Drug Administration Metabolism 2011

7/29/2019 Drug Administration Metabolism 2011

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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 receivingeither 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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Link

Link

Review Phase 1 Metabolism
http://elearn.pharmacy.ac.uk/flash/view/liver.htmlhttp://elearn.pharmacy.ac.uk/flash/view/Cytochrome_P450.htmlhttp://elearn.pharmacy.ac.uk/flash/view/Cytochrome_P450.htmlhttp://elearn.pharmacy.ac.uk/flash/view/liver.html


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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 drugmust pass through several

membranes


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If orally administered, this begins withthe stomach and continues to the small

and large intestine.


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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 thisratio.

Christopher Lipinski noticed that most of the orally

bioavailable drugs on the market seemed to havelogP values less than 5.

There are now computer programs that will attempt tocalculate this number from the structure. Thiscalculated 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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R

N

H

H

+ H2O

R

N

H

H

+ HOH

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.

R

N

H

H

+ H2O

R

N

H

H

+ HOH


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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 unprotonatedstate, as shown.

C

N

H

H

+ H2O

C

N

H

H

+ HOH

O

R X

O

R


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Carboxylic acids are evenly distributed

between charged, and uncharged form at

pH = 4

R

C

OH

O

+ H2O+ H3O

R

C

O

O

At pH = 7.4, the equilibrium lies in favor of the charged

form.

R

C

OH

O

+ H2O + H3O

R

C

O

O


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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 chargedversion, which dissolves readily in water

As well as an uncharged form, which can easily cross

membranes.

O

HO

H

NH

CH3

HO1

2

3

4

5

6

7

8

9

10

11

12

1314

15 16

Morphine (Astramorph)

HO- Group is needed for activity

HO- Group not important to activity

Basic Nitrogen of Drug


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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 ionicstates in different regions of the body.


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http://soolin.sunderland.ac.uk/fdcps/pharmacokinetics.ht

ml
http://soolin.sunderland.ac.uk/fdcps/pharmacokinetics.htmlhttp://soolin.sunderland.ac.uk/fdcps/pharmacokinetics.htmlhttp://soolin.sunderland.ac.uk/fdcps/pharmacokinetics.htmlhttp://soolin.sunderland.ac.uk/fdcps/pharmacokinetics.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) that occurs when theheart is deprived of oxygen

Nitroglycerin relaxes blood vessels allowing moreblood to flow through. This reduces the workload onthe 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

Matrifen Fentanyl Patch
http://www.matrifen.com/en/Menu/Pharmacology/PharmacoKinetics/AbsorptionAndDistribution/Absorption.htmhttp://www.matrifen.com/en/Menu/Pharmacology/PharmacoKinetics/AbsorptionAndDistribution/Absorption.htm


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Parenteral Routes

Intravascular (IV, IA)- placing a drug

directly into the blood stream

Intramuscular (IM) - drug injected intoskeletal muscle

Subcutaneous - Absorption of drugs

from the subcutaneous tissues Inhalation - Absorption through the

lungs


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Intraosseous infusion is the process of injectiondirectly into the marrow of the bone. The needle isinjected through the bone's hard cortex and into thesoft marrow interior.


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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.

I t th l I j ti


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Intrathecal Injection

This route is also used for some infections, particularlypost-neurosurgical. The drug needs to be given this way toavoid the blood brain barrier. If the drug were given viaother 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 upspecially by a pharmacist or technician because theycannot contain any preservative or other potentially harmfulinactive ingredients that are sometimes found in standard

injectable drug preparations.


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Metabolism

Link

Link
http://davisplus.fadavis.com/tabers21/Animations/animations.cfm?exercise=Medication_Distribution&title=Medication%20Absorption,%20Distribution,%20Metabolism%20and%20Excretion%20Animationhttp://www.icp.org.nz/http://www.icp.org.nz/http://davisplus.fadavis.com/tabers21/Animations/animations.cfm?exercise=Medication_Distribution&title=Medication%20Absorption,%20Distribution,%20Metabolism%20and%20Excretion%20Animation


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Pharmacokinetics and

Pharmacodynamics

Ph ki ti


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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 thevolume cleared of drug per unit time

Link

Low clearance may be due to renal impairment, liver

impairment, enzyme inhibition, age (old age orneonate).

Link
http://www.icp.org.nz/http://pharmamotion.com.ar/half-life-of-drugs-video-lecture-for-nurses/http://pharmamotion.com.ar/half-life-of-drugs-video-lecture-for-nurses/http://www.icp.org.nz/


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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.

Depending on the structure of the drug the proportioneliminated metabolically versus that eliminated

renally will change.

Thus dosage must be adjusted to accommodate

these factors. Link
http://www.icp.org.nz/http://www.icp.org.nz/


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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 anequilibrium 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%

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 thedrug 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 thebeginning 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 inthe liver and also in the gut wall.

Link

Ph d i


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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.

Pharmacodynamics


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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


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The efficacy of a drug is defined as the

absolute value of the maximum effect

(Emax) (e.g. morphine is more efficacious asa 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

Pharmacogentics


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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


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Examples include individuals of Asian descent who lack

aldehyde dehydrogenase, thus do not tolerate alcohol

and individuals who do not produce enough CYP2D6 inthe 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 theirmetabolism, thus resulting in higher than expected Cp.

Link
http://www.icp.org.nz/html/saturable_metabolism.htmlhttp://www.icp.org.nz/html/saturable_metabolism.html


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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 itstarget.

The protein-bound form of the drug must also dissociate

from the protein in order to be cleared.

H d Ph ki ti


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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 < 7), are ionized in basicmedia (pH > 7).

Drugs which are basic (pKa > 7) are ionized in acidic

media (pH < 7)

The ionized form of the drug provides it with improvedwater 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.

Drug dosing may also need to be adjusted

during pregnancy. Link

Drug Interactions


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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)

P Glycoprotein


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P-Glycoprotein

P-glycoprotein can transport drugs back out ofthe 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 intothe 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, 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 Gilmans Pharmaceutical Basis of

Therapeutics, 12th edition, Chapter 6, pp. 123-143
http://web.ebscohost.com/ehost/detail?vid=1&hid=112&sid=c062b5ac-69b1-4391-9718-d819b7d983a8%40sessionmgr113&bdata=JmxvZ2lucGFnZT1Mb2dpbi5hc3Amc2l0ZT1laG9zdC1saXZlJnNjb3BlPXNpdGU%3dhttp://pubs.acs.org/doi/abs/10.1021/mp0500871?source=chemporthttp://pubs.acs.org/doi/abs/10.1021/mp0500871?source=chemporthttp://web.ebscohost.com/ehost/detail?vid=1&hid=112&sid=c062b5ac-69b1-4391-9718-d819b7d983a8%40sessionmgr113&bdata=JmxvZ2lucGFnZT1Mb2dpbi5hc3Amc2l0ZT1laG9zdC1saXZlJnNjb3BlPXNpdGU%3d


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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?

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Drug Administration Metabolism 2011

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