Toxicology I

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Toxicology I

• ACS 668

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Toxicology IWhat is Pharmacology?

• Pharmacology is defined as the study of drugs.
• There is No distinct definition of a drug.
• A drug can be defined as any molecule used to
  alter body functions thereby preventing or
  treating disease.
• Therefore the aim of the drug therapy is to
• Rapidly deliver, maintain therapeutic, yet
• non-toxic Pharmacology is defined as the
• study of drugs. levels of drug in
  the target
• tissues.
• Most pharmacologists include both Medical
  Pharmacology (the study of agents used for the
  diagnosis, prevention, or treatment of disease)
  Toxicology (the study of the untoward effects of
  chemical agents) within the scope of
  pharmacology.

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Toxicology I
What is the Goal of Pharmacology? The Goal is
to study The speed of onset of drug
action, The intensity of the drugs effect,
and The duration of the drug action.
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Toxicology I

• How are these goals controlled in the study of
  Pharmacology?
• These goals are controlled by THREE fundamental
  pathways
• Site of administration (pathway I)
• Leads to entry of the drug into Plasma
  (Absorption or Input)
• b. Distribution of Drug (pathway II)
• Plasma ----------? Intracellular and Interstitial
  Fluids (tissues)
• c. Elimination (pathway III)
• Hepatic metabolism -? excretion via urine feces
  (excretion or output)

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Toxicology I

• How old is the Field of Pharmacology?
• The earliest written records come from the
  ancient civilizations of the Chinese, the Hindus,
  the South American Mayas, and Egyptians.
• The Scholar-Emperor Shen Nung (2735 BC) compiled
  a book of herbs is credited with observing the
  antifebrile effects of Chang Shang, which has now
  been shown to contain antimalarial alkaloids. He
  also noticed the stimulatory effect of the drug,
  Ma Huang, from which, almost 5,000 yrs later,
  Nagai isolated the active alkaloid Ephedrine.
• Indians knew about the antileprotic action of
  chaulmoogra fruit

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Toxicology IHow old is the field of
Pharmacology? (continued)

• Ipecacuanha root (contains emetine) was known
  used in Brazil the far East for the treatment
  of dysentery diarrhea.
• South American indians also Chewed cocoa leaves
  as a stimulant and euphoric.
• The first pharmacoepias were edited in
• A. Florence (1498)
• B. Nerenberg (1535)
• C. Basel (1561)
• D. London (1618)
• These reference works tried to bring order
  reason into the chaotic world of herbal medicine.

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Toxicology IHow old is the field of
Pharmacology? (cont.)

• Materia medica the science of drug preparation
  the medical use of drugs began to develop as
  the Precursor to Pharmacology (near the end of
  the 17th century)
• In the late 18th early 19th centuries,
  Francois Magendie later his student Claude
  Bernard began to develop the methods of
  experimental animal physiology pharmacology.
• Further development of physiology in the 18th,
  19th, early 20th centuries laid the foundation
  needed for the understanding of how drugs work at
  the organ and tissue levels.

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Toxicology IHow old is the field of
pharmacology? (cont.)

• The concept of clinical trial was reintroduced
  into medicine about 50 yrs ago.
• Some examples
• 1850 Iodide recognized as dietary
  prevention of goiter.
• 1881 Mercuric chloride was shown to kill
  anthrax bacillus.
• 1890-1990 Resistance to drugs studied.
• 1891 The term Chemotherapy coined.
• 1899 Aspirin introduced as mild analgesic
  antipyretic
• 1908 Sulpha drugs
• 1911 Vitamin the term coined.

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Toxicology I

• What is Pharmacogenomics?
• It is the study of the relation of the
  individuals genetic makeup to his or her
  response to specific drugs.

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Toxicology I

• What is meant by the term Knockout Mice?
• One of the most powerful of the new genetic
  techniques is the ability to breed animals
  (usually mice) in which the gene for the receptor
  or its endogenous ligand has been knocked out,
  i.e. MUTATED so that the gene product is absent
  or nonfunctional.
• Homozygous knockout mice will usually have
  complete suppression of that function.
• Heterozygous mice will usually have partial
  suppression.

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Toxicology I

• What is a Receptor?
• The drug molecule interacts with a specific
  molecule in the biologic system that plays a
  regulatory role. This molecule is called a
  receptor.
• Drug Receptor -? Drug-Receptor Complex -?
  EFFECT

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Toxicology IWhat are the most common routes of
drug administration?

• I. Enteral (means within the intestine )
• Rectal 50 of the drainage of the rectal region
  bypasses the hepatic portal circulation (absorbed
  by epigastric vein) thus the biotransformation of
  drugs by the liver is minimized.
• This system will prevent destruction of the drug
  by intestinal enzymes or by low pH in the stomach
  (also sublingual).
• This is especially useful if the drug induces
  vomiting when given orally or if the patient is
  already vomiting.
• This also eliminates the issue of taste.

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Toxicology IEnteral routes (cont.)

• Oral The most common route.
• The most complicated pathway to the tissues.
• Some drugs are absorbed from the stomach.
  However, the duodenum is often the major site it
  provides a large absorptive surface.
• A drug enters via the portal circulation and
  encounters the liver before they are distributed
  throughout the general circulation.

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Toxicology I

• Sublingual Placement under the tongue allows the
  drug to diffuse into the capillary network and to
  enter the systemic circulation directly.
• The advantage is that the drug bypasses the liver
  and is NOT inactivated by the liver (for example,
  90 of nitroglycerin is metabolized during a
  single passage or first pass thru the liver
  when taken orally.)

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Toxicology IMost common routes of drug
administration (cont.)

• II. Parenteral Route
• Used for drugs that are poorly absorbed from the
  GI tract. Or drugs such as insulin, that are
  unstable in the GI tract. This is for the
  unconscious patients. It will provide rapid
  onset of action. This will also provide the most
  control over the Actual Dose Delivered to the
  body.
• Intravenous (IV)
• The most common parenteral route
• The first-pass metabolism by the liver is avoided
• Rapid effect
• Maximal degree of control over the circulatory
  levels of the drug
• May induce hemolysis or other adverse reactions
  caused by the rapid delivery of high
  concentrations of drug to the plasma and tissues.

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Toxicology III. Parenteral Routes (cont.)

• Intramuscular (IM)
• A. Used for specialized depot preparations
  (into nonaqueous vehicle such as ethylene
  glycol or peanut oil). As the vehicle diffuses
  out of the muscle, the drug precipitates at the
  site of injection (may be painful). The drug
  then dissolves slowly, providing a sustained dose
  over an extended period of time.
• For example
• B. Protamine zinc insulin
• C. Also used for rapid action such as
  epinephrine in anaphylaxis.
• D. Relatively large volumes can be delivered.

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Toxicology IMost common Routes of drug
administration (cont.)

• III. Other Routes
• Inhalation used for drugs that can be dispersed
  in an aerosol or drugs that can vaporize easily.
• a. Provides the rapid delivery of a drug
  across the large surface area of the alveolar
  membrane.
• b. Can produce actions almost as rapidly as
  IV.
• Topical Used for local effects.
• Transdermal
• Achieves systemic effects by application of drugs
  to the skin usually via a transdermal patch.
• Used for the sustained delivery of drugs such as
  antimotion sickness agent (scopolamine) or the
  antianginal drug (nitroglycerin).
• Lack of first-pass effect

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B. DRUG SIZEThe molecular size of drugs varies
from very small (lithium ion, MW 7) to very large
(eg, alteplase t-PA, a protein of MW 59,050).
However, most drugs have molecular weights
between 100 and 1000. The lower limit of this
narrow range is probably set by the requirements
for specificity of action. To have a good "fit"
to only one type of receptor, a drug molecule
must be sufficiently unique in shape, charge, and
other properties, to prevent its binding to other
receptors. To achieve such selective binding, it
appears that a molecule should in most cases be
at least 100 MW units in size. The upper limit in
molecular weight is determined primarily by the
requirement that drugs be able to move within the
body (eg, from site of administration to site of
action). Drugs much larger than MW 1000 do not
diffuse readily between compartments of the body
(see Permeation, below). Therefore, very large
drugs (usually proteins) must often be
administered directly into the compartment where
they have their effect. In the case of alteplase,
a clot-dissolving enzyme, the drug is
administered directly into the vascular
compartment by intravenous or intra-arterial
infusion.
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C. DRUG REACTIVITY AND DRUG-RECEPTOR BONDSDrugs
interact with receptors by means of chemical
forces or bonds. These are of three major types
covalent, electrostatic, and hydrophobic.
Covalent bonds are very strong and in many cases
not reversible under biologic conditions. Thus,
the covalent bond formed between the acetyl group
of aspirin and its enzyme target in platelets,
cyclooxygenase, is not readily broken. The
platelet aggregation-blocking effect of aspirin
lasts long after free acetylsalicylic acid has
disappeared from the bloodstream (about 15
minutes) and is reversed only by the synthesis of
new enzyme in new platelets, a process that takes
about 7 days. Other examples of highly reactive,
covalent bond-forming drugs are the
DNA-alkylating agents used in cancer chemotherapy
to disrupt cell division in the
tumor.Electrostatic bonding is much more common
than covalent bonding in drug-receptor
interactions. Electrostatic bonds vary from
relatively strong linkages between permanently
charged ionic molecules to weaker hydrogen bonds
and very weak induced dipole interactions such as
van der Waals forces and similar phenomena.
Electrostatic bonds are weaker than covalent
bonds.Hydrophobic bonds are usually quite weak
and are probably important in the interactions of
highly lipid-soluble drugs with the lipids of
cell membranes and perhaps in the interaction of
drugs with the internal walls of receptor
"pockets."The specific nature of a particular
drug-receptor bond is of less practical
importance than the fact that drugs that bind
through weak bonds to their receptors are
generally more selective than drugs that bind by
means of very strong bonds. This is because weak
bonds require a very precise fit of the drug to
its receptor if an interaction is to occur. Only
a few receptor types are likely to provide such a
precise fit for a particular drug structure.
Thus, if we wished to design a highly selective
short-acting drug for a particular receptor, we
would avoid highly reactive molecules that form
covalent bonds and instead choose molecules that
form weaker bonds.A few substances that are
almost completely inert in the chemical sense
nevertheless have significant pharmacologic
effects. For example, xenon, an "inert" gas, has
anesthetic effects at elevated pressures.
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Toxicology Iwhat is absorption?

• It means the transfer of a drug from its site of
  administration to the bloodstream.
• The rate and efficiency of absorption
  depend on the route of administration.
• For IV administration absorption is
  complete, i.e. the total dose of drug reaches the
  systemic circulation.
• Drug administration by other routes may
  result in only partial absorption.
• For example
• Oral administration requires that a
  drug dissolve in the
• GI fluid and then PENETRATE the
  epithelial cells of the
• Intestinal mucosa.

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Toxicology ITransport of Drug from the GI Tract

• Passive Diffusion (PD)
• The driving force for passive absorption of a
  drug is the concentration gradient across a
  membrane separating two body compartments.
• The drug moves from a region of high
  concentration to a region of low concentration.
• P.D. does not involve a carrier
• Is not saturable
• Shows a low structural specificity
• The vast majority of drugs gain access to the
  body by this mechanism.

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Toxicology IPassive Diffusion (cont.)

• Passive Diffusion
• Lipid-soluble drugs Water soluble drugs
• Readily move across Penetrate the cell
• Most biological membranes membrane thru
• aqueous channels.
• A drug tends to pass thru membranes if it is
  uncharged.
• Uncharged drugs are more lipid soluble than
  charged drugs.

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Toxicology IActive Transport (AT)

• This mode of drug entry involves specific carrier
  proteins and shows saturation kinetics.
• Energy dependent
• Is driven by the hydrolysis of ATP
• It is capable of moving drugs against a
  concentration gradient, i.e., from a region of
  low concentration to a region of high drug
  concentration.
• A few drugs that closely resemble the structure
  of a naturally occurring metabolite are actively
  transported across cell membranes using these
  specific carrier proteins.

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Toxicology IActive Transport (cont.)

• Remember
• Very small water-soluble molecules and ions (e.g.
  K,Cl) evidently diffuse thru aqueous channels
  of some kind.
• Lipid-soluble molecules of any size diffuse
  freely thru the cell membranes.
• Water-soluble molecules and ions of moderate
  size, including the ionic forms of many (most)
  drugs cannot enter cells readily except by
  special transport mechanisms.
• Since proteins do gain access to cell interiors,
  it may be that pinocytosis plays some role here.

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Toxicology IWhat is Pinocytosis?

• Pinocytosis resembles phagocytosis. It is a
  cellular process of actively engulfing liquid. A
  phenomenon in which minute invaginations are
  formed in the surface of the cell membrane and
  close to form fluid filled vesicles.
• Around 1939, a series of experiments were
  conducted on the penetration of nonelectrolytes
  into the large cells of the marine plant CHARA
  CERATOPHYLA. The findings turned out to be
  generally relevant to penetration of other kinds
  of cells by nonelectrolytes.
• Various nonelectrolytes of wholly unrelated
  structures produce general anesthesia when they
  are present in sufficient concentration in the
  CNS.
• Ether (diethyl ether),
  cyclopropane, nitrous oxide, the
• primary alcohols, carbon
  disulfide chloroform are examples.
• The diversity of molecular
  structure among these drugs has always
• been puzzling.

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Toxicology IWhat is pinocytosis? (cont.)

• A systemic relationship is found, however,
  between anesthetic patency and oilwater partition
  coefficient. In alcohols (from methyl, to ethyl,
  to isopropyl) as the length of hydrophobic chain
  increases, so does the oilwater partition
  coefficient and also the anesthetic patency, the
  required aqueous concentration becoming lower and
  lower.

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Toxicology IPinocytosis (cont.)

• The carrier complex DC is assumed to be freely
  diffusible in the membrane.
• DC is formed at surface I and cleaved at surface
  II. Its concentration gradient will run down
  from I to II BUT that of free carrier will run
  down from II to I.
• Thus, diffusion can provide the means for cycling
  (or shuttling) the carrier across the membrane.
• If the concentration of D remains lower at II
  than at I (as when it is metabolized inside a
  cell), then the transport is downhill and
  requires No Net Expenditure of Energy by the
  cell.
• Ex. Glucose in erythrocytes known
  as facilitated diffusion.
• If the concentration of D is higher at II, the
  transport is uphill. Chemical energy must then
  be expanded to drive the unidirectional
  transport, for otherwise the same system would
  operate to move D in the opposite direction, from
  II to I. Transport requiring energy is called
  Active Transport. Work done by the cell at the
  expense of energy derived from metabolism.

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Toxicology IExample Sodium Pump

• The carrier is assumed to be activated by enzymes
  at the inside surfaces.
• The activated form Y has a high affinity for Na
• The deactivated form Z carries K
• Thus, a one-for-one exchange is mediated.

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Toxicology IOther examples of Active Transport

• Secretion of H into the stomach and into the
  renal tubular urine.
• The accumulation of iodide ions in the thyroid
  gland.
• The reabsorption of glucose and amino acids in
  the kidneys.
• The secretion of numerous organic anions and
  cations by the proximal renal tubules.
• Renal tubular secretion of penicillin.
• Secretion of penicillin into the bile.
• Transport of some drugs from CSF into blood.
• Membrane transport can be blocked by drugs that
  interfere with energy production.

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Toxicology IOther examples of Active Transport
(cont)

• The mature PLACENTA is far more than a semi
  permeable membrane. It contains energy-coupled
  specific transport systems for amino acids.
• L-Histidine, for example (but not D-Histidine) is
  transported from maternal blood to the fetal
  blood by an active placental transport system
  (almost similar to that found in human
  erythrocytes).
• 131-I is transferred much more rapidly from
  mother to fetus than in the reverse direction.
• 32-P-orthophosphate accumulates in placenta to
  many times its concentration in maternal blood,
  presumably serving as a reservoir to supply the
  large requirements for fetal growth.

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Toxicology IEffect of pH on Drug Absorption

• Many drugs are either weak acids or weak bases.
• Weak acids are Hydrogen Ion donors.
• HA ?? H A-
• They are happy to give up a hydrogen ion and
  become charged. Just remember good old HCL.
• HCL ? ? H Cl- acids donate hydrogen
  and become charged
• If we decrease the pH by adding more H, we will
  drive the reaction to the LEFT, which is the
  unionized (uncharged form).
• If we take away H, making the pH higher, we will
  drive the equilibrium towards the RIGHT. This
  increases the concentration of the ionized form
  of the weak acid.
• For a weak acid, when the pH is less than the
  pKa, the protonated form (unionized)
  predominates. When the pH is greater than the
  pKa, the unpronated (ionized) form predominates.

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Toxicology IWeak Bases are Hydrogen Ion
Acceptors

• A weak base sits around in solution looking sad
  and lonely. If, by chance, hydrogen ions courses
  along and says, what is a nice kid like you
  doing in a place like this ! May I join you?
  Yes, please!
• B H ? ? BH
• If it accepts the hydrogen ion, then it becomes
  charged.
• Adding H to lower the pH will drive the
  equilibrium to the RIGHT towards the protonated
  (charged form) form. Removing H to raise the pH
  will drive the equilibrium to the left towards
  the uncharged (unprotonated) form of the base.
• For a weak base, when the pH is less than the
  pKa, the ionized form (protonated) predominates.
  When the pH is greater than the pKa, the
  unprotonated (unionized) form predominates.

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Toxicology IWhy is it so important to discuss
all this?

• In the stomach (pH2), weak acids are uncharged
  and will be absorbed into the bloodstream, while
  weak bases are charged and will remain in the GI
  tract.
• Test Questions
• 1. In the
  intestine (pH 8.0), which will be better
• absorbed, a
  weak acid (pKa 6.8) or a weak base
• (pKa 7.1) ?
• Answer Weak
  Base (uncharged form)
• 2. If we
  alkalinize urine to a pH of 7.8, will a lower
• or a higher
  of a weak acid (pKa 7.1) be ionized,
• compared to
  when the urine was 7.2 ?
• Answer
  Higher. More weak acid will be ionized
• 
  the more the pH exceeds pKa.

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Toxicology IWhat have we learned out of this
discussion?

• The pKa is a measure of the strength of the
  interaction of a compound with a proton. The
  lower the pKa, the stronger the acid.
• The effective concentration of the permeable form
  of each drug at its absorptive site is determined
  by relative concentrations of the charged and
  uncharged forms. This in turn is determined by
  the pH at the site of absorption and by the
  strength of the weak acid or weak base which is
  represented by the pKa.
• When Ph is less than pka the PROTONATED forms HA
  and BH predominate.
• When pH is greater than pKa the DEPROTONATED
  forms A- and B predominate.

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Toxicology I

• Pharmacokinetics What the body does to the drug.
• The movement of drugs within the body from
  administration to elimination Pharmacokinetics
  encompasses
• Absorption
• Distribution
• Metabolism, and
• Excretion of Drugs

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Toxicology I

• Pharmacodynamics What the drug does to the body.
• It refers to the action of the drug at the
  cellular level.
• This term encompasses the binding of a drug to
  its receptor or binding site.
• The relationship of dose and therapeutic level to
  the physiological response
• The relationship of drug action and efficiency to
  dosage interval.

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Toxicology IWhat is the relevance of this
discussion in Pharmacology?

• Drugs can only pass thru cell membranes in
  non-ionized (unionized or neutral) form,
  OPTIMIZING the pH of the compartment to the pKa
  of the drug will result in more drug molecules
  existing in non-ionized form (as calculated by
  Henderson-Hasselbach equation). This will result
  in a greater absorption of drug in that
  compartment.
• For Example, Ca is better absorbed in acidic
  environment
• In Ca-carbonate for
  it is NOT efficiently absorbed if
• pH of the stomach is
  NOT low enough (as is the case
• with older
  patients). Taking Ca-carbonate with a
• small glass of
  orange juice can increase the
• absorption OR buy
  Cacitrate form which will cost a
• fortune.
• Another Example, Codeine is a weak base with
  a pKa of 8.2 will be 61.4
• absorbed in
  the basic environment of the duodenum
• (pH8), but
  less than 0.0002 of the drug will be absorbed
• in the acidic
  environment of the stomach.

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Toxicology IWhat is Drug Absorption?

• It refers to the entrance of the drug INTO
  the blood stream.
• Therefore, the term is only applicable to
  drug administered by an enteral or topical route.
• As injectable drugs are administered directly
  into the bloodstream, they are not ABSORBED.

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Toxicology IWhat would be the effect of
concurrent administration of antacids and aspirin?

• Ingestion of an antacid (alternatively) and H2
  blocker or proton pump inhibitor results in an
  increase in the pH of the gastric environment.
• The pKa of aspirin (a weak acid) is 3.5 and
  exists mainly in nonionized form in the gastric
  environment, an increase in gastric pH would
  shift the equilibrium to the RIGHT, resulting in
  an increase in the ionized form and decreased
  absorption of the drug.

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Toxicology IWhat is the partition coefficient
for a drug?

• It is a measure of how lipophilic a drug is. The
  more lipophilic the drug is, the HIGHER is its
  partition coefficient. The better its ability to
  move across membrane barriers.

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Toxicology IWhat is the significance of the
partition coefficient?

• Drugs with low partition coefficients are likely
  to distribute in the plasma and thus are more
  likely to have peripheral effects.
• They are also more likely to be eliminated by
  renal filtration.
• Drugs with high partition coefficients will
  distribute in adipose tissue and are more likely
  to cross the blood-brain barrier and distribute
  into the CNS with CNS effects.
• These drugs are likely to undergo hepatic
  metabolism and be eliminated in the bile.

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Toxicology IWhat is the role of the partition
coefficient in the rapidity of onset of a CNS
drug?

• In general lipid soluble drugs have a higher
  partition coefficient.
• The brain and spinal cord contain a large amount
  of fatty tissue (e.g. myelin) and are protected
  by the blood brain barrier, the more lipophilic a
  drug is, the better it will cross into the CNS.
• This will also result in a faster onset and
  faster withdrawal of effects as well, the drug
  will cross VERY RAPIDLY into (and out of) the
  lipophilic environment of the CNS.

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Toxicology IWhat is meant by the term- drug
distribution?

• After a drug is absorbed into the bloodstream it
  is distributed among the bodily compartments such
  as plasma and adipose tissue (or the process by
  which a drug leaves the bloodstream and enters
  the cells of the tissues).

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Toxicology IBy what THREE biochemical
mechanisms are drugs absorbed into cells

• Passive Diffusion This is governed by a
  concentration gradient across a membrane, which
  makes a drug move from an area of high
  concentration to one of low concentration. It is
  one of the MOST COMMON modes of drug transport.
• Transport by special carrier proteins A form of
  passive diffusion that is facilitated by a
  carrier protein.
• Active Transport Transport against a
  concentration gradient. The energy for this
  mechanism comes from dephosphorylation of ATP.

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Toxicology IWhat does distribution depend upon?

• The degree of ionization at physiological pH
• On the partition coefficient
• Binding to plasma proteins such as albumin/or/it
  may bind to more specialized proteins in the
  plasma. (e.g. thyroid binding proteins or
  IGF-binding protein)
• Drugs that are less hydrophilic may also bind to
  tissue proteins.

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Toxicology IWhich types of drugs extensively
bind to plasma albumin?

• Aspirin
• Phenytoin
• Prednisone
• Etc.

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Toxicology IWhat are the pharmacological
ramifications of the TYPE of plasma protein to
which a drug binds?

• For example, albumin is in relatively high
  concentrations in the plasma, thus providing
  plentiful and relatively constant binding sites
  for drugs, under a variety of conditions.
• Drugs that bind to plasma globulins and to alpha,
  -acid glycoproteins, however, may fluctuate in
  level under inflammatory conditions, as the
  amounts of these proteins may INCREASE when
  inflammation is present and DECREASE at other
  times. Thus, the concentration of the FREE drug
  in the plasma (and the pharmacologic effect) is
  MORE DIFFICULT TO PREDICT.

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Toxicology I

• What would be the effect of concurrent
  administration of drugs that are highly protein
  bound?
• What is the volume of distribution? (Vd)
• Volume of distribution is the amount of space
  available in the body in which drugs may be
  stored.
• In theory, it refers to a homogenous distribution
  of drug.

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Toxicology I

• What is the significance of a large Vd?
• A large Vd signifies that most of the drug is
  being absorbed sequestered in some organ or
  compartment.
• In general, it means that a higher dose can be
  tolerated. A drug with a large volume of
  distribution allows a corresponding higher
  therapeutic dose.

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Volume of DistributionVolume of distribution
(Vd) relates the amount of drug in the body to
the concentration of drug (C) in blood or
plasma     
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Toxicology I

• How is Vd Calculated?
• VdTotal drug in the body
• Plasma concentration of the drug

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Toxicology I

• How are drugs eliminated from the system?
• By liver metabolism
• By Renal Filtration
• By Redistribution

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Toxicology IMetabolism within major organs such
as

• The Lung
• Intestine
• Cardiac myocytes
• Blood/Vascular system
• E.g. Drugs such as acetylcholine are metabolized
  by plasma esterases PG analogues are metabolized
  by the lung and eliminated. Some drugs are so
  poorly absorbed (e.g. Sulfasalazine) as to pass
  thru the feces to be metabolized by intestinal
  flora.

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Toxicology IWhat is Redistribution?

• Redistribution is the process by which the drugs
  that are concentrated will have activity in one
  particular tissue or organ and may be eliminated
  by removal of drug from the target tissue to
  other storage sites in the body.
• E.g. with drugs that are active in the CNS (such
  as general anesthetics). These drugs rapidly
  concentrate in the CNS, resulting in a rapid
  onset of drug effects. An equally rapid
  redistribution to site on the periphery terminate
  the drug action.

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Toxicology I

• Proximal tubular secretion
• Some drugs are actively secreted into the
  proximal tubule.
• Distal tubular resorption
• Changing pH

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Toxicology IWhat kinds of drugs are eliminated
by renal filtration?

• Drugs that are small in molecular size, and
  highly soluble in water, may be eliminated
  unchanged thru renal filtration. The degree of
  elimination is dependent upon urinary pH.
  (Glomeruler filtration).
• Drugs that are less soluble in water are first
  metabolized by enzymes in the liver. (e.g.
  cytochrome P450).

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Toxicology IKinds of drugs eliminated by renal
filtration (cont.)

• Phase I reaction frequently involve the
  cytochrome P450 system. Phase I reactions
  convert lipophilic molecules into more polar
  molecules by Introducing or Unmasking a polar
  functional group such as OH or NH2. Most of
  these reactions utilize the microsomal P450
  enzymes.
• Phase II- reactions are conjugation reactions.
  These combine a glucuronic acid, H2SO4, CH3COOH
  or an amino acid with the drug molecule to make
  it more polar. The highly polar drug can then be
  excreted by the kidney (glucorinated drugs such
  as aspirin, barbiturates, opiates diazepam,
  meprobamate, acetaminophen, digitabes
  glycosides.)

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