Pharmacokinetics Flashcards
Pharmacokinetics
- Absorption
- Distribution
- Metabolism
- Excretion
Pharmacodynamics
- Drug-receptor interaction
- Patient’s functional state
- Placebo effects
Factors affecting drug absorption
- rate of dissolution
- surface area
- blood flow
- lipid solubility
- pH partitioning
3 ways for drugs to cross the cell membrane
- facilitated diffusion through channels and pores (rare)
- active transport system (requires energy, saturable)
- direct penetration of the membrane = simple diffusion
Polar drugs have either:
- a fixed charge
- no net charge but charge separation
(are more readily dissolved in polar solvents. Do not dissolve in and cannot readily cross cell membranes)
Nonpolar drugs
- readily dissolve in nonpolar solvents
- readily cross cell membranes
pKa
pH where exactly one half of weak acid is ionized
Weak acids and bases can only cross membranes in their _______ form
unionized
Ka
rate constant for absorption
S
salt factor
- drugs often administered as their salt, but only parent compound is measured
F
bioavailability, fraction of drug that reaches the bloodstream
Amount absorbed equation
S x F x Dose
F equation
AUC(oral) / AUC(iv)
Factors affecting drug distribution
- ability of drugs to enter the cells
- blood flow to tissues
- ability of drugs to exit the vascular system
Protein binding of drugs
- get partial retention of drugs in vasculature
- there’s a finite number of protein binding sites in the plasma. because of this, addition of new drug can displace bound protein
- of concern if drug has small therapeutic window
Blood-Brain Barrier
barrier to ionized or polar drugs unless they have a transporter
Concentration in Plasma (Cp) Equation
S x F x Dose / Vd
Vd = volume of distribution
Vd Equation
Amount of Drug in body / Plasma concentration
Sites of Peripheral Drug Concentration
- fat (lipid soluble)
- tissue
- bone (calcium rich regions)
- transcellular reservoirs (GI tract for drugs slowly absorbed or undergoing enterohepatic circulation)
Primary site of biotransformation
- liver
Drug metabolism
- may activate a pro-drug, but primarily inactivates drugs
- metabolites may be more or less active and have a longer or shorter half-life
- crucial for the renal elimination of lipophilic drugs, which must be made more polar so they can be trapped in the renal tubular fluid
Secondary Sites/Organs of Drug Metabolism
- kidney proximal tubules
- lungs (type II cells)
- intestines
- testes (Sertoli cells)
- skin epithelial cells
- brain
- plasma
Biotransformation
- types of drug metabolism
Phase I metabolism
Oxidation, reduction, hydrolysis
Phase II metabolism
conjugation
Phase I biotransformation
- products are usually more polar metabolites (from unmaking or introducing a functional group)
- oxidative processes often involve enzymes located in the SER
CYP P-450 inducers
- increase level of the enzyme and speeds up metabolism
- phenobarbitol
- carbamazepine
CYP P-450 inhibitors
- inhibit enzyme and slows metabolism
- can lead to toxic level
- erythromycin
- ketoconzaole
Grapefruit juice
- inhibitor of CYP3A4 enzyme
- inhibition in the intestinal epithelial cells increases the bioavailability of other drugs metabolized by the enzyme
Phase II Biotransformation
- synthesis reactions
Phase II - conjugation
- usually makes drugs more water soluble and more excretable since the molecule added is highly polar
- glucoronidation
- sulfanation
Glucaronidation
- major route of metabolism for drugs and endogenous compounds (steroids, bilurubin)
- occurs in ER
- inducible
Sulfanation
- another major route of drug metabolism
- occurs in cytoplasm
Phase II - acetylation and methylation
- typically makes drugs less water soluble
- addition of these groups by transferases tends to reduce drug activity; inactivates drug
First-Pass Metabolism
- can greatly decrease the bioavailability of orally administered drugs
Drug Elimination
- renal route of drug excretion (major)
- nonrenal routes of drug excretion (bile, sweat, breath, breast milk)
Steps in Renal Drug Excretion
- glomerular filtration: small drugs
- passive tubular reabsorption: lipid soluble drugs, unionized weak acids and bases
- active tubular secretion: protein-bound drugs
Factors that modify renal drug excretion
- pH dependent ionization
- competition for active tubular transport
- age: GFR falls as we age
Excretion Rate
- mass eliminated per unit time
- increases as plasma concentration increases in first order kinetics
Clearance
- the plasma volume from which all of the solute is removed per unit time
- with first order kinetics, remains constance as plasma concentrations change
Total Clearance
renal clearance + hepatic clearance + other clearance
