Pharmacotherapeutics Guide PDF - Advanced Practice

Pharmacotherapeutics for Advanced Practice INTRO Pharmacology is used to alter a physiologic or pathophysiologic process; Your physical exam, vitals, and other assessments (labs, imaging) are used to monitor the patient’s response to pharmacologic therapy. Need understanding: pharmacotherapeutics, pharmacokinetics, and pharmacodynamics to understand drugs, how they work, and to be a responsible provider. Physiologic example: genetic Pathophysiologic example: cancer, inflammation, infection, autoimmunity The connection between "patho" (pathophysiology) and "pharm" (pharmacology) in assessment lies in understanding the underlying disease process (pathophysiology) to accurately interpret pa:ent signs and symptoms, which then guides the selec:on and administra:on of appropriate medica:ons (pharmacology) during pa:ent assessment. ISSUES FOR PRACTITIONER SAFETY IN DRUG THERAPY Scheduled Meds (AKA Controlled Substances) Clinical Trials Provider Iden:ﬁca:on Prescrip:on (Rx) vs. Over the Counter (OTC) Generic versus Brand/Trade meds Complimentary and Alterna:ve Medica:ons Foreign Medica:ons Prescrip:on Considera:ons for Safe Prac:ce SCHEDULES OF CONTROLLED DRUGS Schedule I – Highest abuse potential Only for research (heroin) Schedule II – Higher abuse potential relative to schedule III; No telephone prescrip:ons for outpa:ent; no reﬁlls (morphine) Schedule III – Moderate abuse potential; Rewrite prescrip:ons every 6 months or 5 reﬁlls; telephone prescrip:ons possibly okay (codeine) Schedule IV – Lower abuse potential relative to schedule III; alprazolam (Xanax), lorazepam (A:van) Schedule V – Lowest abuse potential; states may vary; diphenoxylate (Lomo:l) See Appendix in Drug Guide and/or Prescribing Guide Pharmacies in Michigan most often require scheduled drugs to be prescribed via an electronic system; most have 2-factor authentication. ROLE OF THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) IN CLINICAL TRIALS Conducting and monitoring clinical trials which could last up to 9 years before a drug is approved. Approving new drugs for market and manufacture. Ensuring safe drugs for public consumption through purity and safety guidelines plus prescribing guidelines for some drugs. Prescribers, such as physicians and healthcare providers, are concerned about the processes mentioned (conducting and monitoring clinical trials, approving new drugs, and ensuring drug safety) because these steps are crucial in providing eﬀective and safe healthcare to patients. Here's why prescribers care about each aspect: 1.Conducting and Monitoring Clinical Trials: 1. Reason: Clinical trials are conducted to assess the safety and efficacy of new drugs before they are approved for widespread use. Prescribers are interested in the results of these trials as they provide essential information about the drug's effectiveness, potential side effects, and optimal dosages. 2. Impact on Prescribers: Knowing the outcomes of clinical trials helps prescribers make informed decisions about whether to incorporate a new drug into their treatment options. They can understand the drug's benefits, risks, and how it compares to existing therapies. 2.Approving New Drugs for Market and Manufacture: 1. Reason: Regulatory bodies, such as the FDA in the United States, review and approve new drugs for market entry based on rigorous evaluation of scientific and clinical data. This process ensures that drugs meet certain standards of safety, efficacy, and quality before they are available to the public. 2. Impact on Prescribers: Prescribers rely on the approval process to trust that the drugs they prescribe have undergone thorough evaluation. It gives them confidence that the medications they recommend have met regulatory standards and are likely to be safe and effective. 3.Ensuring Safe Drugs for Public Consumption: 1. Reason: Drug safety is paramount to protect public health. Regulatory agencies set purity and safety guidelines to ensure that drugs are manufactured and distributed under strict quality control measures. Prescribing guidelines help guide healthcare providers on the appropriate use of medications. 2. Impact on Prescribers: Prescribers follow safety guidelines to minimize the risk of adverse reactions and ensure the well-being of their patients. They rely on the assurance that drugs in the market meet quality standards and are safe for consumption. In summary, prescribers care about the processes involved in drug development, approval, and safety assurance because it directly influences the quality, safety, and eﬃcacy of the medications they prescribe. Staying informed about these aspects allows healthcare providers to make sound clinical decisions for the benefit of their patients. PHASES OF CLINICAL TRIALS FOR NEW DRUGS FDA RISK MANAGEMENT Risk management programs are designed to detect, evaluate, prevent, and mitigate drug adverse events for drugs with the potential for serious adverse drug reactions. Risk Minimization Action Plans (RiskMAPS) in 2005 – FDA only had the authority to mandate post-marketing commitments from drug manufacturers before the drug was approved; however, these requirements could not be enforced after the drug was approved. Food and Drug Administration Amendments Act of 2007 – gave the FDA authority to subject drugs to new risk identification and communication strategies, called Risk Evaluation and Mitigation Strategies (REMS), in the post-marketing period. Earlier attempts included: use of patient package inserts medication guides restricted access programs classification of drugs as controlled substances Risk Minimization Action Plans (RiskMAPS) in 2005 - FDA only had the authority to mandate postmarketing commitments from drug manufacturers before the drug was approved; however, these requirements could not be enforced after the drug was approved. REMS - COMPONENTS Can be required for any drug or drug class that is associated with serious risks to ensure that the benefits outweigh the potential risks of the drug. Can require a REMS either as part of the drug approval process or during the post-marketing period if new information becomes available. May include a medication guide, a patient package insert, a communication plan, other elements to ensure safe use, and/or an implementation system. Must be communicated to the patient (YOUR responsibility) BOXED WARNINGS (BLACK BOX WARNING) FDA's most serious safety alert for approved drugs. Found in prescribing information, package inserts, and promotional materials. Alerts to risks of serious adverse reactions or restrictions on use. May indicate potential for death, serious injury, or highlight safety concerns like dosing, monitoring, or interactions. Must be communicated to patients (YOUR responsibility). A boxed warning indicates reasonable evidence of a serious hazard associated with the drug, even if a definite causal relationship hasn’t been confirmed. The boxed format highlights that the adverse reaction could result in death or serious injury. PURPOSES OF THE NATIONAL PROVIDER IDENTIFIER (NPI) Identify all health care providers by a unique number in standard transactions and health care claims. This unique number is name only and does not include specialty or practice location. Identify health care providers on prescriptions. Link provider ID numbers in internal files. Coordinate benefits between health plans. This one number replaced inconsistent legacy numbers like Medicare UPINs and proprietary provider numbers in 2007. GENERIC VERSUS TRADE NAMES Drugs have a chemical name and a generic name that never change. Trade names belong to the pharmaceutical company that manufactures the drug and can vary if more than one company makes the same drug) or change (if company name changes or another company takes the drug over). Sometimes this is called “Brand name”. Drugs become available as generic after the patent expires (usually 20 years). Trade names are written with an upper-case letter and generics are lower-case. Example acetaminophen (Tylenol) Example: N-(4-hydroxyphenyl)acetamide, N-(4-hydroxyphenyl)ethanamide (chemical); acetaminophen (generic); Tylenol (Trade) Another example: (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid (chemical); ibuprofen (generic); Advil (Trade); Motrin (Trade) OTHER ISSUES RELATED TO PRESCRIPTION DRUG THERAPY Complementary and alternative medicines (such as herbal remedies or homeopathic drugs) can have interactions with pharmaceutical drugs. Discuss openly and nonjudgmentally with your patient. Consider this when prescribing. Use of foreign medications means that names can be unrecognizable. Consult the pharmacy when not familiar. Example: We usually know paracetamol which is foreign name for acetaminophen. Prescribers are concerned about the potential interactions between complementary and alternative medicines (CAM) and pharmaceutical drugs for several reasons: 1.Interaction Risks: 1. Reason: CAM, including herbal remedies and homeopathic drugs, may contain active compounds that can interact with pharmaceutical drugs. These interactions can affect the efficacy, safety, or metabolism of either the CAM or the prescribed medication. 2. Impact on Prescribing: Prescribers need to be aware of potential interactions to avoid adverse effects, reduced drug effectiveness, or unexpected outcomes when combining CAM and pharmaceuticals. 2.Open and Nonjudgmental Discussion: 1. Reason: Some patients may choose to use CAM alongside conventional medications for various reasons, including cultural beliefs, personal preferences, or perceived benefits. It's important for prescribers to create an open and nonjudgmental space for patients to discuss their use of CAM. 2. Impact on Prescribing: By fostering open communication, prescribers can gain insights into patients' health practices, allowing for better-informed decision-making. Patients are more likely to share relevant information if they feel comfortable discussing their use of CAM. 3.Consideration in Prescribing: 1. Reason: Prescribers should consider the potential interactions between CAM and pharmaceuticals when making prescribing decisions. This involves taking into account the patient's overall health, the specific medications they are on, and any CAM they may be using. 2. Impact on Prescribing: Considering potential interactions allows prescribers to tailor treatment plans, adjust dosages, or choose alternative medications to ensure the best possible outcomes for the patient. In summary, prescribers are mindful of CAM interactions due to the potential risks and the need for open communication with patients. By discussing CAM use openly and nonjudgmentally, prescribers can gather essential information to make informed decisions that prioritize patient safety and optimize treatment eﬀectiveness. Taking these considerations into account helps create a patient-centered approach to healthcare. GENERAL PRESCRIPTIVE AUTHORITY Health care providers who prescribe the drug are specifically trained and/or certified. Pharmacies, practitioners, or health care settings that dispense the drug are specifically trained and/or certified. The drug is dispensed to patients only in certain health care settings, such as hospitals, or physicians’ oﬃces. The drug is dispensed only to patients with evidence or other documentation of safe-use conditions, such as laboratory test results. Patients using the drug are subject to certain monitoring. Patients using some drugs are enrolled in a registry. What are the diﬀerences among the words prescribe, dispense, and administer? PRESCRIPTIVE AUTHORITY FOR NPS IN MICHIGAN Since 1999, NPs in Michigan are allowed to write prescriptions, including Schedule III-V meds. HB 5400 (2016) would have allowed NPs to write for non controlled substances independently (not passed). SB 680 (2022) allows NPs to prescribe pharmacological and nonpharmacological interventions and treatments that are within the advanced practice specialty role (passed). SB 279 (introduce April 2023) would eliminate a state mandated contract with a physician in order for a NP to practice (removes the state mandate for nurse practitioners to contract with a supervising physician in order to serve patients). Currently in health committee. NPs are not allowed to practice in any setting without career-long oversight by a supervising provider (practice authority is delegated). NPs must have an NPI number to prescribe. NPs can independently prescribe medications that are not scheduled. For controlled substances, NPs must have a collaborative agreement with a physician (MD or DO) in order to apply for a DEA number. Must have a DEA number and a collaborating physician (MD or DO) to prescribe scheduled medications. Contract with physician must be kept in oﬃce with signature of NP and MD/DO (establish at start of practice). MONITORING OF PRESCRIPTIVE AUTHORITY Federal Government with the Drug Enforcement Agency (DEA) number. NPI and Federal DEA numbers track prescriptions electronically by your name; the number of scheduled medications you prescribe is tracked and a report is sent to you each year. Prescriptive authority is regulated by state and national laws, and healthcare professionals must adhere to specific guidelines and protocols when prescribing medications to ensure patient safety and well-being. The types of medications that can be prescribed may be restricted based on the healthcare professional's specialty and training. PROCESS FOR PRESCRIBING MEDICATIONS FIGURE 1.2 Process for prescribing. Multiple steps (Figure 1.2) are involved in prescribing drugs and evaluating their effectiveness. Again, the first step is determining an accurate diagnosis based on the patient’s history, physical examination, and pertinent test findings. ROLE OF THE PRACTITIONER IN THE PRESCRIBING PROCESS Gather data through history and physical examination Formulate diagnoses and establish treatment plan Conduct risk–benefit analysis of drug therapy chosen Consider ethical and practical issues Educate the patient Shared decision making Appropriate and responsible use of resources: UpToDate.com, prescriber’s guide, Davis Drug Guide, an app like Epocrates, evidence based guidelines, consult a colleague or the pharmacy. TAKING A DRUG HISTORY – MEDICATION RECONCILIATION Allergies and eﬀect Adverse drug reactions Current drugs: dose, route, frequency, reason Perceived eﬃcacy Adherence to regimen Nonprescription med use: alternative, OTC, and complimentary Caﬀeine, nicotine, ETOH, illegal drug use PRESCRIPTION DRUG SELECTION Consider age, genetic gender, and size of patient (BMI, height, weight). Get the history of allergies, adverse drug reactions, and/or cross-sensitivities. Determine if the genetically female patient is pregnant or lactating (must prove a negative pregnancy test for some medications). Consider the potential for drug-drug interactions by doing medication reconciliation. Consider the patient’s medical history (comorbidities) and genetic (inherited) conditions. Consider renal, liver, nutritional, and hydration status. Can the patient tolerate the potential medication side eﬀects or ADRs? Can the patient take the medication as prescribed? How is the med available? Example: is it IV only? Is this ethical? Weigh risk versus benefit. Consider the patient’s support systems and financial resources if needed. Caution with guidelines; Remember to treat the patient as an individual. PATIENT EDUCATION IS THE NP RESPONSIBILITY Adequate education will increase adherence and promote therapeutic regimen Caution – illiteracy Assess patient’s need/willingness to learn Larger percentage of patients are using online resource Much information out there, must decipher for patient, good vs. bad info Watch for “.org”, “.gov”, “.edu” as potentially better than “.com” which are commercial sites. INCLUDE IN PATIENT EDUCATION Drug name (generic/trade) Purpose and expected action Proper use (route, dose, schedule) Common side eﬀects, how to treat, when to call provider Interactions What to do if missed a dose Special precautions (driving etc.) What to do when med runs out RULES TO WRITE BY: It is BEST to not write prescriptions for family or friends and outside of your practice environment. Remember: you are responsible legally for what you write. If you treat a relative/friend and are in error, you are liable. Rule of thumb: Never write for scheduled/controlled substances outside of the practice environment to keep you in good favor with the DEA and FDA. Never try to “manage” a chronic condition outside of your practice environment especially if outside of your scope of practice. Example: a friend asks you to refill their cardiac or psych medications. PROPERTIES OF AN IDEAL DRUG: THREE MOST IMPORTANT OTHERWISE, WHY GIVE THE DRUG? Eﬀectiveness: elicits responses for which it is given - most important Safety: Cannot produce harmful eﬀects even at very high dosages and for long :me No such thing as completely safe drug Selectivity: Only elicits response for which it is INTENDED, no side eﬀects No such thing as a selective drug, all have ADRs OTHER PROPERTIES OF IDEAL DRUGS Reversible action: most drugs should be reversible Predictability: Know with certainty exactly how individual patient will respond – impossible, must individualize Ease of administration: simple, convenient route - enhances compliance and decreases errors Freedom from drug interactions: few drugs are without drug interaction Low cost: easy to aﬀord; significant factor in adherence, esp. with elderly Chemical stability: drugs ability to be stored for long time without loss of eﬀectiveness – variable between drugs Possession of simple generic name: easier to remember and less confusion amongst drugs DRUG INTERACTIONS When two or more drugs are given together, they can react with each other: Can be positive (synergis:c) Can be negative (compete with each other) May be planned or unplanned Interactions don’t happen with one drug given alone POSSIBLE EFFECTS OF DRUGS GIVEN TOGETHER: Incompatibility Physical: precipitate Chemical: inactivate each other Change in Absorption – decreased by laxatives, increased with constipation causing drugs Altered Protein binding – warfarin & aspirin Biotransformation – cimetidine (Tagamet) inhibits enzymes, interacts with many drugs Must be aware of and consult resources for possible interactions of new drugs with current drugs. ADVERSE DRUG REACTIONS (ADRS) Unfavorable or unintended response to a drug that is given in normal dosages. Diﬀerent from side eﬀect (SE) which is usually an undesirable or desirable additional eﬀect that is known. ADR may be : Inherent pharmacologic eﬀect (hypoglycemia/insulin) An allergic reaction: typical immunological response A local irritant eﬀect: inflammation Often function of the P450 enzyme system and biotransformation alteration. Report serious ADRs to FDA Medwatch Reporting Program (anyone can, patient or provider) ANAPHYLAXIS AND ALLERGIES Immune system mediated; often related to age, genetics, prior drug exposure, drug dose, and route. Detailed drug history important. Skin testing (pros and cons) Penicillin and cephalosporin cross sensitivity 5-15% Anaphylaxis and epinephrine Generalized hypersensitive reactions vs. pseudoallergic reactions. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093068/ Prevent reaction: history, desensitization Despite the frequency of adverse reactions to drugs, allergic reactions are relatively uncommon. About 80% of adverse reactions are type A, or predictable, drug reactions that are explicable from the known pharmacology of the drug. Of the type B, or unpredictable, reactions many are due to drug intolerance (usually occurring at low doses of the drug), idiosyncratic reactions or pseudoallergy that is produced by the direct release of mediators from cells such as mast cells and basophils. The remainder of type B reactions have an immunological basis which is the requirement for true drug allergy. DRUG INTERACTIONS WITH FOOD Decrease eﬀectiveness of medication: Eating dairy products with tetracycline chelates and decreases eﬀectiveness Increase eﬀectiveness of medication: Eating a high fat diet within 30 minutes of taking ramelteon (Rozerem) increased eﬀectiveness Grapefruit juice increases blood levels and increases risk of toxicity with statins Many, many: must read literature in Drug Guide; self educate continually DRUG INTERACTIONS WITH ALCOHOL Acute alcohol use: may inhibit metabolism of drug by competing for same metabolizing enzymes. Chronic alcohol use: releases metabolic enzymes that are then constantly available even if drinker ceases habit which causes rapid breakdown of certain medications. Disulfirum reaction—helps them stop drinking DRUG INTERACTIONS WITH OVER THE COUNTER (OTC) DRUGS Evaluate individually for interactions Common: ASA and Coumadin Antacids with Magnesium, Aluminum, or Calcium: high potential for drug interaction we’ll talk more about this in GI lecture UNLABELED OR “OFF-LABEL” USES Not as well studied but perceived beneficial May be liability issues May be very helpful to some patients Weigh benefit versus risk Sometimes oﬀ-label uses become labeled over time with research evidence (proof) This is legal and best practice is to clearly document rationale and education provided to patient. Pharmacotherapeutics The treatment of all aspects of disease with medication to diagnose, treat, prevent, or cure. Note that all drugs are intended to have some eﬀect on the body: least side eﬀects... most therapeutic… What we don’t want/intend: toxic…fatal… Goal = benefit rather than detriment to the patient! THERAPEUTIC WINDOW: CONCENTRATION VS RESPONSE FIGURE 2.2 Therapeutic window: concentration versus response. The concentration of the drug in the body produces specific effects. A low concentration is considered subtherapeutic, producing an insufficient response. As the concentration increases, the desired effect is produced at a given drug level. A drug concentration that exceeds the upper limit of the desired response may produce a toxic reaction. The concentration range within which a desired response occurs is the therapeutic window. Minimal Eﬀective Concentration (MEC) – plasma drug level at which therapeu:cs eﬀects will occur and below which therapeu:c eﬀects will not occur. Therapeutic Index or Range – margin of safety The wider or bigger it is, the safer the drug. Example 1: Drug A: normal dose is 1 mg, toxic dose is 10 mg Acetaminophen’s therapeutic range is 30 times the MEC Example 2: Drug B: normal dose is 9 mg, toxic dose is 10 mg Lithium’s therapeutic range is 3 times the MEC. Pharmacokinetics: “What the body does to the drug.” Absorption Distribution Biotransformation (Metabolism) Excretion Pharmacodynamics: “What the drug does to the body” Biochemical and physiologic eﬀect of drugs on living organisms. RELATIONSHIP BETWEEN PHARMACOKINETICS AND PHARMACODYNAMICS FIGURE 2.1 Relationship between pharmacokinetics and pharmacodynamics. Note the two-way relationship between the concentration of drug in the plasma and the concentration of drug at the site of action, depicting the interrelationship between pharmacokinetics and pharmacodynamics. The purpose of pharmacokinetic processes is to get the drug to the site of action where it can produce its pharmacodynamic eﬀect. There is a minimum amount of drug needed at the site of action to produce the desired eﬀect. Although the amount of drug concentrated at the site of action is diﬃcult to measure, the amount of drug in the blood can be measured. The relationship between the concentration of drug in the blood and the concentration at the site of action (i.e., the drug receptor) is diﬀerent for each drug and each person. Therefore, measuring blood concentrations is only a surrogate marker, an indication of concentration at the receptor. Figure 2.1 shows the relationship between pharmacokinetics and pharmacodynamics. PHARMACOKINETICS – ABSORPTION Entry of the drug into the bloodstream Usually occurs by passive diﬀusion of drug through cell membranes (next slide) Absorption depends on: Blood flow at site of administration Drugs lipid solubility ( >lipid = >absorption) Local pH and drug ionization (non ionized absorbed better) Pharmaceutical processing (coatings, additives to eﬀect drug absorption) Methods of absorption: enteral absorption (after the drug is administered by the oral or rectal route) parenteral absorption (associated with drugs administered IM, SQ, or topically). The first aspect of pharmacokinetics to consider is how drugs are administered, how they are absorbed into the body, and how they eventually reach the bloodstream. Merely introducing the drug into the body does not ensure that the compound will reach all tissues uniformly or even that the drug will reach the target site. Commonly recognized methods of absorption include enteral absorption (after the drug is administered by the oral or rectal route) and parenteral absorption (associated with drugs administered intramuscularly [IM], subcutaneously, or topically). The various administration routes and other factors aﬀect a drug’s ability to enter the bloodstream. Most drugs are absorbed through passive diﬀusion, esp. drugs that are lipid soluble (we say they “directly penetrate membrane” or dissolve in lipid layer) Blood brain barrier: allow lipid soluble only, may pump out any drug that it sees as foreign… hard to treat CNS infections Placenta: allows lipid drugs so does not protect from lipid soluble drugs…why pregnant patients are limited in drugs… Must consider route of administration also, properties of each route eﬀect absorption Blood Brain Barrier Only lipid soluble and non tightly bound Tight junctions and absence of intracellular pores Active transport system pumps drugs away if diﬀusion allows them in Placenta Lipid soluble DRUG MOVEMENT ACROSS CAPILLARIES BIOAVAILABILITY Portion or percent of an administered dose of drug that is absorbed and able to cause eﬀect: Most important clinically. Aﬀected by hepatic first pass eﬀect, gastric pH, other pre- systemic factors May also be aﬀected by all the factors that aﬀect absorption (previous slide) Listed in Drug Guide under Absorption and in text under Oral Bioavailability and the First-Pass Eﬀect. Example: If 100mg of a drug is given, and 70% of the drug is unchanged by the metabolic first pass eﬀect, absorption, and systemic factors, then it is considered as having 70% bioavailability. BIOEQUIVALENCE Generic vs. Brand/Trade Issue New Trade drug must be bioequivalent with generic proprietary substance. Important for writing scripts: “dispense as written” if requiring a Trade/Brand name drug or a specific formulation. Example is phenytoin (Dilantin): individualize PHARMACOKINETICS – DISTRIBUTION The process by which drugs are carried throughout the body and delivered to targets of action. Dependent on blood flow in target area and ability to pass through cell membranes Aﬀected by plasma protein binding Aﬀected by fat ratio and hydration status; volume of distribution (Vd) In patients with compromised blood flow (e.g., from shock), relying on the blood to deliver a drug to a site of action, such as the kidney, may be risky. Plasma protein binding (competitive): Reversible Bound drug molecules – attached to protein (usually albumin) Unbound or free drug is available to produce eﬀect Once the free drug is eliminated from the body through metabolism or excretion, the bound drug can be released from the protein to become active Consider the patient’s albumin levels FIGURE 2.3 Relationship between bound and unbound drugs and plasma proteins. Protein Binding After absorption into the blood (and lymph), a drug may circulate throughout the body unbound (free drug) or bound to carrier proteins such as albumin. The extent of drug binding to carrier proteins depends on the aﬃnity of the drug for the carrier protein and the concentrations of both the drug and the protein. Acidic drugs commonly bind to albumin and basic drugs commonly bind to alpha1-acid glycoprotein or lipoproteins. Plasma protein binding is typically a reversible phenomenon, with binding and unbinding occurring within milliseconds. Therefore, the bound and unbound forms of the drug can be assumed to be at equilibrium at all times. As such, the degree of binding to plasma proteins can be expressed as a percentage of bound drug to total concentration (bound plus unbound). It is only the unbound or free drug that can exert a pharmacologic eﬀect. If the drug becomes bound, it becomes inactive because it cannot leave the bloodstream or bind to an enzyme or receptor and exert its therapeutic action (Figure 2.3). Once the free drug is eliminated from the body through metabolism or excretion, the bound drug can be released from the protein to become active. In essence, the bound drug may serve as a storage site or reservoir of the drug. The percentage of the free drug usually is constant for a single drug but varies among drugs. Patient-specific factors, such as nutritional status, renal function, and levels of circulating protein or albumin, can change the percentage of the free drug. Fat ratio changes may alter distribution, especially as people age. Fat soluble drugs may be accumulated: weight loss will release these drugs Water soluble drugs are aﬀected by dehydration Review: BOX 2.3 Calculating the Apparent Volume of Distribution (Vd) The Vd is a direct measure of the extent of distribution of a drug in the body and represents the apparent volume that a drug must distribute to contain the amount of drug homogenously. In addition, drug distribution may be aﬀected by obesity, both immediately after absorption and after achieving an equilibrium or steady state in the body. Lipid-soluble drugs readily distribute into the fatty tissues, where they may be stored and even concentrated. Water-soluble drugs, however, tend to remain in the highly vascularized spaces of the skeletal muscle. Ideal body weight is usually considered the standard for determining drug dosage, which is often adjusted for obese or cachectic patients. Vd is usually measured in liters (L); amount in body is usually measured in milligrams (mg); and plasma drug concentration is usually measured in milligrams per liter (mg/L). The apparent volume of distribution is a theoretical parameter calculated by determining the amount of drug in the body (usually the dose administered) divided by the concentration of drug in the plasma taken at an appropriate time interval after administration. Drugs that are highly water soluble or highly bound to plasma proteins remain in the blood compartment and do not distribute or bind to fatty tissue. These drugs have a low Vd, usually less than the volume of total body water (approximately 50 L, or 0.7 L/kg). Drugs with a low Vd usually circulate at high levels in the blood. In contrast, drugs that are not highly protein bound and are highly lipophilic have a high Vd (greater than 150 L, which is greater than the volume of total body water). These drugs distribute widely throughout the body and may even cross the blood–brain barrier. Retention of Protein-Bound Drug Within the Vasculature PHARMACOKINETICS – METABOLISM OR BIOTRANSFORMATION Hepatic “First Pass Eﬀect” breaks PO meds down to some degree, some are protected with coating, but coatings don’t always work as intended. Some drugs, however, may be biologically transformed from an inactive parent drug into an active metabolite (called a pro-drug). Parenteral (IV or IM) meds bypass this enzymatic eﬀect temporarily. Not all drugs are metabolized the same. In fact, some drugs are not metabolized at all. —Propranolol example first pass, Aminoglycosides not metabolized Drugs become more hydrophilic (water soluble) for excretion. Failing liver produces fewer enzymes, drugs available longer: caution Genetic diﬀerences account for why some people break down certain drugs faster than others or have reactions unique to them. Cytochrome P450 system A group of enzymes in the liver that are membrane-bound proteins found in the endoplasmic reticulum of the liver. They function as mono-oxygenases, transferring one oxygen atom to cause oxidation. Most lipophilic drugs are substrates for one or more of the CYP enzymes. Subsets of P450 system can be altered by certain drugs causing alterations in the breakdown of other drugs. A substrate is a drug or other substance that is metabolized by cytochrome enzymes. Substrates bind to the active site of an enzyme and are transformed into metabolites. Inducers of CYP enzymes activate them and cause faster drug metabolism. Inhibitors of CYP de-activate them and cause slower drug metabolism. Common P450 inducers: Phenytoin Griseofulvin St. John's Wort Carbamazepine Rifampin Barbiturates Chronic alcohol use Smoking nicotine specifically activates CYP1A2, increasing the speed at which drugs are metabolized. Some foods that induce the CYP enzymes include: Charcoal-grilled foods Cruciferous vegetables (e.g., broccoli) Genetic differences account for why some people break down certain drugs faster than others or have reactions unique to them. Subsets of P450 system can be altered by certain drugs causing alterations in the breakdown of other drugs. Ex: Fluoxetine (Prozac) blocks the P450 enzyme from converting codeine in Tylenol #3 to its active form leading to poor pain relief from codeine in patients who take prozac. Metabolism Metabolism is a function of the body designed to change substances into water soluble, more readily excreted forms. The liver primarily performs the body’s metabolic functions because of its high concentration of metabolic enzymes. This is why the first-pass effect is significant to the bioavailability of a drug administered orally. Other organs, such as the kidneys and intestines, as well as circulating enzyme systems, also contribute to the metabolism of drugs. Metabolic processes are used to detoxify drugs and other foreign substances as well as endogenous substances. Drugs may be metabolized from active components into inactive or less active ones. Some drugs, however, may be biologically transformed from an inactive parent drug into an active metabolite. This type of drug is called a prodrug because it is a precursor to the active drug (Table 2.1). Not all drugs are metabolized to the same extent or by the same means. In fact, some drugs, such as the aminoglycosides (e.g., gentamicin [Garamycin]), are not metabolized at all. PHARMACOKINETICS – EXCRETION Process by which medications are eliminated from the body unchanged or as metabolites. All drugs must eventually be eliminated from the body to terminate their eﬀect by: Metabolism (or biotransformation) of the drug from an active form to an inactive form. Elimination by bladder and bowel. Elimination is a combination of the metabolism and excretion of drugs from the body. All drugs must eventually be eliminated from the body to terminate their effect. Drugs can be eliminated through metabolism (or biotransformation) of the drug from an active form to an inactive form. Drugs can also be eliminated by excretion from the body. Therefore, elimination is a combination of the metabolism and excretion of drugs from the body. Important concepts in understanding drug elimination are half-life, steady state, and clearance. Knowledge of these phenomena in any given patient helps practitioners understand how long a drug will last in the body and how much should be given to maintain therapeutic levels and therefore helps in determining the appropriate dose and dosing intervals. Important concepts in understanding drug elimination are half-life, steady state, and excretion via bowel or bladder. Kidneys are main organ of excretion. Drugs are also eliminated via respiration, breast milk, defecation. Tears, sweat, saliva not as significantly. If poor renal or liver function, drug may accumulate (patient may need to less of drug), may need to prescribe less of drug (renal dosing or hepatic dosing). Enterohepatic recirculation (reabsorbs drug from small intestine). Important concepts in understanding drug elimination are half-life, steady state, and clearance. Knowledge of these phenomena in any given patient helps practitioners understand how long a drug will last in the body and how much should be given to maintain therapeutic levels and therefore helps in determining the appropriate dose and dosing intervals. Metabolites Usually less active, less toxic, easier to excrete Prodrugs - inactive in form given but metabolized to active drug (ex: enalapril) Liver function determined by liver enzymes Failing liver produces fewer enzymes, drugs available longer: caution PHARMACOKINETICS – ELIMINATION BY HALF LIFE Half-Life: amount of time it takes to reduce the plasma concentration by 50% (4 or 5 t1/2 for a drug to be totally excreted) Steady State: rate of administration = rate of excretion (takes 4 or 5 t1/2) Significant to understand half life to allow accumulation of drug to a steady state. 300 mg goes to 150 mg, goes to 75 mg, goes to 37.5 mg goes to 18.75 mg etc. That is why we have to keep giving doses and why doses are spaced the way they are… keeps therapeutic levels up. It takes 4 half lives to reduce a medication to amount that is so tiny that drug is considered negligible DRUG HALF LIFE EFFECT ON ACCUMULATION AND PLATEAU PHARMACODYNAMICS: “EFFECT OF DRUG ON THE BODY” Receptors: Drugs must bind to for eﬀect Help a process happen: agonist Block a process from happening: antagonist Know that: All drugs have an eﬀect A drug’s ability to cause a response is called its eﬃcacy If you give a bigger dose you will get a bigger eﬀect up to a point, most drugs have a ceiling. EFFICACY Eﬃcacy is an important quality for a drug to have. But remember, if a drug has a greater eﬃcacy than another drug it does not mean that that drug is better, it depends on how much eﬀect we need for the person’s condition (see figure on next slide). For example, not everyone needs morphine for pain when ibuprofen (Motrin) or acetaminophen (Tylenol) could suﬃce. A figure of a chart depicting the relationship between degree of pain relief and dose of the drugs meperidine and pentazocine in the form of a dose-response curve. The interpretation is that lower doses of meperidine produce a higher degree of pain relief. However, if a patient has a smaller degree of pain, pentazocine may be just as efficacious. DRUG POTENCY & SELECTIVITY A potent drug is strong, but not necessarily better (2 nickels equals one dime, i.e. same) Potency is not an important drug quality as you can give more of another drug to reach the same potency Selectivity: the intended eﬀects of a drug Seldom only one eﬀect, usually many (side eﬀects). A figure depicting a comparison of morphine and meperidine potencies using a dose-response curve. The interpretation is that both drugs can achieve the same potency, however a smaller dosage of morphine can be used to achieve the same degree of relief as a higher dose of meperidine. SPECIAL DOSING CONSIDERATIONS: PEDIATRIC & GERIATRIC Diﬀerent people react diﬀerently to meds: age, organ function, protein levels, metabolism… Must watch all people for variant reactions: individualize We are most mindful of those at extremes of age: very old, very young PEDIATRIC ADMINISTRATION ISSUES Children represent about 25% of the United States population. The FDA defines pediatric patients as people aged 21 or younger at the time of their diagnosis or treatment. Children receive an average of 3 prescription medications before 5 years of age. According to the FDA, before the implementation of a pediatric program, only about 20% of FDA-approved drugs were labeled for pediatric use. According to a 2018 NCBI article, the rates of oﬀ-label prescribing for children in the United States ranges from 62% to 85%. According to an emergency physician at Boston Children's Hospital, less than 50% of medication labels have guidance for providers on a drug's use in children. NCBI = National Center for Biotechnology Information part of the National Institutes of Health PHARMACOKINETICS (AGE=/>1 YEAR) By age one year, most organs are approximate to maturity of adults, so pharmacokinetics is similar. Metabolism peaks at age two (higher than adult!) and gradually decreases to adult level. Important diﬀerence:. Drug-metabolizing capacity is markedly elevated between the ages of 1-2 years, and then gradually declines. Give more frequent or someAmes higher dose to that age group. PHARMACOTHERAPEUTICS FOR CHILDREN CONSIDERING PHARMACOKINETICS Absorption: GI absorption may be increased or decreased (unreliable and erratic). Gastric emptying prolonged and gastric pH is very low which leads to increased absorption of some drugs (stomach, acid labile), decreased of others (intestine). Transdermal absorption is rapid and complete (toxicity risk). Distribution: Protein binding of drugs: low albumin and competition from other substances (increased amount of free drug in circulation) Blood brain barrier is immature which results in increased free drug when in system of children sometimes and infant susceptibility to drugs that aﬀect CNS. Metabolism Hepatic drug metabolism: liver immature Immature hepatic function in infants. Until two weeks old, meds may be toxic to neonate. Metabolism peaks at age two (higher than adult!) and gradually decreases to adult level. Excretion Renal drug excretion: kidneys immature Renal function reaches normal at 5 weeks of age Prior to that caution, drug accumulation Solution is sometimes to give a lower dose to an infant or child but watch blood levels, a more frequent dosing schedule may be appropriate. PEDIATRIC DOSE CALCULATIONS Usually best to consult manufacturer’s recommendations for pediatric dosages. If not available: use formula with body weight or body surface area as variable. Body Surface Area is most accurate method. More common to use dose/kg but not as accurate. Sometimes extrapolated from adult dose. Always an approximation. CONSIDER DRUG ROUTES IN CHILDREN Elixirs: liquid suspensions that do not settle in solution, easily absorbed. Oral pills: may be poorly absorbed IM: painful, often not well absorbed but sometimes necessary Buccal: requires cooperative, mature child Inhalation or Intranasal: okay if cooperative child Rectal: okay in very young unless defecated out or feces present. Older child slow, unreliable absorption. CHANGES IN BODY COMPOSITION WITH GROWTH AND AGING DRUG THERAPY AND THE OLDER ADULT In 2022, the United States had nearly 58 million adults aged 65 and older, which is about 17.3% of the country's population. Almost 90% of older adults regularly take at least 1 prescription drug, almost 80% regularly take at least 2 prescription drugs, and 36% regularly take at least 5 diﬀerent prescription drugs. Consume greatest amount (over 30%) of OTC drugs use. The elderly are more likely to suﬀer and be hospitalized from ADRs and drug-drug reactions. AGE-INDUCED DRUG RESPONSES Slower emptying of stomach & GI motility Changes: increased ↑ body fat, decreased ↓ lean tissue, ↓ muscle, ↓ total body water, ↓ serum albumin Water soluble: increased concentration Fat soluble: distributed and long residual eﬀect Decreased cardiac output & arterial elasticity Potentially decreased liver function Decreased renal blood flow & GFR Sensory & perceptual changes PHARMACOKINETICS & THE OLDER ADULT Absorption: ↓ GI acidity, ↑ pH, ↓ GI motility Distribution: ↓ CO, ↓ albumin, changes in body mass (lean/fat/water composition) Metabolism: ↓ liver function, ↓ hepatic blood flow Excretion: ↓ renal blood flow, ↓ drug excretion CAUSES OF COMPLICATIONS IN THE OLDER ADULT Multiple medications Complex regimens Noncompliance/Nonadherence OTC Drug interactions Multiple prescribers Expense Cognitive alterations No perceived need for medication, unknown eﬀect of medication TIPS FOR PRESCRIBING TO ELDERLY Give very clear directions, slowly, write out in large legible handwriting; be patient and prepared to answer the same questions more than once. Have family there if possible Check on drug costs before prescribing; use generics if possible Start with smaller quantities (1 week) to see eﬀect Eliminate unnecessary meds Use lowest dose possible Consult the Beer’s List; criteria of potentially inappropriate medication use in older adults DRUG THERAPY IN PREGNANCY AND BREAST FEEDING Physiological changes in pregnancy that impact drug dosing are in the: Kidney (increased clearance) Liver (increased metabolism) Gastrointestinal tract (decreased↓tone) PLACENTAL DRUG TRANSFER All drugs cross the placenta Drug transfer is: Easier—lipid soluble drugs Diﬃcult—ionized, highly polar or protein-bound drugs But…must assume that all drugs cross to some extent Remember that there are few studies: most of our knowledge is from clinician observations ADVERSE REACTIONS DURING PREGNANCY Teratogenesis/Birth defects Eﬀect of a teratogen is highly dependent on when the drug is given during the pregnancy Uterine stimulation (prostaglandins) Uterine suppression (aspirin late) Drug-dependent infant (wean) Respiratory neonate suppression (CNS meds) IDENTIFICATION OF TERATOGENS Teratogens may be Proven Unproven Every teratogen exposure does not result in a birth defect Risk of malformation from teratogen is 10% Drug teratogen Causes malformations Acts in a specific time frame Causes an increase in malformations related to dosages and exposure QUIZ: An average sized 85-year-old patient has been placed on a water-soluble drug at the maximum amount of normal dosage for a young adult. The nurse practitioner should: —evaluate for toxic eﬀects since plasma levels could be increased. The chance of the development of an adverse drug reaction is linked to which factors? 1-Client age 2-Genetic factors 3-Personal history of prior drug reactions 4-Amount of exposure to medication 5-Health insurance coverage — 1, 2, 3 and 4 Pharmacokinetics can be defined as: — drug absorption, distribution, metabolism, and excretion. Clinical judgment in prescribing medication includes (choose the best answer): — factoring in the cost to the patient of the medication prescribed. Which of these statement about genetic considerations of metabolism and clopidogrel (Plavix) is true? — Poor metabolizers are not capable of producing the active metabolite of clopidogrel and should therefore be treated with an alternate medication. A drug interaction when two or more drugs are given together can be synergistic (positive). — True The three MOST important properties of an IDEAL drug are: — Selectivity — Eﬀectiveness — Safety An NP is considering prescribing a potentially teratogenic drug to a 25-year old woman. The NP knows that all of the following are true: — The patient should be counseled regarding potential side eﬀects of the drug. — A proven teratogen should NOT be prescribed to this patient if safer alternatives exist. — Prescription birth control should be oﬀered to this patient if she begins the medication. A nurse practitioner would like to prescribe a medication to an elderly man who is complaining of insomnia. This NP wants to be cautious about her choice of medication for this man. What resource is specific to safe medication use in the elderly and readily available online? — The Beer's List Medications with a wider therapeutic index require closer monitoring than medications with a narrow therapeutic range. — False When a patient’s pain medication is changed from the IV to the PO route, the NP must order a larger dose because: — of the hepatic first pass eﬀect. Anti-infective Therapy: Part One—Antibacterial Agents DEFINITION: Antibiotic: a medicine that inhibits the growth of or destroys microorganisms. Antibacterial: active against bacteria Bactericidal: causing the death of bacteria Bacteriostatic: inhibiting or retarding the multiplication of bacteria Broad-spectrum: acts against a wide range of disease-causing bacteria (both Gram- positive and Gram-negative) Narrow-spectrum: eﬀective against specific families of bacteria Colonization: infection, bacterial growth which does not cause tissue damage or illness, with the potential to infect others, examples: asymptomatic bacteriuria, strep carrier. People who are colonized will have no signs or symptoms. Contamination: the organism isolated in the sample was accidentally introduced from outside; not from within the patient -The MBC is complementary to the MIC; whereas the MIC test demonstrates the lowest level of antimicrobial agent that inhibits growth (visible on petri dish), the MBC demonstrates the lowest level of antimicrobial agent that results in microbial death. EMPIRIC THERAPY Only the most common/expected pathogens, are covered with empiric therapy. This does NOT mean that all possible pathogens are covered, again, only the expected. Based on: – Most likely site and organism(s) – Community or health care organization acquired – Patient age – Patient immune status – Community Patterns +Empiric treatment = treatment by means that experience has proved to be beneficial FACTORS IN SELECTING AN ANTIMICROBIAL REGIMEN 1. Perform H&P; identify source & site 2. Consider comorbidities & social conditions 3. Consider allergies & potential drug-drug interactions 4. Consider how/where the infection was acquired 5. Provide empiric therapy based on “most likely infecting organism” (Table 8.1) + “sensitivity of organism to specific agents” (Table 8.2) 6. Obtain culture & sensitivity; case by case; often determined by guidelines. The gold standard of diagnosis in infectious diseases is to be able to grow the causative organism in culture and perform antibiotic susceptibility testing to determine which agents are most likely to be eﬀective in eradicating the pathogen. Social variables: Age, Pregnancy, Socio-economic/Insurance (ideally & ethically shouldn’t consider this, however reality = we do) Identifying the causative pathogen is the ultimate goal because it allows for optimal antibiotic selection and patient outcome. Causative agent identified and susceptible to initial antimicrobial agent = monitor patient for eﬃcacy, toxicity, and response; no change needed if improving as expected and no ADRs requiring new agent selection. Causative agent identified and resistant to initial antimicrobial agent = will need to change to a diﬀerent agent; considering #2 & #3 on previous slide. Sometimes more than one causative pathogen is identified! May have to utilize than than one new agent! What would we do if no PO forms of the necessary antimicrobial agents are available or if patient allergic to all options that pathogens are sensitive to?? Or if the patient CANNOT aﬀord the agent??? Thinking about sensitivity & resistance: The MBC is complementary to the MIC; whereas the MIC test demonstrates the lowest level of antimicrobial agent that inhibits growth (visible on petri dish), the MBC demonstrates the lowest level of antimicrobial agent that results in microbial death. Minimum Inhibitory Concentration (MIC): the lowest concentration of a chemical that prevents visible growth of a bacterium Minimum Bactericidal Concentration (MBC): the lowest concentration of an antibacterial agent required to kill a particular bacterium Autoimmune conditions and malignancies can mimic infections. If fever, consider and rule out drug-induced fever. Site specific s/s predict the most likely pathogen What makes pathogens sensitive or resistant? Think about anaerobic/aerobic, gram negative/ gram positive, location (ex: prostate harder to reach; need to cross blood brain barrier) COMBINATION THERAPY Synergy - increased eﬀect (greater than the sum of both antibiotics) Prevents resistance for select situations (example: TB) PROPHYLACTIC THERAPY Surgery Bacterial endocarditis Patients that are immunosuppressed HIV – Pneumocystis jiroveci pneumonia Neutropenia Recurrent UTI ANTIBIOTIC STEWARDSHIP 1.Diagnostic testing to avoid unnecessary use of antibiotics (flu swab, strep screen, etc.) 2.Culture and sensitivity to promote use of narrow spectrum antibiotics when able. 3.Patient should meet the clinical picture/profile for testing (to avoid unnecessary testing & costs). 4.Dosing for antibiotic and choice for empiric antibiotic should be based on literature showing eﬃcacy, guidelines, and severity of illness. 5.Dose for minimal eﬀective duration. 6.De-escalate initial empiric dosing whenever possible. VARIOUS WAY ANTIMICROBIALS WORK Cell wall synthesis Cell membrane permeability Protein synthesis Synthesis of nucleic acids Antimetabolites Viral enzyme inhibitors Bactericidal drugs kill bacteria, whereas bacteriostatic drugs only suppress growth. SUPERINFECTION Antibiotic-associated colitis (Pseudomembranous colitis) caused by toxin Clostridium difficile growth following antibiotics Candida (yeast) overgrowth- mycostatin oral solution ALLERGIES Anaphylaxis Urticaria (hives) Stevens-Johnson Syndrome Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe skin reaction most often triggered by particular medications. Although Stevens-Johnson syndrome and toxic epidermal necrolysis were once thought to be separate conditions, they are now considered part of a continuum. Stevens-Johnson syndrome represents the less severe end of the disease spectrum, and toxic epidermal necrolysis represents the more severe end. Penicillins Weaken the bacterial cell wall, causing bacteria to take up excessive water and rupture (bactericidal) Most of the penicillins are unstable in the acid environment of the stomach and must be administered parenterally. Those that are acid stable are given orally. Most penicillins are excreted by the kidneys, and renal impairment necessitates dosage. Susceptible to beta lactamases (discussed later). The mechanism of action of the penicillins is the inhibition of bacterial cell growth by interference with cell wall synthesis. Penicillins bind to and inactivate the penicillin-binding proteins (PBPs). Most penicillins are excreted by the kidneys, and renal impairment necessitates dosage adjustment. The half-life of the penicillins in adults with normal renal function is 30 to 90 minutes. The penicillins are removed by hemodialysis, with the exception of nafcillin and oxacillin. The penicillins exhibit time-dependent bactericidal activity and a postantibiotic eﬀect (PAE) against most gram-positive organisms. Note: Dosage adjustment of all above drugs required in patients with impaired renal function, with the exception of penicillinase-resistant penicillins. Narrow spectrum: natural penicillins & pencillinase resistant Broad spectrum: aminopenicillins Extended spectrum (includes anti-pseudomonas): ureidopenicillins Extended Spectrum ticarcillin (Ticar) – no longer available alone piperacillin (Pipracil) - no longer available alone + Beta-Lactamase resistance piece: resist beta-lactamase, enzyme produced by bacteria that inactivates penicillins ticarcillin clavulanate (Timentin)* piperacillin tazobactam (Zosyn)* CLINICAL USES OF PENICILLINS Although the use of penicillin itself is limited due to widespread resistance, the penicillin class is eﬀective in many infections. Examples: upper and lower respiratory tract, urinary tract, central nervous system, and sexually transmitted diseases. They are the agents of choice for treating gram-positive infections. Both the carboxypenicillins and ureidopenicillins are useful in treating infections caused by Pseudomonas aeruginosa. Beta-lactamase inhibitors are used in treating polymicrobial infections, intra-abdominal and gynecologic infections, skin and soft tissue infections (including human and animal bites). PENICILLINS – ADRS & INTERACTIONS ADRs: Penicillins are the most common cause of drug allergy Diarrhea Rash Interactions: Probenecid - inhibits renal tubular excretion of penicillins, results in higher serum concentrations— Probenecid is primarily used to treat gout and hyperuricemia. Probenecid is sometimes used to increase the concentration of some antibiotics (ex: PCN = probenecid can be used to treat gonorrhea) Oral Contraceptives – may decrease eﬃcacy Do not mix penicillins & aminoglycosides (i.e. tobramycin, gentamycin) in IV solution! PENICILLINASES (BETA-LACTAMASES) Enzymes that render penicillins and other beta-lactam antibiotics inactive Penicillins are combined with beta-lactamase inhibitors, extends the antimicrobial spectrum Beta lactamase inhibitors – Clavulanic acid + amoxicillin (Augmentin), + ticarcillin (Timentin) Anti-pseudomonas – Tazobactam + piperacillin (Zosyn)* – Sulbactam + ampicillin (Unasyn) An enzyme produced by many species of bacteria that disrupts the four-membered β-lactam ring of penicillin and cephalosporin groups of antibiotics, destroying their antimicrobial activity. The role of the beta-lactamase inhibitor is to prevent the breakdown of the beta-lactam by organisms that produce the enzyme, thereby enhancing antibacterial activity. Gram-negative bacteria that produce an enzyme, beta-lactamase that can break down commonly used antibiotics, such as penicillin and cephalosporins, making infections with ESBL (extended spectrum beta-lactamase) producing bacteria more diﬃcult to treat. Enterobacter, E.coli and Klebsiella are common producers of ESBL, and they usually cause urinary tract infections and bacteremia. Risk Factors for ESBL: Extensive treatment with antibiotics Prolonged stay in a health care institution, particularly in an ICU Severity of illness: neutropenia, organ transplant, hemodialysis or tube feeding Indwelling catheters Communal living setting Cephalosporins A beta-lactam group (structurally similar to the penicillins). Weaken the bacterial cell wall, causing bacteria to take up excessive water and rupture (bactericidal). Like other beta-lactams, the cephalosporins interfere with bacterial cell wall synthesis by binding to and inactivating the PBPs. Susceptible to beta lactamases Cephalosporins are well absorbed from the GI tract; in some cases, food enhances absorption. Most of the oral and parenteral cephalosporins are excreted by the kidney, with the exception of ceftriaxone (Rocephin), which is eliminated by the liver. – 1st generation - cephalexin (Keflex)* – 2nd generation - cefoxitin (Mefoxin) – 3rd generation - ceftriaxone (Rocephin)* – 4th generation - cefepime (Maxipime) – 5th generation – ceftaroline (Teflaro) As move up (1-5) in generation: – increasing activity against Gm (–) bacteria and anaerobes (no oxygen needed) – increasing resistance to destruction by beta-lactamases (2nd) – increasing ability to reach CSF (3rd and 4th) – activity against MRSA (5th) The cephalosporins, a beta-lactam group, are structurally similar to the penicillins. Substitutions on the parent compound, 7-aminocephalosporanic acid, produce compounds with diﬀerent pharmacokinetic properties and spectra of activity. The cephalosporins are divided into “generations” based on their antimicrobial spectrum of activity. The progression from first to fourth generation in general reflects an increase in gram-negative coverage and a loss of gram-positive activity. Although a myth persists that approximately 10% of patients with a history of penicillin allergy will have an allergic reaction if given a cephalosporin, the overall cross-reactivity rate is approximately 1% when using first-generation cephalosporins or cephalosporins with similar R1 side chains. However, a single study reported the prevalence of cross reactivity with cefadroxil as high as 27%. For penicillin-allergic patients, the use of third- or fourth- generation cephalosporins or cephalosporins with dissimilar side chains than the oﬀending penicillin carries a negligible risk of cross allergy CLINICAL USES OF CEPHALOSPORINS 1st-generation treat gram-positive skin infections, pneumococcal respiratory infections, urinary tract infections, surgical prophylaxis. 2nd-generation treat community-acquired pneumonia, other respiratory tract infections, and skin infections. 3rd-generation treats community-acquired bacterial meningitis. 4th –generation treats nosocomial infection and covers pseudomonas. 5th–generation Ceftaroline fosamil (Teflaro) is the only cephalosporin that covers MRSA. PRECAUTIONS & ADRS Probenecid can delay excretion Allergy/rash - cross-sensitivity with penicillins Bleeding (may give prophylactic VIT K) Thrombophlebitis ceftriaxone (Rocephin) majorly eliminated by liver – Can increase risk of bleeding, careful with NSAIDS, anti-coagulants, anti-platelets – Never mix in same IV as calcium or calcium containing-diluents (Ringer’s Lactate) Carbapenems (IV only, not absorbed PO) Inhibit cell wall synthesis and cell metabolism (bactericidal) The carbapenems, ertapenem (Invanz), doripenem (Doribax), imipenem (Primaxin), and meropenem (Merrem), are bicyclical beta-lactams with a common carbapenem nucleus Less susceptible to the beta lactamase enzymes Neurotoxicity, a well-known eﬀect of the carbapenems, is characterized by seizure activity (lowers seizure threshold) Used for the treatment of infections known or suspected to be caused by multidrug- resistant (MDR) bacteria The most broad-spectrum agents commercially available. Similar to the penicillins and cephalosporins, the carbapenems bind to the PBPs on the cell wall and interfere with bacterial cell wall synthesis. They frequently have stability against beta-lactamases and bind to several PBPs. Concomitant administration of probenecid and meropenem or doripenem results in decreased clearance of these agents and a substantial increase in half-life; therefore, the concurrent administration of meropenem or doripenem with probenecid is not recommended. Fluoroquinolones Prevent bacterial DNA from unwinding and duplicating (bactericidal) Agents: norfloxacin (Noroxin); ciprofloxacin (Cipro); ofloxacin (Floxin); levofloxacin (Levaquin); moxifloxacin (Avelox); gemifloxacin (Factive) Activity broad spectrum against aerobic gram-negative organisms Broad Spectrum The quinolone antibiotics are strong inhibitors of deoxyribonucleic acid (DNA) gyrase and topoisomerase IV. These enzymes are critical to the process of supercoiling DNA. Without such enzymatic activity, bacterial DNA cannot replicate. CLINICAL USE OF FLUOROQUINOLONES Ciprofloxacin and levofloxacin have activity against pseudomonas (only PO agents available). Treat many infections: urinary tract, community acquired pneumonia, STIs, skin and soft tissue infections, GI infections (in combination with an agent for anaerobic coverage), traveler’s diarrhea, and osteomyelitis. Rare but serious side eﬀects include QTc prolongation, tendon rupture, tendonitis, and peripheral neuropathy. Avoid if 400 mg/day) Onset 1 hr Peak 2-3 hr No DEA schedule Similar side eﬀects to opioids May cause seizures with therapeutic doses Especially in patients with decreased seizure threshold or taking drugs that lower the seizure threshold Available as tramadol/acetaminophen and as a long acting agent (Conzip) Tapentatol (Nucynta) Indications: Moderate to severe pain Action: Mu receptor agonist and inhibits uptake of norepinephrine ADR: seizures, respiratory depression, N/V, sedation, physical dependence Interactions: serotonin syndrome Dose: PO 50-100mg initially, then q 4-6 hr, not to exceed 700 mg first day and 600mg/day thereafter Nucynta ER – 12 hr dosing STEP 3 OPIOIDS morphine (MS Contin, Kadian, Mitigo) hydrocodone (Zohydro, Hysingla ER) hydromorphone (Dilaudid, Hydromorphone ER) oxycodone (Roxicodone, Oxaydo, OxyContin, Xtampza ER) fentanyl (Sublimaze, Duragesic, Actiq, Fentora, Lazanda, Subsys) oxymorphone (Opana) Methadone (Dolophine, Methadose) Drug Oral Parenteral Morphine 30 mg 10 mg Codeine 200 mg 130 mg NR EQUIANALGESIC OPIOID DOSES Hydromorphone 7.5 mg 1.5 mg EQUIANALGESIC EXAMPLE Meperidine 300 mg 75 mg Morphine 10 mg IV q 3 hr Oxycodone 20 mg Not available X 24 hrs = 80 mg Hydrocodone 20-30 mg Not available Dilaudid Dilaudid 1.5 mg IV = Morphine 10 mg IV Methadone 10 mg 5 mg Dilaudid 7.5 mg PO = Morphine 10 mg IV Fentanyl Not available 100 mcg/hr 1.5 = x 10x = 120 x = 12 mg/24 hr 10 80 10 10 2 mg IV-q 4 hr —————————————————————————————- 7.5 = x 10x = 600 x = 60 mg/24 hr 10 80 10 10 10 mg q 4 hr EQUIANALGESIC EXAMPLE Oxycodone 5/325 2 tabs q 3hrs X 24 hrs = 8 doses x 10 mg = 80 mg/24 hr ———— OxyContin 10 mg/12 hr 0xycodone 20 mg = Hydrocodone 20-30 mg 80 mg hydrocodone = 80 mg oxycodone 80 mg / 12 hrs = 40 mg bid TITRATION OF OPIOID DOSES When titrating opioid doses, increases of 25-50% should be administered until there is either a 50% reduction in the patient's pain rating on a numerical or visual analog scale or the patient reports satisfactory pain relief. A repeat dose can be safely administered at the time of the peak if previous dose is ineﬀective and side eﬀects are minimal. OPIOID DOSING Around the clock doses are more eﬀective than prn administration for pain that is expected to continue. Analgesic is more eﬀective if given before pain becomes severe. Provide analgesia to allow for uninterrupted sleep. Sudden increases in pain should worked up and require a dose increase ROUTES OF ADMINISTRATION Noninvasive is best! The oral route is eﬀective for even severe pain if doses are high enough The IV route is the fastest and safest for titration The IM route is painful and unreliable, and should be avoided Transdermal administration is useful for chronic pain OPIOID AGONIST ANTAGONIST ANALGESICS Not recommended as first line therapy Bind to kappa receptors Have partial agonist Have partial antagonist properties May cause withdrawal in patients physically dependent on opioid agonists Have a greater risk of dysphoric side eﬀects pentazocine (Talwin IM/IV) butorphanol nalbuphine buprenorphine (Buprenex) Buprenorphine transdermal (Butrans) Buprenorphine film (Belbuca) Buprenorphine/naloxone (Suboxone – SL film or tablet), Bunavail (buccal film), Zubsolv (SL tablet) buprenorphine transdermal (Butrans) Indicated for moderate to severe chronic pain Transdermal patch lasts up to 7 days Available in 5 mcg/hr, 10 mcg/hr & 20 mcg/hr If patient is already taking opioids, must be titrated down slowly to 100mcg/ Pain relief declines before 72 hours Fever Direct external heat source Solution Immediately replace patch Use multiple patches Evaluate increased dose, then consider 48-hour dosing Increase monitoring, consider dose reduction Avoid direct external heat source Methadone Inexpensive Accumulates with repeated dosing 85% protein bound Slowly released up to 10 days after dose increase Available in tablets (5 mg or 10 mg), oral solution (5 mg/5 mL or 10 mg/5 mL) or oral concentrate (10 mg/mL) Patient may be subjected to scrutiny (observation) d/t misconceptions EPISODIC PAIN Breakthrough pain is a transitory flare of pain superimposed on an otherwise controlled stable pain syndrome. Incident pain is predictable ‘episodic pain’ caused by a physical or psychosocial-spiritual stimulus ‘End of dose failure is when a long-acting opioid does not last expected duration TREATMENT OF BREAKTHROUGH PAIN Immediate-release or short-acting opioids (IR) Rapid-onset opioids (ROOS) BREAKTHROUGH PAIN Doses of immediate release opioids should be equivalent to about 10%-20% of the 24-hour total dose Doses may be given every 2 hours as needed Doses of immediate-release opioid may be taken as same time as sustained-release opioid Do not use sustained-release opioid for breakthrough pain Transmucosal immediate-release fentanyl (TIRF) (ROOS) Management of breakthrough pain in opioid-tolerant cancer patients; 18 yr or older who already receive opioids for persistent cancer-related pain (60 mg/day of oral morphine or equivalent) Actiq – transmucosal lozenge Fentora – buccal tablet Lazanda – nasal spray Subsys – sublingual spray TIRF REMS Prescribers of TIRF medicines for outpatient use are required to enroll in the TIRF REMS Access program. Required every two years from the date of enrollment. Information can be found at www.TIRFREMSaccess.com TIRF REMS Access Patient-Prescriber Agreement Form must be signed before writing the patient’s first TIRF prescription Must provide patients with a copy of the Medication Guide during counseling about proper use of their TIRF medicine Pharmacists dispensing TIRF medicines are required to enroll in the TIRF REMS program and re-enroll every 2 yrs. Patients are enrolled by the pharmacy at the time their first prescription is filled. Locate a participating pharmacy by consulting prescriber or calling TIRF REMS Access program at 1-866-822-1483 ACTIQ uses the oral transmucosal system (OTS™) delivery system for rapid non-invasive delivery of fentanyl and patient- controlled administration. Pain relief was observed at 15 minutes following administration, the first time point measured. Pain relief was still seen at 60 minutes following administration, the last time point measured. Fentanyl buccal (Fentora) Indicated for breakthrough pain Buccal tablets each deliver 100-800 mcg fentanyl Takes 14-25 minutes to dissolve Fentanyl sublingual spray (Subsys) Dose must start with 100 mcg If inadequate analgesia after first dose, a second dose may be used after 30 min. No more than 2 doses may be used to treat an episode of breakthrough pain. Episodes should be separated by at least 4 hrs. Other rescue medications may be used as directed. OPIOID-INDUCED SIDE EFFECTS constipation nausea & vomiting sedation respiratory depression CONSTIPATION Cause - decreased peristalsis Assess bowel function routinely. Prevention of constipation should be instituted with increased intake of fluids and bulk and with laxatives to minimize constipating eﬀects. Stimulant laxatives (ie. Senokot) should be administered routinely if opioid use exceeds 2-3 days, unless contraindicated. methylnaltrexone (Relistor) Treatment of constipation caused by opioid use in patients with advanced illness being treated palliatively, when laxative therapy has failed (SQ) or for cancer or chronic noncancer pain (PO, SQ). Acts peripherally as a mu-opioid receptor antagonist, blocking opioid eﬀects on the GI tract. Blocks constipating eﬀects of opioids on the GI tract without loss of analgesia. SQ injection qod or PO qd naloxegol (Movantik) Oral pill for opioid-induced constipation in patients with chronic noncancer pain Once daily 25 mg or 12.5 mg. Take 1 hr before or 2 hrs after meals. DC laxatives. 44% with 25 mg increased bowel movements/week – compared to 29% with placebo Onset to first BM – 6-12 hours vs 15-36 hours in patients with placebo naldemedine (Symproic) Oral pill for opioid-induced constipation in patients with chronic noncancer pain Once daily 0.2 mg tablet, with or without food; with or without laxatives Less likely to be eﬀective for patients on opioids for less than 4 wks 48-53% increased bowel movements per week – compared to 34-35% with placebo CAUSES OF NAUSEA AND VOMITING Stimulation of the chemoreceptor trigger zone Inhibition of GI motility Vestibular stimulation MANAGEMENT OF NAUSEA AND VOMITING Tolerance Change opioids Multiple antiemetics Decrease ambulation CAUSES OF SEDATION Opioid-induced CNS depression Exhaustion from uncontrolled pain MANAGEMENT OF SEDATION Tolerance Decrease opioid dose & add an NSAID Change opioids Add a stimulant Consider other causes organic pathology other CNS depressants psychological causes No patient has succumbed to respiratory depression while awake. SEDATION SCALE S - Sleeping, easily aroused. Requires no action. 1 - Awake & alert. Requires no action. 2 - Occasionally drowsy, easy to arouse. Requires no action. 3 - Frequently drowsy, arousable, drifts oﬀ to sleep during conversation. ↓ opioid dose. 4 - Somnolent, minimal or no response to stimuli. DC opioid; consider naloxone. RESPIRATORY DEPRESSION If respiratory rate is 14 years, adults, & immunocompromised patients Shingles (Herpes Zoster) vaccine available – acyclovir – famciclovir – valacyclovir Post-herpetic Neuralgia – capsaicin (Zostrix) cream or capsaicin (Qutenza) 8% patch – Gabapentin (Neurontin) or pregabalin (Lyrica) INFLUENZA A & B Vaccine – inactive, contains no live virus, cannot cause influenza. BEST therapy. Antiviral therapy – If administered within 2 days of onset, reduce symptoms by 1 day, may also be preventative – zanamivir (Relenza) – patients > 5 years Powder for inhalation – oseltamivir (Tamiflu) – patients > 1 year – baloxavir marboxil (Xofluza) – patients > 12 years Newest agent, 40-80mg x1 dose within 48 hours; avoid dairy Prevent or decrease severity of influenza, eﬀectiveness best in first 24 hours. Inhibit influenza neuraminidase except for baloxavir which inhibits viral replication by inhibiting viral polymerase acidic protein endonuclease activity Definition of endonuclease: an enzyme that breaks down a nucleotide chain into two or more shorter chains by cleaving the internal covalent bonds linking nucleotides Ex: DNA, RNA INFLUENZA VACCINE New vaccines created yearly by most likely strains agreed upon by WHO, FDA, & CDC SC: Fluarix, Fluzone, Fluvirin (dead) Intranasal – FluMist (weakened, live, attenuated) Recommended for most individuals Pregnant women and those who are immunocompromised or immunosuppressed should NOT receive live virus Should NOT be adminstered to individuals with history of Guillain-Barré, allergy to the vaccine, or allergy to eggs Wait until febrile illness subsides, however can be given with mild cold virus Protection begins 1-2 weeks after administration, antibody titers can decline as early as 4 months CORONAVIRUS-19 (COVID) Mild-moderate cases require no medical treatment besides fluids & rest (like a common cold). Remdesivir, an antiviral agent, is currently the only drug that is approved by the Food and Drug Administration for the treatment of COVID-19. Dexamethasone has been shown to PROLONG viral shedding, contagious LONGER. Risk v. benefit consideration, if the patient can’t breathe without it – give it; if no breathing issues then there is no indication for a corticosteroid for COVID (or any other viral URI). The anti-SARS-CoV-2 monoclonal antibodies bamlanivimab and casirivimab plus imdevimab are available through Emergency Use Authorizations for outpatients who are at high risk for disease progression. Chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19 in hospitalized patients NOT recommended (there is currently a trial for non- hospitalized patients). High-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19 NOT recommended. lopinavir/ritonavir or other HIV protease inhibitors to treat COVID-19 NOT recommended (except in a clinical trial). Ivermectin for the treatment of COVID-19 NOT recommended (except in a clinical trial). Two vaccines are currently available to the public, released in phases of need, varies by state; for ages 16 and older. Pfizer – 2 doses given 3 weeks apart Moderna – 2 doses given 4 weeks apart They do NOT contain a dead virus or a weakened virus; mRNA vaccine with the “blueprint” for the spike protein on the COVID surface; tells the cells to begin making the protein and begin the immune response (antibodies are formed). HUMAN IMMUNODEFICIENCY VIRUS (HIV) HIV is a retrovirus Target cells CD4 (helper lymphocytes) Transmission - blood and body fluids Stages: HIV enters CD4 cell; converts RNA to DNA with reverse transcriptase; HIV virus replication, ready to infect other cells. Diagnosis – ELISA: highly sensitive/specific. Repeated X2 – Western blot: confirmatory test – Caution: window of 1-2 months between infection and development of antibodies to HIV A retrovirus is a single-stranded positive- sense RNA virus with a DNA intermediate and, as an obligate parasite, targets a host cell. Once inside the host cell cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, translating and transcribing the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. It is diﬃcult to detect the virus until it has infected the host. At that point, the infection will persist indefinitely. Blue line = CD4 counts Red line = Viral load Green line = HIV antibodies (Similar to Table 73-2 p. 1693) If untreated: 1. Retroviral syndrome (adenopathy, sore throat/pharyngitis, rash, muscle aches, lethargy, fever) 2-3 weeks 2. Seroconversion 2-4 weeks Seroconversion is the time period during which a specific antibody develops and becomes detectable in the blood. After seroconversion has occurred, the disease can be detected in blood tests for the antibody 3. Asymptomatic HIV (about 8 years) 4. AIDS/infection/secondary infections (about 1.3 years) GOALS OF THERAPY Because currently available antiretroviral regimens cannot achieve eradication of HIV, goals of therapy primarily focus on sustained suppression of viral replication to undetectable levels: Achieve maximal suppression of viral load as long as possible Prevent the development of resistance and preserve future treatment options Preserve CD4 cells and strengthen the immune system Confer clinical benefits: decrease HIV related morbidity and mortality and improve QOL A CD4 count is a blood test to check the level of CD4 cells in your body. CD4 cells are a type of white blood cell that play an important role in your immune system. They’re also called T- cells. They alert other immune cells to the presence of viruses and bacteria in your body. Certain receptors on your CD4 cells make them prime targets for HIV. If you contract an HIV infection, the virus will attack your CD4 cells. This will cause the number of CD4 cells in your body to drop, weakening your immune system. A normal CD4 count ranges from 500–1,600 cells per cubic millimeter. GENERAL RULES OF THERAPY To maximize the benefits of ART, it is important to select drug regimens carefully based on: drug resistance testing (assays) pretreatment viral load (e.g., greater than or less than 100,000 copies/mL) adverse eﬀects convenience patient preference drug interaction profile pregnancy or pregnancy potential comorbidities cost. ART = antiretroviral therapy Because of the significant association between the presence of drug-resistant HIV and failure of antiretroviral treatment regimens, HIV resistance assays have become useful mechanisms for guiding the selection of appropriate therapy. Although guidelines exist for the combinations of agents to be used in ART, each patient must have a highly individualized regimen. TREATMENT OF HIV INFECTION HAART – highly active antiretroviral therapies Recommended initial therapy is comprised of two NRTIs (also known as the dual nucleoside “backbone”) plus a third drug, either a boosted PI or INSTI. WHO Recommended Regimens suggest that first-line HIV therapy be a combination of an NNRTI plus 2 NRTIs. —(1) Atripla (efavirenz + tenofovir disoproxil fumarate + emtricitabine) or (2) Sustiva (efavirenz) + Viread (tenofovir disoproxil fumarate) + Epivir (lamivudine). These two regimens are also those recommended for women who are pregnant or breastfeeding. Prognosis was poor in the pre-HAART era HAART is used = highly active antiretroviral therapy = multiple medications used at once. Medications regimens recommended by the World Health Organization (WHO) NRTI= Nucleoside reverse transcriptase inhibitor PI= Protease inhibitor NNRTI= Non-nucleoside reverse transcriptase inhibitor HIV therapy is also called antiretroviral therapy (ART) or highly active antiretroviral therapy (HAART). It consists of a combination of antiretroviral drugs (ARV) designed to keep the virus from spreading by targeting diﬀerent proteins or mechanisms the virus uses to replicate. Slowing the spread of HIV gives the immune system and CD4 count time to recover. A combination of at least three drugs is used to reduce the likelihood of the virus developing resistance to treatment. Start HIV therapy if CD4 counts fall below 350 cells per cubic millimeter. May begin therapy earlier if CD4 counts are as high as 500 cells per cubic millimeter but experiencing a rapid drop in your CD4 count or a high viral load. WHO Recommended Regimens The WHO guidelines suggest that first-line HIV therapy be a combination of an NNRTI plus 2 NRTIs. INDICATIONS FOR THE INITIATION OF ANTIRETROVIRAL THERAPY IN THE CHRONICALLY HIV-1 INFECTED PATIENT When considering treatment of patients with HIV infection, it is important to note that all patients, regardless of CD4+ count, should be oﬀered treatment with ART Symptomatic any CD4 and viral count = always treat Asymptomatic with CD4500 and >100,000 viral copies = some clinicians may consider treatment Asymptomatic CD4>500 and 3 weeks of daily dosing for response ADRs – minimal: dry mouth, irritated throat, unpleasant taste, headache Not for acute attack but do decrease frequency and intensity of attacks in general, including cold air and exercise-induced bronchospasm Okay for children > 5yrs Used oﬀ label. Label indications = mastocytosis, food allergies, IBD mainly eﬀective as a prophylaxis for allergic and exercise-induced asthma, not as a treatment for acute attacks, does not help with bronchospasm Aﬀect mast cell stabilization. Mast cells stimulate release of histamine, prostaglandins, and leukotrienes which leads to bronchospasm and inflammation. LEUKOTRIENE RECEPTOR ANTAGONISTS Antagonize eﬀects of Leukotrienes, which mediate: – airway edema – smooth muscle constriction – altered cellular activity Result in: – decreased inflammatory process – decreased frequency & severity of acute asthma attacks Oral agents, adjuncts to inhalers Leukotrienes use lipid signaling to convey information to either the cell producing them (autocrine signaling) or neighboring cells (paracrine signaling) in order to regulate immune responses. Leukotriene production is usually accompanied by the production of histamine and prostaglandins, which also act as inflammatory mediators One of their roles (specifically, leukotriene D4) is to trigger contractions in the smooth muscles lining the bronchioles; their overproduction is a major cause of inflammation in asthma and allergic rhinitis. Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes. Uses – long term control of asthma, in conjunction with meds considered first-line, often at night – many teens/adults prefer PO to inhaler, not BEST – may gradually decrease dose of inhaled corticosteroids – not eﬀective during acute asthma attacks – Ceiling eﬀect- what does this mean? Agents – monteleukast (Singulair), once daily HS, OK >1yr old (also available in granules) – zafirlukast (Accolate), BID dose, OK>5yrs old (administer on empty stomach, 1 hour before or 2 hours after meals) The ceiling eﬀect reflects the limit of some drug classes to product a particular eﬀect. Above a certain dosage no further increase in eﬀect is observed. Doses above those needed to produce the ceiling eﬀect usually cause other undesired, often toxic, drug eﬀects. AKA “peak eﬀect” METHYLXANTHINE AGENTS: OLDER THERAPY aminophylline theophylline Routes: oral or IV (rare; severe cases) Sometimes long-term or for night symptoms Not recommended for exacerbations Narrow therapeutic index- serum level monitoring is mandatory Many adverse eﬀects, elevated serum levels dangerous, rarely used now Action - phosphodiesterase inhibitors (enzyme that destroys cAMP) ADRs - nervousness, insomnia, HA, nausea Serum Levels – 5-15 mcg/mL Toxic levels - tremor, agitation, N/V, HA, tachycardia, seizures, death Used to be common in asthmatics, now replaced with inhalers in most patients IMMUNOMODULATORS Omalizumab (Xolair) an0-IgE Monoclonal antibody that selectively binds to human IgE on the surface of mast cells and basophils. Adjunct therapy for >12 years old with sensitivity to allergens (dust mite, cockroaches, cats, dogs) Severe persistent allergic asthma not controlled with inhaled corticosteroids Caution: Prescriber must be prepared to treat anaphylaxis- given subcutaneously Q 2-4 weeks in clinic with emergency equipment SC injection administered every 2 or 4 weeks Dose dependent on body weight and IgE level prior to therapy Pain and bruising at injection site in 5-20% of patients Pt teaching, after reconstituted must be used within 4 hours. Anaphylaxis in 0.2% of patients, must have meds and equipment available to Tx anaphylaxis, if needed Rare: Churg Strauss syndrome An autoimmune form of vasculitis showing eosinophilic granulomatosis with polyangiitis. Malignant neoplasms in 0.5% of treated pts compared with 0.2% receiving placebo (don’t know if statistically significant diﬀerence, but book notes that relationship to drug is unclear. Benralizumab (Fasenra); mepolizumab (Nucala) interleukin-5 antagonist Binds to interleukin-5 receptor, reducing eosinophil production and survival Adjunct therapy for >12 years old SC injection administered weekly for 3 doses (benra) or every 4 weeks (mepol) Severe persistent allergic asthma not controlled with inhaled corticosteroids Caution: Prescriber must be prepared to treat anaphylaxis- given in clinic with emergency equipment on hand Helminth infection SC (subcutaneous) injection administered weekly for 3 doses (weeks) Used for eosinophilic phenotype Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with NUCALA. Decreases in corticosteroid doses, if appropriate, should be gradual and under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. Hypersensiti

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