to the organ systems. A prerequisite to absorption is drug dissolution.8 For those drugs administered other than directly into the bloodstream, an absorbed drug must cross at least two layers of cells.8 The physicochemical properties of drugs, their dosage formulations, and routes of administration determine the level of drug absorption and the response that occurs. The primary routes of administration include oral, buccal, sublingual, rectal, parenteral, topical, and inhalational (Table 9-2). As the target cells become exposed to increasing concentrations of the drug, increasing numbers of receptors become activated, and the magnitude of the response increases until there is a maximal response. In pharmacology, the term bioavailability is used to describe the rate and extent of a therapeutically active drug that reaches the systemic circulation and is available at the site of action. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages. The concept of equivalence among drug products is also important in making clinical decisions:

• Chemical equivalence refers to drug products that contain the same compound in the same amount and that meet current official standards; however, inactive ingredients in drug products may differ.
• Bioequivalence refers to chemical equivalents that, when administered to the same person in the same dosage regimen, result in equivalent concentrations of drug in the blood and tissues.
• Therapeutic equivalence refers to drug products that, when administered to the same person in the same dosage regimen, provide essentially the same therapeutic effect or toxicity. Bioequivalent products are expected to be therapeutically equivalent.

Thus, the physicochemical properties of a drug govern its absorptive potential, but the properties of the dosage form (which partly depend on its design and manufacture) and the mode of administration can largely determine drug bioavailability.

The volume of distribution is used to indicate how a systemic dose of the medication is ultimately dispersed throughout the body. Volume of distribution represents how much of the drug appears in the plasma relative to the total amount of drug administered, thus having important implications as to the amount of drug that reaches the target tissue. Because of high levels of blood flow, well-perfused organs such as the heart, liver, kidney, and brain rapidly receive most of the drug during the first few minutes after absorption.9 Tissues with less vascular perfusion such as muscle, skin, and fat require several minutes longer to achieve a steady state. The process of absorption, distribution, biotransformation, and excretion of a drug as related to passage across cell membranes is dependent upon the characteristics of the drug's molecular size, shape, solubility, site of absorption, degree of ionization, and relative lipid solubility of its ionized and nonionized forms.9 Clearance is the rate at which the active form of the drug is removed or eliminated from the body. It is the time taken to clear the drug from blood plasma. The rate of the process to inactivate a drug or eliminate it from the circulation is referred to as the elimination half-life (see later).

Transport Across Cell Membranes

When given by most routes (excluding intravenously), a drug must traverse semipermeable cell membranes at several locations before reaching the systemic circulation (Fig. 9-1). These membranes are biologic barriers that selectively inhibit the passage of drug molecules and are composed primarily of a bimolecular lipid matrix, containing mostly cholesterol and phospholipids. The lipids provide stability to the membrane and determine its permeability characteristics. Globular proteins of various sizes and composition are embedded in the matrix; they are involved in transport and function as receptors for cellular regulation. Drugs may cross a biologic barrier by diffusion through the water-filled channels or specialized ion channels, passive diffusion through the lipid membrane, carrier-mediated processes that include a facilitated diffusion, active transport, or pinocytosis.

Diffusion

Most drugs are weak organic acids or bases, existing in nonionized and ionized forms in an aqueous environment. The nonionized form is usually lipid soluble and diffuses readily across cell membranes. The ionized form cannot penetrate the cell membrane easily because of its low lipid solubility and the high electrical resistance provided by the lipid portion of the membrane. Steroids are nonionized (lipid soluble), the receptors for which are located inside the cell rather than on the external surface of the cell. Distribution of an ionizable drug across a membrane at equilibrium is determined by the drug's pKa (the pH at which concentrations of nonionized and ionized forms of the drug are equal) and the pH gradient, when present. For a weak acid, the higher the pH, the lower the ratio of nonionized to ionized forms. In plasma (pH, 7.4), the ratio of nonionized to ionized forms for a weak acid (e.g., with a pKa of 4.4) is 1:1000; in gastric fluid (pH, 1.4), the ratio is reversed (1000:1). When the weak acid is given orally, the concentration gradient for nonionized drug between stomach and plasma tends to be large, favoring diffusion through the gastric mucosa. At equilibrium, the concentrations of nonionized drug in the stomach and in the plasma are equal because only the nonionized drug can penetrate the membranes; the concentration of ionized drug in the plasma would then be about 1000 times greater than that in the stomach. For a weak base with a pKa of 4.4, the outcome is reversed. Thus theoretically, weakly acidic drugs (e.g., aspirin) are more readily absorbed from an acid medium (stomach) than are weak bases (e.g., quinidine).

Passive Diffusion

In this process, transport across a cell membrane depends on the concentration gradient of the solute. Most drug molecules are transported across a membrane by simple diffusion from a region of high concentration (e.g., gastrointestinal [GI] fluids) to one of low concentration (e.g., blood). Because drug molecules are rapidly removed by the systemic circulation and distributed into a large volume of body fluids and tissues, drug concentration in blood is initially low compared with that at the administration site, producing a large gradient. The diffusion rate is not only directly proportional to the gradient but also depends on the molecule's lipid solubility, degree of ionization, and size and the area of the absorptive surface. Because the cell membrane is composed of lipids, lipid-soluble drugs diffuse across the membrane more rapidly than relatively lipid-insoluble drugs. Small molecules tend to penetrate membranes more rapidly than large ones.

Facilitated Passive Diffusion

For certain molecules (e.g., glucose), the rate of membrane penetration is greater than predicted due to their low lipid solubility. One theory is that a carrier component combines reversibly with the substrate molecule at the cell membrane exterior, and the carrier–substrate complex diffuses rapidly across the membrane, releasing the substrate at the interior surface. Carrier-mediated diffusion is characterized by selectivity and saturability: The carrier transports only those substrates with a relatively specific molecular configuration, and the process is limited by the availability of carriers. The process does not require energy expenditure, and transport against a concentration gradient does not occur.

Active Transport

This process is characterized by selectivity and saturability and requires energy expenditure by the cell. Substrates may accumulate intracellularly against a concentration gradient. Active transport appears to be limited to drugs structurally similar to endogenous substances. These drugs are usually absorbed from sites in the small intestine. Active transport processes have been identified for various ions, vitamins, sugars, and amino acids.

Pinocytosis

A cell engulfs fluid or particles. The cell membrane invaginates (encloses) the fluid or particles, then fuses again, forming a vesicle that later detaches and moves to the cell interior. This mechanism requires energy expenditure. Pinocytosis probably plays a minor role in drug transport, except for protein drugs.

Distribution of Drugs

The distribution of a drug refers to the movement or transport of a drug to the site of action. Once a drug enters the systemic circulation, it is distributed to different parts of the body including the interstitial and intracellular fluid, and extravascular tissues. The rate at which this occurs depends on a variety of factors including the following10:

• The rate of organ blood flow.
• The degree of drug ionization in different compartments.
• The binding of a percentage of the drug molecules to serum protein. The primary protein that binds drug molecules is serum albumin. Binding prevents the drug from exerting any pharmacologic action. The unbound molecules are the portions of the drug that can penetrate capillary walls to reach the site of action.
• The number of competing drugs within the system. Some drugs compete for the same binding sites. This competition may result in higher levels of the unbound drug acting on the body.
• Molecular weight.
• Blood–brain barrier. Many drugs that easily penetrate other body organs do not appreciably enter the brain because of the sieve-like action of the blood–brain barrier.
• Lipid solubility.
  • Lipid soluble drugs are more likely to penetrate the blood–brain barrier than other drugs because they pass through the cell membrane.
  • Lipid soluble drugs may be stored in adipose tissue, which acts as a drug repository.
• Any local metabolism that occurs at any tissue other than the target organ.

Metabolism of Drugs

Metabolism refers to the process of transforming a drug into a compound that can be excreted. Metabolism occurs primarily in the liver, which reduces the drugs pharmacological activity and lipid solubility. Drug metabolism involves two processes or phases:

• Phase I. These reactions are catabolic and involve oxidation, reduction, full hydrolysis reactions, with oxidation occurring most frequently.
• Phase II. During this phase the drug undergoes conjugation reactions.

Drug Elimination

Drugs are eliminated from the body by a variety of routes including elimination in fluids (urine, breast milk, saliva, tears, and sweat), through the GI tract in the feces, and expelled in exhaled air through the lungs. The kidney is the primary organ for the excretion of drugs that have been inactivated by the liver into water-soluble metabolites.11 Excretion of a drug by the kidneys occurs by two processes10:

• Glomerular filtration. The process in which drugs are filtered through the glomerulus and then carried through the tubule into the urine. The rate of drug excretion depends upon renal blood flow. Renal blood flow may be diminished with kidney pathology and the aging process.8
• Active secretion of the drug by the tubule into the urine.

Drug Half-Life

The rate at which a drug disappears from the body, through metabolism, excretion, or a combination is called the half-life. It is the amount of time required for half of the drug that is in the body to be eliminated. Two terms are used to describe half-life:

• Elimination half-life.
  • The time in which the concentration of the drug in the plasma falls to one-half of its original amount.
  • A drug's rate of disappearance from the body, whether by metabolism, excretion or a combination of both.
• Biological half-life.
  • The time in which the duration of action falls to one-half of its original duration.
  • The time of the drug's response rather than its plasma concentration.

Knowing the half-life of a drug is critical in determining how often and in what dosage a drug must be administered to achieve and maintain therapeutic levels of concentration. The dosage interval (time between administrations of the drug) is equal to the half-life of a particular drug. The shorter the half-life, the more often the patient must take the medication. Theoretically a steady state will be reached when the amount of the drug taken will equal the amount that is excreted. A steady state is usually reached after five half-lives of the drug have occurred. Thus, drugs with long half-lives may take several days to weeks to reach a steady state.

Drug Allergy and Drug-Induced Illnesses

Drug allergies or hypersensitivities range from mild presentations to very severe life-threatening events. For a drug to produce a reaction, it must have antigenic effects and stimulate antibody formation or the formation of sensitized T-lymphocytes, which is immune-related. Drug allergies are generally classified into four types:

• Type I (anaphylactic reactions). Anaphylaxis is the most severe allergic reaction and involves the skin and pulmonary and cardiovascular systems, producing cardiovascular and respiratory collapse. The signs and symptoms associated with anaphylactic shock, which usually occur within minutes after antigen exposure, but may still occur up to 1 hour later, include:
  • Neurological: dizziness, weakness, and seizures.
  • Ocular: pruritus, lacrimation, edema around the eyes.
  • Respiratory: nasal congestion, hoarseness, stridor, cough, dyspnea, tachypnea, bronchospasm, and respiratory arrest.
  • Cardiac: tachycardia, hypotension, arrhythmias, myocardial infarction.
  • Integumentary: flushing, erythema, urticaria.
  • Gastrointestinal (GI): nausea, vomiting, and diarrhea.
• Type II (cytotoxic reaction). The antigens adhere to the target cell and begin to destroy the target tissue. The clinical manifestations include:
  • Fever
  • Arthralgia
  • Rash
  • Splenomegaly
  • Lymph node enlargement.
• Type III (autoimmune reaction). A complex mediated hypersensitivity reaction in which the body has difficulty in eliminating antigen–antibody complexes. Manifestations include serum sickness, glomerulonephritis, vasculitis, and pulmonary disorders.
• Type IV (cell-mediated hypersensitivity). This type of reaction is mediated through T-lymphocytes as opposed to antibodies. Manifestations include local or tissue reaction.

The Effects of Exercise on Pharmacokinetics

The bioavailability of drugs can be altered with exercise, primarily because of the influence upon the drug's absorption site caused by exercise.12 The effects of exercise on drug distribution are complex and are dependent on factors that pertain to the characteristics of each drug as well as exercise-related factors such as exercise intensity, mode, and duration.2 According to the limited information available, the effects of exercise on bioavailability following oral drug administration have produced conflicting results. Exercise increases muscular blood flow and temperature and the subsequent enhancement of absorption through molecular diffusion across biological membranes. For example, there is an increased binding of digoxin (a heart medication that reduces the ventricular rate) in working skeletal muscle.12 On the other hand, exercise may sequester some drugs such as propranolol (a medication used to treat hypertension) in muscle and reduce the availability of the drug for elimination. In addition, exercise decreases the clearance of highly extracted drugs and increases their plasma concentration. Hepatic blood flow has been found to be reduced as much as 50% with an exercise intensity level of 70% of maximal oxygen uptake.13 Decreasing hepatic blood flow could potentially decrease the clearance of drugs that are metabolized as a function of blood through the liver. In a similar fashion, since exercise reduces renal blood flow, the plasma concentrations of those drugs that are primarily eliminated by the kidneys may increase.13

However, exercise does appear to enhance absorption from intramuscular, subcutaneous, transdermal (iontophoresis, phonophoresis), and inhalation sites. However, exercise at the site of administration also increases cutaneous blood flow which, in the case of iontophoresis and phonophoresis, could be therapeutically unfavorable as the target site of drug administration could become diluted below therapeutic levels.8

The Effects of Physical Agents on Pharmacokinetics

Similar to exercise, physical therapy modalities have the potential to alter the pharmacokinetics of locally and systemically administered drugs, primarily by affecting blood flow and tissue kinetic and metabolic activity.8,14 Thermal agents that increase regional blood flow can potentially increase delivery of a drug to a specific tissue site, although there are a few studies that have documented whether these changes have any clinical relevance. However, application of local heat to the site of the drug administration will almost certainly increase dispersion of the drug away from the delivery site.2 Theoretically, cold can restrict drug delivery by causing vasoconstriction at the cryotherapy site.2

The Effects of Manual Techniques on Pharmacokinetics

Manual techniques that increase blood flow to an area, such as massage, increase drug absorption from local subcutaneous injection sites.15 Whether massage has an effect on the delivery of systemically administered drugs is not known at present.

In conclusion, because some physical therapy interventions are capable of producing complex changes in the pharmacokinetics of certain drugs, any variation in the clinical response that is observed during or after a physical therapy session, should raise the suspicion about the potential pharmacokinetic affect of a drug.8 In addition, if maintaining the plasma concentration of a drug at a certain level is important, consideration should be given to alternative drugs if the patient is to receive a treatment that may affect the absorption, distribution, and metabolism of a drug.14

An understanding of the potential effects of certain types of drugs commonly encountered during the rehabilitation process is essential.15

Musculoskeletal Pharmacology

Drugs are widely used in the management of both acute and chronic pain and inflammation. By far the most frequently encountered and/or prescribed drug agents in physical therapy practice are those that are prescribed to control pain and/or inflammation.

Opioid Analgesics

Most of the narcotics used in medicine are referred to as opioids, as they are derived directly from opium or are synthetic opiates.16 Examples of these opioids include codeine, Darvon (propoxyphene hydrochloride), morphine, and Demerol (meperidine) (see “Narcotic Analgesics”). Opioid analgesics are more effective in controlling pain of a constant duration versus sharp intermittent pain.17

Nonopioid Analgesics

Nonopioid analgesics comprise a heterogeneous class of drugs including the salicylates (aspirin and diflunisal), para-aminophenol derivatives (primarily acetaminophen), and the NSAIDs, such as ibuprofen, Voltaren, Relafen, Naprosyn, Motrin, Indocin, Feldene, Lodine, Celebrex, and many others. Despite their diverse structures, nonopioid analgesics have similar therapeutic effects, oral efficacy, and similar side effect profiles. Nonopioid analgesics are better tolerated compared to opioids by ambulatory patients, have less sedative effects, and are much less likely to produce tolerance or dependence. Conversely, the hazards of long-term administration of these drugs are recognized.

Salicylates7

Aspirin, an acetylsalicylic acid, has been recognized for its pharmaceutical properties for centuries. The pharmacology of aspirin is quite consistent with that of other NSAIDs and it remains the prototype for comparisons of the efficacy and safety of new medications in its class. Aspirin continues to be the first-line drug for a variety of conditions, including mild pain, fever, osteoarthritis, rheumatoid arthritis, stroke prevention therapy, and potential reduction of prostate cancer incidence.18 Other NSAIDs differ from aspirin in kinetics, duration of action, and patient tolerance, but the overall efficacy is very similar.

Para-Aminophenol Derivatives

Of the para-aminophenol derivatives, only acetaminophen (Tylenol) is widely used. Acetaminophen is not typically classified as an NSAID because of its lack of an anti-inflammatory effect (it does not inhibit prostaglandin synthesis in peripheral tissues). Acetaminophen is primarily centrally-acting yet exerts its analgesic and antipyretic effects peripherally by weak inhibition of both isoforms of cyclooxygenase through an unknown mechanism.19

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs are distinguished from true steroid agents such as cortisone (cortisol), prednisone (see later), and from the opiate derived analgesics.

NSAIDs have antipyretic, anticlotting (nonselective NSAIDs only), analgesic, and anti-inflammatory effects and are by far the most frequently encountered form of drug in physical therapy practice. NSAIDs are the first-line drug choice for the treatment of mild to moderate pain, soft tissue injury, osteoarthritis, gout, and inflammatory rheumatic disorders.7 Of those patients seeing physical therapists, 25–40% are taking prescription anti-inflammatory agents, with about 40% of those using multiple NSAIDs concomitantly.7,20,21 While it has been shown that NSAIDs may be of benefit in muscle and tendon healing, there is growing evidence of impairment of bone and cartilage healing due to NSAIDs.7

The analgesic and anti-inflammatory activity of NSAIDs is primarily due to the inhibition of arachidonic acid metabolism.22 Arachidonic acid is present on cell membranes throughout the body and acts as a substrate for prostaglandin, prostacyclin, and thromboxane synthesis.7 Arachidonic acid is released from cell membranes in response to physical, chemical, hormonal, and bacterial or other stimuli.7

NSAIDs also seem to promote the inhibition of the release of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) and the synthesis of prostaglandins at an injury site.22

• COX-1 inhibitors. COX-1 is constitutively present in virtually all tissues under normal conditions.7 The inhibition of COX-1 by NSAIDs has a tendency to produce a number of adverse effects on multiple organ systems, including GI inflammation, ulceration, bleeding, and increased potential for perforation. 23 Other possible side effects include an alteration of normal function in the GI mucosa and kidney blood flow, delayed wound healing, edema, nausea, dyspepsia, and fluid retention. NSAIDs may also alter kidney blood flow by interfering with the synthesis of prostaglandins in the kidney involved in the autoregulation of blood flow and glomerular filtration.24
• COX-2 inhibitors. Much attention has been given to the selective COX-2 inhibitors, such as celecoxib (Celebrex), which were developed to provide NSAID benefits without affecting the GI mucosa, renal tissue, or platelet aggregation.7 COX 2 is typically not found on cell membranes under baseline conditions but is induced and upregulated by cytokines, such as interleukin-1 in the presence of cell stress or injury.7 Because COX-2 inhibitors do not produce the same GI effects as COX-1 inhibitors, they are safer to use in patients who are predisposed to gastric or kidney malfunctions. COX-2 drugs block only the COX-2 enzyme, which is responsible for triggering pain and inflammation.22 Because COX 1 is not affected, the patient's stomach lining is protected and bleeding tendencies are avoided. However, the enthusiasm for the coxibs have been somewhat tempered by data suggesting they are associated with a higher risk of cardiovascular events than the nonselective NSAIDs, which led to the withdrawal from the market of two widely distributed drugs: Vioxx and Bextra.25

The pharmacokinetics of NSAIDs have been studied extensively7:

• Absorption. NSAIDs are typically lipid-soluble weak acids and are ideally suited for rapid absorption from the acidic stomach and duodenum. After ingestion, most NSAIDs will exhibit an effect within 15–30 minutes. The time interval to perceive symptom relief varies with the rate of enzymatic breakdown of previously synthesized prostaglandins and the time required for the ingested drug agent to inhibit replacement. Once in the bloodstream NSAIDs, except for aspirin, are heavily bound to plasma proteins. Despite the high level of NSAID protein binding, a therapeutic effect is exerted by the constant dissociation of the drug from its binding protein and release as free or active fraction within the serum. Because of NSAIDs' high-protein affinity they may displace other more weakly protein-bound drugs unintentionally, such as warfarin (Coumadin), sulfonyl-urea hypoglycemic agents (Diabinese, Glucotrol, Micronase, etc.), and methotrexate (Folex, Mexate, and Rheumatrex).
• Distribution. NSAIDs are widely distributed throughout most body tissues.
• Metabolism. The liver is responsible for metabolism and bioconversion of NSAIDs. Integration of NSAID half-life data into modality selection permits its planning for maximal drug benefit and minimized adverse impact on therapy. It is worth noting that drugs with longer half-lives are associated with the highest risk for adverse effect. The effect of a given NSAID will vary among individual patients, sometimes leading to a trial of several different agents in an effort to obtain the best therapeutic effect. In clinical practice, 7–10 days are generally long enough to ascertain the effect of a given drug.
• Elimination. NSAIDs are eliminated by renal excretion. Alterations in urine pH can affect the level of ionized or nonionized drug residue and, therefore, rates of elimination.

Local Anesthetics

Local anesthetics decrease sensation in a body part without a loss of consciousness or impairments of vital functions that are associated with the use of a general anesthetic.17 All local anesthetics are membrane stabilizing drugs that act by reversibly decreasing the rate of depolarization and repolarization of nociceptor membranes by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell membrane. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is inhibited. The local adverse effects of anesthetic agents include neurovascular manifestations such as prolonged anesthesia and paresthesia, which are symptoms of localized nerve impairment. Depending on the local tissue concentrations of local anesthetics, there may be excitatory or depressant effects on the central nervous system, which can include generalized convulsions, coma, respiratory arrest, and death.

Corticosteroids

Corticosteroids can be classified as natural or synthetic. The natural form (mineralocorticoids) is produced by the adrenal glands, under the control of the hypothalamus, and is involved in maintaining fluid and electrolyte balance. Glucocorticoids (cortisol, and drugs such as prednisone), are used primarily for the treatment of a range of immunological and inflammatory musculoskeletal conditions. Although glucocorticoids affect nearly every major organ system in the body, their primary role is to regulate blood glucose. Corticosteroids exert their anti-inflammatory effects by binding to a high-affinity intracellular cytoplasmic receptor present in all human cells,26 which in turn interact with discrete nucleotide sequences to alter gene expression. Because most steroid receptors in target cells are located in the cytoplasm, they need to get into the nucleus to alter gene expression. The side effects from excess corticosteroids are associated with a number of negative side effects, including a catabolic effect on all types of supportive joint tissue. Exogenous steroid use leads to Cushing's syndrome27:

• Cutaneous manifestations. Cutaneous manifestations of hypercortisolism include delayed wound healing, acanthosis nigricans (a velvety, thickened, hyperpigmented plaque that usually occurs on the neck or in the axillary region), acne, ecchymoses after minor trauma, hyperpigmentation, hirsutism, petechia, and striae.
• Hypokalemia. Hypokalemia (a potentially fatal condition in which the body fails to retain sufficient potassium to maintain health) is a well-recognized side effect of corticosteroid therapy and is probably related to the mineralocorticoid effect of hydrocortisone, prednisone, and prednisolone. Dexamethasone has no mineralocorticoid effect.
• Myopathy. There are two recognized forms of corticosteroid-induced myopathy: acute and chronic. Acute myopathy may in part be caused by hypokalemia, although corticosteroids (especially massive dosages) may have a direct effect on skeletal muscle. Both proximal and distal muscle weakness occur acutely, usually with an associated and significant elevation in serum creatinine phosphokinase, which is indicative of focal and diffuse muscle necrosis. In the more chronic form of myopathy, weakness is more insidious in onset and primarily involves proximal muscle groups.
• Hyperglycemia. Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. When hyperglycemia is combined with the immunosuppressive effect of corticosteroids, there is a significant increase in the risk for infection.
• Neurological impairments. These can include vertigo, headache, convulsions, and benign intracranial hypertension.
• Osteoporosis. Corticosteroids inhibit bone formation directly via inhibition of osteoblast differentiation and type I collagen synthesis and indirectly by inhibition of calcium absorption and enhancement of urinary calcium excretion.
• Ophthalmologic side effects. Corticosteroids increase the risk of glaucoma by increasing intraocular pressure, regardless of whether administered intranasally, topically, periocularly, or systemically.
• Growth suppression. Corticosteroids interfere with bone formation, nitrogen retention, and collagen formation, all of which are necessary for anabolism and growth.

Disease Modifying Antirheumatic Drugs

Disease modifying antirheumatic drugs (DMARDs), sometimes referred to as slow acting antirheumatic drugs (SAARDs), are a group of drugs that appear to decrease inflammation, though they are not categorized as anti-inflammatory drugs. DMARDs differ from NSAIDs since they do not decrease prostaglandin production, do not directly relieve pain, nor reduce fever. In effect, DMARDs slow the disease process by modifying the immune system. DMARDs are most commonly used in the treatment of rheumatoid arthritis, when combined with anti-inflammatory agents, and corticosteroids, but some are also used for ankylosing spondylitis, psoriatic arthritis, and lupus. Studies throughout the years have shown DMARDs to be very effective drugs, with uncommonly observed serious side effects. The newest DMARDs are biological agents that specifically target and block interleukin-1 or tumor necrosis factor, both of which are cytokines that play a role in the inflammatory process in diseases such as rheumatoid arthritis.

Skeletal Muscle Relaxants

Skeletal muscle relaxants, such as Flexeril, Robaxin, and Soma, are thought to act by decreasing muscle tone without causing an impairment in motor function, and by acting centrally to depress polysynaptic reflexes. As muscle guarding and spasm accompany many musculoskeletal injuries, it was originally thought that these drugs, by eliminating the spasm and guarding, would facilitate the progression of a rehabilitation program. However, other drugs with sedative properties, such as barbiturates, also depress polysynaptic reflexes, making it difficult to assess if centrally acting skeletal muscle relaxants are actually muscle relaxants as opposed to nonspecific sedatives.28 There presently exists a discrepancy between the common clinical use of skeletal muscle relaxants and the results of controlled clinical trials evaluating their efficacy in comparison with placebo. Supporting evidence does not exist for their efficacy in pain of myogenic origin nor is it clear if they provide an additive effect with exercises aimed at muscle relaxation.

Because nearly all of the oral skeletal muscle relaxants have the potential to produce drowsiness, sedation, or muscle weakness, these agents can have an effect on the patient's ability to perform motor-related tasks or participate in therapy programs.17

Examples of Disease-Specific Drugs

Musculoskeletal System Pharmacology

Osteoporosis

While estrogen therapy is still used in the treatment of osteoporosis, there are a number of medication options presently being used. The current drug options for osteoporosis fall into four categories:17

1. Bisphosphonates (alendronate [Fosamax] and risedronate sodium [Actonel]). These are antiresorptive agents that decrease osteoclastic bone resorption. The results are decreased bone remodeling, indirectly increased bone mass, and a reduced risk of fractures.

2. Calcitonin (Miacalcin). This is a calcium lowering hormone secreted by the thyroid gland that exerts its effects by direct inhibition of osteoclast activity, and promotion of renal excretion of calcium and other minerals.

3. Selected receptor molecules (raloxifene hydrochloride [Evista]). This is a nonhormonal medication that acts as an estrogen agonist in bone to suppress bone remodeling without unfavorable stimulation of the estrogen receptors located on the breast tissue or the uterus.

4. Strontium Ranelate. A drug that offers the dual mechanisms of action of combining the antiresorptive effect with the anabolic effect of new bone formation.

Gout

The medications prescribed to treat gout usually depend on whether the patient produces too much uric acid or does not excrete uric acid properly. If the body produces too much uric acid, a drug such as allopurinol (Lopurin, Zyloprim) is used to slow uric acid production. In the case where the body does not excrete uric acid well, another drug such as probenecid (Benemid, Probalan) can be used.

Neurologic System Pharmacology

Antianxiety Medications

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed psychotherapeutic agents. Serotonin is a neurotransmitter synthesized from the amino acid L-tryptophan. Synthesis is necessary in both the central and peripheral nervous systems because serotonin cannot cross the blood–brain barrier. Once synthesized, serotonin is either stored in neuronal vesicles or metabolized by monamine oxidase (MAO) to 5-hydroxyindoleacetic acid. The most serious drug-related adverse effect of SSRIs is the potential to produce serotonin syndrome (SS). SS, characterized by mental status changes, neuromuscular dysfunction, and autonomic instability, is thought to be secondary to excessive serotonin activity in the spinal cord and brain. Symptoms attributed to serotonin excess may include

• restlessness
• hallucinations
• shivering
• diaphoresis
• nausea
• diarrhea
• headache

Commonly prescribed SSRIs include sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil), and fluvoxamine (Luvox).

Monoamine Oxidase Inhibitors (MAOIs)29

Neurotransmitters are generally monoamines. When released into the synaptic space, neurotransmitters are either reabsorbed into the proximal nerve or destroyed by monoamine oxidase (MAO) in the synaptic cleft. The two types of MAO are MAO-A and MAO-B. MAO-A is found primarily in the liver and GI tract with some found in the monoaminergic neurons. MAO-A present in the liver is involved in the elimination of ingested monoamines, such as dietary tyramine. Circulating monoamines such as epinephrine, norepinephrine, and dopamine are inactivated when they pass through a liver rich in MAO-A. MAO-B, on the other hand, is found primarily in the brain and in platelets.

MAOIs act by inhibiting the activity of MAO preventing the breakdown of monoamine neurotransmitters (norepinephrine, serotonin, and dopamine) thereby increasing the available monamines available within the central nervous system (CNS).

The MAOI agents currently available in the United States include phenelzine sulfate (Nardil), tranylcypromine sulfate (Parnate), isocarboxazid (Marplan), and selegiline (specific for the MAO-B enzyme), all of which irreversibly bind to MAO.

Benzodiazepines30

Benzodiazepines (BZDs) are sedative/hypnotic agents that are used for a variety of situations, including seizure control, anxiety, alcohol withdrawal, insomnia, control of drug-associated agitation, as muscle relaxants (antispasticity agents), and as preanesthetic agents. They also are combined frequently with other medications for conscious sedation before procedures or interventions.

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. BZDs exert their action by potentiating the activity of GABA. They bind to a specific receptor on the GABAA receptor complex, which facilitates the binding of GABA to its specific receptor site. BZD binding causes increased frequency of opening of the chloride channel complexes with the GABAA receptor. The reversal potential for GABAA/chloride complexes is negative to threshold for generating an action potential. In this way, activation of the GABAA receptor/chloride pore is inhibitory.

Enhanced GABA neurotransmission results in sedation, striated muscle relaxation, anxiolysis, and anticonvulsant effects. Stimulation of peripheral nervous system (PNS) GABA receptors may cause decreased cardiac contractility, vasodilation, and enhanced perfusion.

Beta-Blockers

Beta-blockers, for example, Propranolol, are a class of drugs used for various indications, including the management of cardiac arrhythmias, hypertension, cardioprotection after myocardial infarction, and to block the autonomic response in persons with social phobia.

Sedatives/Hypnotics

Sedative/hypnotics are a group of drugs that cause CNS depression and are mainly used in the treatment of insomnia, but can also be used to treat anxiety, depression, and psychosis. BZDs, which are non-barbiturates (see above) are the most commonly used agents in this class.31 Although barbiturates produce a sedative-hypnotic effect, the associated rapid development of tolerance carries with it a high risk of physical and psychological dependence, withdrawal syndromes, and fatalities by overdose. For these reasons, barbiturates are not routinely prescribed. BZDs induce sleep by decreasing the number of arousals between the different stages of sleep thereby allowing for more continuous total sleep time. Most sedative/hypnotics stimulate the activity of GABA, the principal inhibitory neurotransmitter in the CNS. γ-Hydroxybutyric acid (GHB) is a sedative/hypnotic recently banned for sale to the public because of frequent abuse and serious adverse toxic effects. GHB is a neuroinhibitory neurotransmitter or neuromodulator in the CNS. It also appears to increase GABAB receptor activity and dopamine levels in the CNS. Three other types of medications act on the same receptor as BZDs and, therefore, share some of the same pharmacological properties. These include the following:

• Zolpidem. Zolpidem is used to treat insomnia, and is particularly effective in initiating sleep. Zolpidem can also be used as an anticonvulsant and muscle relaxant.
• Zaleplon. Zaleplon is effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. The side effects of zaleplon are similar to the side effects of BZDs, although with less next-day sedation.
• Zopiclone. Zopiclone is a non-BZD hypnotic agent used in the treatment of insomnia. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the names Lunesta.

Mild toxicity of sedative/hypnotics resembles ethanol intoxication and can include excessive drowsiness, impaired psychomotor coordination, decreased concentration, and cognitive deficits.31 Moderate poisoning leads to respiratory depression and hyporeflexia. Severe poisoning leads to flaccid areflexic coma, apnea, and hypotension.

Occasionally, hyperreflexia, rigidity, clonus, and Babinski signs are present. Miosis is common, but mydriasis may be present with certain agents. The nonbarbiturates, such as methyprylon and glutethimide, more commonly present with mydriasis. Hypotension is usually secondary to vasodilation and negative cardiac inotropic effects.

Narcotic Analgesics

The term narcotic specifically refers to any substance that induces sleep. In current practice, narcotic refers to any of the many opioids or opioid derivatives.

Activation of the opiate receptors results in the inhibition of synaptic neurotransmission in the CNS and PNS. Opioids bind to opiate receptors thereby inducing a postsynaptic response. The physiological effects of opioids are mediated principally through μ and κ receptors in the CNS and periphery. μ receptor effects include analgesia, euphoria, respiratory depression, and miosis. κ receptor effects include analgesia, miosis, respiratory depression, and sedation. Two other opiate receptors that mediate the effects of certain opiates include σ and δ sites. σ receptors mediate dysphoria, hallucinations, and psychosis; δ receptor agonism results in euphoria, analgesia, and seizures. The opiate antagonists (e.g., naloxone, nalmefene, naltrexone) antagonize the effects at all four opiate receptors.

Common classifications divide the opioids into agonist, partial agonist, or agonist–antagonist agents and natural, semisynthetic, or synthetic. Opioids decrease the perception of pain, rather than eliminate or reduce the painful stimulus. Inducing slight euphoria, opioid agonists reduce the sensitivity to exogenous stimuli. The GI tract and the respiratory mucosa provide easy absorption for most opioids.

Peak effects are generally reached in 10 minutes with the IV route, 10–15 minutes after nasal insufflation (e.g., butorphanol, heroin), 30–45 minutes with the IM (intramuscular) route, 90 minutes with the PO (by mouth) route, and 2–4 hours after dermal application (i.e., fentanyl). Following therapeutic doses, most absorption occurs in the small intestine. Toxic doses may delay absorption because of delayed gastric emptying and slowed gut motility.

Most opioids are metabolized by hepatic conjugation to inactive compounds that are excreted readily in the urine. Certain opiates (e.g., propoxyphene, fentanyl, and buprenorphine) are more lipid soluble and can be stored in the fatty tissues of the body. All opioids have a prolonged duration of action in patients with liver disease (e.g., cirrhosis) because of impaired hepatic metabolism. This may lead to drug accumulation and opioid toxicity. Renal failure also leads to toxic effects from accumulated drug or active metabolites (e.g., normeperidine).

Opioid toxicity characteristically presents with a depressed level of consciousness. Opiate toxicity should be suspected when the clinical triad of CNS depression, respiratory depression, and pupillary miosis are present. Drowsiness, conjunctival injection (redness of the white sclera of the eye), and euphoria are seen frequently. Other important presenting signs are ventricular arrhythmias, acute mental status changes, and seizures.

Examples of commonly prescribed opioids include codeine phosphate, Demerol, Dilaudid, Empirin with codeine, Subli-maze, Synalgos-DC, Talwin 50, propoxyphene, morphine, Hydrocodone, Lorcet, Lortab, Zydone, Hydrocet, Oxycontin (Oxycodone), Percodan (Percocet), Darvon (Darvocet), and Vicodin (Vicoprofen).

Antidepressants

Tricyclic Antidepressants32

Tricyclic antidepressants (TCAs) are used in the treatment of depression, chronic pain, and enuresis (involuntary discharge of urine, especially while asleep). Patients with depression and those with chronic pain are at high risk for abuse, misuse, and overdosing of these drugs.

TCAs affect the cardiovascular, pulmonary, and GI systems, and the CNS. The toxic effects on the myocardium are related to the blocking of fast sodium channels, which involves the same mechanism as type IA antiarrhythmics (e.g., quinidine). The result is a slowing myocardium depolarization that leads to arrhythmia, myocardial depression, and hypotension. Hypotension also results from peripheral α-adrenergic blockade, which causes vascular dilatation. Inhibition of norepinephrine reuptake and subsequent depletion causes further hypotension. The effects on the pulmonary system include pulmonary edema, adult respiratory distress syndrome, and aspiration pneumonitis. The etiologies of the first two remain unclear, but the third, aspiration pneumonitis, is secondary to an altered mental status.

The anticholinergic effects of TCAs cause a slowing of the GI system, which results in delayed gastric emptying, decreased motility, and prolonged transit time.

CNS toxicity results from the anticholinergic effects and direct inhibition of biogenic amine reuptake. An excitation syndrome is the initial result and manifests as confusion, hallucinations, ataxia, seizures, and coma.

Examples of commonly prescribed TCAs include Amitriptyline, Clomipramine, Doxepin, Trimipramine, Desipramine, Nortriptyline, Protriptyline, Imipramine, Amoxapine (dibenzoxazepine), and Maprotiline (tetracyclic antidepressant).

Parkinson Disease and Parkinsonian Syndrome32

Parkinson disease (PD) is a progressive neurodegenerative disease affecting every 100–150 per hundred thousand individuals, or about 1% of those over 60 years of age, in the US population.33–35 PD is characterized clinically by tremor, bradykinesia, rigidity, and postural instability. The basal ganglia motor circuit modulates cortical output necessary for normal movement.

Levodopa, coupled with a peripheral decarboxylase inhibitor (PDI), remains the criterion standard of symptomatic treatment for PD. It provides the greatest antiparkinsonian benefit with the fewest adverse effects.

Dopamine agonists provide symptomatic benefit comparable to levodopa/PDI in early disease, but lack sufficient efficacy to control signs and symptoms by themselves in later disease.

Medications for PD usually provide good symptomatic control for 4–6 years. Whether levodopa has a toxic or protective effect in the brain with PD is unknown. As PD progresses, fewer dopamine neurons are available to store and release levodopa-derived dopamine. The patient's clinical status begins to fluctuate more and more closely in concert with plasma levodopa levels. Fluctuating levodopa-derived dopamine concentrations in association with advancing disease, therefore, may be responsible for development of motor fluctuations and dyskinesia.

In contrast to levodopa, the long-acting dopamine agonists (i.e., bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) provide relatively smooth and sustained receptor stimulation.

The selection of medication depends in part on the nature and cause of the disability. If disability is due solely to tremor, a tremor-specific medication, such as an anticholinergic agent, is often used. Anticholinergic medications provide good tremor relief in approximately 50% of patients, but do not improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication and not another, a second anticholinergic usually is tried if the first is not successful. These medications are usually introduced at a low dose and escalated slowly to minimize adverse effects, which include memory difficulty, confusion, and hallucinations. Adverse cognitive effects are relatively common, especially in the elderly.

If disability is due to a dopamine-responsive symptom such as bradykinesia, rigidity, decreased dexterity, slow speech, or shuffling gait, a dopaminergic medication (dopamine agonist or levodopa/PDI) are typically introduced. Symptomatic medications are started at a low dose, escalated slowly, and titrated to control symptoms. Most patients require symptomatic dopaminergic therapy to ameliorate bradykinesia and rigidity within 1–2 years after diagnosis.

For patients younger than 65 years, symptomatic therapy is normally initiated with a dopamine agonist and then add levodopa/PDI when the dopamine agonist alone no longer controls symptoms adequately. Dopamine agonists provide antiparkinsonian efficacy comparable to levodopa/PDI for 6–18 months or longer and may control symptoms adequately for several years.

For patients who are demented or those older than 70 years, who may be prone to adverse effects from dopamine agonists, and for those likely to require treatment for only a few years, physicians may elect not to use a dopamine agonist but depend on levodopa/PDI as the primary symptomatic therapy. For patients aged 65–70 years, a judgment is made based on general health and cognitive status.

Medications for Cerebrovascular Accidents

The ischemic cascade is a series of biochemical reactions that take place in the brain and other aerobic tissues after seconds to minutes of ischemia (inadequate blood supply; Table 9-3).36 Since the ischemic cascade is a dynamic process, the efficacy of interventions to protect the ischemic cascade also may prove to be time dependent.

Theoretically, calcium channel blockers (e.g., nimodipine) should have the narrowest window of therapeutic opportunity, since calcium influx is one of the earliest events in the ischemic cascade.

Neuroprotectants affecting later events in the ischemic cascade include free-radical scavengers (e.g., tirilazad, citicoline) and neuronal membrane stabilizers (e.g., citicoline). Monoclonal antibodies against leukocyte adhesion molecules also are being evaluated as late neuroprotectants (e.g., enlimomab).

Anticoagulants are considered as potential treatments for cerebrovascular accidents (CVA). However, although heparin prevents recurrent cardioembolic strokes and may help inhibit ongoing cerebrovascular thrombosis, no definitive evidence exists to show that initiating anticoagulation reduces brain injury in acute ischemic stroke.

Anticoagulation drug treatment is not without risk. Overall, intracranial hemorrhage occurs in 1–4% of patients who receive an anticoagulant for TIA or acute stroke. Accordingly, uncontrolled hypertension, intracranial hemorrhage, and uncontrolled bleeding at another site are contraindications to anticoagulation.

Several new oral anticoagulant medications, including ximelagatran, are in the final stages of clinical trials for use in the prophylaxis of ischemic thromboembolic stroke. Once approved for use, the potential of such drugs in the arena of stroke treatment may be significant.

Antiepileptic Drugs

Many structures and processes are involved in the development of a seizure, including neurons, ion channels, receptors, glia, and inhibitory and excitatory synapses.37 The antiepileptic drugs (AEDs) are designed to modify these processes to favor inhibition over excitation in order to stop or prevent seizure activity. The AEDs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups are as follows.

Sodium Channel Blockers

The sodium channel blockade is the most common and the most well-characterized mechanism of currently available AEDs. AEDs that target these sodium channels prevent the return of the channels to the active state by stabilizing their inactive form. In doing so, repetitive firing of the axons is prevented. The presynaptic and postsynaptic blockade of sodium channels of the axons causes stabilization of the neuronal membranes, blocks and prevents posttetanic potentiation, limits the development of maximal seizure activity, and reduces the spread of seizures. AED examples include carbamazepine, oxcarbazepine, lamotrigine, zonisamide, and the hydantoins: phenytoin, fosphenytoin.

Side Effects and Toxicity

AEDs can produce dose-related adverse effects, which include dizziness, diplopia, nausea, ataxia, and blurred vision. Rare idiosyncratic adverse effects include aplastic anemia, agranulocytosis, thrombocytopenia, and Stevens–Johnson syndrome. Asymptomatic elevation of liver enzymes is observed commonly during the course of therapy in 5–10% of patients. Rarely, severe hepatotoxic effects can occur.

GABA Receptor Agonists

GABA has two types of receptors:

• GABAA. GABAA receptor is stimulated and chloride channels open to allow the influx of negative ions (i.e., chloride). The GABAA receptors have multiple binding sites for BZDs, barbiturates, and others substances such as picrotoxins, bicuculline, and neurosteroids.
• GABAB. The GABAB receptor is linked to a potassium channel.

Direct binding to GABAA receptors can enhance the GABA system by blocking presynaptic GABA uptake, by inhibiting the metabolism of GABA by GABA transaminase, and by increasing the synthesis of GABA. The BZDs most commonly used for treatment of epilepsy are lorazepam, diazepam, clonazepam, and clobazam. The two barbiturates mostly commonly used in the treatment of epilepsy are phenobarbital and primidone.

Side Effects and Toxicity

The most common effect is sedation. Other adverse effects include dizziness, ataxia, blurred vision, diplopia, irritability, depression, muscle fatigue, and weakness.

ABA Reuptake Inhibitors

At least four specific GABA-transporting compounds help in the reuptake of GABA; these carry GABA from the synaptic space into neurons and glial cells, where it is metabolized. Nipecotic acid and tiagabine (TGB) are inhibitors of these transporters; this inhibition makes increased amounts of GABA available in the synaptic cleft, which serves to prolong GABA-mediated inhibitory postsynaptic potentials (IPSPs).

Side Effects and Toxicity

The most common adverse effects include dizziness, asthenia, nervousness, tremor, depressed mood, and emotional lability. Diarrhea also was significantly more frequent among TGB-treated patients than placebo-treated patients. Other adverse effects included somnolence, headaches, abnormal thinking, abdominal pain, pharyngitis, ataxia, confusion, psychosis, and skin rash.

GABA Transaminase Inhibitor

GABA is metabolized by transamination in the extracellular compartment by GABA-transaminase (GABA-T). Inhibition of this enzymatic process leads to an increase in the extracellular concentration of GABA. Vigabatrin (VGB) inhibits the enzyme GABA-T.

Side Effects and Toxicity

The most common adverse effect is drowsiness. Other important adverse effects include neuropsychiatric symptoms, such as depression (5%), agitation (7%), confusion, and, rarely, psychosis. Minor adverse effects, usually at the onset of therapy, include fatigue, headache, dizziness, increase in weight, tremor, double vision, and abnormal vision.

Glutamate Blockers

Glutamate and aspartate are the most two important excitatory neurotransmitters in the brain. The glutamate system is a complex system with macromolecular receptors with different binding sites (i.e., AMPA, kainate, NMDA, glycine, metabotropic site).

Examples of glutamate blockers include topiramate and felbamate.

Side Effects and Toxicity

Common adverse effects include insomnia, weight loss, nausea, decreased appetite, dizziness, fatigue, ataxia, and lethargy. Polytherapy is associated with increases in adverse effects.

Neuroleptics (Antipsychotics)

The term neuroleptic refers to the effects on cognition and behavior of antipsychotic drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses.38 Also known as major tranquilizers and antipsychotic drugs, neuroleptic agents comprise a group of the following classes of drugs:

• Phenothiazines
• Aliphatics
• Piperidines
• Piperazines
• Thioxanthenes (e.g., droperidol)
• Butyrophenones (e.g., haloperidol)
• Dibenzoxazepines (e.g., loxapine)
• Dihydroindolone (e.g., molindone)
• Diphenylbutylpiperidine (e.g., pimozide)
• Benzisoxazole (e.g., risperidone)

The adverse effects of neuroleptics are not confined to psychiatric patients. Neuroleptics also are used as sedatives, for their antiemetic properties, to control hiccups, to treat migraine headaches, as antidotes for drug-induced psychosis, and in conjunction with opioid analgesia.

The major tranquilizers have complex CNS actions that are incompletely defined. Their therapeutic action is thought to be primarily antagonism of central dopaminergic (D-2 receptor) neurotransmission, although they also have antagonist effects at muscarinic, serotonergic, α1-adrenergic, and H1-histaminergic receptors.

Although all antipsychotic preparations share some toxic characteristics, the relative intensity of these effects varies greatly, depending on the individual drug. Generally, all neuroleptic medications are capable of causing the following symptoms:

• Hypotension: Phenothiazines are potent α-adrenergic blockers that result in significant orthostatic hypotension, even in therapeutic doses for some patients. In overdose, the hypotension may be severe.
• Anticholinergic effects: Neuroleptic agent toxicity can result in tachycardia, hyperthermia, urinary retention, toxic psychosis, and hot dry flushed skin.
• Extrapyramidal symptoms: Alteration in the normal balance between central acetylcholine and dopamine transmission can produce dystonia, oculogyric crisis, torticollis, acute parkinsonism, akathisia, and other movement disorders. Chronic use of major tranquilizers is associated with buccolingual dysplasia (tardive dyskinesia, TD), parkinsonism, and akathisia.
• Neuroleptic malignant syndrome: All of the major tranquilizers have been implicated in the development of neuroleptic malignant syndrome (NMS)—a life-threatening derangement that affects multiple organ systems and results in significant mortality.
• Seizures: Most major tranquilizers lower the seizure threshold and can result in seizures at high doses and in susceptible individuals.
• Hypothermia: Certain major tranquilizers prevent shivering, limiting the body's ability to generate heat.
• Cardiac effects: Prolongation of the QT interval and QRS can result in arrhythmias.
• Respiratory depression: Hypoxia and aspiration of gastric contents can occur in children and in mixed overdose.

Spasticity

Spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome (see Chapter 3).39,40

Two types of GABA receptors, called A and B types, are found on neurons in the brain and spinal cord (see “Antiepileptic Drugs”). The drugs used to reduce spasticity work as agonists or antagonists at these receptors.

BZDs—Diazepam and Clonazepam

The BZDs bind GABAA receptor complexes on neurons located in the brainstem and at the spinal cord level and increase the affinity of GABA for the GABAA receptor complex. This results in an increase in presynaptic inhibition and the reduction of monosynaptic and polysynaptic reflexes. These drugs may improve passive range of motion and reduce hyperreflexia, painful spasms, and anxiety. Diazepam has a half-life of 20–80 hours and forms active metabolites that prolong its effectiveness. The half-life of clonazepam ranges from 18 to 28 hours.

Sedation, weakness, hypotension, adverse GI effects, memory impairment, incoordination, confusion, depression, and ataxia may occur. Tolerance and dependency can occur, and withdrawal phenomena, notably seizures, have been associated with abrupt cessation of therapy.

Baclofen—Oral and Intrathecal Pump

Baclofen is a GABA agonist, and its primary site of action is the spinal cord, where it reduces the release of excitatory neurotransmitters and substance P by binding to the GABAB receptor. Studies show that baclofen improves clonus, flexor spasm frequency, and joint range of motion, resulting in improved functional status.

Adverse effects include sedation, ataxia, weakness, and fatigue.

Intrathecal baclofen is approved in the United States for the treatment of spasticity of spinal or cerebral origin. In children, intrathecal baclofen is particularly effective for the treatment of spasticity of the lower extremities. Complications of the procedure are relatively few and usually are limited to mechanical failures of the pump or the catheter. Adverse drug effects are usually temporary and can be managed by reducing the rate of infusion.

Oral Agents

• Dantrolene sodium: Dantrolene sodium is useful for spasticity of supraspinal origin, particularly in patients with cerebral palsy or traumatic brain injury. It decreases muscle tone, clonus, and muscle spasm by acting at the level of the muscle fiber, affecting the release of calcium from the sarcoplasmic reticulum of skeletal muscle and thus reducing muscle contraction. It is, therefore, less likely than the other agents to cause adverse cognitive effects. Its peak effect is at 4–6 hours, with a half-life of 6–9 hours.

Adverse effects include generalized weakness, including weakness of the respiratory muscles, drowsiness, dizziness, weakness, fatigue, and diarrhea.

• Tizanidine. Tizanidine (Zanaflex) is a new and effective therapeutic option for the management of spasticity due to cerebral or spinal damage. The antispasticity effects of tizanidine are the probable result of inhibition of the H-reflex. It may also facilitate inhibitory actions of glycine and reduce the release of excitatory amino acids and substance P, and may have analgesic effects. When combined with baclofen, tizanidine presents the opportunity to maximize therapeutic effects and minimize adverse effects by reducing the dosages of both drugs.

Tizanidine hydrochloride is a short-acting drug with extensive first-pass hepatic metabolism to inactive compounds following an oral dose. The half-life is 2.5 hours with peak plasma level at 1–2 hours, and therapeutic and side effects dissipate within 3–6 hours. Therefore, use must be directed to those activities and times when relief of spasticity is most important.

Dry mouth, somnolence, asthenia, and dizziness are the most common adverse events associated with tizanidine. Liver function problems (5%), orthostasis, and hallucinations (3%) are rare tizanidine-related adverse events.

Cardiovascular System Pharmacology

Many cardiovascular medications have the potential to alter responses to both acute and chronic exercise in a predictable manner. Knowledge of how common drugs alter these responses can assist the clinician in assessing the safety and appropriateness of exercise and in determining the effectiveness of exercise training.41 Most medications that are prescribed for cardiovascular disease have either a direct or indirect effect on the heart or vascular system, including alteration of the myocardial oxygen consumption, peripheral blood flow, and cardiac preload or afterload.41 Medications may either increase or decrease exercise capacity, or alter the expected changes in heart rate and blood pressure that normally occur with an increase in activity or at rest (Table 9-4).41

α-Adrenergic Blocking Drugs (α1-Antagonists/Alpha-Blockers)

These drugs work through the autonomic nervous system (ANS) by blocking alpha-receptors. Alpha-receptors normally promote constriction of the arterioles. Blocking constriction promotes dilation of vessels and lowers blood pressure as well as reducing the work of the heart in some situations. Alpha-blocking drugs also inhibit the actions of norepinephrine that raises blood pressure as part of the fight-or-flight response. Alpha-blockers are usually prescribed along with other blood-pressure-lowering drugs, such as a beta-blocking drug and/or a diuretic. There are now several medications available that combine the effects of blocking both the beta- and alpha-receptors (Labetalol [Normo-dyne, Trandate]).

Examples of alpha-blockers include doxazosin (Cardura), prazosin (Minipress), and terazosin (Hytrin).

Possible Adverse Side Effects

Nausea and indigestion; these usually subside with long-term use. Less frequent effects are cold hands and feet, temporary impotence, and nightmares. Dizziness may occur initially or as the dosage is increased.

Angiotensin-Converting Enzyme Inhibitors

These drugs act to prevent production of a hormone, angiotensin II, which constricts blood vessels. They belong to the class of drugs called vasodilators—drugs that dilate blood vessels, an effective way to lower blood pressure and increase the supply of blood and oxygen to the heart and various other organs. In addition to dilating blood vessels, angiotensin-converting enzyme (ACE)-inhibiting medications may produce some beneficial effects indirectly by preventing the abnormal rise in hormones associated with heart disease, such as aldosterone. ACE inhibitors are widely used to treat high blood pressure, or hypertension, a major risk factor for cardiovascular disease. Used alone or in combination with other drugs, ACE inhibitors have also proved effective in the treatment of congestive heart failure.

Examples include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec, Vasotec I.V.), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril erbumine (Aceon), quinapril (Accupril), ramipril (Altace), spirapril (no brand names listed), and trandolapril (Mavik).

Possible Adverse Side Effects

Common side effects are dizziness or weakness, loss of appetite, a rash, itching, a hacking, unpredictable cough, and swelling.

Antiarrhythmic Drugs

These drugs, which are potent medications, correct an irregular heartbeat (arrhythmia) and slow a heart that is beating too fast (tachycardia).

Examples of antiarrhythmic drugs include amiodarone (Cordarone), digoxin (Lanoxin), disopyramide phosphate (Nor-pace), flecainide (Tambocor), propafenone (Rhythmol), lidocaine (Xylocaine), mexiletine (Mexitil), procainamide (Procan SR, Pronestyl, Pronestyl SR), quinidine gluconate (Duraquin, Quinaglute Dura-Tabs, Quinalan Sustained-Release), quinidine sulfate (Quinidex Extentabs), and tocainide (Tonocard).

Possible Side Effects

The most significant common side effects are weakening of heart contractions, worsening of some arrhythmias, weight loss, nausea, and tremors. Other less common effects are fever, rash, dry mouth, depressed white blood cell count, liver inflammation, confusion, loss of concentration, dizziness, and disturbances in vision. About 0.1–0.2% of patients suffer lung inflammation, a potentially serious side effect.

Anticoagulants, Antiplatelets, and Thrombolytics

These drugs are sometimes referred to as “blood thinners,” but this term is not truly accurate, as they inhibit the ability of the blood to clot—preventing clots from forming in blood vessels and from getting bigger. Anticoagulants, antiplatelet agents, and thrombolytics each have specific indications and uses. Any patient who has had a heart valve replaced with a mechanical valve requires lifelong oral anticoagulants in order to prevent clots from forming on the valve. Patients who develop atrial fibrillation may require anticoagulants; clot formation in the left atrium is a potential hazard of this rhythmic disturbance. Oral anticoagulants are prescribed for patients who develop thrombophlebitis, an inflammation of the veins in the legs or pelvis. One of the dangers of this condition is the development of blood clots that may travel to the lungs and cause pulmonary emboli. Lastly, some patients who have a serious heart attack involving the anterior surface of the heart are prescribed an anticoagulant to prevent clots from forming on the inner lining of the scar.

Heparin is an anticoagulant that is administered intravenously when rapid anticoagulation is necessary. All patients undergoing open-heart surgery are treated with heparin while their blood is being oxygenated by the heart–lung machine. At the end of the operation, medication is given to reverse the effects of heparin.

Aspirin is not an anticoagulant but has a profound effect on platelets—blood cells that stick together and cause clots to form. Because of aspirin's ability to inhibit the clotting action of platelets, it is designated as an antiplatelet and is frequently prescribed in patients who have recovered from a heart attack, in order to prevent clots from forming in the veins used for coronary bypass surgery.

The most recent and exciting classes of drugs that are useful for people with heart attacks are the thrombolytic drugs. These agents are given intravenously as soon as possible with the goal of dissolving the offending clot within a coronary artery before it causes permanent, debilitating damage. The three most commonly used thrombolytics are t-PA, streptokinase, and APSAC.

Examples of these drugs are acetylsalicylic acid or aspirin (Alka-Seltzer, Anacin, Ascriptin, Bayer, Bufferin, Easprin, Ecotrin, St. Josephs, Zorprin), dipyridamole (Persantine), and warfarin (Coumadin, Panwarfin).

Possible Side Effects

Adverse effects are rare, but may include nausea, headache, flushing, dizziness or faintness, or rash.

β-Adrenergic Blockers

These drugs probably reduce blood pressure by reducing cardiac output (or perhaps by blocking the production of angiotensin). Beta-blockers are also used to treat hypertension. Specifically, they block responses from the beta nerve receptors. This serves to slow down the heart rate and to lower blood pressure. Beta-blockers also block the effects of some of the hormones that regulate blood pressure. During exercise or emotional stress, adrenaline and norepinephrine are released and normally stimulate the beta-receptors—sensors that transmit messages to the heart to speed up and pump harder. By blocking the receptors, beta-blockers act to reduce heart muscle oxygen demands during physical activity or excitement, thus reducing the possibility of angina caused by oxygen deprivation.

Examples of these drugs are acebutolol (Sectral), atenolol (Tenormin), betaxolol (Betoptic, Betoptic S, Kerlone), bisoprolol (Zebeta), metoprolol (Lopressor), carteolol (Cartrol Oral, Ocupress Ophthalmic), labetalol (Normodyne, Trandate), levobetaxolol, levobunolol, metoprolol (Lopressor, Toprol XL), nadolol (Corgard), penbutolol (Levatol), pindolol (Visken), propranolol (Inderal), sotalol (Betapace AF, Betapace), timolol (Betimol, Blocadren, Timoptic-XE, Timoptic, Timoptic, OcuDose).

Possible Side Effects

Lethargy and cold hands and feet because of reduced circulation may occur. These drugs may also cause nausea, nightmares or vivid dreams, and impotence.

Calcium Channel Blockers

Calcium plays a central role in the electrical stimulation of cardiac cells and in the mechanical contraction of smooth muscle cells in the walls of arteries. Calcium channel blockers are relatively new synthetic drugs that work by blocking the passage of calcium into the muscle cells that control the size of blood vessels. All muscles need calcium in order to contract; by preventing the muscles of the arteries from contracting, blood vessels dilate, allowing blood to flow through them more easily, and reducing blood pressure.

Examples of these drugs are diltiazem (Cardizem), nicardipine (Cardene), nifedipine (Procardia, Procardia XL), nimodipine (Nimotop), and verapamil (Calan, Isoptin, Verelan).

Possible Side Effects

Excessively slow heart rate, low blood pressure, headache, swelling of ankle/feet, constipation, nausea, tiredness, dizziness, redness of face and neck, palpitations, and rash.

Digitalis Drugs

Like many drugs, digitalis was originally derived from a plant, in this case the foxglove. Digitalis has the primary effect of strengthening the force of contractions in weakened hearts and is also used in the control of atrial fibrillation. The most commonly used digitalis products are digoxin and digitoxin. The drug penetrates all body tissues and reaches a high concentration in the muscle of the heart. Its molecules bind with cell receptors that regulate the concentration of sodium and potassium in the spaces between tissue cells and in the bloodstream. These two minerals determine the level of calcium. Digitalis preparations act by increasing the amount of calcium supplied to the heart muscle and thus enhancing its contractions. Digitalis drugs also affect electrical activity in cardiac tissues. They control the rate at which electric impulses are released and the speed of their conduction through the chamber walls. These two actions determine the two major uses of digitalis drugs in heart disease—treatment of heart failure and control of abnormal heart rhythms. Digitalis may be given on a short-term basis in acute heart failure or over a long period of time to treat chronic heart failure. Digitalis drugs can be used to treat disturbances of the heartbeat, particularly the abnormally rapid contractions of the atria referred to as atrial or supraventricular arrhythmias (especially atrial fibrillation). The drugs restore the normal heartbeat either by interrupting the abnormal rhythm or by slowing down the rapid beats to a rate at which effective and coordinated heart contractions are possible.

Example of these drugs are digoxin (Lanoxicaps, Lanoxin).

Possible Side Effects

Some side effects include tiredness, nausea, loss of appetite, and disturbances in vision.

Diuretics

Diuretics, commonly referred to as water pills, lower blood pressure by increasing the kidney's excretion of sodium and water, which in turn reduces the volume of blood. There are several types of diuretics, which are classified according to their site of action in the kidney.

• Thiazide diuretics work in the tubules (the structures that transport urine in the kidneys).
• Loop diuretics are more potent than the thiazide diuretics. They are so named because they work in the area of the kidney called the loop of Henle. They are usually prescribed when a thiazide diuretic proves insufficient or for patients with heart failure or compromised kidney function.
• Potassium-sparing diuretics work in the area of the kidney or distal tubule of the nephrons in the kidney where potassium is excreted. They prevent the excessive loss of potassium that sometimes occurs with the thiazides. They are most often given in conjunction with a thiazide or loop diuretics.

Examples of diuretics are chlorthalidone (Hygroton) and hydrochlorothiazide (Esidrix, Hydrodiuril, Oretic), and examples of potassium-sparing diuretics are amiloride (Midamor), spironolactone (Aldactone), and triamterene (Dyrenium).

Possible Side Effects

Although uncommon, lethargy, cramps, rash, or impotence may occur. Some of these effects may be caused by a loss of potassium and may be avoided by including a potassium supplement or potassium-sparing agent in the regimen.

Nitrates

The oldest and most frequently used coronary artery medications are the nitrates. Nitrates are potent vein and artery dilators, causing blood to pool in the veins and the arteries to open up, thus reducing the amount of blood returning to the heart. This decreases the work of the left ventricle and lowers the blood pressure. Nitrates may also increase the supply of oxygenated blood by causing the coronary arteries to open more fully, thus improving coronary blood flow. Nitrates effectively relieve coronary artery spasm. They do not, however, appear to affect the heart's contractions.

Example of nitrates are nitroglycerin (Deponit NTG, Mini-tran, Nitro-Bid, Nitrogard, Nitroglyn, Nitrol, Nitrolingual, Nitrong, Nitrostat, Transderm-Nitro, Tridil) and isosorbide dinitrate (Dilatrate-SR, Iso-Bid, Isordil, Sorbitrate, Sorbitrate SA).

Possible Side Effects

Headaches, flushing, and dizziness may occur.

Pulmonary System Pharmacology

The delivery of a drug to the lungs allows the medication to interact directly with the diseased tissue and reduce the risk of adverse effects, specifically systemic reactions, while also allowing for the reduction of dose compared to oral administration. The prescription of any pulmonary medication is founded on four basic goals42:

• Promotion of bronchodilation or relief of bronchoconstriction.
• Facilitation of the removal of secretions from the lungs.
• Improvement of alveolar ventilation or oxygenation.
• Optimization of the breathing pattern.

The relative importance of each of these goals depends on the specific disease process and the resultant respiratory problem.42

Most inhaled drugs are administered through a pressurized metered-dose inhaler. Dry pounder inhalers or breath-activated devices are delivery devices that scatter a fine powder into the lungs by means of a brisk inhalation. The other major drug delivery system for pulmonary problems is the nebulizer, a device that dispenses liquid medications as a mist of extremely fine particles in oxygen or room air so that is inhaled.

Bronchodilator Agents

Bronchodilator agents are a group of medications that produce an expansion of the lumina of the airway passages of the lungs. The primary goal of bronchodilator therapy is to influence the ANS via two opposing nucleotides: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP).42 cAMP facilitates smooth muscle relaxation and inhibits mast cell degranulation, resulting in bronchodilation.42 cGMP facilitates smooth muscle contraction and may enhance mast cell release of histamine and other mediators, resulting in bronchoconstriction.42 Bronchodilator agents, which either stimulate (sympathomimetics) or inhibit (sympatholytics) adrenergic receptors, are central to the symptomatic management of chronic obstructive pulmonary disease (COPD) and asthma (Table 9-5).

Ancillary Pulmonary Medications

In addition to bronchodilators, several other drug groups are frequently used in the treatment of respiratory disorders, including decongestants, antihistamines, antitussives, mucokinetics, respiratory stimulants and depressants, and paralyzing and antimicrobial agents.42

Antitussives

Antitussives are drugs that suppress an ineffective, dry, hacking cough by decreasing the activity of the afferent nerves or decreasing the sensitivity of the cough center. The stimulus to cough is relayed to the cough center in the medulla and then to the respiratory muscles via the phrenic nerve. The primary adverse effect of antitussive agents is sedation, although GI distress and dizziness may also occur.42

Decongestants

Decongestants are used to treat upper airway mucosal edema and discharge by binding with the alpha-1 receptors in the blood vessels of the mucosal lining of the upper airways thereby stimulating vasoconstriction.42 Primary side effects include headache, dizziness, nausea, nervousness, hypertension, and cardiac irregularities.42

Antihistamines

Histamines play a role in the modulation of neural activity within the CNS and the regulation of gastric secretion by means of two types of receptors:

• H1-receptors. These are primarily located in vascular, respiratory, and GI smooth muscles and are specifically targeted for blockade by antihistamines in the treatment of asthma. H1-antagonist drugs decrease the mucosal congestion, irritation, and discharge caused by inhaled allergens. The adverse effects most often attributable to antihistamines include sedation, fatigue, dizziness, blurred vision, loss of coordination, and GI distress.
• H2-receptors. These act via G-proteins (guanine nucleotide binding proteins) to stimulate adenylate cyclase, the enzyme that synthesizes cAMP from adenosine triphosphate (ATP). Among the many responses mediated by these receptors are gastric acid secretion, smooth muscle relaxation, inotropic and chronotropic effects on heart muscle, and inhibition of lymphocyte function.

Mucokinetics

This class of drugs is responsible for promoting the mobilization and removal of secretions from the respiratory tract.42 There are four basic types of mucokinetics agents42:

• Mucolytics act by disrupting the chemical bonds in mucoid and purulent secretions, decreasing the viscosity of the mucus and promoting expectoration. The primary adverse effects of these drugs include mucosal irritation, coughing, bronchospasm, and nausea.
• Expectorants increase the production of respiratory secretions, thus facilitating their ejection from the respiratory tract.
• Wetting agents make expectoration easier for the patient and are delivered by either continuous aerosol or intermittent ultrasonic nebulization.
• Surface active agents (surfactant) lower the surface tension of the medium in which these are dissolved. They are primarily used to stabilize aerosol droplets thereby enhancing their efficacy as carrier vehicles for nebulized drugs.

Antimicrobial Agents/Antibiotics

Penicillins are the mainstay in the treatment of respiratory infections.42 First, second, and third generation cephalosporins are generally considered as alternatives to the penicillins, when penicillins are not tolerated by the patient or when they are ineffective.42

Oxygen42

Oxygen should be considered a drug when it is breathed in concentrations higher than those found in the atmospheric air. The therapeutic administration of oxygen can elevate the arterial oxygen tension and increase the arterial oxygen content, improving peripheral tissue oxygenation. When used judiciously, oxygen therapy has few side effects.

Metabolic and Endocrine System

Physical therapists routinely treat patients who are diagnosed with diabetes mellitus (DM). People with DM are at increased risk of developing chronic complications related to ophthalmic, renal, neurological, cerebrovascular, cardiovascular, and peripheral vascular disease.43,44 The major classes of DM are insulin-dependent diabetes mellitus (IDDM), also known as type 1 DM, and noninsulin-dependent diabetes mellitus (NIDDM), also known as type 2 DM, and subclassed as obese or nonobese.45 Type 1 DM results from autoimmune beta cell destruction, whereas type 2 DM is related to deficiency in insulin production or a condition of insulin resistance. Malnutrition-related DM, gestational DM, and other types of DM associated with specific conditions complete the classification. By its action on carbohydrate, protein, and lipid metabolism, insulin exerts a dominant effect on the regulation of glucose homeostasis.45 Through various actions, insulin, a hormone which is secreted by the beta cells of the pancreas, lowers blood glucose by either suppressing glucose release from the liver, or by promoting uptake of glucose into peripheral tissues, especially muscle. Insulin also affects adipose tissue by activating lipogenesis (conversion of glucose into triglyceride).45 Glucagon, catecholamines, glucocorticoids, and growth hormone act in opposition to insulin by increasing blood glucose.

The classic intervention approach to DM is the triad of diet (weight management), exercise, and drug therapy.45 Patients with IDDM require insulin replacement, with diet and exercise completing the treatment plan, whereas patients with NIDDM are often managed by diet and exercise prior to any use of pharmacological agents.

Drugs for Diabetes

Because patients with type 2 (NIDDM) diabetes have both insulin resistance and beta cell dysfunction, oral medication to increase insulin sensitivity is often given with an intermediate-acting insulin at bedtime or a long-acting insulin given in the morning or evening. The medications prescribed for DM have a variety of actions:

• Exenatide (Byetta) is an incretin-mimetic agent that mimics glucose-dependent insulin secretion and several other anti-hyperglycemic actions of incretins.
• Chlorpropamide (Diabinese) may increase insulin secretion from pancreatic beta cells.
• Tolbutamide (Orinase) increases insulin secretion from pancreatic beta cells.
• Tolazamide (Tolinase) increases insulin secretion from pancreatic beta cells.
• Acetohexamide (Dymelor) increases insulin secretion from pancreatic beta cells.
• Glyburide (DiaBeta, Micronase, PresTab, Glynase) increases insulin secretion from pancreatic beta cells.
• Glipizide (Glucotrol, Glucotrol XL) is second-generation sulfonylurea; stimulates insulin release from pancreatic beta cells.
• Repaglinide (Prandin) stimulates insulin release from pancreatic beta cells.
• Acarbose (Precose) delays hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose; inhibits metabolism of sucrose to glucose and fructose.
• Miglitol (Glyset) delays glucose absorption in small intestine; lowers after-dinner hyperglycemia.
• Pioglitazone (Actos) improves target cell response to insulin without increasing insulin secretion from pancreas.
• Rosiglitazone (Avandia) is an insulin sensitizer; major effect in stimulating glucose uptake in skeletal muscle and adipose tissue.
• Pramlintide acetate (Symlin) is a synthetic analog of human amylin, a hormone made in beta cells; slows gastric emptying, suppresses after-dinner glucagon secretion, and regulates food intake.

Exercise has the effect of increasing glucose uptake of insulin-sensitive tissues by two mechanisms45:

• Increasing blood flow and thus enhancing glucose and insulin delivery to muscle.
• Stimulation of glucose transport by muscle contraction.

In a nondiabetic person, insulin levels fall during acute exercise and hepatic glucose production rises to meet the demands of the exercising muscle. In a diabetic patient, exercise lowers blood glucose concentration and transiently improves glucose tolerance during acute exercise. The metabolic response to exercise is based on the fitness level of the individual, the intensity and duration of the exercise, and timing of exercise in relation to insulin administration and meals.45

Additional benefits of exercise in a diabetic population include improved whole-body insulin sensitivity, improved glycemic control, reduction of certain cardiovascular risk factors, and an increase in psychological well-being.

Ergogenic AIDS

Ergogenic aids is a term used to describe a broad category of topics including physiologic, pharmacologic, psychologic, and nutritional enhancement.46 The most common pharmacologic enhancement used by athletes are anabolic–androgenic steroids, a synthetic derivative of the male hormone testosterone. The more appropriate term “anabolic–androgenic steroids” is frequently shortened to anabolic steroids.

Anabolic–Androgenic Steroids

The use of anabolic steroids for nonmedical purposes has been in existence for over 50 years. These synthetic agents have a core steroid structure that gives them both anabolic (tissue building) and androgenic (masculinizing) effects, although physiologically these effects are inseparable.47 Anabolic steroids may be taken orally or parenterally. Orally ingested steroids are well absorbed from the stomach, excreted fairly rapidly from the body because of their short half-lives, are more toxic to the liver than injectable steroids, and are highly potent.46,48–50 Injectable steroids are characterized by delayed uptake from the body, slower excretion, increased detectability in drug tests for longer periods of time, less liver toxicity, and have less potency than oral steroids.46,48–50

Studies on the effects of anabolic steroids on muscle strength provide inconsistent results.46 Muscle strength increases will result from anabolic steroid use only if the following criteria are met46,51:

• The athlete must have been intensively trained in weightlifting immediately prior to the steroid regimen and must continue with intense weightlifting during the steroid regimen.
• The athlete must maintain a high protein, high calorie diet.
• Strength must be assessed with a single repetition, maximal-weight technique using the specific exercises with which the athlete trains, as opposed to single-joint, isolation-testing techniques.

Weight gain is commonly associated with anabolic steroid use. Whether these gains reflect muscle mass increases or fluid retention remains unclear.46

Although the potential benefits associated with anabolic steroid use remain questionable, the immediate and long-term side effects are well-established and include46

• increased risk of myocardial infarction and stroke;
• liver toxicity;
• significant decreases in plasma testosterone, testicular atrophy, impotence, prostate enlargement, decreased sperm counts, and a decrease in testosterone production from the testes;
• gynecomastia, characterized by a subareolar, button-like unilateral or bilateral plaque of tissue, and/or the development of breast tissue;
• increased musculotendinous injury;
• premature closure of the epiphysis in children, resulting in decreased adult height;
• alterations in lipid profiles—a significant rise in total serum cholesterol level and a decrease in high density lipoprotein (HDL); and
• alterations in mental status including, euphoria, aggressiveness, irritability, nervous tension, changes in libido, mania, depression (with withdrawal from steroids), and psychosis.

Amphetamines

The phenylethylamine structure of amphetamines is similar to catecholaminergic, dopaminergic, and serotonergic agonists (biogenic amines), which may explain their actions, with the clinical presentation being dependent on the type of amphetamine used. For example, methamphetamine lacks much of the peripheral stimulant properties of amphetamine while still offering euphoric and hallucinogenic properties. These actions are similar to those of cocaine; however, while effects of cocaine last for 10–20 minutes, duration of amphetamine action is much longer, lasting as long as 10–12 hours.

The routes of amphetamine administration may be oral (ingestion), inhalation (smoke), or injection (IV). Oral use is associated with an approximate one-hour lag time before onset of symptoms, whereas inhaled and IV methods yield effects within a few minutes. Peak plasma concentrations occur within 5 minutes with IV use, 30 minutes with nasal or IM use, and 2–3 hours postingestion.

Central Nervous System

Amphetamine compounds cause a general efflux of biogenic amines from neuronal synaptic terminals (indirect sympathomimetics). They inhibit specific transporters responsible for the reuptake of biogenic amines from the synaptic nerve ending and presynaptic vesicles. Amphetamines also inhibit MAO, which degrades biogenic amine neurotransmitters intracellularly. The net effect is an increase of monoamine neurotransmitter release into the synapse. Physiological adaptation occurs through receptor or coupling down regulation; this tolerance and an accompanying psychological tolerance can lead to escalating use of the drug and increased toxicity. Chronic use can lead to a depletion of biogenic amine stores and a paradoxical reverse effect of the drug—a wash out.

Elevated catecholamine levels usually lead to a state of increased arousal and decreased fatigue. Increased dopamine levels at synapses in the CNS may be responsible for movement disorders, schizophrenia, and euphoria. Serotonergic signals may play a role in the hallucinogenic and anorexic aspects of these drugs.

Other serotonergic and dopaminergic effects may include resetting the thermal regulatory circuits upward in the hypothalamus and causing hyperthermia. The hyperthermia produced by amphetamines is similar to that of the SS.

Peripheral Nervous System

Catecholaminergic (sympathomimetic) effects of amphetamines include inotropic and chronotropic effects on the heart, which can lead to tachycardia and other dysrhythmias. The vasoconstrictive properties of the drugs can lead to hypertension and/or coronary vasospasm.

The serotonergic action of amphetamines on peripheral vasculature can lead to vasoconstriction, which is especially problematic in placental vessels. Animal studies have shown that serotonergic actions of amphetamines effect changes in plasma levels of oxytocin, somatostatin, gastrin, and cholecystokinin.

Patients with amphetamine intoxication often are identified by a change of mental status alone or associated with another injury and/or illness. These changes include disorientation, headache, dyskinesias, agitation, symptoms of stroke, cardiovascular signs and symptoms (chest pain, palpitations), GI problems (dry mouth, nausea and vomiting, diarrhea), genitourinary dysfunction (difficult micturition), and skin changes (diaphoresis, erythematous painful rashes, needle marks, infected deep ulcerations (ecthyma)).

• 1. Describe the differences between pharmacodynamics and pharmacokinetics?

• 2. In relation to pharmacology and the ANS, what is the dominant tone?

• 3. Which two organs are primarily responsible for metabolizing drugs?

• 4. What effects do exercise and thermal physical agents have on drug metabolism?

Answers