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.
Review Phase 1 Metabolism
• Link
• Link
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.
“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 1octanol 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
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.
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
H 2O
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
H 2O
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
H 2O
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
H 2O
OH
+
C
R
H 3O
O
At pH = 7.4, the equilibrium lies in favor of the charged
form.
O
O
+
C
R
OH
H 2O
+
C
R
O
H 3O
H O - G ro u p is n eed ed fo r activ ity
2
HO
3
1
11
4
10
15
12
O
9
13
5
14
H
H
HO
Basic Nitrogen of Drug
16
8
6
N
CH3
7
M o rp h in e (A stram o rp h )
H O - G ro u p n o t im p o rtan t to activ ity
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 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.
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) that occurs when the
heart is deprived of oxygen
• 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
• Matrifen Fentanyl Patch
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.
• 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.
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.
Metabolism
Link
Link
Pharmacokinetics and
Pharmacodynamics
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.
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)
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
• Low clearance may be due to renal impairment, liver
impairment, enzyme inhibition, age (old age or
neonate).
• Link
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.
• Depending on the structure of the drug the proportion
eliminated metabolically versus that eliminated
renally will change.
• Thus dosage must be adjusted to accommodate
these factors. Link
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
The Half-Life of the Drug
• The half-life of a drug is the amount of time
required to reduce the concentration by 50%
• 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
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
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
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.
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
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
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.
Saturable Metabolism
• A few drugs may saturate the enzymes responsible for their
metabolism, thus resulting in higher than expected Cp.
• Link
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.
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 < 7), are ionized in basic
media (pH > 7).
• Drugs which are basic (pKa > 7) are ionized in acidic
media (pH < 7)
• The ionized form of the drug provides it with improved
water solubility
• But the unionized form generally passes nonpolar
membranes more readily.
• Link
Dosing and Age
• The dosing of drugs needs to be adjusted
with the age of the patient.
• Drug dosing may also need to be adjusted
during pregnancy. Link
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
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)
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
Reading Assignment:
Goodman and Gilman’s Pharmaceutical Basis of Therapeutics, 12th edition,
Chapter 2, pp. 17-39
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
Graduate Students Only: Goodman and Gilman’s Pharmaceutical Basis of
Therapeutics, 12th edition, Chapter 6, pp. 123-143
Homework Questions
1) 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).
4) Why has the concept of ‘personalized medicine’ been so difficult to
implement?
5) What is the best approach to designing a drug which is structurally
optimized to elude P-gp?