15/16 Pharmacokinetics

Question 1

Absorption

Answer 1

Movement of a Drug from site of administration to bloodstream

Routes of admin:

• Enteral: oral, sublingual, rectal
• Parenteral: IV, IM, SubQ
• Other: inhalation, intranasal, topical (locally and don’t go into bloodstream like eye drops, ear drops, creams), transdermal (applied to skin but reach bloodstream)

[Peak] re: IV is immediate, [peak] re: oral is delayed after admin

Depends on bioavailability

Question 2

bioavailability

Answer 2

• Fraction of drug that makes it into systemic circulation
• When a drug is admin orally, only part of the admin dose appears in plasma
• Defined as “F” (a fraction)
  
  • Ftotal = FGI X FHEP (so if 50% not metabolized/lost in GI and 25% of that not metabolized/lost in liver, .5 x .25 = .125 = 12.5% bioavailability, or 1.25mg of an original 10mg dose)
• Takes into account:
  
  • First pass
    
    • Large first pass = low bioavailability
  • Solubility
  • Chemical instability (can impede how they are absorbed in GI tract)
    
    • Eg salts have “salt fraction”
    • “S”
    • Amt drug system = SxFxdose
  • Drug formulation (some drugs are not meant to be absorbed well, like GI drugs)
• AUC = area under the curve for blood serum [drug] over time
  
  • = total [drug] absorbed over time
  • Ratio = AUC oral/AUC injected x 100 = 100 bioavailability

Question 3

Distribution

Answer 3

• Movement of drug from plasma to tissues
• As soon as the drug enters plasma, it undergoes distribution
• Affecting distribution:
  
  • Physicochemical properties
    
    • Size (more trouble distributing)
    • Ionization (non ionized, uncharged, nonpolar will dist more easily)
  • Protein Binding
    
    • Albumin
    • Tissue proteins
  • Fat solubility
    
    • Will dist in fatty tissues
  • Active transport
    
    • Rapid uptake into tissues
    • Eg iodine in thyroid
• Vd
  
  • Proportionality term
  • Apparent volume into which a drug distributes (volume we think a drug distributes in)
  • Often known
  • L/kg or L/70kg
  • Vd = quantity (mg)/concentration
  • C = Q/Vd
    
    • Quantity takes into account the bioavailability
• Distribution of drugs throughout the body is not instantaneous
• Vd can exceed any physical volume in the body because the Vd represents the total volume and a homogenous concentration
• NOT related to drug class

Question 4

large vs small Vd

Answer 4

• Small Vd = drug resides mostly in plasma
  
  • Some drugs don’t cross membranes readily and have a restricted distribution
  • <1 L/kg
  • Eg caffeine 0.5 L/kg
• Large Vd = drug resides mostly outside plasma compartment
  
  • Some drugs accumulate in body as a result of protein binding, active transport, or high lipid solubility
  • >1 L/kg
  • Eg cyclic antidepressants: desipramine 22-36 L/kg

Question 5

first order elimination

Answer 5

• Fixed PROPORTION of a drug eliminated per unit time
  
  • Rate of elim is [] dependent
  • Most common
  • Linear
  • More effective
• K = rate constant for elmin is just a proportionality constant (like 10%/hr)
• Rate varies as concentration to first power
• Ct = lnC0 - kt
  
  • Slope = -k
  • Negative slope is the elmination constant, k
  • y-intercept is lnC0
    
    • So e ^ y-int = C0

Question 6

zero order elmination

Answer 6

• Fixed AMOUNT of drug is elminated per unit time
  
  • Eg 10 mg of drug per houror 10 mg/100 ccs per hour
  • Independent of concentration
  • Nonlinear (counter-intuitively)
  • Ethanol, aspirin phenytoin
    
    • Ethanol is 25 mg/dL per hour until [] is less than 10 mg (slightly more in chronic alcoholics)

Question 7

elimination

Answer 7

Drug elimination refers to the irreversible removal of drug from the body by all routes of elimination

• May be divided into 2 major components:
  
  • Biotransformation (drug metabolism, usu the liver, could be kidneys or other)
  • Excretion (removal of intact drug, usu in the urine, could be bile, feces, or pulm)
    
    • Intact drug and pharmacologically active metabolites

Question 8

Half life

Answer 8

• Time it takes for 50% of the dose to be eliminated from the body
• Thus, time required for the [drug] in the plasma to decrease by 1/2 is the half-life
• Units for half-life = hr, min, days
• t1/2 = 0.693/k
  
  • Can det how and how frequently to dose a drug!
• t1/2 is inversely proportional to the elmination constant, k
  
  • Big k, steep slope = short half life
• Does not depend on size of administered dose
• 97% of total amount of drug is elminated after 5 t1/2
• Applicable to drugs eliminated via 1st order
• Not applicable to drugs elmin via zero order

Question 9

Clearance

Answer 9

• Clearance (CL) is the volume of plasma from which the drug is completely eiminated per unit time
• Expressed in mL/min or mL/min/kg
  
  • CL = k X Vd
• Useful to calculate the maintenance dose of a drug
  
  • MD = Css X CL
  • MD = Css X k X Vd
    
    • Css is the target concentration = steady state concentration

Question 10

Continuous IV infusion

Answer 10

• Constant infusion of a maintenance dose (MD)
• Continuous IV infusion: a drug is administered continuously and accumulates exponentially to plateau level (Css) with half-time to plateau equal to its elimination half-life
• Time to attain Css is dependent only on drug’s half-life
• It takes 5 elmination 1/2 lives for a constantly infused drug to reach steady state
• MD based on CL
  
  • MD = Css X CL
• Comparing maintenance doses (MD)
  
  • Doubling infusion or giving at a faster rate will double steady state but will happen in the same amount of time
• To reach Css quickly: loading dose
• To be at steady state: maintenance dose
• Loading dose (LD) is not dependent on CL but on Vd
  
  • LD = Vd X Css
• MD based on LD
  
  • MD = LD X k = LD X 0.693/t1/2

Question 11

cockcroft-gault equation

Answer 11

men:

Clcr = ((140-age)*ideal body weight)/(72*Serum cr)

women

Clcr = .85((140-age)*ideal body weight)/(17*Serum cr)

Question 12

clearance and renal vs hepatic insufficiency

Answer 12

• renal
  
  • Decreased renal function will definitely affect clearance of a renally-excreted drug
• Hepatic
  
  • Decreased hepatic function does not necessarily affect the clearance of a drug metabolized in the liver (because the liver metabolizes that well)

Question 13

dose adjustment factor

Answer 13

• Two basic approaches to adjusting the dose of a drug for a patient with renal insufficiency:
  
  • Both require calculation of Creatinine clearance (CLcr)
  • CLcr is a good estimation of renal function : find with labs or crockcroft-gault equations
• Math intensive
  
  • DAF = 1-[fe(1-(CLcr patient/CLcr normal))]
    
    • CLcr patient / CLcr normal is a ratio
  • New Dose = Usual Dose X DAF
  • New interval = Usual Interval/DAF

USER friendly tables are the best

• eg CrCl > 30 to <50, then give 25 mg daily ( = moderate renal disease)
• eg CrCl <30, then give 50 mg daily (= severe renal disease)