Exam 1 - Lecture 3 & 4, Drug ADME Flashcards
Structure and physiochemical properties of cell membranes
Lipid bilayer with protein embedded…
Polar, ionized groups of molecules located on surfaces
Hydrophobic, non-polar lipid side chains oriented toward inside of membrane bilayer
Membrane contains aqueous channels of small diameter so permit passage only of water of small water-soluble molecules or ions
Most drugs must cross membrane by diffusion through it, therefore they must dissolve in lipid layer.
Factors determining diffusion of drugs across membrane
Concentration gradient (Fick’s law”
Lipid solubility of drug, many drugs weak acids or bases
Drug ionization acids
If pH is lower than pKa -> 50% non-ionized
If pH is above pKa -> 50% ionized
Drug transport bases
If pH is lower than pKa -> 50% ionized
If pH is above pKa -> 50% non-ionized
Drug trapping
Weak acids excreted faster in alkaline urine
Weak bases excreted faster in acidi urine
Drug diffuses across membrane, then becomes ionized and trapped so cant be reabsorbed and thus gets excreted
Body fluids in which pH differences from blood pH cause trapping
stomach (pH 1.9-3)
small intestine (pH 7.5 -8)
Rates of permeation
log P > -5.0 = good permeation
log P < -5.0 = bad permeation
Active transport
requires energy, selective, saturable
can operate against electrochemical gradient
Facilitated transport
no energy required
cannot operate against electrochemical gradient
Facilitated transport transporters
NET, SERT, VMAT
Active transport transporters
MDR1 ( transport xenobiotics out of cells)
MRP1 ( Leukotriene secretion)
Factors that modify absorption
Lipid solubility and degree of ionization
Dissolution rate - solubility at absorption site
Concentration at site of absorption
Circulation to site of absorption
Area of absorptive surface
Molecular size
Oral administration
Advantages: safest, most convenient and economical, no special devices
Disadvantages: low pH or food can alter absorption are, patient compliance
weak acids best absorbed in stomach (pH 1)
weak bases best absorbed in intestine (pH 1-7)
sublingual administration
special form of oral drug admin
absorption across oral mucosa of certain non-ionized, lipid soluble drugs
IV administration
Advantages: speed, accuracy, control, useful in emergency situations, titrate dosage, can give large volume
disadvantages: no turning back, must inject slowly, risk of adverse effect from too rapid injection
IM administration
Advantages:
can control rate of absorption, suitable for depot-type injection, less pain than s.c.,
sites with highest blood flow allow fastest absorption.
slow absorption from oils or other vehicles
SC administration
Advantages:
can control rate of absorption; suitable for insoluble suspensions, pellet implants
Disadvantages:
possible pain, necrosis at injection site
Topical administration
at mucous membranes - absorption is rapid
at skin surface - most drugs not readily absorbed; proportional to lipid solubility at epidermis
Inhalation administration
absorption across pulmonary alveolar epithelium
rapid access to circulation due to large surface area
major means by which toxic substances enter body; allergens and environmental contaminants
Intrathecal administration
injection into spinal subarachnoid space
for admin to cerebrospinal axis of drugs which do not cross BBB
Intra-arterial
for high local conc of drug in certain tissue
Intraperitoneal
used in experimental lab procedures, rarely used clinically
Drug route + bioavailability
IV = 100%, most rapid onset IM = 75-100%, larger volumes more often feasible SC = 75-100%, smaller volumes than IM Oral = 5-100%, most convenient Rectal = 30 - <100%, less 1st pass than oral Inhalation = 5 - <100%, rapid onset Transdermal = 80 - <100%, used for lack of 1st pass
Factors which contribute to unequal distribution of drugs
BBB, drug reservoirs
Drug distribution factors BBB
Capillary endothelium lacks intracellular pores
Astrocyte “glial feet” surround capillaries
“tight junctions” between endothelial cells
Plasma protein binding as reservoir
many drugs bind to albumin
binding usually reversible, provides depot
plasma protein binding limits conc of free drug in tissues
as unbound drug conc falls, protein bound drug is freed; process prolongs drug effect
protein binding capacity limited, therefore saturable
drugs can compete for binding sites, displacement of 1 can increase activity of other (adverse drug interactions)
Fat as a reservoir
many lipid soluble drugs conc in fat
a “stable” reservoir since blood flow is low
Renal excretion
most important route
Ionized, polar form better eliminated than unionized
3 proceses in kidney excretion
Glomerular filtration:
blood filtered, unbound drug passes through pores into filtrate, protein bound drug cannot pass pores and remains in blood
Active tubular secretion:
ionized drug actively transported from blood into proximal tubule
Passive reabsorption:
unionized drug can passively diffuse out of proximal and distal tubules back into blood
Maintenance dose
Dosing Rate/F X Dosing interval
Dosing rate = Clearance X Target Conc
F = f X (1 - ER)
ER = CLliver / Q
Loading dose
Volume of Distribution X Target Conc
promptly raises the concentration of drug in plasma to the target concentration
Bioavailability
the fraction of unchanged drug reaching the systemic circulation
Zero - Order kinetic processes
Constant amount of drug is processed per unit time, rate is constant, independent of drug concentration and encountered rarely
1st order kinetic processes concept equation
Constant fraction (or %) of drug is processed per unit time. rate of process is exponential
ka = rate constant for absorption ke = rate constant for elimination
Capacity - limited elimination
If dosing exceeds elimination capacity, steady state cannot be achieved.
concentration keeps rising as dosing continues
Flow - dependent elimination
Drugs cleared very readily by organ of elimination, so that any clinically realistic concentration of the drug is eliminated on 1st pass.
These drugs are known as “high-extraction” drugs
T1/2
time required for 50% completion of the process
in 4 half-times, 95% drug gone/ process complete
k X T1/2 = 0.693
Clearance
measure of the ability of body to eliminate drug
CL = rate of elimination / C
Volume of distribution
measure of apparent space in body available to contain drug
V = Amount of drug in body / C
