Pharmacokinetics:

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Week 2 outline

• Pharmacokinetics
• How drugs are handled by the body
• Overview followed by details!!

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Lets say you have a headache or a really really
really bad reaction to poison ivy and you take
some meds This illustrates the basic
processes in the branch of pharmacokinetics
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pharmacokinetics.......

• the route of administration
• - how a drug is taken into the body
• absorption and distribution
• - factors affecting its absorption and how it
  gets distributed to the brain

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• 3. metabolism (detoxification or breakdown)
• how a drug is broken down or made into inactive
  forms
• 4. excretion (elimination)
• how the drug is eliminated

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• Knowing about pharmacokinetics tells us critical
  information about insight into the actions of a
  drug.
• Ex. benzodiazepenes
• ultra short acting, short acting, long acting

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• lorazepam (Ativan) and triazolam (Halcion)
  pharmacokinetics
• lorazepam persists for at least 24 hr
• triazolam 6 8 hours
• midazolam 1 2 hrs

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Drug Absorption

• Absorption the process by which a drug enters
  the bloodstream without being chemically altered
  or
• The movement of a drug from its site of
  application into the blood

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What are the routes of drug administration?

• oral
• injection
• iv, im, sc, intrathecal, intraperitoneal

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oral administration

• most common, sometimes referred to as po
• safe, self administered, economical BUT blood
  levels are often irregular (most complicated
  route of adm)
• liquid more readily absorbed than solids

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What are the qualities a drug needs to be
absorbed orally?

• soluble and stable in stomach (not destroyed by
  stomach enzymes more acidic)
• enter intestine penetrate lining of intestine,
  pass into bloodstream and reach site of action
• absorption favored if the drug is nonionized and
  more lipophilic

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What do orally administered drugs have to deal
with?

• chemicals in stomach must deal with
• stomach acids
• digestive enzymes
• first pass metabolism through liver
• other items in stomach
• ex. tetracycline

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Advantages of oral administration

• Convenient - can be self- administered, pain
  free, easy to take
• Absorption - takes place along the whole length
  of the GI tract
• Inexpensive - compared to most other parenteral
  routes

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oral administration

• disadvantages of oral administration
• vomiting/stomach distress
• variability in dose
• effect too slow for emergencies
• unpleasant taste of some drugs
• unable to use in unconscious patient
• first pass metabolism

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First-pass metabolism

• First pass metabolism - term used for the hepatic
  metabolism of a drug when it is absorbed from the
  gut and delivered to the liver via the portal
  circulation.
• The greater the first-pass effect, the less the
  agent will reach the systemic circulation when
  the agent is administered orally

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first pass metabolism
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oral administration

• disadvantages of oral administration
• vomiting
• stomach distress
• variability in dose
• first pass metabolism
• ex. buspirone (BuSpar) antianxiety drug
• 5 reaches central circulation and is distributed
  to brain
• metabolism can be blocked by drinking grapefruit
  juice (suppresses CYPp450 enzyme)

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Grapefruit Juice Increases Felodipine Oral
Availability in Humans by Decreasing Intestinal
CYP3A Protein Expression
Hours
J.Clin. Invest. 9910, p.2545-53, 1997
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Some additional interesting points regarding oral
adm

• Drugs that are destroyed by gastric juice or
  cause gastric irritation can be administered in a
  coating that prevents dissolution in acidic
  gastric contents (however may also preclude
  dissolution in intestines)
• Controlled Release Preps -

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Factors that affect rate of absorption following
PO route

• GI motility- speed of gastric emptying affects
  rate of absorption
• ex. migraine and analgesics vs metoclopramide
• Malabsorptive States -
• GI diseases, ex. Crohns disease can affect
  absorption

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Factors that affect rate of absorption following
PO route

• Food -
• iron, milk alters tetracycline
• fats
• first pass metabolism

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Parenteral or Injection

• chemicals delivered with a hypodermic needle
• most commonly - injected into vein, muscle or
  under the upper layers of skin, in rodents also
  intraperitoneal cavity
• requirements for parenteral
• must be soluble in solution (so it can be
  injected)

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B. Parenteral (Injection)

• Intravenous
• Intramuscular
• Subcutaneous
• Intracranial
• Epidural
• Intraperitoneal

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Intramuscular

• absorption more rapid than SC
• less chance of irritation
• ways to speed up or slow down absorption
• depot injections -

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Intravenous

• extremely rapid rate of absorption
• adv useful when you need rapid response or for
  irritating substances
• Disadv rapid rate of absorption

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Absorption for parenteral route

• contingent on blood flow SO
• IV, intraperitoneal, IM, SC
• increasing or decreasing blood flow affects drug
  absorption
• Drugs leave bloodstream and are exchanged between
  blood capillaries and body tissues

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What if a drug is injected in oil?

• bolus or depot shots
• related - drugs that accumulate in fat
• ex. THC

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Mucosal membranes

• nasal, oral, buccal
• medications include nitroglycerine, fentanyl
  (1998) , nicotine gum, lozenges, buprenorphine
• cocaine
• snuff, cigars

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Advantages and Disadvantages of Buccal

• Advantages
• rapid absorption
• avoid first-pass effect
• Disadvantages
• inconvenient
• small doses
• unpleasant taste of some drugs

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transdermal or transcutaneous

• 1990s several medications incorporated into
  transdermal patches
• estrogen, nicotine, fentanyl, nitroglycerin,
  scopolamine
• controlled slow release for extended periods of
  time

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Rectal Administration

• usually suppository form
• for unconscious, vomiting or unable to swallow
• disadv not very well regulated dose
  irritation (yikes)

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Inhalation

• not really used for psychotropics

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Route for administration -Time until effect-

• intravenous 30-60 seconds
• inhalation 2-3 minutes
• sublingual 3-5 minutes
• intramuscular 10-20 minutes
• subcutaneous 15-30 minutes
• rectal 5-30 minutes
• ingestion 30-90 minutes
• transdermal (topical) variable (minutes to hours)

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Drug Absorption

• The rate at which a drug reaches it site of
  action depends on
• Absorption - involves the passage of the drug
  from its site of administration into the blood
• Distribution - involves the delivery of the drug
  to the tissues

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Drug Absorption

• Factors which influence the rate of absorption
• routes of administration
• dosage forms
• the physicochemical properties of the drug
• protein binding
• circulation at the site of absorption
• concentration of the drug

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Distribution

• drugs are distributed throughout body by blood
• very little at site of action at any one time
• role of passive diffusion, concentration gradient

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Absorption

• Mostly a passive process -
• from higher conc to lower (in blood)

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Concentration Gradient
Drug goes from higher concentration to lower
concentration
? DRUG receptors DRUG circulation
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Absorption and Distribution

• Mostly a passive process -
• from higher conc to lower (in blood)
• Binding to plasma proteins
• results in a store of bound drug in plasma
• examples -
• 95-99 - chlorpromazine, diazepam, imipramine
• 90 - 95 - valproate, propanolol, phenytoin

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Factors that can play a role in reducing the
amount of drug bound to proteins

• Renal insufficiency
• last trimester of pregnancy
• drug interactions (other drugs that bind to
  proteins)
• diseases

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Additional issue for drugs to reach the CNS

• Blood brain barrier-
• layer of thickly packed epithelial cells and
  astrocytes that restrict access of many
  toxins/drugs to the brain

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3 Factors that affect how well a drug can cross
the blood brain barrier (or placental barrier)

• Lipid solubility how soluble the drug is in
  fats
• cell membranes are lipid bilayers
• similar characteristics allow drugs to cross
  brain as to cross into cells

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3 Factors that affect how well a drug can cross
the blood brain barrier

• Lipid solubility
• Size of molecule
• Ionization whether the degree has a charge (
  or -)

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• pKa
• the pH at which ½ of the molecules are ionized
• most drugs are either weakly basic or weakly
  acidic
• Basic drugs are highly ionized in acidic
  environment
• Acidic drugs are highly ionized in basic
  environment

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• pKa
• the pH at which ½ of the molecules are ionized
• the closer the pKa of the drug is to the local
  tissue pH, the more unionized the drug is.
• ex. morphine pKa of 8
• stomach pH 3
• caffeine pH .5

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Distribution half-life and therapeutic levels

• Distribution half-life the amount of time it
  takes for half of the drug to be distributed
  throughout the body
• Therapeutic level the minimum amount of the
  distributed drug necessary for the main effect.

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Until this time, drug movement has been mostly
passive from regions of higher concentration to
lower concentration. Elimination of drugs
usually requires more of an active process
(except gaseous drugs).
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How are drugs eliminated?

• 1. Biotransformation (metabolism)
• chemical transformation of a drug into a
  different compound in the body (metabolite)
• Most biotransformation takes place in the liver

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• Excretion - removal of drug to outside world
• Drug elimination may be by both or either of
  these mechanisms

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Biotransformation

• role of liver
• most significant organ in biotransformation

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Biotransformation

• role of liver
• most significant organ in biotransformation
• largest organ in body
• serves many functions
• transforms molecules via enzymes

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Liver enzymes biotransform drugs (and other
compounds) by

• deactivating the molecule
• ionize the molecule
• make it less lipid soluble
• product of biotransformation is called a
  metabolite

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Cytochrome p450 enzyme family

• located primarily in hepatocytes
• important for metabolism of alcohol,
  tranquilizers, barbiturates, antianxiety drugs,
  estrogens, androgens, PCBs and other agents
• oxidative metabolism makes drugs more water
  soluble (so more easily excreted)

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Can metabolism rate be altered?

• CYP enzymes -
• enzyme induction -
• liver produces extra enzyme to break down drug
  with continued exposure

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Can metabolism rate be altered?

• CYP enzymes -
• enzyme induction -
• liver produces extra enzyme to break down drug
  with continued exposure
• Genetics

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Can metabolism rate be altered?

• CYP enzymes -
• enzyme induction -
• liver produces extra enzyme to break down drug
  with continued exposure
• Genetics
• Liver disease

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cirrhotic liver
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In some cases, biotransformation can be to
another psychoactive compound ex.
benzodiazepenes diazepam nordiazepam
oxazepam
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Routes of Excretion- fluid

• all drugs not in gaseous state need to use fluid
  routes of excretion
• fluid routes include -sweat, tears, saliva,
  mucous, urine, bile, human milk
• amount of drug excreted in each of these fluids
  is in direct proportion to amount of fluid
  excreted SO.

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Kidneys

• numerous functions
• filters out metabolic products

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Kidneys

• numerous functions
• main function maintain correct balance between
  water and salt in body fluids
• filters out metabolic products
• blood continuously flowing through kidneys
• factors that influence a substance not being
  resorbed
• not lipid soluble
• ionized
• dialysis

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absorption distribution and excretion do not
occur independently
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first pass metabolism
brain
blood
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Other factors that affect drug pharmacokinetics

• Body weight - smaller size
• concentration of drug based on body fluid
• Sex differences
• Age

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Other factors that affect drug pharmacokinetics

• Interspecies differences
• rabbits belladonna (deadly nightshade)
• Intraspieces differences
• Disease states
• Nutrition
• Biorhythm

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Blood level
2 4 6 8 10 12 14
Time in hours
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• half-life - time takes for the blood
  concentration to fall to half its initial value
  after a single dose
• ½ life tells us critical information about how
  long the action of a drug will last

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How long would it take for a drug to reach 12.5
remaining in blood if its ½ life is 2 hours?
How long would it take for a drug to reach
12.5 remaining in blood if its ½ life is 100
hours?