Drug disposition & Fate of drugs Flashcards
MUST have some ability to dissolve in WATER to move around (be
absorbed, reach sites of action.)
Drugs
must also have a
certain degree of lipid solubility to move around (leave and enter capillaries,
enter and leave cells.)
Drugs
Drug concentrations in the ____ (measured in either serum or plasma)
are USUALLY proportional (and usually linear) to drug concentrations at the
site of action.
blood stream
Drug concentration in the _______ is ALMOST ALWAYS an excellent
predictor of drug action (either efficacy or toxicity)
blood stream
are the consequence of physiologic process (that may or
may not be altered by disease.)
Pharmacokinetics
are the PRIMARY difference between basic and clinical
pharmacology.
Disease-included differences
are the PRIMARY difference between
Veterinary pharmacology and Human pharmacology”.
Species differences in pharmacokinetics
General Principles of Routes of Administration (Drug Absorption)
Drug dissolve in body fluid (water).
Drugs enter the circulatory system as fluid enters the circulatory system.
Drugs must enter the circulatory system before they can distributed to sites of
action.
(Drugs for enteric effects are an obvious exception.)
Therefore, drugs are not IN the body until they are IN the bloodstream.
Advantages of Oral administration
Convenient, cheap, no need for sterilization, variety of dose forms
(fast release tablets, capsules, enteric coated layered tablets, slow release,
suspensions, mixtures)
You can get the dose back of you move fast enough.
Disadvantages of Oral administration
Variability due to physiology, feeding, disease, etc.
Intractable patients
First-pass effect
Efficiently metabolized drugs eliminated by the liver before they reach the
systematic circulation.
Patient and Pharmaceutical Factors
Pill compression, coatings, suspending agents, etc.
GI transit time (too slow or too fast), inflammation, malabsorption, syndromes
Regional Differences of Oral administration
Stomach
mechanical preparation
“flat” absorptive surface
pH extreme
Rumenoreticulum
stratified squamous epithelium
pH varies with diet
metabolism by bacterial flora
significant volume of fluid compared to body water
Small Intestine
large absorptive functions
relatively neutral pH
Colon/Rectum
accessible
large absorptive surface
The bolus remains relatively spherical.
Liqid soluble vehicle
entry of drug into
circulatory system limited by rate of drug ______ (Movement from the
“bolus” to the tissue fluid).
“dissolution”
Advantages of Subcutaneous Administration
Can be given by the owner (small patients)
Vasoconstrictor can be added to prolong effect at site of interest
Disadvantages of Subcutaneous Administration
Variability
Much like intramuscular (though the architecture of the tissue is much different)
process of subcutaneous
Patient and Pharmaceutical Factors of Subcutaneous
More autonomic control over blood flow (than muscle)
dehydration, heat, cold, stress
Topical Advantages
IF systemic therapy – easy painless application (e.g. mass medication of cattle)
IF skin therapy – reduced systemic effects/enhanced skin effects
Topical Disadvantages
Patients groom themselves (topically applied, orally absorbed)
Toxic skin reactions
Variable blood flow to skin
COMPLEX relationship between drug, vehicle , skin physiology
process of topical
Diffusion through stratified epithelium
“Passage” through adnexal structures
Patient and Pharmaceutical Factors of Topical
Lipid solubility and molecule size
Skin hydration and abrasion
Area of application
Ambient an patient temperature
Vehicle Effects of Topical
“like” vehicles retain drug on skin surface
(e.g, aqueous drug in aqueous vehicle, lipid drug in lipid vehicle)
Drugs in “unlike” vehicles leave the vehicle to move on to skin
(e.g, aqueous drug in lipid suspension, lipid drug in aqueous suspension)
Intraperitoneal Advantages
Larger absorptive surface are than IM / Subcutaneous
Intraperitoneal Disadvantages
Drugs or vehicles may cause peritonitis
Damage to organs by needles
Injection into organs
Patient and Pharmaceutical Factors of Intraperitoneal
Generally restricted to laboratory animals.
Intrathecal Advantages
Direct delivery to site of action
Disadvantages Intrathecal
Difficult dose calculation
Intrathecal
CSF volume is not proportional to body weight
Toxicity likely, and toxicity may be unusual
Introduce infection into a VERY bad location
Process Intrathecal
Absorption is usually by diffusion and very slow
Intra-actular Advantages
Direct delivery to site of action. High concentrations can be produces in the
joint.
Disadvantages Intra-actular
It may be difficult to hit the joint space depending on the species (size of joint
space).
Difficult dose calculation
Joint space volume depends on disease
Introduce infection. (PSGAG - Adequan® - interjections now generally get
“antimicrobial chaser”)
Joint “flushes: don’t count.
Process Intra-actular
Absorption from the site to systemic is variable but often quite fast. Systemic
concentrations of the drug may be produced. Effects in joint may not persist.
(Drug and dose form dependent)
Used primarily for anti-tumor therapy and infectious
disease therapy when blood supply is questionable.
Intra-arterial
Produce extremely high concentrations “pointed at” (this is not really targeting)
the tissue of interest.
Intra-arterial (advantage)
Disadvantages Intra-arterial
Dose calculation is best guess.
Intra-arterial lines difficult to insert/maintain.
Dosing is still really systemic.
Limited number of efficacy studies (especially in animals)
Process of Intra-arterial
Produce AND SUSTAIN high blood-to-tissue gradient to increase tissue
concentrations of drug. Requires sustained infusion or application of tourniquet
following bolus dosing.
Per rectum advantages
Access to GI absorption in unconscious or vomiting patients
Drug can be recovered before absorption is complete
Per rectum disadvantages
Animals may not willingly retain the drug
Process Per rectum
As for oral without mechanical preparation by stomach
Drug Distribution Physiologic “spaces”
Vascular space (plasma / plasma water + RBC’s)
There is also “tissue space”
Size -7% of body weight
Equilibria
between water and various plasma / serum proteins
between ionized and unionized drug
between ionized and unionized drug
between plasma and cells
Distribution in 10 to 30 minutes (mixing)
Extracellular Space (exist in both vascular and tissue spaces)
Size
15 – 20% of body weight
includes extracellular fluid in bloodstream (plasma)
Equilibria
between water and proteins
between ionized and unionized drug
Distribution in 30 minutes to 1.5 hours
Intracellular space (exist in both vascular and tissue spaces)
Size
35 – 45% of body weight
Equilibria
between ionized and unionized drug
intracellular pH different (lower) than extracellular
Distribution in 30 minutes to 12+hours
Reserved spaces
Special barriers between plasma and tissue fluid CSF
aqueous humor
prostatic fluid
Distribution in minutes to never
Movement between spaces
Vascular space (extracellular) to tissue (extracellular) space
Transcytotic
Endothelial junctions wit inflammation
Diffusion through endothelial cell membranes
Carried in cells or on proteins in very special circumstances
Extracellular space (of tissue) to intracellular space (of tissue)
Diffusion through lipid bilayer of cells
Vascular extracellular space to vascular intracellular space (drugs can mocve
into RBC’s and WBC’s)
Diffusion through lipid bilayer of cells
WBC may actively acquire certain drugs
Diffusion Limited Distribution
Diffusion is usually slow (relative to mixing and distribution within vascular
system)
Tissue distribution of the drug controlled by the ability of the drug to diffuse into
the tissue
Blood flow limited distribution
Diffusion can be VERY rapid
Tissue distribution of the drug controlled by the rate of drug delivery to the tissue
(total mg/minute) which is controlled by blood flow / gram of tissue
Brain and liver concentration rise faster than muscle or fat
_____________ concentration rise faster than muscle or fat
Brain and liver
How does Enterohepatic Circulation work?
Drug or it’s Phase II conjugate excreted in bile
Drug reabsorbed or Conjugate cleaved by bacteria and drug reabsorbed
Why do you care? (Enterohepatic Circulation)
interrupt to improve drug elimination
Insecticide poisonings, Phenobarbital overdoses, et
How does Mammary Excretion work?
Non – ionic Diffusion (lipid solubility and size dependence)
Inflammation reduces barriers to penetration (masititis)
Ion trapping
normal milk pH = 6.6 (slightly acidic versus blood)
Mastitic milk pH is slightly higher
Why do you care? (Mammary Excretion)
May affect treatment of some bacterial infections of the mammary gland
Nursing animals may be exposed to toxic concentrations of drug in the milk
The volume of fluid that “appears” to contain the amount of drug in the
body
Volume of Distribution
Partially determines the relationship between dose and plasma concentration
Volume of Distribution
Roughly describes “tissue penetration”
Volume of Distribution
Units
Liters or milliliters describing the whole animal
Liters/kg or milliliters/kg
Defines the volume of fluid that must be processed by organs of elimination
Volume of Distribution
is usually slow (relative to mixing and distribution within vascular
system)
Diffusion
How does Salivary Excretion work?
Non – ionic diffusion into salivary secretions
Drug in saliva passes into GI tract
They can recycle certain drugs like enteroheptic circulation (prolonged elimination)
Can also trap certain drugs in the rumen pH dependent (enhanced elimination)
Ruminants
Conversion of a drug entity to a metabolite
Biotransformation
Chemical Mechanisms of Biotransformation
Oxidation, hydroxylation, hydrolysis, reduction, conjugation, (acetylation,
glucuronidation, sulfation, etc.)
Efficiency (rate) of Biotransformation
Metabolic activity for a specific drug
Blood flow to the organ
Health of the organ and health of the circulatory system
organs involved in biotransformation
Liver (most important for most drugs)
Lungs (especially for autocoids)
Kidneys
Types of Biliary Excretion
Active secretion
Passive secretion
Drugs with molecular weights > 300
mostly conjugates of original drug
Active secretion
Drugs with molecular weights < 300
biliary concentrations similar to plasma water
Passive secretion
Process of Renal Elimination
(Glomerular filtration + tubular secretion) – passive reabsorption = renal
elimination
passive elimination of drug dissolved in plasma water
ionized and unionized
NOT protein bound drug
Glomerular filtration
energy dependent excretion by proximal kidney tubule
organic acid and organic base pumps
includes protein bound drugs
Tubular secretion
Passive reabsorption can be reduced by_____ or by ______
disease (accidental)
therapy (intentional)
The volume of plasma water cleared of the drug during a specified time period.
Clearance
Organ clearance is calculated by determining the ___
flow (Q) and the efficiency of
extraction
C𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 𝑄 𝑥 𝐸
is the sum of all organ clearances
Total body clearance (Clt)
Units of Clearance
Volume / unit time (1/hr, 1/min, ml/hr etc) describing whole animal
Volume / kilogram / unit time (1/kg/hr, ml/kg/min etc.)
The time for elimination of one half of the total amount in the body.
Elimination Half – Life or Half life
longest half – life
gentamicin example
is an initial dose of drug given to shorten the time to reach the
steady-state concentrations.
loading dose
describes the rate of drug movement (oral,
IM, SC, etc.) from the dose to the circulatory system.
Absorption Rate Constant
is a common measure used to
compare two different drug formulations (tablets vs. elixir) or to compare
products sold by two different manufacturers (trade name drugs vs. generics).
Bioavailability
The fraction of the dose absorbed determines a drug’s ____
bioavailability
Attempt to describe the actual events which control drug absorption,
distribution, and elimination
Physiologic models
Attempt to accurately predict the time course of drug concentrations in one
(usually blood or plasma) or two (urine as well) body fluids. Predictions area
generally made for tissues which can be sampled from intact patients.
Mathematic Models
Enumerate Body Compartments
Central Compartment
Blood volume
Organs of elimination
Peripheral compartment
Muscle
Subcutis
Lung Tissue
Deep compartments
Fat (poor blood supply, lipid soluble drugs)
Kidneys (amino glycosides)
If the pharmacokinetics of ABSORPTION change when we increase the dose , the drug is said to exhibit -_____
dose – dependent
absorption
If the pharmacokinetics of ELIMINATION change when we increase the dose ), the drug is said to exhibit____
dose – dependent elimination.
The sum of all individual organ
clearances. Usually determined by
plasma sampling
Clearance, Total
( Clt )
The clearance “performed” by the
kidney.
Clearance, Renal (Clr)
The clearance “performed’ by the
liver.
Clearance, Hepatic (Clh)
Highest plasma concentration
achieved following a single non-
intravenous dose of a drug.
Peak plasma concentration ( Cmax )
Plasma concentration , may be
followed by a subscript for time (Cpt –
see Cp0 below)
Plasma concentration ( Cp )
The plasma concentration at zero
time. Determine by extrapolating the
plasma concentration versus time
“curve” back to the Y (concentration)
axis.
Plasma concentration at
time zero
( Cp0 )
Portion of a non-intravenous dose of
drug that reaches the systemic
circulation.
Fraction of dose absorbed ( F )
Time required to eliminate 50% of
any amount of drug from the body.
Half-life of elimination ( T1/2 )
The time that the Cmax (above) is
achieved following a single non
intravenous dose of drug.
Time of the peak
plasma concentration (Tmax)
The volume calculated using the
intercept of the “z” portion of a curve
and the Y axis
Volume of distribution
( Vz )
Unit for Clearance, Total (Clt)
1/hr/kg
Unit for Clearance, Renal (Clr)
1/hr/kg
unit for Peak plasma concentration (Cmax),
Plasma concentration ( Cp), and
Cp0
mg/ml
(or)
mg/liter
Unit for Fraction of dose absorbed (F)
None or
%
unit for Half-life of elimination (T1/2) and Tmax
hrs (or)
minutes
unit for Volume of distribution ( Vz)
L/kg
