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8/6/2019 Common Sources

1/10

amount of active drugs - - - increase recommended dose fororal drugs

Lidocaine extensive 1st pass not given orallyo Plasma

o Kidneys

o Membranes of intestine

yProcess by which body changes a drug from its dosage form to a more watersolubleform that can then be excreted

yCan be metabolized in several ways:o Most drugs metabolized into inactive metabolites (products ofmetabolism), which are then excretedo Other drugs converted to active metabolites capable of exerting theirown pharmacologic action

May undergo further metabolism or may be excreted frombody unchanged

Prodrugs some drugs administered as inactive drugs whichdont 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 groupon the parent compound (i.e. alkylation, alipathic hydroxylation,oxidation, deamination, hydrolysis, microsomal oxidases)

Cytochrome p450 inducer inc drug metabolism, decBioavailability

Cytochrome p450 inhibitor dec drug metabolism, inc levelsof drug prolonged effect & inc toxicityo Phase 2 conjugation reactions that lead to formation of covalentlinkage 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 liverInfants immature livers dec rate of metabolismo Area of absorbing surface to which a drug is exposed (+) chemicalagents may destroy the drug


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o Types of transport diffusion, active, pinocytosis

o Routes of administration skin absorption slower than IM

Absorption with in seconds/minutes: sublingual, IV, byinhalation route

Slower rate absorption: oral, IM SC routeso Bioavailability consideration of highest importance in drugeffectiveness & safety

Subcategory of absorption% of administered drug does that reaches systemic circulationOral route 89% of drug is bound to proteinyDiazepam, piroxicam, valproic acid

Moderately highly protein bound drugs (61-89% boundprotein)

yErythromycin, phenytoin

Moderately protein bound drugs 30-60%yAspirin, lidocaine, pindolol, theophyliine

Low protein-bound drugs - < 30% bound to protein (amikacin,amoxicillin)


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DISTRIBUTION BLOOD FLOW PROTEINBINDING BODY TISSUE AFFINITY PHARMACOLOGIC

EFFECT

Elderlies dec liver size, blppd flow, enzyme production - - - slowsmetabolism

Environment cigarette smoke may affect rate of some drugso Stressful environment prolonged illness, surgery, injuryIII. Excretion/elimination removal of drug from the body: drug is changed intoinactive form & excreted by the body

Routes:o Kidney main organ for drug elimination: leaves the body throughurine

Free/unbound/water soluble drugs filtered in kidneyProtein bound drug cannot be filtered in kidney(+) kidney dose dose must be decreasedo Lungs, exocrine (sweat, salivary, mammary) glands, skin, intestinaltract

Factors affecting drug excretiono Urine ph normal: 4-5.8Acid urine promotes elimination of weak base drugsyi.e. cranberry juice dec urine ph - - - (-) elimination ofaspirin

alkaline urine (+) elimination of weak acid drugyoverdose aspirin - - - give Nabicarbonate inc urine ph- - - (+) excretion of drugo glomerular filtration rate (GFR) dec GFR - - - drug excretionslowed/impaired

can result to drug accumulationextent of filtration directly proportional to GFR & to fraction ofunbound drug to plasma

yratio of clearance = fu x GFR - - - cleared by filtration

yratio of clearance < fu x GFR - - - cleared tubularreabsorption

yratio of clearance > fu x GFR - - - cleared by tubularSecretion

o creatinine clearance most accurate test to determine renal function

creatinine excreted in kidneydec renal GFR inc serum creatinine level & dec urinecreatinine clearance

12-24 hrs urine collection & blood sampleNormal 85-135 ml/min; elderly 60ml/minRenal clearance amount of substance removed from the blood by thekidneysHalf-life/elimination half-life (t ) time it takes for one half of drugconcentration to be eliminatedo 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


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Effects of drugs on the cells biological & physiological functions &mechanisms of action

Interactions between chemical components of living systems & foreignchemicals including drugs that enter these system

Mechanism of action: means by which a drug produces alteration in functionof their action

Drug actions:a. To replace/act as substitute for missing chemicalsb. To inc or stimulate certain cellular activitiesc. To depress/slow cellular activitiesd. To interfere with functioning of foreign cells (i.e. invadingmicroorganisms/neoplasms) chemotherapeutic Agents

Theories of Drug Actionsa. Drug-receptors interaction certain portion of drug molecule (activesite) 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.; reactwith certain chemicals to cause an effect with in celllock & key theory specific chemical (key) approaches a cellmembrane & finds a perfect fit (the lock) at receptor site affects enzymes system within a cell produce certain effects

Specificity selectivity theoryDrug action may be:yAgonists drugs that produce a response

o insulin reacts with specific insulin receptor site to change cell membrane permeability - - - (+) movementof glucose into cell

ycompetitive antagonist act with receptor sites to block normal stimulation producing no effecto curare use on spear in Amazon to paralyzeprey & cause death: occupies receptor sites for

Acetylcholine (needed in muscle contraction & movement) - - - prevents nerve stimulationcausing paralusis

o noncompetitive antagonist - prevent reaction of another chemical with different receptor site onthat cell

b. drug-enzymes interaction interferes with enzyme systems that act ascatalyst from various chemical reations

enzyme systems cascade effect; one enzyme activatinganother - - - causing cellular reactionif single step in one of enzyme system is blocked normal cellfunction is disruptedex: acetazolamide (diamox) diuretic that block carbonicanhydrase 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 apathogen or neoplastic cell & will nor affect healthy cells

ex: penicillin


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unfortunately most of it cause destruction of normal humanCells

Drug response may be:1. primary always desirable / physiologic effects2. secondary desirable or undesirable

ex: diphenhydramine (benadryl) 1st effect: antihistamine, treat symptoms ofallergy; 2: CNS depression - - - drowsinessdesirable: 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 drugis 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 doseToxic level plasma concentration at which a drug produces adverse effects

Therapeutic range range of plasma concentration that produces the desire effect without toxicity (rangebetween 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 neededto produce desired drug response

yi.e. some clients respond to lower drug dose while others need a highdose

Maximal efficacy (maximum drug effect) all drugs give a maximum drug effect(maximal efficacy)

yi.e. simvastatin 40mg vs rouvastatin 10mgDrug-response relationship:


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Biologic half-life (t1/2) = time required to reduce to amount of unchanged drug that isin the body

yshort t1/2 drugs need to be administered more often than one with alonger t1/2

Lethal dose (

LD50) dose lethal to 50

%of animals tested

Effective dose (ED50) dose required to produce therapeutic effect on 50% animalsTested

Therapeutic index (TI) ratio between LD50 and ED50; the closer the ratio is to 1, thegreater the danger involved in giving the drug to humans

yestimates the margin of safety of a drug through the use of a ratio thatmeasures 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 adjustdrug dose & plasma drug levels need to be monitored

yhigh therapeutic index: wide margin of safety less danger of producingtoxic 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 - - - incdefecation

Drug potency relative amount of drug required to produce desired response yalso used to compare adrugdose 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 furtherincreases, drug response increases markedly, at certain point however, inc dose yield little or noinc in response - - - drug have reached Maximum Effectiveness

Factors Affecting Dose Response Curve:

- nurse must be aware that human factor has tremendous influence onwhat 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 toperfuse & inc receptor site in some reactive tissues)- dec weight dec dose


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2. age children (immune system for handling drugs) & older adults- older patients: less absorption, distribution between fewer plasmaproteins & 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 drugresponse because of genetic factors or hereditary influence

ypeople have different genetic makeup do not always respond identically to adrug dosage or planned drug therapy

yex: African Americans do not respond as well as whites to some classes ofantihypertensive medications5. route of administration6. emotional factors7. pre-existing disease state liver disease8. drug history drug interaction synergistic/excretion9. tolerance10. cumulative effect11. drug- drug interaction12. BMR inc BMR inc drug metabolism & excretion

Drug Interaction1. 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 eachdrug 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

UndesirableyResult mostly from drugs that lack specificity

yMight be used interchangeably with adverse reactions

y

Not a reason to discontinue drug therapyyNurses 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 drugthat cause mild-severe side effects: anaphylaxis (cardiovascular collapse)

yAlways undesirable

yMust always be reported & documented because they represent variancesfrom planned therapy.


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TOXIC EFFECT/TOXICITY

yCan be identified by monitoring the plasma (serum) therapeutic range of thedrug

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.


9/10

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 largestdiagnostics company -- announced the Food and Drug Administration approval of its newcervical cancer diagnostic test.

The test, which the company refers to as the cobas HPV Test, works to identify two of the mostcommon 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 beadministered 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 theFDA 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 administeredfollowing a routine pap smear.

No mention is made in the release about the expected frequency at which the test will beadministered. 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 fromprevious 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 vaccinedebuted 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 than280,000 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 inits earliest stages -- could drop dramatically.


10/10

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 cancerto 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 ofliver canceris 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, thecancer 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 toimage 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 ofhepatitis, 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 cancer-

targeting 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 medicalscience 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 onthe 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.

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