Transcript Is a Drug Polar or Non-polar (and why does this matter?)

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.
Is a Drug Polar or Non-polar
(and why does this matter?)
•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.
• http://health.howstuffworks.com/adam200142.htm
“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.
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
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.
At approximately pH = 12, the equilibrium below is
evenly distributed between ammonium salt and
amine.
H
H
+
N
R
H
H2O
R
H
+
N
HO
H
At the pH of blood, pH = 7.4, the equilibrium below is
strongly shifted toward the ammonium salt.
H
H
+
N
R
H
H
H2O
N
R
H
+
HO
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.
H
H
+
N
R
C
O
H
H2O
H
X
R
N
C
O
H
+
HO
Carboxylic acids are evenly distributed
between charged, and uncharged form at
pH = 4
O
O
+
C
R
H2O
OH
+
C
R
H3O
O
At pH = 7.4, the equilibrium lies in favor of the charged
form.
O
O
+
C
R
OH
H2O
+
C
R
O
H3O
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.
• 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.
http://soolin.sunderland.ac.uk/fdcps/pharmacokinetics.ht
ml
Ways to administer a drug
• Enteral = Through or within the
intestines or gastrointestinal tract.
• Parenteral = Not in or through the
digestive system.
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
• 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.
Suppositories
• Rectal: the substance crosses the rectal
mucosa into the bloodstream
• Vaginal: commonly used to treat
gynaecological ailments, including
vaginal infections such as candidiasis.
Transdermal
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
•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.
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.
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