NUR 153: Chapter Objectives

Lehne: Pharmacology for Nursing Care, 5th Edition
Chapter 1: Orientation to Pharmacology
  1. Four Basic Terms
    1. Drug: Any chemical that can affect living processes
    2. Pharmacology: The study of drugs and their interactions with living systems
    3. Clinical Pharmacology: The study of drugs in humans
    4. Therapeutics (or Pharmacotherapeutics): Use of drugs to diagnose, prevent, or treat disease or to prevent pregnancy
  2. Properties of an Ideal Drug
    1. Effectiveness
    2. Safety
    3. Selectivity
  3. Additional Properties of an Ideal Drug:
    • Reversible action
    • predictability
    • ease of administration
    • freedom from drug interactions
    • low cost
    • chemical stability
    • possession of a simple generic name
  4. Therapeutic Objective: Provide maximum benefit with minimum harm
  5. Factors Determining Intensity of Drug Responses
    1. Administration: Dosage, route, and timing of administration
    2. Pharmacokinetics: How the body affects drugs
      • Drug absorption
      • Drug distribution
      • Drug metabolism
      • Drug excretion
    3. Pharmacodynamics:How the drug affects the body
  6. Individual Variation: Physiology, genetics, and pathophysiology
  7. Key Points
Chapter 2: Application of Pharmacology in Nursing Practice
  1. Evolution of Nursing Responsibility
    1. The Original 5 Rights of Drug Administration: Right drug, right patient, right dose, right route, and right time
    2. Anticipating Drug Reactions: Benefits and harms
    3. Therapeutic Objective
    4. The Nurse as the Patient Advocate
  2. Application of Pharmacology in Patient Care
    1. Preadministration Assessment
      • Collecting baseline data to evaluate therapeutic and adverse responses
      • Identifying high-risk patients
      • Assessing patient’s capacity for self-care
    2. Dosage and Administration: Guidelines for safe administration
    3. Evaluating and Promoting Therapeutic Effects
      • Evaluate: Know rationale for treatment, desired response with dosage and time
      • Compliance: Active participation by patient in drug therapy
      • Nondrug measures
    4. Minimizing Adverse Effects: Identify high-risks and measures to decrease risks
    5. Minimizing Adverse Interactions: Combinations and over-the-counter drug effects
    6. Making PRN Decisions
    7. Managing Toxicity: Know signs of toxicity
  3. Application of Pharmacology in Patient Education
    1. Nurse as Educator
    2. Specifics to Teach Patients: Dosage, administration, duration of drug use, drug storage, promoting therapeutic effects, minimizing adverse effects, minimizing adverse interactions
  4. Application of the Nursing Process in Drug Therapy
    1. Review of the Nursing Process
      • Assessment
      • Analysis: Nursing Diagnosis
      • Planning
      • Implementation
      • Evaluation
    2. Applying the Nursing Process in Drug Therapy
      • Preadministration Assessment
      • Collection of baseline data to evaluate therapeutic responses
      • Collection of baseline data needed to evaluate adverse effects
      • Identification of high-risk patients
      • Assessment of the patient’s capacity for self-care
    3. Analysis and Nursing Diagnosis
    4. Planning
      • Determining goals
      • Setting priorities
      • Identifying interventions
      • Establishing criteria for evaluation
      • Implementation
      • Drug administration
      • Patient education
      • Interventions to promote therapeutic effects
      • Interventions to minimize adverse effects
    5. Evaluation: Monitoring and documenting
      • Therapeutic responses
      • Adverse drug reactions and interactions
      • Compliance
      • Satisfaction with treatment
    6. Use of a Modified Nursing Process Format to Summarize Nursing Implications in this Text
  5. Key Points
Chapter 3: Drug Regulation, Development, Names, and Information
  1. Landmark Drug Regulation
    1. Federal Pure Food and Drug Act of 1906: Required drugs to be free of adulterants
    2. The Food, Drug, and Cosmetic Act (1938): Regulated drug safety and development of the Food and Drug Administration (FDA)
    3. Kefauver-Harris Amendments (1962): Established rigorous procedures for new drugs
    4. Controlled Substances Act (1970): Established rules for manufacture and distribution of drugs having potential for abuse (Schedules I–V)
    5. Food and Drug Administration Modernization Act (1997): Included several revisions in FDA regulations including fast track system, informing patients six months prior to discontinuing manufacture of drug, drug testing in children, and establishment of clinical trial data base; allowed drug companies to give information on “off-label” uses of drugs
  2. New Drug Development
    1. The Randomized Controlled Trial
    2. Use of controls
    3. Randomization
    4. Blinding
  3. Stages of New Drug Development
    1. Preclinical testing: Done on animals for toxicities, pharmacokinetic properties, and potentially useful biologic effects
    2. Clinical testing: Done with humans
      • Phase I: Drug metabolism and determination of effects
      • Phase II and III: Tested in patients, usually a few hundred for 3–6 months
      • Phase IV: Postmarketing surveillance for observation of adverse effects after general distribution
    3. Limitations of the Testing Procedures
      • Limited information with women and children
    4. Failure to detect all adverse effects not possible before new drug is released; requires careful detection when working with new drugs to look for unreported reactions
    5. Exercising Discretion Regarding New Drugs
  4. Drug Names
    1. Three Types of Drug Names: Chemical, generic, and trade
    2. Which Name to Use: Problems with different names
    3. Generic Versus Brand Names: See FDA-approved generic equivalents on the Internet at
  5. Over-the-Counter (OTC) Drugs
    1. Those Drugs That Can Be Purchased Without Prescription: Since 1970, more than 60 prescription drugs have been switched to OTC status
    2. Knowledge Needed to Choose Most Appropriate Drug
  6. Sources of Drug Information
    1. People as Resources
    2. Published Information as Resources
  7. Key Points
Chapter 4: Pharmacokinetics
  1. Application of Pharmacokinetics in Therapeutics
    1. Definition: Study of drug movement throughout the body
    2. Four Basic Processes: Absorption, distribution, metabolism, and excretion
    3. Knowledge: To help maximize benefits and minimize harm
  2. Note to Chemophobes
  3. Passage of Drugs Across Membranes
    1. Membrane Structure (Figure 5-2 in the text)
    2. Three Ways to Cross a Cell Membrane
      • Passage through channels or pores: Only for smallest compounds
      • Passage with the aid of a transport system: Very selective and may use energy
      • Direct penetration of the membrane itself (most common): Must be lipid soluble (lipophilic)
      • Polar Molecules: Uneven electrical charges (i.e., water with no net charge)
      • Ions: Molecules with a net electrical charge (positive or negative) don't usually cross membranes
        • Quaternary Ammonium Compounds: Nitrogen and those with positive charge
        • pH-dependent Ionization: Acid or base (Figure 5-5 in the text)
        • Ion trapping (pH partitioning): Drugs accumulate on side of membrane where pH favors ionization (i.e., base to acid side): Especially important to fetuses and for poisonings
  4. Absorption
    1. Factors Affecting Drug Absorption: Rate of dissolution, surface area, blood flow, lipid solubility, and pH partitioning)
    2. Characteristics of Commonly Used Routes of Administration
      • Parenteral
        • Intravenous (IV) (1) Advantages: Absorption is instantaneous and complete; rapid onset; precise control over levels; can use large volumes of fluids; used for irritating drugs (2) Disadvantages: High cost; cannot self-administer; cannot reverse injection; could cause fluid overload; increased risk of infection; risk of embolism; chance of error in administration (not all drugs can be given IV)
        • Intramuscular (IM) (1) Advantages: Only barrier is capillary wall; used for poorly soluble drugs; for depot preparations to decrease number of injections (2) Disadvantages: Inconvenience; discomfort with administration
        • Subcutaneous (SC): Almost identical to IM for advantages and disadvantages
      • Enteral: Via gastrointestinal tract (PO); must cross GI tract and capillary wall; highly variable absorption
        • Advantages: Administration is easy, convenient, and inexpensive
        • Disadvantages: High variability, inactivated by pH and first-pass effect; requires compliance; local irritation
      • Comparing oral administration with parenteral administration
        • PO preferred to parenteral except for certain situations (i.e., emergencies, drugs destroyed by gastric acidity, when drug levels are to be tightly controlled, when severe irritation would occur, for depot preparations, and when patients cannot take oral drugs)
    3. Pharmaceutical Preparations for Oral Administration
      • Bioavailability also dependent on formulations (packages): tablets, enteric-coated preparations, and sustained-release preparations as well as liquid
    4. Additional Routes of Administration: Topical, inhaled, rectal or vaginal suppositories
  5. Distribution: Movement of drugs throughout the body
    1. Blood Flow to Tissues: Abscesses and tumors affect drug therapy
    2. Exiting the Vascular System
      • Typical capillary beds
      • Blood-brain barrier: Capillaries serving CNS; drugs must be lipid-soluble
    3. Placental drug transfer: Not an absolute barrier to passage of drugs; allows passage of lipid-soluble and nonionized substances
    4. Protein binding: Plasma albumin most important
    5. Entering Cells: Consider lipid solubility and transport system
  6. Metabolism (biotransformation): Enzymatic alteration of drug structure (Figure 5-11 in the text)
    1. Hepatic Drug-Metabolizing Enzymes: Cytochrome P450 is key component of the microsomal enzyme system; P450 is not a single molecular entity but a group of 12 related enzyme families with CYP1, CYP2, and CYP3 metabolizing drugs
    2. Therapeutic Consequences of Drug Metabolism
      • Accelerated renal drug excretion (most important): Decreasing lipid solubility
      • Drug inactivation: Conversion to inactive forms
      • Increased therapeutic action
      • Activation of prodrugs (in body conversion to active drug)
      • Increased or decreased toxicity
    3. Special Considerations in Drug Metabolism: Age, induction of drug-metabolizing enzymes, first-pass effect, nutritional status, competition between drugs
  7. Excretion: Removal of drugs from the body
    1. Renal Drug Excretion: Majority of drug excretion
      • Steps in renal drug excretion (glomerular filtration, passive tubular reabsorption, active tubular secretion)
      • Factors that modify renal drug excretion (pH-dependent ionization, competition for active tubular transport, age)
    2. Nonrenal Routes of Excretion
      • Breast milk: Can expose infant to drugs and needs to be discussed with health care provider
      • Other nonrenal routes of excretion (bile, lungs, sweat, and saliva)
  8. Time Course of Drug Responses: Time drug responses start, when most intense, and time when they cease
    1. Plasma Drug Levels
      • Clinical significance of plasma drug levels: Usually direct correlation between therapeutic and toxic responses and plasma drug levels
      • Two plasma drug levels defined
        • Minimum effective concentration (MEC)
        • Toxic concentration
        • Therapeutic range: Objective of drug dosing (between MEC and toxic levels)
    2. Single-Dose Time Course (Figure 5-13 in the text)
    3. Drug Half-Life: Time required for amount of drug in the body to decrease by 50%
    4. Drug Levels Produced with Repeated Doses
      • Process by which plateau drug levels are achieved: plateau level is the steady state (elimination equals administered dose)
      • Time of plateau: Reached in about 4 half-lives
      • Techniques for reducing fluctuations in drug levels
        • Continuous infusion
        • Reduce dosage size while reducing dosing interval
      • Loading doses versus maintenance doses
      • Decline from plateau: About 94% eliminated in 4 half-lives
  9. Key Points
Chapter 5: Pharmacodynamics
  1. Definition of Pharmacodynamics: Study of biochemical and physiologic effects of drugs and the molecular mechanisms by which those effects are produced
  2. Dose-Response Relationships
    1. Basic Features of the Dose-Response Relationship
      • Dose-response curve (Figure 6-1 in the text)
      • Phases of response
        Maximal Efficacy and Relative Potency
        • Maximal efficacy: Largest effect drug can produce (Figure 6-2A in the text)
        • Relative potency: Amount of drug needed to elicit an effect (Figure 6-2B in the text)
    2. Drug-Receptor Interactions
      1. Introduction
        • Receptors: Any functional macromolecule in a cell to which a drug binds to produce its effects
        • Binding of drug-receptor: Response is either to mimic or block normal receptor activity regulated by endogenous compounds (Figure 6-3 in the text)
      2. Receptors and Selectivity of Drug Action
        • Number of different receptors acted upon determines variety of responses: Similar to master key for doors versus specific key for one lock (Figure 6-4 in the text)
        • Increased receptor response increases potential of side effects
        • Selectivity does not guarantee safety of a drug
      3. Theories of Drug-Receptor Interaction (Figure 6-5 in the text)
        • Simple occupancy theory: Assumes ability to bind and influence receptor
        • Intensity of response proportional to number of receptors occupied
        • Maximal response occurs when all available receptors have been occupied
      4. Modified Occupancy Theory: Assumes independence of affinity and intrinsic activity
        • Affinity: Strength of attraction between drug and receptor; high affinity drugs are very potent
        • Intrinsic activity: Ability of drug to activate receptor after binding; high-intrinsic-activity drugs have maximal efficacy (intense receptor activation)
      5. Agonists, Antagonists, and Partial Agonists
        • Agonists: Mimic action of endogenous regulatory molecules; have affinity and high-intrinsic activity
        • Antagonists: Block actions of endogenous regulatory molecules
        1. Responses (1) If no agonist present, then no affect by antagonists (2) If agonists present, then antagonists can shut down activation process
        2. Classes of antagonists (1) Competitive: Bind reversibly (2) Noncompetitive: Bind irreversibly
      6. Partial agonists: Mimic action like agonists but with reduced intensity
      7. Four Primary Receptor Families (Figure 6-7 in the text)
        • Cell membrane embedded enzymes
        • Ligand-gated ion channels
        • G protein-coupled receptor systems
        • Transcription factors
      8. Regulation of Receptor Sensitivity
        • Desensitized (refractory or down regulation)
        • Hypersensitive (supersensitive or up regulation)
    3. Drug Responses That Do Not Involve Receptors: Physical or chemical interactions
    4. Interpatient Variability in Drug Responses
      1. Measurement of Interpatient Variability (Figure 6-8 in the text)
        • Define objective (endpoint)
        • Frequency distribution curve
      2. The ED50-Effective Dose (therapeutic response for 50% of the population)
      3. Clinical Implications of Interpatient Variability
        • Initial dose is an approximation; fine-tune subsequent doses
        • With an average ED50, some patients will be undertreated, others overtreated
        • Doses not completely predictable; need to look at the patient
        • Actual responses must be evaluated
    5. The Therapeutic Index: Measure of drug's safety (Figure 6-9 in the text)
      1. Ratio of LD50 (Lethal Dose) to Its ED50
    6. Key Points
Chapter 6: Drug-Drug and Drug-Food Interactions
  1. Drug-Drug Interactions: Can occur any time two or more drugs are taken
    1. Consequences of Drug-Drug Interactions
      • Intensification of effects: Increased therapeutic or adverse effects
      • Reduction of effects: Inhibited drug effects; either beneficial or detrimental
      • Creation of a unique response
    2. Basic Mechanisms of Drug-Drug Interactions
      • Direct chemical or physical interaction: Can occur with drugs mixed together
      • Pharmacokinetic interaction: Can alter all four processes
        1. Absorption: Increase or decrease (e.g., pH, laxative, changes in blood flow)
        2. Distribution: Competition for protein binding or changes in extracellular pH
        3. Metabolism: Induction of drug-metabolizing enzymes, inhibition of metabolizing, and competition of metabolism
        4. Excretion: Altered renal excretion (e.g., filtration, reabsorption, and secretion)
      • Pharmacodynamic interaction
        1. Interactions at same receptor: Almost always inhibitory
        2. Interactions resulting from actions at separate sites (if drugs influence same physiologic process)
      • Combined toxicity
    3. Clinical Significance of Drug-Drug Interactions
  2. Drug-Food Interactions
    1. Impact of Food on Drug Absorption: Decreasing rate and/or extent of absorption; some foods can increase extent of drug absorption
    2. Impact of Food on Drug Metabolism: The grapefruit juice effect (can inhibit metabolism of certain drugs? increased drug levels)
    3. Impact of Food on Drug Toxicity: MAOIs with tyramine, caffeine with theophylline, salt substitutes with spironolactone
    4. Impact of Food on Drug Action: Vitamin K with warfarin
    5. Timing of Drug Administration with Respect to Meals: With foods or on empty stomach
  3. Drug-Herb Interactions
  4. Key Points
Chapter 7: Adverse Drug Reactions And Medication Errors
  1. Scope of the Problem
    1. Drugs Can Adversely Affect All Body Systems: Varying degrees of intensity
    2. Mild to Severe Reactions
    3. Adverse Reactions: Most common in older adults and very young
    4. Clinical Significance: Many drug-induced deaths
  2. Definitions
    1. Side Effect: A nearly unavoidable secondary drug effect produced at therapeutic doses
    2. Toxicity: An adverse drug reaction caused by excessive dosing
    3. Allergic Reaction: An immune response with intensity largely independent on drug dosage
    4. Idiosyncratic Effect: An uncommon drug response resulting from a genetic predisposition
    5. Iatrogenic Disease: Produced by a physician or by drugs
    6. Physical Dependence: A state in which the body has adapted to prolonged drug exposure leading to an abstinence syndrome if the drug is discontinued
    7. Carcinogenic Effect: Ability of certain medications and environmental chemicals to cause cancers
    8. Teratogenic Effect: A drug-induced birth defect
  3. Identifying Adverse Drug Reactions
  4. Assessment to determine whether symptoms are due to drugs or disease
  5. Adverse Reactions to New Drugs: Report to FDA
  6. Ways to Minimize Adverse Drug Reactions
    1. Responsibility of Everyone Associated with Manufacture and Use of Drug
    2. Anticipation of Adverse Reactions
    3. Individualization of Drug Therapy
    4. Education of Patients and Testing Organs Vulnerable to Drugs
  7. Medication Errors
    1. What's a Medication Error and Who Makes Them?
    2. Types of Medication Errors
    3. Causes of Medication Error
    4. Ways to Reduce Medication Errors
    5. How to Report a Medication Error
  8. Key Points
Chapter 8: Individual Variation in Drug Responses
  1. Body Weight and Composition: Adjust for body surface rather than actual weight
  2. Age: Infants and elderly especially sensitive
  3. Gender: Males and females may not respond to drugs the same way; reason for pressure from FDA in 1997 to mandate that women be included in drug trials
  4. Pathophysiology
    1. Kidney Disease: Decreases excretion
    2. Liver Disease: Decreases ability to metabolize drugs
    3. Acid-base Imbalance: pH partitioning may change absorption, distribution, metabolism, and excretion
    4. Altered Electrolyte Status: Changes cell physiology
  5. Tolerance: Decreased responsiveness as a result of repeated drug administration
    1. Pharmacodynamic Tolerance: Due to long-term administration
    2. Metabolic Tolerance: Accelerated drug metabolism
    3. Tachyphylaxis: Reduction in drug responsiveness brought on by repeated dosing over a short time (not a common occurrence)
  6. Placebo Effect: A placebo is a preparation devoid of intrinsic pharmacologic activity
  7. Genetics: Idiosyncratic effects (usually alters metabolism)
  8. Variability in Absorption
    1. Bioavailability: Ability of drug to reach the circulation from site of administration
    2. Other Causes of Variable Absorption (gastric pH, diarrhea, constipation, foods)
  9. Failure to Take Medicine as Prescribed: Compliance, medication errors
  10. Drug Interactions: Process by which one drug alters the effect of another drug
  11. Diet
  12. Key Points
Chapter 10: Drug Therapy in Pediatric Patients
  1. Introduction: Most differences in response to drugs are quantitative due to organ system immaturity instead of degeneration as in elderly
    1. Age Groups
      • Premature infants (less than 36 weeks gestation)
      • Full-term infants (36 to 40 weeks gestation)
      • Neonates (first 4 postnatal weeks)
      • Children (1 to 12 years)
      • Adolescents (12 to 16 years)
    2. Pediatric Drug Therapy: More difficult due to insufficient drug information (less than 10% of drugs in Physician's Drug Reference (PDR) have been approved for children)
  2. Pharmacokinetics: Neonates and Infants: IV and subcutaneous injections have higher levels and effects are prolonged; infants highly sensitive due to drug absorption, renal drug excretion, hepatic drug metabolism, protein binding of drugs, and exclusion of drugs from CNS by blood-brain barrier
    1. Absorption
      • Oral administration
        1. GI physiology different from adults; drug absorption can be enhanced or impeded
        2. Gastric emptying time is prolonged and irregular (reaches adult values by 6-8 months)
        3. Gastric acidity very low 24 hours after birth (increases absorption of acid-labile drugs) and reaches adult values by 2 years
      • Intramuscular administration: Slow and erratic in neonate due to low blood flow through muscle; early infancy absorption more rapid than in neonates or adults
      • Percutaneous absorption: Greater than in older children or adults due to thin skin, which increases the risk of toxicity from topical drugs
    2. Distribution
      • Protein binding: Limited in infant due to low albumin and competition of endogenous compounds with binding sites, increasing free amounts and intensifying effects
      • Blood-brain barrier: Not fully developed at birth, so drugs pass easily into CNS
    3. Hepatic Metabolism: Low in newborns; capacity increases at about 1 month with complete maturation at 1 year
    4. Renal Excretion: Reduced at birth due to low renal blood flow, glomerular filtration, and active tubular secretion with adult levels achieved about 1 year
  3. Pharmacokinetics: Children 1 Year and Older: Similar to adults except that they metabolize drugs faster than adults until age 2 and then rate declines gradually until puberty
  4. Adverse Drug Reactions: More vulnerable to unique adverse effects related to immature state of organ systems and ongoing growth and development
    1. Examples of reactions: See Table 11-3 in the text Glucocorticoids affect growth suppression; tetracyclines stain developing teeth; sulfonamides cause kernicterus
    2. Therapy: Avoid drugs in patients vulnerable to actions
  5. Dosage Determination: Approximation formula based on body surface (dose = body surface area of child X adult dose divided by 1.73 m2)
  6. Promoting Compliance: Achieve accuracy and timing of dosing; provide written instructions, including estimation of spitting out of drugs
  7. Key Points
Chapter 11: Drug Therapy in Geriatric Patients
  1. Introduction
    1. Geriatric Factors in Drug Therapy
      • Drug use is disproportionately high (12% of population take 31% of drugs)
      • Older adults more sensitive to drugs with wider individual variation to drugs
      • Experience more drug-drug and adverse drug interactions
      • Principal factors underlying complications include altered pharmacokinetics, multiple and severe illnesses, multiple drug therapies, and poor compliance
      • Each patient must be monitored for desired and adverse responses and regimen adjusted accordingly
  2. Pharmacokinetic Changes in Older Adults: Gradual progressive decline in organ function; increased sensitivity (from reduced hepatic and renal drug elimination) but also increased variability
    1. Absorption: Percentage of oral doses not changed with age, but rate of absorption is delayed due to decreased gastric emptying and decreased splanchnic blood flow leading to delayed action; gastric acidity also is reduced, which alters some drug absorption
    2. Distribution: Altered by increased percent body fat, decreased percent lean body mass, decreased total body water, and reduced concentration of serum albumin
    3. Metabolism: Hepatic drug metabolism declines with age due to reduced hepatic blood flow, reduced liver size, and decreased activity of some hepatic enzymes
    4. Excretion: Renal drug function progressively declines beginning in early adulthood, which leads to accumulation of drugs, which accounts for most adverse reactions; should be measured with creatinine clearance, not serum creatinine levels
  3. Pharmacodynamic Changes in Older Adults: Alterations in receptor properties
  4. Adverse Drug Reactions and Drug Interactions: 7 times more common; accounts for 16% of hospital admissions, 50% of drug-related deaths, not so much due to aging but to drug accumulation due to renal function, polypharmacy, severity of disease, multiple pathologies, more drugs with low therapeutic index, altered pharmacokinetics, inadequate supervision, and poor patient compliance; these can be avoided by getting thorough history, accounting for changes due to aging, low-dose therapy, monitoring response, simplest method of therapy, monitoring interactions, destroying old drugs, and becoming compliant
  5. Promoting Compliance: 40% lack compliance, improvement by simplifying regimen, explaining treatment plan, choosing appropriate dosage form, labeling containers clearly, using calendar to record drugs, choosing affordable drugs, enlisting help, monitoring responses
  6. Key Points
Chapter 12: Basic Principles of Neuropharmacology
  1. Introduction: Neuropharmacology is the study of drugs that alter processes controlled by the nervous system
    1. Agents Divided into Two Categories: Peripheral and central nervous system drugs
  2. Neuron Regulation of Physiologic Processes (Figure 13-1 in the text): Axonal conduction and synaptic transmission
    1. Three Basic Steps in Process on Neuronal Influence on Postsynaptic Cell
      • Conduction of an action potential along the axon of the neuron
      • Release of neurotransmitter from the axon terminal
      • Binding of transmitter molecules to receptors on the postsynaptic cell
  3. Basic Mechanisms by Which Neuropharmacologic Agents Act
    1. Sites of Action: Axons versus synapses (most agents affect synaptic transmission)
      • Axonal conduction: Drugs acting here are less selective in action (local anesthetics and maybe general anesthetics are only drugs with therapeutic effects)
      • Synaptic transmission: Highly selective
      • Receptors: Impact of drug on neuronally regulated process is dependent upon ability of drug to directly or indirectly influence target receptor activity
    2. Steps in Synaptic Transmission (Figure 13-2 in the text)
      • Synthesis: Transmitter (T) made from precursor molecules (Q, R, and S)
      • Storage: Transmitter molecules stored in vesicles of axon terminal
      • Release: Triggered by arrival of action potential at axon terminal
      • Receptor Binding: After release, transmitter molecules diffuse across synaptic gap and reversibly bind to receptors on postsynaptic cell, altering its behavior
      • Termination: Can be by following processes: (1) reuptake, (2) enzymatic degradation, and (3) diffusion
    3. Effects of Drugs on the Steps of Synaptic Transmission: Enhance or reduce receptor activation
      • Transmitter synthesis: Drugs (1) can increase transmitter synthesis, (2) can decrease transmitter synthesis, or (3) can cause synthesis of transmitter molecules that are more effective than natural ones.
      • Transmitter storage: If drugs interfere with storage, receptor activation decreases
      • Transmitter release: Drugs can promote or inhibit release
      • Receptor binding: Drugs bind to receptors (1) causing activation, (2) preventing activation by other agents, or (3) enhancing receptor activation by natural transmitter at the site
      • Termination of transmitter action: Drugs can interfere by (1) blockade of transmitter reuptake or (2) inhibition of transmitter degradation
  4. Multiple Receptor Types and Selectivity of Drug Action (Figure 13-3 in the text): The more types of receptors, the greater chance of producing selective drug effects
  5. An Approach to Learning About Peripheral Nervous System Drugs: Need to know:
    1. Type or types of receptors through which the drug acts
    2. Normal response to activation of those receptors
    3. What the drug does to receptor function
  6. Key Points
Chapter 13: Physiology of the Peripheral Nervous System
  1. Divisions of the Nervous System
    1. Central Nervous System
      • Brain
      • Spinal cord
    2. Peripheral Nervous System
      • Somatic motor system: Controls movement of voluntary muscles
      • Autonomic nervous system: Regulates many involuntary processes
        1. Parasympathetic nervous system
        2. Sympathetic nervous system
    3. Overview of Autonomic Nervous System Functions: Regulates heart, secretory glands, and smooth muscles
      1. Functions of the Parasympathetic Nervous System: "Housekeeping"
        • Slows heart rate
        • Increases gastric secretion
        • Empties bladder
        • Empties bowel
        • Focuses eyes for near vision
        • Constricts pupils
        • Contracts bronchial smooth muscle
      2. Functions of the Sympathetic Nervous System
        • Regulates cardiovascular system: Maintains blood flow to the brain, redistributes blood flow during exercise, and compensates for blood loss
        • Regulates body temperature: Regulates blood flow to skin; sympathetic nerves then increase or decrease heat loss; promotes secretion of sweat to cool body; induces piloerection to conserve heat
        • Implements "fight or flight" reaction: Increases heart rate and blood pressure, shunts blood away from skin and viscera to skeletal muscles, dilates bronchi, dilates pupils, and mobilizes stored energy
  2. Basic Mechanisms by Which the Autonomic Nervous System Regulates Physiologic Processes
    1. Patterns of Innervation and Control: Usual dual innervation (parasympathetic and sympathetic for opposition or complementary) except blood vessels (sympathetic only)
    2. Feedback Regulation: Process allowing system to adjust itself with incoming information with main reflex elements including sensor, effector, and neurons connecting the effector and sensor
    3. Baroreceptor Reflex: Located in carotid sinus and aortic arch to monitor and adjust changes in blood pressure
    4. Autonomic Tone: Day-to-day influence on organ or organ system
  3. Autonomic Considerations
    1. Parasympathetic Nervous System (Figure 14-3 in the text): (1) synapses between preganglionic neurons and postganglionic neurons and (2) junctions between postganglionic neurons and effector organs
    2. Sympathetic Nervous System (Figure 14-3 in the text): (1) synapses between preganglionic and postganglionic neurons (also adrenal medulla) and (2) junctions between postganglionic neurons and effector organs
    3. Somatic Motor System (Figure 14-3 in the text): Only one site of action (neuromuscular junction)
  4. Introduction to Transmitters of the Peripheral Nervous System (Figure 14-4 in the text)
    1. Acetylcholine: Released by
      • (1) all preganglionic neurons of parasympathetic nervous system,
      • (2) all preganglionic neurons of sympathetic nervous system,
      • (3) all postganglionic neurons of parasympathetic nervous system,
      • (4) all motor neurons to skeletal muscles, and
      • (5) most postganglionic neurons of sympathetic nervous system going to sweat glands
    2. Norepinephrine: Transmitter released by practically all postganglionic neurons of sympathetic nervous system except sweat glands
    3. Epinephrine: Transmitter released by adrenal medulla
    4. Dopamine: May serve also as peripheral transmitter (considered as adrenergic)
  5. Introduction to Receptors of the Peripheral Nervous System
    1. Primary Receptor Types: Cholinergic (mediate responses to acetylcholine) and adrenergic (mediate responses to epinephrine and norepinephrine) receptors
    2. Subtypes of Cholinergic and Adrenergic Receptors
      • Cholinergic receptors: NicotinicN, nicotinicM, and muscarinic
      • Adrenergic receptors: Alpha1, alpha2, beta1, and beta2
  6. Exploring the Concept of Receptor Subtypes
    1. What Is Meant by "Receptor Subtypes"?: Receptors responding to same transmitter butdifferent from each other
    2. How We Know Receptor Subtypes Exist: Based on observing responses to drugs and now being able to clone receptors using DNA hybridization technology
    3. How Can Drugs Be More Selective Than Transmitters at Receptor Subtypes? (Figure 14-5 in the text): Developed different structures from natural transmitters
    4. Why Do Receptor Subtypes Exist?
    5. Do Receptor Subtypes Matter to Us?: Allow for increased selectivity of drugs
  7. Locations of Receptor Subtypes (Figure 14-6 in the text)
  8. Functions of Cholinergic and Adrenergic Receptor Subtypes
    1. Functions of Cholinergic Receptor Subtypes (Table 14-2 in the text)
    2. Functions of Adrenergic Receptor Subtypes (Table 14-3 in the text)
  9. Receptor Specificity of the Adrenergic Transmitters
    1. Cholinergic Receptors: All three subtypes are activated by acetylcholine
    2. Adrenergic Receptors: More specific
      • Epinephrine can activate all alpha and beta but not dopamine (beta2 prepares for fight or flight by dilating blood vessels to heart, lungs, and skeletal muscles; dilating bronchi; stimulating glycogenolysis; relaxing uterine muscle)
      • Norepinephrine can activate all alpha, only beta1
      • Dopamine can activate dopamine, alpha1 and beta1 receptors
  10. Transmitter Life Cycles (Figures 14-7 and 14-8 in the text): Drugs alter different steps in process
    1. Life Cycle of Acetylcholine (ACh): Synthesis from choline and acetyl coenzyme A; stored in vesicles; released due to action potential; binds to receptors on postjunctional cell; after dissociation from receptor ACh instantly destroyed by acetylcholinesterase into acetate and choline (choline is taken back for reuse)
    2. Life Cycle of Norepinephrine: Synthesis from precursors; storage in vesicles; released and bound to adrenergic receptors; transmission terminated with reuptake back into the nerve terminal to be reused in vesicles or inactivated by monoamine oxidase (MAO)
    3. Life Cycle of Epinephrine: Synthesis in chromaffin cells of adrenal medulla (first norepinephrine is made and converted to epinephrine); stored in vesicles; released and travels via blood to target organs; termination via hepatic metabolism
  11. Key Points
Chapter 27: Opioid (Narcotic) Analgesics
  1. Introduction to the Opioids
    1. Terminology: Opioid is any drug, natural or synthetic, with actions like morphine; narcotic (preferred term) refers to opioids, cocaine, marijuana, and LSD
    2. Endogenous Opioid Peptides: Enkephalins, endorphins, and dynorphins found in CNS and peripheral tissues and endogenous opioid peptides serve as neurotransmitters, neurohormones, and neuromodulators
    3. Opioid Receptors: Mu (the most important), kappa, and delta
      • Mu activation includes analgesia, respiratory depression, euphoria, and sedation
      • Kappa activation produces analgesia and sedation
      • Delta not really interacted with opioids
    4. Classification of Drugs That Act at Opioid Receptors
      • Pure opioid agonists: Activate mu and kappa and divided into strong opioid agonists (morphine) and moderate-to-strong opioid agonists (codeine)
      • Agonist-antagonists opioids: Five are available (pentazocine, nalbuphine, butorphanol, dezocine, and buprenorphine); when administered alone, produce analgesia, but given to a person taking opioids, produce an antagonistic effect
      • Pure opioid antagonists: Antagonize mu and kappa receptors and are used for reversal of respiratory and CNS depression
  2. Basic Pharmacology of the Opioids
    1. Morphine: The "standard" that produces analgesia, sedation, euphoria, respiratory depression, cough suppression, and decreased bowel motility
      • Overview of pharmacologic actions: Relieves pain, causes drowsiness, mental clouding, reduced anxiety, and sense of well-being
      • Therapeutic use: Relief of pain (moderate to severe), acute, chronic, for labor and delivery, MI pain and dyspnea associated with LVF and pulmonary edema, and preoperatively for sedation and anxiety Pain based on sensation and suffering which is decreased by morphine
      • Mechanism of analgesic action: Mimics endogenous opioid peptides (mu receptors)
      • Adverse effects: Respiratory depression, constipation, orthostatic hypotension, urinary retention, cough suppression, biliary colic caused by morphine, emesis, increased intracranial pressure (ICP), euphoria/dysphoria, sedation, and miosis
      • Pharmacokinetics: Administered orally, intramuscularly, intravenously, subcutaneously, epidurally, and intrathecally; it does not cross blood-brain barrier easily; inactivated by hepatic metabolism, especially first-pass effect when orally taken
      • Tolerance and physical dependence
        1. Tolerance: Dose produces smaller response with continued use: tolerance develops to analgesia, euphoria, sedation, and respiratory depression; little tolerance to constipation and miosis; cross- tolerance occurs with other opioid agonists
        2. Physical dependence: Abstinence syndrome occurs when drug abruptly withdrawn; body needs drug to function normally; to minimize abstinence syndrome, withdraw opioids slowly
      • Abuse liability: Classified under the Controlled Substances Act, Schedule II
      • Precautions: With those who have decreased respiratory reserve, pregnancy, labor and delivery, head injury, infants and elderly, patients with inflammatory bowel disease, patients who are hypotensive especially if due to decreased blood volume, those with prostatic hypertrophy due to urinary retention
      • Drug interactions: CNS depressants, anticholinergic drugs, hypotensive drugs, monoamine oxidase inhibitors, agonist-antagonist opioids, opioid antagonists, antiemetics of phenothiazines reduce nausea
      • Toxicity: Triad of signs: coma, respiratory depression and pinpoint pupils: provide support and give antagonist (naloxone)
      • Preparations, dosages, and administration: Individualize; oral requires higher dosages because of first-pass effect metabolism
    2. Other Strong Opioid Agonists: None are superior to morphine, includes meperidine (Demerol), methadone, levomethadyl, heroin, fentanyl (can be given parenterally, transdermally, transmucosally, or as lozenges or lozenges on a stick), alfentanil or sufentanil, remifentanil, hydromorphone, oxymorphone, and levorphanol
    3. Moderate-to-Strong Opioid Agonists: Difference is mainly quantitative (less)
      • Codeine: Maximal effects less than with morphine; 30 mg codeine produces about same pain relief as 325 mg aspirin or acetaminophen, good cough suppressant (10 mg); frequently combined with nonopioid drug for maximum effect
      • Propoxyphene (Darvon, Dolene): Combined with nonopioid
      • Hydrocodone (only with ASA or Tylenol) or Oxycodone (alone or with nonopioid)
    4. Agonist-Antagonist Opioids
      • Pentazocine (Talwin): For mild to moderate pain, agonist at kappa receptors (get analgesia, sedation, and respiratory depression), antagonist at mu receptors (get no euphoria; can get hallucinations, anxiety); if given to a person who is physically dependent on an opioid agonist, can precipitate abstinence syndrome
      • Nalbuphine (Nubain): Analgesia less than with morphine
      • Butorphanol (Stadol): Similar to pentazocine
      • Buprenorphine (Buprenex): Only one significantly different from others; partial agonist at mu and antagonist at kappa; naloxone cannot reverse toxicity already developed
  3. Clinical Use of Opioids
    1. Dosing Guidelines
      • Dosage determination: Individual variation, fixed schedule; remember that with standard dose of 10 mg of morphine, 70% will receive adequate relief, and 30% will be undertreated; use of patient-controlled device provides greater protection from pain recurrence
      • Avoiding withdrawal (>20 days of opioids can lead to physical dependence); taper dosage
    2. Physical Dependence, Abuse, and Addiction as Clinical Concerns
      • Definitions
        1. Physical dependence: State in which abstinence syndrome occurs if drug abruptly withdrawn
        2. Abuse: Drug use inconsistent with medical or social norms
        3. Addiction: Behavior pattern characterized by continued use of psychoactive substance despite physical, psychologic, or social harm
      • Minimizing fears about physical dependence: Little to fear with opioids in hospitalized patient; even if physical dependence occurs, rarely will patients develop addictive behavior and continue opioid use after pain is gone
      • Minimizing fears about addiction: Addiction to opioids from clinical exposure is extremely rare; based on persons who are prone to drug abuse and those who are not
      • Balancing the need to provide pain relief with the desire to minimize abuse: Administer with discretion in effort to minimize abuse
  4. Opioid Antagonists: Drugs that block effects of opioid agonists, for overdosage, reversal of postoperative opioid effects, and management of opioid addiction
    1. Naloxone (Narcan): Mechanism of action (structural analog of morphine as competitive antagonist at receptors; reverses respiratory depression, coma, and analgesia); pharmacologic effects (none without opioid; those physically dependent on opioids will develop withdrawal reaction); pharmacokinetics (IV, SC, IM); therapeutic uses (reversal of opioid overdose, reversal of postoperative opioid effects, reversal of neonatal respiratory depression)
    2. Other Opioid Antagonists: Naltrexone, Nalmefene
  5. Nonopioid Centrally Acting Analgesics
    1. Tramadol (Ultram) moderately strong with minimal potential for dependence, abuse or respiratory depression; does intensify other CNS depressants
    2. Clonidine, administered by epidural infusion, also treats hypertension; therefore, greatest concern is hypotension due to massive vasodilation; must assess for infection from catheter placement
  6. Key Points
  7. Summary of Major Nursing Implications
    1. Pure Opioid Agonists
    2. Agonist-Antagonist Opioids
    3. Naloxone
Chapter 28: Pain Management in Patients with Cancer
    Cancer pain can be relieved with simple interventions in 90% of cancer patients. Undertreatment can occur due to inadequate training in pain management, unfounded fears of addiction, and a health care system that focuses on disease treatment instead of relief of suffering. Goal to minimize pain and maintain quality of life. See Management of Cancer Pain sponsored by AHCPR.
  1. Pathophysiology of Pain
    1. Defining Pain: "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage"; personal and subjective
    2. Neurophysiologic Basis of Painful Sensations: Net result of two opposing neuronal pathways (pain sensation and suppressing conduction to diminish pain sensation); three types of stimuli (mechanical, thermal, and chemical); prostaglandins and substance P enhance sensitivity of pain receptors; brain can suppress pain conduction
    3. Nociceptive Pain Versus Neuropathic Pain: Nociceptive pain from tissue injury and neuropathic pain from injury to peripheral nerves; must differentiate between these for best treatment
      • Nociceptive pain: Somatic (bones, joints, muscles) and visceral (visceral organs); responds to opioid analgesics and may respond to nonopioids
      • Neuropathic pain: Burning, shooting, jabbing, tearing, numb, cold; responds poorly to opioids; does respond to adjuvant analgesics (some antidepressants, anticonvulsants, and local anesthetic/antidysrhythmics)
    4. Pain in Cancer Patients: Pain caused by cancer or therapy; incidence and intensity based on cancer type, stage, and therapeutic interventions
  2. Overall Treatment Strategy: Ongoing process (see Figure 29-1 in the text)
  3. Assessment and Ongoing Evaluation: Assessment is foundation of treatment
    1. Comprehensive Initial Assessment: Characterize pain and identify cause
      • Assessment of pain intensity and character: The Patient Self-Report is cornerstone of pain assessment; ask: onset and temporal pattern, location, quality, intensity, modulating factors, previous treatment, and impact
      • Physical and neurologic examinations
      • Diagnostic tests
      • Psychosocial assessment: Patient and family; assess impact, coping responses, preferences, concerns, changes in mood, impact on family, and level of care by family
      • Pain intensity scales: Visual analog scale (VAS) to assess and set goals
    2. Ongoing Evaluation: Reassess frequently and watch for new pain
    3. Barriers to Assessment: Self-report not always accurate (under- or over-report); language and cultural barriers; assessing those based on nonverbals (children, etc.)
  4. Drug Therapy: Analgesic drugs relieve about 90%; three types use World Health Organization drug selection ladder based on mild to moderate pain (nonopioid analgesics, NSAIDs, and acetaminophen); for more severe pain, add opioid analgesics of moderate strength; for severe pain, substitute powerful opioids for the weaker ones and use adjuvant analgesics at any point; guidelines: comprehensive pretreatment assessment, individualize treatment, use the WHO ladder to guide selection, use orals when possible; for persistent pain, used fixed schedule around the clock plus rescue, and evaluate frequently
    1. Nonopioid Analgesics: Initial drugs for mild to moderate pain; use recommended dose
      • Nonsteroidal anti-inflammatory drugs (NSAIDs): Pain relief, suppression of inflammation, and reduction of fever; consider effects on COX-1 and COX-2; be concerned about interference with platelets when on chemotherapy
      • Acetaminophen (Tylenol, others): Works in CNS, not periphery; lacks inflammatory action; concern of interaction with alcohol and warfarin
    2. Opioid Analgesics: Most effective; many patients denied proper dosage
      • Mechanism of action and classification: Mimic endogenous opioid peptides primarily at mu receptors and partly at kappa receptors; pure opioids can control more severe pain whereas agonists-antagonists may block full effect of pure opioid
      • Tolerance and physical dependence: Over time, opioids do this after 1-2 weeks; tolerance (state in which specific dose produces smaller effect); physical dependence (state in which an abstinence syndrome occurs if drug withdrawn)
      • Addiction: Disease process characterized by continued use of a psychoactive substance despite physical, psychologic, and social harm
      • Drug selection: Preferred opioids (pure opioids, see Table 29-4 in the text); opioids to use with special caution (methadone and levorphanol because of prolonged half-lives); opioids to avoid (meperidine since it can be used only a few days and with great CNS effect); agonist-antagonists avoided since less effective, affect pure opioid, and cause adverse psychologic reactions
      • Dosage: Individualize; determined by temporal pattern of pain; consult Table 29-4 in the text for equivalents
      • Routes of administration: Oral as preferred method, rectal, transdermal, IV and SC, intraspinal, intraventricular, patient-controlled analgesia (PCA); avoid IM
      • Managing side effects: Respiratory depression, sedation, constipation, orthostatic hypotension, nausea and vomiting; most managed by decreasing dose by 25%
  5. Adjuvant Analgesics: Used to complement effects of opioids, not substitute
    1. Tricyclic Antidepressants: Amitriptyline and others
    2. Anticonvulsants: For neuropathic pain; carbamazepine most widely used but suppresses bone marrow
    3. Local Anesthetics/Antidysrhythmics: Lidocaine and mexiletine second-line agents for neuropathic pain
    4. CNS Stimulants: Dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) to enhance opioid-induced analgesia and counteract sedation; problem of appetite suppression and insomnia
    5. Antihistamines: Hydroxyzine (Vistaril); reduces pain, anxiety, and nausea and has sedative action
    6. Glucocorticoids: Help manage painful cancer-related conditions, reduce cerebral and spinal edema, improve appetite, and decrease cachexia; safe for short-term use, dangerous over long term
    7. Bisphosphonates : May reduce cancer-related bone pain
  6. Nondrug Therapy
    1. Invasive Procedures: Last resort for relieving intractable pain
      • Neurolytic nerve block: Destroys neurons that transmit pain from limited area so permanent pain relief
      • Neurosurgery: Destroy neurons transmitting pain, implant opioid infusion systems, and neuroaugmentation
      • Tumor surgery: Debulk tumor
      • Radiation therapy: Regresses tumor and is palliative treatment
    2. Physical and Psychosocial Interventions: Degree of pain relief is limited
      • Physical interventions: Include heat, cold, massage, exercise, acupuncture, and transcutaneous electrical nerve stimulation
      • Psychosocial interventions: Help patients cope by increasing sense of control, reversing negative thoughts, and offering social support through relaxation and imagery, cognitive distraction, and peer support groups
  7. Pain Management in Special Populations
    1. Older Adults: Concern regarding undertreatment of pain and increased risk for adverse effects with heightened drug sensitivity contributing to both problems
    2. Young Children: Assessing children more difficult; assessment tailored to child's developmental level and personality using either verbalization for those over 4 years and preverbal and nonverbal for children who cannot self-report; treatment can include PCA pump for those over 7 years; neonates and infants are highly sensitive to drugs and should be treated cautiously due to blood-brain barrier being incomplete and kidneys/liver poorly developed
  8. Opioid Abusers: Two obligations: Try to relieve pain and try to avoid giving opioids just for the high; PCA can be most helpful
  9. Patient Education: An integral part of cancer pain management
    1. General Issues: Accurate, comprehensive, and understandable; include nature and causes of pain, assessment and honest self-reporting, and plans for therapy
    2. Drug Therapy: Maximize pain relief with minimum harm; need to know drug name and category, dose size and schedule, route and technique, therapeutic response, duration of treatment, method of drug storage, adverse effect symptoms, adverse drug-drug and drug-food interactions, whom to contact; correct misconceptions about tolerance, physical dependence and addiction, and fear of severe side effects
    3. Nondrug Therapy: Psychosocial interventions and how they complement
  10. JCAHO Pain Management Standards
  11. Key Points
Chapter 50: Anticoagulants, Antiplatelet Drugs, and Thrombolytics
  1. Introduction: Drugs used to prevent formation of thrombi and to dissolve thrombi
  2. Physiology and Pathophysiology of Coagulation
    1. Hemostasis: Physiologic process by which bleeding is stopped
      • Stage 1: formation of a platelet plug: Begins when platelets come in contact with collagen on exposed surface of damaged vessel, adhere to area, release adenosine diphosphate (ADP) and thromboxane A2? platelet plug and bleeding stopped; platelet aggregation ends with fibrinogen bridges
      • Stage 2: coagulation (reinforcement of platelet plug with fibrin): Occurs in series of cascading reactions (see Figure 50-1 in the text) from extrinsic and/or intrinsic systems; four coagulation factors (VII, IX, X, and prothrombin) require vitamin K for synthesis
      • Keeping hemostasis under control: Antithrombin III prevents widespread coagulation
      • Physiologic removal of clots: Essential in healing process using plasmin
    2. Thrombosis: A blood clot formed within a vessel or in the heart
      • Arterial thrombosis: Result is localized tissue injury owing to lack of perfusion
      • Venous thrombosis: Usually develops when blood flow is slow; this initiates coagulation cascade; part can become embolus
  3. Overview of Drugs Used to Treat Thromboembolic Disorders: Three categories of drugs: anticoagulants (to prevent venous thrombosis), antiplatelet drugs (most effective at preventing arterial thrombosis), and thrombolytic drugs
  4. Parenteral Anticoagulants I: Heparin and Related Drugs
    1. Heparin (unfractionated): Rapid-acting anticoagulant
      • Source: From mammalian tissues; prepared from lungs of cattle or intestines of pigs
      • Chemistry: Mixture of polysaccharide chains with range of molecular weights (3000 to 30,000); many negatively charged groups are highly polar, so cannot readily cross membranes
      • Mechanism of anticoagulant action: Helps antithrombin III inactivate thrombin, factor Xa, and other factors; fibrin formation is then suppressed and is especially useful for prophylaxis of venous thrombosis; acts in minutes
      • Pharmacokinetics: Cannot be given orally since cannot cross membranes; bind nonspecifically to plasma proteins, mononuclear cells, and endothelial cells; therefore, careful monitoring required; hepatic metabolism and renal excretion with short half-life (1.5 hours); begin therapy with bolus and adjust, especially with hepatic and renal disease
      • Therapeutic uses: Preferred during pregnancy and for situations requiring rapid onset: for pulmonary embolism, evolving stroke, and massive deep vein thrombosis (DVT), as well as patients undergoing open heart surgery and renal dialysis; low-dose heparin to prevent postoperative venous thrombosis; heparin used for treating disseminated intravascular coagulation (DIC) and as adjunct therapy with thrombolytic to treat an acute MI
      • Adverse effects: Hemorrhage, thrombocytopenia, hypersensitivity reactions; local irritation and hematoma from subcutaneous administration; vasospastic reactions; long-term use with high doses may cause osteoporosis
      • Warnings and contraindications: Contraindicated for patients with thrombocytopenia; uncontrollable bleeding; during and immediately after eye, brain, or spinal cord surgeries and lumbar puncture and regional anesthesia; warnings include patients with high likelihood of bleeding (hemophilia, increased capillary permeability, dissecting aneurysm, peptic ulcer, severe hypertension, threatened abortion, liver or kidney disease)
      • Drug interactions: Any drug that suppresses platelet formation (aspirin, ibuprofen, indomethacin) weakens last defense against hemorrhage
      • Protamine sulfate for heparin overdose: A small protein with positive charges that bonds with negative charges of heparin; occurs immediately and lasts for about 2 hours; slow IV of no faster than 20 mg/min or 50 mg in 10 min; usual dosage is 100 units of heparin; neutralized by 1 mg of protamine
      • Laboratory monitoring: Use-activated partial thromboplastin time (APTT); normal value for APTT is 40 seconds; therapeutic levels increase APTT by 1.5 to 2 times (60-80 sec.); check every 4-6 hours
      • Unitage and preparations: Prescribed in terms of units not milligrams; defined as amount of heparin that prevents 1.0 ml of sheep plasma from coagulating for 1 hour; preparations as heparin sodium or calcium
      • Dosage and administration: Injection only (IV intermittent or continuous or SC); dosage varies with application and blood levels
    2. Low-Molecular-Weight (LMW) Heparins
      • Group properties: Shorter molecules; as effective as standard heparin; fixed dosage; no APTT monitoring
      • Production: Depolymerizing standard heparin so molecular weights range between 1000 and 9000
      • Mechanism of action: Same process as standard heparin except LMW preferentially inactivates factor Xa and fewer effects to inactivate thrombin
      • Therapeutic use: Only for prophylaxis of DVT after hip or abdominal surgery
      • Pharmacokinetics: Differs from standard heparin in relation to nonspecific binding and half-life (up to 6 times more), so more predictable
      • Administration, dosing, and monitoring: LMW by SC; dosage based on body weight; begin in perioperative period and continue for 5-10 days
      • Adverse effects and interactions: Bleeding but less than with standard heparin; can cause thrombocytopenia; can cause neurologic injury
      • Cost: $13/day compared with $3/day for standard heparin but can be used at home and require no APTT monitoring, so overall cost actually less
      • Individual preparations: Two available in U.S.
        1. Enoxaparin (Lovenox): Overdosage treated with protamine sulfate (1 mg per each mg of enoxaparin)
        2. Dalteparin (Fragmin): Begin 1-2 hours before surgery and continue 5-10 days; antidote is 1 mg protamine sulfate for every 100 anti-factor Xa IU of dalteparin
        3. Tinzaparin (Innohep) should be used in conjunction with warfarin
        4. Fondaparinux (Arixtra): enhances the activity of antithrombin
        5. Danaparoid (Orgaran) is similar to LMW heparin; contains heparin, which acts like heparin
  5. Parenteral Anticoagulants II: Direct Thrombin Inhibitors
    1. Bivalirudin: An IV anticoagulant given in combination with aspirin to prevent clot formation in patient with unstable angina who is undergoing coronary angioplasty
    2. Lepirudin: An intravenous anticoagulant that works by direct inhibition of thrombin
    3. Argatroban: An intravenous anticoagulant that works by direct inhibition of thrombin
  6. Oral Anticoagulants: To prevent thrombosis; delayed onset of action; not for emergency use; carry significant risk of hemorrhage; risk amplified by many drug interactions; only two available in U.S. (warfarin and anisindione)
    1. Warfarin (Coumadin, Panwarfin, Sofarin): the oldest oral anticoagulant
      • History: Originally used only to kill rats
      • Mechanism of action: Antagonist of vitamin K at synthesis sites (factors VII, IX, X and prothrombin), so blocking of biosynthesis occurs
      • Pharmacokinetics: Readily absorbed after oral administration; 99% bound to albumin; that which is free crosses membranes; hepatic metabolism and excretion in urine and feces; doesn't affect clotting factors already present, only those being synthesized (may be delayed 6 hours to 2.5 days); after discontinuing drug, effects still present for 2-5 days
      • Therapeutic uses: Long-term prophylaxis of thrombosis for those needing prevention of pulmonary embolism, patients with prosthetic heart valves, and those with atrial fibrillation
      • Monitoring treatment: By prothrombin time (PT); average is 12 seconds with results reported as international normalized ratio (INR); most need INR of 2-3 while some need INR of 3-4.5; PTs done daily with first 5 days, then 2 times for next 1-2 weeks, then once/week for 1-2 months, then every 2-4 weeks after that (if giving heparin at same time, draw PT levels 5 hours after IV heparin or 24 hours after SC); new monitoring equipment for PT evaluation at home
      • Adverse effects: Hemorrhage; fetal hemorrhage and teratogenesis with use during pregnancy; not for use during breastfeeding; other (skin necrosis, alopecia, urticaria, dermatitis, fever, GI disturbances, and red-orange urine)
      • Drug interactions: More interactions than probably any other drug (see Table 50-4 in the text); three major categories (drugs that increase anticoagulant effects, drugs that promote bleeding, and drugs that decrease anticoagulant effects); especially of concern are heparin, aspirin; acetaminophen now thought to inhibit warfarin degradation
      • Warnings and contraindications: Contraindicated for patients with thrombocytopenia or uncontrollable bleeding; patients undergoing lumbar puncture, regional anesthesia, or surgery of the eye, brain, or spinal cord; patients at high risk for bleeding (hemophilia, increased capillary permeability, dissecting aneurysm, GI ulcers, HTN, women planning abortion, people with vitamin K deficiency, liver disease, or alcoholism); and pregnant or lactating patients
      • Vitamin K1 for warfarin overdose: For mild bleeding, give orally with levels normalizing within 24 hours; for severe bleeding, 5-50 mg parenterally; if emergency, give fresh whole blood, fresh frozen plasma, or plasma concentrates of vitamin K-dependent clotting factors; IV of vitamin K can cause anaphylactic reactions
      • Contracts between warfarin and heparin: Work differently, monitored by different tests, different management of overdosage
      • Preparations, dosage, and administration: Initial 10 mg/day with maintenance of 2-10 mg/day; use INR to target dosage
    2. Anisindione: Like warfarin but greater side effects
  7. Antiplatelet Drugs: Suppress platelet aggregation, principal indication to prevent thrombosis in arteries; three groups (aspirin, ADP receptor antagonists, and GP IIb/IIIa)
    1. Aspirin (discussed in Chapter 67)
    2. Mechanism of antiplatelet action: Causes irreversible inhibition of cyclooxygenase (enzyme to synthesize thromboxane A2); inhibits prostacyclin by blood vessel wall, which promotes vasodilation and suppresses platelet aggregation
    3. Indications for antiplatelet therapy: Three applications: prophylaxis of MI, prevention of reinfarction, prevention of stroke
    4. Dosing: Low dosing (325 mg/day or less)
    5. Adenosine Diphosphate Receptor Antagonists: Two now available (ticlopidine and clopidogrel); both cause irreversible blockade of ADP receptors on platelet surface
      • Ticlopidine (Ticlid): Oral antiplatelet drug; effects similar to aspirin; can get thrombocytopenia; for prevention of ischemic stroke
      • Clopidogrel (Plavix): For prevention of MI and stroke
    6. Glycoprotein IIb/IIIa Receptor Antagonists
      • Group Properties: Called "super aspirins"; most effective antiplatelet drugs marketed; three available (abciximab, tirofiban, and eptifibatide); IV and expensive; reversible blockade of platelet GP IIb/IIIa receptors
    7. Other Antiplatelet Drugs
      • Dipyridamole (Persantine): Only for prevention of thromboembolism after heart valve replacement surgery and used with warfarin
      • Dipyridamole plus aspirin (Aggrenox)
      • Cilostazol (Pletal): Platelet inhibitor and vasodilator
  8. Thrombolytic Drugs: To remove thrombi, which have already formed; also known as fibrinolytics
    1. Streptokinase
      • Mechanism of action: Indirect mechanism by binding with plasminogen to form a complex that acts on molecules of plasminogen to convert it to plasmin to digest fibrin meshwork of clot (also affect fibrinogen and other clotting factors, which increase risk of hemorrhage)
      • Therapeutic uses: For acute coronary thrombosis (MI), for DVT and for massive pulmonary emboli
      • Pharmacokinetics: IV infusion or directly into occluded coronary artery; half-life of only 40-80 minutes
      • Adverse effects
        1. Bleeding: Especially intracranial hemorrhage (1%); control minor oozing sites with pressure; if severe, give fresh whole blood or blood products; reverse with aminocaproic acid (Amicar)
        2. Antibody production: Allergic reactions and neutralization of streptokinase can occur
        3. Hypotension: Not related to bleeding or allergic reactions, monitor carefully
        4. Fever: More than one-third have temperature elevations of 1.5o F or more; give acetaminophen as treatment
      • Preparations, dosage, and administration: Reconstitute for use; give IV loading dose over 30 minutes
    2. Alteplase (tPA): Produced commercially by recombinant DNA; does not induce hypotension and no allergic reactions; much more expensive ($2300 versus $300)
    3. Tenecteplase (TNKase): Approved for treating patients undergoing acute MI
    4. Other Thrombolytic Drugs: Similar to streptokinase and alteplase except differences in half-life, source, antigenicity, cost, and specific indications
      • Urokinase (Abbokinase): Occurs naturally in human urine; no allergic reactions occur; short half-life (15-20 minutes); used for acute MI, DVT, and clearance of IV catheters
      • Anistreplase (APSAC): Acylated complex of streptokinase plus human plasminogen; may cause hypotension
      • Reteplase (Retavase): Derivation of tPA; only for MI at present; not to be used with line that contains heparin
    5. Streptokinase Versus Alteplase: The Gusto Trial: 41,000 patients participated from over 15 countries; mortality with tPA less than with streptokinase but risk of hemorrhagic stroke greater with tPA; the largest study on treatment of acute MI. Mortality in patients receiving alteplase (tPA) was somewhat lower than those receiving streptokinase, but risk of hemorrhagic stroke higher; however, these patients received drugs in first 2-4 hours; selecting a thrombolytic the most important decision
  9. Key Points
  10. Summary of Major Nursing Implications
    1. Heparin
    2. Warfarin
    3. Thrombolytic Drugs
Chapter 73: Drugs for Peptic Ulcer Disease
  1. Introduction: Peptic ulcer disease (PUD) refers to group of upper GI disorders with erosion of gut wall; ulceration usually occurs in lesser curvature of stomach and duodenum; most common cause is by Helicobacter pylori
  2. Pathogenesis of Peptic Ulcer Disease: Peptic ulcers develop when imbalance between defensive factors and aggressive factors exist
    1. Defensive Factors: Major factors are mucus and bicarbonate
      • Mucus: Secreted by cells of GI mucosa to form barrier
      • Bicarbonate: Secreted by epithelial cells of stomach and duodenum, from pancreas bicarbonate secreted into duodenum
      • Blood flow: Essential for mucosal integrity
      • Prostaglandins: Stimulate secretion of mucus and bicarbonate and promote vasodilation and suppress secretion of gastric acid
    2. Aggressive Factors
      • Helicobacter pylori: A gram-negative bacillus that colonizes the stomach and duodenum; not destroyed by acid or pepsin; can remain for decades; eradication of the bacterium minimizes ulcer recurrence (from ~100% to as low as 1%); also associated with gastric adenocarcinoma
      • Nonsteroidal anti-inflammatory drugs: Underlying cause of many gastric and some duodenal ulcers
      • Gastric acid: An absolute requirement for peptic ulcer formation; causes ulcers by injuring cells of GI mucosa and by activating pepsin; Zollinger-Ellison syndrome is primary disorder in which hypersecretion of acid alone appears to be sole cause of ulcer formation
      • Pepsin: A proteolytic enzyme present in gastric juice; pepsin can injure unprotected cells
      • Smoking: Delays ulcer healing and increases risk of recurrence
    3. Summary: H. pylori most common cause of gastric and duodenal ulcers
  3. Overview of Treatment
    1. Drug Therapy: Goals are to alleviate symptoms, promote healing, prevent complications, and prevent recurrences; only antibiotics alter disease process
      • Classes of antiulcer drugs: Five major classes including antibiotics, antisecretory agents, mucosal protectants, antisecretory agents that enhance mucosal defenses and antacids (three important functions: eradicate H. pylori, reduce gastric acidity and enhance mucosal defenses)
      • Drug selection
        1. Helicobacter pylori-associated ulcers: All patients with gastric or duodenal ulcers and documented H. pylori infection should be treated with antibiotics
        2. NSAID-induced ulcers: Prophylaxis (misoprostol is approved for prophylaxis of NSAID-induced ulcers); omeprazole may be just as effective and better tolerated
      • Evaluation: Monitor for relief of pain and perform radiologic or endoscopic examination of
      • Nondrug Therapy
        • Diet: Minor role; may need to change to 5-6 small meals rather than three large meals to reduce pH fluctuations
        • Other nondrug measures: Avoid cigarettes, NSAIDs, and behaviors that contribute to symptoms
  4. Antibacterial Drugs: Give to all ulcer patients with confirmed H. pylori infection
    1. Tests for H. pylori: Invasive tests (endoscopic to stain and view for bacteria, assay for presence of urease, and culture and assay for H. pylori) or noninvasive tests (breath tests using radiolabeled urea to check for radiolabeled carbon dioxide; serologic test to evaluate for antibodies to H. pylori)
    2. Antibiotics Employed: None are effective alone; resistance may develop with using metronidazole or clarithromycin alone
      • Bismuth compounds: Act topically to disrupt cell wall of H. pylori, causing lysis and death; inhibit urease activity and prevent H. pylori from adhering to gastric surface; may color tongue and stool black; in U.S. available as bismuth subsalicylate (Pepto-Bismol, etc.) or with ranitidine (Tritec)
      • Clarithromycin: Rate of resistance is 10%; highly effective; suppresses growth of H. pylori by inhibiting protein synthesis
      • Amoxicillin: Kills bacteria by disrupting cell wall; antibacterial activity highest at neutral pH; most common side effect is diarrhea
      • Tetracycline: Inhibits bacterial protein synthesis; staining of teeth limits use with pregnant women and children
      • Metronidazole: Cornerstone of triple antibiotic therapy to avoid resistance; side effects include nausea and headache; do not use with alcohol; avoided during pregnancy
    3. Antibiotic Regimens: See Table 73-2 in the text for combination therapy; compliance is difficult because of numerous medications/day and because side effects are common
  5. Histamine2-Receptor Antagonists (H2RAs): First-choice drugs for treating gastric and duodenal ulcers; promote healing and suppress gastric acid secretion; all four available drugs effective with few side effects
    1. Cimetidine (Tagamet)
      • Mechanism of action: H2 cells are located on parietal cells of stomach; promotes secretion of gastric acid; blocking H2 receptors reduces volume and hydrogen ion concentration; suppresses basal acid secretion and reduces stimulation of acid secretion by gastrin and acetylcholine
      • Pharmacokinetics: Oral, IV, or IM; taken orally, food decreases rate of absorption; crosses blood-brain barrier, so CNS effects can occur; most of drug eliminated in urine with liver hepatic metabolism; short half-life
      • Therapeutic uses
        1. Gastric and duodenal ulcers: Therapy for 4-6 weeks for duodenal ulcers and 8-12 weeks for gastric ulcers; prophylaxis dosage
        2. Gastroesophageal reflux disease: Drug of choice for symptoms
        3. Zollinger-Ellison syndrome: Hypersecretion of gastric acid and development of peptic ulcers; use high doses but ? side effects
        4. Aspiration pneumonitis: Occurs from suppression of glottal reflex; damage can be fatal; high risks are obesity and pregnancy; administer 60-90 minutes before procedure
        5. Heartburn, acid indigestion, and sour stomach: OTC drug now
      • Adverse effects: Incidence of side effects low and usually benign
        1. Antiandrogenic effects: Gynecomastia, reduced libido, and impotence
        2. CNS effects: Especially with older adults or if renal or hepatic impairment; confusion, hallucinations, CNS depression, or excitation
        3. Other adverse effects: As IV bolus, can cause hypotension or dysrhythmias; Candida in stomach caused by increased pH; hematologic effects; minor effects include headache, dizziness, GI disturbances, rash, and pruritus
      • Drug interactions
        1. Interactions related to inhibition of drug metabolism: Causes levels of other drugs to rise (warfarin, phenytoin, theophylline, and lidocaine)
        2. Antacids: Decrease absorption; administer 1 hour apart
      • Preparations, dosage, and administration: Oral, parenteral
    2. Ranitidine (Zantac): Shares many properties of cimetidine; differs in that it is more potent, produces fewer adverse effects, and causes fewer drug interactions
      • Actions: Blocks H2 receptors on parietal cells
      • Pharmacokinetics: Oral, IM, and IV; oral bioavailability is 50%; food makes no difference on absorption; hepatic and renal elimination
      • Adverse effects: Uncommon; very rare CNS effects; no antiandrogenic effects
      • Drug interactions: Few because ranitidine is a very weak inhibitor of hepatic drug-metabolizing enzyme; antacids have only small effect
      • Therapeutic uses: Same as cimetidine
      • Preparations, dosage, and administration: Tablets, effervescent tablets/granules, injection
    3. Ranitidine Bismuth Citrate: Dissociates into ranitidine and bismuth in stomach acid
    4. Famotidine (Pepcid) and Nizatidine (Axid Pulvules): Similar to ranitidine
      • Contracts with ranitidine: Neither inhibit hepatic drug-metabolizing enzymes, OTC preparations for heartburn
      • Dosage: Differ for the two drugs; for ulcers dosage higher than OTC drug
    5. Nizatidine: Similar to ranitidine and famotidine
  6. Proton Pump Inhibitors
    1. Omeprazole (Prilosec): Most effective agent for suppressing secretion of gastric acid; minimal side effects with short-term therapy; with long-term, concern about possible carcinogenesis
      • Mechanism of action: A pro-drug converts in parietal cells; causes irreversible inhibition of hydrogen, potassium ATPase; inhibits basal and stimulated acid release; 30 mg oral dose reduces gastric acid production by 97% in 2 hours
      • Pharmacokinetics: Orally administered; capsule dissolves in stomach, but granules dissolve in duodenum; hepatic metabolism and renal excretion
      • Therapeutic use: Short-term therapy (4-8 weeks) for duodenal and gastric ulcers and for gastroesophageal reflux disease; long-term therapy for hypersecretory conditions
      • Adverse effects: With short-term, may get headache, GI disturbance; with long-term, concern about risk of cancer (only in rats), but limited research
      • Preparations, dosage, and administration: Once/day 20 mg
    2. Lansoprazole (Prevacid): Should be taken before breakfast; like omeprazole
    3. Rabeprazole (AcipHex): Much like omeprazole and lansoprazole
    4. Pantoprazole (Protonix)
    5. Esomeprazole (Nexium)
  7. Other Antiulcer Drugs
    1. Sucralfate (Carafate): Effective antiulcer medication with minimal side effects and lack of significant drug interactions; protective barrier
      • Mechanism of antiulcer action: Undergoes polymerization and cross-linking reactions to produce viscid and sticky gel that adheres to ulcer crater and lasts for 6 hours
      • Pharmacokinetics: Orally, 3%-5% absorption; 90% eliminated in feces
      • Therapeutic uses: Acute and maintenance therapy
      • Adverse effects: No serious ones known; can get constipation (2%)
      • Drug interactions: Antacids may interfere with effectiveness since need less than pH of 4 to convert; administer 30 minutes apart; does impede absorption of some drugs (phenytoin, theophylline, digoxin, warfarin, and fluoroquinolone antibiotics)
      • Preparations, dosage, and administration: Tablets and suspension; take on empty stomach (1 hour before meals); large pills hard to swallow; may need suspension
    2. Misoprostol (Cytotec)
      • Therapeutic use: An analogue of prostaglandin E1; only for preventing gastric ulcers caused by long-term therapy with NSAIDs; has been used with RU-486 for abortion
      • Mechanism of action: Prostaglandins normally help protect stomach by suppressing secretion of gastric acid, promoting secretion of bicarbonate and cytoprotective mucus, and maintaining submucosal blood flow; aspirin inhibits this protective mechanism; misoprostol serves as a replacement for the prostaglandins
      • Adverse effects: Dose-related diarrhea (13%-40%) and abdominal pain (7%-20%); women may get spotting and dysmenorrhea; not for use during pregnancy; if used in childbearing years, must be able to comply with birth-control measures, given oral and written warnings, have a negative serum pregnancy test within 2 weeks of beginning therapy, and begin therapy only on second or third day of next normal menstrual cycle
      • Preparations, dosage, and administration: Tablets with meals and at bedtime
    3. Antacids: Alkaline compounds to neutralize stomach acid; used in peptic ulcer disease and gastroesophageal reflux disease
      • Beneficial actions: Neutralizing acid decreases destruction of gut wall; if pH > 5, get decrease in pepsin; may enhance mucosal protection by stimulating production of prostaglandins; poorly absorbed except for sodium bicarbonate
      • Therapeutic uses: Peptic ulcer disease; administered prior to anesthesia to prevent aspiration pneumonitis; used prophylactically to prevent stress-ulcers
      • Potency, dosage, and formulations: Potency expressed in terms of acid-neutralizing capacity (ANC), which is number of mEq of HCl that can be neutralized by given weight/volume of antacid (see Table 73-3 in the text)
      • Adverse effects: Constipation (aluminum hydroxide) or diarrhea (magnesium hydroxide); some contain substantial amounts of sodium, which can exacerbate HTN and heart failure
      • Drug interactions: By increasing pH, can affect dissolution and absorption; can change urinary pH
      • Antacid families: Four groups: aluminum compounds, magnesium compounds, calcium compounds, and sodium compounds
      • Representative antacids: See Table 73-5 in the text
        1. Magnesium hydroxide: Rapid-acting, high ANC, long duration of action; common problem is diarrhea; avoid in patients with potential intestinal problems; used as laxative
        2. Aluminum hydroxide: Low ANC, slow-acting, long duration; significant amounts of sodium in agents; get constipation; absorbs compounds (tetracyclines, warfarin, digoxin); can cause hypophosphatemia
        3. Calcium carbonate: Rapid-acting, high ANC, long duration; get acid rebound; get constipation; can cause eructation and flatulence; rare change of milk-alkali syndrome
        4. Sodium bicarbonate: Unfit for treating ulcers; rapid onset but short-acting; increases intra-abdominal pressure; absorption of sodium exacerbates HTN and heart failure; if renal impairment, get systemic alkalosis
    4. Anticholinergics: Limited role; high doses produce muscarinic blockade throughout body
      • Pirenzepine (Gastrozepin): Unique muscarinic antagonist for PUD; it produces selective blockade of muscarinic receptors that regulate gastric acid secretion
  8. Key Points
  9. Summary of Major Nursing Implications
    1. H2-Receptor Antagonists
    2. Antacids
Chapter 74: Laxatives
  1. Introduction: Laxatives used to ease or stimulate defecation (soften stool, increase stool volume, hasten fecal passage through intestine, and facilitate evacuation from rectum); laxative effect refers to production of soft formed stool over a period of 1 or more days; catharsis refers to prompt, fluid evacuation of bowel
  2. General Considerations
    1. Function of the Colon: Absorb water and electrolytes; minimal absorption of nutrients;absorbs ~50% of the 1500 ml of water that enters colon; bowel function varies with individuals
    2. Dietary Fiber: Proper function dependent on dietary fiber; facilitates in two ways (absorb water ? softening feces and increasing mass, digested by colonic bacteria to increase fecal mass); need 20-60 g/day
    3. Constipation: Determined by degree of hardness of stool; frequency is of secondary importance; principal cause is poor diet (deficient in fiber and fluid); some drugs cause constipation; mild exercise helps
    4. Indications for Laxative Use: Softening stool can reduce the painful elimination; helps those with cardiovascular disease, older adults, patients with hemorrhoids; can be used for obtaining fresh stool for analysis, emptying bowel prior to treatment, facilitating export of dead parasites following anthelmintic use, emptying bowel prior to surgery and diagnostic procedures, modification of effluent from ileostomy or colostomy, prevention of fecal impaction in bedridden patients, removal of ingested poisons, and correction of constipation
    5. Contraindications to Laxative Use: Those with abdominal pain, nausea, cramps, other symptoms of appendicitis, regional enteritis, diverticulitis, ulcerative colitis, and acute surgical abdomen
    6. Laxative Classification Schemes: According to mechanism of action; four major categories (bulk-forming laxatives, surfactants, stimulants, and osmotics; from a clinical perspective classify according to effect time: group I (act in 2-6 hours), group II (6-12 hours), and group III (1-3 days); see Table 74-2 in the text
  3. Basic Pharmacology of Laxatives
    1. Bulk-Forming Laxatives: Have actions and effects much like dietary fiber; natural or semisynthetic polysaccharides and celluloses; belong to category III
      • Mechanism of action: Identical to dietary fiber; fecal volume enlarged by growth of colonic bacteria; fecal mass softened and bulk increased; peristalsis stimulated
      • Indications: Preferred for temporary constipation, for diverticulosis, irritable bowel syndrome, relief of diarrhea with increased bulk
      • Adverse effects: Minimal; rare systemic reactions; esophageal obstruction can occur if taken without sufficient fluids; if passage through intestine arrested, can get obstruction or impaction
      • Preparation, dosage, and administration: Psyllium, methylcellulose and polycarbophil; administer with full glass of water or juice
    2. Surfactant Laxatives
      • Actions: Group III laxatives to produce a soft stool several days later; alter stool consistency by lowering surface tension; surfactant acts on intestinal wall to inhibit fluid absorption and stimulate secretion of water and electrolytes
      • Preparation, dosage, and administration: Three docusate salts
    3. Stimulant Laxatives: Have two effects on bowel: stimulate motility and increase water and electrolytes within intestinal lumen; widely used and abused
      • Bisacodyl (Dulcolax, etc.): Taken orally or by rectal suppository; acts within 6-12 hours (suppositories act in 15-60 minutes); swallow enteric tablet intact to prevent gastric irritation; do not use milk or antacids within an hour of the drug to prevent coating from dissolving
      • Anthraquinones: Ingredients in cascara sagrada and senna; produce soft or semifluid stool in 6-12 hours; can get harmless yellowish-brown or pink color to urine
      • Phenolphthalein: Similar to bisacodyl; acts within 6-8 hours, with effects persisting for 3-4 days; pink tint to urine; recent research indicates may cause cancer in mice; FDA recommended banning it from OTC sales
    4. Osmotic Laxatives
      • Laxative salts: Actions and uses: poorly absorbed salts whose osmotic action draws water into the intestinal lumen, increases fecal mass, and softens it; this stretches intestinal wall and stimulates peristalsis; low-dose effects seen in 6-12 hours; high-dose effects seen in 2-6 hours; preparations: magnesium, sodium, and potassium salts; see Table 74-3 in the text; adverse effects: substantial loss of water; to avoid dehydration, treatment should be accompanied by intake of fluids; some absorption does occur and those with renal dysfunction could develop toxic levels of potassium or magnesium
      • Polyethylene glycol: Nonabsorbable compound retains water in intestinal lumen
    5. Miscellaneous Laxatives
      • Mineral oil: Mixture of indigestible and poorly absorbed hydrocarbons; action produced by lubrication; adverse effects can include aspiration of oil droplets; anal leakage can cause pruritus and soiling; systemic absorption can produce deposition of mineral oil in liver; excessive doses may decrease absorption of fat-soluble vitamins
      • Lactulose: A semisynthetic disaccharide composed of galactose and fructose; poorly absorbed; resident bacteria metabolize lactulose to lactic, formic, and acetic acids, which have mild osmotic action that produces a formed, soft stool in 1-3 days; more expensive than equivalent agents; causes unpleasant side effects of cramping and flatulence; enhances intestinal excretion of ammonia used for hepatic encephalopathy or portal HTN secondary to chronic liver disease
      • contraction; evacuation 30 minutes after suppository inserted; helps to establish normal bowel habits of chronic laxative users
      • Polyethylene glycol-electrolyte solutions: Bowel cleansing solutions; polyethylene glycol, potassium chloride, sodium chloride, sodium sulfate, and sodium bicarbonate; isosmotic; need huge volume about 4 liters (ingest 250-300 ml every 10 minutes for 2-3 hours); bowel movements begin in about 1 hour after beginning drug
  4. Laxative Abuse
    1. Causes: Most believe in daily and bountiful bowel movements, that leads to use of OTC laxatives; continued use perpetuates use; after purging bowel, it takes 2-5 days to replenish
    2. Consequences: Chronic exposure diminishes defecatory reflexes; get more pathologic changes such as electrolyte imbalance, dehydration, and colitis
    3. Treatment: Break laxative habit; inform patient of absence of bowel movement for several days; increase fiber consumption; exercise daily especially after meals; if laxative is a must, use smallest effective dosage; avoid catharsis
  5. Key Points
  6. Summary of Major Nursing Implications
    1. Laxatives
Chapter 75: Other Gastrointestinal Drugs
  1. Antiemetics: Used to suppress vomiting; most important application is suppression of chemotherapy-induced emesis
    1. The Emetic Response: Complex reflex started by activation of vomiting center (nucleus of neurons in medulla oblongata) either directly or indirectly; indirect acting stimulates the chemoreceptor trigger zone (CTZ); receptors that are important in vomiting response include serotonin, dopamine, acetylcholine, and histamine; antiemetic drugs can block more than one receptor type
    2. Antiemetic Drugs: See Tables 75-2 and 75-3 in the text
      • Serotonin receptor antagonists: Most effective drugs available for suppressing nausea and vomiting caused by cisplatin and other highly emetogenic anticancer drugs; three agents available
        1. Ondansetron (Zofran): Approved for suppressing chemotherapy-induced emesis; blocks 5-HT3 receptors in the CTZ and on afferent vagal neurons in upper GI tract; side effects include headache, diarrhea, and dizziness; no extrapyramidal effects; given orally or IV; give IV 30 minutes before chemotherapy
        2. Granisetron (Kytril): Suppresses emesis by blocking serotonin receptors; common effects are headache, weakness, tiredness, and diarrhea or constipation; infuse over 5 minutes, starting 30 minutes before chemotherapy
        3. Dolasetron: For preventing nausea of chemotherapy
      • Dopamine antagonists
        1. Phenothiazines: Block dopamine2 receptors in CTZ; can get extrapyramidal reactions,anticholinergic effects, hypotension, and sedation
        2. Butyrophenones (haloperidol and droperidol): Used as antiemetics; suppress emesis by blocking dopamine2 receptors in CTZ; for postoperative nausea and vomiting, chemotherapy, radiation therapy, and toxins; side effects similar to phenothiazines
        3. Metoclopramide (Reglan): Suppresses emesis by blocking receptors for dopamine in CTZ.
      • Glucocorticoids: Two drugs (methylprednisolone and dexamethasone) used for cancer chemotherapy; more effective with other antiemetics; since used intermittently and short-term, serious side effects do not occur
      • Dronabinol: A Cannabinoids: Approved for cancer chemotherapy; dronabinol is principal psychoactive agent in Cannabis sativa (marijuana); will stimulate appetite in patients with AIDs; adverse effects similar to smoking marijuana (CNS effects)
      • Benzodiazepines (Lorazepam): Used in combination to suppress nausea and vomiting caused by cancer chemotherapy; benefits include sedation, suppression of anticipatory emesis, and production of antegrade amnesia
    3. Management of Chemotherapy-Induced Emesis: Three types of emesis (anticipatory, acute, and delayed); use combination of therapies: see Table 75-4 in the text
  2. Drugs for Motion Sickness: Symptoms are nausea, vomiting, pallor, and cold sweats; drugs effective when taken prophylactically
    1. Scopolamine: A muscarinic antagonist; suppresses nerve traffic in neuronal pathway from vestibular apparatus of inner ear to vomiting center; common side effects are dry mouth, blurred vision, and drowsiness; more severe side effects include urinary retention, constipation, and disorientation; available as oral, subcutaneous, and transdermal
    2. Antihistamines: Most common ones are dimenhydrinate (Dramamine), meclizine (Antivert) and cyclizine (Marezine); block receptors for acetylcholine as histamine; side effects of sedation and typical anticholinergic effects
  3. Antidiarrheal Agents: Diarrhea is symptom caused by infection, maldigestion, inflammation, and functional disorders of bowel; complication of dehydration and depletion of electrolytes; management includes diagnosis and treatment of underlying cause, replacement of lost water and salts, relief of cramping and reducing passage of unformed stool; drugs are in two groups (specific and nonspecific antidiarrheal drugs)
    1. Nonspecific Antidiarrheal Agents
      • Opioids: Most effective; decrease intestinal motility and decreasing fluidity and volume of stools
      • Diphenoxylate: Dispensed in combination with atropine known as Lomotil; the atropine discourages abuse of the opioid
      • Loperamide (Imodium): Structural analogue of meperidine; reduces volume of discharge from ileostomies; little potential for abuse, so not classified as controlled substance
      • Difenoxin: Like diphenoxylate; given only with atropine
      • Paregoric: Diluted solution of opium and contains morphine
      • Opium tincture: Alcohol-based solution with 10% opium by weight; active ingredient is morphine at 10 mg/ml; high potential for abuse
      • Other nonspecific antidiarrheals
        1. Bulk-forming agents: Give stool firmer, less watery consistency
        2. Anticholinergic antispasmodics: Muscarinic antagonists relieve cramping; limited use due to anticholinergic effects
    2. Management of Infectious Diarrhea
      • General considerations: Produced by variety of bacteria and protozoa; usually self-limited; manage mild diarrhea with nonspecific agents; save antibiotics for Salmonella, Shigella, Campylobacter, or Clostridium infections
      • Traveler's diarrhea (sometimes called "Montezuma"s revenge", "Aztec two-step", or "Rangoon runs"); usually caused by Escherichia coli; usually lasts only 1-2 days; if severe, treat with quinolone antibiotics; for milder symptoms, treat with loperamide, but this may prolong infection; can treat prophylactically with quinolones; avoid local drinking water and wash foods
  4. Drugs for Irritable Bowel Disease (IBD): Two forms (Crohn's disease and ulcerative colitis)
    1. Nonspecific Drugs: Four groups of drugs: antispasmodics, bulk-forming agents,antidiarrheals, and tricyclic antidepressants
    2. IBS-Specific Drugs
      • Alosetron (Lotronex): Potentially dangerous drug approved for diarrhea-predominant IBS in women; safety and efficacy in men have not been demonstrated.
        1. Indications
        2. Mechanism of action and clinical effects
        3. Pharmacokinetics
        4. Drug interactions
        5. Adverse effects and contraindications
        6. Risk management program
        7. Preparation, dosage, and administration
      • Tegaserod
    3. Drugs for Irritable Bowel Syndrome
      1. Aminosalicylates: For mild or moderate IBD and to maintain remission
        • Sulfasalazine (Azulfidine): Similar to sulfonamides; not used to treat infection; actions (metabolized by intestinal bacteria into two compounds, the 5-ASA and sulfapyridine; the 5-ASA responsible for reducing inflammation); therapeutic uses (most effective for acute episodes of ulcerative colitis; does help with Crohn's also); adverse effects (nausea, fever, rash, arthralgia; more severe including hematologic disorders; safe during pregnancy and lactation); preparations (oral tablets)
        • Mesalamine: Generic name for 5-ASA; for acute treatment of mild to moderate IBD and for maintenance therapy; administered by retention enema, rectal suppository, and by mouth (dissolve in terminal ileum); less side effects than with sulfasalazine; adverse effects (headache and GI upset)
        • Olsalazine (Dipentum): A dimer composed of 5-ASA; for maintenance therapy; adverse effect is watery diarrhea
      2. Glucocorticoids: Usually dexamethasone or budesonide to relieve symptoms of IBD; benefits from anti-inflammatory effects; to induce remission
      3. Immunomodulators: For long-term therapy
        • Azathioprine and mercaptopurine: Discussed together since azathioprine is converted to mercaptopurine; not approved for IBD, but has been used with success in those who did not respond to other therapy; more toxic than other therapies (pancreatitis and neutropenia)
        • Cyclosporine: A stronger immunosuppressant and faster-acting; IV continuous infusion for rapidly inducing remission; can cause renal dysfunction, neurotoxicity, and suppression of immune system
        • Infliximab (Remicade): New and unique drug for Crohn's disease; inactivates tumor necrosis factor-alpha
        • Methotrexate: Can produce short-term remission, which reduces need for glucocorticoids
      4. Other Drugs
        • Nicotine: Ulcerative colitis occurs in nonsmokers
        • Metronidazole (Flagyl): As effective as sulfasalazine; requires long-term therapy; can get peripheral neuropathy with long-term use
    4. Prokinetic Agents
      1. Metoclopramide
        • Actions: suppresses emesis and increases upper GI motility
        • Therapeutic uses: Used for suppressing nausea vomiting caused by highly emetogenic anticancer agents
        • Adverse effects: Sedation and diarrhea are common
        • Preparation, dosage, and administration
    5. Pancreatic Enzymes: Four enzymes are produced (lipase, amylase, chymotrypsin, and trypsin); deficiency compromises digestion, especially of fats; available in two basic preparations (pancreatin and pancrelipase); may need antacids and histamine2 receptor blockers with pancreatic enzyme therapy
    6. Drugs Used to Dissolve Gallstones: Cholelithiasis; usually treat with cholecystectomy; if without symptoms, may treat with following medications
      1. Chenodiol (Chenodeoxycholic Acid): Actions (reduces hepatic production of cholesterol, which gradually dissolves cholesterol gallstones that are radiolucent stones; not for radiopaque stones); therapeutic use (success most likely in women with low cholesterol, stones of small size, and ability to tolerate drug; complete disappearance in 20%-40% of patients; may need therapy for 2 years); adverse effects (diarrhea occurs in 30%-40% of patients; can damage liver; not for use with pregnancy)
      2. Ursodiol (Ursodeoxycholic Acid): Analogue of chenodiol; reduces cholesterol content of bile; well-tolerated; adverse effects are rare
      3. Monooctanoin (Moctanin): Semisynthetic vegetable oil that can dissolve cholesterol gallstones; only use is removal of stones remaining in common bile duct after cholecystectomy; administration by direct continuous perfusion into common bile duct for 2-10 days; ~30% effective
    7. Anorectal Preparations: For relief of discomfort of hemorrhoids and other anorectal disorders; local anesthetics, hydrocortisone, emollients, and astringents; available in suppositories, creams, ointments, foams, tissues, and pads
    8. Key Points
Chapter 79: Basic Principles of Antimicrobial Therapy
  1. Introduction: 30% of hospitalized patients receive drugs for infectious diseases; two themes of this chapter are microbial susceptibility to drugs and how to use antimicrobial agents properly; definitions to understand include chemotherapy (chemicals against invading organisms for cancer and infections diseases), antibiotics (chemicals that are produced by one microorganism and have the ability to harm other microbes) and antimicrobial drug (any agent that has the ability to kill or suppress microorganisms); antibiotics and antimicrobials are frequently used interchangeably
  2. Selective Toxicity
    1. What Is Selective Toxicity?: Ability of a drug to injure target cells or target organisms without injuring other cells/organisms that are in intimate contact with target
    2. How Is Selective Toxicity Achieved?: Based on differences in cellular chemistry of mammals and microbes
      • Disruption of the bacterial cell wall: Bacteria are encased in a rigid cell wall; drugs that interfere with cell wall allow water to enter, bacteria swell, and then burst (e.g., penicillins, cephalosporins, etc.)
      • Inhibition of an enzyme unique to bacteria: Sulfonamides suppress bacteria by inhibiting enzyme required to synthesize folic acid from PABA; doesn't affect mammalian cells since they do not synthesize folic acid
      • Disruption of bacterial protein synthesis: Requires cellular components called ribosomes (bacteria cells' ribosomes are different from mammalian cells)
  3. Classification of Antimicrobial Drugs: Two methods of classification
    1. Classification by Susceptible Organism: Narrow-spectrum antibiotics and broad-spectrum antibiotics within the three groups: antibacterial, antifungal, and antiviral drugs (see Table 79-1 in the text)
    2. Classification by Mechanism of Action: Antimicrobial drugs in seven groups:
      • Drugs that inhibit bacterial cell wall synthesis or activate enzymes that disrupt the cell wall (e.g., penicillins, cephalosporins)
      • Drugs that increase cell membrane permeability (e.g., amphotericin B)
      • Drugs that cause lethal inhibition of bacterial protein synthesis (only drugs in this group are aminoglycosides: e.g., gentamicin)
      • Drugs that cause nonlethal inhibition of protein synthesis (e.g., tetracyclines)
      • Drugs that inhibit bacterial synthesis of nucleic acids: rifampin and quinolones
      • Antimetabolites (e.g., trimethoprim and sulfonamides)
      • Inhibitors of viral enzymes: Two classes include protease inhibitors and nucleoside analogs (e.g., zidovudine, acyclovir, and saquinavir)
  4. Acquired Resistance to Antimicrobial Drugs
    1. Mechanisms of Microbial Drug Resistance: Due to alterations in functions/structure
      • Microbes may elaborate drug: Metabolizing enzymes
      • Microbes may cease active uptake of certain drugs
      • Microbial drug receptors may undergo change, resulting in decreased antibiotic binding and action
      • Microbes may synthesize compounds that antagonize drug actions
    2. Mechanisms by Which Resistance Is Acquired: By changes in microbial genome
      • Spontaneous mutation: Random changes in microbe's DNA; to only one drug
      • Conjugation: Most significant; process by which extrachromosomal DNA is transferred from one bacterium to another; usually gram-negative; multiple drug resistance occurs
    3. Relationships Between Antibiotic Use and the Emergence of Drug-Resistant Microbes: Use of antibiotics promotes emergence of drug-resistant microbes
      • How do antibiotics promote resistance?: Microbes secrete compounds that are toxic to other microbes, and microbes compete with one another for nutrients
      • Which antibiotics promote resistance?: Some more likely than others (e.g., broad-spectrum drugs)
      • Does the amount of antibiotic use influence the emergence of resistance?: The more you use, the faster drug-resistance emerges; hospitals use many antibiotics, which then result in nosocomial infections that become hard to treat
    4. Suprainfection: Special example of emergence of drug resistance
    5. Delaying the Emergence of Resistance: Use only when actually needed, narrow-spectrum agents used whenever possible, and newer antibiotics should be reserved for situations where older drugs are dangerous or no longer effective
  5. Selection of Antibiotics: Maximal effects with minimal harm to host; consider three principal factors (identity of infecting organism, drug sensitivity of infecting organism, and host factors such as site and host defenses); choosing alternate agents when first choice is inappropriate (allergy to drug of choice, inability of drug to penetrate site of infection, and unusual susceptibility of patient to toxicity); see Table 79-4 in the text
    1. Empiric Therapy Prior to Completion of Laboratory Tests: Cultures
    2. Identification of the Infecting Organism: "Match drug with bug" (gram stain)
    3. Determination of Drug Susceptibility
      • Disk-diffusion test: Most widely used method
      • Broth dilution procedure: Can establish estimates of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)
  6. Host Factors That Modify Drug Choice, Route of Administration, or Dosage
    1. Host Defenses: Primarily immune system and phagocytic cells
    2. Site of Infection: Getting to site of infection in concentration >MIC
    3. Other Host Factors
      • Age: Infants and elderly highly vulnerable to drug toxicity
      • Pregnancy and lactation: Drugs can cross placenta and breast milk
      • Previous allergic reaction: Penicillin most common
      • Genetic factors: Affect responses and rate of metabolism
  7. Dosage Size and Duration of Treatment: Must be at site of infection in an effective concentration for sufficient time; may need dosages 4-8 times the MIC; duration of therapy depends on a number of variables
  8. Therapy With Antibiotic Combinations: Only for specific situations
    1. Antimicrobial Effects of Antibiotic Combinations: Combinations can be additive,potentiative, or antagonistic
    2. Indications for Antibiotic Combinations
      • Initial therapy of severe infection
      • Mixed infections
      • Prevention of resistance
      • Decreased toxicity
      • Enhanced antibacterial action
    3. Disadvantages of Antibiotic Combinations: Increased risk for toxic and allergic reactions, possible antagonisms of antimicrobial effects, increased risk for suprainfection, selection of drug-resistant bacteria, and increased cost
  9. Prophylactic Use of Antimicrobial Drugs: About 30%-50% used as prophylaxis; approved use for the following
    1. Surgery: Decreased incidence of infection in certain surgeries
    2. Bacterial Endocarditis: In patients with congenital or valvular heart disease
    3. Neutropenia: Patients are at high risk for infections
    4. Other Indications for Antimicrobial Prophylaxis: For women with recurrent urinary tract infection, for prophylaxis against type A influenza, following exposure to organisms responsible for STDs
  10. Misuses of Antimicrobial Drugs
    1. Attempted Treatment of Untreatable Infection
    2. Treatment of Fever of Unknown Origin
    3. Improper Dosage: Too low or too high
    4. Treatment in the Absence of Adequate Bacteriologic Information
    5. Omission of Surgical Drainage: Have limited efficacy in presence of foreign material, necrotic tissue, or pus
  11. Monitoring Antimicrobial Therapy: Monitor clinical responses and laboratory results
  12. Special Interest Topic: Antibiotics in Animal Feed: Hastening Antibiotic Armageddon
  13. Key Points
Chapter 80: Drugs that Weaken the Bacterial Cell Wall I: Penicillins
  1. Introduction to the Penicillins: Are practically ideal antibiotics; active against variety of bacteria with low toxicity; allergic reactions principal adverse effect; widely prescribed; have beta-lactam ring
    1. Mechanism of Action: Weaken cell wall allowing water to enter cell and cause rupture; usually bactericidal only to bacteria undergoing active growth and division; weaken cell wall by inhibition of transpeptidases and disinhibition of autolysins; molecular targets are known collectively as penicillin-binding proteins (PBPs); no adverse effects on host since mammalian cells lack cell wall
    2. Mechanism of Bacterial Resistance: Bacterial resistance determined by two factors (inability of penicillins to reach targets and inactivation of penicillins by bacterial enzymes); all bacteria surrounded by cell envelope but gram-positives are different from gram-negatives (see Figure 80-3 in the text)
      • The gram-negative cell envelope: Three cell layers (cytoplasmic membrane, thin cell wall, and outer membrane); only small penicillins can pass through pores of outer membrane; since most can't do this, penicillins are inactive against the gram-negative (gram-positive have only two layers: cytoplasmic membrane and thick cell wall; penicillins can penetrate this cell wall)
      • Penicillinases (beta-lactamases): Enzymes that cleave beta-lactam ring, making penicillins inactive (called penicillinases)
    3. Chemistry: All penicillins derived from common nucleus (see Figure 80-1 in the text); individual ones determined by additions made to nucleus which determine affinity for PBPs, resistance to penicillinases, ability to penetrate gram-negative cell envelope, resistance to stomach acid, and pharmacokinetic properties
    4. Classification: Based on antimicrobial spectrum; four major groups (narrow-spectrum that are penicillinase-sensitive; narrow-spectrum that are penicillinase-resistant; broad-spectrum penicillins; and extended-spectrum penicillins
  2. Properties of Individual Penicillins
    1. Penicillin G (Benzylpenicillin) was first available; bactericidal to gram-positive and some gram-negative bacteria
      • Antimicrobial spectrum: Not effective against penicillinase: producing staphylococci, gram-negative cocci, anaerobic bacteria, and spirochetes
      • Therapeutic uses: First-choice drug for infections caused by sensitive gram-positive cocci (pneumonia, meningitis, endocarditis); also important for prophylactic applications (syphilis from infected partners, recurrent rheumatic fever, etc.)
      • Pharmacokinetics: Four different salts (sodium, potassium, procaine, and benzathine) of penicillin G
        1. Absorption: Oral administration is rare since unstable in acid; IM but absorption of the different salts varies; IV when need high blood levels fast
        2. Distribution: To most tissues and body fluids; without inflammation, penetration to meninges, joints and eye not good
        3. Elimination: By kidneys by active tubular secretion (90%); short half-life (30 minutes); renal excretion can be delayed with probenecid
      • Side effects and toxicities: Least toxic of all antibiotics; allergic reactions only real problem; may get pain at site of injection; if given into peripheral nerve, get motor and sensory dysfunction; if use large doses of potassium penicillin, can get hyperkalemia; overload with sodium if large doses of sodium penicillin used
      • Penicillin allergy
        1. General considerations: Most common cause of drug allergy (1%-10%); reactions vary; cross-sensitivity develops; need Medic-Alert bracelet
        2. Types of allergic reactions: Immediate (anaphylaxis), accelerated, and late; keep epinephrine available
        3. Development of penicillin allergy: Has to bind (usually) to a protein; called "hapten"; this combination completes antigen, which stimulates antibody formation
        4. Skin tests for penicillin allergy: Allergy can decrease over time; those with severe allergic reactions have little risk with skin test using special preparations, not penicillin itself
        5. Management of patients with a history of penicillin allergy: Ask whether past reaction to penicillin; if mild allergy, may give cephalosporin; if severe reaction, use vancomycin or erythromycin; can do desensitization, but there are risks
      • Drug interactions a. Aminoglycosides: Penicillins weaken cell wall and aminoglycosides enter cell; cannot be mixed in IV or will be inactivated b. Probenecid: Delays renal excretion of penicillin c. Bacteriostatic antibiotics: Don't know effects with bacteriostatic
      • Preparation, dosage, and administration: Be sure to give right method of penicillin ordered
    2. Penicillin V: Similar to penicillin G; acid stability only real difference; can be taken with meals
    3. Penicillinase-Resistant Penicillins (Antistaphylococcal Penicillins): Done by altering side chain; narrow spectrum; drug of choice for most staph infections
      • Nafcillin: IM or IV; oral not recommended
      • Oxacillin, cloxacillin, and dicloxacillin: These are similar; acid stable so oral, IM, and IV; can take with meals; see Table 80-2 in the text
      • Methicillin (Staphcillin): Oldest of penicillinase-resistant penicillins; not used much now and not available in U.S.
    4. Broad-Spectrum Penicillins (Aminopenicillins): Same antimicrobial spectrum as penicillin G, but increased activity against gram-negative; inactivated by beta-lactamases, so not helpful for Staphylococcus Aureus (see Table 80-2 in the text)
      • Ampicillin: Preferred or alternate for strep, etc.; side effects are rash and diarrhea; not preferred for oral dosage
      • Amoxicillin: Preferred for oral dosage; less diarrhea; most frequently prescribed antibiotic in U.S.
      • Bacampicillin: Prodrug form of ampicillin; take with meals; no real advantage
    5. Extended-Spectrum Penicillins (Antipseudomonal Penicillins): Four drugs
      • Ticarcillin (Ticar): Antimicrobial spectrum and therapeutic use (one of the broadest antimicrobial spectra of all penicillins; is susceptible to destruction by penicillinase; primary indication for Pseudomonas aeruginosa); adverse effects (allergic reactions, sodium overload can occur, interferes with platelet function); preparations (unstable in acid, given IM or IV; when giving with aminoglycoside, give separately)
      • Carbenicillin indanyl (Geocillin): Acid-stable and given orally; converted to active form once absorbed; concentrated in urine; only for UTIs caused by Pseudomonas aeruginosa or indole-positive Proteus; do not take with meals
      • Mezlocillin and piperacillin: For infections with Pseudomonas aeruginosa; given IM or IV; less risk for sodium overload
    6. Penicillins Combined with a Beta-Lactamase Inhibitor: Combine with penicillinase-sensitive penicillin to extend antimicrobial spectrum of penicillin; three are used in U.S. and are dispensed with combinations of penicillin to have four products available; minimal toxicity
      • Ampicillin + sulbactam (Unasyn), amoxicillin + clavulanic acid (Augmentin), ticarcillin + clavulanic acid (Timentin), and piperacillin + tazobactam (Zosyn)
  3. Key Points
  4. Summary of Major Nursing Implications
    1. Penicillins
Chapter 81: Drugs that Weaken the Bacterial Cell Wall II: Cephalosporins, Imipenem, Aztreonam, Vancomycin, and Teicoplanin
  1. Cephalosporins: Produce bacteria lysis and death; are beta-lactam antibiotics similar in structure and actions to penicillins; bactericidal; broad spectrum with low toxicity
    1. Chemistry: All derived from same nucleus, which contains beta-lactam ring
    2. Mechanism of Action: Similar to penicillins; bind to penicillin-binding proteins (PBPs), which disrupts cell wall synthesis and activates autolysins; most effective against cells undergoing active growth and division
    3. Resistance: Cause is production of beta-lactamases; different generations vary in susceptibility of beta-lactamases (first generation destroyed and third and fourth generation highly resistant to beta-lactamases)
    4. Classification and Antimicrobial Spectra: Four generations with increasing activity against gram-negative bacteria and anaerobes, increasing resistance to destruction by beta-lactamases, and increasing ability to reach the CSF
    5. Pharmacokinetics
      • Absorption: Poorly absorbed from oral administration; most given IM or IV, only two given orally
      • Distribution: Distributed well to most fluids and tissues, in CSF the third and fourth generations are effective
      • Elimination: By kidney except for two (cefoperazone and ceftriaxone)
    6. Adverse Effects: Generally well tolerated and one of safest groups of antimicrobial drugs
      • Allergic reactions: Most frequent adverse effect with maculopapular rash; may have cross-sensitivity with penicillins
      • Bleeding: Three cause bleeding tendencies by reduction of prothrombin levels by interference with vitamin K; to counter this for long-term therapy, check prothrombin time/bleeding time and parenteral vitamin K to correct these; caution with anticoagulants or thrombolytic agents; caution with aspirin and other NSAIDs
      • Thrombophlebitis: With IV infusion, rotate sites and administer slowly with dilute solution
      • Other adverse effects: Pain at site, may cause colitis and nephrotoxicity
    7. Drug Interactions
      • Probenecid: Delays renal excretion
      • Alcohol: Three induce state of alcohol intolerance (a disulfiram-like reaction); do not use any alcohol with these drugs
      • Drugs that promote bleeding: Caution with those drugs that promote bleeding tendencies
    8. Therapeutic Uses: Broad-spectrum, bactericidal drugs with high therapeutic index; can be used for those with mild penicillin allergy; third generation equally effective and less expensive; therefore, preferred
      • First-generation cephalosporins: For gram-positive, for staph, and strep infections in patients with mild penicillin allergy
      • Second-generation cephalosporins: Limited use for pneumonia, otitis, sinusitis, respiratory tract infections and abdominal and pelvic infections by specific organisms
      • Third-generation cephalosporins: Drugs of choice for meningitis and nosocomial infections resistant to other drugs; should not be used routinely, only with specific need to prevent emergence of resistance
  2. Drug Selection: 23 cephalosporins used in U.S.; choose based on antimicrobial spectrum, adverse effects, and pharmacokinetics
    • Antimicrobial spectrum ("match drug with bug"): Adverse effects (a few have unique reactions, including the three with bleeding tendencies and the intolerance to alcohol); pharmacokinetics: route of administration (11 can be given orally and used for mild to moderate infections); duration of action (with normal renal function, half-life is 30 minutes to 9 hours); distribution to CSF (only third and fourth generations have effects in CSF); route of elimination (by kidneys except for two that are eliminated by nonrenal route so useful for renal patients)
    • Dosage and Administration: most must be given IM or IV (see Table 81-2 in the text)
  3. Carbapenems
    1. Imipenem (Primaxin): New beta-lactam antibiotic with broadest antimicrobial spectrum of any drug; for mixed infections; given in fixed-dose with cilastatin, which inhibits destruction of imipenem by renal enzymes
      • Mechanism of action: Binds to two penicillin-binding proteins
      • Antimicrobial spectrum: Highly effective against gram-positive and most gram-negative cocci and bacilli and anaerobic bacteria
      • Pharmacokinetics: Not absorbed from GI so IV or IM; renal excretion
      • Adverse effects: GI effects most common; hypersensitivity reactions and suprainfections (4%); rare seizures from drug
      • Therapeutic use: Widely used; some resistance with Pseudomonas aeruginosa, so combine with another antipseudomonal drug
      • Preparation, dosage, and administration: Dispensed in fixed-dose with cilastatin
    2. Meropenem: Similar to imipenem
    3. Ertapenem: Weakens the bacterial cell wall and causes cell lysis and death.
  4. Other Inhibitors of Cell Wall Synthesis
    1. Aztreonam (Azactam): New class known as monobactams with beta-lactam ring not fused to second ring; does not bind to PBPs produced by anaerobes or gram-positive bacteria; narrow antimicrobial spectrum; not active against gram-positive bacteria or anaerobes; not absorbed from GI tract; renal elimination; get pain and thrombophlebitis at site of injection
    2. Vancomycin (Lyphocin, Vancoled, Vancocin): Potentially toxic drug used only for serious infections like pseudomembranous colitis, methicillin-resistant Staphylococcus aureus and penicillin-allergy patients; no beta-lactam ring; reaction of ototoxicity most serious; do not give by rapid infusion (give over 60 minutes)
    3. Teicoplanin (Targocid): An investigational drug similar to vancomycin; can administer this one by IM as well as IV; ototoxicity rare; can use as once/day dosing, shorter duration of administration (30 minutes)
    4. Fosfomycin (Monurol): New bactericidal agent as single dose for uncomplicated UTIs
  5. Key Points
  6. Summary of Major Nursing Implications
    1. Cephalosporins
Chapter 82: Bacteriostatic Inhibitors of Protein Synthesis: Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, and Spectinomycin
  1. Tetracyclines: These agents suppress growth of, do not outright kill, second-line agents; broad-spectrum antibiotics; all six similar in structure, antimicrobial actions and adverse effects
    1. Mechanism of Action: They bind to 30S ribosomal subunit inhibiting the binding of transfer RNA; selective toxicity determined in part by relative inability of these drugs to cross mammalian cell membranes; entry into bacteria by energy-dependent transport process; microbial resistance results from reduced drug accumulation, increased drug inactivation, and decreased access to ribosomes
    2. Therapeutic Uses
      • Treatment of infectious diseases: For first-line treatment of rickettsial diseases, infections caused by Chlamydia trachomatis, brucellosis, cholera, pneumonia caused by Mycoplasma pneumoniae, Lyme disease and gastric infection with H. pylori
      • Treatment of acne: Topically and orally used for severe acne vulgaris
      • Peptic ulcer disease: Helicobacter pylori is major contributing factor to peptic ulcer disease; combined with metronidazole and bismuth subsalicylate for treatment to eradicate organism
      • Rheumatoid arthritis: Minocycline can reduce symptoms
      • Periodontal disease: Doxycycline orally or topically
    3. Pharmacokinetics: Differ in half-life and route of elimination (see Table 82-1 in the text)
      • Duration of action: Three groups (short-, intermediate-, and long-acting)
      • Absorption: All are orally effective; short- and intermediate-acting are reduced in presence of food; food does not affect long-acting; with certain minerals they form insoluble chelates; do not administer with calcium supplements, milk products, iron supplements, magnesium-containing laxatives, and most antacids
      • Distribution: To almost all tissues; penetration to CSF poor and inadequate to treat meningeal infections; cross placenta to fetus
      • Elimination: Via renal (short- and intermediate-acting ones) and hepatic (for long-acting tetracyclines) routes; excreted by liver into bile
    4. Adverse Effects
      • Gastrointestinal irritation: Can be reduced by giving with meals, but this may decrease absorption; may cause ulceration, so don't give at bedtime
      • Effects on bones and teeth: Affects developing teeth; can suppress long-bone growth in premature infants (is reversible)
      • Suprainfection: Greater risk with these broad-spectrum drugs
      • Hepatotoxicity: Fatty infiltration of liver, especially with IV
      • Renal Toxicity: Exacerbate renal dysfunction with preexisting kidney disease; only two not excreted by kidney (doxycycline and minocycline)
      • Photosensitivity: To ultraviolet light
      • Other adverse effects: Vestibular toxicity; pain at injection sites, thrombophlebitis with IV and other rare effects
    5. Drug and Food Interactions: Avoid foods and drugs with specific chelating agents (give 2 hours before or after)
    6. Dosage and Administration: Given orally, IM, or IV; orally take 1 hour before or 2 hours after meals with full glass of water
    7. Summary of Major Precautions: Tetracyclines (except doxycycline and minocycline) can accumulate to toxic levels with kidney disease; discoloration of teeth, suprainfection of bowel; high doses lead to liver disease especially in pregnant and postpartum women with kidney disease
    8. Summary of Unique Properties of Individual Tetracyclines
      • Tetracycline: Least expensive and most widely used
      • Oxytetracycline: Principal difference is cost
      • Demeclocycline: Expensive; stimulates urine flow
      • Methacycline
      • Doxycycline: Absorption not diminished by food; nonrenal elimination; first-line drug for Lyme disease and chlamydial infections
      • Minocycline: can damage vestibular system; very costly
  2. Macrolides: Broad-spectrum antibiotics; act by inhibiting bacterial protein synthesis; large size; used alone are devoid of serious toxicity; some, if combined, cause toxicity
    1. Erythromycin: Preferred or alternative treatment for infectious diseases; safe
      • Mechanism of action: Binds to ribosomal subunit and blocks addition of new amino acids to growing peptide chain; usually bacteriostatic but can be bactericidal in high doses to susceptible organisms; can't cross host mitochondrial membrane
      • Antimicrobial spectrum: Similar to penicillin; against most gram-positive and some gram-negative; response based on access to cell
      • Therapeutic uses: First-choice for several infections (pneumonia caused by Legionella pneumophila, Bordetella pertussis, Corynebacterium diphtheriae) and as alternative to allergy to penicillin
      • Pharmacokinetics a. Absorption and bioavailability: Oral forms have coating to protect from stomach acid; also IV form b. Distribution: Readily to most tissues and body fluids; poor penetration in CSF; crosses placenta; no adverse effects to fetus c. Elimination: Primarily by hepatic mechanisms; small amount in urine
      • Adverse effects: Generally free of serious toxicity; concern with liver injury with erythromycin estolate a. Gastrointestinal effects: Most common adverse effect; may need to take with food, but use forms not affected by food b. Liver injury: In adults only; do not give erythromycin estolate to adults with previous hepatic damage; symptoms are reversible c. Other adverse effects: Suprainfection of bowel, thrombophlebitis, transient loss of hearing
      • Drug interactions: Can increase half-life and plasma levels of several drugs; possible with two antihistamines (astemizole and terfenadine) not available in U.S. now; also theophylline, carbamazepine, and warfarin should be carefully monitored; do not give concurrently with chloramphenicol or clindamycin
      • Preparation, dosage, and administration: Oral and IV (rarely used)
    2. Other Macrolides
      • (Tao): Like other Clarithromycin (Biaxin): For respiratory tract, skin infections, and prevention of Mycobacterium avium complex of HIV patients; can cause diarrhea; can affect drugs that are metabolized by liver
      • Azithromycin (Zithromax): Like erythromycin and for respiratory tract infections; well tolerated; do not take with food (1 hour before or 2 after)
      • Dirithromycin: For bronchitis caused by Streptococcus pneumoniae; does not inhibit metabolism of other drugs
      • Troleandomycin macrolides
  3. Other Bacteriostatic Inhibitors of Protein Synthesis
    1. Clindamycin (Cleocin): Can promote severe antibiotic-associated pseudomembranous colitis, which can be fatal; limited uses (anaerobic infections outside of CNS)
      • Mechanism of Action: Binds to subunits of bacterial ribosomes
      • Antimicrobial Spectrum: Against most anaerobic bacteria; usually bacteriostatic
      • Therapeutic Use: Abdominal and pelvic infections by Bacteroides fragilis; can be alternative for penicillin G in severe anaerobe infections
      • Pharmacokinetics: Orally, IM, IV; not affected by food; may get toxic levels with combined hepatic and renal disease
      • Adverse Effects
        1. Antibiotic: Associated pseudomembranous colitis: 10 to 20 stools/day; drugs that decrease bowel motility may make condition worse
        2. Other adverse effects: Hypersensitivity, hepatotoxicity, blood dyscrasias, problems with rapid infusion
      • Preparations, Dosage, and Administration: Oral, IV, and IM
    2. Chloramphenicol: Broad-spectrum with potential for causing fatal aplastic anemia and other blood dyscrasias; use limited to serious infections not responding to other drugs
      • Mechanism of Action: Usually bacteriostatic; may affect mitochondrial protein synthesis of host (may account for blood dyscrasias)
      • Antimicrobial Spectrum: Against many organisms
      • Resistance: Same as tetracyclines
      • Pharmacokinetics: Available in three forms for oral and IV administration; has low therapeutic index; must monitor drug levels; also need to monitor drugs that are metabolized by liver
      • Therapeutic Use: Drug of choice for acute typhoid fever
      • Adverse Effects
        1. Gray syndrome: Potentially fatal in newborns because of lack of clearing drug by liver
        2. Reversible bone marrow depression: Usually reverses 1 to 3 weeks after discontinuing drug
        3. Aplastic anemia: Can be fatal and cannot be predicted
        4. Other adverse effects: GI effects, Herxheimer reactions during treatment of typhoid fever, neurologic effects, and suprainfections
      • Drug Interactions: Inhibits drug metabolizing enzymes in liver, so concern with phenytoin, warfarin, two oral hypoglycemics
      • Preparation, Dosage, and Administration: Orally or IV, peak levels between 10-20 mcg/ml
    3. Linezolid: Has activity against multidrug-resistant gram-positive pathogens, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus
      • Mechanism, Resistance, and Antimicrobial Spectrum
      • Pharmacokinetics
      • Adverse Effects
      • Drug Interactions
    4. Dalfopristin/Quinupristin: Known as steptogamins; given as fixed dose of both drugs for vancomycin-resistant Enterococcus faecium; hepatotoxicity is major problem
    5. Spectinomycin: Active against many gram-negative bacteria, but resistance develops frequently; use limited; for anogenital gonorrhea in those who cannot tolerate ceftriaxone; well tolerated
  4. Key Points
  5. Summary of Major Nursing Implications
    1. Tetracyclines
    2. Erythromycin
    3. Clindamycin
    4. Chloramphenicol
Chapter 83: Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
  1. Introduction: Narrow-spectrum antibiotics, against aerobic gram-negative bacilli; disrupt protein synthesis and cause bacteria death; can injure kidney and inner ear; not absorbed from GI tract
  2. Basic Pharmacology of the Aminoglycosides
    1. Chemistry: Composed of two or more amino sugars connected by glycoside linkage; are polycations, so cannot cross membranes
    2. Mechanism of Action: Bind to 30S ribosomal subunit, which inhibits protein synthesis and produces abnormal proteins; bactericidal
    3. Microbial Resistance: Production of enzymes can inactivate aminoglycosides; patterns of resistance to aminoglycosides complex; amikacin least susceptible to inactivation; use amikacin when infections unresponsive to others
    4. Antimicrobial Spectrum: Almost exclusively aerobic gram-negative bacilli; ineffective against anaerobes because can't be transported into cells
    5. Therapeutic Use
      • Parenteral therapy: Serious infections like Pseudomonas aeruginosa and Enterobacteriaceae; gentamicin and tobramycin preferred
      • Oral therapy: Not absorbed from GI tract; only for local effects in intestine
      • Topical therapy: For eyes, ears, and skin
    6. Pharmacokinetics: All aminoglycosides similar
      • Absorption: IM or IV required since only 1% would cross membranes; can irrigate wounds and amounts absorbed could be toxic
      • Distribution: Mostly extracellular fluids; binds to renal tissues creating dangerously high levels there (nephrotoxic)
      • Elimination: By kidneys; normal renal function half-life is 2-3 hours; if kidney dysfunction, either decrease dose or increase interval dosing time
      • Interpatient variation: Wide variations in response to drug dependent on age, percentage of body fat, and pathophysiology; amount per kg varies greatly to achieve serum drug levels
    7. Maintaining Appropriate Serum Drug Levels: Must maintain serum levels in narrow range (trough levels not exceeding 2 mcg/ml with peak levels not exceeding 12 mcg/ml); timing of levels important (peak 1 hour after IM or 30 minutes after IV; trough measurements just before next dose)
    8. Adverse Effects: Produce serious toxicities, which limit use of drugs
      • Ototoxicity: Impair balance and hearing (damage to hair cells); contributing factors include kidney disease, concurrent use of ethacrynic acid, and administration of excessive doses for > 10 days; if ototoxicity extensive, permanent impairment may occur
      • Nephrotoxicity: Injure proximal renal tubules causing proteinuria, casts in urine, dilute urine, and elevations in serum creatinine and BUN; usually injury can be reversed
      • Neuromuscular blockade: Get flaccid paralysis and potentially fatal respiratory depression; reversed with calcium (rare occurrence now)
      • Other adverse effects: Hypersensitivity, blood dyscrasias, streptomycin associated with neurologic disorders, paresthesias of face and hands, neomycin causes suprainfections of bowel and intestinal malabsorption; topical neomycin can cause dermatitis
  3. Drug Interactions
    • Penicillins: Combination to enhance bacterial kill; do not mix together in same IV solution since penicillins can inactivate drug
    • Ototoxic drugs: Increased with use of ethacrynic acid
    • Nephrotoxic drugs: More likely with other nephrotoxic drugs
    • Skeletal muscle relaxants: Intensify neuromuscular blockade
  4. Properties of Individual Aminoglycosides
    1. Gentamicin (Garamycin, Jenamicin)
      • Therapeutic use: For aerobic gram-negative bacilli; preferred drug if no resistance has developed; low cost; increased incidence of resistance; combined with ampicillin or penicillin to treat enterococcal endocarditis
      • Adverse effects and interactions: Toxic to kidneys and inner ear; inactivated by penicillins, so do not mix together
      • Preparation, dosage, and administration: For IM or IV; peak levels of 4-8 mcg/ml and trough not exceed 2 mcg/ml for 7-10 days
    2. Tobramycin (Nebcin)
      • Uses, adverse effects, and interactions: More active against Pseudomonas aeruginosa but less against enterococci and Serratia
      • Preparations, dosage, and administrations: IM or IV (see Table 81-1 in the text); similar to gentamicin
    3. Amikacin (Amikin)
      • Uses, adverse effects, and interactions: Two main features: broadest spectrum of action against gram-negative bacilli, and least vulnerable to inactivation by bacterial enzymes
      • Preparations, dosage, and administrations: IM and IV; IV must be diluted and given slowly (1-2 hours for infants)
    4. Other Aminoglycosides
      • Netilmicin (Netromycin): Similar to gentamicin
      • Neomycin: Most toxic of aminoglycosides; not administered parenterally; used topically for eye, ear, and skin; orally to suppress bowel flora prior to surgery; but can cause bowel suprainfection
      • Kanamycin (Kantrex): Bacterial resistance common; not used as much now; can be used to suppress intestinal flora
      • Streptomycin: used in combination with other drugs to treat TB but newer and safer drugs preferred; used for uncommon infections
      • Paromomycin (Humatin): Only for local effects in intestine; for intestinal amebiasis and tapeworm infestations
  5. Key Points
  6. Summary of Major Nursing Implications
    1. Aminoglycosides
Chapter 84: Sulfonamides and Trimethoprim
  1. Sulfonamides: First drugs for systemic treatment of bacterial infections; still used primarily for UTIs
    1. Basic Pharmacology
      • Chemistry: Structural analogues of PABA (see Figure 84-1 in the text)
      • Mechanism of action: Suppress bacterial growth by inhibiting synthesis of folic acid (different from host because bacteria must synthesize their own folate, not absorb it from environment)
      • Microbial resistance: Much resistance has occurred; principal mechanisms of resistance are synthesis of PABA in amounts sufficient to overcome sulfonamide-mediated inhibition of dihydropteroate synthetase, alteration in structure of dihydropteroate synthetase, and reduced sulfonamide uptake
      • Antimicrobial spectrum: Against broad spectrum of microbes
      • Therapeutic uses: Has declined for two reasons (introduction of bactericidal antibiotics with less toxicity and development of bacterial resistance)
        1. Urinary tract infection: 90% are Escherichia coli, which is sulfonamide-sensitive
        2. Other uses: Drug of choice for nocardiosis and alternative for other antibiotics
      • Pharmacokinetics: Absorption (well absorbed from oral and topical); distribution (to all tissues, cross placenta); metabolism (by liver); excretion (by kidney)
      • Adverse effects: Multiple effects
        1. Hypersensitivity reactions: Mild to most severe (Stevens-Johnson syndrome with 25% mortality)
        2. Hematologic effects: Hemolytic anemia
        3. Kernicterus: Disorder in newborns caused by deposition of bilirubin in brain; neurotoxic with severe neurologic deficits and even death
        4. Renal damage from crystalluria: Low solubility in older sulfonamides, which come out of solution forming crystalline aggregates in kidney; decrease risk by output of 1200 ml and drinking 8-10 glasses of water/day
        5. Drug interactions: Intensifies warfarin, phenytoin, and oral hypoglycemics
    2. Sulfonamide Preparations
      • Systemic sulfonamides: Based on duration of action (short-acting and intermediate-acting drugs); the long-acting produce a high incidence of Stevens-Johnson syndrome and have been removed from U.S. market (see Table 84-1 in the text)
      • Sulfisoxazole (Gantrisin): Short-acting for UTIs; minimal risk for crystalluria; can be combined with penicillin to treat otitis media and prophylaxis for rheumatic fever for those allergic to penicillin
      • Sulfamethoxazole (Gantanol, Urobak): Only intermediate-acting; for same uses as sulfisoxazole; maintain adequate hydration to prevent renal damage
      • Sulfadiazine: Short-acting; less soluble than others; must maintain high urine flow; crosses blood-brain barrier with ease; prophylaxis for meningitis; preferred for nocardiosis
      • Sulfamethizole (Thiosulfil forte): Short-acting for UTIs only
      • Trisulfapyrimidines (triple sulfa): Contains three sulfonamides to help decrease renal damage; used topically for Candida albicans
      • Topical sulfonamides: Sulfacetamide; silver sulfadiazine, and mafenide; high incidence of hypersensitivity reactions; not used routinely
  2. Trimethoprim (Proloprim, Trimpex): Against broad-spectrum of microbes
    1. Mechanism of Action: An inhibitor of dihydrofolate reductase the enzyme that convertsdihydrofolic acid to active form; suppresses bacterial synthesis of DNA, RNA, and proteins
    2. Microbial Resistance: Acquire resistance by three mechanisms (synthesis of increased amounts of dihydrofolate reductase, production of altered dihydrofolate reductase, and reduced cellular permeability to trimethoprim)
    3. Antimicrobial Spectrum: against many gram-positive and some gram-negative bacilli
    4. Therapeutic Uses: Only for initial therapy of acute, uncomplicated UTIs; more applications when combined with sulfamethoxazole
    5. Pharmacokinetics: Absorbed rapidly and completely from GI tract
    6. Adverse Effects: Generally well tolerated; most frequent is itching, rash, and GI effects
      • Hematologic effects: Rare and only in those with preexisting folic acid deficiency
      • Use in pregnancy and lactation: Large doses cause fetal malformations in animals; no abnormalities noted yet in humans
    7. Preparation, Dosage, and Administration: 10 days of treatment
  3. Trimethoprim (TMP)-Sulfamethoxazole (SMZ): Marketed together in fixed-dose
    1. Mechanism of Action: Inhibits consecutive steps in synthesis of tetrahydrofolic acid
    2. Microbial Resistance: Less than either drug alone
    3. Antimicrobial Spectrum: Wide range of gram-positive and gram-negative
    4. Therapeutic Uses
      • Urinary tract infections
      • Pneumocystis carinii infections
      • Gastrointestinal infections: For Shigellosis; in combination with chloramphenicol and ampicillin for typhoid fever
          Other infections: Otitis media, bronchitis, whooping cough, nocardiosis, brucellosis, melioidosis, and chancroid
      • Pharmacokinetics: Orally and IV; crosses placenta; optimal level when ration of TMP to SMZ is 1:20; renal excretion
      • Adverse Effects: Well tolerated; most common effects are nausea, vomiting, and rash; same effects as with two drugs separately
      • Drug Interactions: Intensify warfarin, phenytoin, and oral hypoglycemics
      • Preparations, Dosages, and Administration: Tablets, oral suspension, and IV
  4. Key Points
  5. Summary of Major Nursing Implications
    1. Sulfonamides (Systemic)
    2. Trimethoprim
    3. Trimethoprim-Sulfamethoxazole
Chapter 85: Drug Therapy of Urinary Tract Infections
  1. Introduction: Urinary tract infections (UTIs) are most common infections; more common in females; bacteria invading urinary tract (urethritis, cystitis, pyelonephritis, and prostatitis; UTIs classified according to location: lower UTIs (cystitis and urethritis), upper UTIs (pyelonephritis); classified according to complicated (predisposing factors such as calculi, indwelling catheter, prostatic hypertrophy) or uncomplicated (women of childbearing age without predisposing factors)
  2. Organisms That Cause Urinary Tract Infections: Community-acquired (80% are Escherichia coli) versus hospital-acquired (nosocomial)
  3. Specific Urinary Tract Infections and Their Treatment: Most can be treated with oral therapy on outpatient basis
    1. Acute Cystitis: Symptoms (dysuria, urinary urgency, frequency, suprapubic discomfort, pyuria, and bacteriuria); 30% of women with cystitis also have asymptomatic upper urinary tract infections; three forms of therapy (single-dose therapy, short-course therapy, and conventional therapy); see Table 85-3 in the text
    2. Acute Pyelonephritis: Common in young children, elderly, and women of childbearing age; symptoms include fever, chills, severe flank pain, dysuria, urinary frequency and urgency, pyuria, and bacteriuria; E. coli causative agent in more than 90% of cases; mild-to-moderate infections treated as outpatient with oral TMP-SMZ; severe infection requires hospitalization and IV
    3. Complicated Urinary Tract Infections: Occurs in males and females who have a structural or functional abnormality of the urinary tract that predisposes them to developing infection.
    4. Recurrent Urinary Tract Infections: from relapse or reinfection
      • Reinfection: More than 80% of recurrent UTIs are due to reinfection; if infrequent (less than 2/year), treat as single infections; if >3/year, may use long-term prophylaxis (TMP-SMZ, trimethoprim, or nitrofurantoin for 6-12 months)
      • Relapse: Indicates structural abnormality, involvement of kidneys, or chronic bacterial prostatitis (most common in males); use progressive therapy from short-term to long-term therapy
    5. Acute Bacterial Prostatitis: High fever, chills, malaise, myalgia, localized pain, various urinary tract symptoms; 80% caused by E. coli; may be associated with indwelling catheter, etc.; responds well to TMP-SMZ and quinolones
  4. Urinary Tract Antiseptics: All four concentrated in urine; active against common pathogens in urinary tract only; second choice of drugs
    1. Nitrofurantoin (Furadantin, Macrodantin, Macrobid): Bacteriostatic in low concentrations and bactericidal in high concentrations; damages DNA
      • Antimicrobial spectrum: Against large number of gram-positive and gram-negative bacteria
      • Therapeutic use: Acute infections of lower urinary tract and prophylaxis of recurrent lower UTIs; not for upper UTIs
      • Pharmacokinetics: Two forms based on length of time of absorption with both equally effective (slow form has fewer GI effects); most degraded in liver and color urine brown but should not be used for those with decreased renal function (drug doesn't get to site and plasma levels will rise too high)
        • Adverse effects
        • Gastrointestinal effects: Most frequent; give with milk or food, decrease dosage, or use the slow-acting macrocrystalline form
        • Pulmonary reactions: Acute (probably hypersensitive reaction) and subacute (prolonged treatment)
        • Hematologic effects: Numerous effects; not to be given to infants < 1 month or to pregnant women near term
        • Peripheral neuropathy: Sensory and motor nerve damage and more likely in those with renal impairment and chronically taking nitrofurantoin
        Other adverse effects: Reversible neurologic effects and rare hepatotoxicity
      • Preparation, dosage, and administration: Tablets and capsules; can be given with milk or foods to decrease GI distress
    2. Methenamine
      • Mechanism of action: In acidic (urine pH of 5.5 or less) conditions, this drug decomposes into ammonia and formaldehyde; no systemic toxicity
      • Antimicrobial spectrum: All bacteria are susceptible to formaldehyde; resistance does not exist; if bacteria increase pH, then not effective
      • Therapeutic uses: Chronic lower UTI; not for acute infections
      • Pharmacokinetics: Rapidly absorbed; about 30% converted to ammonia and formaldehyde in acidic environment of stomach (use enteric-coated preparations); eliminated by kidneys
      • Adverse effects and precautions: Generally safe and well tolerated; may get GI distress, so use enteric-coated form; chronic high-dose therapy causes bladder irritation; methenamine salts are not to be used by patients with renal impairment
      • Drug interactions: Do not give alkalinizing agents; should not be combined with sulfonamides
      • Preparation, dosage, and administration: Tablets and oral suspension
    3. Nalidixic Acid (NegGram)
      • Mechanism of action: Similar to quinolones; inhibit replication of bacterial DNA
      • Microbial resistance: Resistance occurs by production of altered DNA and by reduced bacterial uptake
      • Antimicrobial spectrum: Most gram-negative urinary tract pathogens
      • Therapeutic uses: Only for UTIs; acute and prophylaxis for recurrent UTIs
      • Pharmacokinetics: Well absorbed from GI tract; rapid hepatic metabolism; excreted in urine
      • Adverse effects: Can cause multiple untoward effects, but incidence is very low; most common are GI disturbances and visual disturbances; not for children <3 months because of intracranial hypertension; blood dyscrasias are rare; need to check blood if on drug >2 weeks
      • Drug interactions: Intensifies oral anticoagulants
      • Preparation, dosage, and administration: Tablets and suspension
    4. Cinoxacin (Cinobac): Relative of nalidixic acid; cross-resistance occur
  5. Key Points
Chapter 86: Antimycobacterial Agents: Drugs for Tuberculosis, Leprosy, and Mycobacterium Avium Complex Infections
  1. Introduction: Mycobacteria are slow-growing microbes, and infections require prolonged treatment; drug toxicity and patient compliance are significant clinical problems; TB is worldwide and kills more adults than any other infectious disease; decrease incidence in U.S. but increased cases in rest of world
  2. Tuberculosis I: Clinical Considerations: Increasing cases due to AIDs and multidrug-resistance mycobacteria
    1. Pathogenesis: Caused by Mycobacterium tuberculosis (tubercle bacillus)
      • Primary infections: Transmitted by inhaling infected sputum; starts with lung and can spread to other sites; in most cases infection brought under complete control in a few weeks; drug therapy necessary to prevent reactivation; if immune system fails, clinical disease develops
      • Reactivation: Renewed multiplication of tubercle bacilli that have been dormant following primary infection; only 60% of cases are reactivation; other 40% may be new transmission
    2. Diagnosis and Treatment of Active Tuberculosis: Detect and treat individuals with asymptomatic infection; screen all high-risk persons; most common testing with tuberculin skin test
      • Diagnosis: If positive test, then do chest x-ray and microbiologic evaluation of sputum (smears and cultures)
      • Drug resistance: Major impediment to successful therapy; resistance acquired in two ways (contact with someone who harbors resistant bacteria and repeated ineffectual courses of therapy); resistance increasing; principal cause of resistance is inadequate drug therapy; cost $180,000 to treat resistant TB compared with $12,000 for nonresistant TB
      • The prime directive: always treat tuberculosis with two or more drugs: Always have two or more drugs to which infecting organism is sensitive; five facts (resistance occurs because of spontaneous mutations; each mutational event confers resistance to only one drug; mutations conferring resistance to single drug occur in ~1:100 million bacteria; bacterial burden in active TB is well over 100 million bacteria; M. tuberculosis grows slowly so treatment prolonged; combinations decrease risk of resistance, reduce incidence of relapse, and increase chance of complete kill
      • Determining drug sensitivity: Actual sensitivity takes several weeks, so beginning therapy is more empiric; then adjust therapy
      • Treatment regimens: Based on susceptibility of organism and immunocompetence of host; can have as many as seven drugs (see Table 86-1 in the text); treatment in two phases (eliminate actively dividing bacilli and eliminate intracellular persisters) a. Drug-sensitive tubercle bacilli: Initial treatment lasts 2 months with daily therapy, and second phase lasts for 4 months; other choice is daily or biweekly therapy followed by daily therapy for 1 month and daily or biweekly for another 8 months b. Multidrug-resistant tubercle bacilli: Defined as resistance to at least isoniazid and rifampin; use at least three drugs and continue for 12-24 months after sputum conversion c. Therapy in patients with HIV infection: 2% to 20% of patients with HIV infection develop TB; need more aggressive therapy; therapy longer; if take protease inhibitors and NNRTIs to treat HIV, they can't take rifampin or rifabutin for TB
      • Duration of treatment: Ideal duration not established up to 24 months
      • Evaluating treatment: Bacteriologic evaluation of sputum, clinical evaluation, and chest x-ray
    3. Diagnosis and Treatment of Latent Tuberculosis
      • Targeted Tuberculin Skin Testing
        1. How Do We Test for Latent Tuberculosis?
        2. Who Should be Tested?
        3. Interpreting the Results: Who Should be Treated?
      • Treatment of Latent Tuberculosis
        1. Isoniazid
        2. Short-Course Therapy: Rifampin Plus Pyrazinamide
        3. Short-Course Therapy: Rifampin Alone
  3. Tuberculosis II: Pharmacology of Individual Antituberculous Drugs: Two groups: first-line drugs (isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin) and second-line drugs (PAS, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin, and ofloxacin); see Table 86-3 in the text
    1. Isoniazid (Laniazid, Nydrazid): Primary agent for treatment and prophylaxis of TB; should be taken by all who can tolerate drug
      • Antimicrobial spectrum and mechanism of action: Highly selective; is bactericidal to mycobacteria actively dividing but bacteriostatic to "resting" organisms
      • Resistance: From spontaneous mutation; cross-resistance also to ethionamide but not others
      • Therapeutic use: Only for treatment and prophylaxis of TB; take in combination with at least one other drug
      • Adverse effects a. Peripheral neuropathy: Dose-related is most common; paresthesias; prophylaxis with pyridoxine (B6) b. Hepatotoxicity: Death has occurred; greatest risk is advancing age (8% for those >65) c. Other adverse effects: CNS effects, anemia, GI distress, dry mouth, and urinary retention and allergy
      • Drug interactions
        1. Phenytoin: Interferes with metabolism? increased levels
        2. Alcohol, rifampin, and pyrazinamide: Increases risk of hepatotoxicity
    2. Rifampin (Rifadin, Rimactane)
      • Antimicrobial spectrum: A broad-spectrum antibiotic, bactericidal
      • Mechanism of action and bacterial resistance: Inhibits bacterial DNA-dependent RNA polymerase, thereby suppressing RNA synthesis; resistance occurs from production of altered form of RNA polymerase
      • Pharmacokinetics: Well absorbed on empty stomach; decreased absorption if taken with food; widely distributed (lipid-soluble); eliminated by hepatic metabolism
      • Therapeutic use
        1. Tuberculosis: One of most effective drugs, used for pulmonary TB and disseminated disease; always used in combination
        2. Leprosy: Bactericidal to Mycobacterium leprae, so important agent for leprosy
        3. Meningococcus carriers: Highly effective
      • Adverse effects: Generally well tolerated; rarely toxic
        1. Hepatotoxicity: Most common; most likely in alcoholics and persons with preexisting liver disease; check serum transaminase levels prior to treatment and every 2-4 weeks; inform patients of symptoms
        2. Discoloration of body fluids: Red-orange urine, sweat, saliva, and tears; can stain soft contact lenses
        3. Other adverse effects: GI, cutaneous reactions; high-dose therapy, get flu-like syndrome; high doses also may see shortness of breath, hemolytic anemia, shock, and renal failure
        4. Drug interactions
          1. Accelerated metabolism of other drugs: Concern with oral contraceptives, warfarin, and methadone (need increased dosage)
          2. Isoniazid and pyrazinamide: Combined usage increases risk for liver injury
    3. Rifapentine: Long-acting form; difference is dosing schedule
    4. Rifabutin: Close relative of rifampin; treat MAC TB patients with HIV
    5. Pyrazinamide
      • Antimicrobial activity and therapeutic use: Bactericidal; mechanism unknown; regimen of choice is this drug with rifampin and isoniazid for first 2 months, then only other two for next 4 months; well absorbed
      • Adverse effects
        1. Hepatotoxicity: Principal adverse effect; rarely fatal hepatic necrosis; measure AST and ALT levels every 2-4 weeks
        2. Other adverse effects: Inhibit renal excretion of uric acid, GI, arthralgia, and photosensitivity
    6. Ethambutol (Myambutol)
      • Antimicrobial action: Only active against mycobacteria; bacteriostatic, not bactericidal
      • Therapeutic use: For treatment of TB and retreatment of patients who have received treatment previously; part of multidrug regimen
      • Adverse effects: Well tolerated; only significant effect is optic neuritis
      a. Optic neuritis: Dose-related; usually resolves after discontinuing treatment; assess color discrimination and visual acuity b. Other adverse effects: Allergic reactions, GI upset, confusion; inhibits uric acid excretion, peripheral neuropathy, renal damage, and thrombocytopenia
    7. Streptomycin: An aminoglycoside antibiotic was first effective anti-TB drug; toxicity is to eighth cranial nerve; given by IM injection
    8. Second-Line Antituberculous Drugs: Less effective and more toxic; use if first-line drug resistance has occurred
      • Para-aminosalicylic acid (PAS): Like sulfonamides, poorly tolerated by adults (GI); check for discolored tablets and do not use (purple or brown); administer with food for GI problems
      • Ethionamide (Trecator-SC): Relative of isoniazid but less effective; GI disturbance major problem; liver toxicity can occur
      • Cycloserine (Seromycin Pulvules): Rapidly absorbed; can accumulate to toxic levels in renal patients; CNS effects most severe
      • Capreomycin (Capastat Sulfate): Antibiotic derived from Streptomyces; should not be taken by patients with renal disease
      • Kanamycin and Amikacin (Kantrex): Aminoglycosides; nephrotoxic and may damage eighth cranial nerve
      • Ofloxacin and Ciprofloxacin: Fluoroquinolones; prophylaxis and for multidrug-resistant organisms
  4. Drugs for Leprosy (Hansen's disease) is caused by Mycobacterium leprae; still worldwide problem; exposure from another infected person; isolation not required if adequate treatment; objectives of treatment: conversion of patient to noninfectious state, prevention of bacterial multiplication, and avoidance or reduction of complications of leprosy
    1. Overview of treatment: Multidrug therapy to prevent resistance (see Table 86-4 in the text)
    2. Pharmacology of individual antileprosy drugs
      • Rifampin: Bactericidal to M. leprae; always combined with antileprosy drug; the most effective agent
      • Dapsone: Mainstay of therapy; effective with low toxicity and inexpensive; used in combination with other drugs (rifampin and clofazimine); can take 4 years without adverse effects (GI, headache, rash, mononucleosis-like syndrome)
      • Clofazimine (Lamprene): Weakly bactericidal to M. leprae; dangerous reactions uncommon; red-brown color to skin and fluids; pigmentation usually clears 6-12 months after drug stopped
  5. Drugs for Mycobacterium Avium Complex (MAC) Infection: Two organisms (Mycobacterium avium and Mycobacterium intracellulare); begins in lungs and GI tract then spreads to blood, bone marrow, liver, and lymphatic system; disseminated infection common in patients with HIV (50%); symptoms of disseminated MAC are fever, night sweats, weight loss, lethargy, anemia, and abnormal liver function tests
    1. Macrolide Antibiotics: Azithromycin and Clarithromycin: Drugs of choice for MAC; all should receive one of these combined with another agent; side effects include GI disturbances
    2. Ethambutol: Also used in combination with another agent; get optic neuritis
    3. Additional Agents: If ethambutol is insufficient, numerous other combinations may be combined with a macrolide, including rifampin
  6. Key Points
  7. Summary of Major Nursing Implications
    1. Implications That Apply to All Antituberculosis Drugs
    2. Rifampin
    3. Pyrazinamide
    4. Ethambutol