MIDTERM NOTES.
CHAPTER FOUR: Pharmacokinetics, Pharmacodynamics, and Drug Interactions
Pharmacokinetics
-the study of drug movement throughout the body
-made up of 4 processes:
absorption: drug's movement from its site of administration into the blood
distribution: drug's movement from the blood to the interstitial space of tissues and from there into the
cells
metabolism: aka biotransformation; the enzymatically mediated alteration of drug structure
excretion: movement of drugs and their metabolites out of the body
metabolism + excretion= elimination
Passage of Drugs Across Membranes
-3 ways to cross a membrane
passage through channels or pores: very few drugs do this b/c channels and pores are very small and
are specific for certain molecules
passage with the aid of a transport system: carriers that move drugs from one side of the cell
membrane to another; all are selective and depend on the drug's structure; PGP (P-glycoprotein)
transports a variety of drugs out of cells
direct penetration of the membrane (most common)
Polar Molecules and Ions
-certain kinds of molecules are not lipid soluble and therefore can't penetrate membranes; this group
consists of polar molecules and ions
- ions must become nonionized to cross one side to the other
-most drugs are weak organic acids or weak organic basics
-acids tend to ionize in basic media, whereas bases ionize in acidic media
-therefore, drugs that are weak acids are best absorbed in an acidic environment such as gastric acid bc
they maintain their nonionized form
pH Partitioning (Ion Trapping)
-ionization of drugs is pH dependent
-when the pH of fluid on one side of the membrane differs from the other side, drug molecules
accumulate on the side where the pH favors their ionization
-accordingly, bc acidic drugs tend to ionize in basic media and vice versa, when there is a pH gradient
between two sides of a membrane, the following occurs:
acidic drugs accumulate on the alkaline
side basic drugs accumulate on the acidic
side
*this is called ion trapping
Absorption
-movement of drug from its site of administration into systemic circulation
-rate of absorption determines how soon effects will begin
-amount of absorption determines how intense the effects will be
chemical equivalency: when 2 drug preparations have the same amount of identical chemical compound
(drug)
bioavailability: if the drug each formula contains is absorbed at the same rate and to the same extent
,MIDTERM NOTES.
Rate of Dissolution
-helps determine the rate of absorption
-faster onset with rapid dissolution
Surface Area
-the SA available for absorption is a major determinant of absorption (more SA-faster absorption)
Blood Flow
-drugs are more rapidly absorbed in areas of greater blood flow
-newly absorbed drug will be replaced by drug-free bloo, thereby maintaining a large gradient between
the concentration of the drug outside the blood vs inside the blood
-greater concentration gradient equals more rapid absorption
Lipid Solubility
-highly lipid soluble drugs are absorbed more rapidly than drugs with low lipid solubility
pH Partitioning
- absorption is enhanced when the difference between the pH of plasma at the site of administration is
such that the drug molecules will have a greater tendency to be ionized in the plasma
Distribution
-movement of drugs from systemic circulation to the site of drug action
-determined by blood flow to the tissues and the ability of drug to exit the vascular system, and to a
lesser extent, the ability of the drug to enter cells
Blood Flow to Tissues
-in the first phase of distribution, drugs are carried by the blood to tissues and organs of the body
(determined by blood flow)
-when a pt has an abscess or tumor, this can affect drug therapy
Exiting the Vascular System
-after a drug has been delivered to an organ or tissue by blood circulation, the next step is to exit the
vascular system
-because most drugs don't produce their effects within the blood, their ability to leave is important
-drugs leave vascular system at the capillary beds
Typical Capillary Beds
-most capillary beds offer no resistance to the departure of drugs
-most drugs leave by passing through the pores in the capillary wall; because most drugs pass between
capillary beds and not through them, movement into the interstitial fluid is not impeded
Blood-Brain Barrier
-refers to the unique anatomy of capillaries in the CNS
-there are tight junction between the cells that compose the walls of most capillaries in the CNS;
they are so tight they prevent drug passage
-only drugs that are lipid soluble or have a transport system can cross the BBB to a significant degree
-in addition to tight junction, the BBB has another protective component: PGP
-PGP pumps drugs back into the blood and thereby limits their access of the brain
,MIDTERM NOTES.
-BBB is not fully developed at birth; newborn have highest sensitivity to medicines that act on the brain
and are vulnerable to CNS toxicity
Placental Drug Transfer
-membranes of the placenta separate the maternal circulation from the fetal
-most drugs cross the placenta via diffusion
-lipid- soluble, nonionized compounds readily pass from the maternal bloodstream into the fetus
-compounds that are highly ionized, highly polar, or protein bound are largely excluded, as are drugs that
are substrates for PGP transporter (pumps drugs out of placental cells into maternal blood)
Protein Binding
-drugs can form reversible bonds with various proteins in the body
-plasma albumin is most important; it is a large molecule thats too big to leave the bloodstream
-even though most drugs can bind albumin, only some molecules will be bound at any moment; this is
determined by strength of attraction between albumin and the drug
-protein binding leads to restriction of drug distribution (drugs bound to albumin can't leave circulation
and distribute)
-bound molecules can't reach their site of action until the protein bond is broken
-protein binding can be a source of drug interactions; because the number of binding sites is limited,
the drug with the strongest attraction will bind, displacing the other drug bound there before, leading
to a rise in free concentration of the displaced drug, resulting in toxicity
Entering cells
-most drugs produce their effect by binding with receptors located on the external surface of the cell
membrane
-the factors that determine the ability of a drug to cross cell membranes are the same factors that
determine the passage of drugs across all other membranes, namely lipid solubility, the presence of a
transport protein, or both
Metabolism
-aka biotransformation
-enzymatic alteration of drug structure
-most metabolism takes place in the liver
Hepatic Drug-Metabolizing Enzyme
-most metabolism that occur sint he liver is performed by the hepatic microsomal enzyme system, aka
the P450 system
-P450 refers to cytochrome P450, a key component of this enzyme system
-cytochrome P450 is a group of 12 closely related enzyme families
-3 of these families metabolize drugs: CYP1, CYP2, CYP3
-other 9 metabolize endogenous compounds (steroids, fatty acids)
Therapeutic Consequences of Drug Metabolism
-accelerated renal excretion of drugs ** most important
**kidneys are the major organs of drug excretion; they are unable to excrete drugs that are highly lipid
soluble; hence, by converting lipid-soluble drugs into more hydrophilic (water-soluble) forms, metabolix
conversion can accelerate renal excretion
-drug inactivation
, MIDTERM NOTES.
drug metabolism can convert pharmacologically active compound sinto non-active ones; most common
end result of drug metabolism
-increased therapeutic action
metabolism can increase the effectiveness of some drugs; for example, metabolism converts codeine
into morphine, the analgesic effect of morphine is greater (accounts for the pain relief that occurs after
codeine administration)
-activation of prodrugs
a prodrug is a compound that is pharmacologically inactive as administered and then undergoes
conversion to its active form through metabolism; they have many advantages; for example a drug
that cannot cross the BBB may be able to do so as a lipid-soluble prodrug that is converted to its active
form in the CNS
-increased toxicity
example: conversion of acetaminophen into a hepatotoxic metabolite; its th eproduct of metabolism, not
the acetaminophen itself that causes injury to the liver when taken in overdose
-decreased toxicity
First-Pass Effect
-refers to the rapid inactivation of certain oral drugs
-when drugs are absorbed in the GI tract, they are carried directly to the liver through the hepatic portal
vein before they enter systemic circulation; if the capacity of the liver to metabolize a drug is extremely
high, that drug can be completely inactivated on its first pass through the liver
-to circumvent the first pass effect, a drug that undergoes rapid hepatic metabolism is often given
parenterally (so it can bypass the liver)
Enterohepatic Circulation
-a repeating cycle in which a drug is transported from the liver into the duodenum (through the bile
duct) and then back to the liver (through the portal blood)
-this process is limited to drugs that have undergone glucuronidation, a process that converts lipid
soluble drugs into water soluble drugs by binding them to glucuronic acid
-after glucuronidation, these drugs can enter the bile and then pass to the duodenum
-in the intestine, some drugs can be hydrolyzed by intestinal beta glucuronidase, and enzyme that breaks
the bond between the original drug and the glucuronide moiety, thereby releasing the free drug
-because the free drug is more lipid soluble than the glucuronidated form, the free drug can undergo
reabsorption across the intestinal wall, followed by transport back to the liver, where the cycle can start
again
-because of this enterohepatic recycling, drugs can remain in the body much longer than they otherwise
would
Renal Drug Excretion
-removal of drug from the body
-excretion can happen through urine, bile, sweat, saliva, breast milk, and expired air, but most occurs
through the kidneys
-if renal failure occurs, both the duration and intensity of drug responses may increase
-net result of 3 processes:
glomerular filtration
-renal excretion begins at the glomerulus of kidney tubule
CHAPTER FOUR: Pharmacokinetics, Pharmacodynamics, and Drug Interactions
Pharmacokinetics
-the study of drug movement throughout the body
-made up of 4 processes:
absorption: drug's movement from its site of administration into the blood
distribution: drug's movement from the blood to the interstitial space of tissues and from there into the
cells
metabolism: aka biotransformation; the enzymatically mediated alteration of drug structure
excretion: movement of drugs and their metabolites out of the body
metabolism + excretion= elimination
Passage of Drugs Across Membranes
-3 ways to cross a membrane
passage through channels or pores: very few drugs do this b/c channels and pores are very small and
are specific for certain molecules
passage with the aid of a transport system: carriers that move drugs from one side of the cell
membrane to another; all are selective and depend on the drug's structure; PGP (P-glycoprotein)
transports a variety of drugs out of cells
direct penetration of the membrane (most common)
Polar Molecules and Ions
-certain kinds of molecules are not lipid soluble and therefore can't penetrate membranes; this group
consists of polar molecules and ions
- ions must become nonionized to cross one side to the other
-most drugs are weak organic acids or weak organic basics
-acids tend to ionize in basic media, whereas bases ionize in acidic media
-therefore, drugs that are weak acids are best absorbed in an acidic environment such as gastric acid bc
they maintain their nonionized form
pH Partitioning (Ion Trapping)
-ionization of drugs is pH dependent
-when the pH of fluid on one side of the membrane differs from the other side, drug molecules
accumulate on the side where the pH favors their ionization
-accordingly, bc acidic drugs tend to ionize in basic media and vice versa, when there is a pH gradient
between two sides of a membrane, the following occurs:
acidic drugs accumulate on the alkaline
side basic drugs accumulate on the acidic
side
*this is called ion trapping
Absorption
-movement of drug from its site of administration into systemic circulation
-rate of absorption determines how soon effects will begin
-amount of absorption determines how intense the effects will be
chemical equivalency: when 2 drug preparations have the same amount of identical chemical compound
(drug)
bioavailability: if the drug each formula contains is absorbed at the same rate and to the same extent
,MIDTERM NOTES.
Rate of Dissolution
-helps determine the rate of absorption
-faster onset with rapid dissolution
Surface Area
-the SA available for absorption is a major determinant of absorption (more SA-faster absorption)
Blood Flow
-drugs are more rapidly absorbed in areas of greater blood flow
-newly absorbed drug will be replaced by drug-free bloo, thereby maintaining a large gradient between
the concentration of the drug outside the blood vs inside the blood
-greater concentration gradient equals more rapid absorption
Lipid Solubility
-highly lipid soluble drugs are absorbed more rapidly than drugs with low lipid solubility
pH Partitioning
- absorption is enhanced when the difference between the pH of plasma at the site of administration is
such that the drug molecules will have a greater tendency to be ionized in the plasma
Distribution
-movement of drugs from systemic circulation to the site of drug action
-determined by blood flow to the tissues and the ability of drug to exit the vascular system, and to a
lesser extent, the ability of the drug to enter cells
Blood Flow to Tissues
-in the first phase of distribution, drugs are carried by the blood to tissues and organs of the body
(determined by blood flow)
-when a pt has an abscess or tumor, this can affect drug therapy
Exiting the Vascular System
-after a drug has been delivered to an organ or tissue by blood circulation, the next step is to exit the
vascular system
-because most drugs don't produce their effects within the blood, their ability to leave is important
-drugs leave vascular system at the capillary beds
Typical Capillary Beds
-most capillary beds offer no resistance to the departure of drugs
-most drugs leave by passing through the pores in the capillary wall; because most drugs pass between
capillary beds and not through them, movement into the interstitial fluid is not impeded
Blood-Brain Barrier
-refers to the unique anatomy of capillaries in the CNS
-there are tight junction between the cells that compose the walls of most capillaries in the CNS;
they are so tight they prevent drug passage
-only drugs that are lipid soluble or have a transport system can cross the BBB to a significant degree
-in addition to tight junction, the BBB has another protective component: PGP
-PGP pumps drugs back into the blood and thereby limits their access of the brain
,MIDTERM NOTES.
-BBB is not fully developed at birth; newborn have highest sensitivity to medicines that act on the brain
and are vulnerable to CNS toxicity
Placental Drug Transfer
-membranes of the placenta separate the maternal circulation from the fetal
-most drugs cross the placenta via diffusion
-lipid- soluble, nonionized compounds readily pass from the maternal bloodstream into the fetus
-compounds that are highly ionized, highly polar, or protein bound are largely excluded, as are drugs that
are substrates for PGP transporter (pumps drugs out of placental cells into maternal blood)
Protein Binding
-drugs can form reversible bonds with various proteins in the body
-plasma albumin is most important; it is a large molecule thats too big to leave the bloodstream
-even though most drugs can bind albumin, only some molecules will be bound at any moment; this is
determined by strength of attraction between albumin and the drug
-protein binding leads to restriction of drug distribution (drugs bound to albumin can't leave circulation
and distribute)
-bound molecules can't reach their site of action until the protein bond is broken
-protein binding can be a source of drug interactions; because the number of binding sites is limited,
the drug with the strongest attraction will bind, displacing the other drug bound there before, leading
to a rise in free concentration of the displaced drug, resulting in toxicity
Entering cells
-most drugs produce their effect by binding with receptors located on the external surface of the cell
membrane
-the factors that determine the ability of a drug to cross cell membranes are the same factors that
determine the passage of drugs across all other membranes, namely lipid solubility, the presence of a
transport protein, or both
Metabolism
-aka biotransformation
-enzymatic alteration of drug structure
-most metabolism takes place in the liver
Hepatic Drug-Metabolizing Enzyme
-most metabolism that occur sint he liver is performed by the hepatic microsomal enzyme system, aka
the P450 system
-P450 refers to cytochrome P450, a key component of this enzyme system
-cytochrome P450 is a group of 12 closely related enzyme families
-3 of these families metabolize drugs: CYP1, CYP2, CYP3
-other 9 metabolize endogenous compounds (steroids, fatty acids)
Therapeutic Consequences of Drug Metabolism
-accelerated renal excretion of drugs ** most important
**kidneys are the major organs of drug excretion; they are unable to excrete drugs that are highly lipid
soluble; hence, by converting lipid-soluble drugs into more hydrophilic (water-soluble) forms, metabolix
conversion can accelerate renal excretion
-drug inactivation
, MIDTERM NOTES.
drug metabolism can convert pharmacologically active compound sinto non-active ones; most common
end result of drug metabolism
-increased therapeutic action
metabolism can increase the effectiveness of some drugs; for example, metabolism converts codeine
into morphine, the analgesic effect of morphine is greater (accounts for the pain relief that occurs after
codeine administration)
-activation of prodrugs
a prodrug is a compound that is pharmacologically inactive as administered and then undergoes
conversion to its active form through metabolism; they have many advantages; for example a drug
that cannot cross the BBB may be able to do so as a lipid-soluble prodrug that is converted to its active
form in the CNS
-increased toxicity
example: conversion of acetaminophen into a hepatotoxic metabolite; its th eproduct of metabolism, not
the acetaminophen itself that causes injury to the liver when taken in overdose
-decreased toxicity
First-Pass Effect
-refers to the rapid inactivation of certain oral drugs
-when drugs are absorbed in the GI tract, they are carried directly to the liver through the hepatic portal
vein before they enter systemic circulation; if the capacity of the liver to metabolize a drug is extremely
high, that drug can be completely inactivated on its first pass through the liver
-to circumvent the first pass effect, a drug that undergoes rapid hepatic metabolism is often given
parenterally (so it can bypass the liver)
Enterohepatic Circulation
-a repeating cycle in which a drug is transported from the liver into the duodenum (through the bile
duct) and then back to the liver (through the portal blood)
-this process is limited to drugs that have undergone glucuronidation, a process that converts lipid
soluble drugs into water soluble drugs by binding them to glucuronic acid
-after glucuronidation, these drugs can enter the bile and then pass to the duodenum
-in the intestine, some drugs can be hydrolyzed by intestinal beta glucuronidase, and enzyme that breaks
the bond between the original drug and the glucuronide moiety, thereby releasing the free drug
-because the free drug is more lipid soluble than the glucuronidated form, the free drug can undergo
reabsorption across the intestinal wall, followed by transport back to the liver, where the cycle can start
again
-because of this enterohepatic recycling, drugs can remain in the body much longer than they otherwise
would
Renal Drug Excretion
-removal of drug from the body
-excretion can happen through urine, bile, sweat, saliva, breast milk, and expired air, but most occurs
through the kidneys
-if renal failure occurs, both the duration and intensity of drug responses may increase
-net result of 3 processes:
glomerular filtration
-renal excretion begins at the glomerulus of kidney tubule
