Absorption describes how the medication moves from its site of administration into the systemic circulation (into the bloodstream). Some common routes of administration are shown in Table 13-1. Most medications must move from the site of administration into systemic circulation to be effective. Others, such as topical creams or inhalers, may provide therapeutic benefits through a localized effect. Although systemic absorption may not be necessary for effectiveness of topically applied medications, it can occur and result in side effects. For example, high dose, long-term use of inhaled corticosteroids to treat asthma has been shown to result in enough systemic absorption to increase the risk of developing osteoporosis.^12,15

Table 13-1

List of Common Routes of Administration

Route	Description	Example Medication(s)
Oral (PO)	Swallowed; uses the gastrointestinal tract	Most commonly used route of administration in U.S.; tablets, capsules, oral liquids
Sublingual (SL)	Under the tongue; medication rapidly absorbs into systemic circulation	Nitroglycerin tablets for chest pain
Rectal	Administered through the rectum; some absorb into systemic circulation, others provide a local laxative effect	Glycerin suppositories (laxatives) Promethazine (Phenergan) for nausea

Inhalation Into the lungs

Bronchodilators for asthma, such as albuterol inhalers

Corticosteroids for asthma such as flunisolide (AeroBid) inhalers

Intranasal Into the nose; some absorb into systemic circulation, others provide a local effect

Systemic absorption required for effectiveness: calcitonin (Miacalcin) nasal spray for osteoporosis

Localized effect: intranasal decongestants (Afrin)

Intravenous (IV) Directly into the veins; most rapid onset of action Common route of administration in hospitals; morphine, antibiotics Intramuscular (IM) Into the muscle Some vaccinations, penicillin G benzathine Subcutaneous (SQ, SC, SubCut) Into the subcutaneous layer of skin

Insulin

Teriparatide (Forteo) for osteoporosis

Intraarticular Into the joint space; causes a localized effect within the joint, some systemic absorption may occur Triamcinolone, methylprednisolone, hyaluronic acid (Orthovisc, Hyalgan) for osteoarthritis Epidural Into the epidural space (within the spinal column but outside the dura mater) Fentanyl, lidocaine, corticosteroids Transdermal (TD) Medication patches where the medication moves through the skin into systemic circulation Patches including: nicotine, nitroglycerin, clonidine, contraceptives, fentanyl, and lidocaine Topical Creams and ointments applied to the skin with an expected localized effect; systemic absorption may or may not occur Creams and ointments including BENGAY cream, capsaicin (Zostrix), hydrocortisone

The rate and extent of drug absorption through the skin can be dramatically increased by application of heat; therefore heat generating modalities (e.g., heating pads, ultrasound, infrared lamps, and warm hydrotherapy) should not be applied near transdermal medication patches. Electromagnetic (e.g., ultraviolet radiation, lasers, and diathermy) and electrical current modalities (e.g., transcutaneous electrical nerve stimulation [TENS]) should also not be used near medication patches because many patches have metallic backings that conduct electric currents, leading to significant heat generation and burns.³

Distribution describes movement of the medication from the bloodstream into various areas of the body such as the central nervous system (CNS), breast milk, and adipose (fat) tissue. This concept can be helpful in understanding medication actions and side effects. For example, opioid pain relievers act on the CNS to relieve pain; therefore an opioid will be most effective if it can easily distribute into the CNS. Only antibiotics with good distribution into bone tissue will be effective in treating osteomyelitis.

Medications are cleared from the body through metabolism, excretion, or both. Metabolism is the biotransformation or chemical alteration of the medication. The byproduct of drug metabolism is called a metabolite. Through metabolism, some medications are inactivated, whereas others remain active (active metabolite) but are more water soluble for easier elimination by the kidneys. Generally, metabolism takes place in the liver but it can occur through enzymatic processes in the kidneys, lungs, and bloodstream. Differences in drug response, side effects, and safe dose can be greatly affected by genetic differences in drug metabolism.²¹

Excretion describes elimination of the medication without prior metabolism (excreted unchanged) or, more commonly, elimination of the metabolites. Generally, excretion takes place through the kidneys (renal excretion, urine) but also occurs through the gastrointestinal tract (feces), lungs (breath), and skin (sweat).

The rate at which a drug is cleared from the body is referred to as half-life. Technically speaking, half-life is the amount of time it takes to reduce the concentration of the drug in the body by half. Drug half-lives can range from seconds to days. Anything that slows a drug’s clearance will lengthen its half-life. Liver metabolism and renal clearance are slower in older adults (>70 years) as compared with younger adults, and likewise for persons with acute or chronic liver or kidney disease.⁷ The most common type of clinically significant drug-drug interaction occurs when the presence of one drug slows the metabolism of a second drug.²¹ When drug clearance is decreased for whatever reason and the patient’s daily dose is not also decreased, drug accumulation and toxicity can occur.

A medication’s duration of action (the length of time it is active in the body) is related to its half-life. Drugs with a long half-life will have a long duration of action. Medications with a short duration of action usually require multiple daily administrations, three or four times daily, as compared to those with longer durations of action, which may only require dosing once or twice daily. One way medications can overcome a short duration of action is if they are formulated as a sustained release product. A sustained release product is usually in tablet or capsule form and is specially designed to dissolve very slowly in the intestines. By dissolving gradually over 12 or 24 hours, its effects will last longer. In general, sustained release products should not be chewed, crushed or broken open. Doing so can destroy the product’s sustained release properties, causing the entire dosage to be released at once.

Pharmacodynamics

Simply put, pharmacodynamics is a term used to describe what the medication does to the body. It is a study of the relationship between the amount of drug in the body and the response observed.⁷ Pharmacodynamics include a wide variety of principles, such as the dose–response relationship, therapeutic window, adverse reactions, and toxicity.

The dose–response relationship describes the relationship between the amount of drug in the body and its expected effectiveness and likelihood and severity of side effects (e.g., the higher the dose, the more side effects seen). This is closely tied to the concept of therapeutic window. A drug’s therapeutic window may be described as wide or narrow. The window is defined as the minimum drug concentration needed for the drug to show effectiveness, without causing toxicity in the patient. Penicillins and most cephalosporin antibiotics have wide therapeutic windows. Drugs with narrow therapeutic windows include the anticoagulant, warfarin (commonly used after orthopedic surgeries), and antiseizure medications (commonly used to treat phantom pain after amputation or in diabetic neuropathic pain).

The term adverse drug reaction (ADR), also termed side effect, describes any unintended effect of the medication including an exaggerated medication response. An example of an exaggerated response is extreme hypotension after receiving a high blood pressure medication. Certain ADRs may be particularly problematic in the orthopedic population, including medications that may reduce safety or increase fall risk (e.g., orthostatic hypotension, dizziness, blurred vision, hypoglycemia, ataxia, gait abnormalities) or medications that affect cognitive function. There are also many medications that cause cardiovascular side effects that may complicate exertional activity by increasing heart rate (tachycardia) or blood pressure (hypertension), by blunting the expected exercise-induced increase in heart rate, or by reducing heart rate (bradycardia). The term toxicity is often used interchangeably with ADR or side effect, but it is most accurate to reserve the term for situations where the serum concentrations have exceeded normal levels.

Tolerance occurs when the reaction to a drug diminishes over time. Tolerance can occur to both the benefits of a medication (making it less effective over time) and the ADRs (making it better tolerated over time).⁴ Withdrawal symptoms indicate physical dependency and are expected to occur with certain medications when used over a prolonged period. Withdrawal symptoms are generally the opposite of the pharmacologic effects of the medication. For example, one withdrawal symptom of a medication used to lower blood pressure would be hypertension.

Psychological dependency, also called addiction, occurs with certain medications such as opioid analgesics, amphetamines, and benzodiazepine sleep aids, as well as other substances with abuse potential, including cocaine, heroin, alcohol, caffeine, and nicotine. Withdrawal symptoms do contribute to the development of addiction in that the patient continues to use the substance to avoid the unpleasantness of the withdrawal symptoms; but having withdrawal symptoms alone does not meet the definition of addiction. It is important to understand the difference between physical and psychological dependency.⁴ Psychological dependency and addiction involve strong cravings and desires for the drug that overwhelm daily life. There is a loss of control over its usage and use continues despite its negative impact on quality of life.^4,6 Drug addiction is most strongly associated with medications that rapidly distribute into the CNS causing high levels of euphoria and dysregulation of the neurotransmitters involved in the body’s natural reward and pleasure centers.