Module 1
N609

Issues for the Practitioner in Drug Therapy

Describe the approval process for prescribed drugs in the United States.
Analyze the practitioner's role and responsibilities in prescribing.
Explain the process for prescribing, whether in writing or through the electronic health record.

Role of the U.S. Food and Drug Administration (FDA)
Conducting and monitoring clinical trials
Approving new drugs for market and manufacture
Ensuring safe drugs for public consumption

It has been determined by the FDA that a new drug causes no apparent serious adverse effects and the dosage range is appropriate. Double-blind studies are planned to compare the drug to a placebo. This drug is in what phase of clinical trials?
A. Phase I
B. Phase II
C. Phase III
D. Phase IV

C. Phase III
Rationale: In Phase III, double-blind research methods are used for data collection, and the drug is compared with a placebo. In Phase I, an initial evaluation of the drug is conducted. In Phase II, drug effects are monitored on up to several hundred patients who have the disease. Postmarketing surveillance occurs in Phase IV.

Four categories for which pharmaceutical companies request review
Fast track
Breakthrough therapy
Accelerated approval
Priority review

Five categories of scheduled drugs:
Schedule 1: high potential for abuse; no routine therapeutic use
Schedule 2: valid medical use; high potential for abuse
Schedule 3: Potential for abuse is lower than drugs on Schedule 2; prescriptions cannot be refilled.
Schedule 4: low potential for abuse; limited physiologic dependency
Schedule 5: least potential for abuse; moderate amount of opioids

A practitioner prescribes codeine for a patient who is postoperative following knee surgery. What schedule drug is being prescribed?
A. Schedule 1
B. Schedule 2
C. Schedule 3
D. Schedule 4
E. Schedule 5

C. Schedule 3
Rationale: Examples of Schedule 3 drugs are certain narcotics such as codeine and nonbarbiturate sedatives. Examples of Schedule 1 drugs are heroin and lysergic acid diethylamide. Examples of Schedule 2 drugs are certain amphetamines and barbiturates. Examples of Schedule 4 drugs are nonnarcotic analgesics and antianxiety agents. Examples of Schedule 5 drugs include antitussives and antidiarrheals containing small amounts of narcotics.

Drug selection
Concerns related to ethics and practice
Patient education
Prescriptive authority
Drug sampling

Identify all health care providers by a unique number in standard transactions (e.g., health care claims).
Identify health care providers on prescriptions.
Link provider ID numbers in internal files.
Coordinate benefits between health plans.
Update patient medical-record systems.
Use in program integrity files.

Selecting the most appropriate agent
Considerations of special populations
Identifying outcomes

Date, name, address, and date of birth
Prescriber's name, address, and phone number
Name of drug
Dose, dosage regimen, and route of administration
Allowable substitutions
Prescriber's signature and license number

A health care provider performs a physical examination of a patient who presents with high blood pressure. When choosing a hypertensive for the patient, what step in the prescribing process follows the formulation of the diagnosis of hypertension?
A. Review the pathophysiology of the disease.
B. Select the most appropriate agent.
C. Evaluate the patient's response to the therapy.
D. Consider second-line therapy for the patient.

A. Review the pathophysiology of the disease.
Rationale: The order of the process for prescribing a drug is assess, diagnose, review pathophysiology of disease, select a first-line therapy, evaluate patient response, maintain regimen or move to second-line therapy, reevaluate, maintain regimen, or move to third-line therapy.

Improved legibility of prescriptions and rate of completed prescriptions
Greater patient convenience at pharmacy
Increased compliance with formulary requirements
Decreased drug-drug interactions
Reduced medication errors with use of drug-checking software

Approachability of health care provider
Perception of respect with which they are treated by the practitioner
Belief the therapy is beneficial
Belief the benefits of therapy outweigh the risks or side effects
Degree to which the patient participates in developing the treatment regimen
Cost of the regimen

Simplicity and understanding of the regime
Degree to which the patient feels that expectations are being met
Degree to which the patient perceives their concerns are important and being addressed
Degree to which the practitioner motivates the patient to adhere to the regimen
Degree to which the regimen is compatible with the patient's lifestyle

Lack of drug knowledge
Lack of patient information
Poor communication
Special population considerations

Many different genes influence the way a person responds to a drug.
Without knowing all the genes involved in drug response, it has not been possible to develop genetic tests that could predict a person's response to a drug.

Reference books
Pharmacists
Easy-to-carry drug handbooks
Pocket guides

Drug therapy is often the mainstay of acute and chronic diseases, and in many cases, health care practitioners include it in the patient treatment plan.
Many issues require consideration when planning drug therapy, including product safeguards, writing the prescription, patient adherence, follow-up measures, and keeping up-to-date with new developments.
It is imperative that prescribers have the best knowledge of the principles of prescribing to prevent errors and develop safe, appropriate, and effective drug therapy.

Pharmacokinetic Basis of Therapeutics and Pharmacodynamic Principles

Describe the difference between pharmacokinetics and pharmacodynamics.
Discuss the impact of each of the four pharmacokinetic principles on medications administered to a patient: absorption, distribution, metabolism, and elimination.
Describe the concept of affinity and differentiate between an antagonist and an agonist.
Apply the knowledge of pharmacokinetic principles to considerations of a patient case scenario.
Given patient details, calculate renal function utilizing the Cockcroft-Gault formula and the Modification of Diet in Renal Disease (MDRD) equation.

Pharmacokinetics
Refers to the movement of the drug through the body and how the body affects the drug.
Drug administration, absorption, distribution, and elimination are involved.
Pharmacodynamics
Refers to how the drug affects the body; how the drug initiates its therapeutic or toxic effect at the cellular level and systemically.

Factors affecting absorption
Movement through membranes and drug solubility
Passive diffusion
Active transport
Pharmaceutical preparation
Blood flow
Gastrointestinal motility
Enteral absorption
Oral administration
Sublingual administration
Rectal administration
Parenteral absorption
Inhalation
Intravenous administration
Subcutaneous administration
Intramuscular administration
Topical administration
Transdermal administration

A patient is given a medication for hypertension that is absorbed enterally. Via what route might this medication be administered?
A. Intramuscular
B. Subcutaneous
C. Oral
D. Topical

C. Oral
Rationale: Enteral absorption occurs after a drug is administered by the oral or rectal route. Parenteral absorption is associated with drugs administered intramuscularly, subcutaneously, or topically.

A health care practitioner orders a loading dose of an antibiotic for a patient with bacteremia. What would be the preferred route to ensure maximum bioavailability?
A. Oral
B. Subcutaneous
C. Intramuscular
D. Intravenous

D. Intravenous
Rationale: The intravenous route provides rapid access to the circulatory system with a known quantity of drug; the IV route of administration assures 100% bioavailability, thus it is considered the gold standard. Absorption after oral administration is slow and depends on the patient's gastric emptying time. Subcutaneous administration produces a slower, more prolonged release of medication into the bloodstream. A wide variability in the rate of absorption results from injections given intramuscularly due to use in different muscles and in different patients.

Protein binding
Volume of distribution

Metabolism
Drug excretion
Half-life
Steady state
Clearance

Drug receptors
A receptor is the component of the cell (or an enzyme) to which an endogenous substance binds, or attaches, initiating a chain of biochemical events.
The capacity of a drug to bind to a receptor depends on the size and shape of the drug and the receptor.
Drug receptors are commonly classified by the effect they produce.

Gated ion channels
Transmembranous receptors: cytoplasmic enzyme or tyrosine kinase activated
G protein-coupled receptors
Intracellular receptors

Affinity: degree to which a drug is attracted to a receptor.
Chirality: drugs exist in two forms with mirror-image spatial arrangements called enantiomers or isomers, which affect interaction with receptors.
Agonists: drugs that display a degree of affinity for a receptor and stimulate a response.
Antagonists: drugs that display an affinity and do not elicit a response.

Patient variables
Pathophysiology
Genetics
Age
Sex
Ethnicity
Diet and nutrition

Medications are prescribed to alleviate symptoms, cure disease, or prevent severe morbidity or mortality.
Underpinning the treatment process is the intricate relationship between the body and the medications.
Practitioners must be aware of the effect of pharmacokinetics (movement of the drug through the body) and pharmacodynamics (how the drug affects the body) when prescribing drug therapy for patients.

Impact of Drug Interactions and Adverse Events on Therapeutics

Drug-drug interactions
Drug-food interactions
Drug-herb interactions
Drug-disease interactions

Absorption
Distribution
Metabolism
Excretion

Acidity (pH): one drug may alter the acidity of the gastrointestinal (GI) tract
Adsorption: occurs when one agent binds the other to its surface to form a complex
GI motility and rate of absorption: drugs that affect the GI tract can affect the rate of absorption instead of affecting the amount of drug absorbed
GI flora and absorption: bacteria present in the GI tract are responsible for a portion of the metabolism of some agents

Most are bound to plasma proteins such as albumin or 1-acid glycoprotein.
Only an unbound drug is free to interact with its target receptor site and is therefore active.
The percentage of drug that binds to plasma proteins depends on the affinity of that drug for the protein-binding site.
Clinically significant drug displacement interactions normally occur only when drugs are more than 90% protein bound and have a narrow therapeutic index.

Main sites of metabolism
Liver (hepatocytes)
Small intestine (enterocytes)
Kidneys, lungs, brain play minor role
Classification of cytochrome P-450 isoenzymes
Family (>36% homology in amino acid sequence)
Subfamily (77% homology)
Individual gene

Affinity: the greater the affinity of an inhibiting drug for an enzyme, the more it blocks binding of other drug molecules
Half-life: determines duration of the interaction
Concentration: threshold concentration must be reached or exceeded to inhibit an enzyme
Toxic potential of the object drug
Efficacy: effectiveness of the object drug

A practitioner is prescribing amiodarone for a patient with cardiac arrhythmia. Which factor affecting the duration of the drug must a practitioner consider if an adverse interaction occurs?
A. Efficacy
B. Half-life
C. Concentration
D. Toxic potential

B. Half-life
Rationale: Along with affinity, the half-life (t12) of the inhibiting drug determines the duration of the interaction. The longer the half-life of the inhibiting drug, the longer the drug interaction lasts. Efficacy refers to the effectiveness of the drug. Concentration is a factor contributing to a drug's ability to inhibit hepatic enzymes. A threshold concentration must be reached or exceeded to inhibit an enzyme. Serious toxic potential may cause a drug to be removed from the market.

Result of the action of one drug (inducer) stimulating the metabolism of an object drug (substrate)
Enhanced metabolism produced by an increase in hepatic blood flow or an increase in the formation of hepatic enzymes
Increases the amount of enzymes available to metabolize drug molecules, thereby decreasing the concentration and pharmacodynamic effect of the object drug

Drugs are removed from the bloodstream by the kidneys by filtration or urinary secretion.
Reabsorption from the urine into the bloodstream may also occur.
Absorption may be affected by acidification or alkalinization of the urine and alteration of secretory or active transport pathways.
Although most drugs cross the membrane of the renal tubule by simple diffusion, some drugs are also secreted into the urine through active transport pathways.

Inhibition or induction of P-glycoprotein (P-gp), an energy-dependent efflux transporter, can result in interactions involving absorption or excretion (biliary or renal).
P-gp pumps drug molecules out of cells and is found in the epithelial cells of the intestine (enterocytes), liver, and kidney.

A practitioner prescribes a bicarbonate for a patient with severe heartburn. The practitioner knows that what factor caused by the drugs plays a key role in its excretion?
A. Enterohepatic recirculation
B. Alteration active transport pathways
C. Alkalinization of the urine
D. Induction of P-glycoprotein

C. Alkalinization of the urine
Rationale: Administration of bicarbonate can potentially increase the urine pH. This leads to the increased excretion of acidic drugs and the increased reabsorption of basic drugs.

Pharmacodynamic profile: responses or effects produced by a drug's actions.
Drugs that have a similar characteristic in their pharmacodynamic profile may produce an exaggerated response.
Drugs may also produce opposing pharmacodynamic effects causing the expected drug response to be diminished or even abolished.

Absorption: food can alter extent of drug absorption or change rate of drug absorption.
Metabolism: grapefruit juice inhibits the 3A4 subset of intestinal cytochrome P-450 enzymes and increases the serum concentration of drugs dependent on these enzymes for metabolism; food may also induce drug metabolism and therefore decrease drug efficacy.
Excretion: ingestion of certain fruit juices can alter the urinary pH and affect the elimination and reabsorption of drugs such as quinidine and amphetamine.

Food may oppose or potentiate pharmacologic action.
Warfarin reacts with foods containing vitamin K.
Monoamine oxidase (MAO) inhibitors can react with foods containing tyramine.
Some drugs can deplete nutrients or minerals found in foods.
Drug-induced malabsorption can occur in patients with preexisting poor nutritional status.
Drugs can change nutrient excretion.

A healthcare practitioner prescribes warfarin for a patient who Afib. The patient should avoid foods high in:
A. Potassium
B. Tyramine
C. Vitamin C
D. Vitamin K

D. Vitamin K
Rationale: Warfarin exerts its anticoagulant effects by inhibiting synthesis of vitamin K-dependent clotting factors. Vitamin K is required for activation by several protein factors of the clotting cascade, namely, factors II, VII, IX, and X. When foods rich in vitamin K are ingested, they can significantly oppose the anticoagulatory efficacy of warfarin.

Most herbal supplements are not regulated by the Food and Drug Administration (FDA).
Some herbs can prevent absorption of medications and reduce the effectiveness of those medications.
Acacia may impair the absorption of amoxicillin.
Dandelion may reduce effectiveness of quinolones.
Meadowsweet and black willow may displace highly protein-bound drugs.
Certain herbs can be inducers or inhibitors of the cytochrome P-450 enzyme system.

Some herbs may inhibit platelet activity and/or increase the INR.
Kava, lavender, and valerian may potentiate effects of central nervous system (CNS) depressants such as barbiturates and narcotics.
Kava may interfere with effects of dopamine or dopamine antagonists and is potentially hepatotoxic.
Aloe may cause hypoglycemia in patients taking glibenclamide.
Bitter orange may interfere with MAO inhibitor action.

Absorption depends on the physiologic processes that maintain normal GI function.
Vitamin B12 deficiency is common in patients undergoing stomach surgery.
Diarrhea, a manifestation of many diseases, can pose a problem for oral absorption of drugs as well as food and nutrients.

Conditions that may decrease plasma albumin levels:
Burns, bone fractures, acute infections, inflammatory disease, liver disease, malnutrition, and renal disease
Conditions that may increase plasma albumin levels:
Benign tumors, gynecologic disorders, myalgia, and surgical procedures

Metabolism of drugs can be altered by disease that affect the functions of the liver (cirrhosis).
Heart failure is another disease that can cause direct reduction in ability of liver to metabolize drugs.
Use of a prodrug in patients with liver dysfunction can potentially reduce the efficacy of the drug.

Renal function can influence serum drug concentrations.
Glomerulonephritis, interstitial nephritis, long-term and uncontrolled diabetes, and hypertension are primary causes of declining renal function.
Drugs such as H2 receptor antagonists and fluoroquinolone antibiotics commonly require dose adjustments for patients with renal insufficiency.

Drugs used to treat one medical condition can exacerbate the status of another comorbid disease.
This is particularly important in the elderly who have multiple concomitant diseases and often take multiple medications.
Detected rates of drug-disease interactions range from 6% to 30% in older adults.

Heredity
Disease
Environment
Smoking
Nutrition
Alcohol intake

Definition: drug-induced toxic reactions
Two types of drug reactions
Type A reactions: exaggeration of the principal pharmacologic action of the drug
Type B reactions: unrelated to the principal pharmacologic action of the drug itself; precipitated by the secondary pharmacologic actions of the drug

Causes of medication errors: look-alike and sound-alike drugs, dosage conversions, foreign drugs, illegible handwriting, unacceptable abbreviations
Tracking drug interactions and adverse drug reactions (ADRs)
The initial source of documented ADRs comes primarily from the experience gained while using a drug during clinical trials
MedWatch program: enhances the effectiveness of surveillance of drugs and medical products after they are marketed and as they are used in clinical practice

Arcangelo, V. (2022). Pharmacotherapeutics for Advanced Practice: A Practical Approach. 5th ed.
Wolters Kluwer. Philadelphia, PA
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