Unit 2 pharmacokinetics and pharmacodynamics Flashcards
4 components of pharmacokinetics:
Absorption
How does drug get into the plasma; routes of administration; bioavailability
Distribution
The movement of drug in plasma to the “target tissue” and other tissues.
Metabolism
Biotransformation. 1st pass effect
Elimination
How drug gets out of the body; renal elimination; enterohepatic recycling
Pharmacokinetics is
the movement of drugs into, through and out of the body
Pharmacodynamics involves
how drugs interact with tissues to exert physiological changes
Movement of drug molecules across lipid membranes
With the exception of IV routes, all other administration routes require that the drug molecule crosses at least one layer of vascular endothelium. Drugs given per os, must also cross GI barriers
Four mechanisms by which drugs cross lipid membranes:
Passive diffusion
Facilitated diffusion
Active transport
Pinocytosis and phagocytosis
Passive diffusion is
Most common; most important
Random movement
From high to low concentration
Across a semipermeable membrane
Unlimited
Drug must be:
Lipid soluble (lipophilic, hydrophobic)
Non-ionic
Small
Facilitated diffusion is
Larger molecular weight drugs
Very similar to passive diffusion, except that diffusion occurs across pores/channels located in the lipid bilayer
Some selectively because specific pores may only let certain types of molecules through
Still required a high to low concentration gradient’
Active transport is
Active movement of a drug molecule across a lipid membrane via a pump or transporter
Use of energy allows movement from low to high concentration; allows high drug accumulation in tissues
transporter/pump will only bind to specific drugs
Ex. P-glycoprotein pump
Phagocytosis and pinocytosis is
Active “swallowing” or “drinking” of drug molecules by the cell
May be through “random sampling” of molecules in the extracellular environment OR, may result from drugs binding to receptors in the cell surface
Factors that affect rate of drug molecule movement
Drug form
Smaller sized drug diffuse more readily across membrane
Carrier molecule ability, for those drugs dependent on a carrier
How quick does it reset
How many carriers available
Speed of transport
Saturation limit
Concentration gradient difference
Temp
Thickness of the membrane
Lipophilic nature of the drug molecule
Lipophilic is
dissolves readily in fat but not readily dissolve in water
To move across membrane, drug molecules must be lipophilic (fat loving)
Hydrophilic is
dissolves readily in water but not in fat
Absorption is
Describes movement of drug from site of administration until it enters the plasma (i.e., what happens during the absorption period)
Absorption is affected by
Chemical nature of the drug
How it is formulated
Route of administration
The patient
Absorption also influences how much of the initial dose ends up in the plasma (this is measured as “bioavailability”)
Bioavailability is
A measure of drug absorption
% of drug administered into the body that enters the systemic circulation
How bioavalible are IV drugs
100% bioavailability
Fastest onset of action greatest bioavailability
#1 choice for emergency drug delivery
Be aware of increased risk of entering toxic range with rapid bolus administration
How bioavalible are IM drugs
have close to 100% bioavailability
Active muscle has increased blood flow compared to inactive muscle
How bioavalible are PO drugs
Bioavailability quite variable when given PO
May be affected by “first pass effect”
Drug formulation is and determines what
Formulation includes anything added to the pharmaceutically active ingredient
Syrups, other liquids, flavours, color, gel coats for tablets, sustained-action coatings, creams and ointment bases, saline, alcohols….
Formulation determines which route(s) of administration can be used
Drugs formulated for oral dosing cannot be given IM,etc…
Generics equivalents may have different bioavailability because
Generic equivalents have the same active drug molecule. They do not necessarily have the same formulation
Formulation affects absorption and drug stability
Therefore, generic equivalents may have different absorptions and different bioavailability
Formulation is specific to a DIN
Important when comparing equivalents; not all generic equivalents act the same (mostly because they are absorbed differently)
Effect of lipophilic or hydrophilic nature of drug on absorption
Whether a drug exist in a hydrophilic or lipophilic form when administered, will affect the ability for the drug molecule to dissolve or pass through the cellular membrane
The drug has to be proper ionization for the route of administration
Where is a hydrophilic drug form more rapidly abosrbed
IM or SQ route
Where is a lipophilic drug form more rabidly absorbed
PO
Drug pH and environment pH effect on absorption
Drug act as either weak acids or weak bases
RULE: “like is non-ionized in like”
What does “like is non-ionized in like” mean
Ex. a drug that is a weak acid, will be non-ionized in an acid environment. Because it ti nonionized it will be more lipid soluble
The same drug in a basic enviro will be less ionized (less lipid soluble)
Non-ionized = HCl vs ionized = H+ Cl-
Aspirin works how
Aspirin (Acetylsalicyclic acid) is a weak acid
Aspirin is given by mouth and enters the stomach (also acidic)
If you apply the rule that “like drug in a like environment is non ionized”, then aspirin (which is a weak acid)→ in stomach acid →is non-ionized
Non-ionized molecules are lipophilic; therefore, aspirin is more likely to cross cellular membranes in the stomach
In fact, aspirin is absorbed from the stomach (compared to the intestines)
Ion trapping is
Movement of a drug into a compartment where it changes from a hydrophobic state to a hydrophilic state, and stays in that compartment
How does aspirin doe ion trapping
Aspirin in the stomach is non-ionized (lipophilic)
This allows aspirin to move across the stomach wall, across blood vessels walls into the circulation
Blood has a higher relative pH than the stomach.
Once the aspirin molecule enters the plasma, it is in a “less similar environment”. As a result, aspirin in blood becomes more ionized (more hydrophilic).
Result is aspirin tends to be “trapped” in plasma
P-Glycoprotein and MDR1 gene is and does what
P-glycoprotein is encoded by the MDR1 gene
It is an active transport pump found in cells of the intestinal epithelium and BBB.
P-Glycoprotein and MDR1 gene mutation does what
A genetic mutation of the MDR1 gene can lead to a lack of functional P-glycoprotein which leads to increased susceptibility to drug toxicosis.
Drug levels build up in CNS as pumps not pumping it out.
MDR1 gene deficiency can be in what animals
Many herding dog breeds (e.g. Collies, Shelties, Border Collie, Australian Shepherds) and very young kittens
Can test via Washington State University
MDR1 gene deficiency is what
Heterozygous mutation produces some functional pumps; are less affected
Homozygous mutation more severely affected
Pump can also be inhibited by certain drugs
Cytochrome P450 (CYP enzymes). is what
Enzyme located in cells of the intestinal wall
Metabolizes the same drugs that P glycoprotein removes from the cell.
Need to keep in mind if drugs or disease or other drugs inhibit the function of these enzymes a correct dose will deliver a larger than expected quantity of drug
Alternatively some drugs with long term use may induce these enzymes therefore dose may need to increase over time e.g. phenobarbital
Why does PO have the lowest bioavailability
Degradation in saliva
Degradation in stomach acid
Digestion in small intestine
Degradation by GI flora
-Per os is not commonly used in ruminants due to the large number of microbes in the rumen that will degrade most medications before they can be absorbed
If peristalsis is too fast, drug will pass through without a chance to absorb
-Note that GI transit times in dogs/cats much faster than humans; will affect bioavailability of human formulations
-Transit time is faster if there is diarrhea
-Oral drugs may be absorbed MORE if constipation
1st Pass Effect
-Drugs that are absorbed through the small intestine enter the portal vein and are transported to the liver, where they may be metabolized (partially or completely) before entering the systemic circulation
Patient factors affecting absorption
Young animals may have poor oral absorption
Vomit and diarrhea decrease oral absorption
Constipation may increase oral absorption
Fever and heating sources increase rate of absorption for IM, ID, SQ, transdermal routes
Cold causes vasoconstriction and disease ID, SQ absorption
BCS- fat has poor perfusion; decrease SQ absorption
Ruminants -PO absorption typically poor
Drug distubution describes what
Describes the movement of drug from the plasma into the tissues
A drug is only effective if it makes it to the target tissue
There is constant movement of drug between plasma and the different tissues
Drug factors affecting distribution
Chemical nature of the drug; especially its solubility in aqueous solution versus fat- solubility
Degree to which the drug binds to albumin and other plasma proteins
“Volume of distribution”–a pharmacological measure of how much of a drug leaves or stays in the plasma….more to follow
Size and ionization matters because
Small molecules have increased ability to cross semi-permeable membranes by passive diffusion
Large molecules cannot pass through fenestrations of blood capillaries
Non-ionized (lipophilic) molecules will diffuse across lipid membranes. Ionized (hydrophilic) molecules will not.
Plasma protein binding is done by
Many drugs bind to plasma proteins, such as albumin and globulins, as soon as they reach the circulation
Protein bound drugs are not active- they are too big to leave the circulation; only unbound drugs are active and can leave the circulation into tissues
Plasma protein binding is a dynamic equilibrium
I.e., constantly binding and detaching
Dosage take into account plasma protein binding by drugs
Concurrent drug use:
If two highly protein bound drugs are given at the same time but one has more affinity for protein binding (e.g. phenylbutazone) it makes preferentially bind to protein leaving more of the drug “free” to be active, therefore see increased effects from the other drug
Volume of distribution (VD) is
Property of the drug determined in testing phase
Measure of how much drug leaves the circulation and enters the extracellular fluid
What does a high and low VD mean
Drugs with a high VD leave the plasma more readily and enter the tissues
Drugs with a low VD have a harder time leaving the circulation
Used to determine drug dosage
Patient factors affecting distribution
Blood flow
%body water
Tissue barriers and membrane permeability
How does % body water affect drug distribution
Degree of hydration affects the total concentration of dissolved drug in plasma, other extracellular fluids and intracellular fluids
Dehydrated and older animals have lower %BW therefore may require lower doses of drugs to achieve a given plasma concentration
