Elimination and Pharmacokinetics

What is pharmacokinetics?

quantitative study of the time course of drug absorption, distribution, metabolism, and excretion

What is pharmacokinetics in simpler terms?

study of what the body does to a drug

What is pharmacodynamics in simpler terms?

study of what a drug does to the body

What does it mean to have a narrow therapeutic index?

dose of drug that induces desired repsonse is close to dose that induces a toxic response

What is the major organ of elimination?

kidney

What steps does a solid drug have to go through before it is absorbed?

disintegration into particles and dissolution to be a solution and then it can go through absorption

What are enteral routes of drug administration?

oral, rectal, and buccal

What are parenteral routes of drug administration?

go around the GI tract; IV, IM, SQ

Which of the following lists the compound of drug from fastest to slowest rate of absorption?

solution, suspension, capsule, tablet

What is an enteric coated formulation?

doesn’t dissolve in stomach, waits until better pH

What are the characteristics of the stomach to absorb a drug?

small surface area, thick mucus covered membrane, low pH

What are the characteristics of the small intestine to absorb a drug?

large surface area, thin epithelial membrane, neutral pH

What is the first pass effect?

loss of drug as it passes through the gastrointestinal membrane and the liver, for the first time, during absorption process

What is bioavailability?

fraction of the dose that reaches the systemic circulation unchanged

What does the rate of absorption from IM and SQ sites depend on?

surface area of capillaries, blood flow, solubility in interstitial fluids

What is an ionized form of a drug?

charges, polar, water soluble

What is an nonionized form of a drug?

uncharged, nonpolar, lipid soluble

The ratio of ionized to nonionized drug molecules depends on what?

pH of environment and dissociation constant (pKa)

What is pKa?

pH at which the nonionized and ionized drug concentrations are equal; 50% water soluble and 50% lipid soluble

Weak acids are ionized at what pH?

above their pKa (basic) and unionized below their pKa (acidic)

Weak bases are ionized at what pH?

below their pKa (acidic) and unionized at pH above their pKa (basic)

In what environment are weak acids well absorbed?

acidic

In what environment are weak bases well absorbed?

basic

What is volume of distribution used to describe?

various areas where drugs may be distributed; not a physiological volume

What drug is known to have a small volume of distribution? What does this mean?

water soluble have high concentrations in the blood and low concentrations in the tissues; stay in the blood

What drug is known to have a large volume of distribution? What does this mean?

lipid soluble have low concentrations in the blood and high concentrations in the tissues; well distributed

How do protein bindings impact volume of distribution?

decreases it due to not being about to pass cell membrane

What is the total body water volume?

600 mL/kg - 0.6 L/kg

What drug is known for having a high volume of distribution due to loving heart muscle tissue?

digoxin

What form of a drug is the pharmacologically active form?

unbound (free)

What protein does acidic drugs commonly bind to?

albumin

What protein does basic drugs commonly bind to?

alpha-one acid glycoprotein

Why should the dose of highly protein-bound drugs be reduced in animals with liver disease, protein-losing enteropathy (intestinal disease), or protein-losing nephropathy (kidney disease)?

don’t have enough bound protein in blood due to disease meaning there is an increase in free form protein in blood causes an increase action in drug and possible toxicity

How does protein binding impact drug interactions?

if a highly protein-bound drug is co-administered with a drug that uses the same protein-binding site, it can displace the first drug from the plasma protein and thus increase the amount of the first drug available for pharmacological action

What is an example of protein binding impacting drug interactions?

phenylbutazone has a higher affinity which causes an increase in free warfarin therefore increasing its pharmacological affect with a risk of toxicity

Is distribution for highly lipid-soluble drugs into the blood brain barrier (BBB) restricted?

no because it can pass cell membranes

Is distribution for highly water-soluble drugs into the blood brain barrier (BBB) restricted?

yes due to not being able to pass cell membranes

What are the protections the BBB has to prevent entry of water-soluble drugs?

tight junctions between epithelial cells of choroid plexus, tight junctions and astrocytic glial sheaths around capillary endothelium

What active transport mechanism in the choroid plexus promotes efflux of drug?

P-glycoproteins

What animal breed is known to have inactive P-glycoproteins causing the administration of ivermectin to be dangerous?

collie and collie cross breeds

Why is the administration of ivermectin dangerous in collie and collie cross breeds?

normally active P-glycoproteins will grab drug at BBB and push out into circulation however due to these dogs having an inactive P-glycoprotein you need to increase the dose 10x to elicit a pharmacologic effect in circulation but the inactive P-glycoproteins allow drug to enter BBB causes a CNS toxicity

What is a pro-drug?

when a drug that is normally inactive is metabolized to an active form

What drug form cannot be eliminated so is reabsorbed into systemic circulation?

lipid soluble

What drug form can be eliminated and does not have to be reabsorbed into systemic circulation?

water soluble

What must occur to a drug in order for it to be eliminated?

metabolized to polar, water-soluble products

What does the process of drug metabolism usually look like?

converts pharmacologically active lipid soluble drug to inactive water soluble metabolite

What is phase I metabolism?

metabolic reactions which add polar groups or removes non-polar groups to be either directly excreted by biliary or renal processes or provide functional groups to which conjugates may be added in phase II

What is phase II metabolism?

functional group is combined with an activated endogenous substrate to form a conjugate (conjugation)

Why is phase II difficult in cats?

lack glucuronyl transferases

Why is phase II difficult in dogs?

lack acetyltransferases

What are the conjugation reactions?

glucuronidation, acetylation, glutathione conjugation, glycine conjugation, sulfate conjugation, methylation

What are three the renal processes involved in renal excretion?

glomerular filtration, reabsorption, active tubular secretion

What is glomerular filtration?

only non-protein bound drug (free) is eliminated by this non-saturable process

What is active tubular secretion?

free and bound drugs are secreted via this method, but saturation and competition can occur, these transporters excrete drugs not removed by glomerular filtration due to size, charge or protein

What is an example of competition during active tubular secretion?

probenecid or phenylbutazone will inhibit secretion of penicillin since they compete for transport sites

What is passive tubular reabsorption?

depends on lipid solubility of non-ionized drug, urine pH, and urine flow rate

In what urinary pH are weak acids reabsorbed with passive tubular reabsorption?

low (acidic conditions)

In what urinary pH are weak bases reabsorbed with passive tubular reabsorption?

high (alkaline conditions)

What animals have an acidic urinary pH?

carnivores

What animals have an basic urinary pH?

herbivores

What route do small molecular weight molecules do to be excreted?

urine

What route do medium molecular weight molecules do to be excreted?

both biliary and renal

What route do large molecular weight molecules do to be excreted?

biliary active transport systems

What is enterohepatic recirculation?

reabsorption of drug molecule from the intestine after its secretion into bile which increases the time a drug is in the animal’s body

What is first order or linear kinetics?

constant fraction of the drug present is eliminated per unit time, clearance is constant; rate of elimination of drug from the body at any time is proportional to the amount of drug in the body at that time

What are majority of drug eliminated by? first order or zero-order

first-order

What is zero-order or non-linear?

constant quantity of drug is eliminated per unit of time, clearance varies with time; if absorption, distribution, or elimination mechanisms become saturation (high dosage concentrations)

How many half-lives does it take to reach the concentration steady state?

4-5

How many half-lives does it take to completely eliminate a drug from the body?

7

What is steady state?

defined as the time during which concentration remain stable or consistent from dose to dose (rate in = rate out)

What is used to calculate loading dose?

volume of distribution

What is a loading dose?

gives steady-state immediately

What is systemic clearance?

volume of blood or plasma that is completely cleared of drug per unit of time

What is used to calculate maintenance dose?

systemic clearance

What is the equation for half life?

Vd/Cls

What is phenobarbital?

anticonvulsant for long-term control of seizures in dogs and cats

How long does it take to attain steady-state serum levels of phenobarbital?

2-3 weeks

What is autoinduction?

drug induces cytochrome P-450 in liver to increase own rate of clearance; reason why dogs develop tolerance to repeated doses

How long does enzyme induction (autoinduction) begin for phenobarbital?

3-6 months

How often should you recheck your patient for clinical judgment of phenobarbital?

every 6 months

What is the equation for adjusting a dose?

old dose x new Cp/old Cp