clinical pharmacology introduction

7/29/2019 Clinical Pharmacology Introduction

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Introduction toCLINICAL PHARMACOLOGY

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CLINICAL PHARMACOLOGY AND SCOPE OFCLINICAL PHARMACOLOGY

Introduction to Clinical Pharmacology

Clinical pharmacology can be defined as the study ofdrugs in humans.

Clinical pharmacology is a relatively new science.It isrelated to pharmacotherapy but is not the same

science.Clinical pharmacologyis a science about drugs. It isclosley linked to fundamental pharmacology.


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The fundamental problemes with which the science ofpharmacologyis concerned are following:

1. The relationship between dose and biological effect.

2. The localization of the site of action of a drug.3. The mechanism (s) of action of drug.

4. The absorption,distribution,metabolism,and excretionof a drug.

5. The relationship between chemical structureandbiological activity.

Clinical pharmacology has been termed a bridgingdiscipline because it combines elementes of classical

pharmacologywith clinical medicine.Clinical pharmacologists are concerned both with the

optimal use of existing medications and with thescientific study of drugs in humans.


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CLINICAL PHARMACOLOGY include both evaluation of:

1. The safety and efficacy of currently available drugs

2. Development ofnew and improvedpharmacotherapy.

A few personalities had an significantly influence on clinicalpharmacology development:

1.Rudolph Bucheim (1820-1879) has been credited withestablishing pharmacology as a laboratory-based discipline.

2. Harry Gold and Walter Modell began in the 1930 s toprovide thefoundation for the modern discipline of clinical

pharmacology. They inovated (invention) of the double-blind design for clinical trials and the use of effect kinetics to

measure the absolute bioavailability of digoxin. They havebeen put foundation of Clinical Pharmacology andTherapeutics.


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A great challange for the pharmacologists and physicians

was adverse drug reaction (ADR) to thalidomide an

inofensive anxiolytic and antivomiting drug.

Few drugs have focused as much public attention on

problem of adverse drug rection as did

thalidomide,which was first linked in in 1961 to

catastrophic outbreaks ofphocomelia

The thalidomide tragedy provided an major impetus for

developing a number of NIH-funded academic centers of

excellence ofclinical pharmacology.


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Adverse drug reaction(ADR)The causes that contributes to high incidence of are following:

1.Inappropriate polypharmacy.

2.Failure of prescribing physicians to establish and adhere to cleartherapeutic goals.

3.Failure of medical personnel to atribute new symptomes or changes in

laboratory test results

to drug therapy.

4.Lack of priority given to the scientific study of adverse drug reaction

mechanisms.

5.General ignorance of basic and applied pharmacology and therapeutics

principles.

Most adverse reactions encountered in clinical practice occured withcommonly used, rather than newly introduced,drugs,and were dose

related,rather than idiosyncratic.

Recognition of the considerable variation in response of patients treated

with standard drug doses provided the impetus for the development of

laboratory methods to measure drug concentration in patient blood

samples.


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Paul Martini described the use of placebos,control

groups,stratification,rating scales,and the n of 1 trial design,and

emphasized the need to estimate the adequacy of sample size and

to establish baseline conditions before beginning a trial.

Investigation that summarized his experience in scientific drug

evaluation and probably entitles him to be considered the first

clinical pharmacologistHe also introduced the term clinical pharmacology.

Gold and other academic clinical pharmacologists also have made

important contributions to the design of clinical trials.

More recently,Sheiner outlined a number of improvements thatcontinue to be needed in the use of statistical methods for drug

evaluation,and asserted that clinicians must regain control over


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ADVERSE DRUG EVENTS (AEs)

Hurwitz and Wade proposed four categories of AEs.

categoryA

1.Side effect

2.Excess effectcategory B

3.Allergy (hypersensitivity)

4.Idiosyncrasy


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DeSwarte classified ADRs into eight categories.

1.Overdose2.Side effect

3.Secondary,indirect effect

4.Interaction5.Intolerance

6.Idiosyncrasy (primary toxicity)

7.Allergy8.Pseudoallergy (anaphylactoid)


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Type A adverse event

Rawlins and Thompson have calssified AEs into type

A and type B.A type A event is one that is due an extension of the

active pharmacologic properties of the drug (Aindicates augmented).

They are also calledpredictable or anticipated events.

They are generally less severe and more frequentthan type B events.

They are usually detected during the clinical trialsdone before marketing.


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Type A adverse event- Two subclasses:

1.Exaggerated desired effect

The exaggeration of a desired pharmacologic effect after a normal

dose in a susceptibile subject or after a higher than normaldose.

Orthostatic hypotension with an antihypertensive; daytimesomnolence after a sedative-hypnotic taken for sleep ;

Hypoglycemic shock after insulin are examples of thisphenomen

2.Undesired effect- The appearance of an undesiredpharmacologic effect,known as lateral or parallel

stimulation,can be seen after a normal dose or a higher thannormal dose in a susceptible subject.

Constipation due to morphine; Gastrointestinal irritation withNSAIDs; Hair loss from chemotherapy


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Type B adverse event

A type B(bizare) reaction is one that is not due to anextension of the active pharmacologic propertiesof the drug.

They are called pharmacologicallyunexpected,unpredictable,or idiosyncratic adverse

reactions.


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They are two subclasses:

1.Immunologic

An allergic or hypersensitivityreaction occurs as a result of an

immunologic mechanism.A pseudoallergy or anaphylactoid

reaction is the result of amechanism involving the releaseof the same mediators realesed

during an immunologic reactiondue to immunoglobulin E(IgE).Such reactions can occur

with radiocontrastagents,NSAIDs,dextrans etc.

2.Idiosyncratic

The term of idiosyncratic is oftenused in a broad sense to designate

qualitatively abnormal adversereactions that occur in a givenindividual and whose mechanismis not yet understood.

This is also known as primarytoxicity. due to glucose-6-phosphate dehydrogenase(G6PD) deficiency.

Congenital enzyme abnormalitiesmay produce the hemolyticanemia


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Types C,D,and E are not mechanisms but characteristics of

their manifestations.

They are not reffered to frequently in the literature.

The letter C refers to continuous,chronic.

Type D refers to delayed in appearance,making them

difficult to diagnose.

Type E refers to end of use.


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DRUG THERAPY IN PREGNANCY

Most drugs taken by pregnant women can cross the placentaand expose the developing embryo and fetus to their

pharmacologic and teratogenic effect.Drug passage across the placenta is dependent on lipid

solubility and the degree of drug ionization.

Lipophilic drugs tend to diffuse readily across the placenta

and enter the fetal circulation.For example,thiopental,a drug comonly used for cesarean

sections,crosses the placenta almost immediately and canproduce sedation or apnea in the newborn infant.

Highly ionized drugs such as succinylcholine andtubocurarine,also used for cesarean sections,cross theplacenta slowly-achieve low concentrations in the fetus

The molecular weight of the drug also influences the amount

of drug trensferred across the placenta.


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DRUG THERAPY IN INFANTS & CHILDREN

Special attention must be paid to pharmacokineticsin the first year of life,particularly during the firstfew months.

Pharmacodynamic differences between pediatricand other pateints have not been explored in great

detail and are probably small except for thosespecific target tissues that mature at birth orimmediately thereafter.


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Drug absorbtion in infants and children folows the samegeneral principles as in adult.

Drug distribution depend on percentage of water in body

wheight (70-75 % in neonates versus 50-65 % in adult).Ingeneral,protein binding of drugs is reduced in the neonate.

Drug metabolism.Because of the neonatess decreasedability to metabolize drugs,many drugs have slow clearance

rates and prolonged elimination half-lives.Drug excretion.

The glomerular filtration rate is much lower in newborns thanin older infants,children,or adults,and limitation persist

during the first few days of life.Calculated on the basis of body surface area,glomerular

filtration in the neonate is only 30-40 % of the adult value.


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Contemporary drug development

is a complex process that is conventionally dividedinto preclinical research and development and anumber of clinical development phases.

Two main steps:

I.Preclinical Development

II.Clinical Development


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This model is for the drugs licensed by the United StatesFood and Drug Administration.

After a drug candidate is identified and put through in vitroscreens and animal testing,an Investigational New Drugapplication (IND) is submitted to the FDA.

When the IND is approved,Phase I clinical developmentbegins with a limited number of studies in healthy

volunteers or patients.

The goal of these studies is to establish a range of tolerateddoses and to characterize the drug canditatespharmacokinetic properties and intial toxicity profile.

If these results warrant further development of thecompound,short-term Phase II studies are conducted in aselected group of patients to obtain evidence oftherapeutic efficacy and to explore patient therapeutic and

toxic responses to several dose regimens.


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These dose-response relationships are used to design longerPhase III trials to confirm therapeutic efficacy and documentsafety in a larger patient poulation

The material obtained during preclinical and clinicaldevelopment is then incorporated in a New DrugApplication (NDA) that is submitted to the FDA for review.

Adverse drug reaction monitoring and reporting is mandatedafter NDA approval.

Phase IV studies conducted after NDA approval,may includestudies to support FDA licensing for additional therapeuticindications or over-the-counter (OTC) sales directly toconsumers.

Although the expertises and resources needed


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Orphan Drug Program


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Orphan Drug Program

The Orphan Drug Act of 1983 was passed to encourage the development

and marketing of products used to treat rare diseases.

The act defines a rare disease as a condition affecting fewer than

200,000 individuals in the United States. The National Organization of Rare Disorders reports that there are more

than 6000 rare disorders that affect approximately 25 million individuals.

Examples of rare disorders include Tourettes syndrome, ovarian cancer,

acquired immunodeficiency syndrome (AIDS), Huntingtons disease, and

certain forms of leukemia. The act provides for incentives, such as research grants, protocol

assistance by the FDA, and special tax credits, to encourage

manufacturers to develop orphan drugs.

If the drug is approved, the manufacturer has 7 years of exclusive

marketing rights. More than 100 new drugs have received FDA approvalsince the law was passed.

Examples of orphan drugs thalidomide for leprosy, triptorelin pamoate

for ovarian cancer, tetrabenazine for Huntingtons disease, and zidovudine

for AIDS.


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clinical pharmacology introduction

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