Lecture 4: pharmacokinetics Flashcards
whats is the acronyms for pharmacokinetics
“ADME” absorption distribution metabolism excretion
Factors Affecting Drug Absorption
- rate of dissolution (e.g., of tablet)
- surface area
- blood flow
- lipid solubility
- pH partitioning
what kind of transport do most drugs use?
simple diffusion- non protein mediated transport
what is a major transporter of drugs OUT of cells?
P-glycoprotein (active transport)
why is aspirin better absorbed in the stomach?
is a weak acid
becomes trapped in basic compartments (looses H+ and becomes charged)
why is amphetamine no absorbed in the stomach?
weak base
becomes trapped in acidic compartments because can’t lose extra H+
what factors effect drug distribution?
• ability of drugs to enter the cells (= same considerations as for absorption above) • blood flow to tissues • ability of drugs to exit the vascular system (next)
what kind bind drugs in vasculature?
protein (albumin)
-drug is not bioactive
what type of drugs does the blood brain barrier let through?
lipid soluble
ionized or polar ONLY IF HAVE TRANSPORTER
what are sites of peripheral drug concentration?
1) Fat
2) tissue (muscle, liver)
3) bone (tetracyline)
4) transcellular reservoirs (GI tract)
what is the primary site of biotransformation or metabolism?
liver
what does the liver do with drugs?
1) may activate a prodrug
2) crucial for renal elimination of lipophilic drugs (makes them more polar so trapped)
what are secondary areas of drug metabolism?
– kidney proximal tubules – lungs (type II cells) – intestines – testes (Sertoli cells) – skin epithelial cells – brain – plasma
what are the two phases of drug metabolism (biotransformation)?
phase 1: oxidation, reduction, hydrolysis
phase 2: conjugation
what enzymes do oxidative process use?
those found on smoother ER (cytochrome P 450)
phase II biotransformation: conjugation
makes drugs more water soluble and more excretable (molecule added= very polar)
Glucuronidation
–major route of metabolism for drugs and
endogenous compounds (steroids, bilirubin)
–occurs in the endoplasmic reticulum
–inducible
sulfation
–another major route of drug metabolsim
–occurs in the cytoplasm
– acetylation and methylation
• typically makes drugs less water soluble
• addition of these groups by transferases tends to reduce drug activity;
i.e., inactivates drug
what decreases bioavailability of orally administered drugs?
first pass metabolism
-goes into portal vein to liver and doesn’t get into bloodstream
what is the major route of drug excretion?
renal
what are nonrenal routes of drug excretion?
- bile
- sweat
- breath
- breast milk
what are the steps in renal drug excretion
1) glomerular filtration
- small molecules filter
- proteins dont
2) passive tubular reabsorption
- lipid soluble drugs
- unionized weak acids and bases
3) active tubular secretion
- protein bound drugs
Factors that Modify
Renal Drug Excretion
• pH-dependent ionization (shown above under absorption) • competition for active tubular transport • age... GFR falls in all as we age
Excretion rate:
the mass eliminated per unit time
3⁄4 with first order kinetics, this increases as the plasma
concentration increases
Clearance:
the plasma volume from which all of the
solute is removed per unit time (i.e., ml/min = a flow rate)
3⁄4 with first order kinetics, this remains constant as plasma
concentrations change
Zero order kinetics
• constant amount eliminated per unit • the drug elimination process is saturated • consequently, the amount of drug eliminated is independent of the drug concentration
First order kinetics
constant fraction is eliminated per unit
time
drug elimination process is not saturated
the mass of drug eliminated is
directly related to the drug concentration
Capacity-Limited Reactions
• displays zero order kinetics initially
• displays first order kinetics as the drug
concentration falls
loading dose
initial large dose followed by maintenance dose for drugs with a long half life
ex= digoxin
in the clinic after how many 1/2 lives does steady state need to be approached
4 is minimal acceptable time
