1. Pharmacokinetics
(Drug disposition)

2. Mental picture of what’s happening inside…
This is intended to provoke a visualization of an intramuscular injection (only – other routes, you’re on your own).
When you press the plunger on the syringe:
The drug (and vehicle) is “sprayed” from the tip of the needle. It is thought that this high pressure spray is the cause of some of the pain. Injections through large needles may actually produce less pain.
The volume in the syringe is forced into a tissue space that did not exist before the injection (roughly spherical).
The absorption behavior is influenced by the way the “ball of drug” that you put in the muscle interacts with the fluid in the space where you put it.
Some number of IM injections end up in tissues between muscles (fat and connective tissue)
Some number of IM injections disrupt blood vessels . (What are the consequences of this?)
… really might help.

3. General Rules Drug action (effects)
Proportional to concentration at site of action
Concentration predicts better than dose
A drug concentration vs effect (response) curve is almost always more accurate and certainly less variable (between patients and even between species) than a dose vs effect (response) curve.

4. General Rules Everything happens in water Drugs dissolve in body water
Semipermeable membranes create spaces
Drugs must be soluble in both water and lipid
Equillibria between spaces determine where drug “is”
This shouldn’t surprise anyone. ALL of biochemistry is in water. The ability of a drug to dissolve in water relates directly to the size of the dose required for a particular effect. Also though, many drugs must pass through lipid membranes to reach sites of action. Some degree of lipid solubility becomes very important if they are to have the expected effect.

5. General Rules Pharmacokinetics “happens”
…because physiologic process happen
Veterinary pharmacology is (mostly) about species differences in pharmacokinetics.
Clinical pharmacology is (mostly) about how disease affects pharmacokinetics.
Drugs are absorbed, distributed and eliminated by the same physiologic functions that work for nutrients. It’s differences in physiology that produce differences between species. Pathology alters physiology to produce differences in pharmacokinetics between classes of patients (e.g. neonatal vs geriatric).

6. General Rules Pharmacokinetics “happens”
We can only sample from the bloodstream.
Inside is sometimes still outside
Drug molecules that have not been absorbed are outside
Injection site
GI tract
Techniques necessary to measure drug concentration at the site of action (or in any particular tissue OTHER than blood) simply do not exist. Our view of this world is quite limited. We resort to models that don’t always seem to be based on physiologic reality.
Sometimes understanding pharmacokinetics means you’re thinking about where a drug is going or where it’s been in addition to where it IS…

7. General Rules It’s fractional A “fraction” of the drug dose was…
…absorbed
…eliminated unchanged
…eliminated in the urine
This brings us to the way pharmacokinetics tend to be portrayed on drug labels. “Bioavailability was 60%” “75% of an intravenous dose was eliminated unchanged in urine”

8. General Rules Only if it’s a large fraction
Not everything that actually happens is actually important
Protein binding <90% and interactions can’t be important
If organ function is at least 80% of normal, we call it normal
If the fraction absorbed is >80%, bioavailability is not going to be a factor in dosing
On of the hardest parts of pharmacokinetics is deciding whether to act on a particular pharmacokinetic fact. This this is because meaningful effects (or changes in effects) are only detected if the fraction of the drug that’s IN a particular state changes dramatically. Example:
IF a drug is 99% protein bound, this means that only 1% of the dose you administered is running around free to interact with receptors (this sounds like many non-steroidal anti-inflammatory drugs). If something can dislodge 1% of the drug from binding sites, the effect will DOUBLE (now 2% of the dose can interact with receptors). If on the other hand, the drug is 80% protein bound and 1% is dislodged, you change the free drug from 20% to 21% and you are unlikely to notice the change.

9. Drug Administration Drugs dissolve in body water
Drugs enter circulation as water enters circulation
Drugs must circulate before they reach sites of action
DRUGS ARE NOT IN THE BODY UNTIL THEY ARE IN THE BLOODSTREAM.

10. Oral administration Advantages Disadvantages
Cheap, non-sterile, dose forms that control release
You CAN recover the dose (if you move quickly)
Disadvantages
Variability (feeding, physiology, disease)
Intractable patients
First pass effect
Where does the portal circulation go first?

11. Oral administration Table 1. Location of processes Process
Primary Location
Secondary Location(s)
Tablets disintegrate
(a suspension forms)
Stomach
Duodenum for enteric coated forms
Drug dissolves from suspension
Duodenum
Drug in lipid suspension may be picked up by lacteals
(absorption)
Duodenum, jejunum, ileum
Drug in solution crosses mucosa (absorption)
Duodenum, jejunum
Stomach, Ileum, colon
The specific list of processes depends on the oral dose form:
Enteric coatings on drugs prevent tablet disintegration in acid (they dissolve in neutral fluids).
Oral suspensions do not need to disintegrate but they still must dissolve before the drug is absorbed (skip a step).
Oral solutions do not have to disintegrate but must mix with water in the gi tract and remain in solution (it is possible for the drug to fall out of solution in the GI tract)

12. Oral administration Patient and pharmaceutical factors
Pill compression, coatings, suspending agents, etc.
GI transit (stomach emptying #1)
inflammation, malabsorption
The pharmaceutical industry spends a great deal of time, effort, and money to produce dose forms that behave in predictable ways (predictability is a hallmark of useful pharmaceutical agents). Beware of compounded pharmaceuticals until you either have experience with them or are advised by someone with clinical experience. Compounding pharmaceuticals yourself is risky business.
Patient factors are beyond your control but not beyond your understanding. Careful evaluation of a patient may lead to better use of pharmaceutical products (this is the essence of clinical pharmacology).

13. Oral administration Regional differences Stomach Small Intestine
Lowest absorptive surface
Mechanical prep
Extreme pH
Small Intestine
Most absorptive surface
Neutral pH
Colon rectum
Intermediate absorptive surface
These regional differences are amplified when you consider species differences. For example:
Ruminants have 4 stomachs. Most of these are specialized in terms of pH, volume, presence of bacteria, etc. Only one is analogous to the monogastric stomach.
Camelids are a little less interesting but not much.
Stomachs in horses and rats are certainly different than dogs and mice.
Ceca may be interesting or boring depending on the digestive function of the animal in question. Drugs may have an adverse effect on flora. You may need to worry about the amount of drug reaching the cecum following oral administration (horses are very touchy in this regard).

14. Intramuscular Administration
Advantages
More consistent than oral or subcutaneous
Certainty of administration
Can manipulate to produce a depot
Viable for unconscious, vomiting or fractious
Almost always the same as IV for efficacy and potency
Viable route for emergencies / life-threatening disease

15. Intramuscular Administration
Disadvantages
More difficult for owners
Pain on injection
Muscle damage
Can’t recover the dose

16. Intramuscular Administration
Drug
Vehicle
Dose Form
Water Sol
Aqueous Solution
Lipid Sol
Suspension
Lipid Solution
There are really two kinds of suspensions – lipid suspensions (I’m not sure, but I think this usually means a lipid suspended in water) and aqueous suspensions (again, I’m not sure, but I think this usually means water soluble things suspended in lipid).
For the two solution types, the nature of the vehicle will dominate what happens. Water soluble vehicles will mix with tissue fluids. Lipid soluble vehicles will not.

17. Non-intravenous injection
Drug in suspension or lipid solution must dissolve in tissue fluid
Drug in aqueous solution only has to mix with tissue fluid
Drug DISSOLVED in tissue fluid transits to capillaries.
Usually when a SERIES of processes must be completed to reach a goal, ONE of them controls how fast the goal can be reached. That ONE is considered to be “rate limiting.”
Any of these may be “rate limiting” for absorption.

18. Non-intravenous injection
Aqueous solution: sphere falls apart
Suspensions or lipid solution: sphere holds its shape
If sphere holds its shape, drug must dissolve from the surface into the tissue fluid.
Integrity of the sphere controls absorption.
When you double the volume, you do NOT double the surface of the sphere. For suspensions and lipid solutions, large volumes produce slow absorption.

19. Subcutaneous administration
Advantages
Less injection pain
Owner can be taught to do it.
Disadvantages
Variability (ambient temperature)
Variability (hydration status)
Variability (excitement)
Variability (location)

20. Subcutaneous administration
Variability comes from autonomic control of blood flow
Variability comes from physiologic factors.

21. Topical administration
Make sure you think about what you’re trying to do!
Topical for action on the skin surface
Reduced systemic effects
Enhanced skin effects
Topical for systemic action
Easy painless administration
Want quick absorption
So the drug doesn’t become an oral med
So you don’t medicate an affectionate owner

22. Topical administration
Disadvanteges
Patients groom themselves
Toxic skin reactions
Blood flow variability
Physiology and autonomic control
Drug induced effects

23. Topical administration
Be cautious about topical formulations from compounding pharmacies
Just because it would be NICE to give something topically (and somebody makes something in a topical form), doesn’t mean that it can be made to work.
SEE: Hoffman SB, Yoder AR, Trepanier LA. Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats. J Vet Pharmacol Ther Jun;25(3):

24. Topical administration
Patient and pharmaceutical factors
High lipid solubility and small molecule size favor absorption
Skin hydration and abrasion favor absorption
Large area of application favors absorption
Increased patient and ambient temperature favor absorption.

25. Topical administration
Drugs in “like” vehicles stay in the vehicle
(e.g., aqueous in aqueous)
Drugs in “unlike” vehicles move to the skin surface
(e.g., aqueous in lipid)

26. Intraperitoneal Advantage Disadvanteges
Relatively large absorptive surface
Disadvanteges
Peritonitis (drugs or needles)
Damage to organs
Injection into organs
Really used only in very small animals (e.g., rodents) and where other routes are, for some reason, precluded.

27. Intrathecal Advantages Disadvanteges Direct deposit into (onto) CNS
Difficult to calculate dose
Toxicity likely (toxicity may be unusual)
Infection
You won’t see this often, and this is NOT the same thing as epidural (for regional analgesia/anesthesia).

28. Intra-articular Advantage Disadvantages
High concentration directly to affected tissue
Disadvantages
Difficult to hit joint space (depends on species)
Difficult to calculate dose
Joint size? Absorption from joint?
Irritate joint surfaces/joint capsule
Introduce infection
NOT SAME AS “JOINT FLUSH”

29. Regional administration
Routes of administration designed to “target tissues”
Intra-arterial, Inter-osseous, Intravenous with tourniquet.
Produce AND SUSTAIN high blood-to-tissue gradient
Many variations on the technique
Systemic IV dose with tourniquet
Supplement systemic dose with smaller regional dose
Systemic dose in bone marrow
etc., etc., etc.

30. Regional administration
Advantage
Probably does increase tissue concentration “some” for “some” period of time
Disadvantage
Dose calculation is difficult
Dosing is still (really) systemic
Limited actual efficacy studies
Few strong pharmacokinetics studies

31. Regional administration
GO GET TRAINING
Remain suspicious of the value of this compared to the difficulty and expense (there is little clinical outcome data to support the practice(s).

32. Per rectum administration
Advantages
Access (unconsious or vomiting patients)
Can recover drugs before aborption is complete
Disadvantages
Drug may not stay where you put it.
Basically like oral without mechanical prep of stomach.

33. Intravenous administration
No absorption (it’s just “in there”)
Bolus
Be careful
Slow push
Most drugs this means 1-2 minutes
Some drugs this should be minutes
Constant rate
Drug concentrations rise according to elimination rate
Hold stable concentrations for extended periods
This particular route is missing from your notes. I’ve always thought about this section of the notes as being related to absorption. There is no absorption in the case of intravenous administration. The rest of what happens always seemed relatively obvious to me.

34. Intravenous administration
Bolus administration
Cardiac and respiratory problems
Drug and vehicle are in EXTREMELY high concentration in peripheral vein.
Dilution begins in vena cava
Lung gets high concentrations (pulmonary emboli)
Heart muscle gets high concentrations
Otherwise and in general:
Mixing is very fast
Evenly distributed in peripheral blood in 5 – 10 minutes
If bolus is too fast: Animal may experience respiratory difficulties, animal may experience arrhythmias or poor contractility
In general, it’s almost impossible to take samples fast enough to describe the mixing activity.