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Pharmacokinetics (Drug disposition)

Pharmacokinetics (Drug disposition). Mental picture of what’s really happening inside…. 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.

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Pharmacokinetics (Drug disposition)

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  1. Pharmacokinetics (Drug disposition)

  2. Mental picture of what’s really happening inside…

  3. 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.

  4. General Rules • Some of this won’t make sense until you see all the parts…

  5. General Rules (solubility) • Drug must be water soluble to move around. • Drug must be lipid soluble to cross barriers. • All useful drugs have some solubility in both.

  6. 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.

  7. General Rules (solubility) • Pharmacokinetics result from interaction of drug chemistry and patient physiology. • Species differences affect pharmacokinetics • Diseases affect pharmacokinetics

  8. 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.

  9. 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?

  10. Oral administration

  11. Oral administration • Patient and pharmaceutical factors • Pill compression, coatings, suspending agents, etc. • GI transit (stomach emptying #1) • inflammation, malabsorption

  12. 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

  13. 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

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

  15. Intramuscular Administration

  16. 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.

  17. 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.

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

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

  20. 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

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

  22. 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.

  23. 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.

  24. 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)

  25. Intraperitoneal • Advantage • Relatively large absorptive surface • Disadvanteges • Peritonitis (drugs or needles) • Damage to organs • Injection into organs

  26. Intrathecal • Advantages • Direct deposit into (onto) CNS • Disadvanteges • Difficult to calculate dose • Toxicity likely (toxicity may be unusual) • Infection

  27. 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”

  28. 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.

  29. 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

  30. 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).

  31. 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.

  32. 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

  33. 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

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