amount of active drugs - - - increase recommended dose for oral drugs Lidocaine extensive 1st pass not given

en orally o Plasma o Kidneys o Membranes of intestine yProcess by which body changes a drug from its dosage form to a more watersoluble form that can then be excreted yCan be metabolized in several ways: o Most drugs metabolized into inactive metabolites (products of metabolism), which are then excreted o Other drugs converted to active metabolites capable of exerting their own pharmacologic action May undergo further metabolism or may be excreted from body unchanged Prodrugs some drugs administered as inactive drugs which dont become active until theyre metabolized o Permits the body to inactive a potent drug before it accumulates & produces toxic effects yPhases of drug metabolism: o Phase 1: endoplasmic reticulum; introduce/expose a functional group on the parent compound (i.e. alkylation, alipathic hydroxylation, oxidation, deamination, hydrolysis, microsomal oxidases) Cytochrome p450 inducer inc drug metabolism, dec Bioavailability Cytochrome p450 inhibitor dec drug metabolism, inc levels of drug prolonged effect & inc toxicity o Phase 2 conjugation reactions that lead to formation of covalent linkage between parent compound with glucoronic acid, sulfate, glutathione or acetate (glucoronidation, sulfation, acetylation); synthetic reactions yFactors affecting biotransformation: o Genetic some people metabolize drugs rapidly, other more slowly o Physiologic Liver diseases (cirrhosis), heart failure dec circulation in liver Infants immature livers dec rate of metabolism o Area of absorbing surface to which a drug is exposed (+) chemical agents may destroy the drug

o Types of transport diffusion, active, pinocytosis o Routes of administration skin absorption slower than IM Absorption with in seconds/minutes: sublingual, IV, by inhalation route Slower rate absorption: oral, IM SC routes o Bioavailability consideration of highest importance in drug effectiveness & safety Subcategory of absorption % of administered drug does that reaches systemic circulation Oral route <100%(usually 20-40%); IV route = 100% Factors that alter bioavailability: yDrug form (tablet, capsule) yRoute of administration yGI mucosa & motility yFood & other drugs (+) food - - - pord of gastric acid inc drug absorption (i.e. azole) yChanges inliver metabolism, liver disorder dec liver function inc bioavailability II. distribution process by which drug becomes available to body fluids & tissues the ways a drug is transported from the site of administration to the site of action (transportation) factors affecting distribution: o size of the organ o blood flows drug is quickly distributed to organs with large supply of blood (heart, liver, kidneys) distribution to other internal organs, skin, fat, muscle is slower o solubility lipid soluble drugs can also cross the blood-brain barrier & enter the brain o Binding as drug travels trough the body, it comes in contract with proteins (albumin). The drug can remain free or bind to protein. Portion of drug bound to protein is inactive, no therapeutic affect Free/unbound portion active - - - - (+) pharmacologic response Highly protein bound drug - > 89% of drug is bound to protein yDiazepam, piroxicam, valproic acid Moderately highly protein bound drugs (61-89% bound protein) yErythromycin, phenytoin Moderately protein bound drugs 30-60% yAspirin, lidocaine, pindolol, theophyliine Low protein-bound drugs - < 30% bound to protein (amikacin, amoxicillin)

DISTRIBUTION BLOOD FLOW PROTEINBINDING BODY TISSUE AFFINITY PHARMACOLOGIC EFFECT Elderlies dec liver size, blppd flow, enzyme production - - - slows metabolism Environment cigarette smoke may affect rate of some drugs o Stressful environment prolonged illness, surgery, injury III. Excretion/elimination removal of drug from the body: drug is changed into inactive form & excreted by the body Routes: o Kidney main organ for drug elimination: leaves the body through urine Free/unbound/water soluble drugs filtered in kidney Protein bound drug cannot be filtered in kidney (+) kidney dose dose must be decreased o Lungs, exocrine (sweat, salivary, mammary) glands, skin, intestinal tract Factors affecting drug excretion o Urine ph normal: 4-5.8 Acid urine promotes elimination of weak base drugs yi.e. cranberry juice dec urine ph - - - (-) elimination of aspirin alkaline urine (+) elimination of weak acid drug yoverdose aspirin - - - give Nabicarbonate inc urine ph - - - (+) excretion of drug o glomerular filtration rate (GFR) dec GFR - - - drug excretion slowed/impaired can result to drug accumulation extent of filtration directly proportional to GFR & to fraction of unbound drug to plasma yratio of clearance = fu x GFR - - - cleared by filtration yratio of clearance < fu x GFR - - - cleared tubular reabsorption yratio of clearance > fu x GFR - - - cleared by tubular Secretion o creatinine clearance most accurate test to determine renal function creatinine excreted in kidney dec renal GFR inc serum creatinine level & dec urine creatinine clearance 12-24 hrs urine collection & blood sample Normal 85-135 ml/min; elderly 60ml/min Renal clearance amount of substance removed from the blood by the kidneys Half-life/elimination half-life (t ) time it takes for one half of drug concentration to be eliminated o Short t = 4-8 hrs: given several times a day (i.e. penicillin G) o Long t = > 12 hrs: given 2x or 1x / day (digoxin) II. PHARMACODYNAMICS refers to action of drug to the body What happens to the body in response to the drug

Effects of drugs on the cells biological & physiological functions & mechanisms of action Interactions between chemical components of living systems & foreign chemicals including drugs that enter these system Mechanism of action: means by which a drug produces alteration in function of their action Drug actions: a. To replace/act as substitute for missing chemicals b. To inc or stimulate certain cellular activities c. To depress/slow cellular activities d. To interfere with functioning of foreign cells (i.e. invading microorganisms/neoplasms) chemotherapeutic Agents Theories of Drug Actions a. Drug-receptors interaction certain portion of drug molecule (active site) selective combines with some molecular structure (reactive site) on the cell to produce a biologic effect Receptor site drugs act at specific areas on cedil memb.; react with certain chemicals to cause an effect with in cell lock & key theory specific chemical (key) approaches a cell membrane & finds a perfect fit (the lock) at receptor site affects enzymes system within a cell produce certain effects Specificity selectivity theory Drug action may be: yAgonists drugs that produce a response o insulin reacts with specific insulin receptor site to change cell membrane permeability - - - (+) movement of glucose into cell ycompetitive antagonist act with receptor sites to block normal stimulation producing no effect o curare use on spear in Amazon to paralyze prey & cause death: occupies receptor sites for Acetylcholine (needed in muscle contraction & movement) - - - prevents nerve stimulation causing paralusis o noncompetitive antagonist - prevent reaction of another chemical with different receptor site on that cell b. drug-enzymes interaction interferes with enzyme systems that act as catalyst from various chemical reations enzyme systems cascade effect; one enzyme activatinganother - - - causing cellular reaction if single step in one of enzyme system is blocked normal cellfunction is disrupted ex: acetazolamide (diamox) diuretic that block carbonic anhydrase alters H+ & H2O exchange systems in kidneys & eye c. nonspecific drug interaction act by biophysical means that do not affect cellular enzymatic reactions d. selective toxicity all chemotherapeutic agent would act only on 1 enzyme system needed for life of a pathogen or neoplastic cell & will nor affect healthy cells ex: penicillin

unfortunately most of it cause destruction of normal human Cells Drug response may be: 1. primary always desirable / physiologic effects 2. secondary desirable or undesirable ex: diphenhydramine (benadryl) 1st effect: antihistamine, treat symptoms of allergy; 2: CNS depression - - - drowsiness desirable: when given at bedtime: undesirable: when client is driving Classification of drug action: 1. rapid few seconds to minutes (IV, SL, inhalation) 2. intermediate 1-2 hrs after administration (IM, SC) 3. Delayed/slow several hrs after administration (rectal, oral) Parameters of Drug Action: 1. onset of action latent period: interval between time drug is administered & 1st sign of its effect ytime it takes to reach the minimum effective concentration (MEC) after a drug is administered ytime from drug administration to 1st observable effect _T0 T1) 2. duration of action period from onset until drug effect is no longer seen ylength of time the drug exerts pharmacologic effect (T1 T3) 3. peak action drug reaches its highest blood / plasma concentration (T0 T2) Termination of action point from onset at which drug effect is no longer seen Minimal effective concentration lowest plasma concentration that produces the desire effect Peak plasma level highest plasma concentration attained from a dose Toxic level plasma concentration at which a drug produces adverse effects Therapeutic range range of plasma concentration that produces the desire effect without toxicity (range between minimal effective concentration & toxic level) Loading dose bolus of drug given initially to attain rapidly a therapeutic plasma concentration ylarge initial dose; when immediate drug response is desired ygiven to achieve a rapid MEC in the plasma yi.e. digoxin - - - requires LD Maintenance dose amount of drug necessary to maintain a steady therapeutic plasma concentration Dose response relationship between minimal vs. maximal amount of drug dosed needed to produce desired drug response yi.e. some clients respond to lower drug dose while others need a high dose Maximal efficacy (maximum drug effect) all drugs give a maximum drug effect (maximal efficacy) yi.e. simvastatin 40mg vs rouvastatin 10mg Drug-response relationship:

Biologic half-life (t1/2) = time required to reduce to amount of unchanged drug that is in the body yshort t1/2 drugs need to be administered more often than one with a longer t1/2 Lethal dose (LD50) dose lethal to 50% of animals tested Effective dose (ED50) dose required to produce therapeutic effect on 50% animals Tested Therapeutic index (TI) ratio between LD50 and ED50; the closer the ratio is to 1, the greater the danger involved in giving the drug to humans yestimates the margin of safety of a drug through the use of a ratio that measures the effective (therapeutic or concentration) dose (ED) in 50% of persons/animals (ED50) & lethal dose in 50% of animals (LD50) TI=LD50/ED50 ylow therapeutic index: narrow margin of safety; might need to adjust drug dose & plasma drug levels need to be monitored yhigh therapeutic index: wide margin of safety less danger of producing toxic effects 4 Categories of Drug Action: 1. stimulation/depression ystimulation inc rate of cell activity/secretion from the gland ydepression dec cell activity & function of a specific organ 2. replacement replaces essential body compounds; i.e. insulin 3. inhibition/killing of organism interfere with bacterial cell growth ; i.e. antibiotics 4. irritation i.e. laxative irritate inner wall of colon - - - inc peristalsis - - - inc defecation Drug potency relative amount of drug required to produce desired response yalso used to compare a drug dose response curve graphical representation of relationship between dose of drug & response it produces ylow dose low response ydosage increased produce slight increase response, as dose further increases, drug response increases markedly, at certain point however, inc dose yield little or no inc in response - - - drug have reached Maximum Effectiveness Factors Affecting Dose Response Curve: - nurse must be aware that human factor has tremendous influence on what actually happens when it enter the body - no 2 people react in exactly the same way to any given drug 1. weight heavier patient larger dose to get therapeutic effect (more tissue to perfuse & inc receptor site in some reactive tissues) - dec weight dec dose

2. age children (immune system for handling drugs) & older adults - older patients: less absorption, distribution between fewer plasma proteins & less efficient perfusion: geriatric dosages - nurse should monitor closely for desired effects (may adjust dose) 3. toxicity 4. pharmacogenetics effect of a drug action that varies from a predicted drug response because of genetic factors or hereditary influence ypeople have different genetic makeup do not always respond identically to a drug dosage or planned drug therapy yex: African Americans do not respond as well as whites to some classes of antihypertensive medications 5. route of administration 6. emotional factors 7. pre-existing disease state liver disease 8. drug history drug interaction synergistic/excretion 9. tolerance 10. cumulative effect 11. drug- drug interaction 12. BMR inc BMR inc drug metabolism & excretion Drug Interaction 1. Additive effect 2 drugs with similar actions are taken for a doubled effect (desirable/undesirable) (1 + 1 = 2) yIbuprofen + paracetamol + added analgesic effect 2. Synergistic combined effect of 2 drugs is greater than sum of the effect or each drug given alone (1 + 1 = 3) yAspirin + codeine = greater analgesic effect 3. potentiation a drug that has no effect enhances the effect of a 2nd drug (0 + 1= 2) 4. Antagonistic one drug inhibits the effect of another drug (1 + 1 = 0) yTetracycline + antacid = dec absorption of tetracycline SIDE EFFECTS yPhysiologic effects not related to desired drug effects yAll drugs have side effects Desirable: diphenhydramine (Benadryl) at bedtime s/e: drowsiness Undesirable yResult mostly from drugs that lack specificity yMight be used interchangeably with adverse reactions yNot a reason to discontinue drug therapy yNurses role: teach clients to report any side effects ADVERSE REACTIONS yMore severe than side effects yRange of untoward effects (unintended, occurring at normal doses) of drug that cause mild-severe side effects: anaphylaxis (cardiovascular collapse) yAlways undesirable yMust always be reported & documented because they represent variances from planned therapy.

TOXIC EFFECT/TOXICITY yCan be identified by monitoring the plasma (serum) therapeutic range of the drug yNarrow TI (aminoglycoside & antibiotics) therapeutic range is monitored yWhen drug level exceeds therapeutic range, toxic effects are likely to occur from overdosing or drug accumulation.

New Cervical Cancer Diagnostic Test Wins FDA Approval Meaghan Ringwelski Wed Apr 20, 1:48 pm ET The approval of a new diagnostic test might help to prevent many advanced cases of cervical cancer in the future. Today, Roche Holding AG -- a drug company and the world's largest diagnostics company -- announced the Food and Drug Administration approval of its new cervical cancer diagnostic test. The test, which the company refers to as the cobas HPV Test, works to identify two of the most common strains of the human papillomavirus, or HPV; it can also identify 12 additional strains of the sexually transmitted disease, which is the leading cause of cervical cancer. Indeed, the cobas HPV Test is capable of identifying forms 16 and 18 of HPV. The test can be administered after a woman's regular annual pap smear to determine whether or not she is at increased risk of developing cervical cancer. Roche Holding AG, which is based on Basel, Switzerland, released a news release about the FDA approval of its cobas HPV Test. According to the release, the test is fully automated, which means that it can be seamlessly added to the other diagnostic tests that are administered following a routine pap smear. No mention is made in the release about the expected frequency at which the test will be administered. Its approval was based on the findings of the ATHENA study, which involved more than 47,000 women. The primary thing that distinguishes the cobas HPV vaccine from previous diagnostic methods is that it can identify forms 16 and 18 of HPV simultaneously. As a result, it's more likely to efficiently determine a woman's likelihood of developing cervical cancer. More than 12,000 women in the U.S. die as a result of cervical cancer each year. The vast majority of them develop the deadly cancer after contracting HPV. Although the HPV vaccine debuted a few years ago, it has yet to be used in a widespread manner. Forms 16 and 18 of the HPV virus are responsible for about 70 percent of the cases of cervical cancer; more than 280,000 women die of cervical cancer in the world each year. With the approval of Roche Holding's new diagnostic test, it is hoped that cases of the disease - which is largely treatable in its earliest stages -- could drop dramatically.

Earlier Diagnosis Of Liver Cancer Main Category: Liver Disease / Hepatitis Also Included In: Cancer / Oncology; Radiology / Nuclear Medicine Article Date: 23 Jun 2011 - 3:00 PDT Hepatocellular carcinoma is the most common cancer to strike the liver. More than 500,000 people worldwide, concentrated in sub-Saharan Africa and Southeast Asia, are diagnosed with it yearly. Most of those afflicted die within six months. A big obstacle to treatment of liver cancer is the lack of early diagnosis. Current techniques, including ultrasound, CT and MRI scans, spot tumors only when they have grown to about 5 centimeters in diameter. By that time, the cancer is especially aggressive, resisting chemotherapy and difficult to remove surgically. Now a research team led by Brown University reports some promising results for earlier diagnosis. In lab tests, the team used gold nanoparticles ringed by a charged polymer coating and an X-ray scatter imaging technique to spot tumor-like masses as small as 5 millimeters. The approach, detailed in the American Chemical Society journal Nano Letters, marks the first time that metal nanoparticles have been used as agents to enhance X-ray scattering signals to image tumor-like masses. "What we're doing is not a screening method," said Christoph Rose-Petruck, professor of chemistry at Brown University and corresponding author on the paper. "But in a routine exam, with people who have risk factors, such as certain types of hepatitis, we can use this technique to see a tumor that is just a few millimeters in diameter, which, in terms of size, is a factor of 10 smaller." The team took gold nanoparticles of 10 and 50 nanometers in diameter and ringed them with a pair of 1-nanometer polyelectrolyte coatings. The coating gave the nanoparticles a charge, which increased the chances that they would be engulfed by the cancerous cells. Once engulfed, the team used X-ray scatter imaging to detect the gold nanoparticles within the malignant cells. In lab tests, the nontoxic gold nanoparticles made up just 0.0006 percent of the cell's volume, yet the nanoparticles had enough critical mass to be detected by the X-ray scatter imaging device. "We have shown that even with these small numbers, we can distinguish these [tumor] cells," Rose-Petruck said. The next step for the researchers is on the clinical side. Beginning this summer, the group will attach a cancertargeting antibody to the nanoparticle vehicle to search for liver tumors in mice. The antibody that will be used was developed by Jack Wands, director of the Liver Research Center at Rhode Island Hospital and professor of medical science at the Warren Alpert Medical School of Brown University. "We have developed a monoclonal antibody that targets a cell surface protein highly expressed on liver cancer cells," Wands said. "We plan to couple the antibody to the gold nanoparticles in an attempt to detect the growth of early tumors in the liver by X-ray imaging." The researchers say the X-ray scatter imaging method could be used to detect nanoparticle assemblies in other organs. "The idea should be that if you can figure out to get that [nanoparticle] to specific sites in the body, you can figure out how to image it," said Danielle Rand, a second-year graduate student in chemistry and the first author on the paper. Source: Richard Lewis Brown University Contributing authors include Yanan Liu from Brown, Wands, Zoltan Derdak and Vivian Ortiz from the Liver Research Center, and Milan Taticek at the Czech Technical University in Prague.