Download Pharmacokinetics and pharmacodynamics

ION TRAPPING and absorption of drugs
*Aspirin is an acidic drug.
*When aspirin is in the acidic environment of the stomach (pH 2-3), it exists predominantly in the
nonionized/lipophilic form.
*Aspirin will easily enter the cells of the stomach.
*The inside of these cells have a pH of 7.4.
*Most of the drug molecules will shift to the ionized/hydrophilic form in this pH, which will “trap” those
molecules inside the cells.
*There will always be some nonionized/lipophilic molecules inside the stomach cells.
*As a nonionized/lipophilic molecule leaves the stomach cell and enters the circulatory system, an
ionized/hydrophilic molecule is converted to the nonionized/lipophilic form to preserve the ratio.
*This action continues until all aspirin molecules have exited the stomach cells and entered the circulation.
Effect of dissolution and GI motility on absorption of orally administered drugs
• Oral medication must be in the lipophilic form to be absorbed into the cells of the
GI tract. The medication must also be small enough to enter the cells.
• ___________________ is the dissolving of a drug.
• _____________ medications do not have to go through a dissolution process.
• _____________ medications must go through dissolution and be broken apart to be
absorbed.
• Because PO liquid meds do not have to go through dissolution, they are usually absorbed
more rapidly than PO solid meds and may have a quicker onset of action.
Effect of dissolution and gi motility on absorption of orally administered drugs
• _________________________ tablets dissolve slowly over minutes to hours, releasing small
amounts of medication for absorption. There will be a ____________ peak in blood
concentration than if the tablet were regular-release.
• Most absorption for PO drugs occurs in the _________________, so dissolution needs to occur
__________ the meds get there.
• Alteration of the GI tract’s motility can effect how much time a medication has to dissolve and
be absorbed.
•Increased intestinal motility = ________________ absorption of drug
•Decreased intestinal motility = ________________ absorption of drug
First-pass effect
• All blood from the stomach, small intestines, and upper large intestines
must travel through the liver on its way to the systemic circulation.
• The HEPATIC PORTAL SYSTEM conducts blood from the GI tract to the liver via the
Portal Vein. The contents are filtered before reaching the systemic circulation.
• Some drugs are considered foreign by the liver and never reach systemic circulation,
therefore PO is not a practical route of administration for them.
Effect of perfusion on absorption of parenterally administered drugs
• Perfusion is the extent to which a tissue is supplied with blood.
• Tissues that are well perfused with blood absorb injected drugs much
___________ than tissues that are poorly perfused.
• Injecting a drug in an area that is far away from the blood stream, or an area that has
very few vessels will slow absorption.
• Muscle is well perfused compared to fat so IM medications should be absorbed
faster than SQ.
• An inactive muscle is less perfused than an active muscle.
• Cold temps cause vasoconstriction in SQ capillaries, decreasing the rate of
absorption. Warm temps have the opposite effect.
• DISTRIBUTION: the movement of a drug from the
systemic circulation into tissues
• Drugs enter and exit the circulation at the capillaries
• With the exception of the brain, capillaries have
________________ that allow fluid and
molecules to enter and exit the circulation.
• Both hydrophilic and lipophilic molecules can fit
through fenestrations.
• IN THE BRAIN, fenestrations are replaced by tight
junctions and there are additional cells
surrounding the capillaries to act as a barrier.
• The only type of drugs that can pass through the
BBB are lipophilic molecules who pass through
the cell membranes.
Barriers to drug
distribution
• Capillaries of the placenta have fenestrations, which
gives drugs that were administered to the mother
access to the fetus.
Effect of tissue
perfusion
on drug distribution
• Drugs are distributed faster and in larger amounts to
tissues that are well-perfused (active skeletal
muscle, liver, kidneys).
• _____________________ occurs after the drug
molecules have been distributed to the tissues. Drug
molecules move back and forth between the blood
and tissues due to diffusion and the presence of a
concentration gradient.
• Redistribution continues until there is equilibrium
between the blood and tissues.
• Plasma is filled with proteins that are too large to leave
the circulation.
• Many drugs are made so that a percentage of their
molecules bind to these proteins.
• Only the UNBOUND drug molecule is small enough to leave
the capillaries and have an effect on the tissues.
• When an UNBOUND molecule leaves circulation, a protein
releases a BOUND molecule to replace it.
• Drugs that are highly protein-bound must be used with
caution in animals with _________________________ (GI,
liver, renal issues) as more drug will be UNBOUND in those
animals than in healthy ones. Drug dose should be lowered
in these animals.
Effect of plasma
protein binding on
drug distribution
Volume of distribution
• Vd: a value that indicates the extent to which a drug is distributed throughout
the body.
• It assumes that the drug is equally distributed throughout the body and that the
concentration of the blood is in equilibrium with the concentration in the rest of the body.
• The larger the volume of distribution, the ______________ the blood concentration of
the drug.
• Excess body fluid and dehydration can affect the VOD and drug concentration levels.
• Actual Vd is not usually known.
100
mg
100
mg
5 Liters H2O
2 Liters H2O
• Neurotransmitters and hormones have receptors on
the surface of cells. When they bind with the receptor,
they stimulate that receptor to produce or to inhibit a
specific action in the cell.
• Drugs are made to bind with these same receptors.
The effect that the drug has on the cell is the drug’s
_______________ ____________.
• Even if a drug is distributed throughout the body, it
won’t have an effect on all the tissues that it is
distributed to.
• In order for a drug molecule to have an effect on a
cell, the cell must have a ____________ on its
membrane that is a fit for the drug like a lock for a
key.
Pharmacodynamics:
the way drugs exert
their effects
• Every cell does not have a receptor to fit every drug molecule.
• A cell will be very sensitive to the effects of a drug if it possesses a large number of
receptors that the drug can bind to. This number can change over time.
• A drug’s ______________ for a receptor describes how well a drug bonds to its
receptor site.
• Some drugs act as _______________, stimulating the receptor in the same way that
the body’s neurotransmitters and hormones do. Other drugs act as
_________________, blocking the action of the natural substance on the receptor.
Antagonists and agonists
Competitive and Noncompetitive Antagonists
•______________________ ANTAGONISM exists when two different drugs fit
in the same receptor site and their intrinsic activities are opposite of one
another. The effect that is seen depends on which drug is present in greater
quantities. This exists with drugs that reverse one another.
•_________________________ ANTAGONISM exists when one drug either
combines better with the shared receptor or one drug alters the shape of the
other drug’s receptor. The latter would prevent the noncompetitive antagonist
from binding.
Partial Agonists and Antagonists
• If Drug X increases the heart rate by 50% and Drug Y also increases the
heart rate, but only by 25%, Drug Y is a PARTIAL AGONIST to Drug X. These
drugs attach to the same receptor, but cause different levels of intrinsic
activity.
• If Drug X increases the heart rate by 50% and Drug Z decreases the heart
rate by 25%, Drug Z is a PARTIAL ANTAGONIST to Drug X. It is not a reversal
agent, but can reduce the effects of another drug.
Biotransformation and metabolism
• METABOLISM: The biotransformation of a drug by enzymes into a form that can be
eliminated by the body.
• THE MAJORITY OF BIOTRANSFORMATION OCCURS IN THE ___________ by cytochrome P450
enzymes (aka the mixed function oxidase system).
• Phase 1 of Biotransformation:
• Original drug molecule is chemically transformed into a less active ________________ by the
addition or removal of oxygen, hydrogen, or other substances.
• Phase 2 of Biotransformation:
• The metabolite is conjugated, or joined with another molecule to make it more hydrophilic and
able to be excreted in the urine.
Drug Interactions Affecting Biotransformation
• Multiple drugs in the body at the same time can affect each other’s
biotransformation.
• They may compete for the same enzymes, slowing the metabolism of each.
• Toxic concentrations of one drug may result.
• The number of enzymes in this system can increase with repeated exposure to
the drug. These drugs end up being metabolized at an increased rate. This is
referred to as ______________ ________________.
• Shortens the amount of time that the drug can be effective in the body (also known as
________________).
•Any drugs that use these same enzymes would have increased metabolism, requiring an increase in dose.
Species and age differences in drug
biotransformation
• Just because a drug is safe to use in one species, does not mean it is
safe to use in all species.
• _________ are very prone to drug toxicities as they are limited in
the enzymes that they can use to biotransform drugs during
metabolism.
• The liver may need a few weeks after birth to finish developing.
• Older animals may have a decline in liver and/or kidney function.
Dosages should be adjusted or alternative medications used if these
organs are needed for their metabolism and/or elimination.
Drug elimination
• ELIMINATION: also known as excretion, is the movement of drug molecules out
of the body
• Routes of elimination: feces, urine, sweat, exhalation, milk, saliva, keratin
• *Major routes of elimination are into the urine (__________), and the feces (bile from the
______________).
• Drugs eliminated via the milk should not be used in nursing animals or lactating dairy cows
• Two ways that drugs are eliminated via the kidney: filtration
at the glomerulus and active secretion in the tubules
Renal
elimination
(FILTRATION)
• FILTRATION occurs as blood flows through the glomerulus into
Bowman’s Capsule.
• Proteins are too large to be filtered. Protein-bound drugs will remain in
the bloodstream at this point (unless animal is hypoproteinemic).
• Decreased renal blood flow will cause lower numbers of drug
molecules to be filtered at the glomerulus.
• Ex: Hypotension, dehydration, blood loss, shock, or fight/flight response.
• Increased renal blood flow will cause drug molecules to be removed
from the body more rapidly.
• IV fluids, drugs that increase renal perfusion, or hypertension.
• Two ways that drugs are eliminated via the kidney: filtration
at the glomerulus and secretion into the tubules.
Renal
elimination
(SECRETION)
• SECRETION involves drug molecules being actively transported from
the peritubular capillaries into the urine.
• If a protein-bound drug detaches from its protein (in the blood) and
binds to a transport molecule on the cell membrane of the PCT, the
drug can be transported into the urine to be excreted.
• If the drug is lipophilic, it can be reabsorbed via diffusion back into
the bloodstream as it travels to the Loop of Henle.
• After the Loop of Henle, drug concentrations in the urine seldom
change.
• Drugs excreted by the liver diffuse into hepatocytes and
then enter the ___________.
• Bile is collected in the ________________ and then
dumped into the duodenum.
• _______________ drug molecules in bile have the
opportunity to be reabsorbed in the small intestines and go
through the Hepatic Portal System. This is known as
ENTEROHEPATIC CIRCULATION. These drugs can affect the
body for a longer duration of time than those that don‘t
reenter the circulation.
• Like the kidneys, drug dosages must be reduced when giving
drugs eliminated via billiary excretion to patients with liver
insufficiency.
Hepatic
elimination
Half-life and clearance
• HALF-LIFE OF ELIMINATION/CLEARANCE: the rate at which drugs leave the
body.
• Measure of how fast a volume of blood is cleared of the drug
• Time value that describes how long the drug concentration takes to decrease by ______%
• Can dictate how frequently the drug must be given to maintain concentrations in
therapeutic range
• Can reflect how well the organs that eliminate the drug are functioning
• Half life will increase if the organ that eliminates a drug is compromised
Relation of Half-life to Steady-state concentrations
• STEADY-STATE: point at which drug levels plateau and all
peak concentrations are the same and all trough
concentrations are the same
• Happens when a drug is given repeatedly
• The amount of drug being administered equals the amount of
drug being eliminated
• After the time of one half life has passed, the peak and trough
concentrations are approx. 50% of what they will be when they
achieve steady-state
• The time from beginning of therapy to steady state is approximately ___
times the half life
• Example: a drug with a half life of 6 hours will take 30 hours to reach
steady state
Drug withdrawal times
• WITHDRAWAL TIME: the time (in days) from the last dose of medication until
the food animal can be sent to slaughter.
• Drug residues in food are a growing concern for people
• All drugs approved for use in food animals have a withdrawal time
• Drug must not only be out of the bloodstream, but also the tissues (no ______________ )
• Waiting period can result in loss of money to the food animal producer, but there are
severe fines/penalties for not following withdrawal times.
• The FARAD (Food Animal Residue Avoidance Databank) produces a compendium of drugs
with their withdrawal times.