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148 Cards in this Set
- Front
- Back
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What is the Federal Food, Drug, and Cosmetic Act? |
Proposed in 1933 to protect consumers 1937- Public outcry due to >100 deaths from improperly prepared sulfanilamide Passed by Congress in 1938 Created the FDA (Food and Drug Administration) Establishes classes of drugs Prescription vs non-prescription |
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What is an IND? |
Investigational New Drug Application Based on preliminary testing completed on animals Basis of proposing human research |
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The IND Appraisal by the FDA is done in conjunction with what? |
A local institutional Review Board (IRB) Appraisal |
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What does an IRB examine? |
The specifics of a clinical trial, consent issues, patient protection |
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What is the FDA drug approval process? |
Drug developed and animals tested > IND application > Clinical trials (phase I, II, and III) |
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What is the impact of the FDA? |
Frances Oldham Kelsey (FDA scientist) kept thalidomide off the U.S. market |
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What happens in Phase I trials? |
Involves 20-80 healthy subjects Focus on identifying frequent side effects Drug metabolization and excretion is studied |
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What happens in phase II trials? |
24 to 300 subjects with the disease Focus on effectiveness of new compound Comparison of drug vs placebo Gathers data on safety and side effects |
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What happens in phase III trials? |
FDA and drug sponsor agree on structure of phase III trials 100 to 3,000 subjects Different dosages and drug interactions studied Safety and effectiveness data continues to be collected and evaluated |
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What is an NDA? |
New drug application Submitted with data from completed studies Takes 6 to 10 months Package Insert (PI) submitted for approval and may require revision |
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What happens after clinical trials? |
Review meeting > NDA > Application reviewed > Drug labeling > Facility inspection > Drug approval > Post-marketing (FDA's Post-approval risk assessment systems) |
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What is the Controlled Substances Act (CSA)? |
Passed by Congress 1971 "Scheduled" drugs- DEA and DOJ jurisdiction Categorizes drugs into schedules or controlled classes (CI, CII, CIII, CIV, CV) Use and distribution is controlled base on potential for abuse, addiction, and widely accepted medical use |
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What are Schedule I drugs? |
High potential of abuse or risk No safe or accepted medical uses Heroin, LSD, PCP, crack cocaine, marijuana, mescaline |
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What are schedule II drugs? |
High risk of abuse Safe and acceptable medical uses Severe potential for psychological and physical dependence Hydrocodone, morphine, cocaine, oxycodone, methyphenidate, dextroamphetamine |
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What are schedules III-V drugs? |
Low risk of abuse Safe and acceptable medical uses Contain smaller amounts of narcotics, anti-anxiety, tranquilizers, sedatives, stimulants |
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How is TX PA prescriptive authority delegated? |
Delegated by supervising physician to the PA through formal agreement |
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Can controlled substances be prescribed by Pas? |
Yes, with specific limitations |
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What must Pas who prescribe controlled substances have? |
DPS registration number DEA registration number |
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Can PAs prescribe schedule II drugs? |
Only under physician delegation in the following circumstances: In a hospital to a patient who has been admitted to the for an intended stay of >24 hours To a patient who is receiving services in the ED of a hospital Part of a plan of care for treatment of a patient with a terminal illness or in hospice |
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How often is physician consultation required when prescribing controlled substances? |
Consult for refills after initial 90 day supply When prescribing controlled substances for children <2 |
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What is a pregnancy category A drug? |
Studies in pregnant women indicate no risk to fetus |
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Wha is a pregnancy category B drug? |
Animal studies indicate no risk to fetus |
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What is a pregnancy category C drug? |
Animal studies report adverse affects on fetus Potential benefits may indicate use despite risks |
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What is a pregnancy category D drug? |
Positive human fetal risk Benefit may outweigh risk in some select cases |
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What is a pregnancy category X drug? |
Fetal abnormalities reported Positive human fetal risk Risks outweigh benefits Drug should not be used during pregnancy |
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What pregnancy drug categories can be prescribed during pregnancy? |
Category A and B |
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What are the written prescription components? |
Clinician Identification Patient identifiers Inscript- Drug name and strength Subscript- Dosage from and number of units to dispense Signa/Sig- Words on bottle (directions for patients) Number of refills Date of Rx written Prescriber's DEA number Generic vs Trade |
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What is pharmacokinetics? |
What the body does to the drug
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What is pharmacodynamics? |
What the drug does to the body |
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What are the properties of pharmacokinetics |
Absorption Distribution Metabolism Elimination |
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What is absorption? |
Entry of the drug to the plasma via the administration site |
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What is distribution? |
Drug may reversibly leave the blood stream and distribute into interstitial and intracellular fluids |
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What is metabolism? |
Drug is biotransformed by metabolism in the liver or other tissue |
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What is elimination? |
Drugs and metabolites are excreted via urine, bile, or feces |
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How are routes of administration determined? |
Drug properties (water or lipid soluble, ionization) Therapeutic objectives (rapid onset needed, long term treatment, restriction of drug to a local site) |
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What is the enteral route? |
By mouth |
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What is an enteric coated drug? |
Coated to protect from stomach acid Coating dissolves in small intestine |
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What is an extended release drug? |
Coatings or ingredients delay drug release (slow absorption/prolonged duration) Improves patient compliance Less peaks and troughs |
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What are the sublingual/buccal routes? |
Under tongue/in cheek Drug diffuses into capillary network and goes directly to systemic circulation Rapidly absorbed Avoids harsh gastric pH and 1st pass metabolism |
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What are some advantages of the enteral route? |
Safe Convenient Economical |
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What are some disadvantages of the enteral route? |
Limited absorption Affected by food Patient compliance concerns 1st pass metabolism effects |
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What is the parenteral route? |
Drug goes directly into systemic circulation via blood stream Highest degree of bioavailability Irreversible May cause pain, irritation, tissue damage, and infection |
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When is the parenteral route ideal? |
Drugs are unstable in the GI tract Drugs are poorly absorbed from the GI tract Patient not able to take oral medications Rapid onset of effect is needed |
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What is the intravenous route? |
Directly into vein Rapid onset Maximum control over amount of drug delivered Bolus dosing vs Continuous infusion (Bolus is for quick effect and continuous infusion is for maintenance effect) |
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What is the intramuscular route? |
Directly into the muscle Prepared in aqueous solutions (rapid absorption) or in a specialized depot injection (slow absorption) |
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What is the subcutaneous route? |
Injection into the subcutaneous tissue Minimizes risk of hemolysis or thrombosis Can cause pain and tissue necrosis |
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What are the advantages of the parenteral route? |
Immediate effects Large volumes can be easily administered Helpful in emergencies Easy to titrate to effect Used for high molecular weight proteins and peptide drugs |
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What are the disadvantage of the parenteral route? |
Unsuitable for oily or poorly absorbed substances Bolus injections can cause adverse effects Need for prolonged injection times Aseptic technique required |
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What are the oral and nasal inhalation routes? |
Rapid administration through mucous membranes Beneficial in patients with respiratory disorders (drug can go directly to lungs) |
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What are the intrathecal/intraventricular routes? |
Introduces drugs directly to the cerebrospinal fluid |
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What is the topical route? |
Applied to local area of skin Local effects |
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What is the transdermal route? |
Skin patches often used for sustained drug delivery Thickness of skin and lipid solubility influence absorption |
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What is the rectal route? |
Drug administered into rectum Useful when patients are unconscious or vomiting Absorption is often erratic and incomplete Bypasses the liver and GI |
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What absorbs better, solutions, suspensions, or tablets? |
Solutions absorb better than suspensions or tablets |
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What factors influence absorption? |
Factors related to the drug- Degree of ionization (highly ionized drugs are poorly absorbed) Degree of solubility (high lipid/water partition coefficient increases absorption) |
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What is the amount of drug that reaches systemic circulation? |
Bioavailability |
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What is bioavailability highly dependent on? |
Apsorption |
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How are most drugs absorbed into systemic circulation? |
Passive diffusion |
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What are other mechanisms that drugs can be absorbed by? |
Active transport Facilitated diffusion |
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What is passive diffusion? |
Drugs move from high to low concentrations across a membrane No carrier Not saturable Low structural specificity Water soluble drugs diffuse through pores Lipid soluble drugs diffuse across membranes |
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What is facilitated diffusion? |
Transmembrane carrier proteins facilitate the passage of large molecules Conformational changes allow passage of drugs into cells Move from high to low concentration No energy required Saturable Competing compounds can inhibit the process |
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What is active transport? |
Specific carrier proteins Carrier proteins transport specific drugs that closely resemble the naturally occurring metabolites across membranes Energy dependent (ATP) Drugs can go from low to high concentration Saturable Can be competitively inhibited |
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How are exceptionally large molecules transported in the body? |
Endocytosis (engulfment of drug by cell membrane for transport into the cell) Exocytosis (secretes substances out of the cell) |
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Are most drugs weak or strong acids and bases? |
Weak acids and bases |
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What does a weak acid look like? |
HA <=> H+ + A- Weak acids release a proton (H+) causing a charged anion (A-) to form |
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What does a weak base look like? |
BH+ <=> B + H+ Weak bases release a proton (H+) producing an uncharged base (B) |
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What type of drugs pass through membranes more readily than cations and anions? |
Uncharged drugs (HA and B) |
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What is pKa? |
The measure of the strength of interaction of a compound with a proton |
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What type of drug has a lower pKa? |
More acidic drugs |
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What type of drug has a lower pKa? |
More basic drugs |
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What happens when pH = pKa? |
HA = A- BH+ = B |
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When the pH is less than pKa, what forms predominate? |
HA and BH+ |
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When the pH is greater than pKa, what forms predominate? |
A- and B |
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How does blood flow influence absorption? |
More blood flow = greater absorption Intestines receive more blood flow than stomach |
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How does total surface area influence absorption? |
Greater surface area = greater absorption Intestines have 1000x more brush border containing microvilli |
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How does contact time influence absorption? |
More contact time = greater absorption If a drug moves too quickly (diarrhea) it won't be absorbed as well Delaying passage of drugs from the stomach to the intestines will slow absorption (take with food > slow gastric emptying) |
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How does the expression of P-glycoprotein influence absorption? |
Increased P-glycoprotein = less absorption P-glycoprotein pumps drugs out of cells P-glycoprotein is found in the kidneys, placenta, intestines, and brain |
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How can you determine bioavailability? |
Compare plasma levels after various routes of administration IV = 100% Oral = variable Calculate the AUC (area under the curve) by plotting plasma concentrations over time |
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What does oral bioavailability depend on? |
The amount absorbed and the amount metabolized before reaching systemic circulation (first pass metabolism) |
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What is first pass metabolism? |
Metabolism of orally administered drug in the liver before it reaches systemic circulation Significant first pass metabolism limits drug's bioavailability Consider other routes of administration for drugs with high first pass metabolism |
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How does solubility influence bioavailability? |
Extremely hydrophilic or lipophilic drugs are poorly absorbed Ideal- largely lipophilic with some solubility in aqueous solution |
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How does chemical instability influence bioavailability? |
Certain drugs can unstable or destroyed in the GI tract |
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How does the nature of the formulation influence bioavailability? |
Drug absorption may be altered by factors unrelated to the chemistry of the drug Ex. Particle size, salt form, crystal polymorphism, enteric coating and excipients |
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What is bioequivalence? |
Two drugs that have comparable bioavailability and similar times to achieve peak blood concentrations Brand vs. generic |
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What is therapeutic equivalence? |
Pharmaceutically equivalent Same dosage form, active ingredient and route Similar clinical and safety profiles |
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Does bioequivalence = therapeutic equivalence? |
No |
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What is distribution of a drug from systemic circulation to tissues dependent on? |
Lipid solubility Ionization Molecular size Binding to plasma proteins Rate of blood flow |
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What does it mean if a drug has an uncommon distribution parameter? |
Ex. VD, protein binding, storage in fat depots Have to be dosed carefully to avoid toxicity while ensuring therapeutic efficacy |
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How are drugs present in the blood? |
Free form- Active, diffusible, available for metabolism and excretion Bound form- Inert, not available for metabolism and excretion (acts as a reservoir for drug) |
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Is binding of a drug to albumin reversible? |
Yes |
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What is the significance of a drug binding to albumin? |
Drugs may have affinity for protein binding sites Drugs can compete and cause drug interactions Drugs highly bound to plasma proteins are in general expected to persist in the body longer than those less bound and are expected to have lower therapeutic activity |
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Drug molecules in the blood are in what two forms? |
Bound to plasma proteins (albumin) Unbound or free |
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What type of drug can distribute into tissues and exert its action? |
Free drug |
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Affinity of protein binding site for a drug determines what? |
Bound/unbound concentrations |
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Saturation of binding sites may result in what? |
A large increase in unbound drug concentration Toxicity may be a problem |
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Competitive protein binding can cause what? |
Significant drug interaction In general, only drugs that are highly protein bound (90%) are involved in drug interactions due to competitive binding |
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What can hypoalbuminemia lead to? |
Increases in free drug |
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What is volume of distribution (Vd)? |
The hypothetical volume of blood and body tissue into which the drug distributes No physiologic or physical basis Amount of drug in the body/Concentration at time zero |
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What can Vd be altered by? |
Tissue binding (Increase tissue affinity = increased Vd) Tissue perfusion (Decrease perfusion = decreased Vd) Plasma protein binding (Increased protein binding = decreased Vd) |
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What is the primary location of metabolism? |
Hepatic (phase I and II) |
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What are other locations (extrahepatic) of metabolism? |
Kidneys Lungs Blood |
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What happens in Hepatic Phase I metabolism? |
Oxidation, reduction, and/or hydrolysis Following Phase I, the drug may be activated, unchanged, or, most often, inactivated |
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What happens in Hepatic Phase II metabolism? |
Results in conjugation products Conjugated drug is usually inactive |
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What is cytochrome P450? |
Super-family of cytochrome P450 enzymes has a crucial role in the metabolism of drugs Almost every drugs is processed by some of these enzymes, which causes a reduction in bioavailability Responsible for drug interactions |
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What impact can genetic variability have on a person's reaction to a drug? |
May alter drug efficacy and increase risk of adverse events Ex. 2D6 mutations result in low capacity to metabolize substrates which causes little analgesic effect with opioids like codeine Ex. Poor metabolizers of 2C19 have a higher risk of cardiovascular events when taking the prodrug clopidogrel |
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What are the type of cytochrome P450 drug interactions? |
Inhibition Induction |
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What results from CYP450 inhibition? |
Leads to decrease rates of metabolism of other drugs metabolized by the same enzyme, resulting in higher drug levels and increased potential for toxicity Usually reversible Irreversible inhibition can occur, requiring new CYP450 enzyme to be synthesized Tends to occur quickly with maximal effect occurring when highest concentration of the inhibitor are reached |
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What results from CYP450 induction? |
Increased clearance of concomitant medications metabolized by the same enzyme The body responds by increasing the production of specific enzymes of the CYP450 system Increased enzyme production can lead to increased metabolism and decreased drug concentrations |
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What factors affect drug metabolism? |
Enzyme induction increases drug clearance Aging Diseases (hyperthyroidism) Drugs Conditions (smoking, alcoholism) Higher doses of drugs may be required or other options for drug therapy may be needed |
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What are the effects of aging on drug metabolism? |
Decreased hepatic blood flow is often associated with decreased first pass effect and reduced phase I metabolism Phase II reactions are well preserved with age and severe liver disease |
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What is the Beers criteria for the elderly? |
Clinical tool developed to assist healthcare providers in improving medication safety in older adults Purpose is to inform clinical decision-making concerning the prescribing of medications for older adults in order to improve safety and quality of care |
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What is the principle of elimination? |
Dosing of drugs needs to be adjusted according to the elimination characteristics of the patient (ex. renal impairment) in order to avoid toxicity from or metabolite accumulation |
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What is the main organ of drug excretion? |
Kidneys |
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How are drugs eliminated from the kidneys? |
Passive glomerular filtration Active proximal tubular secretion Passive distal tubular reabsorption |
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What occurs during passive glomerular filtration? |
Free/unbound drug flows through capillary slits |
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What happens during active proximal tubular secretion? |
Transport systems for acids and bases Low specificity (can see competition between drugs) |
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What happens during passive distal tubular reabsorption? |
Solute and water are removed from the tubular fluid and transported into the blood |
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What are other routes of elimination? |
GI tract (salivary glands, stomach, large intestines, liver) Sweat Lungs Milk |
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What is linear (first order) elimination? |
Amount of drug eliminated per unit of time is directly proportional to the amount in the body Non-saturable elimination Most drugs |
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What is non linear (zero order) elimination? |
Amount of drug eliminated per unit of time is constant, regardless of the amount in the body Saturable elimination Few drugs Small changes in dose lead to large changes in concentration Never double the dose |
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What is half-life (t1/2)? |
Time required for the amount of drug (or concentration) in the body to decrease by 50% |
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What are the two types of half-life? |
Distribution t1/2- a (alpha) Elimination t1/2- B (beta) |
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What does elimination t1/2 determine? |
Duration of pharmacologic effect Optimum dosage regimen Time to reach steady state |
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What is steady state (Css) |
Time at which the rates of drug administration and drug elimination are equivalent Concentration of drug is constant Attained after 3-5 t1/2 at a constant dosing rate Ideal time for serum drug concentration measurements |
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What is designing and optimizing drug regimens? |
Process of determining the patient plasma concentrations to optimize drug therapy Maximize therapeutic benefits Minimize toxic effects |
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What is assumed when designing and optimizing drug regimens? |
Serum drug concentration reflects concentration at the receptor site Intensity and duration of pharmacodynamic effect is correlated with the receptor site drug concentration |
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What is a maintenance dose? |
Keeps concentrations in a therapeutic response window to minimize toxicity and side effects Caution with drugs that have narrow therapeutic index |
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What is a loading dose? |
Rapidly obtains desired plasma levels Often seen with antibiotics and antiarrythmics Increased risk of toxicity Usually followed by maintenance dose |
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What are serum drug levels influenced by? |
Timing of sample Correct dosing regimen and dose Patient's clinical state Drug's pharmacokinetics Renal or hepatic function Analytical methodology used |
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What does pharmacodynamics focus on? |
The mechanism, intensity, peak, and duration of a drug's physiological actions |
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What is a drug-receptor complex? |
Drug binds to the receptor and elicits an effect |
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What are the two receptor states? |
Inactive and active |
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What are the major receptor families? |
Ligand gated ion channels (cholinergic nicotinic receptors) G-protein coupled receptors (a & B receptors) Enzyme liked receptors (insulin receptors) Intracellular receptors (steroid receptors) |
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What occurs during transduction? |
Receptors transduce their recognition of a bound agonist by initiating a series of reactions that ultimately result in a specific intracellular response |
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What is signal amplification? |
G protein and enzyme linked receptors can amplify intensity and duration |
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What is desensitization and down regulation of receptors? |
Protective Repeated agonist exposure can lead to tachyphylaxis Chronic use of antagonists can lead to up-regulation of receptors |
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What are agonists? |
Affinity- the ability of the agonist to bind to the receptor Efficacy- the ability to cause a response via the receptor interaction |
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What are antagonists? |
Have affinity but no efficacy |
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What are full agonists? |
Activate receptors to produce an effect similar to a physiologic signal molecule Maximal efficacy |
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What is an inverse agonist? |
Activates receptors to produce an effect in the opposite direction of the agonist |
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What is a partial agonist? |
Activates receptors to produce sub maximal effects but antagonizes a full agonist |
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What is an antagonist? |
Prevents the action of an agonist on a receptor Does not have an affect of its own |
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What are competitive antagonists? |
Compete with agonist for the receptor Reversible (can be overcome by increasing the agonist concentration) Displaces the agonist dose response to the right Reduces the apparent affinity of the agonist |
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Wha are non competitive antagonists? |
Drug binds to the receptor and stays bound Irreversible As more and more receptors are bound the agonist drug becomes incapable of eliciting a maximal effect |
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What is efficacy? |
Maximum intensity of response to a drug |
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What is ED50 (effective dose-50%)? |
The dose of a drug that gives rise to the designated response in 50% of the subjects Easier to measure than maximum effect and is used to determine efficacy |
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What is potency? |
A comparison of the ED50 of two or more drugs that have parallel log dose-response curves The drug that reaches the ED50 at the lower dose is the more potent Potency is not important if you can increase the dose of the less potent drug without causing side effects |
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What is therapeutic index? |
The ratio of the dose that leads to toxic effects in 50% of cases, to that that leads to therapeutic effect in 50% of the cases Safer-Large therapeutic index More toxic- Narrow therapeutic index |
