ADME Flashcards
First order kinetic processes
Remove a constant proportion (percentage) of drug
- applies to most oral and extra-vascular administrations
- elimination rate constant primarily determines terminal drug concentrations
Drug disposition is composed of
Absorption
Distribution
Metabolism
Excretion
Biotransport
Movement of drug across biological membranes
Filtration
Open channels allow small molecules to move
- bulk flow
- ex: filtration of drugs at the glomerulus
- water flows freely thru pores
Facilitated diffusion
Passive diffusion that utilizes carrier protein for the solute to cross the membrane (carries substances that would not normally cross)
- uses no energy
- follows concentration gradient
- can become saturated
- ex: glucose
Active transport
Uses carrier protein to move drug against a concentration gradient
- relies on direct expenditure of ATP as energy source
Pinocytosis
Type of endocytosis (cell drinking) used to move very large molecules in a solution inside the cell
- takes in dissolved water soluble molecules that would not normally enter the cell
Passive diffusion
Most common method of biotransport, drugs must pass 3 interfaces (phospholipid bilayer)
- outer water-lipid interface
- lipid membrane
- inner water-lipid interface
- drugs must be water soluble enough to enter aqueous solutions, but lipid soluble enough to traverse lipid membrane*
What allows a substance to cross the lipid membrane?
Lipid solubility
all drugs are water soluble
What attributes must a drug have for biotransport by passive diffusion?
- small: diffusion coefficient inversely related to sq root of MW
- unbound (free) drugs
- lipid solubility
- unionized
What effect does protein binding of a drug have on its ability to passively diffuse?
Most drugs are nonspecifically bound to proteins (acidic drugs bind to albumin, basic drugs bind to glyco/lipoproteins)
- weak (reversible) binding via electrostatic interactions, van der Waals, hydrogen binding
- drug-protein complex is too large to allow for passive diffusion
Regarding drug binding, is bound, unbound (free), or both in an active state to interact with receptors?
Unbound*
Fick’s Law of diffusion
dQ/dt = rate of diffusion A = surface area of membrane h = membrane thickness D = diffusion coefficient Characteristics of solute (drug): Kp = partition coefficient C1-C2 = concentration difference for solute
Rate of diffusion characteristics
- larger the surface area = greater rate of diffusion
- thicker the membrane = slower rate of diffusion
- diffusion coefficient = characteristics of membrane
Lipid-solubility
Oil:water partition coefficient
- greater partition coefficient, higher the lipid-solubility of the drug, and the greater its diffusion across membranes
Most drugs are ______
Weak acids or weak bases
Unionized characteristic
Ionized particles attract water –> cannot pass thru lipid bilayer
- fraction of drug that is unionized depends on chemical nature, pKa, and local pH
Brodie pH partition hypothesis
Uses Henderson-Hasselback equation to predict drug concentration across a membrane
- acidic drugs concentrate on more basic side of membrane (outside cell)
- basic drugs concentrate on more acidic side of membrane (inside cell)
- need to know the pKa and the pH)
Clinical application of Brodie pH partition hypothesis
Basic drugs penetrate intracellularly better than acidic drugs
- ion trapping can be used to enhance renal elimination of a drug or toxin
pKa
pH at which half of a molecule is in its ionized form
Bioavailability versus bioequivalence
Bioavailability: fraction of drug absorbed (F)
Bioequivalence: refers to extent of absorption (bioavailability) and rate of absorption
A drug is considered to be absorbed when it enters _________
Central circulation
Generic formulations must show _______ to pioneer product in order to be approved
Bioequivalence
First pass effect
Removal of the drug by the liver before it enters the central circulation after oral dosing
____ and _____ administration may bypass the first effect
Rectal and buccal
What is enterohepatic recirculation and how does it affect bioavailability?
Drug already in the central circulation is removed by the liver but then reenters the circulation
- falsely increases value of F to greater than 100%
- give activated charcoal to prevent drugs/toxins from being reabsorbed
Diffusion limited distribution
Distribution is diffusion (permeability) rate limited when:
- drug is ionized and polar (water soluble), such that physiological barriers restrict the diffusion of such drugs into the cell
- most drugs
Perfusion limited distribution
Perfusion rate is the volume of blood that flows per unit time per unit volume of the tissue (ml/min per kg of tissue)
- greater blood flow = faster distribution
- extent to which a drug is distributed in a particular tissue depends on the size of the tissue and the tissue blood partition coefficient of the drug
Distribution is perfusion rate limited when
- drug is highly lipophilic
- drug is easily diffused through highly permeable membrane (capillaries, muscles)
Restricted vascular space (category 1)
Most restrictive
- can not pass thru endothelium
- drugs bound to blood constituents (ex: protein bound portion of drug)
- rare (ex: hetastarch)
Restricted to extracellular space (category 2)
Free portion of drug with moderate protein binding able to pass thru endothelium
- limited lipid solubility (primarily water soluble)
- highly ionized
- ex: penicillin, does not cross inside cell, but can move into extracellular fluid
Category 3
Crosses most cell membranes and tissue barriers
- moves into WBC, overcomes blood-placenta, blood-milk, blood-prostate barriers
- free portion of drugs with moderate protein binding
- moderate lipid solubility
- unionized drug (ion trapped, as tissue pH is acidic vs plasma)
Category 4
Crosses all barriers
- blood brain, blood aqueous humor, blood testicular barriers
- highly lipid soluble, low protein binding, non ionized
How do neonates differ from adults relative to percentage of body water and how might this affect the dose of a water-soluble drug given to a neonate
Neonates have a larger percentage of body water
- larger Vd for drugs that distribute primarily to extracellular space (cat 2 distribution)
- lower albumin –> lower protein binding and greater distribution with greater excretion (unbound drug)
How effective is the blood-placental barrier against penetration of most drugs?
No barrier!
- exception: heparin
Storage sites for drugs
- fat
- bone: chelation to calcium, or active transport using calcium transporter
- stored drug is biologically inactive until mobilized
How do lipid soluble drugs differ from water soluble drugs regarding absorption and excretion?
Lipophilic: readily absorbed/stored
Hydrophilic: readily excreted
Major routes of elimination
Kidney - filtration, secretion, reabsorption - pH influence Liver - digestive tract (feces)
Urine and feces are ________
Aqueous media
- lipophilic agents cannot partition into urine or feces and cannot be excreted (bioaccumulation)
____ has a large influence on reabsorption
pH
Minor routes of elimination
- respiratory tract (major route for volatile anesthetics)
- tears, sweat, milk
Which domestic animals are born with renal function near adult levels?
Foals and ruminants
- GFR adult at 2 days, secretion adult at 2-4 days
Which domestic animals are born with hepatic function near adult levels?
Foals
- rapid hepatic metabolic development occurs in the first 3 days of life
What is biotransformation
Metabolism
- chemical alteration of molecule
- tissues: liver most active, kidney, skin, intestine, adrenal are moderately active
- enzyme-mediated (protein, chemical catalyst, lowers activation energy for rxn)
Cytochrome P450
Enzyme family with broad substrate specificities
- most significant of all drug oxidation reactions
- important in detoxification of many compounds
- can cause bioactivation
In what organ does biotransformation primarily occur?
Liver
Does biotransformation always inactivate a drug?
No, could result in no change in toxicity or result in greater toxicity
Phase 1 of biotransformation rxn
Nonsynthetic reaction
- adds or uncovers a reactive group
- makes molecule more chemically reactive, metabolite can be same, less, or more active
- more likely to undergo phase 2 metabolism
- oxidation or hydrolysis
Phase 2 of biotransformation rxn
Synthetic reaction
- adds an endogenous ligand
- makes more polar and water soluble, and usually detoxifies
- ligand interacts with reactive group and metabolite is inactive (rare exceptions)
- conjugation reactions
Cats are deficient in what enzyme system involved in biotransformation? State an example where this deficit makes cats more susceptible to drug toxicity
Glucuronyl transferase
- metabolism of many drugs altered, leading to toxicity
- ex: acetaminophen toxicity, if body has enough glutathione then body is safe, if not intermediates build up and covalently bind leading to cell death
Enzyme inhibitor
Decreases activity of metabolic enzymes, thereby decreasing the rate of metabolism of other drugs
- immediate onset due to chemical reaction
Enzyme inducer
Increases the amount of enzymes available for metabolism, thereby increasing the rate of metabolism of itself (autoinduction) or other drugs (induction)
- requires several weeks
