Double-blind Clinical Trials

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Double-blind Clinical Trials

• A double-blind or double-masked study is one in
  which neither the participants nor the study
  staff know which participants are receiving the
  experimental treatment and which ones are
  receiving either a standard treatment or a
  placebo.
• These studies are performed so that neither the
  patients nor the doctors expectations about the
  experimental drug can influence the outcome.

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Is a Drug Polar or Non-polar(and why does this
matter?)
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• To reach its target, the drug must pass through
  several membranes
• If orally administered, this begins with the
  stomach and continues to the small and large
  intestine.

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• Link
• Link

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Like Dissolves Like

• To get across most membranes, the drug must be
  relatively non polar
• To be soluble in water, a drug must be polar
• If a drug is too nonpolar, it may be not be water
  soluble, or may bind too tightly to components in
  food, or to proteins in the blood.

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The polarity of a substance is measured by its
partition coefficient in a two phase system
consisting of 1-octanol and water

• P amount of drug dissolved in octanol
• amount of drug dissolved in water
• Usually the logarithm logP, is used to describe
  this ratio.
• Christopher Lipinski noticed that most of the
  orally bioavailable drugs on the market seemed to
  have logP values less than 5.
• There are now computer programs that will attempt
  to calculate this number from the structure.
  This calculated version is usually referred to as
  clogP, meaning calculated logP

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On the x-axis is plotted logP, and on the y-axis
is plotted the permeability coefficient of rat
brain capillaries in cm/sec. Note that, in
general, more lipophilic compounds penetrate
brain more rapidly.
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But some drugs change their ionic form, depending
on the pH of the surrounding medium. Ionized
(I.e. charged) states of molecules are always
more polar than the uncharged forms.
Two such classes of drugs are amines, R-NH2, and
Carboxylic acids, RCOOH.
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At approximately pH 12, the equilibrium below
is evenly distributed between ammonium salt and
amine.
At the pH of blood, pH 7.4, the equilibrium
below is strongly shifted toward the ammonium
salt.
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• This is NOT true for amides RCONH2,
• Which are significantly different electronically
  from amines.
• Amides are Much harder to protonate.
• At pH 7.4, amides exist in the unprotonated
  state, as shown.

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• Carboxylic acids are evenly distributed between
  charged, and uncharged form at pH 4

At pH 7.4, the equilibrium lies in favor of the
charged form.
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• Lots of drugs have amines (primary, secondary,
  and tertiary) as a part of their structure.
• This allows the drug to exist in two forms, a
  charged version, which dissolves readily in
  water
• As well as an uncharged form, which can easily
  cross membranes.

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• pH stomach 1 to 3 (the stomach itself is
  protected by a layer of mucous).
• pH small intestine 8
• pH blood 7.4
• Thus each drug will exist in different ionic
  states in different regions of the body.

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http//soolin.sunderland.ac.uk/fdcps/pharmacokinet
ics.html
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Ways to administer a drug

• Enteral Through or within the intestines or
  gastrointestinal tract.
• Parenteral Not in or through the digestive
  system.

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Oral Administration

• Easiest
• Disadvantages
• Some drugs (eg proteins) are not stable to the
  acidic environment and digestive enzymes of the
  stomach
• May cause emesis
• Drug may not be absorbed properly

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• Sublingual Under the tongue.
• Example Nitroglycerin (brand name nitrostat)
• This medication is a nitrate used to relieve and
  prevent chest pain (angina). Nitroglycerin
  relaxes blood vessels allowing more blood to flow
  through. This reduces the workload on the heart
  and improves blood flow to the heart.

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Suppositories

• Rectal the substance crosses the rectal mucosa
  into the bloodstream
• Vaginal commonly used to treat gynaecological
  ailments, including vaginal infections such as
  candidiasis.

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Transdermal

• http//www.watsonurology.com/consumer/consumer_ani
  mation_modem.html

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Parenteral Routes

• Intravascular (IV, IA)- placing a drug directly
  into the blood stream
• Intramuscular (IM) - drug injected into skeletal
  muscle
• Subcutaneous - Absorption of drugs from the
  subcutaneous tissues
• Inhalation - Absorption through the lungs

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• Intraosseous infusion is the process of injection
  directly into the marrow of the bone. The needle
  is injected through the bone's hard cortex and
  into the soft marrow interior.
• This route of fluid and medication administration
  is an alternate one to the preferred IV route
  when the latter can't be established in a timely
  manner especially during pediatric emergencies.
  When IV access cannot be obtained in pediatric
  emergencies, intraosseous access is usually the
  next approach. It can be maintained for 24-48
  hours, after which another route of access should
  be obtained. Intraosseous access is used less
  frequently in adult cases due to greater
  difficulty penetrating denser adult bone.

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Intrathecal Injection

• An intrathecal injection (often simply called
  "intrathecal") is an injection into the spinal
  canal (intrathecal space surrounding the spinal
  cord), as in a spinal anaesthesia or in
  chemotherapy or pain management applications.

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Intrathecal Injection

• This route is also used for some infections,
  particularly post-neurosurgical. The drug needs
  to be given this way to avoid the blood brain
  barrier. If the drug were given via other routes
  of administration where it would enter the blood
  stream it would be unable to reach the brain.
• Drugs given intrathecally often have to be made
  up specially by a pharmacist or technician
  because they cannot contain any preservative or
  other potentially harmful inactive ingredients
  that are sometimes found in standard injectable
  drug preparations.

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Metabolism

• Link
• Link
• Link

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Pharmacokinetics and Pharmacodynamics
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Pharmacokinetics

• Defined as what the body does to the drug
• Absorption
• Distribution
• Metabolism
• Excretion
• Pharmacokinetics uses mathematical models to
  predict the time-course of drug concentration in
  body fluids.

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Goal of Therapeutics

• Achieve efficacy without toxicity
• Plasma concentration (Cp) must be within the
  therapeutic window
• Cp units are mg/L
• That is, it must be above the minimum effective
  concentration (MEC), and below the minimum toxic
  concentration (MTC)

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Fundamental Equations

• Cp (dose rate)/Cl
• Dose rate has units mg/h
• Cp has units mg/L
• Cl clearance (units are L/h), representing the
  volume cleared of drug per unit time
• Link
• Link
• Low clearance may be due to renal impairment,
  liver impairment, enzyme inhibition, age (old age
  or neonate).
• Link

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Drug Clearance

• To a first approximation, drugs are cleared from
  plasma in two ways, by metabolism in the liver
  and by being eliminated (unchanged) through the
  kidneys.
• The fraction unchanged (fu) represents the
  proportion cleared by kidneys, while 1-fu
  represents the fraction cleared by metabolism.
  Link
• Depending on the structure of the drug the
  proportion eliminated metabolically versus that
  eliminated renally will change. Link
• Thus dosage must be adjusted to accommodate these
  factors. Link

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Volume of Distribution

• However, drugs are distributed throughout the
  body, not just in plasma
• Thus, as the drug spreads throughout the body,
  the plasma concentration falls, while maintaining
  an equilibrium concentration with other
  compartments
• Ab (Vd)(Cp)
• Ab total amount of drug in body (Amount in
  body, milligrams)
• Vd volume of distribution (liters)
• Cp plasma concentration (milligrams/liter)
• Link

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The Half-Life of the Drug

• The half-life of a drug is the amount of time
  required to reduce the concentration by 50
• Link
• The larger the volume of distribution, the longer
  it takes to clear the drug, at a constant rate of
  clearance.
• t1/2 (0.693)Vd/Cl
• 0.693 ln2
• Link

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Dosing Forms and Techniques

• Oral availability is less than by IV
• F AUCpo/AUCIV
• F fraction of the drug given orally that
  reaches systemic circulation
• AUCpo is the area under the concentration-time
  curve for the drug given orally (po)
• AUCIV is the area under the concentration-time
  curve for the drug given by IV
• Loading Doses are larger than normal doses
  given at the beginning of treatment to rapidly
  increase Cp.
• Link

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Oral Availability and Metabolism

• Oral availability depends on both absorption and
  first pass metabolism
• First pass metabolism can occur both in the liver
  and also in the gut wall.
• Link

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Pharmacodynamics

• Pharmacodynamics is defined as what the drug does
  to the body
• Pharmacodynamics refers to the time-course and
  intensity of drug action and response.

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Pharmacodynamics

• The potency of a drug is defined as the
  concentration need to achieve its maximum effect.
  It is often measured as EC50, the concentration
  required to achieve 50 of the maximum effect
• The efficacy of a drug is defined as the absolute
  value of the maximum effect (Emax) (e.g. morphine
  is more efficacious as a pain reliever than
  acetaminophen)
• Link

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Therapeutic Index

• The therapeutic index represents the ratio of the
  concentration required to cause an adverse effect
  to the that required for the desired effect.
• Therapeutic Index EC50 (adverse effect) / EC50
  (desired effect)
• Pharmaceutical companies prefer drugs with a
  large therapeutic index.
• Link

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Pharmacogentics

• Among a population, different genotypes may
  result in different phenotypes that have
  different expression of receptors, drug
  metabolizing enzymes, or transporters, thus
  resulting in different susceptibility to a drug.
• For a metabolizing enzyme, for example, one
  abberant allele can result in an intermediate
  metabolizer, while two abberant alleles may
  result in a poor metabolizer. Link
• Examples include individuals of Asian descent who
  lack aldehyde dehydrogenase, thus do not tolerate
  alcohol and individuals who do not produce enough
  CYP2D6 in the liver to metabolize codeine to
  morphine and thus may not experience normal pain
  relief with this drug.

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Saturable Metabolism

• A few drugs may saturate the enzymes responsible
  for their metabolism, thus resulting in higher
  than expected Cp.
• Link

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Protein Binding of Drugs

• Human serum albumin is the most abundant protein
  in human blood plasma
• Acidic drugs, in particular, bind to serum
  albumin
• The protein-bound form of the drug is unavailable
  to hit its target.
• The protein-bound form of the drug must also
  dissociate from the protein in order to be
  cleared.

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pH and Pharmacokinetics

• Acidic drugs usually contain weakly acidic
  functionalities, such as COOH.
• Basic drugs usually contain weakly basic
  functionalities, such as amines.
• Drugs which are acidic (pKa lt 7), are ionized in
  basic media (pH gt 7).
• Drugs which are basic (pKa gt 7) are ionized in
  acidic media (pH lt 7)
• The ionized form of the drug provides it with
  improved water solubility
• But the unionized form generally passes nonpolar
  membranes more readily.
• Link

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Dosing and Age

• The dosing of drugs needs to be adjusted with the
  age of the patient.
• Link
• Drug dosing may also need to be adjusted during
  pregnancy. Link

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Drug Interactions

• Clearance can be altered by interaction with one
  or more drugs in a regimen
• Enzyme inducers can serve to increase clearance
  and lower the plasma concentration of drugs.
  Examples include phenytoin, carbamazepin, and
  rifamycin. Drugs metabolized by CYP3A4 are
  particularly susceptible.
• Enzyme inhibitors will decrease clearance and
  increase Cp. Examples include erythromycin,
  selective serotonin reuptake inhibitors (SSRIs),
  ketoconazole, amiodarone, cimetidine, grapefruit
  juice.
• Link

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Drug Transporters

• Specific transporters may aid influx, or
  alternatively, promote efflux of a drug.
• One of the most important such systems is
  P-glycoprotein (permeability glycoprotein).
• P-glycoprotein is a membrane-associate protein in
  the ATP binding cassette transporter superfamily
  (ABC transporter)

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P-Glycoprotein

• P-glycoprotein can transport drugs back out of
  the gut wall and into the gut lumen, thus
  reducing absorption
• It helps keep some drugs out of the brain
• It transports drugs out of the kidney and into
  the urine.
• P-glycoprotein has been implicated as a cause
  of multidrug resistance in tumor cells.
• Link

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Reading Assignment Goodman and Gilmans
Pharmaceutical Basis of Therapeutics, pp. 1-22
(Large type only) Lin, Jiunn H..
Pharmacokinetic and pharmacodynamic variability
a daunting challenge in drug therapy. Current
Drug Metabolism (2007), 8(2), 109-136.
(assigned reading is only pp. 109-110, sections 1
and 2.0 and 129-132, sections 4-5). Link Raub,
Thomas J. P-Glycoprotein Recognition of
Substrates and Circumvention through Rational
Drug Design. Molecular Pharmaceutics (2006),
3(1), 3-25 (assigned is pp. 3-9 and 24-25 only).
Link
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• Homework Questions
• Mathematically define the following parameters,
  and
• their units (Cl, Cp, Vd, Ab, fu, t1/2)
• 2) What is meant by the therapeutic index?
• 3) Explain what is meant by targeted therapy,
  using two examples of transtuzumab (Herceptin)
  and imatinib (Gleevec).
• Why has the concept of personalized medicine
  been so difficult to implement?
• What is the best approach to designing a drug
  which is structurally optimized to elude P-gp?