General Rules Flashcards
Get a mental picture of what’s going on “inside” (Think about anatomy and histology in terms of “how things work.”)
_______ is a preference not an absolute. “Water Soluble”. “Lipid Soluble”
Solubility
Drug dissolve in
body fluid (water).
Drugs enter the ________ as ____ enters the circulatory system.
circulatory system
fluid
Oral Administration
Advantages
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.
Oral administration
Disadvantages
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.
Oral administration
Patient and Pharmaceutical Factors
Pill compression, coatings, suspending agents, etc.
GI transit time (too slow or too fast), inflammation, malabsorption, syndromes
Oral administration
Regional Differences
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. Mixing and dissolution in tissue fluid occurs from surface of bolus, so entry of drug into circulatory system limited by rate of drug “dissolution” (Movement from the “bolus” to the tissue fluid).
Occassionally, vehicle may be absorbed more rapidly than drug. Then the drug “falls” of solution in the tissue and dissolves very slowly.
Produces tissue residues
Reduces effect
Patient and Pharmaceutical Factors
Drug and vehicle solubility
pH extremes
Regional blood flow variability
Liqid soluble vehicle
Subscutaneous Administration
Advantages
Can be given by the owner (small patients)
Vasoconstrictor can be added to prolong effect at site of interest
Subscutaneous Administration
Disadvantages
Variability
Subscutaneous Administration
Process
Much like intramuscular (though the architecture of the tissue is much different)
Subscutaneous Administration
Patient and Pharmaceutical Factors
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
Topical
Process
Diffusion through stratified epithelium
“Passage” through adnexal structures
Topical
Patient and Pharmaceutical Factors
Lipid solubility and molecule size
Skin hydration and abrasion
Area of application
Ambient an patient temperature
Topical
Vehicle Effects
“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
Intraperitoneal
Process
Similar to subcutaneous
Greater blood flow
Less flow regulation
Intraperitoneal
Patient and Pharmaceutical Factors
Generally restricted to laboratory animals.
Intrathecal
Advantages
Direct delivery to site of action
Intra-actular
Disadvantages
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
Recommended doses tend to be larger than necessary
Irritation of joint surfaces/capsule (chemical effects, biochemical/physiologic effects.)
Introduce infection. (PSGAG - Adequan® - interjections now generally get “antimicrobial chaser”)
Joint “flushes: don’t count.
Intra-actular
Process
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)
Intra-arterial
Advantages
Produce extremely high concentrations “pointed at” (this is not really targeting) the tissue of interest. Used primarily for anti-tumor therapy and infectious disease therapy when blood supply is questionable.
Intra-arterial
Disadvantages
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)
Intra-arterial
Process
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
Per rectum
Process
As for oral without mechanical preparation by stomach
Drug Distribution
Physiologic spaces
Extracellular space
Intracellular space
Reserved spaces
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
Enterohepatic Circulation
How does it work?
Drug or it’s Phase II conjugate excreted in bile
Drug reabsorbed or Conjugate cleaved by bacteria and drug reabsorbed
Enterohepatic Circulation
What does it mean?
Elimination rate for drug is lower in spite of efficient hepatic metabolism/secretion
Volume of distribution of the drug is higher
Enterohepatic Circulation
Why do you care?
Interrupt to improve drug elimination
Insecticide poisonings, Phenobarbital overdoses, et
Mammary Excretion
How does it 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
Mammary Excretion
Why do you care?
May affect treatment of some bacterial infections of the mammary gland
Nursing animals may be exposed to toxic concentrations of drug in the milk
Salivary Excretion
How does it work?
Non – ionic diffusion into salivary secretions
Drug in saliva passes into GI tract
What does it mean?
Ruminants
Recycle certain drugs like enteroheptic circulation (prolonged elimination)
Trap certain drugs in the rumen pH dependent (enhanced elimination)
Non-ruminants
Limit effect on elimination possible
Drug Elimination
Biotransformation
Conversion of a drug entity to a metabolite
Usually inactivates the drug
generally reduces drug activity
MAY activate the drug
Major route of elimination for lipid soluble and protein bound drugs (because other routes are not efficient)
Drug Elimination
Biotransformation
.Chemical Mechanisms
Oxidation, hydroxylation, hydrolysis, reduction, conjugation, (acetylation, glucuronidation, sulfation, etc.)
Drug Elimination
Biotransformation
Efficiency (rate)
Metabolic activity for a specific drug
Blood flow to the organ
Health of the organ and health of the circulatory system
Drug Elimination
Biotransformation
Organs Involved
Liver (most important for most drugs)
Lungs (especially for autocoids)
Kidneys
Biliary Excretion
Active secretion
Passive secretion
Drugs with molecular weights > 300
mostly conjugates of original drug
Drugs with molecular weights < 300
biliary concentrations similar to plasma water
