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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• http//health.howstuffworks.com/adam-200142.htm

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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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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 the mucous that coats it.
• pH intestine 6.4
• 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
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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.
  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 of drugs 101

• Overall your body is trying to make drug more
  water-soluble
• Phase 1 metabolism may involve oxidation,
  hydrolysis, or reduction, all catalyzed by
  enzymes in the liver
• Phase 2 metabolism involves direct conjugation
  with