Stressors Requiring Medication Phases of Drug Action

Stressors Requiring Medication Phases of Drug Action
NUR101 Fall 2008 Lecture # 11 & 12 K. Burger, MSEd, MSN, RN, CNE PPP by Sharon Niggemeier RN, MS (J. Garnar & R. Kolk) Rev kburger06,07

Three Phases of Drug Action
I. PHARMACEUTICAL PHASE II. PHARMACOKINETIC PHASE III. PHARMACODYNAMIC PHASE A drug has go from its entry point to the tissues where it has to react Where it enters the body ..IM, PO etc to where it has to react For the drug to work, it must penetrate the cell Biotransport refers to the movement of drugs across biologic membranes Cell structure and molecular size of drugs effect the movement across the cell membrane.

I. PHARMACEUTICAL PHASE
A solid drug (tablet) has to disintegrate before it can be absorbed The process where a solid (tablet) goes into solution is known as dissolution ALL drugs must be in solution to cross biologic membranes All drugs must be in solution to cross biologic membranes This is the only way for a drug to reach its site of action

II. PHARMACOKINETIC PHASE
What the body does to the drug- refers to the study of how the body processes drugs It includes the 4 basic components of : 1# Absorption 2# Distribution 3# Metabolism (Biotransformation) 4# Excretion

#1 ABSORPTION Movement of a drug from the site of administration into the bloodstream. Absorption determines how long it takes for a drug to take effect. Usually the more rapid the absorption, faster the drug works Drugs can be absorbed through plasma membranes by various methods but primarily by: Diffusion (lipid soluble molecules) & Active transport (protein bound or water soluble molecules) Talking about Diffusion: Concentration gradient - the driving force of passive diffusion. The larger the difference in concentration of drug on the two sides of the membrane, the faster the drug will move from the area of greater concentration to that of low concentration. The extent of blood flow to the absorptive site is important in maintaining the concentration gradient, since it carries away the newly absorbed Active transport: requires energy as molecules have to move against the concentration gradient Plasma membranes are lipophilic (lipid layers interspersed with proteins & other molecules) Lipophilic membranes are mostly impermeable to large molecules, ions and water soluble molecules. Therefore: small, lipid soluble, nonionized drug molecules will pass more readily through plasma membranes

Factors Affecting Absorption
Surface area Contact time with surface Circulation Solubility (water soluble vs lipid soluble) Ionization (weak versus strong acid/base) Drug form & drug concentration Bioavailability ( after first pass thru liver) Route of administration (enteral & parenteral) Greater the surface area faster the drug will work Longer the drug is in contact with surface area the greater the Bioavailability Circulation- blood flow to the area enhances drug absorption. Drugs placed directly into the blood stream (IV) are totally available for absorption. Solubility - Remember in order to work, a drug must be soluble in body fluids. The more lipid soluble a drug is, the faster it will cross biologic membranes. Water-soluble drugs cross biologic membranes slowly or not at all and may stay in the intestine or in the blood stream. Ionization - An ion is a molecule with an electrical charge. Most drugs are either weak acids or weak bases and can exist in either an ionized or nonionized form depending on the pH. Nonionized drugs are more lipid soluble and readily cross biologic membranes. Drug dosage form-Liquids (suspensions, elixirs) are readily available for absorption because they are already in solution. Solids must first disintegrate and dissolve before absorption can occur. Drug concentration- higher concentrations of drugs are absorbed more rapidly than drugs given at lower concentrations. Bioavailability – readiness to produce a drug effect. It is a percentage of active drug absorbed and available to the target tissue. Intravenous drugs are 100% available. Many antibiotics are given by this route to obtain maximum effect. Drugs given by other routes vary in Bioavailability. Bioavailability affects the : a. time of onset of drug effect.- how long before drug begins to work b. the time and magnitude of peak effect – when it reaches maximum level c. the duration of effect – how long drug response will last Bioavailability – readiness to produce a drug effect. It is a percentage of active drug absorbed and available to the target tissue. Routes of administration- the place in the body where absorption occurs will alter the process of absorption. Two major routes are enteral and parenteral: Routes of administration- the place in the body where absorption occurs will alter the process of absorption. Two major routes are enteral and parenteral:discuss later Routes of administration- the place in the body where absorption occurs will alter the process of absorption. Two major routes are enteral and parenteral:

Additives: alter the location of disintegration of drugs as well as increase or decrease the rate of absorption Enteric coating allows a drug to dissolve only in an alkaline (pH greater than 7.0) environment such as the small intestine. Sustained release drugs:allow drugs to be released slowly over time, rather than quickly, like conventional tablets. SR, LA Size of drug particles: smaller the particle, faster the onset. Ex: The generic drug Glyburide has trade names Micronase and Glynase. Glynase (micronized) onset is faster than Micronase (non-micronized) Manufacturers manipulate the dissolution of drugs to modify solubility characteristics Enteric:This type of drug won’t disintegrate and dissolve in the stomach. Therefore, this type of drug should never be crushed to administer it. Sustained: come in various forms These alterations can aid in disintegration and dissolution of drugs

Drug Absorption varies by form
Liquids, elixirs, syrups Fastest Suspension solutions ê Powders ê Capsules ê Tablets ê Coated tablets ê Enteric-coated tablets Slowest

Look at your Lasix Drug Guide
Is this drug available in more than one form? Which will have the fastest absorption? What is the absorption rate for the oral tablet form?

Absorption:ENTERAL ROUTES
Mucous membranes of the mouth: Buccal or Sublingual forms of drugs Highly vascular absorbing surface Avoids first pass phenomenon that occurs in the liver Absorptive area is small therefore… Only small amounts of drugs can be given

Absorption: ENTERAL ROUTES
Oral Route: Stomach Has low pH (about 1.4) the rate of gastric emptying & pH changes will affect how fast or how slow meds are absorbed. Has rich blood supply Susceptible to first pass phenomenon Lipid soluble substances and those that are relatively nonionized are well absorbed here. Drugs are best absorbed in an empty stomach and taken with a full glass of water, as this allows dissolution of the drug before passing to the small intestine for further absorption. Ø Stomach is not a significant absorption site unless the drug has characteristics allowing rapid absorption. Slowed gastric emptying time slows absorption of drugs that are better absorbed in the intestine.

CONSIDER THIS… Alcohol is extremely lipid soluble
Aspirin is a very weak acid Both are well absorbed in the stomach.

Oral Route: Small Intestines Most important site for absorption of oral drugs as it has extensive absorptive surface due to many villi. Peristalsis and mixing encourage dissolution of drugs. Highly vascular and has a pH of 7.0 to 8.0 In what way do these characteristics influence absorption? Ø Many drugs are susceptible to the first pass phenomenon in the liver. Ø Diarrhea will decrease the level of drug absorption. Why? In what way will diarrhea affect absorption? Why?

Mucus Membranes of the Lower Intestine: Rectal Route Avoids most first pass effects in the liver Has extensive vascularity. Limited surface area Drugs need to be in solution or absorption is erratic and unpredictable.

Absorption: Other Routes
PULMONARY: Lungs Gases or aerosols can be delivered by this route. Rapid absorption occurs due to large surface area, rich blood supply and high permeability of the alveolar membrane. Provides a local effect ( ex: bronchodilation ), but may also produce unwanted systemic effects ( ex: sympathetic nervous system stimulation) Local effect usually desired but may see systemic effects as well. A limited number of emergency drugs can be given by this route in extreme emergencies when no IV exists. Intra nasal – may provide local or systemic affect.

TOPICAL ROUTE: Epidermis is low in lipid and water content, so it is a barrier to absorption. Dermis allows rapid absorption therefore: Abraded skin could allow an overdose of the drug so only use intact skin. Effects are usually local Lipid soluble drugs can penetrate lipid by-layers of the epidermal cells. An occlusive dressing improves absorption as with nitroglycerin paste. Massage to the area or having the drug in an oily base will also increase absorption. Only lipid soluble drugs can be absorbed and application to a large area increases absorption.

Critical Thinking Questions
A client has an order for Benadryl ointment for an itchy rash on his arms. To promote absorption of the drug, the nurse should: Apply an ice pack to the arms after application Wash the area with mild soap and water before applying the ointment Wear sterile gloves before applying the ointment Ask the client to walk around the room after the application.

Transdermal: A disk or patch containing a days or weeks medication-Absorbed at a steady rate Eyes - produces a local effect. Instruct patient to put pressure on the side of the nose after placing drops to decrease possibility of systemic effect. Ears - used for local treatment of infection or wax How should you position a client after instilling ear drops? Nasal mucosa - instilled in droplet form or by swab for local or systemic effect.

Absorption:PARENTERAL
intravenous subcutaneous intramuscular intradermal intraarticular - synovial cavity intrathecal - spinal subarachnoid space or epidural space intraperitoneal Direct access to the site of activity occurs by injection: REMEMBER – Parenteral meds retain 100% bioavailability THEREFORE smaller doses are appropriate

Absorption: PARENTERAL
Subcutaneous and intramuscular injections are affected by tissue composition Intramuscular route is more effective than the subcutaneous route because there is a greater blood supply in muscle tissue. Application of heat or massage can increase vasodilation and improve absorption Composition of the drug solution (i.e. oily or aqueous) and solubility in interstitial tissue Quality of the connective tissue Circulation to the area. Effects of Age on Absorption 1. Neonate Gastric emptying time is two to three times slower, with irregular and unpredictable peristalsis. Gastric acid production is lower in children under three. Skin and conjunctiva are more permeable and increase the risk for systemic absorption. Premature infants have small muscle mass and compromised perfusion, so irregular and unpredictable absorption occurs from intramuscular sites. 2. Gerian/Older adult There is a decrease in gastric acid production, with an increase in pH. (less acid) The small intestine has a 30% reduction in absorptive surface and reduced motility. Since contact time increases, absorption may still maintain normal levels. The intestinal blood flow is reduced 50 to 60%. How would the higher pH of the stomach in the older adult affect the rate of absorption of drugs? (Explain in relation to ionized state)

Critical Thinking Case
Mr. L. is admitted to the trauma unit with multisystem injuries from an automobile accident. He arrived at the unit with multiple abnormal findings, including shock, decreased cardiac output, and urinary output of less than 30 mL/hr. Which route of administration would be indicated for any medications for this patient? Explain your reasoning.

#2 Distribution Distribution: the transport of drugs from the blood to the site of action. A drug must be distributed to its site of action to have an effect Drugs are also distributed to tissues where it has no effect. Competition for drug binding sites affects the amount of drug available for action in the body.

Factors Affecting Distribution
Volume of Distribution (Vd) - The degree of distribution of a drug into various body compartments and tissue Cardiac output and capillary permeability affect the regional blood flow, perfusion of tissues and therefore the volume of distribution Vd is a determinant for drug dosage. Drugs that are lipid soluble and highly tissue bound have a high Vd and a low serum level. Drugs that are water soluble have a low Vd and a high serum level. Volume of distribution (Vd) affects duration of drug action, since drugs with a large Vd are less frequently exposed to sites of elimination and require less frequent dosing. Well perfused tissues such as kidney, liver, heart and brain have a rapid uptake of drugs, the drug is distributed here first. Adipose and muscle tissue are poorly perfused, drug uptake is slower so the drug reaches these areas later.

Plasma Protein Binding - drugs bind to proteins in the blood (albumin, globulins) in varying degrees, from highly bound to poorly bound Protein binding decreases the concentration of free drug in circulation therefore there is a limited amount of drug available to travel to the site of action. Only free drug is able to diffuse into tissues. Only free drug is able to diffuse into tissues, interact with receptors, and produce biological effects. Bound drugs are pharmacologically inactive. . Only free drug is able to diffuse into tissues, interact with receptors, and produce biological effects. Bound drugs are pharmacologically inactive. 2. When free drug is eliminated by the body some of the bound drug is released from the protein binding, which thus functions as a storage (reservoir) mechanism. Some drugs persist in the body for three days by this mechanism. 3. When two drugs given concurrently have small volumes of distribution and are highly bound to the same site on a plasma protein; these drugs will compete for the binding site resulting in a greater proportion of free drug. This effect may increase the free drug to toxic levels. Great care must be taken to avoid this type of drug interaction. Note that eventually the body compensates for excess free drug by increasing the rate of metabolism and excretion of the displaced drugs. Therefore, the most critical period of assessment is during the first few days of adding the drug to the regimen. 4. Drugs that have a very high level of protein binding create the highest risk for the patient to develop a toxic reaction. Example:Coumadin is 98% protein bound

Plasma Protein Binding Continued
When free drug is eliminated by the body some bound drug is released from protein binding. Some drugs persist in the body for three days by this mechanism. (2) drugs given concurrently & highly bound to the same site on a plasma protein will compete for the binding site resulting in a greater proportion of free drug. This effect may increase the free drug to toxic levels. Most crucial time for (2) similarly binding drugs is during 1st 3 days. After this time, the body adjusts it metabolism of the drug and begins to excrete more of free drug.

Critical Thinking What effect would an albumin level of 2.8 have on distribution? What should the nurse be alert to happening ?

Tissue Binding/Affinity: force by which atoms are held together in chemical compounds Lipid soluble drugs have a high affinity for fat tissue and this is where these drugs are stored. Drugs can be held in reservoirs such as adipose tissue or bone. What effect might sudden weight loss or starvation have on a client taking lipid soluble drugs? Obese persons can accumulate a large store of lipid soluble drugs, such as diazepam. 3. Sudden weight loss or starvation would result in the release of the accumulated drug into the blood stream, with resultant toxicity. 4. Cumulation If a drug’s rate of loss from the body is less than the rate of absorption into the blood stream, serum drug levels will continue to rise gradually. The phenomenon is called the cumulative effects

Blood Brain Barrier - The structure of brain capillaries are less permeable than other body capillaries. Most drugs can’t pass this blood brain barrier. This protects the brain from the harmful effects of many drugs. Drugs that DO cross are highly lipid soluble. ( Ex: phenytoin, antidepressants, caffeine, nicotine ) What other substance did we talk about that is highly lipid soluble???????? Placenta: the placental membrane is lipid in nature and readily allows non-ionized, lipid soluble drugs to cross the membrane. The use of many drugs has resulted in teratogenic effects on the developing fetus Elderly patient has less effective blood-brain barrier, so symptoms of dizziness and lightheadedness are more common as side effects to many drugs when taken by the elderly client. Drugs which do cross the blood brain barrier are drugs with: high lipid solubility and minimal plasma protein binding. . Phenytoin, cortisone, streptomycin and antineoplastic drugs are a few examples of drugs that can cause damage. Alcohol and nicotine should be avoided during pregnancy.

CONSIDER THIS… The elderly have less effective blood-brain barriers.
Symptoms of dizziness and lightheadedness are more common as side effects to many drugs taken by the elderly.

What is the site of action for distribution? What does it have to say about the drug’s distribution properties? Is this drug highly protein bound? What does this mean in regards to distribution?

# METABOLISM Biotransformation: process by which the body changes the chemical structure of a drug to another form called a metabolite. Metabolite: a more water soluble compound that can be easily excreted. The major organ for this process is the liver Some water soluble drugs can be excreted by the kidneys in unchanged form. 2. If fat soluble drugs were not metabolized to more easily excreted forms, they could stay in the body for years. 3. Biotransformation does not necessarily yield a compound without pharmacological activity, but generally results in one that is less fat soluble and, as a result, more easily excreted. 4. Drugs exposed to liver biotransformation may be eliminated from the body before the opportunity to be exposed to tissue sites of action. (First pass phenomenon) Presystemic Metabolism - gastrointestinal acid and enzymes, bacterial action, and enzymes in the wall of the intestine are all potential sites of metabolism of drugs before they can be absorbed. Hepatic Microsomal Enzyme System - an important class of liver enzymes responsible for the metabolism of many chemicals, including drugs, insecticides, food additives and chemical pollutants.

METABOLISM (BIOTRANSFORMATION)
First Pass Phenomenon - Drugs are first absorbed through the small intestine than arrive at the liver via the portal circulation There they undergo considerable biotransformation before entering the systemic circulation. There will be less active drug available for action in the body cells after this first Pass through the Liver ! These drugs require much larger doses of oral drugs than parenteral doses to achieve the same effect

Consider this… Enzymes within the liver called cytochromes metabolize lipid soluble drugs. People with liver disease have a reduced amount of cytochromes What will the overall effect then be??

Variations in Metabolism
Pharmacogenetics - hereditary influences on drug responses, refers to variations in which individuals metabolize drugs. Remember our discussion of Acetylator Rates? Circadian Rhythms - the rate of drug absorption, hepatic clearance, half-life and duration of action, have all been shown to differ depending upon the time of day a drug is administered. Effects of Gender and Age – BMR differences GERIATRIC CHGS Much of drug rhythmicity is probably related to hormone cycles, especially the adrenal hormones. b. Corticosteroids are best given in the morning to simulate normal circadian cycles. Hepatic drug metabolizing activity seems highest when plasma cortisol levels are lowest (6 P.M. to 6 A.M.) Effect of Gender and Age Ø Neonate - Prolonged half life occurs due to decreased activity of liver enzymes in the immature liver. This changes rapidly during the first month of life and necessitates frequent dose adjustments. Ø Older children metabolize drugs faster, resulting in a shorter half-life. Some drugs may require higher doses for body weight and shorter dose intervals. Ø Gerian - Several changes in liver function occur: a. Blood flow is reduced 40 to 50% by age 60. b. Microsomal enzymes are somewhat impaired do drugs are less prone to enzyme induction. c. Initial doses of drugs affected by enzyme induction should be reduced to one-half to two-thirds the usual dose.

#4 Excretion Excretion: process where drugs are removed from the body. Kidneys are the major organs of excretion. Lungs excrete gaseous drugs. Biliary excretion (bile & feces) is important for a few drugs. These drugs may be reabsorbed when passing through the intestines from the liver ( enterohepatic re-circulation ). Intestines, sweat, saliva and breast milk constitute minor routes of drug excretion. Kidneys:. Most drugs or their metabolites are excreted by glomerular filtration. Lungs: Anesthetics such as gases and volatile liquids are usually eliminated through the lungs. Biliary excretion:. A drug secreted by the bile and reabsorbed to the liver is said to undergo enterohepatic circulation. Breast milk: Since breast milk has a pH of 6.5, basic drugs such as narcotics achieve a high concentration in this fluid Encourage the post-partum mother to minimize use of narcotics, while maintaining appropriate pain relief. Neonate a. Glomerular filtration is only 30 to 40% and tubular secretion 20 to 30% of adult values when adjusted for body surface area. By 6 to 12 months the rates are the same as adults. b. Prolonged half lives have been identified for renally excreted drugs. Gerian a. There is a 50% decline in renal function between the ages of 20 and 70. b. Dosage reduction is recommended for those drugs whose major mode of elimination is through the kidney. Disease a. Renal impairment, as evidenced by the creatinine clearance test, will require dosage adjustment. b. Biliary or hepatic disease will impair biliary excretion. The course over which a drug is absorbed, distributed, biotransformed, and excreted affects the concentration of the drug in the body, which in turn effects, its therapeutic response. Age, disease, genetic factors, presence of other drugs, and changes in nutrition and hydration also affects Pharmacokinetics.

Excretion Clearance of drugs - elimination of drugs from circulation by all routes. It affects the time a drug remains in the body and the dosage required. Renal Clearance Hepatic clearance Renal clearance is clearance of the drug by the kidney A useful measure of renal function is the creatinine clearance test. Hepatic clearance occurs by biotransformation of the drug to one metabolite or by excretion in the bile. This prolongs the duration of action of the drug.

PLASMA HALF-LIFE The amount of time a drug stays in the body is measured by the elimination half-life. This is the time required for the concentration of drug in the blood to decrease by 50%. Half-life affects the frequency of administration Drugs with short half-lives are quickly eliminated from the body. ( Ex: PCN given several X per day ) Drugs with longer half-lives stay in the body longer (Ex: Digoxin given once a day ) The half-life is important as it can provide information on how the drug is being distributed, and how quickly it is being eliminated. Drugs with short half –lives are quickly eliminated from the body while drugs with longer half-lives stay in the body longer.

Look at your LASIX drug guide
What is the half-life of this drug? What does that mean in regards to dosing? Look at the Route/Dosage for the IV route for adults. What correlation can you make between the instructions there and the drugs half-life’s Time Action Profile?

III. PHARMACODYNAMIC PHASE
What a drug does to the body- refers to the study of the mechanism of drug action on living tissue. Drugs may increase, decrease or replace enzymes, hormones or body metabolic functions. Chemotherapeutic drugs alter an abnormal parasite or growth on the body such as bacteria, viruses or neoplastic tissue. examples: antibiotics and antineoplastic drugs. Pharmacodynamic drugs are capable of changing the normal physiologic function of the body. examples: slowing the heart rate, increasing urinary output. Drugs can only alter an existing function, they cannot create new responses. Drugs exert multiple effects on the body. Drugs act on a biochemical level to alter the normal physiologic function of the organism

THEORY OF DRUG-RECEPTOR INTERACTIONS
The majority of drugs are believed to exert their effects by combining with a specialized area on the cell or within the cell called receptors. Drug + Receptor  Drug receptor (binding) = Response A drug receptor may be on the cell surface or within the cell Receptors come in many shapes that are specific for particular drugs. The greater the degree of specificity and selectivity for receptors, the fewer undesirable side effects and the greater drug efficacy. Receptors may be a portion of cell membrane, a transport protein, a structural protein, an enzyme that is inhibited by drugs, or the nucleic acid of a cell. Receptors come in many shapes that are specific for particular drugs Receptors don’t exist in the body merely to bind drugs rather, their normal function is to bind endogenous molecules such as hormones, neurotransmitters etc.

Types of Drug-Receptor Interactions
Agonists: Drug that has the ability to produce a desired therapeutic effect when bound to the receptor. Antagonists: Drugs that bind well to the receptor but produce no receptor response. This can prevent other drugs from having an effect, thus they are called blockers. Agonists-produce the same response as the receptor it binds to. Antagonists- drug occupies a receptor and prevents the endogenous chemical from reacting. They compete with agonists for receptor sites.

Consider This… Bronchodilators (ie: albuterol ) used for asthma attacks are classified as beta-agonists. They attach to adrenergic receptors in the sympathetic nervous system (SNS) and mimic the action of norepinephrine. Adrenergic antagonists such as beta-blockers (ie: atenolol) attach to the adrenergic receptors in the SNS and block the action of norepinephrine

Types of Drug-Receptor Interactions
Competitive antagonist: agonist drug and antagonist drug are each competing for the same site. The drug present in the greatest number will get bound. Therefore a higher dose of agonist is required to overcome this response This capability can be used when an antidote is needed for certain drugs. Example: Narcon and narcotics: Narcon’s action at the receptor site is as a blocker to receptors for the narcotic already in the person’s system. The blocking action thus serves to decrease the effect of the narcotic as long as the Narcon remains active at the receptor site. Noncompetitive antagonist: inactivates the receptor by binding irreversibly with it. The drug with agonist action cannot get to the receptor site at all. A noncompetitive antagonist can be used therapeutically by blocking a natural body substance such as dopamine when there is too much dopamine being produced. Reversibility: With few exceptions, drug-receptor binding is reversible. When the drug is bound to the receptor, the process is called association. When the drug separates from the receptor, it is called dissociation. The association and dissociation rates are not necessarily equal. If the rate of association is much greater than the rate of dissociation, then the drug binds to the receptor with high affinity. Saturability: Drug receptor binding is saturable; this occurs when all available receptors are occupied. Not all receptors of a particular cell need to be occupied in order for a drug effect to occur. Potent drugs may be effective at very low concentrations, occupying only a fraction of the receptors. Once receptors are saturated, increasing the drug concentration will increase the risk of adverse drug effects.

Saturability Drug receptor binding is saturable
This occurs when all available receptors are occupied Once all available receptors are saturated, increasing the drug concentration WILL NOT increase therapeutic effect but it WILL increase the risk of adverse side effects

Other Ways Drugs Work Enzyme Interaction Some drugs bind to enzymes and block their action on cells ( ie ACE inhibitor) Non-specific Interactions No receptor action. Some drugs (ie antibiotics) get into bacteria cells and interrupt their cell processes leading to cell death

Time Course of Drug Action
The frequency and duration of drug dosing can influence the safety and efficacy of drug therapy. Unless a drug is administered by a continuous infusion, variations will occur in the level of drug in the body.

Onset of drug action is the time it takes after the drug is administered to reach a concentration that produces a response. Duration of action is the time during which the drug is present in a concentration large enough to produce a response. Peak effect is the time it takes for the drug to reach its highest effective action. Onset: There is a threshold for each drug induced response. Doses of drugs below that threshold will produce no observable effect

What is the onset time for the PO route? Compare this to the onset for IV. If you gave your client 40mg of 10am PO, when would you expect the greatest amount of diuresis?

Trough level will occur immediately before a drug is given, or once sufficient drug is eliminated. This is the lowest point of drug concentration Plasma blood levels may be taken for peak and trough levels. The drug must be administered precisely as ordered and a blood sample must be taken just before the next drug dose is scheduled for an accurate trough level. To maintain a steady level give q12h not 10a and 6pm

Consider this… Certain drugs, such as aminoglycoside antibiotics ( Gentamycin ) are extremely ototoxic and nephrotoxic and are administered once daily. It is the responsibility of the nurse administering these medications to utilize therapeutic drug monitoring procedures Check trough levels hrs after previous dose for a < 1mcg/ml level ( or previously set # from MD / Lab / Pharmacy)

Therapeutic Responses
Toxicity studies of drugs determine two dosage levels for drugs. The effective dose is the dose of a drug necessary to produce the desired intensity of effect in one-half of all patients. The lethal dose is the dose of a drug that elicits an undesirable toxic or lethal reaction in one-half of all patients.

Therapeutic Index A drug with a wide therapeutic index has a high safety margin and is relatively safe; the lethal dose is greatly in excess of the therapeutic dose. A drug with a narrow therapeutic index is more dangerous for the patient because small increases over normal doses may induce toxic reactions. Peak and trough levels may need to be monitored The relative safety of a drug can be expressed by its therapeutic index. Dose and plasma concentrations must be carefully adjusted.

Do you think the therapeutic index of Lasix is high or low? Explain your answer.

Maintenance dose: intermittent doses given to maintain plasma levels.
Therapeutic range: plasma drug concentration between minimum and toxic concentrations. Loading doses: higher amount of drug given once or twice to achieve maximum effective dose quickly Maintenance dose: intermittent doses given to maintain plasma levels. Minimum concentration: amount of drug needed to produce a therapeutic effect. Toxic concentration is level of drug that results in serious adverse effects Therapeutic range-can be wide or quite narrow. Loading dose- induces a quick response.

Back to our Case Study The 72 y.o. client with hypertension was prescribed 40 mg of Lasix p.o. b.i.d. Would you say this is a maintenance dose? Why or why not? What is the highest loading dose you see in your Lasix drug guide for the p.o. route. Why didn’t the MD order this dosage?

Adverse Drug Event (ADE)
General broad term that describes any adverse outcome to medication administration. Can be due to: staff error (preventable) OR Can be an adverse drug reaction (non-preventable)

ADVERSE DRUG REACTIONS (ADR)
Unintended, undesirable or unpredictable drug effects. More than 50% of adverse reactions occur from drug-drug, drug-food, or drug-laboratory test interactions.

ADR Adverse Effects: are unwanted and/or unintended action that may occur during drug therapy. Every drug has the potential to produce adverse effects. Side Effects: Undesirable but mild unavoidable/predictable pharmacological effects of a drug. Adverse-

ADR Toxic Effects: More serious effect. Life threatening. Each drug has characteristic toxic effects. May be due to the accumulation of the drug in the body r/t decreased renal function Teratogenic Effects: Drug induced birth defects which follow drug therapy in pregnant women.

Are there any toxic LIFE THREATENING side effects to Lasix therapy? What are the most common side effects?

Drug Interactions Occur when 1 drug and a 2nd drug or element such as food may have an effect on each other. These interactions may ↑ or ↓ the therapeutic effect of 1 or both drugs, create a new effect or ↑ incidence of adverse effects

Drug Interactions Additive effects: 2 or more “similar effect” drugs are combined. The result equals the sum of the individual agents Each drug is given in a lower dose for an equal effect of either drug given separately. =2. Ex: Percodan ( oxycodone + acetominophen) improves pain relief Synergism: The harmonious action of two “unlike” drugs producing an effect which is greater than the total effects of each drug acting by itself =3. Ex: Advicor ( niacin + statin drugs) improves lipid lowering action.

Drug Interactions Potentiation: One drug improves the performance of the other drug. This is a particular type of synergistic effect ½ + 1 = 2 Ex: amoxicillen + probenecid (anti-gout) prolongs serum levels of the antibiotic Idiosyncratic Reactions: Unusual, unexpected reactions to a drug, which may be genetically caused. Sometimes the person will react with the opposite effect to the desired one. (Also called paradoxical reaction) Ex: Genetic G6PD enzyme deficiency (prevents RBC hemolysis) idiosyncratic reactions to ASA, sulfonamides (African American and Kurdish Jewish populations)

Our Case Study Our 72 y.o. client has developed pneumonia and a DVT as complications from his immobility while hospitalized. The MD has ordered Gentamicin IVPB ( an aminoglycoside antibiotic ) and Heparin (an anticoagulant). What type of drug interactions should the nurse be alert to in conjunction with his Lasix therapy?

Case Study - continued The oral Lasix that our client is taking is not producing the desirable effect, and the MD orders a STAT dose of Lasix 40 mg IV. You prepare to inject this into the client’s IV line, but see that the Gentamicin previously ordered is currently infusing. Is it OK to proceed with giving the Lasix IV? Why of why not?

Allergic Reactions Increased reactions with repeated exposure to the drug. Hypersensitivity reactions are exaggerated in response to a drug. Anaphylaxis: A systemic reaction, the most severe of all the allergic reactions. (edema of airways, severe hypotension, cardiac arrhythmia, death) Allergic reactions:Allergic reactions vary widely and are not predictable or dose related. Anaphylaxis also dyspnea and chest painIgE antibodies combine with the antigen to release histamine. This causes a severe, acute, allergic reaction marked by hypotension, sudden contraction of the bronchiolar muscles and edema of the mouth and throat with bronchospasm, vasospasm, severe hypotension, cardiac arrhythmia, C.V., collapse, possible death.

Case Study After starting a new IV line, you administer the Lasix IV. The client almost immediately begins to experience an anaphylatic type reaction. He did not report any past allergies to Lasix, but he is allergic to “sulfa drugs”. Should this information have impacted your administration of the Lasix? Was this a preventable, predictable drug reaction? Was it a medication error?

Nursing Considerations
Take a careful drug history Know what interactions to anticipate Identify the drug reaction by monitoring the patient response to the drug. Educate the patient and the family re the risks and benefits of the drug. Document any drug reactions clearly and specifically Earliest signs of a problem call MD>

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