Intro to PK - L2

Correct answer = C. The additional dosage of digoxin needed to achieve the desired plasma concentration can be calculated using the equation Vd (C2 - C1). C1 is the current plasma concentration (0.4 ng/mL) and C2 is the desired plasma concentration (1.2 ng/mL). Therefore, the additional dosage of digoxin is [400 L × (1.2 - 0.4) ng/mL)] = 320 mcg.

1.10. A 74-year-old man was admitted to the hospital for treatment of heart failure. He received 160 mcg of digoxin intravenously, and the plasma digoxin level was 0.4 ng/mL. If the desired plasma concentration of digoxin for optimal therapeutic activity in heart failure is 1.2 ng/mL, and the patient has an estimated Vd of 400 L, calculate the additional dose of digoxin needed for this patient to achieve the desired plasma concentration. A. 128 mcg B. 160 mcg C. 320 mcg D. 480 mcg E. 640 mcg

Correct answer = E. Phase II metabolic reactions involve conjugation reactions to make phase I metabolites more polar. Sulfation and glucuronidation are the most common phase II conjugation reactions

1.7. Which of the following reactions represents Phase II of drug metabolism? A. Amidation B. Hydrolysis C. Oxidation D. Reduction E. Sulfation

Correct answer = B. A drug will reach steady state in about 4 to 5 half-lives. Therefore, for this drug with a half-life of 12 hours, the approximate time to reach steady state will be 48 hours.

1.8. A pharmacokinetic study of a new antihypertensive drug is being conducted in healthy human volunteers. The half-life of the drug after administration by continuous intravenous infusion is 12 hours. Which of the following best approximates the time for the drug to reach steady state? A. 24 hours B. 48 hours C. 72 hours D. 120 hours E. 240 hours

Correct answer = E. For oral dosing, loading dose = [(Vd) × (desired steady-state plasma concentration)/F]. The Vd in this case is corrected to the patient's weight is 120 L. The F value is 0.9 (because bioavailability is 90%, that is, 90/100 = 0.9). Thus, loading dose = (120 L × 3.0 mg/L)/0.9 = 400 mg.

1.9. A 64-year-old female patient (60 kg) is treated with experimental Drug A for type 2 diabetes. Drug A is available as tablets with an oral bioavailability of 90%. If the Vd is 2 L/kg and the desired steady-state plasma concentration is 3.0 mg/L, which of the following is the most appropriate oral loading dose of Drug A? A. 6 mg B. 6.66 mg C. 108 mg D. 360 mg E. 400 mg

Correct answer = A. Vd = dose/C = 2000 mg/28.5 mg/L = 70.1 L. Because the patient is 70 kg, the apparent volume of distribution in L/kg will be approximately 1 L/kg (70.1 L/70 kg).

A 40-year-old male patient (70 kg) was recently diagnosed with infection involving methicillin-resistant S. aureus. He received 2000 mg of vancomycin as an IV loading dose. The peak plasma concentration of vancomycin was 28.5 mg/L. The apparent volume of distribution is: A. 1 L/kg B. 7 L/kg C. 10 L/kg D. 14 L/kg E. 70 L/kg

Correct answer = D. Because the patient has a renal disorder, she may not be able to excrete the drug effectively. Therefore, the half-life of Drug X will be prolonged. As the half-life is prolonged, the dosage must be reduced so the patient will not have serious toxic effects of Drug X.

A 55-year-old woman is brought to the emergency department because of seizures. She has a history of renal disease and currently undergoes dialysis. She receives an intravenous infusion of antiseizure Drug X. Which of the following is likely to be observed with use of Drug X in this patient?

Correct answer = B. Clopidogrel is a prodrug and requires CYP2C19 activity for conversion to an active metabolite. Because omeprazole is a potent CYP inhibitor, clopidogrel is not converted to the active metabolite, and therefore the antiplatelet activity is reduced, potentially contributing to myocardial infarction

A 68-year-old woman is brought to the emergency department for treatment of a myocardial infarction. She is currently taking clopidogrel (antiplatelet agent) and aspirin daily, as well as omeprazole (potent CYP inhibitor) for heartburn. Which of the following is the most likely contributor to her myocardial infarction today? A. Reduced antiplatelet activity of clopidogrel due to aspirin B. Reduced antiplatelet activity of clopidogrel due to omeprazole C. Hypersensitivity reaction due to clopidogrel D. Increased antiplatelet activity of clopidogrel due to omeprazole E. Increased antiplatelet activity of clopidogrel due to aspirin .

entry bloodstream liver

ADME: Absorption: First, absorption from the site of administration permits _______ of the drug (either directly or indirectly) into plasma. Distribution: Second, the drug may reversibly leave the _________ and distribute into the interstitial and intracellular fluids. Metabolism: Third, the drug may be biotransformed through metabolism by the ______ or other tissues. Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces.

Adjusted BW = IBW + 0.4(TBW-IBW)

Adjusted BW *Adjusted BW = ___________ -When do we "pull the trigger" in using an adjusted BW? you need to be over >30% over ideal body weight before using adjusted body weight -don't just use their actual BW b/c the dose will be too large in overweight people

diabetes mellitus (DM)

Amputees If your patient has had a significant portion of a limb removed, then this will affect your IBW calculations. -A % of body weight will need to be removed from the IBW after you have calculated it -_________ is the most common reason for LE amputations - not just combat or trauma reasons

6% 15% 19%

Amputees You will subtract the noted percent of body weight for the portion of a limb missing from the amuptee. -Ex: if a patient has a below-the-knee amputation (BKA), you will subtract ______% of the body weight. -If an above-the-knee amputation (AKA), you would subtract ____%. -If the entire leg has been amputated then ____% of IBW would be subtracted.

Correct answer = B. The intravenous route of administration is the most desirable because it results in achievement of therapeutic plasma levels of the antidote rapidly.

An 18-year-old female patient is brought to the emergency department due to drug overdose. Which of the following routes of administration is the most desirable for administering the antidote for the drug overdose? A. Intramuscular B. Intravenous C. Oral D. Subcutaneous E. Transdermal

first-pass solubility

Bioavailability (F) -F is influenced by ________ metabolism, ________, & other factors -IV administration = 100% bioavailability -PO drugs often undergo first-pass metabolism (this + chemical and physical characteristics of the drug determines the rate and extent to which the agent reaches the systemic circulation)

70kg 110kg

Cockcroft-Gault Equation: (MUST KNOW THIS) How to estimate renal function (write equation on notecard) Given SCr and gender, must be able to calculate this ^ - Use ideal or actual for a "normal" sized person (these will basically be the same) - plug into the equation -Ex: normal weight for a 5'10" male is ______kg -Overweight for the same height is _______kg

drug elimination drug administration

Concentration Steady State (Css) -Continuous or repeated administration results in accumulation of the drug until a steady state occurs. -Steady-state concentration is reached when the rate of _____________ is equal to the rate of ______________, such that plasma & tissue levels remain relatively constant

liver or kidney metabolism

Concentration Steady State (Css) -The steady state plasma concentration (Css) is directly proportional to infusion rate (if infusion rate is doubled, the Css is doubled) -Css is inversely proportional to the clearance of the drug: any factor that decreases clearance, such as __________ disease, increases the Css of an infused drug (assuming Vd remains constant) -Factors that increase clearance, such as increased ___________, decrease the Css

This is how we avoid destruction in GI tract, avert first-pass metabolism, reduce toxicity, etc.

Describe the rationale of using a Pro-drug

Correct answer = D. Because Drug A is a weakly basic drug (pKa = 7.8), it will be predominantly in the nonionized form in the jejunum (pH of 8.0). For weak bases, the nonionized form will permeate through the cell membrane readily.

Drug A is a weakly basic drug with a pKa of 7.8. If administered orally, at which of the following sites of absorption will the drug be able to readily pass through the membrane? A. Mouth (pH approximately 7.0) B. Stomach (pH of 2.5) C. Duodenum (pH approximately 6.1) D. Jejunum (pH approximately 8.0) E. Ileum (pH approximately 7.0)

Stomach pH GI motility GI blood flow fed/fasted drug solubility drug dissociation molecule charge drug-food interactions (remember di/tri-valent cations!)

Factors impacting PK & ADME: Absorption: List some things that affect absorption: (8 listed in class) -Some drugs like fatty foods, so they do better with a greasy environment (tell pt to take med with fatty food -pH: Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms

Patient's Volume of Distribution/Vd (pregnancy, burns, cachexia) cardiac output (pt in heart failure, heart not pumping well) tissue perfusion (diabetics have decreased tissue perfusion)

Factors impacting PK & ADME: Distribution: list things that impact distribution (3)

Renal function (Kidney failure limits excretion) some biliary considerations

Factors impacting PK & ADME: ·Excretion: list things that affect excretion (2)

1. Liver function (impacts of cancer, hepatitis) 2. drug interactions (drugs either increase enzymes in liver or they suppress them) 3. nutritional status 4. perfusion of liver

Factors impacting PK & ADME: ·Metabolism: lists things that affect metabolism (4)

drug elimination

First Order Kinetics (elimination) -amount eliminated changes, fraction eliminated doesn't -"think 8mg...4mg...2mg...1mg..." (eliminating half the mg each interval) -A constant fraction of the drug is cleared per unit of time. -Therefore, the rate of ____________ increases proportionately as the plasma concentration increases.

B-Blocker propranolol, morphine, lidocaine (not PO option b/c of first-pass!)

First Pass Metabolism (Effect): List Examples of drugs that go through a lot of first pass effect

systemic circulation BIOAVAILABILITY (F)

First Pass Metabolism (Effect): -Liver breaks down absorbed meds (via Portal circulation) BEFORE drug reaches __________ -may significantly REDUCE concentration attainable in body. -This may completely prevent some drugs via PO route. Reflected in reduced ____________

renal

Glomerular Filtration Rate (GFR)/ Creatinine Clearance (CrCl) A CrCl of 50 is WAY below average (normal for older people, even if they are healthy) -GFR/CrCl is MOST applicable to drugs that have a _________ component (if it is totally excreted by the liver this calculation doesn't make much sense)

130 ml/min 120 ml/min

Glomerular Filtration Rate (GFR)/ Creatinine Clearance (CrCl) GFR = Creatine Clearance (CrCl) -CrCl is typically an estimated calculation (there are actual measures but need 24 hr urine, etc) -Value of GFR/CrCl is expressed as ml/min (usually) -Drugs often dosed in ranges: CrCl <30ml/min; 31-50ml/min; >50ml/min (If CrCl is less than 30ml/min, you give a certain dose) -Reference: young healthy adult male is around ______ml/min -Females: ______ ml/min

"decay"

Half-life (T1/2): time for drug level to ________ by 1/2. -The half-life of a drug impacts appropriate dosing interval -Ex: if taking a drug with a half-life of 5 hours, taking 1 pill a day doesn't put you at steady state (take it 3x per day)

0.83kg 0.75kg

Ideal BW (60" = 5 feet) Adjustment for <60"...BEST Guess: Males: SUBTRACT ______kg from IBW for each inch <60" Females: SUBTRACT _______kg from IBW for each inch <60"

Males: 50+ 2.3(each inch > 60") = ____kg Females: 45.5+2.3(each inch > 60") =____kg

Ideal BW Males: ________________ = ____kg Females: ______________ =____kg

Enzyme Inhibitors Enzyme Inducers

Inhibition & Induction (CYP 450 System) -____________: BLOCK metabolism of substrate which leads to INCREASED concentration of said substrate in body (Increased toxicity) -_____________: ACCELERATE metabolism of substrate which leads to DECREASED concentration of said substrate in body

Drug-Drug

Inhibition & Induction (CYP 450 System) CYP 450: MAJOR FACTOR in __________ Interactions! -Leads to sub-therapeutic response OR potential toxicity

problem in the elderly, HIV pts, transplant pts, in seizure meds, etc.

Inhibition & Induction (CYP 450 System) Enzyme inhibitors and enzyme inducers are a problem in what populations of patients?

Correct answer = B. Because of its high molecular weight and high protein binding, KR2250 will be effectively trapped within the plasma (vascular) compartment and will have a low apparent volume of distribution.

KR2250 is an investigational cholesterol-lowering agent. KR2250 has a high molecular weight and is extensively bound to albumin. KR2250 will have a(n) ____________ apparent volume of distribution (Vd). A. High B. Low C. Extremely high D. Normal

toxicity

Loading Dose Disadvantages of loading doses include increased risk of drug __________ and a longer time for the plasma concentration to fall if excess levels occur.

VOLUME F = 1

Loading Dose LD = Concentration desired x Vd (will be given formula on exam) -Loading dose is GREATLY impacted by __________ -Sometimes rapid obtainment of desired plasma levels is needed (for example, in serious infections or arrhythmias). Therefore, a "loading dose" of drug is administered to achieve the desired plasma level rapidly, followed by a maintenance dose to maintain the steady state. -F (bioavailability) if giving a drug IV = _________

volume drug clearance

Loading dose is impacted by the patients ____________, maintenance dose is impacted by a patients ______________

CLEARANCE

Maintenance dose(MD) (important in antibiotics, seizure drugs, antiarrhythmic drugs, etc.) -Accounting for drug LOSS/removal from body (metabolism/excretion) -GEATLY impacted by drug ____________

BMI = Weight (kg) / Height (m2)

Obesity Body Mass Index (BMI): Measure of an adult's weight in relation to height, BMI = ____________

30

Obesity = Body Mass Index (BMI) of _____ or higher

increased decreased liver

PK implications of Obesity Metabolism 1. Higher cardiac output -Short-term obesity: _________ CO (heart trying to pump more blood) -Long-term obesity: __________ CO, water retention, & enlarged liver = body hangs onto drugs & becomes toxic 2. Enlarged _______ with variable effect on metabolic pathways

renal

PK implications of Obesity ·Excretion -Higher ________ blood flow -Higher GFR: How does this relate to "norms?"

Distribution

PK implications of Obesity __________: -Higher percentage body fat (lipid-soluble drugs hang out in fat) -Lower percentage of lean tissue and body water

Absorption Distribution Metabolism Elimination

Pharmacokinetics refers to what the body does to a drug, whereas pharmacodynamics describes what the drug does to the body. Four pharmacokinetic properties determine the onset, intensity, and duration of drug action

polar eliminate

Phase I Rxns: - Simple, mask/unmask a functional group - Outcome makes the molecule more ________ and easier to _________ or conjugate

conjugation bigger

Phase Reactions Phase I and Phase II Reactions ·Phase II Rxns: -Consists of __________ reactions (Often forms a conjugate) - Adds something __________ to molecule (sulfonation, glucuronide formation, etc.) -If the metabolite from phase I is sufficiently polar, it can be excreted by the kidneys. However, many phase I metabolites are still too lipophilic to be excreted. -A subsequent conjugation reaction with an endogenous substrate (such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid) results in polar, usually more water-soluble compounds that are often therapeutically inactive. -The highly polar drug conjugates are then excreted by the kidney or in bile

functional

Phase Reactions Phase I and Phase II Reactions -PK: what the body does to the drug to eliminate it (Phase I & II are ways the body does this) Phase I Rxns: Convert lipophilic drugs into more polar molecules by introducing or unmasking a polar_________ group (such as -H or -NH2) - These rxns involve reduction, oxidation, or hydrolysis -Phase I metabolism may increase, decrease, or have no effect on pharmacologic activity

INACTIVE active

Pro-drug: administered in ____________ form & converted to __________ form in the body via metabolic process

LARGE SMALL

Volume of distribution (Vd): -Although Vd has no physiologic or physical basis, it can be useful to compare the distribution of a drug with the volumes of the water compartments in the body. TAKE AWAY: - drugs with _________ Vd readily distribute in the body (go many places in body) -Drugs with _________ Vd tend to keep significant amounts in circulation & are LESS easily to distribute in tissues (more confined to the vasculature/blood stream/plasma) -It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0)

drug concentration

Zero Order Kinetics (elimination) Ex: 1000mg in body; after 1 hour, 900mg in body; after 2 hours, 800mg in body, etc. -always eliminating 100mg, but 100mg is a different % of 1000mg than it is for 900mg -The rate of metabolism remains constant over time; a constant amount of drug is metabolized per unit of time -The rate of elimination is constant and does not depend on the ____________ · Ex: aspirin, ethanol, phenytoin

Adjusted

___________ BW: An educated calculation to adjust dosing of some drugs in obese patients. -Attempt to prevent UNDER as well as OVER dosing. -Often used in patients who are >about 30% OVER IBW

Volume of distribution (Vd):

___________: the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma -A volume that would be required to account for all drug in body if it were present in the same concentration as plasma

· Ideal

____________ BW: Calculation based upon population averages...what we think somebody "should weigh" for a given height/gender (Assumed weight based on the population average)

Actual (Total)

____________ BW: Sold "as is"....that's skinny or obese

Bioavailability (F)

_____________: Fraction of PO reaching systemic circulation when compared to IV standard of 1 -i.e. IV Ciprofloxacin compared to PO: 400mg IV = 500mg PO; therefore, F = 0.8

Maintenance dose(MD)

______________: ongoing dose required to maintain a given plasma level -Aka the daily/hourly dose needed to keep the drug in the body

Concentration Steady State (Css)

_______________ = Drug concentration in the body at "steady state." Takes 3-5 drug half-lives to attain steady state

Zero Order Kinetics (elimination)

_______________: amount of drug eliminated does NOT change with concentration remaining but FRACTION eliminated does (less common model)

First Order Kinetics (elimination)

________________: amount eliminated over time (a half-life) changes but the FRACTION eliminated is constant (most common model)

Loading dose(LD)

________________: dose to rapidly (initially) achieve a desired plasma concentration

Glomerular Filtration Rate (GFR)/ Creatinine Clearance (CrCl)

__________________: Important for dosing drugs with Renal Clearance - Important in the elderly! Impacts clearance/excretion