Transcript VT PowerPoint Template5

VM 8314
Pharmacokinetics
(Drug disposition)
Dr. Wilcke
VM 8314
Mental picture of what’s really
happening inside…
Dr. Wilcke
VM 8314
General Rules
Pharmacokinetics is about processes
 How things WORK
We can only sample from the blood stream.
We describe what happens to the MASS (the whole
dose) of drug we’ve given.
A drug molecule is not in the body until it is in the
bloodstream.
Dr. Wilcke
VM 8314
General Rules
Some of this won’t make sense until you see all the
parts…
Dr. Wilcke
VM 8314
General Rules (solubility)
1. Drug must be water soluble to move around.
2. Drug must be lipid soluble to cross barriers.
3. All useful drugs have some solubility in both.
Dr. Wilcke
VM 8314
General Rules (solubility)
Effects are proportional to concentration (at site of
action)
Concentration at site of action is controlled by
concentration in bloodstream.
Therefore, concentration in blood stream predicts
action.
Dr. Wilcke
VM 8314
General Rules (solubility)
Pharmacokinetics result from interaction of drug
chemistry and patient physiology.
Species differences affect pharmacokinetics
Diseases affect pharmacokinetics
Dr. Wilcke
VM 8314
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.
Dr. Wilcke
VM 8314
Oral administration
Advantages
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?
Dr. Wilcke
VM 8314
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
Stomach
Duodenum
Drug in lipid suspension may be
picked up by lacteals
(absorption)
Duodenum, jejunum, ileum
Drug in solution crosses mucosa Duodenum, jejunum
(absorption)
Stomach, Ileum, colon
Dr. Wilcke
VM 8314
Oral administration
Patient and pharmaceutical factors
Pill compression, coatings, suspending agents, etc.
GI transit (stomach emptying #1)
inflammation, malabsorption
Dr. Wilcke
VM 8314
Oral administration
 Regional differences
 Stomach
 Lowest absorptive surface
 Mechanical prep
 Extreme pH
 Small Intestine
 Most absorptive surface
 Neutral pH
 Colon rectum
 Intermediate absorptive surface
 Neutral pH
Dr. Wilcke
VM 8314
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
Dr. Wilcke
VM 8314
Intramuscular Administration
Disadvantages
More difficult for owners
Pain on injection
Muscle damage
Can’t recover the dose
Dr. Wilcke
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Intramuscular Administration
Drug
Vehicle
Dose Form
Water Sol
Water Sol
Aqueous Solution
Water Sol
Lipid Sol
Suspension
Lipid Sol
Water Sol
Suspension
Lipid Sol
Lipid Sol
Lipid Solution
Dr. Wilcke
VM 8314
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.
Any of these may be “rate limiting” for absorption.
Dr. Wilcke
VM 8314
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.
Dr. Wilcke
VM 8314
Subcutaneous administration
Advantages
Less injection pain
Owner can be taught to do it.
Disadvantages
Variability (ambient temperature)
Variability (hydration status)
Variability (excitement)
Variability (location)
Dr. Wilcke
VM 8314
Subcutaneous administration
Variability comes from autonomic control of
blood flow
Variability comes from physiologic factors.
Dr. Wilcke
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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
Dr. Wilcke
VM 8314
Topical administration
Disadvanteges
Patients groom themselves
Toxic skin reactions
Blood flow variability
Physiology and autonomic control
Drug induced effects
Dr. Wilcke
VM 8314
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. 2002 Jun;25(3):189-93.
Dr. Wilcke
VM 8314
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.
Dr. Wilcke
VM 8314
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)
Dr. Wilcke
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Intraperitoneal
Advantage
Relatively large absorptive surface
Disadvanteges
Peritonitis (drugs or needles)
Damage to organs
Injection into organs
Dr. Wilcke
VM 8314
Intrathecal
Advantages
Direct deposit into (onto) CNS
Disadvanteges
Difficult to calculate dose
Toxicity likely (toxicity may be unusual)
Infection
Dr. Wilcke
VM 8314
Intra-articular
Advantage
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”
Dr. Wilcke
VM 8314
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.
Dr. Wilcke
VM 8314
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
Dr. Wilcke
VM 8314
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).
Dr. Wilcke
VM 8314
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.
Dr. Wilcke
VM 8314
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 10-30 minutes
Constant rate
Drug concentrations rise according to elimination rate
Hold stable concentrations for extended periods
Dr. Wilcke
VM 8314
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
Dr. Wilcke