Clinical Pharmacology Introduction f5e23

Introduction to CLINICAL PHARMACOLOGY .

CLINICAL PHARMACOLOGY AND SCOPE OF CLINICAL PHARMACOLOGY Introduction to Clinical Pharmacology Clinical pharmacology can be defined as the study of drugs in humans. Clinical pharmacology is a relatively new science.It is related to pharmacotherapy but is not the same science. Clinical pharmacology is a science about drugs. It is closley linked to fundamental pharmacology.

The fundamental problemes with which the science of pharmacology is 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 excretion of a drug. 5. The relationship between chemical structure andbiological activity. Clinical pharmacology has been termed a bridging discipline because it combines elementes of classical pharmacology with clinical medicine. Clinical pharmacologists are concerned both with the optimal use of existing medications and with the scientific study of drugs in humans.

CLINICAL PHARMACOLOGY include both evaluation of: 1. The safety and efficacy of currently available drugs 2. Development of new and improved pharmacotherapy. A few personalities had an significantly influence on clinical pharmacology development: 1.Rudolph Bucheim (1820-1879) has been credited with establishing pharmacology as a laboratory-based discipline. 2. Harry Gold and Walter Modell began in the 1930 s to provide thefoundation for the modern discipline of clinical pharmacology. They inovated (invention) of the doubleblind design for clinical trials and the use of effect kinetics to measure the absolute bioavailability of digoxin. They have been put foundation of Clinical Pharmacology and Therapeutics.

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

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thalidomide,which was first linked in in 1961 to catastrophic outbreaks of phocomelia

The thalidomide tragedy provided an major impetus for developing a number of NIH-funded academic centers of

excellence of clinical pharmacology.

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 clear therapeutic 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 with commonly 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.

• 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 pharmacologist He 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 that continue to be needed in the use of statistical methods for drug evaluation,and asserted that clinicians must regain control over

ADVERSE DRUG EVENTS (AEs) Hurwitz and Wade proposed four categories of AEs. category A 1.Side effect 2.Excess effect category B 3.Allergy (hypersensitivity) 4.Idiosyncrasy

DeSwarte classified ADRs into eight categories.

1.Overdose 2.Side effect 3.Secondary,indirect effect 4.Interaction 5.Intolerance 6.Idiosyncrasy (primary toxicity) 7.Allergy 8.Pseudoallergy (anaphylactoid)

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 (A indicates augmented). They are also called predictable or anticipated events. They are generally less severe and more frequent than type B events. They are usually detected during the clinical trials done before marketing.

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 normal dose. Orthostatic hypotension with an antihypertensive; daytime somnolence after a sedative-hypnotic taken for sleep ; Hypoglycemic shock after insulin are examples of this phenomen 2.Undesired effectThe appearance of an undesired pharmacologic effect,known as lateral or parallel stimulation,can be seen after a normal dose or a higher than normal dose in a susceptible subject. Constipation due to morphine; Gastrointestinal irritation with NSAIDs; Hair loss from chemotherapy

Type B adverse event A type B(bizare) reaction is one that is not due to an extension of the active pharmacologic properties of the drug. They are called pharmacologically unexpected,unpredictable,or idiosyncratic adverse reactions.

They are two subclasses: • 2.Idiosyncratic 1.Immunologic An allergic or hypersensitivity The term of idiosyncratic is often used in a broad sense to designate reaction occurs as a result of an qualitatively abnormal adverse immunologic mechanism. reactions that occur in a given A pseudoallergy or anaphylactoid individual and whose mechanism reaction is the result of a is not yet understood. mechanism involving the release of the same mediators realesed during an immunologic reaction This is also known as primary due to immunoglobulin E toxicity. due to glucose-6(IgE).Such reactions can occur phosphate dehydrogenase with radiocontrast (G6PD) deficiency. agents,NSAIDs,dextrans etc. Congenital enzyme abnormalities may produce the hemolytic anemia

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.

DRUG THERAPY IN PREGNANCY Most drugs taken by pregnant women can cross the placenta and expose the developing embryo and fetus to their pharmacologic and teratogenic effect. Drug age 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 can produce sedation or apnea in the newborn infant. Highly ionized drugs such as succinylcholine and tubocurarine,also used for cesarean sections,cross the placenta slowly-achieve low concentrations in the fetus The molecular weight of the drug also influences the amount of drug trensferred across the placenta.

DRUG THERAPY IN INFANTS & CHILDREN Special attention must be paid to pharmacokinetics in the first year of life,particularly during the first few months. Pharmacodynamic differences between pediatric and other pateints have not been explored in great detail and are probably small except for those specific target tissues that mature at birth or immediately thereafter.

Drug absorbtion in infants and children folows the same general principles as in adult. Drug distribution depend on percentage of water in body wheight (70-75 % in neonates versus 50-65 % in adult).In general,protein binding of drugs is reduced in the neonate. Drug metabolism.Because of the neonatess decreased ability 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 than in 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.

Contemporary drug development • is a complex process that is conventionally divided into preclinical research and development and a number of clinical development phases. • Two main steps: I.Preclinical Development II.Clinical Development

This model is for the drugs licensed by the United States Food and Drug istration. After a drug candidate is identified and put through in vitro screens and animal testing,an Investigational New Drug application (IND) is submitted to the FDA. When the IND is approved,Phase I clinical development begins with a limited number of studies in healthy volunteers or patients. The goal of these studies is to establish a range of tolerated doses and to characterize the drug canditates pharmacokinetic properties and intial toxicity profile. If these results warrant further development of the compound,short-term Phase II studies are conducted in a selected group of patients to obtain evidence of therapeutic efficacy and to explore patient therapeutic and toxic responses to several dose regimens.

These dose-response relationships are used to design longer Phase III trials to confirm therapeutic efficacy and document safety in a larger patient poulation The material obtained during preclinical and clinical development is then incorporated in a New Drug Application (NDA) that is submitted to the FDA for review. Adverse drug reaction monitoring and reporting is mandated after NDA approval. Phase IV studies conducted after NDA approval,may include studies to FDA licensing for additional therapeutic indications or over-the-counter (OTC) sales directly to consumers. Although the expertises and resources needed

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Orphan Drug Program The Orphan Drug Act of 1983 was ed 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 Tourette’s syndrome, ovarian cancer, acquired immunodeficiency syndrome (AIDS), Huntington’s 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 approval since the law was ed. Examples of orphan drugs –thalidomide for leprosy, triptorelin pamoate for ovarian cancer, tetrabenazine for Huntington’s disease, and zidovudine for AIDS.