fundamentals in pharmacology 5

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excretion and elimination kinetics

where and how are drugs excreted
exhaled air

biliary excretion of drugs, enterohepatic circulation
common bile duct
small bowel
reabsorbed in ileum
portal hepatic vein

renal excretion, nephron
bowman’s capsule
proximal tubule
loop of henle
distal tubule
collecting duct

renal excretion-how does it occur?
renal excretion involves three processes
-glomerular filtration-if largely bound to PPs it will not be filtered readily
-active tubular secretion-weak acids and bases; competitive inhibition (penicillin and probenecid)
-passive tubular reabsorption-lipid soluble; non ionized
-the amount of drug excreted is the sum of amount filtered and secreted minus the amount reabsorbed

the nephron and blood supply
metabolism and excretion equals elimination

elimination-what is it?
-process whereby body terminates drug action
-combination of metabolism (biotransformation) and excretion.
-elimination of a drug from the body will require eliminating the drug from several sites-in liver and muscle typically involves biotransormation; in kidney typically excretion
-rate of elimination is called clearance

model of drug metabolism review
free drug goes to adipose tissue, receptor binding, lung, peripheral tissues, kidneys, liver
PP bound drug goes to liver, bile, intestinal reabsorption

-for most drugs rate of elimination is directly proportional to the concentration of the drug attained in clinical settings
-elimination is not saturable-called “first order kinetics”
CL=rate of elimination/concentration (C)

may be defined as a function of clearance from each elimination site
CLkidney=rate of elimination/C or liver or other

the kinetics of drug elimination-first order elimination
-first order kinetics-elimination of drug is directly proportional to plasma concentration
-it is dependent on its half-life
-no matter the concentration 50% eliminated by its first half-life
-it is time dependent
-half-life is 30 minutes; give 2 gm, in 30 minutes 1 gm is left
obedient, follows orders

zero order elimination
-zero order elimination-not dependent on time or concentration
-takes a linear approach on graph
-independent of concentration
-rarely found
-reactants concentration does not change as the process proceeds
-may see in overdose situations-
-drug may follow first order elimination with low dose and zero order in high doses
-unruly, doesn’t follow orders

elimination half-life
-time required to eliminate half of the amount of drug in the body or to reduce the plasma concentration by 50%-denoted as T1/2
-it is calculated from the plasma concentration curve following administration of a single dose of a drug
-only used for first order kinetics drugs
-it will be affected by anything that changes the volume of distribution or the clearance

drug half-life and clearance
-see curve
-plasma drug concentration
-clearance volume
-amount of drug excreted per unit of time

how long does it take for the body to eliminate 100mg of drug x?
-100mg of drug in plasma at time zero and drugs half-life is 4 hrs?
-50% of drug is eliminated in one half life
-50mg remains at 4 hrs
-25mg in 8 hrs
-12.5mg in 12 hrs
-6.25mg in 16 hrs
first order drugs have >90% eliminated in 4 half-lives

-a few drugs exhibit capacity limited elimination
-called zero order kinetics
-ex. include alcohol, phenytoin

alcohol metabolism-zero order kinetics
-150 lb male college student drinks 5 pints of beer (140 mg) over 3 hr period ; goes to bed with blood alcohol concentration of 250mg/dl
-t 1/2=1 hr
-half blood alcohol removed each hour
-blood alcohol level at 8 am, 8 hrs later, is <1mg/dl

alcohol mletabolism
-in realty zero order kinetics applies once metabolizing enyzmes are saturated
-alcohol metabolized at rate of ~8 gms/hr
-after 8 hrs 64 gm will be metabolized
-76 gms remain in body
-BAC will be >120mg/dl

-zero kinetics followed at high concentrations
-constant elimination independent of drug concentration-a straight line
at lower concentrations first order elimination followed; proportional to concentration-a concave line

continuous and multiple dose kinetics
-when first order drug is administered continuously/intermittently it accumulates until it reaches a plateau or steady state concentration
-initially administration exceeds elimination
-rate of elimination gradually increases as administration remains constant
-eventually rate of administration equals the rate of elimination
-this is steady state concentration-administration rate equals elimination rate
-time required to reach steady state is independent of dose or rate of administration

drug accumulation to steady state
-percentage of steady-state plasma drug concentration
-infusion started
-infusion stopped
-steady state approached in 4-5 t1/2

steady state concentration
-steady state concentration reached is directly proportional to the drug dose administered per unit time and the elimination half life
-if drug dose is doubled the steady state concentration is doubled
-if elimination half life is doubled the steady state concentration is doubled

-drug administered by continuous infusion will reach steady state at same rate as drug administered intermittently
-the plasma level of the latter will fluctuate

oral dosing of medication
-single dose is insufficient to achieve therapeutic effect
-repeated doses required to attain steady state and therapeutic concentration
-sufficient number of equivalent doses are given at regular intervals so taht the amount given=the amount eliminated
-half life helps guide frequency of dosing
-if the dosing interval is shorter than 4 half lives drug accumulation will occur
-this results in peaks in concentration after drug administration and trough right before the next dose

relationship between frequency of dosing and
-black slowly rising line is plasma concentration with IV infusion
-large peak/trough blue line 24 hr administration
-smaller peak/trough red line is 8 hrly administration

loading dose vs maintenance dose
-loading dose is done to rapidly achieve therapeutic plasma concentration
-z pack
-maintenance dose is given to establish or maintain a desired steady state concentration

summary of key PK concepts
administration-routes, first pass effect, compliance
absorption-factors that determine bioavailabilty
distribution-Vd, three compartments, plasma proteins
metabolism-phase 1 and 2, pharmacogenomics, drug interactions
kinetics of elimination-elimination half life, first and zero order kinetics
drug concentration-dosing

clinical scenarios that change PK
disease states
-liver failure-reduced phase 1 metabolism and reduced albumin
-renal failure-reduced GFR and secretion
-heart failure-volume expansion, reduced circulation
-pulmonary fibrosis-absorption
Post surgical states
-gastric bypass surgery
poly pharmacy
-drug-drug or drug-food interactions
-enzyme induction or saturation
enzyme polymorphisms

age effects
-higher Vd for fat-soluble drugs and drugs bound to PPs
-reduced oxidative metabolism
-reduced capacity to excrete drugs; reduced GFR, reduced secretion

completed PK section of course
-list elements that make up pharmacokinetics
-differentiate between PK adn pharmacodynamics
-describe different routes of drug administration
-define absroption and identify relationship between administration, absorption and bioavailabiltiy
-describe the determinants of distribution
-identify the primary sites of drug metabolism
-describe the purpose of metabolism and the processes involved
-describe the determinants of drug metabolism
define the process of drug excretion
-identify relationship between drug metabolism and excretion
-describe the concept of steady state concdntration and what impacts it
-define half life and the kinetics of drug metabolism
-describe impact of age on all aspects of pharmacokinetics

Feedback — Quiz 6.2
You have submitted this quiz on Thu 2 Aug 2012 5:35:32 PM PDT. You achieved a score of 4.00 out of 4.00.
Question 1
Drug A is oxidized in the liver and then removed from the blood by the kidneys. Together these processes are called…
Your Answer Score Explanation
Elimination 1.00 Correct: Elimination is a combination of metabolism and excretion. Clearance refers to the rate of elimination.
Total 1.00 / 1.00
Question 2
Which of the following statements is true?
Your Answer Score Explanation
With drugs that follow zero order kinetics, the rate of elimination is saturable 1.00 Correct: In zero order kinetics, the rate of elimination is saturable after which elimination occurs at a constant rate over time.
Total 1.00 / 1.00
Question 3
Which of the following statements concerning steady state concentration is true?
Your Answer Score Explanation
If you double the half-life of a drug, you will double its steady state concentration 1.00 Correct: Steady state concentration is directly proportional to the dosage of a drug and its half life. The time it takes to reach steady state concentration is usually 4-5 half lives.
Total 1.00 / 1.00
Question 4
You are a physician in the Emergency Department treating a patient found to have pulmonary embolism, a large blood clot in the lungs. You know that the best treatment option for this patient is to give him an anti-coagulant and get the blood concentration to a therapeutic level as soon as possible. Which of the following options is best?
Your Answer Score Explanation
Give a loading dose intravenously 1.00 Correct: An IV loading dose is the best way to quickly reach therapeutic drug levels.
Total 1.00 / 1.00

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